A Route to Carbasugar Analogues - Jonathan Clayden - The ...

Dearomatising Addition of Organolithiums
to 2-Aryloxazolines:
A Route to Carbasugar Analogues
A thesis submitted to the University of Manchester
for the degree of Doctor of Philosophy
in the Faculty of Engineering and Physical Sciences
2008
Sean Parris
School of Chemistry

Contents
Abstract 6
Declaration 7
Notes on Copyright and the Ownership of Intellectual Property Rights 7
The Author 8
Acknowledgments 9
Abbreviations & Conventions 10
Chapter 1 – Dearomatising Additions in Organic Synthesis. . . . . . . . . . . . . . . . . 15
1.1 Introduction 15
1.2 Dearomatisation with Electrophilic Functionalisation 15
1.2.1 Von Auwers-Woodward 15
1.2.2 The Birch reduction 16
1.3 Nucleophilic Dearomatisation without Heavy Metals 19
1.3.1 Favourable electron withdrawing groups 20
1.3.2 Dearomatising additions to oxzolines 26
1.3.3 Catalytic systems 36
1.4 Nucleophilic Dearomatisation of Metal Complexes 41
1.4.1 (η 6 -Arene)Cr(CO) 3 41
1.4.2 (η 6 -Arene)Mn(CO) 3 cationic complexes 45
1.4.3 Pd-mediated dearomatisation 48
1.5 Summary of Methods 50
Chapter 2 – Dearomatising Additions to Aryl Oxazolines . . . . . . . . . . . . . . . . . . 51
2.1 Establishing a New Reaction 51
2.2 Optimisation of Reaction Conditions 57
2.2.1 Solvent system 57
2.2.2 Duration of reaction 60
2.2.3 Concentration of organolithium 61
2.2.4 Temperature 61
2.2.5 Order of addition 62
3

2.3 Synthetic Scope 64
2.3.1 Organolithiums 64
2.3.2 Arenes 66
2.3.3 Electrophiles 70
2.4 Mechanistic Discussion 73
2.4.1 Stereoselectivity 73
2.4.2 Reaction pathway: one electron or two? 74
2.4.3 Aggregation in organolithium chemistry 89
2.5 Summary & Future Work 89
Chapter 3 – Oxazoline Synthesis and Removal . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
3.1 The Synthesis of 2,4,5-Oxazolines 95
3.1.1 Literature methods for synthesis 95
3.1.2 General strategies 100
3.1.3 Amine synthesis 100
3.1.4 Oxazoline synthesis 102
3.2 Oxazoline Removal 107
3.2.1 Literature methods for removal 107
3.2.2 General strategies 111
3.2.3 Reduction of oxazolines 114
3.2.4 Oxazoline hydrolysis 118
3.2.5 Quaternisation-reduction 121
3.2.6 Determination of optical purity 128
3.3 Summary and Future work 129
Chapter 4 – The Synthesis of Carbasugars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
4.1 Carbasugars 131
4.1.1 What they are and what they do 131
4.1.2 Existing syntheses 133
4.1.3 Synthetic outlook 137
4.2 Synthesis of a Carbasugar Analogue 138
4.2.1 Synthetic Strategy 138
4.2.2 Influence axial oxazoline on reactivity 140
4.2.3 Oxidation of the dienyl ether 142
4.2.4 Enone reduction 145
4

4.2.5 Protecting group strategy 147
4.2.6 Oxidation of the allylic alcohol 148
4.2.7 Synthesis of an altrose analogue 153
4.2.8 Synthesis of an epoxycarbasugar 155
4.2.9 1,4 transannular relationship for oxazolidine hydrolysis 157
4.3 Revised Synthetic Strategy 157
4.4 The Protecting Group-Free Synthesis of an Altrose Analogue 158
4.4.1 Route A 159
4.4.2 Route B or C: a model dihydroxylation 159
4.4.3 Route B 160
4.4.4 Route C 163
4.5 Synthesis of a Mannose Analogue 164
4.5.1 Strategy I: Lactonisation 166
4.5.2 Strategy II: Cyclohexene oxides 171
4.6 Summary & Future Work 180
References for Chapters 1-4 185
Chapter 5 – Experimental Section . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
5.1 General 193
5.2 Experimental Procedures for Chapter 2 197
5.3 Experimental Procedures for Chapter 3.1 211
5.4 Experimental Procedures for Chapter 3.2 235
5.5 Experimental Procedures for Chapter 4.1 247
5.6 Experimental Procedures for Chapter 4.2 263
5.7 References for Experimental Section 274
Appendix A Selected NMR spectra 275
Appendix B Crystallographic Information Files 285
Word count: 58,000
5

Abstract
Dearomatising Addition of Organolithiums to 2-Aryloxazolines:
A Route to Carbasugar Analogues
A submission for the degree of Doctor of Philosophy at The University of Manchester,
Sean Parris April 2008
Nucleophilic addition to functionalised benzenoid nuclei with concomitant
dearomatisation is a powerful method for the construction of highly substituted
synthetic building blocks. This thesis presents a highly stereoselective dearomatising
addition of organolithium nucleophiles to 2-aryloxazolines A as the key step in the
synthesis of carbasugar analogues.
Ph
O
Ph
N
R
A
i) NuLi, DMPU
ii) MeI
Nu: i-Pr, s-Bu
Ph
O
Ph
N
Nu
R
B
i) H +
ii) MeOTf,
then NaBH 4
iii) H 3 O +
iv) NaBH 4
Nu = i-Pr
R = 4-OMe
HO
OH
>99:1 er
This methodology is analogous to that of Meyers with 2-naphthyloxazolines, but
requires less rigorous conditions than existing dearomatising additions to sixmembered
carbocycles which often use heavy metals (chapter 1). A range of
oxazolines and reaction conditions have been studied and the diphenyl oxazoline A
found to be optimal, with DMPU being crucial for the reaction (section 2.1).
Reactivity of the nucleophile follows 2° > 3° >> 1° alkyllithiums, hinting at a single
electron transfer process, which has been studied by preliminary EPR studies and
cyclisable probes (section 2.4). Oxazolines A may be synthesised in high enantiomeric
purity from trans-stilbene, whilst a number of methods have been studied for the
cleavage of oxazolines to synthetically useful functional groups (chapter 3). The
dearomatising functionalisation has been used as the key step in the protecting groupfree
synthesis of carbasugar analogues C and D, in fewer steps and better yields than
most chiral pool syntheses, whilst permitting far greater flexibility (chapter 4).
HO
HO
HO
HO
HO
H
O
B
Nu = i-Pr
R = 4-OMe
Ox*
O
OH
OH
OH
HO
O
OH
OH
HO
OH
C
HO
HO
HO
OH
D
OH
33%,
6 steps from A
OH
43%,
8 steps from A
HO OH
OH
α-L-Altrose
HO
H
HO
O
HO OH
OH
α-L-Mannose
6

Declaration
No portion of the work referred to in the thesis has been submitted in support of an
application for another degree or qualification of this or any other university or other
institute of learning.
Notes on Copyright and the Ownership of Intellectual
Property Rights
i. The author of this thesis (including any appendices and/or schedules to this
thesis) owns any copyright in it (the “Copyright”) and he has given The
University of Manchester the right to use such Copyright for any
administrative, promotional, educational and/or teaching purposes.
ii.
Copies of this thesis, either in full or in extracts, may be made only in
accordance with the regulations of the John Rylands University Library of
Manchester. Details of these regulations may be obtained from the Librarian.
This page must form part of any such copies made.
iii.
The ownership of any patents, designs, trade marks and any and all other
intellectual property rights except for the Copyright (the “Intellectual Property
Rights”) and any reproductions of copyright works, for example graphs and
tables (“Reproductions”), which may be described in this thesis, may not be
owned by the author and may be owned by third parties. Such Intellectual
Property Rights and Reproductions cannot and must not be made available for
use without the prior written permission of the owner(s) of the relevant
Intellectual Property Rights and/or Reproductions.
iv.
Further information on the conditions under which disclosure, publication and
exploitation of this thesis, the Copyright and any Intellectual Property Rights
and/or Reproductions described in it may take place is available from the Head
of School of Chemistry (or the Vice-President).
7

The Author
The Author graduated from the University of Cambridge in 2004 with a first class
Masters degree in Natural Sciences. He completed his Part III research project under
the supervision of Dr. Stuart Warren concerning the asymmetric synthesis of
dihydrofurans using phosphine oxide chemistry. In the penultimate year of his
undergraduate course, the Author attended the Massachusetts Institute of Technology
where he gained a 5.0 grade point average, and also took the opportunity to work in the
laboratories of Prof. Stephen Buchwald, studying the copper-catalysed amidation of
aryl halides. Since September 2004 he has been engaged in research with Prof.
Jonathan Clayden at the University of Manchester, and the results of these
investigations are embodied in this thesis. All being well, the Author looks forward to
undertaking a Leverhulme Trust postdoctoral research position under the guidance of
Dr Craig Williams at the University of Queensland.
8

Acknowledgments
I would like to thank Jonathan for his guidance, support, barbeques and boat trips over
the last three-and-a-bit years. I am also very grateful to Andy Payne who supervised
me during my period of work at GSK Harlow, and to Bob and Phyllis who made my
stay there much more enjoyable than it would otherwise have been.
I am of course thankful to the technical staff at the University of Manchester,
especially Val, Gareth and Rohana; and to Phil and John at GSK. Madeleine and Jim
have always been very helpful when I’ve been stuck squinting at the crystal structures
they always seem able to solve. Johanna and Eric also deserve a special mention for
their assistance with everything EPR, and for their willingness to let me taint their
machines with organic compounds.
I have enjoyed spending the past years with members of the Clayden group both inside
and outside of lab. Particular thanks to Betson, Wes, and Tim for proof reading and
generally being great friends and lab-neighbours. I am also incredibly grateful to
Nuria, Beckii, Olga and James for the conversations, and over the past months for
allowing me to experiment vicariously. Cousin It for being generally great, Heloise for
being a wonderful hostess, Lluis for general mischief in Japan, Worral for his company
through the night-time hours (both lab and pub), Vas for being Vas, and Simon for his
enthusiastic morning greetings and Glasto. I am been grateful to everyone else for
contributing to a friendly atmosphere, in particular Abby, Riz, Tom, Damo, Steve,
James, Jordi, Boris, Pickworth, and Uli Uli Uli Uli.
I have been very fortunate to have had a string of insightful mentors over the years; to
them I am indebted for the care and time they have taken in educating me and my
peers. I am grateful to my parents for always supporting me in everything I do, and
being there to offer advice or support whenever I need it.
Special thanks of course go to Giudi, for far too many reasons to list. Her support,
tolerance and love over the last three years have helped me to get through the lows and
embrace the highs.
– LLFF
9

Abbreviations & Conventions
Ac acetate
AD Sharpless asymmetric dihydroxylation
Anh. Anhydrous
AIBN azobisisobutyronitrile
Ar aryl
aq aqueous
BHA butylated hydroxyanisole / 2,6-di-tert-butyl-4-methoxyphenol
Bn benzyl
Bu butyl
t-Bu tert-butyl
n-Bu n-butyl
s-Bu sec-butyl
Bz benzoyl
c. circa
cat. catalytic
CDI 1,1’-carbonyldiimidazole
c-Hex cyclohexyl
CI chemical ionisation mass spectroscopy
CIP contact ion pair
CIPE complex-inducted proximity effect
conv. conversion of starting material
COSY
1 H- 1 H correlation spectroscopy
Δ heat under reflux
DCE dichloroethane
DEPT distortionless enhancement by polarisation transfer
DIC N,N'-Diisopropylcarbodiimide
DIAD diisopropyl azodicarboxylate
DMAP N,N-dimethyl-4-aminopyridine
DMF N,N-dimethylformamide
DMPU dimethylpropyleneurea / dimethylhexahydro-2-pyrimidinone
d.r. diastereomeric ratio
10

EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
e.e. enantiomeric excess
e.r. enantiomeric ratio
EI electron impact
ESI electrospray ionisation
eq equivalent
Et ethyl
ET electron transfer
EWG electron-withdrawing group
FT-IR Fourier transform infrared spectroscopy
HMQC heteronuclear multiple quantum coherence
HPLC high performance liquid chromatography
HRMS high resolution mass spectroscopy
IPA isopropyl alcohol
J coupling constant in Hertz
KIE kinetic isotope effect
LDA lithium diisopropylamide
mCPBA meta-chloroperbenzoic acid
Me methyl
MO molecular orbital theory
mpt melting point
MS mass spectroscopy
MTPA α-methoxy-α-trifluoromethylphenylacetate
NMR nuclear magnetic resonance
NMO N-methylmorpholine N-oxide
nr no reaction
Ox* oxazoline
Ph phenyl
PMA dodecamolybdophosphoric acid (TLC stain)
Pl polar
ppm parts per million
i-Pr isopropyl
Pyr. pyridine
11

RDS rate determining step
R f
RC
rt
SIP
SM
sat.
TA
Tf
Thd.
THP
THF
TLC
TMS
retention factor
radical combination
ambient temperature
solvent separated solvent pair
starting material
saturated
Donohoe tethered aminohydroxylation
triflate/trifluoromethanesulfonate
thermodynamic
tetrahydropyran
tetrahydrofuran
thin-layer chromatography
trimethylsilyl
TMANO trimethylamine N-oxide
TMP 2,2,6,6-tetramethylpiperidine
UV ultraviolet
w/w weight percentage
All compounds synthesised by the Author were the single enantiomers shown unless
labelled racemic (±) when their relative geometries and designated by an asterisk (R*,
S*). Enantiomeric purity is measured as the enantiomeric ratio (e.r.) where possible,
but enantiomer excess (e.e.) is quoted when the method was used for its determination
is unclear. Numbering conventions in the main body and experimental sections are:
The suffix to compound numbers 100, 101, 102 & 165 refers to the aromatic
substitution; for example 100a, 101a, 102a and 165a are all phenyl (C 6 H 5 ) derivatives.
12

"To expect a scientist to do philosophy of science, is like expecting a fish
to do hydrodynamics." Imre Lakatos
13

Chapter 1: Introduction
Chapter 1 – Dearomatising Additions in Organic Synthesis
1.1 Introduction
Aromaticity and aromatic compounds have enjoyed a central role in chemistry
throughout its history. Since Kekule’s first visions, the cyclic delocalised systems
have captured the imagination of chemists of all flavours, and their predictable
behaviour means that no undergraduate course goes without early examples of the
manipulation of aromatic compounds. Much work in organic synthesis has involved
the functionalisation of the aromatic nucleus, and it is fundamental to the repertoire of
any synthetic chemist. Arenes are widely available, highly stable and affordable
starting materials, and this pool of available building blocks may extended by
technologies such as cross-coupling, ortho-lithiation, and electrophilic or nucleophilic
substitution.
This thesis concerns the development of a dearomatising functionalisation of a
benzenoid system, and a brief survey of existing methods follows. A recent review by
Ortiz et al. 1 covers a range of methods for dearomatising anthracenes, naphthalenes
and benzene systems. The following survey will study reductive intermolecular
methods for the nucleophilic dearomatisation of the benzene system, although some
exceptions have been made where they are of particular relevance or interest.
1.2 Dearomatisation with Electrophilic Functionalisation
1.2.1 Von Auwers-Woodward
When subjecting ortho- and para- alkylated phenols to Reimer-Tiemann conditions, 2
Von Auwers isolated significant amounts of cyclohexadienone 2, as well as the
expected phenolic aldehyde 1 (Scheme 1.1). 3 First reported in 1902, this appears to be
the first dearomatisation of a benzene nucleus. Like phenol 1, dienone 2 is the product
of addition of dichlorocarbene to p-cresol, but unlike its regioisomer the product of
para-addition is unable to undergo rearomatisation, but must abstract a proton from
elsewhere to become dienone 2.
15

1.2 – Electrophilic dearomatisation
HO
NaOH, CHCl 3
OHC
HO
1
+
O
2
CHCl 2
NaOH, CHCl 3
CHCl 2
HO
O
3 80%
Scheme 1.1 – the first dearomatising addition by Von Auwers 3
Other than providing mechanistic evidence for the Reimer-Tiemann reaction, this
dearomatisation remained unexplored until Woodward proposed its use to introduce
the angular methyl group in the synthesis of sterols. Tetralin 4 was subjected to the
conditions, giving both the aldehyde and the desired dienone 5 (Scheme 1.2a). 4 Upon
gentle hydrogenation alcohol 6 was obtained, whilst stronger conditions led to
dehalogenation. This observation led Woodward to postulate the possible biosynthesis
of the male hormone oesterone from androstone (Scheme 1.2b).
a)
H 2
CHCl 2
HO
4
NaOH, CHCl 3
O
OHC
CHCl 2
15%
5
+
HO
6
b)
Me
O
HO
50%
Me O
proposed
biosynthesis
Me
HO
HO
oestrone
androstone
Scheme 1.2 – a) introduction of the angular methyl group b) proposed biosynthesis 4
1.2.2 The Birch reduction
The most widely used dearomatising reaction is the dissolving metal reduction
discovered by Birch. 5 The reduction yields the product of the 1,4-addition of hydrogen
across the arene system, giving the non-conjugated diene 8 (Scheme 1.3). The
formation of the thermodynamically unfavoured 1,4-diene is due to the kinetically-
16

Chapter 1: Introduction
controlled protonation of cyclohexadienyl anion 7, arguments for which mostly
resemble the principle of least motion analysis. 6 Relatively recent MO calculations of
7 by Zimmerman show that electron density is highest at the centre of the conjugated
H
H
system. 7 Li, NH 3
ROH
ROH, −33 °C
7 8
~70%
Scheme 1.3 – the Birch reduction
The regioselectivity of the reaction of substituted benzenes is highly dependent upon
the substituent, but often follows the Birch rule, 7 in which the product is the
“regioisomer with the maximum number of alkyl and/or alkoxy groups on the residual
double bonds.” The reason for this empirical rule becomes clear when considering the
most stable radical anion resulting from the first reduction, allowing the above
statement to be generalised; electron donating groups result in vinylogous products
(9), 8 whilst electron withdrawing groups give allylic products (11). 9
OMe
OMe
Li, NH 3 , THF
t-BuOH, −33 °C
9
75%
O
NMe 2
K (2.2 eq), NH 3
t-BuOH (1 eq)
THF, −78 °C
OK
NMe 2
NH 4 Cl
O
NMe 2
10 11
92%
Scheme 1.4 – regiomeric products of the Birch reduction
As expected, more electron deficient arenes are reduced more rapidly, and a
conjugated electron withdrawing group, such as an ester, gives stable enolates (10)
which may be quenched with a range of electrophiles. If there is a source of
asymmetry in the enolate, then preferential attack may occur on one of the
diastereotopic faces. This source of diastereoselectivity may be inherent in the
substrate (Scheme 1.5) or by means of a chiral auxiliary (Scheme 1.6, next section).
The former was demonstrated in House’s study of the synthesis of gibberellins, when
the stereochemistry of the quench was shown to be determined solely by the bulk of
17

1.2 – Electrophilic dearomatisation
the γ-carboxylic acid; stereospecifically forming diastereomeric tetrahydroindenes 12a
and 12b.
H
H
i) Li, NH 3 , THF
MeO
CO 2 H
H
CO 2 H
ii) MeI
MeO
Me
H
CO2 H CO 2 H
12a 51%
H
i) Li, NH 3 , THF
H
MeO
CO 2 H
H
CO 2 H
ii) MeI
MeO
Me
CO2 H
12b
H
CO 2 H
46%
Scheme 1.5 – facial selectivity in gibberellin synthesis 10
1.2.2.a Asymmetric Birch reductions
The development of stereocontrol in the Birch reduction by use of chiral auxiliary was
pioneered by Schultz and co-workers, and was reviewed in 1999. 9 Schultz used a
chiral amide to activate the aromatic ring to reduction, and the resulting enolates (14)
trapped by a facially selective electrophilic quench (Scheme 1.6).
13
O
N
OMe
OMe
Na/K, NH 3 ,
t-BuOH
THF, −78 °C
N
O
O M
14
OMe
−78 °C
MeI
i) rt
ii) −78 °C
MeI
O
Me
O
Me
N
N
OMe
OMe
OMe
85%
15 dr 260:1
product of chelate
OMe
80%
dr 99:1
16
product in absence of chelate
11
Scheme 1.6 – use of a chiral auxiliary in the Birch reduction
When used in conjunction with an ortho-methoxy group (13), the proline-derived
amide is found to offer excellent diastereomeric excesses. At low temperature,
chelation by metal ions or ammonia allows the trapping enolate 14 giving diene 15.
However, raising the temperature to 25 °C is afforded the diastereomer 16 in good
18

Chapter 1: Introduction
diastereomeric excess; this is believed to be formed due to the disruption of chelate 14,
allowing the diastereomeric product to be formed.
The methoxy group serves two purposes; firstly an ortho-substituent is essential to
desymmetrise the enolate intermediate, and secondly it participates in the internal
chelate 14. This was demonstrated by replacement of the methoxy group with a
methyl one, giving the thermodynamic diastereomer related to diene 16. The
replacement of the prolinol methoxy has minimal effect, showing that it plays no
significant role. 11 Reduction products 15 and 16 are amenable to a wide range of
functional group manipulations; the diene portion may be further reduced or
functionalised, whilst removal of the auxiliary permits facile lactonisation.
Pioneering work on the asymmetric Birch reduction of aromatic heterocycles has also
been performed in the laboratories of Donohoe, however this is outside of the scope of
this survey. 12
1.3 Nucleophilic Dearomatisation without Heavy Metals
Unlike the electrophilic Birch reduction, nucleophilic dearomatisation permits the
concomitant nucleophilic and electrophilic functionalisation of an aromatic system,
allowing two stereocentres to be formed in a single reaction. The methods presented
below generally employ strong π-acceptors to lower the energy of the benzene LUMO;
however the functional groups which promote the addition are often prone to reaction
themselves which is minimised by judicious choice of reaction conditions, or by the
use of steric bulk to protect the functional groups.
The reactions often suffer from rearomatisation of reaction intermediates, poor
chemoselectivity and poor regioselectivity during either the nucleophilic or
electrophilic functionalisation. The first section presents some examples of the
dearomatisation of benzenoid rings, the next explores Meyers’ dearomatisation of
naphthyloxazolines, before catalytic methods for dearomatisation are briefly discussed.
19

1.3 – Nucleophilic dearomatisation
1.3.1 Favourable electron withdrawing groups
1.3.1.a Nitro group
Perhaps one of the most widely explored electron withdrawing groups in aromatic
chemistry is the relatively inert and strongly π-withdrawing nitro group. In light of the
significant body of work performed with respect to Meisenheimer complexes, it is
perhaps surprising that the dearomatisation of nitrobenzenes has only been generally
achieved by borohydride species, which is beyond the scope of this discussion. 1
However, Bartoli and co-workers were able to achieve the dearomatisation of
dinitrobenzene by Grignard reagents.
O 2 N
17
NO 2
i) RMgX (2 eq)
THF, −70 °C 10 min
ii) NaOCl
O 2 N
R
18
NO 2
R
+ 17
entry R 18 / % 17 / %
a Me 56 31
b Et 30 37
c Me 3 SiCH 2 18 50
d Bn 20 53
e PhCH 2 CH 2 34 38
f CH 2 =CH(CH 2 ) 2 36 37
13
Table 1.1 – dearomatisation of dinitrobenzene
Dearomatisation of dinitrobenzene with Grignard reagents (Table 1.1) suffers from
competing reduction of the nitro group, which upon an oxidative workup returns
starting material 17. It was possible to minimise reduction by performing the reaction
at low temperature. Interestingly, only trace amounts of the mono-alkylated adduct
were obtained when using a single equivalent of the organometallic, presumably
because the intermediate nitroalkene is significantly more electrophilic than the
nitroarene.
It is proposed that the decrease in dearomatisation with increasing bulk (entries a-c) is
indicative of a single electron transfer (SET) mechanism since a bulky radical would
20

Chapter 1: Introduction
combine more slowly with the aromatic radical anion. ESR studies show the presence
of radical species, although these studies were inconclusive since they were unable to
show that the radical anion was an intermediate in the dearomatisation rather than
another trace species, or the reduced nitrobenzene.
1.3.1.b Nitrile
Cyano groups are highly susceptible to 1,2-addition reactions with organolithiums, and
the lithiation of benzonitriles normally requires the use of a non-nucleophilic base. 14
However, in an extension of his dearomatisation of cyanonaphthalenes, 15 Ortiz found
that at very low temperatures, lithiated phosphine boranes (20) underwent
dearomatising addition in a 1,6-fashion.
CN
CN
PPh 2 BH 3
Li 20
CN
H 2 O
PPh 2 BH 3
21
65%
THF, HMPA (6 eq)
−90 °C 12 hr
PPh 2 BH 3
RX
PPh 2 BH 3
R
CN
22
R = Me, 97% 1:1.2 dr
= allyl, 97% 1:1.5 dr
= Bn, 77% 97:1 dr
16
Scheme 1.7 – dearomatisation of benzonitrile
The above summary shows that alkylation of the dearomatised intermediate proceeds
in much better yield than simple protonation; indeed most of the remaining mass
balance accompanying 21 (32%) were products of 1,2-addition. Ortiz does not
comment on these results which apparently show the electrophilic addition affecting
the prior nucleophilic addition, which could indicate a reversible reaction. The
dearomatisation was highly regioselective with no 1,4-addition observed;
dearomatisation was also achieved for 3-chloro (79%) and 3-methyl (36%)
benzonitriles to give 1,3 dienes similar to 21.
21

1.3 – Nucleophilic dearomatisation
1.3.1.c Strained amides
Tertiary amides are often used to direct metalation of aromatic rings and are not prone
to direct addition. During conformational studies of secondary amides, Clayden found
that tetramethylpiperidenes 22 underwent conjugative addition rather than the expected
ortho-lithiation.
R R’ E 23 / %
O N
O N
i) RLi, THF R
ii) E
E
R'
R
22 23
Table 1.2 – dearomatising addition to
TMP amides 17,18
a s-Bu H MeI 55 *
b Me OMe MeI 22
c n-Bu OMe MeI 40
d s-Bu OMe MeI 71 *
e s-Bu OMe EtI 51 *
f s-Bu OMe BnBr 61 *
g s-Bu OMe Me 2 CO 32 *
h s-Bu OMe NH 4 Cl 76 *
* 3:1 exocyclic d.r.
Only trans-adducts were isolated and both nucleophilic and electrophilic additions
were highly regio- and stereoselective, with the mass balance mostly identified as
starting material. The unexpected reactivity is attributed to an amide in which the
ground state is destabilised by torsional strain, reducing the n N →π* C=O interaction and
allowing the carbonyl to accept more electron density from the aromatic system, whilst
direct addition is prevented by the TMP geminal dimethyl groups. Whilst the reduced
π* interaction is not observed in the IR absorption of amides 22 (1620 cm -1 ) this
appears to be the most likely explanation.
22

Chapter 1: Introduction
O
Ar
Cl
TMP
NaH
O
Ar
N
22
12-34%
O
N
O
NH
s-Bu
TMSI, CH 2 Cl 2
rt, 48 hr
s-Bu
OMe
23'
O
24
50%
18
Scheme 1.8 – installation & cleavage of the TMP group
In light of the good regio- and stereoselectivity, this dearomatisation compares
favourably with the other methods. However amides 22 could only be made in very
low yield from the acid chloride (Scheme 1.8) and are very sensitive to strong acid –
presumably with respect to 24 – limiting options for workup. Controlled hydrolysis
could be achieved upon treatment with iodotrimethylsilane in the dark, but this gave
only a modest yield of the secondary amide 24.
23

1.3 – Nucleophilic dearomatisation
1.3.1.d Bulky esters
When studying S N Ar reactions of aromatic esters, Miyano found that BHA benzoate
25 underwent conjugative addition to the aromatic ring for a range of organolithiums
and Grignard reagents.
OMe
i) RM, THF
OMe
OMe
R
COBHA −78 °C
COBHA
COBHA
ii) NH 4 Cl
+ +
iii) DDQ
R R
25 26 27 28
entry RM 26 / % 27 / % 28 / %
a t-BuMgBr * 74 – –
b BnMgBr * 76 – –
c BnLi 71 – –
d n-BuLi – – 70
e n-BuLi ‡ 6 29 42
f i-PrLi 14 57 –
g t-BuLi 33 – 50
h t-BuLi ‡ 45 – 16
i allyl-Li 73 – –
j Me 3 SiLi ‡ 85 – –
k PhLi – – 85
l n-BuMgBr * – – 93
m i-PrMgBr * – – 92
* reactions in diethyl ether at rt ‡ THF-HMPA solvent (4:1)
19
Table 1.3 – dearomatisation-oxidation of aryl esters
COBHA
Whilst exclusive substitution (S N Ar) of the methoxy group was observed in a number
of instances (entries k-m) the bulky ester both resists direct addition and promotes 1,4-
and occasionally 1,6-addition to the unsaturated system. The dearomatised compounds
could not be isolated since they were unstable to chromatography, and were instead
oxidised and characterised as rearomatised adducts 26 and 27. It seems that the
reaction is sensitive to both the nature of the organometallic and the reaction
24

Chapter 1: Introduction
conditions, although the data allow few direct comparisons to be made, and it is
unclear if the results presented have been optimised.
Miyano et al. propose a SET mechanism for this dearomatisation stating that
carbanions have an electron donating ability which follows Bn > allyl- >> t-Bu > i-Pr
> Bu >> Ph, and is consistent with their results. 19 They cite Bartoli as the source of
this data, who had used oxidation potentials of Grignard reagents to propose electron
donating ability i-Pr > Bn ≥ Et > Me >>Ph; 20 contradicting Miyano. Miyano also cites
Yamamoto, who used ionisation potentials of organostannanes to infer an electron
donating ability allyl >> n-Bu > vinyl. 21 Aside from the data appearing to disagree
with the conclusions of the authors, they also fail to note Yamamoto’s advice that
“there must be an argument against extending this substituent order of ionization
potential for organotins to that for organocoppers,” when applying these data.
Further evidence of an SET mechanism is evidenced in the especially high yield
resulting from addition trimethylsilyllithium (entry j), a species which has been used as
single electron reductant for the production of EPR spectra. However, many other
dearomatisations have occurred with silicon nucleophiles in good yield (vide infra)
without stimulating thoughts of an SET reaction.
25

1.3 – Nucleophilic dearomatisation
1.3.2 Dearomatising additions to oxazolines
1.3.2.a Pyridyloxazolines
During the attempted ortho-lithiation of 3-pyridyl oxazoline 30, Meyers and coworkers
isolated dihydropyridine 31, the product of nucleophilic addition (Scheme
1.9).
E
N
O
N
i) RLi
X
ii) E +
O
N
i) RLi,
trace H 2 O
N
ii) E +
N
H
30 31
R
H
O
N
82-100%
R = Ph, Me, n-Bu, t-Bu
Scheme 1.9 – unexpected dearomatising addition to pyridine 22
Use of a chiral oxazoline 32 was found to impart good diastereoselectivity giving
carbamates 33 in high diastereomeric purity (Table 1.4). Nucleophilic addition was
also possible for Grignard nucleophiles (entries d, e).
N
O
N
Ph
OMe
i) Nu-M
ii) ClCO 2 Me
Nu
32 COOMe 33
N
O
N
Ph
entry Nu-M T / °C Yield / % d.r.
a MeLi –45 79 93 : 7
b MeLi –78 79 94 : 6
c n-BuLi –78 92 97 : 3
d MeMgCl 0 88 91 : 9
e n-BuMgCl 0 98 95 : 5
H
OMe
Table 1.4 – asymmetric dearomatising addition to pyridines 23
1.3.2.b Addition to achiral naphthyloxazolines
Meyers and co-workers later managed to extend this reaction to carbocycles in the
form of naphthalene 34 (Table 1.5). 24
Whilst the first reactions were discovered for
26

Chapter 1: Introduction
chiral oxazolines, 25 initial development focused on racemic 1-naphthyloxazoline 34. 26
No mention of the dearomatisation of naphthyloxazolines by Grignard reagents has
been found.
O
N
NuLi
O
NLi
Nu
MeI
O
N
Me
Nu
34 35 trans-36
entry NuLi T / °C Yield / % trans : cis-36
a MeLi –20 65 >99 : 1
b n-BuLi –45 90 >99 : 1
c s-BuLi –45 94 >99 : 1
d t-BuLi –45 99 >99 : 1
e Li –80
95 >99 : 1
f allyl-Li –80 85 >62 : 38
g PhCH 2 Li –80 91 >99 : 1
h Ph-C≡CCH 2 Li –40 90 70 : 30
i
THPO Li –40 74 84 : 16
j NC-CH 2 Li –80 to –10 0 –
k n-Pr-C≡CLi –80 to –10 0 –
l 27
Li
OEt
–10 66 * –
* including 16% ketone
26
Table 1.5 – addition of nucleophiles to 1-naphthyloxazolines
The addition proceeds with high trans selectivity, induced by attack on the less
hindered face of azaenolate 35. Protonation of the azaenolate with weak acids such as
alcohols favoured the products of apparent syn addition, believed to be due to
epimerisation to the more stable trans adduct (vide infra). Initial studies showed that
the addition of HMPA as deaggregating agent made no difference to selectivity or
yields, whilst freshly prepared organolithium gave improved conversion of starting
material. 28
27

1.3 – Nucleophilic dearomatisation
Additions to 2-naphthyloxazoline 37 were also successful (Scheme 1.10) but have
been studied less. Oxazolines were also found to promote dearomatisation of
anthracenes but not phenyloxazolines. 29,30
37
O
N
i) NuLi, −45 °C
ii) MeI
Nu O Me
N Nu = n-Bu, 90%
s-Bu, 91%
t-Bu, 90%
Scheme 1.10 - additions to 2-naphthyloxazoline 26
1.3.2.c Addition to chiral naphthyloxazolines
As with chiral pyridyloxazolines, high levels of asymmetry could be introduced to the
already highly diastereoselective addition. 31 Enantiomerically pure oxazolines 38 were
subject to the same conditions, with the initial addition proceeding in high
diastereoselectivity followed by exclusively trans-addition for alkyl electrophiles
(Table 1.6). Oxazoline cleavage of the major diastereomer (39 to 40) also proceeded
with high fidelity and is discussed further in section 3.2. A comprehensive list of
results has been compiled by Ortiz et al. in their recent review. 1
Ph
O
N
OMe
i) NuLi, 2-4 hr
ii) E
Ph
O
OMe
N
E
Nu
i) MeOTf
then NaBH 4
ii) H +
OHC
38 39 40
NuLi E T / °C 39 / % d.r.* 40 † / % e.e. † / %
a n-BuLi MeI –45 97 94 : 6 – –
b n-BuLi (PhS) 2 –45 91 94 : 6 – –
c n-BuLi ClCO 2 Me –45 99 97 : 3 88 88
d MeLi (PhS) 2 –20 56 86 : 14 62 >99
e PhLi MeI –45 99 83 : 17 89 >99
f 32 vinyl-Li MeI –60 79 94 : 6 – –
g 32 vinyl-Li MeI –60 65 89:11 – –
* ratio of adduct 39 to that of trans addition from opposite face † from 39
31
Table 1.6 – selected nucleophilic additions to chiral 1-naphthyloxazolines
E
Nu
28

Chapter 1: Introduction
Again a large range of nucleophiles and electrophiles were tolerated. Temperature was
found to have a significant effect on the diastereoselectivity of addition by vinyllithium
(Table 1.6, entries f, g). Studies of protic quenches found that the use of trifluoroacetic
acid (TFA) gave the expected trans-dihydronaphthalene 41 rather than its epimer as
had previously been observed (Scheme 1.11). It is proposed that this is due to
trifluoroacetate being too weak a base to epimerise the allylic stereocentre. Quenching
with TFA led to the formation of TFA salt 41 upon workup, which could be reduced to
give carbinol 42 and is discussed further in section 3.2.1.
Ph
O
N
OMe
i) i-PrLi
ii) TFA
O
H
Ph
O
i-Pr
NH 2
OMe
i) LiAlH 4 , Et 2 O
ii) H 2 O, NaOH
H
OH
i-Pr
38 41
42
73%
d.r. 24:1
Scheme 1.11 – TFA quench of dearomatising addition
It has also been possible to perform a tandem addition to naphthalene 38 by tethering
an electrophilic site to the organolithium, giving an effective stereoselective annulation
to yield syn-fused carbocycle 43 in good yield.
Ph
O
N
OMe
i)
Li
Cl
THF −78 °C to rt
Ph
O
OMe
N
ii) NH 4 Cl
H
38
43
84%
Scheme 1.12 – annulation by ambident organolithium 33
29

1.3 – Nucleophilic dearomatisation
The effect of oxazoline substituents on diastereoselectivity was investigated using 2-
naphthyloxazolines 44 (Table 1.7). This work shows that the C4 substituent was key
to determining the stereochemistry of the product (entries a, b, d) whilst the C5
substituent shows minimal effect except when syn to the C4 substituent (entry c).
Similar results were seen for 1-naphthyloxazolines in the same study.
Oxz
i) PhLi
ii) MeI
Ph
Oxz
+
Ph
Oxz
44
45a
45b
Entry T / °C Oxz Yield / % 45a : b
Ph
5 4
a –30 O N
OMe
89 90 : 10
Me
b –78 O N
OMe
90 9 : 91
Me
c –78 O N
OMe
93 25 : 75
d –78 O N
OMe
90 9 : 91
Table 1.7 – the effect of oxazoline substituents on diastereoselectivity 31
To explain the high diastereoselectivity, Meyers proposes a bidentate interaction
between the aryloxazoline and organolithium (Scheme 1.13); the two remaining
coordination sites around lithium being occupied by solvent and the alkyl group, and
are free to interchange. 34
30

Chapter 1: Introduction
34
Scheme 1.13 – reproduction of Meyers’ proposed reaction intermediates
“The two possible complexes should be capable of ligand exchange, placing
R or the solvent (THF) in either of two positions. If the R-Li bond is situated
as shown in 12, then the σ-orbital is aligned parallel to the π-system, whereas
in 13, the R-Li σ-orbital is orthogonal to the π-system. In a formal sense
reaction from 12 may be viewed as a concerted suprafacial 1,5-sigmatropic
rearrangement from the HOMO (ψ3) of the six-electron system, according to
Woodward-Hoffman rules to furnish 14.”
In the proposed mechanism, coordination to the lithium species aligns the σ C-Li orbital
with the aromatic π-system. Meyers provides little evidence to support this
mechanism, and there seems to be no literature precedent for such a polarised process
to be pericyclic. Involvement of a σ C-Li orbital seems unlikely as, although unknown at
the time, the C–Li internuclear axis has very little electron density, and bonding is now
accepted to be 80-90% ionic. 35
Instead, lithium could be viewed as holding the
carbanion in place such that the sp 3 n C orbital is aligned with the aromatic π-system.
a) b) Ph
O
H
H
N
OMe
Li 1,5-sigmatropic rgmnt
R
" Ph OMe "
O N
Li
R
48
Scheme 1.14 – Meyers’ pericyclic interpretation of dearomatising addition
The absence of an available p-orbital on lithium means that whilst a π-bond is broken,
it cannot be replaced as it would in the rearrangement of pentadiene (Scheme 1.14a).
If we assume that the initial association is not covalent then the product would
resemble adduct 48 (Scheme 1.14b).
31

1.3 – Nucleophilic dearomatisation
Later studies of amino acid-derived oxazolines, which only have one Lewis basic
centre and would not be able to form the bidentate chelates, gave some interesting
results.
R
O
N
R'
i) NuLi
ii) MeI
R
O
R'
N
E
Nu
i) MeOTf
then NaBH 4
ii) H +
OHC
E
Nu
52
53
Entry Nu R R’ T / °C 53 / % d.r. e.e. / %
a n-Bu Ph CH 2 OMe –78 97 96 : 4 90
b Ph Ph CH 2 OMe –40 86 83 : 17 78
c n-Bu H i-Pr –78 97 97 : 3 90
d Ph H i-Pr –40 87 87 : 13 74
e n-Bu H t-Bu –78 99 99 : 1 98
f Ph H t-Bu –40 81 95 : 5 90
Table 1.8 – non-chelating vs chelating oxazoline substituents 37
The diastereoselectivity of addition to the chelating oxazoline (entries a, b) are
comparable to those of the oxazoline derived from valine (entries c & d), whilst that of
the oxazoline derived from tert-leucine (entries e & f) is significantly better. Meyers
proposed a new rationale for these monodentate auxiliaries. 37
R
Li
54
Scheme 1.15 – Meyers’ stereochemical rational for “monodentate” oxazolines
In this description, the nitrogen lone pair lies in the plane of the oxazoline and the
bulky C4 substituent favours attack from the opposite face. Complexation with
nitrogen is consistent with the complex-induced proximity effect (CIPE) of Meyers
and Beak, 38 although Meyers does not seem to acknowledge this. This simple
explanation could be applied for Meyers’ earlier chiral auxiliary, but until recently
monodentate and bidentate oxazolines were described as having different mechanisms.
O
N
32

Chapter 1: Introduction
The amino acid-derived naphthyloxazolines have more recently been found to be
superior in the addition of secondary lithium amides, and silyllithiums.
1.3.2.d Heteroatomic nucleophiles
In early investigations, silyllithiums had undergone dearomatising addition to
bidentate naphthyloxazolines 38 in good yield, but poor diastereoselectivity. 31 It had
been postulated that residual HMPA from formation of the silyllithium was responsible
for this by preventing oxazoline from forming a tight complex with the lithium species
(vide supra). By preparing dimethylphenylsilyllithium from lithium wire, and using
valine-derived monodentate oxazoline 55, the diastereoselectivity of addition was
significantly improved (Table 1.9, entry a).
O
N
i) Me 2 PhSiLi
−78 °C
O
N
E
Bu 4 NF
THF/H 2 O
O
N
E
ii) EX
SiPhMe 2
"70-71%"
55 56
57
entry Solvent EX 56 / % d.r. *
a THF MeI 75 25:75
b Et 2 O-THF (3:1) MeI 76 95:5
c Et 2 O-THF (3:1) n-PrBr 70 97:3
d Et 2 O-THF (3:1) allyl-Br 77 95:5
* exclusively trans-addition
39
Table 1.9 – addition of silyllithiums
Use of a less Lewis-basic solvent, diethyl ether, further improved the
diastereoselectivity of the reaction (entries b-d). Protodesilylation was achieved in
good yield by treatment with tetrabutylammonium fluoride in aqueous THF to afford
57 as the major products in >9:1 ratio with the regiomeric alkene.
Meyers and Shimano succeeded in achieving the dearomatising addition of lithium
amides to both 1- and 2-naphthyloxazolines before subsequent alkylation (Table 1.10).
HMPA was essential to the reaction, although a large excess (10 eq) reduced
33

1.3 – Nucleophilic dearomatisation
diastereoselectivity, whilst DMPU was also found to be moderately effective.
Although addition was successful for a number of lithium amides, an equal number did
not show any dearomatisation; including diethylamide, diallylamide and allylamide. It
appears that β-substitution in the lithium amide disfavours addition, as does an
adjacent π-system.
O
N
i) NuLi (3 eq)
HMPA (1.4 eq)
−78 to −50 °C
ii) EX
58 59
O
N
E
Nu
>99:1 dr
entry NuLi EX Yield / %
a Me 2 NLi MeI 93 *
b n-BuN(Me)Li MeI 93
c n-C 5 H 11 N(Me)Li MeI 93
d Li-piperidide MeI 95
e Li-piperidide allyl-Br 92
f Li-piperidide BnBr 67
g Li-piperidide CO(OEt) 2 0
h
O
O
NLi
MeI 96
* + 1% 1,6-adduct
40
Table 1.10 – 1,4-addition of lithium amides to 1-naphthyloxazolines
One particularly surprising result was that upon quenching with diethyl carbonate no
dearomatisation was observed. This led the authors to investigate whether the addition
might be reversible, which was confirmed by the sequential addition of lithium
piperidide and n-butyllithium, which gave only butylated product. That any
dearomatising reaction is under thermodynamic control seems remarkable.
34

Chapter 1: Introduction
It was envisaged that a one-pot hydrolysis of dearomatised adduct 59h would return β-
amino acid 61, but instead a three-step hydrolysis was necessary (Scheme 1.16). The
ethylene glycol group was found to be particularly resilient, but was eventually
removed in concentrated acid before the base-catalysed hydrolysis in the presence of
butylamine gave the free amine 60. Finally, the acid-catalysed hydrolysis of the
oxazoline gave the desired β-amino acid 61.
O
N
59h
N
O
O
i) HCl (conc) rt
ii) NaOH, H 2 O
n-BuNH 2 Δ
O
60
N
CO 2 H
NH 2
HCl (6N)
NH 2
Δ
78%
61
85%
Scheme 1.16 – synthesis of a β-amino alcohol 40
In extension of this work, Shimano and Meyers found that by simply adding a larger
excess of HMPA, they were able to entice some of the unreactive lithium amides to
undergo dearomatisation in a 1,6-manner.
O
N
i) NuLi (1.5 eq)
HMPA (8 eq)
−78 to −60 °C 6 hr
O
N
E
O
N
34
ii) EX, −10 °C
62
Nu
63
Nu
E
entry NuLi EX 62 / % d.r. 63 / %
a Bn 2 NLi MeI 88 5:1 5
b Bn 2 NLi BnBr 93 99:1 0
c BnN(Me)Li allylBr 86 50:1 6
d (allyl) 2 NLi MeI 88 5:1 7
e (allyl) 2 NLi MeOTf 92 5:1 0
f (allyl) 2 NLi allylBr 85 99:1 5
g (allyl) 2 NLi BnBr 92 99:1 0
41
Table 1.11 – 1,6-addition of bulky lithium amides to 1-naphthyloxazolines
35

1.3 – Nucleophilic dearomatisation
For such a small change in conditions regioselectivity is very high, presumably
because the addition remains under thermodynamic control. This was supported when
lithium amides from Table 1.10 were re-subjected to the new conditions still gave 1,4-
adducts. Diastereoselectivities were somewhat less than the previous 1,4-additions, as
would be expected for the formation of such distant stereocentres. Unlike the 1,4-
additions, DMPU did not promote reaction, and adducts 62 were used in the synthesis
of δ-amino acids. 41
1.3.3 Catalytic systems
The above systems have been specific to a single functional group which remains in
the product. Whilst this may be acceptable if that functionality is desired, or can easily
be removed, it places significant restriction on synthetic design. In principle, a
generally applicable catalytic methods offers clear advantages over a comparable
stoichiometric process.
1.3.3.a Bulky Lewis acid
In a series of communications, Yamamoto and Saito have achieved dearomatising
additions to aromatic ketones, 42 aldehydes, 42 acid chlorides 43 and esters. 44 This has
been accomplished by the use of the “carbonyl protector” ATPH (Table 1.12)
promoting 1,6-addition by acting as a Lewis acid and preventing direct addition to the
electron withdrawing group.
36

Chapter 1: Introduction
COR'
i) ATPH, −78 °C
then RM (2-3 eq)
1-12 hr
ii) HCl (conc.)
R
65a
COR'
+
65b
COR'
R
Al
Ph
O
Ph
ATPH
3
entry RM R’ Solvent 65 / % 65a:b
a 42 t-BuLi H PhMe/THF 81 99:1
b 42 n-BuLi H PhMe/THF 47 * 99:1
c 43 MeLi H PhMe 1 -
d 45
e 45
OLi
MeO
H PhMe/THF 23 99:1
OLi
MeO H PhMe/THF 77 99:1
f 44 PhMe 2 SiLi H PhMe 59 99:1
g 42 t-BuLi Me PhMe/THF 93 99:1
h 42 s-BuLi Me PhMe/THF 80 99:1
i 42 n-BuLi Me PhMe/THF 45 99:1
j 45
OLi
MeO
Me PhMe/THF 88 99:1
k 44 PhMe 2 SiLi Me PhMe 44 ** 6:1
l 43 MeLi Cl PhMe 99 2.6:1
m 43 PhLi Cl PhMe 96 99:1
n 43 i-PrMgBr Cl PhMe 71 13:1
o 43 t-BuMgBr Cl PhMe 90 15:1
p 43
OLi
Cl PhMe 75 99:1
MeO
q 44 PhMe 2 SiLi OMe PhMe 34 ‡ 35:13
* + 13% regiomeric 1,3-diene ** + 43% SM ‡+30% SM +35% rearomatised 65a
Table 1.12 – selected dearomatisations by Yamamoto et al.
Initial studies showed the reaction to be highly sensitive to the choice of solvent with a
toluene-THF mixture being preferred at first, whilst more the recent work favours
37

1.3 – Nucleophilic dearomatisation
toluene alone. In particular, degassed solvent was found to be essential, and the use of
aqueous solutions of acid was detrimental to the successful isolation of diene; failure to
observe these measures leads to near quantitative rearomatisation. 42 Regioselectivity
of addition is generally very good, but slightly diminished for acid chlorides, this is
rationalised by comparison of the crystal structures of ATPH-PhCHO and ATPH-
PhCOCl which show one of the ortho-carbons to be exposed in the latter complex.
Interestingly a number of other differences are observed between the acid chloride and
simple carbonyl complexes; the IR carbonyl stretch for ATPH-PhCOCl is 42 cm -1
lower than the free acid chloride, whereas little difference is reported for the ATPH-
PhCHO complex. 43 This is consistent with the crystal data which shows the C=O in
the ATPH-PhCOCl complex to be almost 0.1 Å shorter than the benzaldehyde
complex. Indeed, additions to benzoyl chloride seem to tolerate a larger range of
nucleophiles, including Grignard reagents which do not react with the other systems
studied.
O
i) ATPH, −78 °C
PhMe/THF
then t-BuLi (2 eq)
O
ii) MeOTf
t-Bu
66
68%
d.r. 1:1
O
OMe
i) ATPH, −78 °C
PhMe/THF
then PhMe 2 SiLi (2 eq)
O
OMe
ii) MeOTf
Me 2 PhSi
67
51%
d.r. >95:5
Scheme 1.17 – alkylation of dearomatised ATPH complexes
Whilst the vast majority of the dearomatising additions were γ-protonated with
concentrated acid, methylation with methyl triflate (Scheme 1.17) was highly
regioselective for α-addition. No stereochemical preference was seen for addition of t-
BuLi/MeOTf to acetophenone (66), 42 but addition of the bulky dimethylphenylsilyl
group engendered high diastereoselectivity in the subsequent alkylation, giving silane
67. 44 This is consistent with the observations of 1,6-additions to benzonitriles by
Ortiz, who also found that bulky reagents increased facial selectivity in the distal
addition-alkylation (Scheme 1.7).
38

Chapter 1: Introduction
O
i) ATPH, −78 °C
PhMe/THF
then t-BuLi (2 eq)
O
ii) HCl (conc.)
t-Bu
89%
O
Cl
i) ATPH, −78 °C
PhMe
then MeLi (3 eq)
CO 2 H
CO 2 H
69
ii) HCl (conc.)
70
22% 38%
71
Scheme 1.18 – addition to functionalised aromatic systems
Some degree of aromatic functionalisation is tolerated by the reaction, but only methyl
substituents have been studied and have a significant effect of the regioselectivity of
addition (Scheme 1.18). Dearomatising addition of MeLi to dimethylbenzoyl chloride
69, favours 1,4-addition over 1,6-addition (entry l, Table 1.12) and shows poor
regioselectivity in light of the ‘pocket’ found in the crystal structure of the ATPHcomplex
(vide supra). 43 Equally interesting is that no benzylic lithiation is reported for
these reactions; even addition of t-BuLi to 69 only gives 1,6-addition without any
reported lithiation.
The only attempt to induce asymmetry in the reaction is the use of an O-(+)-menthyl
enolate, with gave the dearomatised adduct with 3% d.e. in 77% yield. 45 There has
been no reported use of any chiral analogues of ATPH, this is possibly because
Yamamoto has found the complexes to be quite labile. 43
39

1.3 – Nucleophilic dearomatisation
1.3.3.b Asymmetric catalysis
Tomioka and co-workers found that bulky alkyl imines 72 reduce direct addition and
preferentially react in a conjugative manner. This process becomes asymmetric in the
presence of chiral diether 73.
Ph
c-Hex
Ph
N
OMe
i) NuLi, OMe 73
ii) H 3 O +
CHO
Nu
NaBH 4
HO
Nu
72
74
Nu = n-Bu, 80%, 91% e.e.
= t-Bu, 79%, 59% e.e.
= Ph, 82%, 94% e.e.
= Me, 19%, 64% e.e.
Scheme 1.19 – asymmetric addition of organolithiums to naphthylimines 46
Whilst the reaction is catalytic in diether 73, stoichiometric amounts are required,
proposed to be due to the azaenolate intermediate competing as a ligand for the
organolithium, reducing the amount of unbound catalyst in solution. Since enolates
are less basic, this work was extended to look at the catalytic asymmetric addition to
BHA ester 75 (Scheme 1.20). In racemic reactions BHA ester 75 was found to offer
the best regio- and diastereoselectivity of a number of ester 47 and a 20% loading of the
chiral ether was found to be optimal for asymmetric catalysis. Only a small sample of
nucleophiles is reported, and both yields and enantiomeric purities are modest.
O
OBHA
i) NuLi, 73 (20 mol%)
Toluene, −45 °C
HO
Nu
75
ii) LiEt 3 BH
iii) MeOH
iv) NaBH 4
74
Nu = 1-Naphthyl, 75%, 67% e.e.
= Ph, 76%, 75% e.e.
= n-Bu, − %, 21% e.e.
Scheme 1.20 – asymmetric addition of organolithiums to naphthylcarboxylates 48
40

Chapter 1: Introduction
1.4 Nucleophilic Dearomatisation of Metal Complexes
High levels of diastereoselectivity have been achieved for a range of nucleophiles and
substrates in the dearomatising addition to transition metal-complexed arenes. Most
widely applied are the chemistries of Cr(CO) 3 and Mn(CO) + 3 arene complexes, which
are discussed below.
1.4.1 (η 6 -Arene)Cr(CO) 3
The chemistry of arene-tricarbonyl chromium complexes is extensive, allowing a
broad range of functionalisations to be performed prior to dearomatisation (Scheme
1.21). These are possible due to the electron-withdrawing properties of the Cr(CO) 3
R=F, Cl, OR
Nu
R
complex. 49 Cr(CO) 3 Cr(CO) 3
NuLi
R
75 76
Nu
E +
[O]
R
77
E
Nu
Crystal Structure for
Nu = dithiane, R = H
R
Nu
6
Scheme 1.21 – general reactivity of (η -arene)Cr(CO) 3 complexes
A range of carbon nucleophiles may attack the chromium-complexed arene 75 from
the face exo to the bulky metal centre, yielding the η 5 -cyclohexadienyl 76 (Scheme
1.21) which has been characterised by crystal structure for the addition of dithiane to
benzene. 50
Addition to the arene complex is relatively facile and labile. This has the advantage of
high levels of selectivity – the thermodynamic product is formed rapidly – but it also
means that regioselectivity is highly substrate-dependent. Furthermore, the addition of
an electrophile other than a proton will often react with the dissociated nucleophile. In
light of this, many studies have been conducted with dithiane as nucleophile since it
41

1.4 – Metal complexation
has a very slow rate of dissociation. A summary of the preferred regioselectivity of
different nucleophiles and aryl substituents is given in a recent review by Kündig. 51
Electron withdrawing groups on the arene can reduce the backwards reaction,
oxazolines and hydrazines are often use since they also tend to direct attack towards
the ortho-position. Below is presented a overview of the possible routes dearomatising
additions might take; the use of these groups in asymmetric synthesis is discussed in
the next section.
R
NuLi
Nu
R
EX
Nu
R
Cr(CO) 3
Cr(CO) 3
75 76
Cr(CO) 3
E
L = CO, MeCN, PhCN
+L
E = Bn, allyl, propargyl
endo migration
R
CO insertion
Nu
R
Nu
E
+ Cr(CO) 2 L 4
E
+ Cr(CO) 2 L 4
Cr(CO) 2 L
E
Cr(CO) 3 L
E
77 O
endo migration L
[O]
Nu
R
Nu
R
E
Cr(CO) 2 L 2
E + Cr(CO) 3 L
O
80
[O]
H 2 (5 bar)
R = H, Nu = dithiane
Nu
R
Nu
O
78
O
79
Scheme 1.22 – dearomatisation strategies of (η -arene)Cr(CO) complexes
6
3
42

Chapter 1: Introduction
Unlike the dearomatising additions discussed in the previous section, the anti addition
of the electrophile is not due to the relative steric bulk of the nucleophile, but is due to
endo migration of the electrophile after alkylation of the chromium centre (76) and can
happen in two ways (Scheme 1.22). In the presence of a suitable ligand such as
acetonitrile, benzonitrile or CO, the electrophile migrates to one of the carbonyl
ligands to form acylated complex 77 before endo-migration delivers the acyl group
opposite to the nucleophile. In the absence of a suitable ligand, or if E is a poor
migratory group (benzyl, allyl, propargyl) non-acylated products 80 are isolated.
Again, the electrophilic quench is highly sensitive to the nature of the substrate and
nucleophile. This facility greatly enhances the scope of the methodology, allowing the
formation of two stereocentres, and the possibility for further functionalisation via the
enolate of acyl diene 78. Furthermore, olefins 79 have been obtained by the addition
of lithium dithiane to a benzene complex, followed by in situ hydrogenation. 52
1.4.1.a Asymmetric addition using Cr(CO) 3 complexes
Asymmetry has been successfully introduced by the use of substrate-bound chiral
auxiliaries (Table 1.13) and chiral ligands (Scheme 1.23). Oxazolines 81, derived
from amino alcohols are effective in directing the asymmetric addition to the benzene
nucleus; tert-leucine-derived oxazolines (entries d-f) react with greater
diastereoselectivity than for those derived from L-valine, consistent with Meyers’
observations of additions to naphthyloxazolines (vide supra). Electrophilic
substitution occurs via addition to the metal centre, without acylation since allyl is a
poor migratory group.
43

1.4 – Metal complexation
R
R
R
O
N
O
N
O
N
i) NuLi
ii) allyl Br, HMPA
Nu
+
Nu
Cr(CO) 3
81
82a
82b
Entry R Nu 82 / % 82a : b
a i-Pr Me 61 96 : 4
b i-Pr n-Bu 54 95 : 5
c i-Pr Ph 48 95 : 5
d t-Bu Me 69 >99 : 1
e t-Bu n-Bu 62 >99 : 1
f t-Bu Ph 51 95 : 5
Table 1.13 – use of chiral oxazoline auxiliaries 53
Asymmetric additions to prochiral arene chromium species 84 has been achieved with
chiral ligand 73 (Scheme 1.23), the same ligand used by Tomioka in the asymmetric
addition to naphthylesters and imines (Scheme 1.20). This ligand is proposed to work
by coordinating either the organolithium nucleophile or the arene-chromium complex.
Whilst an advantage of using a chiral ligand rather than an auxiliary would normally
be that little or no trace of activation remains, the need for a ortho-directing group
seems to negate this.
i) RLi Ph
Ph
O N
OMe O N
73 OMe 2 eq
R
ii)
Br
Cr(CO) 3
84
54
Scheme 1.23 – use of an asymmetric ligand
51-67%
65 - 93% e.e.
The above methods have been utilised by Kündig et al. in the recent synthesis of both
enantiomers of aceteoxytubipofuran via the key intermediates (–)-86 and (+)-86. In
the key step, two stereocentres, one of them quaternary, are formed (Scheme 1.24).
44

Chapter 1: Introduction
Diene (–)-86 is prepared in high enantiomeric excess from the imine of D-valinol,
whilst enantiomeric diene (+)-86 is obtained by the use of the chiral ether 73, but only
in modest optical purity, which is improved by recrystallisation.
N
OMe
i)
EtO
85
Li
−78°C
CHO
H
OEt
Cr(CO) 3
N
c-Hex
ii) MeI, CO, THF/HMPA
iii) NaOEt, MeI, rt
Ph
i) 85,
Ph
OMe
OMe 73 −40°C
O
(−)-86
CHO
H
53%
>95% e.e.
OEt
Cr(CO) 3
ii) MeI, CO, THF/HMPA
iii) NaOEt, MeI, rt
O
OAc
H
(+)-86
42%
>76% e.e.
O
acetoxytubipofuran
55
Scheme 1.24 – complementary enantiomeric syntheses
1.4.2 (η 6 -Arene)Mn(CO) 3 cationic complexes
Cationic arene-tricarbonyl manganese complexes are inherently more reactive than
their neutral chromium counterparts. Whilst this means these species react with a
larger number of nucleophiles, it also causes problems for their handling and
sensitivity to reaction conditions. The predominant difference to the chemistry of
chromium complexes is that the product of nucleophilic addition to the manganese
complex (88) is neutral and electrophilic in character, allowing it to undergo a second
nucleophilic addition, giving syn-adducts 89 (Table 1.14). Bubbling air into a stirred
solution of the manganese complexes is sufficient to obtain the free diene 89.
45

1.4 – Metal complexation
LiAlH 4
R
i) NuLi
or MeLi
+
Mn(CO) 3 Mn(CO) ii) O 2
3
87 88 R = H, Me
Entry R Nu 89 / %
a Me LiCHPh 2 73
b Me LiC(CN)Me 2 58
c Me LiCMe 2 CO 2 Et 43
d H LiCHPh 2 77
e H LiC(CN)Me 2 88
f H LiCMe 2 CO 2 Et 91
R
Nu
±89
51
Table 1.14 – dearomatising additions to Mn(CO) 3 complexes
Complex 88 is only moderately electrophilic in character, and attempted isolation
gives mostly rearomatised adduct, with trace amounts of regioisomeric dienes. Unless
reacting with strong nucleophiles as above, activation of 88 is required, and has been
achieved by ligand exchange, forming a cationic η 5 -complex 90 which is more reactive
than the original η 6 -complex. 56 Addition to this complex may now be performed by
soft carbon nucleophiles or borohydride.
i) RM
R
iii) NuM
R
Mn(CO) 3
+
ii) NOPF 6
Mn(CO) 2 NO
iv) Me 3 NO
Nu
87
90
±89
Entry RM Nu 89 / %
a MeLi NaCH(CO 2 Et)(COMe) 67
b MeLi NaCH(CO 2 Et)CN 59
c MeLi NaCH(CO 2 Me)(SO 2 Ph) 67
d PhMgBr NaCH(CO 2 Et)(COMe) 66
e PhMgBr NaCH(CO 2 Et)CN 59
f PhMgBr NaCH(CO 2 Me)(SO 2 Ph) 62
g PhMgBr NaBH 4 85
51
Table 1.15 – activation of Mn(CO) 3 complexes
46

Chapter 1: Introduction
A scheme summarising this reactivity is presented below.
87
Mn(CO) 3
+
RM
LiAlH 4
or MeLi
R
E +
R
88
Mn(CO) 3 R = H, Me
NOPF 6
DCM
i) NuM
ii) O 2
"Reactive"
nucleophiles
R
i) NuM
ii) Me 3 NO
R
Mn(CO) 2 NO +
Nu
90 ±89
Scheme 1.25 – synthetic summary of Mn(CO) chemistry
3
Due to their more reactive nature, the regioselectivity of addition to these arenes is not
as dependent upon the substrate or nucleophile as Cr(CO) 3 complexes. This is
presumably due to the irreversible nature of the addition.
1.4.2.a Asymmetric synthesis using Mn(CO) 3 complexes
Due to the limitations of the chemistry outlined above, little work has been done
regarding asymmetric additions to these complexes. Miles and co-workers found that
use of chiral oxazolidine enolates as nucleophiles results in diastereoselectivity at the
dearomatised centre. 57
(Scheme 1.26).
This technique was extended to the synthesis of (+)-juvabione
47

1.4 – Metal complexation
Ph
O
O
N
O
i) LDA
ii)
O
Mn(CO) 3
+
Ph
O
O
O
N
H
O
Mn(CO) 3
d.r. = 3.5:1
O
i) LiAlH 4
ii) p-nitrobenzoyl chloride
iii) Recrystallisation O 2 N
O
H
i) NOPF 6
ii) NaBH 4
>97:3 dr
Mn(CO) 3
O
O
O 2 N
O
H
O
H
Mn(CO) 3
O
COOCH 3
(+)-Juvabione
58
Scheme 1.26 – asymmetric synthesis using Mn(CO) 3 methodology
The (η 2 -arene) Os(NH 3 ) 2+ 5 complexes are also susceptible to dearomatisation, and this
chemistry has recently been reviewed. 60 However the toxic nature of the reagent, and
limited use in asymmetric functionalisation of benzenoid rings means it will not be
discussed.
1.4.3 Pd-mediated dearomatisation
The attempted synthesis of homoallyl benzene by the cross-coupling of benzylchloride
and tributylallylstannane (93), yielded tetraene 94 the apparent product of 1,4-addition
(Table 1.16).
48

Chapter 1: Introduction
Cl
R
+
93
SnBu 3
Pd 2 (dba) 3. CHCl 3 (5%)
PPh 3 (40 mol. %)
acetone, rt
R
94
entry R Time / hr Yield / %
a H 24 80
b 2-Me 32 82
c 3-Me 35 80
d 4-Me 37 76
e 4-Ph 60 71
f 4-i-Pr 34 79
g naphthyl 11 85
61
Table 1.16 – Pd-mediated addition of allyl stannanes
Further inspection of the reaction conditions soon belies the likely oxidative additiontransmetallation-reductive
elimination sequence proposed in Scheme 1.27.
Substitution is presumably seen due to the migration of the Pd II species (95 to 96) to
give π-allyl complex 97 before reductive elimination of tetraene 94. Addition has been
possible to a range of aromatic compounds, although only allylstannane 93 has been
used as the cross coupling partner.
Cl
Pd(0)
94
97
95
L
Pd II L
Cl
Pd II SnBu 3
Bu 3 SnCl
PdII L
Cl
61
93
Scheme 1.27 - proposed catalytic cycle for allylative dearomatisation
49

1.5 Summary of Methods
In their recent review, Ortiz et al. cover 16 different functional groups that have
promoted nucleophilic addition to anthracene, naphthalene and benzene systems. Yet
only the 6 methods above do so for the benzene system, and none offer any significant
enantiomeric enrichment in the product. Whilst transition metal-mediated
dearomatisations have been more synthetically useful, if highly substrate dependent,
the metals used are highly toxic and need to be treated under careful conditions. The
most general method discussed is clearly that of Meyers, but is has been restricted to
naphthyl, pyridyl and anthracene aromatic systems.
It is clear that there is a need for a method to achieve the asymmetric dearomatising
bisfunctionalision of benzene-derived systems. The following chapter will present the
development of such a methodology.
50

Chapter 2 – Dearomatising additions to aryl oxazolines
Chapter 2 – Dearomatising Additions to Aryl Oxazolines
2.1 Establishing a New Reaction
Ph
Ph
Ph
Ph
Ph
O
N
Ph
SiO 2
O
N
i) RLi (1.5 eq)
THF:DMPU 25:1
−78 °C
ii) MeI
O
N
Me
R
100a
prepared to attempt
dearomatising cyclisation
101a
102a
R = i-Pr, 102a, 61%
s-Bu, 102a', 91%
(dr 4:1)
Scheme 2.1 – first dearomatising additions by Purewal 63
Whilst attempting the dearomatising cyclisation of benzoyl aziridine 100a, Purewal
unintentionally prepared oxazoline 101a. When subjected to the conditions of
dearomatising cyclisation 62 this material underwent nucleophilic attack by the
organolithium to give dienes 102a’. This was successfully repeated with i-PrLi to give
a single diastereomer, confirming that this reaction is highly diastereoselective,
however dienes 102a were described as aziridines in his thesis. 63 A crystal structure
later obtained by Cabedo confirmed the relative stereochemistry of the diene, and
showed it to be an oxazoline rather than an aziridine, 64 making a clear link to the
chemistry Meyers had developed with 2-naphthyl- and pyridyloxazolines (section
1.3.2).
Personal communication with Meyers confirmed that during the oxazoline research
programme in his laboratories he had been unable to achieve dearomatising addition to
benzenoid aromatics. 36 With this news it was clear that this might be a novel reaction,
differing from Meyers’ in both the oxazoline and co-solvent. This was confirmed by
treating Meyers’ anisoyloxazoline 104b under both sets of conditions. 31
51

2.1 – A new reaction
Ph
OMe
No DMPU
No isolable products
or starting material
O N
OMe
104b
i) i-PrLi, THF
ii) MeI
Ph
O
N
OMe
Ph
O
N
OMe
Me
+ DMPU
OMe
105
24%
OMe
7%
106
Ph
Me
OMe
Ph
Me
OMe
O
N
Me
O
Me
N
22% 4%
OMe
OMe
107 108
Scheme 2.2 – dearomatising addition using the Meyers oxazoline
The contrast between the two sets of conditions was very pleasing; a similarly strong
distinction was seen with the 2-phenyl oxazoline. 64 Although the Meyers’ oxazoline
returned a significant amount of diene 105 (stereochemistry assigned by analogy to
known compounds), it was accompanied by greater amounts of difunctionalised
products 107 and 108. It was clear that the reaction of the Meyers oxazoline was
plagued by side reactions that were not observed with bis-phenyl oxazoline 101a.
para-Anisole 101b was treated under both sets of conditions, and equally stark results
were seen (Scheme 2.3). Addition to the electron rich system was very encouraging;
the structure of 102b was again confirmed by crystallography (Scheme 2.6).
Ph Ph
Ph Ph Ph Ph
O
N
OMe
i) i-PrLi (1.5 eq)
THF, −78 °C
ii) MeI
O
N
Me
OMe
O
N
Me
OMe
Additive 102b 103b
None 22% 73%
DMPU 70% 18%
101b
102b
103b
Scheme 2.3 – effect of DMPU on addition to aryl oxazolines
52

Chapter 2 – Dearomatising additions to aryl oxazolines
These results show that both the presence of the DMPU co-solvent and the nature of
the oxazoline are important. To see if the reaction could be further improved, a
number of other 2-aryloxazolines were made from chiral pool amino alcohols (the
synthesis of oxazolines is discussed in section 3.1) and treated to the reaction
conditions.
i) NuLi (1.5 eq)
DMPU (6 eq), THF
ii) MeI
Me
Nu
R
R
Ph
Ph
Ph
Ph
Ph
Me
Ph
OMe
O
N
O
N
O
N
O
N
O
N
101 110 111
109
104
Entry Oxazoline R Nu Diene † (SM) / % Reaction colour*
a 101a H i-Pr 59-70 (4) dark green
b 101a H s-Bu 76-81 ‡ (1) dark green
c 101b OMe i-Pr 58-70 (3) dark green
d 109a H s-Bu 0 (95)
electric blue,
disappears
e 109b OMe s-Bu

2.1 – A new reaction
anticipated that changing to a cis geometry would only affect the diastereoselectivity
of the addition, as found by Meyers (section 1.3.2.c).
The norephedrine-derived oxazoline 110 (entry f) proved better at promoting the
dearomatising addition than Meyers’ oxazoline (104) had, however it was also
accompanied by benzylic lithiation (114).
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Me
O
N
i) i-PrLi (1.5 eq), DMPU (6 eq)
−78 °C, 30 min
ii) MeI
O
N
Me
+
O
N
Me
+
O
N
Me
40% 12% 5%
110 112 113 114
Scheme 2.4 – dearomatising addition to norephedrine-derived oxazoline
Valine-derived oxazolines had been synthetically useful in many asymmetric reactions,
most notably for additions to naphthyloxazolines 37 and (η 6 -arene)Cr(CO) 3 species. 53
However, valine-derived oxazolines 111 (entries g, h) showed no significant reaction
with the organolithium, and a translucent reaction solution was seen as opposed to the
opaque solutions which had become characteristic of a successful reaction.
The high levels of diastereoselectivity, and the potential for use in asymmetric
synthesis was shown by removing the oxazoline moiety, and derivative 115 was shown
to be enantiomerically pure by HPLC analysis. Oxazoline removal is described in
section 3.2.
Ph Ph
(p-BrBz)O
O N
Section 3.2.6
OMe
101b 115
O(p-BrBz)
Scheme 2.5 – determination of enantiomeric purity
58%, 5 steps
>99:1 er
54

Chapter 2 – Dearomatising additions to aryl oxazolines
2.1.1 Summary of initial reactions
Whilst the dearomatising addition of organolithiums was possible with three of the five
oxazolines, the anti-diphenyl oxazoline is clearly best at promoting the
dearomatisation. Failure of the cis oxazoline (109) after repeated attempts shows that
the trans geometry is key, whilst the benzylic lithiation of the Meyers (104) and
norephedrine (110) oxazolines indicate that the diphenyl system may be successful due
to the mutual hindrance of C4 and C5. Mechanistically, the pseudo-C 2 nature of
oxazolines 101 offers a very appealing rationale for the high levels of
diastereoselectivity observed, although equally high diastereoselectivity was seen with
anti-oxazolines 104 and 110.
The other key component in the reaction is the DMPU co-solvent. DMPU has been
used extensively in organolithium chemistry, largely as a less toxic substitute for
HMPA. 65 It is a Lewis basic ligand for lithium, donating electron density through its
oxygen lone pairs, purportedly making the organolithium more reactive through
deaggregation, which is discussed at the end of the chapter.
Oxazolines are traditionally used to direct ortho-metalation, and Scheme 2.3 shows
that it might be possible to tune the reactivity of the aromatic ring, permitting
functionalisation before dearomatisation. Addition of a range of Grignard reagents
was also attempted to anisole 101b, but neither dearomatisation nor nucleophilic
aromatic substitution were observed and only starting material was isolated. Finally,
Table 2.1 shows that the six reactions in which dearomatisation occurred had similar
opaque brown/green solutions such as that shown below.
Scheme 2.6 – crystal structure and reaction solution of 102b
55

2.1 – A new reaction
The next section will outline the study and optimisation of the stereoselective
dearomatising addition, and the subsequent section looks at its application to a number
of organolithiums, aromatic systems, and electrophiles. Section 2.4 will discuss the
mechanistic implications of these results. Throughout these sections, the anti-diphenyl
oxazoline discussed above will be abbreviated:
Ph
Ox* = O
N
Ph
56

Chapter 2 – Dearomatising additions to aryl oxazolines
2.2 Optimisation of Reaction Conditions
Having established that this chemistry is novel, the reaction conditions were reviewed
to improve the yield of dearomatised adduct, and reduce side reactions. For most of
these studies the para-anisole aromatic system was be used since it showed more
ortho-lithiation than the phenyl ring – the main side-reaction – and its aromatic protons
are easily distinguished by 1 H NMR. Isopropyllithium was generally used for these
test reactions since it gives single diastereoisomers with characteristic diastereotopic
methyl signals.
2.2.1 Solvent system
DMPU is a key additive for dearomatising addition, yet it is unclear whether its role is
simply to deaggregate the organolithium, or to promote a specific reactivity. A direct
comparison of the crude 1 H NMR spectra of reactions in the presence of DMPU,
TMEDA and no co-solvent was made (Table 2.2). HMPA was not studied since
Meyers had not been able to achieve dearomatisation using it, and due to its toxicity, 65
but has recently been found by Karlubíková to make little difference. 66
Ox*
i) i-PrLi (1.5 eq), THF
co-solvent (n eq)
Ox*
Ox*
Me
OMe
101b
ii) MeI
OMe
102b
OMe
103b
Co-solvent (eq) 102b / % 103b / % SM / %
None 22 73 4
TMEDA (6 eq) 23 72 5
DMPU (6 eq) 67 20 4
Table 2.2 – crude ratios of addition with different co-solvent
57

2.2 – Reaction optimisation
% Composition
80%
60%
40%
20%
102b
103b
SM
Misc
Aromatic
0%
0 2 4 6 8 10 12 14 16
Eq. DMPU
Scheme 2.7 – crude reaction composition vs. eq of DMPU (relative to oxazoline)
These data show that the inclusion of TMEDA in the reaction has no impact on the
course of the reaction, indicating that DMPU has a specific mode of action. This study
was extended to investigate the importance of the concentration of DMPU (Scheme
2.7).
The results show that whilst DMPU is essential for the dearomatising addition, higher
concentrations promote side reaction. The miscellaneous aromatics were not
identified, but appear to be products of lithiation, possibly ortho to the methoxy group.
From these studies, it was concluded that six equivalents of DMPU with respect to the
oxazoline were optimal. A small quantity of co-solvent is consistent with the guidance
of Collum, who suggests that higher concentrations are rarely necessary. 67
Ethereal solvents, primarily THF and diethyl ether, are commonly used in
organolithium chemistry since they are both relatively inert and good Lewis bases
which coordinate lithium, making the organic counter ion more reactive. 14 Whilst
both ether and THF gave similar crude reaction mixtures, toluene was also found to be
a promising solvent.
58

Chapter 2 – Dearomatising additions to aryl oxazolines
Ox*
i) s-BuLi (1.5 eq)
−78 °C, DMPU (6 eq)
solvent
Ox*
Ox*
ii) MeI
R
R
R
101 102' 116'
Solvent R 102’ / % 116’ / % SM / %
THF H 81 0 5
PhMe H 66 5 20
THF OMe 71 7 5
PhMe OMe 50 10 20
Table 2.3 – isolated yields comparing toluene and THF as solvents
Although no ortho-lithiation was observed in toluene, less diene was isolated and a
significant amount of rearomatised adduct (116’). This is most likely due to proton
abstraction from the methyl group of the solvent which also explains the increased
amount of recovered starting material, since any ortho-lithiated oxazoline may simply
abstract a proton from the solvent. Whilst this in-situ regeneration of starting material
is appealing, it is more than offset by the losses in the formation of rearomatised 116’.
Other solvents such as DMPU, benzene and hexane, were tried but the reaction failed
either due to poor solvation, or freezing under the reaction conditions. Cumene
presents itself as a less acidic alternative to toluene but initial reactions have shown
little improvement. 66 The role of solvent and aggregation state is discussed in section
2.4.3.
59

2.2 – Reaction optimisation
2.2.2 Duration of reaction
The reaction was known to be relatively rapid since all initial results were obtained
after 30 minutes of reaction, but it was unclear how the reaction progressed with time.
To better understand this, parallel reactions were quenched at time intervals of 1, 5, 15
and 30 minutes and their crude compositions compared.
Ox*
i) i-PrLi (1.5 eq)
THF, DMPU (6 eq),
t mins
Ox*
Ox*
Me
OMe
ii) MeI
OMe
OMe
101b
102b
103b
% composition
70%
60%
50%
40%
102b
103b
30%
SM
20%
10%
0%
0 5 10 15 20 25 30
t / min
Scheme 2.8 – change in crude reaction composition with time
These data show that the reaction is essentially complete within 5 minutes of
organolithium addition, and that a modest period of standing does not cause any
significant decomposition of product. There is no significant change in the ratio of
ortho-lithiation to dearomatisation, implying that the reactions occur at a similar rate.
2.2.3 Concentration of organolithium
Initial analysis of crude reaction mixtures indicated that a larger excess of
organolithium improved the conversion of starting material. However, comparison of
60

Chapter 2 – Dearomatising additions to aryl oxazolines
isolated yields indicates that any variation more likely reflects the capricious nature of
the reaction, and in future it is suggested that 1.5 equivalents is used since these are the
conditions that the concentration of DMPU was optimised for.
Ox*
i) i-PrLi (n eq),
THF, DMPU (6 eq),
Ox*
Ox*
Me
ii) MeI
OMe
OMe
OMe
101b
102b
103b
Entry Equivalents 102b / % 103b / % SM / %
a 1.5 64 22 3
b 1.5 58 - 4
c 2.0 70 17 0
d 3.0 62 12 3
Table 2.4 – variation in isolated yield of diene 102b and eq. of organolithium
The progress of the reaction can be quite delicate. If stirring stopped during reaction,
particularly during addition of the organolithium, this generally resulted in the reaction
turning brown, slowly getting lighter and poor conversion of starting material.
Commercially available isopropyllithium was used, since when made from lithium
wire and i-PrCl 68 filtration of the solids proved impossible and solutions completely
degraded within a week. When this isopropyllithium was used, yields were similar to
those above. Meyers noted improved yields when using organolithiums prepared in
situ from Freeman’s reagent (lithium 4,4’-ditert-butylbiphenyl, LiDBB) 28 including the
generation of i-PrLi from i-PrBr, normally considered impractical. 14
2.2.4 Temperature
When the internal temperature of a two gram reaction was monitored, no significant
change was observed. 69 Whilst no reliable results were obtained from experiments
performed at different temperatures, it was noted that when the reaction was allowed to
warm past –60 °C it would quickly decolourise.
61

2.2 – Reaction optimisation
2.2.5 Order of addition
It was hoped that changing the order of addition of reagents might have a significant
effect upon the outcome of the reaction. A summary of these experiments is given in
Table 2.5 and Table 2.6, in which the presence of the characteristic opaque-green
reaction colour is noted alongside the presence of any product.
Entry Description Reaction vessel Syringe Green? Product?
a
b
RLi last
(Normal)
RLi last, preaggregate
101b in
DMPU/THF,
101b in THF,
c Oxazoline last THF, s-BuLi
d
Oxazoline last,
pre-aggregate
DMPU/THF,
s-BuLi
e 66 Oxazoline last s-BuLi
s-BuLi Y Y
DMPU/THF,
s-BuLi
101b in
DMPU/THF,
N
Disappears
N
N
101b in THF N N
101a in
DMPU/THF,
Y
Y
Table 2.5 – outcome of changing the order of combining reagents in THF
The normal reaction conditions (entry a) involve the organolithium being added last to
the other cooled reagents. All orders of addition in which the organolithium and a
Lewis base were pre-mixed gave no product, presumably due to deaggregation of the
organolithium. This hypothesis was confirmed when reverse addition without premixing
the organolithium and THF was successful (entry e), and yields were
comparable to normal addition. Similar results were seen in toluene:
Entry Reaction Reaction vessel Syringe Green? Product?
a
b
c
RLi last
(Normal)
Oxazoline last,
pre-aggregate
Oxazoline last,
pre-aggregate
– 40 °C
101b in
DMPU/PhMe,
DMPU/ PhMe,
s-BuLi
DMPU/ PhMe,
s-BuLi
d Oxazoline last PhMe, s-BuLi
s-BuLi Y Y
101b in PhMe Y N
101b in PhMe N N
101b in
DMPU/PhMe,
? ?
Table 2.6 – outcome of changing the order of combining reagents in toluene
62

Chapter 2 – Dearomatising additions to aryl oxazolines
Whilst colouration was seen when the organolithium was pre-mixed with DMPU this
did not yield any product despite quenching the reaction after 1 minute whilst still
coloured. It is thought likely that as before, avoiding pre-mixing the organolithium
with the Lewis base is key (entry d) but unwise with the relatively acidic toluene.
It was not expected that the reaction would prove to be so sensitive to reaction
conditions, but it does seem to emphasise the importance of deaggregation of the
organolithium. The role of aggregation in this reaction is discussed in section 2.4.3.
63

2.3 – Synthetic scope
2.3 Synthetic Scope
Until now, most reactions have used secondary organolithiums isopropyllithium and
sec-butyllithium, only two aromatic substituents and iodomethane as electrophilic
quench. For the reaction to be synthetically useful, it should be general to a number of
nucleophiles, electrophiles and tolerate a number of aryl groups.
2.3.1 Organolithiums
2-Phenyl oxazoline 101a was treated with a number of commercially available
organolithiums. The results are summarised below.
Ox*
i) NuLi (1.5 eq),
THF, DMPU (6eq)
−78 °C 5 min
Ox*
Nu
ii) MeI
101a 102a
Entry Nu 102a (SM) / % Lithiated Colour
a n-Bu < 5 (95) 0 Electric blue
b 64 Me < 5 (95) 0 –
c † Me 3 SiCH 2 1 (45) 22 Electric blue
d s-Bu 81 * (1) 8 Dark green
e i-Pr 70 (12) 6 Dark green
f 70 t-Bu 17 (12) 17 Dark green
g 64 PhLi < 5 (95) 0 –
† addition to 101b (Scheme 2.9) * 3:1 exocyclic d.r.
Table 2.7 – survey of organolithium nucleophiles
Primary alkyllithiums (entries a-c) show little or no dearomatisation, indeed diene was
only isolated from addition of (trimethylsilyl)methyllithium (Scheme 2.9). This
reaction saw mainly benzylic lithiation, previously unseen for these oxazolines,
predominantly at the aza-allylic C4 position (117). Diene 102b” is tentatively
assigned by 1 H, COSY and mass spectroscopic data, similar results were seen when
solvated in toluene.
64

Chapter 2 – Dearomatising additions to aryl oxazolines
Ph
Ph
Ph
Me
Ph
Ph
Me Ph
Ph
Ph
O
N
i) Me 3 SiCH 2 Li (3 eq)
THF, DMPU (6 eq)
O
N
O
N
O
N
Me
ii) MeI
SiMe 3
OMe
101b
OMe 20% OMe 2% OMe 1%
117 118 102b"
Scheme 2.9 – addition of (trimethylsilyl)methyllithium
A similar by-product was observed by Cabedo when treating the unsubstituted
aromatic oxazoline with tert-butyllithium. In the absence of both regioisomers, 119
was initially assigned with a methyl at C5, in light of the above result it has been
reassigned as shown.
Ph
Ph
Ph
Ph
Ph Me
Ph
O
N
i) t-BuLi (1.5 eq)
THF, DMPU (6 eq)
O
N
Me
O
N
ii) MeI
17%
17%
101a
102a"'
119
Scheme 2.10 – addition of tert-butyllithium
The modest diastereoselectivity for addition of s-BuLi is likely to be the result of the
kinetic resolution of the organolithium whose stereogenic centre can rapidly invert. A
similar level of diastereoselectivity was observed for the addition to para-anisole
101b.
Ox*
i) s-BuLi (3 eq)
THF, DMPU (6 eq)
Ox* Me
*
Ox*
OMe
101b
ii) MeI
OMe
102b'
71%
*d.r. 7:2
OMe
116b'
7%
Scheme 2.11 – addition of sec-butyllithium to oxazoline 101b
Perhaps the most surprising outcome of these reactions is the specificity for secondary
nucleophiles, in stark contrast with the dearomatising additions of Meyers, which
worked with a vast range of alkyllithiums. The nucleophilicity of organolithiums
65

2.3 – Synthetic scope
generally follows their basicity; tertiary > secondary > primary (steric encumbrance
aside) however this has not be borne out in these studies, which see an effective
nucleophilicity secondary > tertiary >> primary. Whilst the order of reactivity is not
inconsistent with the traditional nucleophilicity once torsional strain is accounted for,
the absence of reaction of primary organolithiums is surprising, and led to the proposal
of a single electron transfer (SET) mechanism. This proposition is supported by
Bartoli’s ranking of the electron donating ability of organomagnesium reagents from
their oxidation potentials: i-Pr > Bn ≥ Et > Me >>Ph. 20 Similar data is not available for
organolithiums due to electrode degradation 71 (vide infra) but this series indicates that
the isopropyl anion as one of the better electron transfer reagents. A SET mechanism
is discussed in section 2.4.2, alongside the role of aggregation state on the reactivity of
different organolithiums in section 2.4.3.
2.3.2 Arenes
Reaction with a number of arenes would allow this methodology to bring the
advantages of aromatic chemistry, primarily good regioselectivity and a wealth of
starting materials, to making aliphatic compounds with dense stereochemistry. A
number of oxazolines were synthesised (section 3.1) and subjected to the reaction in
THF; if addition was unsuccessful then it was repeated in toluene, with a positive
result in two instances.
66

Chapter 2 – Dearomatising additions to aryl oxazolines
Ox*
i) i-PrLi (1.5 eq),
THF, DMPU (6 eq)
−78 °C 5 min
Ox*
Ox*
Ox*
Me
ii) MeI
R R R
101 102 116
R
103
Entry R 102 116 103 SM Colour
a H 70 0 6 12 Dark green
b # p-OMe 64 0 17 6 Dark green (Scheme 2.6)
c m-OMe 54 * 0 9 * 20 Apple green (Scheme 2.12)
d 72 m-F † 10 * 0 10 * 40 Forest green (Scheme 2.13)
e 72 p-F † c. 30 20 c. 40 ‡ 5 Forest green
f p-Ph 32 30 0 14 Cherry red (Scheme 2.13)
g p-CN 0 0 0 0 Wine red
h p-NO 2 0 0 0 >95 Wine red (Scheme 2.14)
i o-OMe 72 0 90 0 0 Wine red
j 2-Me-4- 0 0 65 0 Wine red
OMe
*1,2,3 substituted regioisomer † in toluene ‡ sum of 2 regioisomers # average of 4 reactions
Table 2.8 – addition to different aromatic systems
Addition to the electron-rich meta-anisole system (101c, entry c) proceeded in good,
unoptimised yield and only 1,2,3-substituted regioisomers isolated; confirmed by x-ray
crystallography of 102c. The same regioselectivity was observed for meta-fluoro
101d.
Scheme 2.12 – crystal structure & reaction solution of meta anisole 102c
The stereoelectronic preference for 1,2,3-substitution is quite clear; both oxygen and
fluorine are effective π-donors and equally disfavour addition at C2 and C6, whilst
67

2.3 – Synthetic scope
their electronegativity makes them strong σ-withdrawing groups, favouring C2.
Furthermore by analogy to anisole's propensity to ortho-lithiation, 14 anisole 101c could
direct attack towards C2, possibly explaining the significantly better yield of 102c.
Whilst Meyers also observed high regioselectivity, the choice of carbons to attack was
stark; addition to 1-naphthyloxazolines could only happen at the C2 since attack at C9
position would impact upon the aromaticity of the adjacent ring. Addition to
substituted 2-naphthyloxazolines was not studied by Meyers.
Toluene promoted addition to both fluorinated aromatic systems where THF had
failed, and could be seen in a change of reaction colour from electric blue to forest
green (entries e, f, Scheme 2.13a). Unfortunately these reactions were plagued by
products of rearomatisation which proved hard to separate and characterise. Extensive
preparatory TLC was performed by Baker to separate diene 102d from the orthomethyl
103d; yields for addition to 4-fluoro 101e are estimated from the combined
fractions since mixed regioisomers 103e were not separable from diene 102e. 72
a) b)
Scheme 2.13 – reaction solutions of a) 101d (3-F) in PhMe and b) 101f (p-Ph)
Pleasingly, addition to biaryl 101f (entry f, Scheme 2.13b) showed addition in 60%
yield, however despite being performed in THF, approximately half of the
dearomatised material abstracted protons from the solvent. It is possible that this
reflected the quality of the purchased THF used in this reaction compared to that
distilled from sodium, but no significant depletion in yield was noticed for addition to
anisole 101b under similar conditions.
68

Chapter 2 – Dearomatising additions to aryl oxazolines
Addition to para-cyano 210g resulted in complete consumption of starting material,
with no products isolated. Nitriles are very susceptible to nucleophilic attack, and
lithiation of cyanobenzenes usually requires non-nucleophilic bases such as LDA. 73
The lack of reaction with the para-nitro 101h was disappointing since by lowering the
energy of the LUMO it should make the aromatic ring more susceptible to attack. The
complete absence of reaction is also surprising since Köbrich found that aromatic nitro
groups are readily reduced even when competing with the rapid halogen-lithium
exchange, indeed reduction still dominated at –100 °C. 74 The meta isomers of both
these oxazolines would be better predisposed to dearomatising addition by cumulative
electron withdrawal.
Scheme 2.14 – reaction solution of 101i (p-NO 2 )
ortho-Anisole 101i underwent S N Ar (entry i) which was also observed by Baker for the
2,4-dimethoxyoxazoline; 72 nucleophilic aromatic substitution was also observed by
Meyers for similar compounds. 75 Treatment of ortho-alkylated 103b (entry j, Scheme
2.15) led to benzylic lithiation, reaffirming that the organolithium is still highly basic
under the reaction conditions. Analysis of the crude reaction mixture showed small
quantities of another lithiation product, as well as traces of dearomatisation; a
disappointing outcome in light of Yamamoto’s ATPH-promoted dearomatisation of
similar methyl benzenes by organolithiums (section 1.3.3).
Ox*
i) i-PrLi (3 eq)
THF, DMPU (6 eq)
−78 °C
ii) MeI
Ox*
OMe OMe 65%
103b 120
Scheme 2.15 – reaction of ortho-alkylated oxazoline
69

2.3 – Synthetic scope
The presence of the ortho substituent causes a significant movement in the chemical
shift of the oxazoline protons; all non-ortho substituted oxazolines have characteristic
1 H chemical shifts very close to 5.4 and 5.2 ppm (C5 and C4 respectively, identified by
correlation spectroscopy), always 0.20 ppm apart. In contrast those of anisole 103b
are 5.31 and 5.26 ppm, separated by only 0.05 ppm. Whilst the coupling constants and
13 C NMR chemical shifts are similar to other aryloxazolines, the change in proton
chemical shift might be indicative of a subtle change in the oxazoline environment.
However since few ortho-substituted aromatic systems have been treated, no
correlation with reactivity many be inferred.
It is surprising that the electron-rich anisole derivatives were readily dearomatised
whilst a number of less demanding aromatic systems were not. Strong π-donors such
as methoxy reduce the electrophilicity of the arene by raising the energy of the LUMO,
and would also destabilise a transition state with a developing negative charge.
Generally groups which are relatively π-neutral such as Ph and F would not be
expected to differ from the unsubstituted ring. Meyers only published reactions with
methoxynaphthalenes, and whilst these are synthetically very versatile, it may be
assumed that other aromatic substituents were tried and failed.
2.3.3 Electrophiles
Equally important to the utility of the final compounds is the range of electrophiles
tolerated and the regioselectivity of their addition. Upon addition of the electrophilic
quench, immediate decolourisation was seen, indicating that reaction is rapid.
Regioselectivity was found to be dependent upon the nature of the electrophile, and is
summarised below. The products are identified as α, γ, ε by the site of addition with
respect to C=N, and a brief rationalisation of the selectivity follows.
70

Chapter 2 – Dearomatising additions to aryl oxazolines
Ph
Ph
EX
Ox*
E
Ox*
O
N
i-PrLi, DMPU
THF
R
102α
Ox*
E
R
102ε
Ox*
Ox*
R
101
NH 4 Cl
R
102ε
R
102γ
R
116
Entry R EX 102α / % 102γ / % 102ε / % 116 / % SM / %
a H MeI 70 0 0 0 12
b ‡64 H allyl Br 50 0 10 0 12
c ‡64 H BnBr 24 0 36 0 21
d ‡64 H PhCHO 0 0 0 30 20
e ‡70 H NH 4 Cl 0 47 0 5 32
f †70 F * NH 4 Cl 0 0 53 7 37
g OMe * MeOH 0 30 15 5 29
* PhMe solvent ‡ reaction by N. Cabedo † reaction by T Baker
Table 2.9 – electrophilic additions
Addition of alkyl halides proceeded preferentially at the α position (entries a-c), as
observed with the extended enolates of ketones, esters 76 and most other nucleophilic
dearomatising additions (section 1.3). Increasing the size of the electrophile caused
addition at the less encumbered ε position, giving conjugated dienes 102ε. Soft
electrophiles such as alkyl halides react preferentially with soft nucleophiles; if we
approximate azaenolate 121 as the heptatriene anion (Scheme 2.16), we see that the
HOMO has the largest coefficients at the α and γ carbons. Using this model, addition
to the ε position would not be expected under the kinetic conditions of reaction,
however since the presence of the nitrogen in is likely to perturb the HOMO it is quite
possible the ε carbon has a larger coefficient.
71

2.3 – Synthetic scope
Ph
O
Ph
NLi
R ≈
α
β
γ ε
δ
121
Scheme 2.16 – approximation of the HOMO of the azaenolate
However the hard protic quench of azaenolate 121 shows complete regioselectivity for
the ε position (entry e). This is be explained if proton addition is in equilibrium, since
102ε has the longest conjugated system; also explaining why α-protonation is not seen.
Unfortunately, protonation of para-substituted oxazolines (entries f, g) does not
support thermodynamic protonation, however a change in solvent and method of
protonation means that further experimentation would be necessary to gain further
insight.
This is consistent with the reaction of electrophiles with 2-oxazolinylnaphthalene
azaenolate 122, by Meyers. Whilst iodomethane also gave α addition, protonation
gave the thermodynamic product 124 in low yield, accompanied by rearomatisation. 26
Nu
122
O
N
Li
MeI
MeOH
Nu
Nu
O
N
Me
O
N
124
Nu = n-Bu 90%
= s-Bu 91%
= t-Bu 90%
Nu = n-Bu 18%
= t-Bu 31%
= Ph 74%
Scheme 2.17 – electrophilic quench of 2-oxazolinylnaphthalenes 26
Meyers observed regiospecific α addition to the azaenolates of 1-
oxazolinylnaphthalenes for a large range of electrophiles (section 1.3.2). This is most
likely because the HOMO is likely to be confined to the non-aromatic carbons;
although Ortiz 1 makes the unlikely suggestion that it is a complex-induced proximity
effect (CIPE). 38 Whilst the principle of least motion analysis is often applied to
rationalise the protonation of the hydrobenzene anion in the Birch reduction, it cannot
be applied to this situation since the resonance structures will not contribute equally.
72

Chapter 2 – Dearomatising additions to aryl oxazolines
2.4 Mechanistic Discussion
In the above studies a number of unexpected observations have been made. In this
section a number of these will be discussed in the context of the reaction mechanism
and the relevant literature.
2.4.1 Stereoselectivity
Regio- and stereoselectivity scarcely received mention in the sections above since few
isomers were isolated. It was suggested that the complete stereoselectivity is simply
due to the steric bulk of the pseudo-C 2 symmetric oxazoline strongly favours the attack
of the nucleophile on one face.
R
Li
O
N
Li
O
N
R
Scheme 2.18 – stereochemical rationale for addition to diphenyl oxazolines 101
The nitrogen lone pair lies in the plane of the oxazoline and must coordinate lithium in
the same manner whilst the adjacent phenyl group favours delivery of the organic
ligand from the opposite face. Attack by complexation with nitrogen is consistent with
the complex-induced proximity effect (CIPE), and with the mechanism proposed by
Meyers for monodentate oxazolines (section 1.3.2.c).
monodentate oxazoline
bidentate oxazoline
R
Li
O
N
R
Li
O
N
O
54
126
Scheme 2.19 – Meyers’ reactive complexes
Unlike Meyers, we have been unable to gain insight into the cause of the
stereochemical induction since studies of different substituents at C4 and C5 were
unsuccessful. Since both stereogenic centres direct in the same sense to the pendant
aromatic ring, it is possible that the alkyl group does not exclusively attack from a
73

2.4 – Mechanistic discussion
chelate with nitrogen. Indeed, it is not clear how closely associated the organic and
metallic portions of the organolithium are; whether they exist as contact ion pairs
(CIPs) or solvent separated ion pairs (SIPs). The rationalisation given in Scheme 2.18,
as well as those of Meyers, requires contact ion pairs to direct delivery over the C4
stereocentre.
This stereochemical rationale assumes a two-electron mechanism. Separate electron
transfer and radical coupling steps are not inconsistent with this proposal, but radical
combination would need to occur rapidly, otherwise the neutral organic radical can
diffuse outside of the solvent cage (i.e. is after the rate determining step).
2.4.2 Reaction pathway: one electron or two?
Chemical reactions between occur when valence electrons move from donor to
acceptor whilst the species themselves move. In a perfectly polar, or “two electron”
reaction, these processes are synchronous, whilst the extreme case whereby electron
motion precedes nuclear motion is termed single electron transfer (SET). It has been
suggested that the dearomatising reaction proceeds through an SET mechanism,
requiring an initial electron transfer (ET) and radical coupling (RC) of the resulting
radicals (Scheme 2.20a). Whilst it is commonplace to differentiate one and two
electron reactions in organic chemistry, in his insightful account on the course of
electron and nuclear motion, Pross disagrees with this distinction since chemical bond
making only requires the movement of one valence electron from the donor (Scheme
2.20b). 77
Polar (Pl)
Pl
D−M + A − D−A + M + R−M + E−X
R−E + MX
ET
RC
ET
RC
D • M + + A •−
R • M + + E−X •−
ET
R • E • + Mg + X −
a) Addition Mechanisms b) Substiution Mechanisms
Scheme 2.20 – SET and polar interpretations of addition and substitution reaction
The energetic processes involved in an SET reaction may be depicted in a
configuration model (CM) presented by Pross (Scheme 2.21). Here, the donor (D) and
acceptor (A) exist as separate species before ET, and are represented by the DA curve;
74

Chapter 2 – Dearomatising additions to aryl oxazolines
after ET the species are represented by the line D + A – , and the gap between the lines
represents the energy required for ET. The reaction pathway consists of solvent
reorganisation and geometric distortions that occur before ET to raise the energy of the
DA complex until it is isoenergetic with D + A – (point B), at which time ET occurs and
the species relax to their new ground state. The strong similarity between the CM
diagram and Marcus theory’s avoided crossing diagrams is deliberate – the dashed
lines were added by Pross – and the ET process if often termed outer-sphere electron
transfer.
B
E
Reaction coordinate
Scheme 2.21 – energy profile of electron transfer from species D to A
Like the balance between inner and outer sphere electron transfer, Pross proposes that
SET occurs when the stabilising interactions of synchronous bond formation do not
outweigh the energetic cost of bringing the two sets of nuclei together. The factors
determining where a reaction lies on this continuum have been widely discussed.
Since redox potentials are a direct measure of how readily a species accepts or donates
an electron they are often mooted as allowing prediction about a reaction, although this
is often limited by available data (vide infra). Viewing ET in a molecular orbital
sense, reagents with high energy HOMOs will have little interaction with low lying
LUMOs in a transition state, making a SET reaction likely.
Whilst the nature of the two reagents is important to the manner in which the reaction
proceeds, the difficulties faced when trying to make generalisations indicate that many
other factors influence how the valence electrons move. In the application of Marcus
theory to organic reactions, Eberson also emphasises that any factor that minimises
75

2.4 – Mechanistic discussion
orbital overlap as the transition state is approached will disfavour the polar mechanism
or inner-sphere electron transfer. 78 These can be factors such as steric or geometrical
strain, solvent interactions or simply that a weak bond is being formed.
A number of methods have been developed to study the nature of electron transfer in
organic reactions. The mechanism of halogen-lithium exchange has been a topic of
much investigation and controversy 79 since 1956 when the first observations hinting at
radical intermediates were made. 14 Whilst spectral data confirmed the presence of
radicals, they were not shown to be reaction intermediates until a number of
experiments led to a consensus such as those performed on norbornenes 130 by Ashby
(Scheme 2.22).
Fast
X
130X
t-BuLi
Li
Slow at −78 °C
131
X = I at −78 °C
X = Br at 0 °C
Scheme 2.22 – Ashby’s norbornene radical trapping experiments 80
These and other results strongly support the presence of radical intermediates in
bromine-lithium exchange, 81 and their absence in iodine lithium exchange. 82 This is in
disagreement with predictions based upon electrode potentials (alkyl bromides E ½ –2.5
V and iodides E ½ –1.6 V 83 ) and emphasises the lack of predictability using this
method. Very little electrochemical data is available for organolithiums, presumably
due to electrode decomposition, as reported by Breslow, who was only able to obtain
potentials for allyllithium (–1.63 V) and phenyllithium (–1.43 V). 71
The investigations above highlight that whilst it might be relatively easy to indicate
that a reaction proceeds via SET, it can be particularly difficult to prove so. Ashby
suggests a number of general methods; spectroscopic evidence showing that the rate of
decay of a paramagnetic species is in line with the rate of reaction; loss of
stereochemistry during reaction; and use of a cyclisable probe, preferably of known
lifetime (a radical clock). 79 Rate data from UV-vis spectra of the reduction of
76

Chapter 2 – Dearomatising additions to aryl oxazolines
dimesityl ketone showed that the decaying radical species observed in EPR spectrum
was a radical anion intermediate now known to be present in the reduction of
benzophenone. 84 The stereochemical fidelity of a reaction has been used the lithiation
of pyrolidines 85 and most recently by Hoffmann who monitored racemisation of
enantiomerically enriched Grignard reagents (vide infra). 86 Others have inferred a
SET mechanism from rate data showing more hindered species react faster that less
hindered ones, since it is often found to be a rapid process. 87
The electron transfer (ET) and radical combination (RC) steps of the possible SET
reaction are outlined below, along with the possible polar (Pl) reaction.
Ph Ph
O
N
Li
Ph
Ph
Pl
Ph
Ph
Ph
Ph
O
N
Li
‡Nu
O
N
Li
MeI
O
N
Me
101a
ET
Ph
O
N
Ph
Li
RC
121
102a
‡ET
solvent cage
Scheme 2.23 – possible polar and SET reaction pathways
Often a debate over a polar or SET pathways is only of mechanistic interest, however,
with a reaction that has proved hard to optimise, any insights into the processes
occurring could help focus reaction optimisation. The first strong indication that a
SET mechanism might be involved was the absence of reaction with primary
organolithiums, which would make very unstable radicals and are unlikely to undergo
ET. Other observations are more qualitative such as the opaque reaction solutions
reminiscent of the benzophenone radical anion, high sensitivity to solvation, and the
absence of reaction with syn diphenyl oxazoline 109 or para-nitro 101i, as well as a
remarkably quick reaction.
77

2.4 – Mechanistic discussion
Whilst no mechanistic studies were published, Meyers proposed a polar mechanism for
the dearomatising addition to 2-naphyloxazolines 38 giving azaenolate 132 (Scheme
2.24). Meyers states that the reactions gradually formed red solutions over the course
or an hour, which decolourised upon quench. 31 The reaction also tolerated a large
range of organolithiums.
Ph OMe Ph OMe Ph OMe
O
N
Li
O
NLi
n-Bu
MeI
O
N
n-Bu
n-Bu
38 132
97%
d.r. 47:3
Scheme 2.24 – polar reaction mechanism proposed by Meyers
In contrast, the colour of our dearomatisation reaction varies with substrate, regardless
of whether addition occurs or not. The reaction is complete within minutes, and deep
colouration observed immediately indicating that trace amounts of intermediate form
rapidly. Such a rapid dearomatisation, without warming above –78 °C is quite
remarkable; for example the kinetically more favourable intramolecular dearomatising
cyclisations of Clayden require warming to ambient temperature. 88
Miyano and Bertoli propose that the dearomatising addition of organometallic reagents
to BHA benzoates and dinitrobenzenes respectively proceed through a SET pathway
(section 1.3.1). Whilst these claims were made with different degrees of experimental
support, they lend credence to the possibility of an ET process. Two approaches have
been undertaken to study the mechanism of reaction; EPR spectroscopy and radical
trapping experiments, and are described below.
2.4.2.a Electron paramagnetic resonance (EPR)
The defining characteristic of a radical is its unpaired electron, which it paramagnetic.
Just as NMR spectroscopy measures the energy difference of nuclear spin states in an
applied magnetic field, so does EPR spectroscopy measure the difference of spin states
of the unpaired electron. This energy, denoted g, is of similar magnitude to microwave
radiation, and can be characteristic of the type of compound, but has to be measured
78

Chapter 2 – Dearomatising additions to aryl oxazolines
very accurately since organic radicals normally have a value around 2.00. The g-value
in organic compounds is especially close to that of a free electron since all other
electrons are spin paired and make no contribution to the spin state. Because of this
the term electron spin resonance (ESR) is often applied to organic radicals since the
spin state of a single electron is being measured.
In contrast to NMR, only one spin state is normally studied and only one absorbance is
observed in the EPR spectrum. However, more information is obtained from that peak
by plotting the derivative of absorption, which normally results in hyperfine splitting,
as seen in the spectrum of benzene radical (Scheme 2.25). As observed in NMR
spectroscopy, splitting occurs due to interactions with the magnetic moment of nuclei,
giving 2n+1 lines. The magnitude of the hyperfine coupling, a, depends on the density
of the electron at that nucleus, in the case of benzene, the radical is equally dispersed
across the ring giving a septet.
Scheme 2.25 – EPR spectrum of benzene anion radical (septet, a = 3.75G) 89
Two of the great strengths of EPR spectroscopy are that it is very specific for
identifying radical species and is also very sensitive. The former is very useful for a
number of reasons, but mostly because it means that special solvents do not need to be
used, the latter can be very useful for analysing trace reaction intermediates which may
have low steady-state concentrations before they are consumed in the reaction.
Compared to benzene, radical anion ‡ET has few degenerate protons, and might show
a coupling to a 14 N nucleus. The spectrum would be made more complicated by the
presence of the alkyl radical which generated the radical anion, since the paramagnetic
79

2.4 – Mechanistic discussion
centres would have very similar g-values and the resulting signal would be a
superposition of the two. Fortunately the spectrum of i-Pr• is known which would aid
the analysis.
Sample preparation proved problematic as it required transferring into the narrow
quartz tubes at low temperature under inert conditions. Whilst this was eventually
overcome, it was not possible to obtain a homogenous sample. Once prepared,
samples were cooled in liquid nitrogen and transported to the X-band 90 spectrometer at
the University of Manchester, and one spectrum is below.
101b + s-BuLi in
DMPU/PhMe
Ph
O
N
Ph
3300 3320 3340 3360 3380 3400 3420
OMe
‡ETb
Scheme 2.26 – X-band EPR spectrum acquired at 220K (doublet, A= 20G, g=1.99)
The spectra obtained clearly show the presence of radical species in solution although
the poor resolution means little can be inferred. 91 Sample warming meant that better
spectra could not be acquired, and attempts to re-make samples failed. Karlubíková
has since obtained better resolved spectra under similar conditions showing a sextet
with a strong spin coupling of 11.5 G. 66
Whilst these results show unpaired electrons in the reaction mixture, they indicate little
else. Since EPR is a very sensitive technique, the spectrum might simply be due to a
low concentration species not on the reaction pathway. A spectrum with better
resolution would give information about the environment of the radical which might
indicate its nature. However sufficient information had been gained to continue
investigating the SET mechanism to show whether or not this paramagnetic species is
a reaction intermediate.
80

Chapter 2 – Dearomatising additions to aryl oxazolines
2.4.2.b Radical trap
Internal radical traps are commonly used as mechanistic probes and may be attached to
either the nucleophile or the electrophile. They have often been used to measure the
rate of reaction (radical clocks), but since we are mainly interested in a qualitative
understanding of the reaction such studies will not be made. The radical trap must be
stable under the reaction conditions and the resulting radical should not propagate any
reaction; halogens or dithianes are often used to trap reaction intermediates, but would
also be likely to react under the conditions. Methylcyclopropanes are also often used
but their use as mechanistic probes has been discouraged since non-radical
intermediates have been reported to trigger ring opening. 92
Appending a probe to the oxazoline is preferred since it is synthetically easier, and a
broader range of aromatic substituents have been tolerated than have nucleophiles.
The group that seems best suited is the allyl group since its behaviour in the presence
of organolithiums has been thoroughly studied and its products should be stable and
readily characterised. Allyl ether 101j (Scheme 2.27) is well suited to the task. The
meta-anisole analogue 101c dearomatised in good yield and complete regioselectivity,
whilst O-allylphenol radical 133 is one of the fastest cyclisation probes, 93 with a halflife
determined by Ingold of 0.1 ns at 30 °C 94 (c. 10 ns at –80 °C). 95 Whilst the radical
anion intermediate is likely to be similar to that of benzene (Scheme 2.25), a useful
approximation of the rate of cyclisation of an alkyl radical is given by heptene radical
134. 96 Allyl ether 101j is preferred to the homoallyl analogue because it undergoes
cyclisation more rapidly 94 and it would be prone to benzylic lithiation which might
influence the reactivity of the aromatic system.
Ph
O
N
Ph
133
O
k = 6.3 x 10 9 s -1
t ½ ~0.1 ns
30 °C
O
t ½ ~10 ns
−80 °C
101j
O
134
k = 1.3 x 10 5 s -1
t ½ ~5 ms
25 °C
t ½ ~1 s
−80 °C
Scheme 2.27 – proposed allyl ether radical trap & rate of cyclisation 94
81

2.4 – Mechanistic discussion
Subjecting oxazoline 101j to the dearomatising conditions could have a number of
outcomes; those that are of mechanistic interest are outlined in Scheme 2.28. The
kinetically controlled cyclisation of radical anion ‡ETj, followed by electrophilic
quench should give dearomatised bicycle 136, followed by possible coupling with the
isopropyl radical or proton abstraction from the solvent. If the dearomatising addition
proceeds along a polar pathway (Pl), or RC is significantly faster than cyclisation of
the tether, then allyl ether 102j will be the major product.
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
N
Ph
O
i-PrLi
ET
O
‡ETj
N
O
Li
RC

Chapter 2 – Dearomatising additions to aryl oxazolines
Ph
Ph
Ph
Ph
Ph
Ph
O
N
O
N
O
N
O
O
137 138 139
OH
Ph
Ph
Ph
Ph
Ph
Ph
O
N
O
NLi
O
N
Li
140
O
O
141 142
O
Ox*
Ox*
Ox*
OH
O
Me
O
143
SN2'
144
lithiation
144a
isomerisation
Scheme 2.29 – possible reaction pathways of allyl ether
Still and co-workers found that treatment of allyl ether 133 with n-BuLi led to near
quantitative α- and γ-alkylation, the latter being selective for the cis isomer (144a);
this is presumably due to the formation of a π-allyllithium complex similar to 140. 98
This intermediate might also act as an intramolecular nucleophile in a similar manner
to the work of Kenworthy and Clayden, who found related naphthyloxazoline 145
underwent dearomatising cyclisation. 99 Whilst Kenworthy was performing a
kinetically more favourable 5-exo-trig cyclisation, 6-exo cyclisation to give
tetrahydrochromene 142 might be possible.
O
N
O
SnBu 3
MeLi, THF
−78 °C 1 hr
then MeI
O
N
Me
O
OMe
145
OMe
79%
>25:1 dr
Scheme 2.30 – dearomatising cyclisation onto 2-naphthyloxazolines 99
83

2.4 – Mechanistic discussion
The tethered oxazoline 101j was treated under the reaction conditions, giving a forest
green solution. Mass recovery from the reaction was poor, but the isolated products
were very interesting.
Ox*
i) i-PrLi (2 eq)
THF, DMPU
−78 °C
Ox*
Ox*
Ox*
101j
O
ii) MeI
O
102j
O
O
10% 5% 20%
102j*
142 dr 2:3
Scheme 2.31 – dearomatising addition of allyl tether
The major products of the reaction are believed to be two diastereomers of bicycle 142,
with a combined yield of 20%. However, two discrepancies exist in this assignment;
whilst the 1 H spectra NMR of the separated diastereomers appears to be show single
compounds, adjacent half-intensity peaks appear in the 13 C NMR, resembling a 1:1
mixture of diastereomers. Furthermore the 1 H NMR spectra contain many high
multiplicity peaks with small couplings (1-2 Hz). These spectra are provided in
appendix A.
Dearomatised adduct 102j and its isomer 102j* were characterised by having almost
identical 13 C and 1 H spectra to adduct 102c, which had been identified by crystal
structure, only differing in the pendent allyl system. Importantly, no other products
could be identified in the crude NMR. Unfortunately only 15% of the dearomatised
adducts 102j were recovered, compared with 54% of 102c. Whilst diminished yields
were anticipated due to the reactivity of the allyl group, it means that we cannot be
sure that some tetrahydrobenzofuran 136 was not formed, and cannot exclude two
reaction pathways. As indicated in Scheme 2.28, the absence of a trapped radical does
not exclude electron transfer, but simply gives an upper limit on the lifetime of a
radical anion ‡ETj of around 10 ns. This allows us to rule out a slow RC step which
might have involved diffusion of i-Pr• out of the solvent cage.
Whilst much controversy has surrounded the use of allyl tethers as mechanistic probes,
in Newcomb’s critique on the practice he concludes that the only mechanistic certainty
they provide is in the absence of radical trapping. 92 Although the poor yield means we
cannot be certain, we have shown that free radical intermediates are unlikely.
84

Chapter 2 – Dearomatising additions to aryl oxazolines
2.4.2.c Mechanistic conclusions
The data outlined in the previous sections contradict each other; the EPR studies
indicated a stable, long-lived radical species, whilst trapping studies were unable to
capture the radical anion presumed responsible. If we accept that the poor mass
balance was due to a molecule with too many reactive sites we can conclude that the
lifetime of any radical anion intermediate is less than 10 ns, and that species observed
in the EPR spectra is unlikely to be a reaction intermediate.
Any further studies of the mechanism must focus on measuring changes inside the
solvent cage, by studying the atoms involved in the rate determining step rather than
trying to deduce information from neighbouring groups. Two such methods have been
developed by Yamataka to infer a rate determining ET step in nucleophilic additions to
benzaldehyde (147) and benzophenone (148); the absence of a 14 C kinetic isotope
effect at the carbonyl, and a near zero linear free-energy relationship (ρ). 87
O
O
H
RLi
THF, 0 °C
14 C=O Kinetic isotope effect
Hammett plots
147 148
Entry RLi Electrophile
KIE
12 k/ 14 k
ρ
isomerisation
of 152*
RDS
a 100 MeLi 148 1.000 +0.27 1% 101 ET
b 102 PhLi 148 1.003 +0.24 – ET
c 102 PhLi 147 0.998 +0.18 – ET
d 102 allyl-Li 148 0.994 +0.17 – ET
e 87 PhSCH 2 Li 148 – +0.24 – ET
f 87 PhSCH 2 Li 147 0.998 +0.17 – ET
g 87 NCCH 2 Li 147 0.992 +0.14 5% ET
h 103 Li-Pinacolate 147 1.039 +1.16 1% Pl
i 104 MeMgBr 148 1.056 +0.90 – RC
j 104 PhMgBr 148 1.056 +0.59 – RC
k 104 allylMgBr 148 0.999 -0.02 – ET
* % isomerisation of recovered 152 after 1 hr reaction, Scheme 2.33
Table 2.10 – addition of organolithiums to benzophenone and benzaldehyde
85

2.4 – Mechanistic discussion
Yamataka developed these approaches to monitor nucleophilic attacks since there is
normally no free radical intermediate to intercept with a tethered probe. Yamataka’s
use of 14 C labelling at the site of attack works on the assumption that the transfer of an
electron will not perturb the hybridisation or geometry, whilst a polar reaction, or a
rate determining RC clearly would. The rational for a small ρ-value for an ET rate
determining step is not so well understood, but is taken to be characteristic since a Pl
anionic processes would clearly be assisted by removing electron density. The data
presented in Table 2.10 indicate that Yamataka and co-workers have found a method
for distinguishing the three rate determining steps; they even seem able to differentiate
a change in RDS of Grignard addition (entries h-k). This change from an ET to a RC
rate determining step is reported to reflect how finely balanced SET reaction is.
In a similar manner, Gajewski measured secondary deuterium KIEs of some of these
additions by “α-deuteration” of benzaldehyde. 105 ortho-Deuteration of oxazolines
would allow α-deuteration studies to be undertaken and would be significantly easier
than 14 C. Surprisingly, the ortho-lithiation of oxazolines 101a and 101b was
unsuccessful, however meta-anisole 101c should be particularly amenable to orthodeuteration
and kinetic study of the resulting d-101c (Scheme 2.32). Whilst
unexpected, Meyers reports that ortho-lithiation can be slow when studying the
deuteration of phenyl oxazolines. 106
Ox*
D
Ox*
Ox*
OMe
d-101c
α-deuteration
KIE
R
150
linear free-energy
relationship
t-Bu
151
radical isomerisation
Scheme 2.32 – possible mechanistic probes
Whilst it may not be strictly valid, a Hammett linear free energy study might provide
some insight, possibly through the study of para-aryl oxazolines 150; since reaction
occurs at the aromatic ring, kinetic data could not be collected for substituents on that
ring since they would have both a direct electronic and steric interaction with the
reacting centres. Fortunately a wealth of Hammett substituent constants are available
86

Chapter 2 – Dearomatising additions to aryl oxazolines
for both para and meta-benzenoid rings, 107 the former might be preferred since
torsional strain would be minimised, although Yamataka purports that ET is not
effected by such considerations. Biaryls 150 might be most readily made by aromatic
cross-coupling, along with one of the methods described in the next chapter.
Ashby has identified the isomerisation of cis-enone 152 as a possible measure of the
existence of radical anion intermediates in its reaction with organometallics (Scheme
2.33). Under conditions of excess 152, the E:Z ratio of recovered starting material and
products were taken to indicate the extent to which electron transfer occurred, although
it was acknowledged that like other methods it also depended upon the lifetime of the
radical. The results were far from conclusive, with only partial isomerisation seen
under dissolving metal conditions, and none with MeLi (entry a, Table 2.10).
Yamataka also subjected enone 152 to sub-stoichiometric organolithiums (entries g, h,
Table 2.10) with little isomerisation observed, even for cyanomethyllithium, which
was classified as an ET reagent on the basis of the other results; further questioning the
methods validity.
Whilst this study did not provide any definitive conclusions, it is based upon an very
reasonable idea which could produce interesting results. If it were to be adapted to
studying these additions, para-butenyl 210n might serve a similar function; parasubstitution
is preferred since there have been no successful additions to orthosubstituted
oxazolines (vide supra).
t-Bu
O
t-Bu
RM
t-Bu
O
t-Bu
R
t-Bu
HO
t-Bu
R
Ph
O
Ph
NLi
152
O
t-Bu
t-Bu
O
t-Bu
R
t-Bu
O
t-Bu
t-Bu
t-Bu
trans-152
Scheme 2.33 – isomerisation of cis-alkenes
R
151 −
In his study of the nucleophilic addition of Grignard reagents, Reinhard Hoffmann
took the measures of bond isomerisation to its logical conclusion; the racemisation of
the reacting stereocentre as a radical clock. 86 The first attempt at achieving this was a
87

2.4 – Mechanistic discussion
Gringard derived from norbornane, which was found to have an innate stereochemical
bias in its reaction. However, Hoffmann and co-workers succeeded in generating the
chiral secondary Grignard 154 in 90% e.e. from sulfoxide 153. In their reaction with
achiral substrates any isomerisation of the nucleophilic centre would due to a radical
intermediate; with a barrier to rotation estimated at only 0.5 kcal mol -1 this probe
should identify even the most short-lived radicals.
Ph
Cl
S Ar
O
153
EtMgCl (5 eq)
−78 to −30 °C
Ph
O
MgCl
E =
R H
< −30 °C
154 90% e.e.
R
OH
155
Ph
Entry E Product Yield / % e.e. / %
a R = Ph 155 84 84 & 88
b R = p-OMe C 6 H 4 155 82 84 & 89
c R = C 6 F 6 155 90 43 & 47
d CO 2 HO 2 C-CH(Et)Bn 80 92
e Ph 2 CO Ph 2 CO- CH(Et)Bn 85 12
Table 2.11 – addition of Hoffmann’s chiral Grignard to electrophiles 108
These results show a surprising preference for polar addition, with even addition to
benzophenone apparently exhibiting some polar nature. 108
Confirmation of absolute
configuration showed that the polar reaction proceeded with retention. Intriguingly,
the diastereomers resulting from addition to aldehydes were of different optical purities
(entries a-c, Table 2.11), even though they were isolated from the same reaction; no
explanation is offered for this outcome.
Instead of identifying partial radical nature, it is of course possible that all or some of
these reactions are entirely radical in nature, and that any apparent polar nature is
because the rate of radical combination is greater that bond rotation of 154•. However
this seems unlikely, and with the uncertainty of how to interpret data from other kinetic
methods, radical clocks such as 154 appears to offer the best measure of SET
behaviour, and the use of an organolithium equivalent would almost certainly offer
illumination about the mechanism of the dearomatising addition. Indeed, the 3:1
diastereomeric ratio of the exocyclic centre observed upon addition of s-BuLi could be
88

Chapter 2 – Dearomatising additions to aryl oxazolines
viewed as evidence of an SET reaction. One could dispute that rather than
representing a kinetic resolution of the s-BuLi in solution, that addition of both s-butyl
enantiomers is equally likely and that the bond rotation occurs in the butyl radical
before RC.
2.4.3 Aggregation in organolithium chemistry
Whilst the mechanistic studies are inconclusive, another area that might shed light on
understanding the dearomatising chemistry is the role of aggregates which are
implicated by the sensitivity of the reaction to the order of addition and solvent.
Aggregates form since a monodentate alkyl ligand is unable to adequately stabilise its
lithium counterpart, which is normally tetracoordinate. These aggregates can shift to
their entropically favoured state by the addition of Lewis bases, such as THF, TMEDA
and DMPU, which displace organic ligands around the cation. Deaggregation is often
associated with making organolithiums more reactive since the organic portion no
longer coordinates as many lithium centres, but this has been hard to prove. Indeed,
Collum has authored a critique of the triad of strong solvation, lower aggregation and
higher reactivity, by discussing examples of the behaviour of TMEDA in
organolithium reactions. 109
Collum highlights that the lower aggregation means higher reactivity assumption is
fundamentally flawed since by stabilising lower aggregates of organolithiums, one is
lowering the ground state energy of the reactants without necessarily lowering the
energy of the transition state. Since it is the transition state we hope to stabilise
observed increases in reaction rate cannot be used to infer lower aggregation. Indeed,
a stronger ligand binding lithium would be less labile and the cation disinclined to
coordinate the substrate.
Transition state stabilisation seems especially important when we consider that under
normal conditions, dearomatisation is a very unfavourable process and it is likely that
dearomatised intermediates require significant stabilisation. Hence the subtleties of
how stabilisation takes place are important, and might explain why only certain cosolvents
were found to assist dearomatisation. An example of a similarly solventspecific
effect was observed by Streitwieser who found that the aromatic enolate of p-
89

2.4 – Mechanistic discussion
phenylisobutyrophenone is strongly coordinated by HMPA, weakly by DMPU, and
that PMDTA and TMEDA have no effect. 110
Unfortunately the role of co-solvents in organolithium chemistry is not thoroughly
understood. The most studied co-solvent is hexamethylphosphoramide (HMPA) since
it is an exceptional ligand for Li + and its interactions can be monitored by IR and 31 P
NMR spectroscopy. Reich recently studied the correlation between 1,2- and 1,4-
addition of dithiane to enone systems and its HMPA-induced aggregation state
(Scheme 2.34).
O
Li O
S
S S
−78 °C
HO S
THF
R
S
S
157
100 : 0
+ 2 eq HMPA
5 : 95
Scheme 2.34 – the influence of co-solvent on addition to cyclohexenone 111
The aggregation state of dithiane 157 was measured in solution and the results
compared these to the regioselectivity of parallel reactions. Whilst a direct correlation
was not observed, Reich concludes that the 1,4-addition is performed by trace amounts
of organolithium existing as solvent-separated ion pairs (SIPs). In coming to this
conclusion, he invokes a Curtin-Hammett pre-equilibrium between the predominant
contact ion pairs (CIPs) and the lower concentration SIPs. Whether the conclusions of
Reich are wholly valid, his experiments clearly show how an organolithium can switch
its reactivity depending on its solvation.
Coordinating ligands can also have unpredictable effects on the aggregation state of an
organolithium. For example, Reich and co-workers also found that whilst aryllithiums
158 exist as monomers in THF, addition of excess HMPA can cause them to redimerise
to form bis-chelated triple ions 158-T, with one lithium cation completely
solvated by HMPA. 112 The reactivity of these triple anions has not been studied, but
that HMPA is found to promote aggregation highlights that many different
organolithium species can exist in solution.
90

Chapter 2 – Dearomatising additions to aryl oxazolines
R
Li
HMPA
R
Li
R
Li(HMPA) n
R
R R
158 158-T
R = Me, & i-Pr
65-80% 158-T
Scheme 2.35 – aggregation of aryllithiums by HMPA 112
2.4.3.a The role of aggregation in the dearomatising addition
These studies show just how complex the reactivity of organolithiums can be, and with
numerous possible intermediates, it is perhaps surprising that high degrees of control
are ever achieved. The sensitivity of the dearomatising addition to solvent and order of
addition shown (section 2.2) indicates that transient organolithium species, may be
responsible for the dearomatising addition, and that these species – either reagent or
reaction intermediates – are stabilised by DMPU. The time profile of the reaction
(Scheme 2.8) indicates that ortho-lithiation and dearomatisation occur in parallel, so
mixed aggregates are unlikely to either accelerate or inhibit the reaction. Excess
organolithium appeared to have little impact, implying that product does not
coordinate the reagent as, for example, LDA can. Finally, in common with other
organolithium reactions, some co-solvent was essential to the reaction, whilst excess
was found to promote side reactions.
The reactivity of the nucleophiles further indicates that aggregation might be
important, since the organolithium must be transferred in its native state (Table 2.5,
Table 2.6). In hydrocarbon solvent, n-BuLi exists as a hexamer, and t-BuLi is a
tetramer; below concentrations of 0.1M i-PrLi is also a tetramer but cryoscopic
measurements of more concentrated solutions, and its crystalline form as hexameric; 113
it’s likely that s-BuLi has similar aggregation states as i-PrLi, even though it is
normally reported to be a tetramer. 14 Whilst it is unlikely that the reaction occurs with
the organolithiums in their native state, it is possible that deaggregation in the presence
of DMPU induces the formation of certain reactive species. Therefore primary and
tertiary organolithiums may not react simply because the deaggregation pathway they
follow does not include aggregates which permit dearomatising addition to occur.
91

2.5 Summary & Future Work
It is unsurprising that the development of a reaction that evaded leading researchers for
decades is challenging, and that careful reaction conditions might be necessary.
Currently what is happening in the flask is unclear, but when the correct system is
found encouraging improvements can be achieved; as demonstrated by the reaction of
fluorinated oxazolines in toluene. A broader range of organolithiums, especially ones
containing heteroatoms would make the reaction more synthetically useful, in
particular dimethylphenylsilyllithium would be particularly amenable to future
synthetic manipulation. Importantly, it seems that once a system is found, the reaction
is scalable, with two gram reactions proceeding in excellent yield without the need for
especially rigorous conditions.
The dearomatising cyclisation described in Scheme 2.31 highlights some possible
areas to explore (Scheme 2.36). Since the aromatic system reacted with the lithium π-
allyl system 140 (Scheme 2.29) to give a 6 membered ring, a 5-membered cyclisation
should be move favourable, and certainly more stereoselective. This could be
achieved through homologues 159 or 160, but since a non-pericyclic reaction is
suspected 62 conjugation with the aromatic system (160) would disfavour cyclisation.
If aryl ether 159-O lithiated at the allylic position in the absence of an adjacent
heteroatom, it would form an allyl system similar to 159, and might undergo
cyclisation. Alkenes 159-C or 161 might also generate π-allyl intermediates 159, but
benzylic lithiation could inhibit cyclisation. This could be minimised by use of
lithium-halogen exchange or other related methods.
Ox*
X
159
Li
Ox*
160
Li
Ox*
Ox*
Ox*
O
O
159-O 159-C
Scheme 2.36 – allyl oxazolines promoting 5-membered dearomatising cyclisation
161
92

Chapter 2 – Dearomatising additions to aryl oxazolines
Further suggestions for future work have been made throughout this discussion and a
number have already been undertaken. Future improvements in the methodology will
require further close study of the reaction conditions, which may prove to be substrate
dependent. A number of ways to improve reactions involving organolithiums have
recently be suggested by Collum. 67
93

Chapter 3 – Oxazoline synthesis & removal
Chapter 3 – Oxazoline Synthesis and Removal:
Making & Breaking an Auxiliary
The previous chapter introduced an asymmetric reaction guided by a pendant
oxazoline group. Such stoichiometric “auxiliary” chemistry can only be of synthetic
use if the stereoinducing group can be easily incorporated into a synthesis, meaning i)
it must be easily installed and ii) easily removed. These two measures can be more
important in developing a chiral auxiliary than the stereoselectivity of the intervening
reaction, since diastereoisomers can in principle be separated before its removal.
Hence the facile synthesis and removal of the oxazoline moiety without loss of optical
purity is essential to making the dearomatising methodology synthetically useful.
3.1 The Synthesis of 2,4,5-Oxazolines
2,4,5-Substituted oxazolines are generally synthesised from a carboxylic acid
derivative and a β-amino alcohol which contains both stereogenic centres.
The
oxazolines are required in high optical purity, both enantiomers should be equally
accessible, and their synthesis should tolerate a range of aryl substituents. Whilst
preliminary studies in the previous chapter required a number of different C4 and C5
substituents, the synthesis of diphenyl oxazolines 101 will be the focus of this section.
Ph
5
O N
2
Ar
101
Ph
4
3.1.1 Literature methods for synthesis
Many literature methods are inappropriate for the synthesis of optically pure
oxazolines 101 since they would proceed through achiral intermediates such as
epoxides or electrocyclic transition states, which also presents problems for a number
of asymmetric catalysis. 114
Discussion will be restricted to methods which have been
shown to give enantiomerically pure 2-aryloxazolines in reasonable yield;
comprehensive summaries of the recent literature have been reviewed by Meyers 24 and
Ager. 115
95

3.1 – Oxazoline synthesis
3.1.1.a Hydroxyamides – alcohol activation
O
R
X
H 2 N
OH
O
R
H
N
OH
SOCl 2 , Na 2 CO 3
O N
Δ
R
c. 70%
116
Scheme 3.1 – unfunctionalised oxazolines via amides
Oxazolines are traditionally made by condensation of β-amino alcohol with carboxylic
acids or derivatives, before cyclisation by azeotropic reflux or treatment with excess
thionyl chloride (Scheme 3.2). 117
This method works well for generating oxazolines
without a C5 stereocentre, although significant amounts of the intermediate chloramide
is often isolated, diminishing the yield. A number of milder methods for activating the
amido alcohol have been developed, which are compatible with more sensitive
functional groups.
Ph
Ph
Ph
O
N
H
165a
Ph
O
N
H
166
OH
Ph
OH
Me
DIC 1 eq
Cu(OTf) 2 5%,
dioxane, Δ 6 hr
DIC 1 eq
Cu(OTf) 2 5%,
THF, μω 5 min
Ph
Ph
O
N
Ph
101a
O
Ph
110
N
Ph
Me
78%
> 95:5 dr
88%
> 95:5 dr
R
O
N
H
i-Pr
NH
O
N i-Pr
R
167
61-98%
16 examples
Scheme 3.2 – cyclisation of amides by the method of Linclau 118
Linclau recently developed a method using the coupling agent diisopropylcarbodiimide
(DIC) to promote displacement of the newly activated alcohol. 118
Catalytic copper
triflate is added to promote in situ formation of isoureas 167 and is shown not to affect
the cyclisation step which proceeds exclusively in an S N 2 manner for the examples
shown. This method is particularly appropriate since they make not only diphenyl
oxazoline 101a, but also the norephedrine-derived oxazoline 110 studied in the
previous chapter.
96

Chapter 3 – Oxazoline synthesis & removal
HO
Ph
Ph
OH
Ph
Ph Ph
Ph
Ph
NH
O
H
N
O
NH
Ph
i) MeSO 2 Cl, Et 3 N
ii) NaOH, MeOH,
H 2 O, Δ 4 hr
O
N
H
N
O
N
168
53%
Scheme 3.3 – cyclisation of amides by mesylation 119
Activation has also been achieved by Du and co-workers, by mesylation before
cyclisation under strongly basic conditions (Scheme 3.3). Although an extra step is
required in the isolation of the mesylate, shorter reaction times and cheaper reagents
somewhat offset this practicality. 119 Whilst the synthesis of bis-oxazoline ligand 168
proceeds in lower yield than the Linclau method, each cyclisation effectively takes
place in 70-75% yield. In light of its simplicity it is somewhat surprising that this
method has not been used more widely; given that the diastereoselectivity is not
reported it is unclear how general this method is.
3.1.1.b Acyl aziridines
Ph
Ph
Ph
O
Ph
N
100a
Ph
SiO 2 , CH 2 Cl 2
O N
Ph
101a
94%
> 99:1 dr
> 99:1 er
64
Scheme 3.4 – silica catalysed rearrangement of benzoyl aziridines
Diphenyl oxazoline 101a was first synthesised by Purewal 63 and Cabedo 64 by the
rearrangement of benzoyl aziridine 100a on silica, with only a single stereoisomer
isolated. Although this was unexpected at the time, there is significant precedent for
the ring expansion of acyl aziridines catalysed by iodide, 120 heat, 120 Lewis acid, 121
aqueous acid, 122 and silica, 123 although the stereochemical outcome of the reaction had
not generally been studied.
97

3.1 – Oxazoline synthesis
O
Ar
OH
i) SOCl 2
ii)
HN
O
Ar
N
86%
H 2 SO 4 , Et 2 O
rt, 16 hr
O
Ar
N
75%
Ar =
NC
122
Scheme 3.5 – acid catalysed rearrangement of benzoyl aziridines
The aziridine nitrogen is unable to fully participate in the stabilising n N →π * C–O
interaction since it is constrained in a three membered ring. This is seen in a crystal
structure obtained by Lectka and co-workers in which the aziridine C–N bonds are 68°
out of the C=O plane, and longer than other secondary amines. 121 Therefore the partly
pyramidal acyl aziridines have reactivity akin to amines, and it is postulated by Lectka
that the nitrogen basicity drives the rearrangement. This has been borne out by his
studies which show that the rearrangement takes place in the presence of azaphilic
Lewis acids (Cu II , Sn II , Zn II ) but not oxophilic ones (Yb III , Ti IV , Sb V , Al III , 122 BF 122 3 ).
Another, and perhaps the main, impetus for the rearrangement would be the
developing n N →π* C–O interaction in the transition state, which no doubt explains why
the reverse reaction is not observed.
Ar
N
O
Cu(OTf) 2
THF
Ph
Ph
Cu(OTf) 2
O N
N
O N
THF
Ar
Ph O
Ph
76-89%
169 4 examples 171 172
M
N
O
Ar
170
Scheme 3.6 – acid catalysed rearrangement of aziridines 121
In this work, Leckta synthesises a number of cis-substituted oxazolines 169, and
transition state calculations suggest a heterolytic process via cation 170 rather than a
concerted mechanism favoured by other authors. 120 Under these conditions, optically
pure aziridine 171 rearranges to give the known oxazoline 172 with complete regioand
stereoselectivity; the regioselectivity is consistent with formation of the more
stable cation, whilst the stereoselectivity is attributed to the formation of tight ion
pairs. No yield is given for this final reaction in either the text or supporting
information.
98

Chapter 3 – Oxazoline synthesis & removal
3.1.1.c Activated carbonyl
Whilst the amide methods form the C–O bond of the oxazoline with inversion,
condensation of the amino alcohol with an activated carbonyl proceeds with retention
at the C5 stereocentre. These methods would therefore allow the same amine to be
used to make epimeric oxazolines.
O
NH 2
i) (Et 3 O)BF 4 , CH 2 Cl 2
Ph
O
N
OMe
R
ii)
Ph
HO
OMe
NH 2 Δ
38
R
83-94%
3 examples
Scheme 3.7 – oxazolines from primary amides 32
Although Meyers published a number of ways to make oxazolines, his preferred
method for making chiral oxazolines 38 was via an imidate formed in situ before
addition of the desired amino alcohol. 32 This method has been used for a wide range
of naphthalenes, and since it is a retentive reaction, the stereochemistry and optical
purity of the product depends on the amino alcohol used.
MeO
OMe
OMe
Ph
173
R
HO
R'
NH 2
TFA, DCE
Δ 4 hr
R
O
Ph
N
R
88-97%
3 examples
124
Scheme 3.8 – oxazolines from ortho esters
An analogous method published more recently by Meyers uses aryl ortho esters 173 to
give a small selection of aryl oxazolines in good yield. 124
Since ortho esters can be
made by methanolysis of nitriles, this would offer another route to their synthesis. The
zinc chloride catalysed condensation of aromatic nitriles with amino alcohols under
reflux has also been used to synthesise 2-aryl oxazolines, but has only been used to
make a small range of compounds. 125
99

3.1 – Oxazoline synthesis
3.1.2 General strategies
Retrosynthesis of oxazolines 101 using the three methods outlined reveals that each
would require a different amine. However aziridine 173 might be made from β-amino
alcohol 174.
Retention
Ph
O N
Ph
Ar
100
aroyl aziridine
Retention
B
HN
Ph
173
Ph
Route B
acyl aziridines
Inversion
Ph Ph Inversion
O N
Ar
101
Ar
Ph
O
N
H
O
Ph
R
benzoyl amide,
activated alcohol
Retention
A
Ph
Ph
HO NH 2
174
Route A
Amide alcohols
Retention
H
R O
O
Ar
N
Ph
Ph
activated benzoyl
amide
Retention
C
Ph
Ph
HO NH 2
175
Route C
Activated carbonyl
Scheme 3.9 – retrosynthesis of diphenyl oxazoline 101
Which route is preferred will depend on ease of access to the enantiomerically pure
amine, the optical purity of the resulting oxazolines, and the overall yield of oxazoline
formation.
3.1.3 Amine synthesis
The large scale synthesis (170 g) of amino alcohol 174 from trans-stilbene was
completed by Sharpless in 81% overall yield and near complete enantiomeric purity. 126
The synthesis was completed in comparable yield (Scheme 3.10), with substitution of
CDI for dimethyl carbonate, making cyclic carbonate 177 in quantitative yield instead
of 85%.
100

Chapter 3 – Oxazoline synthesis & removal
Ph
Ph
AD mix α, Me 2 SO 2 NH 2
t-BuOH/H 2 O, 0 °C 2 d
O
Ph Ph CDI, CH 2 Cl 2
O O
HO OH rt 16 hr
98%
Ph Ph
176 177 100%
NaN 3 , DMF
Ph
Ph
H 2 , Pd/C
Ph
Ph
110 °C 2 d
HO
178
N 3
HCl/EtOH
HO
174
NH 2
82% (2 steps)
>99:1 e.r.
Scheme 3.10 – modified Sharpless synthesis of amino alcohol 174
Aziridine 173 was made from the products of this synthesis either by intramolecular
Mitsunobu reaction of amino alcohol 174, or treatment of azide 178 with
triphenylphosphine. 64
phosphazide.
Ph
HO
178
Ph
N 3
The latter reaction presumably proceeding via a Staudinger-type
PPh 3 , Et 2 O
rt 2 hr
HN
Ph
173
Ph
64%
(from carbonate)
Ph
HO
174
Ph
NH 2
Ph
PPh 3 , DIAD
HN
Et 3 N, THF
Ph
rt 18 hr 92%
173
Scheme 3.11 – aziridine synthesis
The asymmetric synthesis of amino alcohol 175 is not trivial since most obvious
intermediates such as cis-stilbene oxide, 179, are meso. It should be possible to invert
the alcoholic centre of 174 by Mitsunobu reaction after deactivating the amine as the
carbamate, by the method of Lipshutz. 127 However this is presently deemed
unnecessary since the racemic amino alcohol can be quickly synthesised (Table 3.1).
101

3.1 – Oxazoline synthesis
mCPBA
O
NH 4 OH, MeOH
Ph
Ph
Ph
Ph
CH 2 Cl 2
Ph Ph Conditions
90%
179
HO NH 2
± 175
Entry NH 4 OH:MeOH Temp / °C Time 175 (SM) / %
a 1:1 100 Δ 24 hr 55 (25)
b 3:1 120 µω 2 min 15 (85)
c 3:1 140 µω 20 min 93 (5)
Table 3.1 – synthesis of racemic amino alcohol
The improvement seen under microwave conditions is believed to be due to the use of
a sealed vessel increasing the partial pressure of ammonia, but is also assisted by a
particularly easy isolation which only requires filtration of the cool reaction mixture.
The synthesis of ±175 would be made particularly atom efficient if an oxidant such as
dimethyldioxirane or hydrogen peroxide were used for the epoxidation. 128
3.1.4 Oxazoline synthesis
The availability of only two of the three amines in near optical purity meant that the
amide and aziridine methods (Scheme 3.9) are the remaining viable routes to the
synthesis of enantiomerically pure diphenyl oxazolines. It is important to note that the
amine syntheses above allow either enantiomer to be synthesised. The third method is
still presented below, since it allows the synthesis of racemic diphenyl oxazoline as
well as most of the other oxazolines studied in the previous chapter.
102

Chapter 3 – Oxazoline synthesis & removal
3.1.4.a Method A: hydroxyamide activation
O
Cl
R
Ph
Ph
HO
(1.2 eq)
NH
174 2
CH 2 Cl 2 , Et 3 N
O
H
N
Ph
OH
Ph
DIC 1 eq
Cu(OTf) 2 5%
Conditions
Ph
R
R
165 101
O
N
Ph
d.r. >95:5
e.r. >99:1
Entry R 165 / % T ‡ / °C t 101 / % Compound
a H 99 105 Δ 7 hr 65 101a
b H 99 150 µω 20 min 58 101a
c 4-OMe 99 140 µω 30 min 48-72 101b
d ** 4-OMe 98 120 Δ 12 hr 46 101b
e 3-OMe 96 120 Δ 17 hr 39 101c
f 2-OMe 99 120 Δ 17 hr 50 101i
g 70 4-F 61 120 Δ 16 hr 42 101e
h 4-Ph 83 ‡ 120 Δ 17 hr 43 101f
i 4-CN 41 ‡ 150 µω 20 min 53 101g
‡ from carboxylic acid *reactions under reflux performed in dioxane, microwave reaction
in THF **10 gram reactions
Table 3.2 – synthesis of oxazolines via amides (Route A)
Linclau had previously synthesised 2,4,5-triphenyl oxazoline 101a in 78% yield with
good diastereoselectivity (section 3.1.1.a). Whilst this result could not be reproduced
(entry a) the method was amenable to a range of 2-aryl groups, although yields were
found to vary significantly, even when repeating the same reaction (entry c). Much of
the losses are believed to be unreacted starting material, which is hard to quantify since
it is inseparable from the urea. Longer reaction times did not improve yields,
presumably due to decomposition of the product. Recently Karlubíková has
synthesised oxazoline 101b by mesylation and cyclisation of amide 165b (vide supra)
in the slightly higher 76-86% yield. 66
103

3.1 – Oxazoline synthesis
3.1.4.b Method B: ring expansion of benzoyl aziridines
Ph
Ph
Ph
Ph
O
Cl
HN
173
Ph
O
N
Ph
SiO 2 , CH 2 Cl 2
O
N
R
Et 2 O, petrol,
Et 3 N, -10 °C
R
R
100 101
e.r. >95:5
Entry R 100 / % SiO 2 t 101 / % d.r.
a H 84 “excess” 18 hr 94 64 >99:1
b 4-OMe 89 “excess” 8 d 58 99:1
c 4-OMe 89 10 x wt 7 hr 80 >95:5
d 3-OMe 87 10 x wt 16 hr 85 >95:5
Table 3.3 – synthesis of oxazolines via aziridines (Route B)
Aziridines 100 were made under low solubility conditions to precipitate the
triethylammonium salt to minimise chloride attack of the aziridine ring. 129 Initial
studies of the aziridine rearrangement made it clear that “excess” silica was not
sufficient for the reaction and known quantities were used. Parallel experiments
showed that phenyl aziridine 100a rearranged approximately twice as quickly as paraanisoyl
aziridine 100b, in disagreement with the observations of Lectka (section
3.1.1.b) but consistent with later results. The transformation of aziridine 100b was
also attempted in the presence of sodium iodide in acetone, 120 but no oxazoline was
detected after 10 days. This is consistent with the findings of Meyers, who postulated
that iodide only catalysed the rearrangement of electron-deficient arylaziridines. 122
Whilst HPLC analysis of the product oxazolines showed them to be optically pure,
some epimeric oxazoline was isolated (entry b) and characterised by comparison with
known sample. Further studies in the group showed that under identical conditions
syn-aziridine 180 gave a 2:1 cis:trans mixture (Scheme 3.12), 130 not dissimilar to the
observations of Aggarwal who found a similar cis-aziridine rearranged in a 3:1
trans:cis ratio, also on silica. 123 A stereoselective reaction is consistent with the
cationic mechanism proposed by Lectka (vide supra).
104

Chapter 3 – Oxazoline synthesis & removal
Ph
Ph
Ph
O
N
Ph
SiO 2 , CH 2 Cl 2
O
N
180
109a
dr 2:1
Scheme 3.12 – stereoselectivity of aziridine rearrangement
Since the reagents for the second step of the reaction were relatively inert, and
numerous methods exist to couple acids and amines, a one-pot method of oxazoline
synthesis was sought.
O
OH
R
HN
Ph
173
Ph
Carbodiimide
SiO 2 , CH 2 Cl 2
Ph
O
N
R
101
Entry R Carbodiimide time / d 173 : 100 : 101*
a H DIC 2 21 : 8 : 71
b H DIC 8 7 : 7 : 86
c H EDC.HCl 1.3 0 : 7 : 93
d 4-F DIC 2.5 1 : 37 : 62
e 4-Ph DIC 2.5 20 : 19 : 61
f 4-OMe DIC 2 60 : 0 : 40
g 4-OMe DIC 10 85 : 0 : 15
* crude 1 H NMR ratio of reaction mixture
Table 3.4 – one-pot synthesis of oxazolines via aziridines (Route B)
Whilst the initial results were promising, extensive studies by Harvey found reaction
times to be highly substrate dependent and could not be improved even with the
addition of Lewis acid. 130
The use of EDC hydrochloride seemed promising (entry c),
but upon purification the product of chloride attack on the aziridine ring was isolated,
indeed isolated yields were often poor. This method was used to synthesise allyl
oxazoline 101j, although reaction was slow, and purification of the final alkylated
product was problematic (Scheme 3.13).
Ph
105

3.1 – Oxazoline synthesis
Ph
Ph
Ph
Ph
O
OH
OH
HN
Ph
173
Ph
EDC.HCl
SiO 2 , CH 2 Cl 2
rt, 30 hr
O
N
101k
AllylBr, K 2 CO 3
DMF, NaI
OH
57%
(80% conv.)
O
N
101j
O
38%
3.1.4.c Method C: benzyl imidate
Scheme 3.13 – synthesis of O-allyl oxazoline
O NH 2
i) (Et 3 O)BF 4 (1.1 eq)
CH 2 Cl 2 , rt 16 hr
ii)
1.2 eq
R 1
R 1
O
N
R 2
R
HO
Δ
16 hr
R 2
NH 2
R
Entry R R 1 (R/S) R 2 (R/S) Yield / % Compound
a 4-OMe Ph (S) OMe (S) 72 104b
b H H i-Pr (S) 82 111a
c 4-OMe H i-Pr (S) 58 111b
d H Ph (S) Ph (R) 70 109a
e 4-OMe Ph (S) Ph (R) 66 109b
f H Ph (RS) Ph (RS) 85 ±101a
g 4-OMe Ph (RS) Ph (RS) 86 ±101b
h 3-F Ph (RS) Ph (RS) 82 ±101d
i 4-NO 2 Ph (RS) Ph (RS) 55 ±101h
j c-Hex Ph (RS) Ph (RS) 93 ±101m
Table 3.5 – synthesis of oxazolines via imidate (Route C)
Although relatively slow, the one-pot imidate method favoured by Meyers proved to
be the most reproducible and highest yielding method used. Whilst an excess of the
amino alcohol is used, the previous amide condensations used a similar excess.
Unfortunately oxazolines 101 can only be made racemically since it had not been
possible to attain optically pure amino alcohol 175; however this would be possible if
the oxazoline could be cleaved to return the optically pure amino alcohol. Recently,
106

Chapter 3 – Oxazoline synthesis & removal
both enantiomers of amino alcohol 175 have become commercially available, but is
approximately four times the price of (+)-174. 131
3.2 Oxazoline Removal
Clean and facile removal of the oxazoline moiety to a synthetically useful functional
group without loss of optical purity is essential to making the dearomatising
methodology described synthetically useful. Ideally any method developed would
allow recovery of optically pure amino alcohol 175 since this cannot be synthesised by
any other method (section 3.1.3), furthermore the ability to recycle material is often
cited as one of the benchmarks of a chiral auxiliary. Ideally two or more orthogonal
methods should be developed to aid synthetic design.
3.2.1 Literature methods for removal
Whilst oxazolines have not seen such broad use in synthetic chemistry as other
heterocycles, they are still often taught in synthetic courses as masked carboxylic acids
resistant to a range of nucleophiles and reducing agents, yet removable under strong
acid hydrolysis. Whilst such robustness may be beneficial in designing a synthesis, it
otherwise makes removing the oxazoline more challenging.
The following literature survey presents three general strategies adopted in unmasking
oxazolines. Only methods compatible with chiral aliphatic substituents are reported,
most are two-step methods, and when possible reference has been made to the relay of
optical purity.
3.2.1.a Hydrolysis
The most commonly encountered oxazolines in text books are geminal dimethyl
oxazolines 185 where high temperature acid catalysed hydrolysis in ethereal or
alcoholic solvent is suggested for removal to give the acid or ester. 6
107

3.2 – Oxazoline removal
O
N
O
OH
3N HCl (aq)
87-95%
Δ
3 examples
D
D
185
Scheme 3.14 – acid hydrolysis of gem-dimethyl oxazolines 132
Whilst this has mainly been used for removal of oxazolines from stable aromatic
systems, Meyers also used acid hydrolysis in his early asymmetric work (Scheme
3.15). 133 This method allowed the chiral amino alcohol 186 to be recovered without
loss of optical purity, in fact, the hydrolysis intermediates were isolated and
recrystallised, allowing enantiomeric ratios to be improved.
Ph
O
H
Me
N
R
R = Et, n-Pr,
n-Bu
OMe
HCl (aq)
Δ, minutes
Ph
O
H
Me
HCl (aq)
Δ
H
Me
OMe
NH 2 Cl
O
R
CO 2 H
R
i) NaHCO 3
ii) recryst.
Ph
68-79%
4:1 e.r.
3 examples
OMe
NH 2
OH 186
O
H
Me
H
Me
Scheme 3.15 – acid hydrolysis of chiral oxazoline 133
H
N
R
HO
CO 2 H
R
Ph
OMe
4N HCl
Δ 3 hr
51-59%
9:1 e.r.
3 examples
Alternatively, alkaline hydrolysis of N-alkylated oxazolines 187 can be employed to
reveal the acid (Scheme 3.16) with good retention of stereochemistry since
enantiomeric excesses were generally in proportion to the preceding diastereomeric
ratios. Mechanistically, alkylation can be thought of as replacing the first protonation
in the hydrolysis sequence, although the amino alcohol can no longer be recycled.
Ph
O
R
HO
N
Ph
OMe
MeI, DMSO
rt
Ph
O N
Me
R
HO Ph
187
OMe
KOH (2M)
Δ 8 hr
134
Scheme 3.16 – alkylation-hydrolysis
R
HO
CO 2 H
Ph
55-73%
13 examples
108

Chapter 3 – Oxazoline synthesis & removal
3.2.1.b N-Quaternisation-reduction
More recent methods have identified the lone pair of the oxazoline nitrogen as a
weakness to be exploited, with an initial quaternisation step making it more reactive to
nucleophiles. This approach is typified by the N-alkylation-reduction method
developed by Meyers which proceeds through reduction of oxazolinonium salt 188,
before hydrolysis of the oxazolidine 189 to unmask the aldehydes and N-methyl amino
alcohol. 25
O
R
N
MeOTf
NaBH 4
(CO 2 H) 2
O N
Me
O N Me
CH 2 Cl 2 MeOH/THF
THF/H 2 O
R
R
188 189
Scheme 3.17 – alkylation-reduction, general scheme
HO
O
R
NHMe
This became Meyers’ preferred method for oxazoline removal from
dihydronaphthalenes 190 and has been applied to much methodology work and a
number of syntheses appearing to be generally applicable and maintaining optical
purity through the sequence. The main draw back with this method is the use of
methyl triflate which will readily alkylate other functional groups such as ethers and
nitriles and is highly toxic. 135,136
Ph
H
O
E
N
Nu
OMe
i) MeOTf, CH 2 Cl 2
then NaBH 4
E
CHO
Nu
R
190
R
ii) H 3 O + 62-97%
>47:1 e.r.
11 examples
Scheme 3.18 – alkylation-reduction-hydrolysis of chiral oxazolines 31
When trying different proton sources for quenching dearomatising additions, Meyers
found that addition of trifluoroacetic acid also protonated the oxazoline, giving esters
194 as their TFA salts upon aqueous workup. 34 This is believed to proceed via
quaternised oxazoline 193 whose hydrolysis is enhanced by the addition of sodium
sulfate (Scheme 3.19). Oxazoline 191 was unmasked to give carbinol 192 in the
synthesis of phyltetralin using this method.
109

3.2 – Oxazoline removal
O
Me
O
N
OMe
i) TFA, H 2 O
OMe
OH
OMe
OMe
OMe
OMe
OMe
MeO
OMe
OMe
191
192
86% MeO OMe
21:4 e.r.
(+)-Phyltetralin
Ph
O NH
R
193
OMe
TFA
ii) LiAlH 4
Na 2 SO 4
H 2 O
MeO
NH 3
O O
Ph
R
194
TFA
Scheme 3.19 – reduction of TFA salt in synthesis 31
Since this technique is generally applied immediately after quenching the
dearomatising addition, the stereochemical fidelity of the process is uncertain,
although Meyers states that no loss in optical purity is observed. Unfortunately the
chemistry of TFA esters such as 194 is not discussed since they are normally reduced
without isolation.
3.2.1.c Reduction
Meyers also demonstrated that reduction of unfunctionalised oxazolines to secondary
amines is possible using DIBAlH. 137 Whilst the reduction works well, cleavage of the
resulting amine is problematic, requiring silylation, chlorination, oxidation and
hydrolysis to give the aldehyde. Silylation is necessary to prevent Grob-type
fragmentation of the N-chloride.
i) TBDMSCl
ii) NCS
Ar
O
N
Ph
OMe
DIBAlH
4 eq, rt
Ar
HN
OMe
OH
Ph
195
70-100%
14 examples
OMe
OMe
H
Al
Ph 2 O
SiO 2
3 Ph
Ar N Ar N
Cl
OTBDMS
OTBDMS
ArCHO
70-75%
4 examples
Scheme 3.20 – direct reduction of oxazoline followed by amine cleavage 137
110

Chapter 3 – Oxazoline synthesis & removal
A similar transformation had previously been developed by Pridgen using diborane
with non-aromatic substituents, giving amines 196. 138 However, unlike the Meyers
reduction the substituents were simple hydrocarbons, and diborane will react with
unsaturated groups.
Ph
O
R
N
B 2 H 6 , THF
Δ
R
H
N
196
Ph
OH
56-94%
3 examples (aliphatic)
Scheme 3.21 – borane reduction of oxazoline 138
In the same publication, Pridgen reports the catalytic hydrogenolysis of the benzylic
carbon-oxygen bond of oxazoline 197 to give secondary amide 198. This method is of
particular interest since both carbon-heteroatom bonds in the diphenyl oxazoline are
benzylic.
O
N
Ph
Pd/C, H 2 (50 psi)
O
N
H
Ph
EtOH/HCl
OMe
OMe
OMe
OMe
197 198
98%
Scheme 3.22 – hydrogenolysis of oxazoline C–O bond 138
3.2.2 General strategy
The methods presented above generally involve two synthetic steps in good overall
yield, but only a few permit the recovery of the amino alcohol. The most promising
route appears to be the one-pot TFA-LiAlH 4 procedure which has been shown to
proceed in good yield and does not appear to affect optical purity. Likewise, acid
hydrolysis permits recovery of the amino alcohol, but has not been employed on many
non-aromatic or chiral substrates. From its extensive use by Meyers, the method most
likely to work is the two-pot alkylation-reduction-hydrolysis procedure which unmasks
the oxazoline as an aldehyde, accompanied by the N-methyl amino alcohol.
111

3.2 – Oxazoline removal
However, the diphenyl oxazoline lends itself to hydrogenolysis since both C–X bonds
are benzylic, although the literature precedent for this reaction contained only the more
labile C–O benzylic bond. Whilst it would not return the amino alcohol, the main
advantage of this method is that it would involve a single reagent with very well
understood reactivity with other functional groups.
3.2.2.a Model compounds
Ph
Ph
Ph
Ph
O
N
O
N
101m
O
201
Scheme 3.23 – model oxazolines
Whilst we are interested in cleaving 2-alkyloxazolines all oxazolines studied so far,
and most of those found in the literature, are 2-aryloxazolines. 2-Cyclohexyloxazoline
101m and enone 201 will be used to study the removal of the oxazoline moiety. The
former is a simple system which can be quickly synthesised, whilst the latter contains a
challenging quaternary centre and functionality that will be encountered in a future
synthesis. Enone 201 can readily be synthesised from diene 102b (Table 3.6).
112

Chapter 3 – Oxazoline synthesis & removal
Ph
Ph
Ph
Ph
O
N
O
N
conditions
OMe
102b
O
201
Entry Conditions Time Yield of 201 (SM) / %
a 1M HCl (aq) / CH 2 Cl 2 workup

3.2 – Oxazoline removal
3.2.3 Reduction of oxazolines
3.2.3.a Catalytic hydrogenolysis
O NH 2
Ph Ph
O N
c-Hex
101m
H 2 , Cat.
HO N
c-Hex Ph
202
Ph
H 2 , cat.
±H
O
c-Hex
203
H
N
H 2 , cat.
Ph
c-Hex
Ph
204
Scheme 3.24 – hydrogenolysis of oxazolines
Whilst the hydrogenolysis of an oxazoline containing a benzylic C–O bond is known
(section 3.2.1.c), diphenyl oxazoline 101m also contains the much stronger C–N bond.
It was unclear how labile this aza-allylic bond would be, but amine N-benzyl bonds are
often resistant to hydrogenolysis, whilst those of amides such as 204 are notoriously
resistant. 117
114

Chapter 3 – Oxazoline synthesis & removal
Ph
O
N
c-Hex
Ph
H 2 / cat.
O
H
N
c-Hex
Ph
Ph
c-Hex
101m 204
205
Entry Catalyst H 2 pressure / T Solvent 204:205*
a Pd/C 50 bar / 50 ºC MeOH 100:0
b Pd/C 50 bar / 50 ºC MeOH:AcOH (9:1) 100:0
c Pd/C 50 bar / 30 ºC EtOAc 100:0
d Ru/Al 2 O 3 50 bar / rt MeOH 100:0
e RaNi 50 bar / rt MeOH 100:0
f Pd(OH) 2 /C 50 bar / 50 ºC MeOH:AcOH (9:1) 98:2
g
H-Cube
Pd(OH) 2 /C 80 bar / 50 ºC AcOH 94:6
h Pd(OH) 2 /C 80 bar / rt AcOH 66:22
i Pd(OH) 2 /C 70 bar / rt EtOAc 85:15
j Pd(OH) 2 /C 80 bar / rt TFA, MeOH/H 2 O 80:20
k
Bomb **
Pd(OH) 2 /C 70 bar / rt TFA, MeOH (pre-stir) 80:20
* Crude 1H NMR ratio ** overnight reactions, c. 14 hr
Table 3.7 – hydrogenation of oxazoline
Unfortunately none of the desired primary amide 203 was formed, only secondary
amides 204 and 205. Aprotic solvent was used in an attempt to minimise tautomerism
of 202 hoping that the aza-allylic intermediate might hydrogenolyse (entries c, i),
however this is unlikely to have worked since the palladium contains up to 50% water.
Bound water is also thought to be responsible for the formation of hydroxyamide 205
(entries f-k), whose stereochemistry is assigned by comparison with a known sample
(vide infra). TFA was added (entries j, k) in an attempt to form the trifluoroacetate salt
of either the oxazoline or ester, again without success.
+
O
H
N
Ph
OH
Ph
115

3.2 – Oxazoline removal
Ph
O
N
Ph
Ph
H
N
O
H 2 , Pd/C
Ph
R
R'
20 bar
Et 3 N
201: R = C=O, R'=H 2 , 96% 206
102b: R = OMe, R'=H, 60% 206
102a: R = R' = H, no isolabe prod
Scheme 3.25 – hydrogenation of unsaturated oxazolines
Similar results were found when dearomatised compounds were hydrogenated
(Scheme 3.25). Enol ether 102b and the related enone 201 both gave ketoester 206,
presumably due to the acidity of the palladium catalyst, despite the presence of a mild
base. This acidity might explain the complete degradation of diene 102a, which
proved sensitive to most conditions it was treated with (vide infra).
R
R'
The outcome of the above reactions is less surprising in light of the outcome of
hydrogenation of oxazoline 207 in the synthesis of (+)-L-733,060, an NK-1 receptor
antagonist (Scheme 3.26). 139 Whilst little comment is made, synthesis of piperidinone
209 from oxazoline 207 appears to require hydrogenation of the benzylic C–O bond
indicated, hydrolysis by residual water and finally cyclisation. This would indicate
that the aza-allylic C–N bond is extremely stable. Alternatively, amino alcohol 208
could form by hydrolysis, possibly expedited by hydrogenolysis of a benzylated
intermediate.
MeO
O
Ph
H 2 /Ph(OH) 2
70 psi
OH
Ph
F 3 C
CF 3
MeO
O
O
HO
Ph
207
Ph
N
Ph
NH
MeOH/AcOH
NH
10:1, rt 3 d
O 76%
209
O
MeO
H 3 O +
Ph
H 2 /Pd(OH) 2
HO NH 3
208
139
Scheme 3.26 – hydrogenation of a 2-phenyloxazoline
O
NH
Ph
(+)-L-733,060
116

Chapter 3 – Oxazoline synthesis & removal
Since neither the aza-allylic nor amide N-benzyl bonds were apparently susceptible to
hydrogenolysis, it was hoped that this bond in the corresponding secondary amine
would be. This could be made by reduction of the amide or by treating oxazolines
directly with DIBAlH (section 3.2.1.c).
3.2.3.b DIBAlH reduction
Ph
O
N
Ph
DIBAlH
solvent,
0 °C
H
N
Ph
OH
Ph
101m 210 205
O
H
N
Ph
OH
Ph
solvent 210/% 205/%
THF (wet) 40 20
THF 60 20
Toluene 80 10
Table 3.8 – DIBAlH reduction of oxazolines
Whilst the procedure 137 did not specify whether wet or dry solvent should be used the
reduction worked well on test substrate 101m using dry THF. The structure of amine
210 was confirmed by synthesis from benzaldehyde and amino alcohol 175.
Catalyst bar / ° C solvent
Pd/C 80 / 50
AcOH in MeOH
(10% to 100%)
Pd(OH) 2 /C 70 / rt AcOH
H
N
Ph
OH
Ph
H 2
Conditions
nr
Pd(OH) 2 /C 70 / rt TFA/MeOH
210
Table 3.9 – hydrogenolysis of secondary amine 210
The benzylic C–N bond of amine 210 was resistant to hydrogenolysis under a similar
range of conditions as the parent compound. Whilst hydrogenation was only
conducted under acid conditions, it is not thought this jeopardised the reaction since
similar N-debenzylations have been conducted in TFA-MeOH. 140 Recently Li has
shown that an equimolar mixture of Pd and Pd(OH) 2 catalysts on carbon can be more
active than either individual catalyst, 141 but this, nor transfer hydrogenation are thought
likely to prove more productive than the methods already attempted.
117

3.2 – Oxazoline removal
3.2.3.c Amide hydrolysis
Amides 204 and 205 were stable to acid and alkaline hydrolysis. Following the
protocol of Clayden, 142 the hydrolysis of N-nitroso amides was attempted, but both
nitrosation and hydrolysis proceeded slowly and in poor yield. McClure had
previously hydrolysed secondary amides by conversion to the imidate and subsequent
acid hydrolysis, but unfortunately it was found that the imidate could only be formed
from aromatic amides. 143
3.2.4 Oxazoline hydrolysis
Ph Ph
NH 3 Cl
Ph
HCl
O N
Ph O O Ph
Reflux
NH 2
Ph
OH
c-Hex
c-Hex
101m 211.HCl
175
Entry Conditions Time 211 / % 175 / %
a 6N HCl:THF, 3:1 2 min 91 0
b 3N HCl:THF, 2:1 2 min 85 0
c 6N HCl:EtOH, 3:1 1 hr 50 40
d 6N HCl:EtOH, 3:1 16 hr 0 70
Table 3.10 – hydrolysis of 2-cyclohexyloxazoline
Hydrolysis of cyclohexane 101m was found to proceed in a similar manner to that
described by Meyers (section 3.2.1.a). Gentle heating quickly gave ester 211.HCl as
the crystalline ammonium salt which could be isolated by simple filtration. Continued
heating allowed amine 175 to be recovered after aqueous work up, although
cyclohexanecarboxylic acid was not isolated. In light of this possible isolation
problem methods for reducing the ester were studied (Scheme 3.27).
118

Chapter 3 – Oxazoline synthesis & removal
Ph
NH 3 Cl
Ph
O
211.HCl
c-Hex
O
Pd/C, H 2
1 atm, 1 hr
LiBH 4 ,
THF, 0 °C
O
c-Hex
O
OH
H
N
HO
c-Hex Ph
205
H 2 N
Ph
quant
Ph
212
Ph
50%
Scheme 3.27 – reduction of ester 211
Cyclohexanecarboxylic acid was easily recovered from the hydrogenation, which did
not require workup, whilst reduction with ethereal lithium borohydride returned mostly
amide 205, rather than the desired alcohol. Disappointingly precipitation could not be
induced with arene 101b, and amide 211, the thermodynamic product, was isolated in
near quantitative yield (Scheme 3.28).
Ph
O
N
Ar
101b
Ph
HCl (aq), EtOH
Δ 12 hr
O
Ar
H
N
211
Ph
OH
Ph
96%
Scheme 3.28 – hydrolysis of aryl oxazolines
Ar =
MeO
Hydrolysis of diol 213 and enone 201 both precipitated the ester as the major product,
although enone 201 gave equal amounts of the ester and an unidentified oil. The IR
spectrum of this oil contained only one strong absorption at 1672 cm -1 , likely to be the
enone, and NMR analysis showed no significant aromatic or isopropyl peaks. Whilst
attempting the epoxide opening of 216, ester 217 was isolated in good yield, but was
not reacted further (Scheme 3.29).
119

3.2 – Oxazoline removal
Ph
Ph
Ph
Ph
O
N
O OR O N
O OR
OH
213
OH
HCl (aq), THF
Δ, 12 hr
OH
214
OH
80%
6N HCl:THF 2:1
Δ, < 18hr
O
O
201 215
45%
R =
Ph
NH 3 Cl
O
Ph
Ph
O
N
Ph
HClO 4 (aq), dioxane
O
OR
O
rt, 28 hr
O
OH
OH
OH
216 217
OH
40% (55% conv)
Scheme 3.29 – hydrolysis of oxazolines to esters
Since the amide would be expected to be the thermodynamic product of these
reactions, and it was isolated in the absence of a precipitate, it is believed that the
precipitate serves to move the hydrolysis equilibrium in favour of the ester. In light of
this, other ammonium salts were tried; exposure and gentle heading of cyclohexane
101m with solutions of HBF 4 , HCl/Et 2 O, H 2 SO 4 and TsOH did not promote any
visible precipitation.
The alkylation-hydrolysis of enone 201 was attempted in a similar fashion to Meyers
(section 3.2.1.a). The resulting ester is closely related to the ammonium salt 211, and
was isolated in slightly improved yield with some starting material recovered.
Ph
Ph
Ph
O
N
MeOTf, 16 hr
then NH 4 Cl (aq)
24 hr, rt
MeHN
Ph
O
O
O
201
O
218
60%
(90% conv.)
Scheme 3.30 – alkylation-hydrolysis of oxazoline 201
120

Chapter 3 – Oxazoline synthesis & removal
3.2.5 Quaternisation-reduction
3.2.5.a Trifluoroacetate salt
Ph Ph
O N
c-Hex
101m
OH
NH 3 TFA LiAlH 4
c-Hex
TFA, THF O O
Ph
then H 2 O, Na 2 SO 4
c-Hex Ph
H
O OH
3 O +
211.TFA
or H 2 /Pd
c-Hex
Scheme 3.31 – possible manipulations of ester-TFA salt
This method seemed particularly appealing, since it had been used a number of times
by Meyers, and hydrolysis of ester 211.TFA would allow recovery the amino alcohol
to be recycled. Cabedo had applied this method to diene 102a, however the reaction
proved unreliable and yields were inconsistent, although in retrospect this may be
attributed to the observed acid sensitivity of alcohol 220. The poor yield of Mosher
ester 221 means that the modest diastereomeric ratio could reflect kinetic resolution of
the alcohol as much as any loss in optical purity during the dearomatisation and
cleavage.
Ph
O
N
Ph
i) TFA,
H 2 O, THF
ii) LiAlH 4
HO
102a 220
F 3 C
(R)-MTPA-Cl Ph
MeO O
Pyr./DMAP
30-50%
CH 2 Cl 2
221
Scheme 3.32 – reduction of diene 102a by Cabedo 64
O
Me
62%
d.r. 95:5
Unfortunately, numerous attempts to reproduce the oxazoline cleavage with model
oxazoline 101m failed; the only identifiable material by crude NMR being amide 205.
This method was not applied to any other compounds since it was anticipated that TFA
would not be compatible with the intended syntheses.
Ph
O
N
c-Hex
101m
Ph
TFA, THF
H 2 O, Na 2 SO 4
O
H
N
c-Hex Ph
205
OH
Ph
60%
(90% conv.)
Scheme 3.33 – TFA hydrolysis of 2-cyclohexyloxazoline
121

3.2 – Oxazoline removal
3.2.5.b N-Alkylation
Meyers’ preferred method of oxazoline removal was alkylation-reduction followed by
hydrolysis of the oxazolidine to reveal the aldehyde (section 3.2.1.b). Early attempts
to reproduce this on two model compounds failed work after repeated attempts.
Ph Ph
O
N
i) MeOTf, 10 hr
then NaBH 4
ii) (CO 2 H) 2 , rt, 36 hr
THF/H 2 O
poor mass recovery,
no isolable product
102a
Ph Ph
O N
c-Hex
101m
i) MeOTf, 5 hr
then NaBH 4
ii) (CO 2 H) 2 , rt, 16 hr
THF/H 2 O
poor mass recovery,
no isolable product
Scheme 3.34 – failed alkylation-reduction-hydrolysis reactions
However, enone 201 underwent a smooth alkylation-reduction sequence to give
oxazolidine 222 as a single observable diastereomer isolated by flash column
chromatography. The relative stereochemistry of 222 was established by forward
reaction (section 4.4.2).
Ph Ph
Ph Ph
O
N
O
N
O
H
MeOTf, 16 hr
Conditions, rt
then NaBH 4
O
201
OH
222
70%
>95:5 d.r
OH
223
>95:5 d.r
Entry Conditions Time conversion / %
a THF/H 2 O, (CO 2 H) 2 40 hr 70
b THF/H 2 O, (CO 2 H) 2 3 d 100
c SiO 2 , CH 2 Cl 2 10 d 50
d THF/pH 9 buffer 24 hr 0
Table 3.11 – hydrolysis of 2-cyclohexyloxazoline
122

Chapter 3 – Oxazoline synthesis & removal
Hydrolysis of oxazolidine 222 was considerably slower than Meyers’ oxazolines,
which are reported hydrolyse in 15 to 20 hours. Comparative hydrolysis of recovered
oxazolidine and a crude mixture confirmed that the slow reaction rate was not due to
thermodynamic resolution of the possible diastereomers. Treatment of enol ether 102b
proceeded in a similar manner, although significant amounts of hydrolysis was
observed during the alkylation, and the ratio was the same whether bench or dry
methanol were used. Interestingly the hydrolysis of the mixed oxazolidines took
considerably longer than of 222 alone (vide infra).
Ph
O
N
Ph
MeOTf
15 hr
then NaBH 4
Ph
O
Ph
NMe
+
Ph
O
Ph
NMe
i) (CO 2 H) 2 , rt 10 d
THF/H 2 O
ii) NaBH 4 , MeOH
HO
OMe
102b
O
224
OH
222
OH
225
55%
Crude ratio
224 : 222
3 : 2
Scheme 3.35 – alkylation-hydrolysis of enol ether 102b
Alkylation of the oxazoline is reported by Meyers to proceed within 1-4 hours by TLC
analysis, however in these studies complete conversion of starting material to baseline
salts was never observed and reaction times are often longer than necessary. Later
experiments indicate that alkylation was complete within 2-3 hours. Whilst the
neopentyl aldehydes were stable to chromatography and for weeks under atmospheric
conditions, they were unstable to purification by acid resin (SCX) with rapid
decomposition observed. The oxazolidines were largely stable to chromatography,
although it was observed that purification of this intermediate reduced the overall yield
of auxiliary removal.
During the synthesis of carbasugars (section 4.2.7), oxazolidine 226 was also found to
hydrolyse very slowly (Table 3.12).
123

3.2 – Oxazoline removal
Ph
Ph
O
N
H
O
BnO
Conditions
BnO
BnO
OBn
OBn
BnO
OBn
OBn
226
Time / d
(total d)
[Oxalic Acid] [Substrate] Temperature
Remaining
oxazolidine* / %
6 (6) 0.5 0.05 rt 88
2 (8) 0.0001 0.05 rt 87
3 (11) 0.5 0.1 rt 80
2 (13) 0.5 0.1 50 °C 67
* calculated from ratio of SM:aldehyde signal in 1 H NMR
Table 3.12 – acid-catalysed hydrolysis of the oxazolidine
Bundgaard and co-workers have conducted comprehensive studies of the hydrolysis of
oxazolidines, finding that whilst hydrolysis occurs in the pH range 2-9, it is fastest
under neutral or slightly alkaline conditions, and also shows a strong dependence on
buffer concentration. 144,145 Buffer solutions of acetate (pH 8) and borate (pH 9), as
well as a silica/THF/water slurry were used with no observable improvement, similar
results were found in the hydrolysis of 222 (Table 3.11). Addition of chloral as a
‘sacrificial’ aldehyde to the original acid conditions gave no rate enhancement.
As expected, study of reaction progress at elevated temperatures (Table 3.13) shows a
significant increase in the rate of hydrolysis, reaching an acceptable speed at around 60
°C, with a half life estimated as 2 days. The reaction was repeated at this temperature
and deemed complete within 7 days in 85% yield, with no significant decomposition of
the aldehyde noted (Table 3.13).
124

Chapter 3 – Oxazoline synthesis & removal
Ph
Ph
BnO
O
N
(CO 2 H) 2 ,
THF/water 4:1
BnO
H
O
BnO
T / Days of rxn
°C (total)
OBn
OBn
226
Remaining
226 * /%
40 7 (7) 82
50 10 (17) 39
60 4.5 (21) 10
60 7 (28.5) 0
* ratio SM:aldehyde in 1 H NMR
T °C
100
80
60
40
20
0
%
BnO
OBn
OBn
40 °C 50 °C 60 °C
0 5 10 15 20 25
Total days of reaction
Table 3.13 – effect of temperature on hydrolysis of oxazolidine
Two significant discrepancies have arisen; firstly, that oxazolidine 222 hydrolysed
significantly faster (3 d) than oxazolidines 224 and 226 (>10 d), and secondly that all
three hydrolyse considerably slower than the reports of either Meyers (c. 20 hr) or
Bundgaard (c. 12 hr 146 ). The solution to the first quandary was found during the
synthesis of carbasugars (section 4.2.9). Neighbouring group participation by the cishydroxyl
group catalyses the reaction through intramolecular attack of Schiff base
228 147 to form cyclic ether 229, which quickly hydrolyses to diol 225.
Ph Ph
Ph
HO
OH
HO
O N
Ph
N Ph Ph
N i-Pr
O
OH
222
pK a ≈ 6.0 144
OH
228
229
OH
225
Scheme 3.36 – neighbouring group participation in the hydrolysis of oxazolidines
The second situation is not as clear. Bundgaard studied both the role of the carbonyl 144
(Scheme 3.37) and amino alcohol 145 portion of the oxazolidine and identified some
clear trends in the rate of hydrolysis.
125

3.2 – Oxazoline removal
Ph
Me
Ph
Me
Ph
Me
O
N
O
N
O
N
230
t ½ (pH 7.4)
0.08
0.3
30
min
t ½ (pH 1.0)
96
70
-
min
144
Scheme 3.37 – half-lives of some oxazolidines at 37 °C
This work clearly shows that a β-quaternary centre on the aldehyde clearly retards
hydrolysis, but the half lives reported are still shorter than those observed for alcohol
222 let alone benzyl ether 226. When looking at the role of amino alcohol substitution,
Bundgaard also found that substitution α to nitrogen led to significant retardation, with
geminal methyl groups causing a 50 times increase in half life than a simple
methylene. However, whilst they did not compare a phenyl group with a methyl
group, it is unlikely to be responsible for such a difference. In addition, recent
calculations by Walker based upon this research shows that cis substituted
oxazolidines hydrolyse more rapidly than their trans epimer, but do not quantify
this. 148
Whilst these combined effects might explain why the diphenyl oxazolidine with an
adjacent quaternary centre hydrolyses much more slowly than many apparently similar
oxazolidines, it does not explain the difference with the similarly substituted Meyers
oxazolidine. Furthermore, the reaction does not seem to share the same pH
dependence as Bungaard reported, meaning that it is possible that a change in
mechanism has occurred. Two pathways for hydrolysis are considered (Scheme 3.38).
126

Chapter 3 – Oxazoline synthesis & removal
Ph
O
Ph
NH
Ph
Ph
O
N
H
+H 2 O
Ph
Ph
HO
N
H
OH
- H +
Ph
Ph
NH
OH
O
+ H + - H+
pKa 6 144
231
pKa −2
Ph
Ph
Ph
O
N
Ph
O
N
H 2
OH
230
232
pKa 10
+ H +
Ph
HO
pKa −2
N
Ph
HO
Ph
N
Ph
+ H 2 O
HO
HO
Ph
NH
Ph
- H +
Ph
Ph
NH
OH
O
233
Scheme 3.38 – hydrolysis of oxazolidine, pKa values are approximate in water
The research of Bundgaard and Fife both identify the appearance and disappearance of
iminium ion 233 during hydrolysis. This is initially surprising since this intermediate
must come from protonation of an ether in the presence of an amine. However, this
occurs on both hydrolytic pathways, and formation of iminium ion 233 is considerably
more favourable than oxonium 231. These equilibria seem to favour the use of acid
conditions, and it remains unclear why hydrolysis should be favoured under neutral
conditions in the studies of Bundgaard.
127

3.2 – Oxazoline removal
3.2.6 Determination of optical purity
Ph
Ph
O
N
i) MeOTf, 18 hr
then NaBH 4
HO
p-BrBzCl
DMAP
O-pBrBz
O
201
ii) Oxalic acid, 3 d rt
iii) NaBH 4
OH
225
94%
> 95:5 dr
Et 3 N, CH 2 Cl 2
O-pBrBz
62%
115
> 99:1 e.r.
Scheme 3.39 – determination of optical purity
The alkylation-reduction-hydrolysis method was applied to enone 201 and the
resulting diol benzoylated to allow HPLC analysis, showing bisbenzoate 115 to be
essentially optically pure. The para-bromobenzoate was chosen since it x-ray
crystallography would allow confirmation of the absolute stereochemistry, however
bisbenzoate 115 could not be crystallised.
128

Chapter 3 – Oxazoline synthesis & removal
3.3 Summary and Future work
Although far from complete, the work presented has permitted the study of
dearomatising additions and the removal of the source chirality to a synthetically
useful functional group without the loss of optical purity. The synthesis of optically
pure oxazoline has been achieved by three methods, whilst a number of promising
results have bee obtained towards its removal.
3.3.1 Moving closer to an auxiliary
3.3.1.a Oxazoline synthesis
Optically pure amino alcohol is readily available as either enantiomer from transstilbene
(Scheme 3.10) or commercial sources. 149 Subsequent amide coupling
followed by cyclisation returns the optically pure oxazoline in 40-70% (Table 3.2).
Alternatively, racemic oxazolines can be synthesised in three steps from the benzamide
and cis-stilbene in 72% overall yield (Table 3.5).
3.3.1.b Oxazoline removal
The current best method for oxazoline removal is the alkylation-reduction-hydrolysis
procedure of Meyers which has returned up to 94% of the aldehyde. Even though it
failed on two substrates, is has been shown to work for a number of oxazolines and
more examples are presented in the following syntheses. The weakness of this method
is the slow oxazolidine hydrolysis, and although literature examples suggest that a
more rapid hydrolysis should be achievable, initial studies have failed to find any.
Presently the best compromise has been to increase the temperature of the reaction
since the resulting neopentylic aldehydes have proved quite stable. Fortunately, in the
majority of cases unprotected alcohols have been available to aid oxazolidine
hydrolysis.
In its current form, this method of removal is inadequate since it either requires a week
long reaction to a stable aldehyde, or places significant constraint on synthetic
planning. One immediate solution might be the hydrolysis of the N-methylated
oxazoline to the ester or acid, rather than reduction to the recalcitrant oxazolidine.
129

Better, however, would be a method involving a reversible association with the
oxazoline allowing the amino alcohol to be recovered.
3.3.1.c Recycling the amino alcohol
Whilst attempts to promote hydrolysis via the oxazoline trifluorosulfonate salt failed, it
is important to note that the two oxazolines treated also did not respond to the methyl
triflate conditions. Since this method would allow the recovery of the amino alcohol,
and would be orthogonal to the current best method, it seems worthy of further
experimentation.
The examples of aqueous acid hydrolysis of oxazolines gave the ester in moderate to
good yield when successful, and it seems likely that extended acid hydrolysis would
give the free acid. However this may not be generally applicable method, since
precipitation of the ammonium salt seems to be key, possibly explaining why Meyers
did not use it with any of his dearomatising additions.
In the next chapter (section 4.5.1) some promising studies of the Lewis acid catalysed
hydrolysis of oxazolines are presented. Whilst this work only studied removal by
lactonisation, it is possible that this might be a more general method than Brønsted
acid hydrolysis.
130

Chapter 4 – Synthesis of carbasugars
Chapter 4 – The Synthesis of Carbasugars
4.1 Carbasugars
4.1.1 What they are and what they do
Carbasugars are sugar analogues in which the endocyclic oxygen is replaced with a
carbon atom, normally a methylene group. Saccharides, in the form of cellulose, are
the most abundant organic compounds on the planet and are responsible for not only
structure and energy storage, but also cell-cell recognition, blood clotting and
intracellular signalling. As such, they play a significant biological role, and can
feature in diseases such as cancer, inflammation and diabetes.
HO
OH
HO
OH
HO
OH
OH
250a
5a-carba-α-DL-talopyranose
HO
OH
OH
250b
5a-carba-α-DL-galactopyranose
Scheme 4.1 – the first carbasugars, synthesised by McCasland
Carbohydrates and their mimics have been studied for a number of years; the first
carbasugars (±250a, b) were synthesised by McCasland in 1966 150 and 1968 151
respectively. McCasland postulated that the resemblance of carbasugars to the natural
compounds might afford similar biological recognition, whilst the absence of the labile
anomeric bonds would render them more stable. Indeed, studies have shown that
humans cannot distinguish the taste of D-glucose from racemic carba-β-DLglucopyranose;
furthermore carba-α-DL-glucopyranose is an effective inhibitor of
glucokinase in pancreatic islets, seemingly by competitive inhibition. 152 Seven years
after McCasland’s first synthesis, naturally occurring carbagalatopyranose +250b was
discovered in the fermentation broth of an actinomycete bacteria. 153 McCasland had
chosen to synthesise carbagalatopyranose by chance as it was accessible by
epimerisation of 250a, providing a rare example of synthesis preceding discovery. No
naturally occuring carbasugars have been found since.
131

4.1 – Introduction
HO
OH
OH
HO
OH
OH
O
Cyclophellitol
OH
OH
O
251
1,6-epi-Cyclophellitol
Scheme 4.2 – some natural cyclitols
There are very few natural cyclitols with the carbapyranose motif; cyclophellitol
(Scheme 4.2) has structural similarities to carbasugars and was isolated in 1990 from
the culture filtration of the mushroom Phellinus sp. 154 It is considered to be an
analogue of β-D-glucose since the epoxide is on the β-face, and has a much more
potent biological profile that the simple carbasugars; it strongly inhibits β-
glucosidases, and is a potential inhibitor of HIV. Interestingly, the unnatural
diastereomer 251 with the epoxide on the α-face is an α-glucosidase inhibitor, which
are important in the treatment of type II diabetes.
OH
HO
HO
HO
HO
HO
OH
NH 2
HO
HN HO
O
OH
O HO
OH
O
OH
OH
O HO
OH OH
O
Valienamine Acarbose
Scheme 4.3 – some natural aminocarbasugars
Aminocarbasugars such as valienamine are more abundant in nature and are found to
exhibit greater biological activity. This is assumed to be due to the basicity of the
amine, and valienamine is a common motif in many biologically active
carbaoligosaccharides such as acarbose, and has been the topic of a recent review. 155
Due to its similarity to α-glucose, many of valienamine’s derivatives are potent α-
glucosidase inhibitors, believed to be so effective because of a resemblance to the
glucopyranosyl cation intermediate in the hydrolysis of α-glucosides. Acarbose was
approved in 1995 as an α-glucosidase inhibitor for use in the treatment of type II
diabetes.
132

Chapter 4 – Synthesis of carbasugars
Superficially, the substitution of an endocyclic oxygen with a methylene should make
little difference to the structure; the conformations of cyclohexane and oxane are
similar despite the C–O bonds being almost 10% shorter. However, sugar chemistry is
dominated by the anomeric n O →σ* C–O interactions, which afford significant
stabilisation of the α-anomer in which the glycosidic bond is axial. The absence of this
interaction in carbasugars means they can adopt conformations that the parent
carbasugar cannot.
4.1.2 Existing syntheses
All 16 racemic carbasugars, and 25 of the possible 32 carbasugar stereoisomers have
been synthesised, as well as a number of analogues. 156 Many approaches have been
taken, the major difference being whether starting from chiral pool materials –
normally a carbohydrate – or from simpler molecules; both methods have been
recently recent reviewed by Gomez and Lopez. 156 This section will discuss syntheses
of historical interest, and also some of general synthetic note and relevance to the use
of compounds made in previous chapters.
4.1.2.a Chiral pool methods
Often the first decision to be made when planning an asymmetric synthesis is where
the source of chirality is to come from. When making analogues of sugars,
carbohydrates themselves are the most widely used starting point since they are fully
oxygenated, optically pure and readily available. There are, however two challenges
involved in the conversion of sugars to carbasugars; the elongation of the carbon chain,
and the cyclisation of the homologue. Quinic acid (Scheme 4.4) is probably the most
widely used chiral pool material after monosaccharides, although the products often
contain the quaternary centre of the starting material. A great number of quinic acid
derivatives have been made, and have been used as starting materials themselves.
HO
CO 2 H
CO 2 H
HO
OH
OH
HO
OMe
OH
HO
OH
OH
HO
OH
OH
HO
OH
OH
HO
OH
OH
(−)-Quinic acid (−)-Shikimic acid
myo-Inositol
L-Quebrachitol
Scheme 4.4 – chiral pool starting materials used in carbasugar synthesis
133

4.1 – Introduction
(–)-Shikimic acid is a very appealing starting material, however with its use in the
commercial synthesis of Tamiflu (oseltamivir phosphate) it is in high demand,
exasperating the paucity of supply and making it unaffordable for most synthetic
purposes. However this might slowly be relieved since a number of microbial
biosynthesis of (–)-shikimic acid have from E. coli mutants been published, most
recently by Johansson using mutants derived from the successful W3110 strain, under
phosphate-limited conditions. 157 Indeed in 2005 Roche confirmed that they already get
a third of the shikimic acid they use for synthesis of Tamiflu from fermentation. 158
Inositols seem to be well suited to the synthesis of cyclitols, however seven of the nine
known inositols contain a mirror plane, including the most abundant myo-inositol
(Scheme 4.4). L-Quebrachitol is a chiral inositol which is reported to have been used
in carbasugars synthesis, but at 2000 times the cost of myo-inositol, 159 is far too
expensive for common usage. Furthermore, the fully saturated system does not
provide a clear synthetic handle as, shikimic acid does.
4.1.2.b Non-chiral pool methods
McCasland’s approach to the first synthesis of a carbasugar proceeded through an
oxanorbornene (252); an approach that has been adopted in many subsequent
syntheses. McCasland synthesised ketone 254 (Scheme 4.5) by the forcing hydrolysis
of bicycle 253, causing ester migration, decarboxylation, and ether hydrolysis in a
single reaction. 150 Reduction, esterification and further reduction yielded the racemic
carba-talopyranose 250a. Peracylation of 250a followed by reflux in strong acid led to
partial epimerisation, giving peracylated carbagalatopyranose (250b) in 14% yield. 151
O
OAc
O
O
O
Δ
O
O
O
i) H 3 O + HO
HO
O
ii) OsO 4
AcO O
AcO
252 253
O
OH
OH
O
H 3 O +
Δ
HO 2 C
MeO 2 C
HO
HO
HO
254
O
OAc
i) NaBH 4
ii) MeOH, TFA
iii) Ac 2 O
AcO
AcO
OAc
OAc
i) LiAlH 4
ii) H 3 O +
HO
OH
HO OH
250a
Scheme 4.5 – McCasland’s synthesis of α-DL-talose analogue 150
134

Chapter 4 – Synthesis of carbasugars
Norbornenes have featured as key intermediates in the synthesis of many carbasugars
in the laboratories of Ogawa; an early example of which is shown in the divergent
synthesis of carbasugars 250b, 257, and 260. 160 Norbornene 255 was made by
cycloaddition, oxidation of which gave lactone 256 and subsequent reduction,
acylation and hydrolysis gave an equimolar mixture of diastereomers 257 and 250b.
O
a
O
b
HO
O
O
256
O
c
HO
HO
HO
257
OH
OH
+
HO
HO
OH
HO OH
250b
HO 2 C
CO 2 H
255
d
Br
O
O
O
e
AcO
AcO
AcO
Br
OAc
f
HO
HO
HO
OH
OH
258
259
d.r. 12:5 260 d.r. 3:1
Major diastereomers drawn. a) hydroquinone, Δ, 45%; b) H 2 O 2 , formic acid, 45%; c) i)
LiAlH 4 , ii) Ac 2 O, pyr., DMAP, iii) Ac 2 O, AcOH H 2 SO 4 , iv) NaOMe, MeOH: 257 (18%), 250b
(19%). d) HOBr, 91%; e) i) LiAlH 4 , ii) AcOH, Ac 2 O, H 2 SO 4 , 46%; f) i) NaOAc, ii) NaOMe,
MeOH, 41%.
160
Scheme 4.6 – Ogawa’s divergent syntheses of carbasugars
Alternatively, treatment of 255 with hydrobromous acid gave bromolactone 258,
which upon reduction and hydrolysis yielded a similar mixture of diastereomers of
bromosugar 259. Acetolysis of the major diastereomer gave a 3:1 mixture of 260 and
250b, whilst acetolysis of the minor diastereomer of 259 yielded further carbasugars.
Using similar methods, Ogawa and colleagues have synthesised many carbasugars and
aminocarbasugar analogues, often simultaneously.
A number of methods offering higher degrees of stereocontrol have come from
unsaturated carbocyclic starting material; the traditional way to access such materials
is by the dissolving metal reduction of benzene derivatives (section 1.2). Landais and
co-workers developed a selective reduction of benzylsilanes to give the meso diene
261 (Scheme 4.7) which was desymmetrised using the Sharpless AD conditions with
good diastereo- and enantioselectivity. Benzylation and a highly selective
cyclopropanation gave bicycle 262, ready for fragmentation. Electrophile-driven
fragmentation of the cyclopropane gave the homoallylic iodide, which was lithiated to
give the Fleming silane 263. Highly anti-selective dihydroxylation of the allylic ether
135

4.1 – Introduction
followed by Fleming-Tamao oxidation gave the β-L-altrose analogue 264 in 16% from
261.
SiMe 2 t-Bu
i) AD mix α
ii) NaH, BnBr
SiMe 2 t-Bu
OBn
OBn
ZnEt 2 , CH 2 I 2
rt
SiMe 2 t-Bu
OBn
OBn
261 76%
262 88%
71% ee
>99:1 dr
OAc
i) NIS, MeCN
rt, 12 hr
OBn
i) OsO 4 , NMO, rt AcO OBn
ii) t-BuLi, PhMe 2 SiCl
−100 °C
OBn ii) Hg(OAc) 2 , CH 3 CO 3 H
OBn
iii) Ac 2 O, pyr, rt
SiMe 2 Ph
OAc
263 66% 264 79%
>99:1 dr
Scheme 4.7 – Landais’ synthesis of altrose analogue 161
Using another desymmetrised diene, Landais reported a complementary synthesis
starting from the Tamao silane 265, which was oxidised and alkylated to give ether
266, ready for [2,3]-Wittig rearrangement. Rearrangement occurred in modest yield
and with high facial selectivity to give allylic ether 267, which again underwent highly
selective anti-dihydroxylation, giving α-D-galactopyranose analogue 268 in 20%
overall yield.
SiMe 2 OMe
O
H 2 O 2 , KF
OH
O
Bu 3 Sn
KH, Bu 3 SnCH 2 I
O
O
265
O
KHCO 3
60 °C, 12 hr
O
O
75%
>99:1 dr 266 82%
n-BuLi
−60 °C 12 hr
OH
267
O
O
51%
i) Ac 2 O, pyr rt
ii) OsO 4 , NMO, rt
HO
OH
OAc
268
O
O
92%
>99:1 dr
Scheme 4.8 – Landais’ synthesis of galactose analogue 161
An alternative method for accessing unsaturated carbocycles is the enzymatic
oxidation of benzene by Pseudomonas putida mutants, first used by Ley and coworkers
in the syntheses of racemic cyclitols. 162 The formation of a meso diol
restricted its utility, but Pseudomonas putida mutants were developed that could
oxidise substituted benzenes, yielding desymmetrised, enantiomerically pure diols
136

Chapter 4 – Synthesis of carbasugars
(270). Numerous research groups have taken advantage of these to access optically
pure cyclitols, one succinct if unselective example by Carless and Malik is shown in
Scheme 4.9. 163
Microbial oxidation of toluene gives optically pure diene 270, which
was protected and dihydroxylated, before the remaining olefin was reduced with good
facial selectivity to give acetonide 271. Hydrolysis gave dehydro α-L-fucose analogue
272 in 14% yield from toluene.
Me
Me
Me
i) Me 2 C(OMe) 2 ,
Pseudomonas putida
OH TFA
ii) OsO 4 , NMO HO
OH
270
OH
Me
Me
H 2 , 20 psi
O AcOH, H 2 O
OH
PtO 2 HO O
100 °C
HO OH
OH
271
70%
6:1
Scheme 4.9 – synthesis of an α-L-fucose analogue by enzymatic dearomatisation 163
OH
272
96%
O
O
66%
2:3
4.1.3 Synthetic outlook
In the recent review by Gomez and Lopez. 156 104 carbapyranose syntheses were
discussed noting the yield, number of steps, type of molecule made and the starting
material; of the 78 optically enriched syntheses only 13 had overall yields above 30%,
interestingly this dropped for the racemic syntheses, of which only one of the 26 had
an overall yield greater than 30%. The yields for the racemic syntheses are
presumably lower for two reasons; most of the racemic syntheses came from less
elaborated starting materials and most research has been focused on enantiomerically
pure sugar analogues.
Since the starting oxazolines can be readily made racemically, a carbasugars synthesis
which used only substrate-controlled selectivity would be equally amenable to racemic
and enantiopure synthesis. Furthermore, the authors of the report took overall yields
from relatively late intermediates such as silane 265 (Scheme 4.8), and it is that a
synthesis of better overall yield can be achieved.
137

4.2 – Carbasugar synthesis
4.2 Synthesis of a Carbasugar Analogue
Ph
O
N
OMe
102b
Ph
HO
HO
OH
OH
OH
275
Stereochemistry:
Relative set by anti-addition
Absolute set by chosen auxilliary
(sugar shown is L )
Scheme 4.10 – a family of possible analogues
The intention of this synthesis is to achieve the complete stereoselective oxygenation
of an adduct produced by the methods outlined in the previous chapters. The most
suitable aromatic derivatives are the anisoles since these are already partially
oxygenated and dearomatisation gives enol ethers. Whilst enol ethers are versatile in
their own right, they readily yield ketones, opening up a plethora of chemistry,
furthermore, adduct 102b can be hydrolysed to an enone (section 3.2), a motif which
has often been used in making cyclitols. In light of this, and that the yields for addition
are slightly higher, the 4-methoxy oxazoline derivative 102b will be used in the initial
synthetic work. Since 275 contains densely packed hydrophilic and hydrophobic
portions its biological activity might be of interest. Furthermore a synthesis including
the isopropyl group might be seen as a guide for future work whilst we learn about the
behaviour of the pendent oxazolinyl group.
Since this synthesis is intended to exemplify the synthetic utility of the oxazoline
chemistry, it is hoped that this substituent may prove useful in two ways; by enhancing
stereoselectivity by hindering one face of the carbocycle, and providing a useful
chromophore for reaction monitoring and purification.
4.2.1 Synthetic strategy
We are afforded the luxury of planning a forward synthesis based upon chemistry we
are most confident will work since all diastereoisomers of 275 are possible synthetic
targets. This is outlined below, with a brief rational of reagents suitable for substratebased
stereoselectivity, much of which is based around the axial position of the
138

Chapter 4 – Synthesis of carbasugars
oxazoline motif, predicted by A-values, and confirmed by vicinal coupling constants
(vide infra).
In this chapter, the oxazoline moiety previously developed will be abbreviated Ox*:
Ph
Ox* = O
N
Ph
Ox*
Ox*
Ox*
[O]
H -
OMe
O
102b 276
OH
anti to
Ox*& i-Pr
OH
213
OH
axial hydride
delivery
213
i) Protect
HO
ii) OsO 4
HO
anti "Kishi"
dihydroxylation
Ox*
OR
277
OR
HO
HO
OH
OH
OH
278
HO
HO
OH
OH
H
O
α-L-altrose
OH
213
[O]
O
H-bonded
syn epoxidation
Ox*
OH
216
OH
Nu
trans-diaxial
opening
Nu
HO
OH
OH
OH
279
OH
H
HO
O
HO OH
OH
α-L-mannose
Scheme 4.11 – proposed divergent synthesis of carbasugars
Regioselective oxidation of diene 102b would give α-hydroxy ketone 276 upon
workup, with facial selectivity guided by the equatorial isopropyl and axial oxazoline.
Axial 1,2-reduction of the resulting enone would furnish allylic alcohol 213, which is
intended as the point of variation in this synthesis. Dihydroxylation of allylic alcohols
normally shows good anti-stereoselectivity, reinforced by the axial oxazoline, giving
the stereocentres of the unnatural sugar α-L-altrose. Alternatively, hydrogen bonddirected
epoxidation of the allylic alcohol, followed by hydrolysis would give the
139

4.2 – Carbasugar synthesis
stereocentres of α-L-mannose. Enone 276 would also allow further functionalisation
of the carbocycle through the vast chemistry associated with this functional group. It
is anticipated that pentaols 275 will be polar and highly water soluble, and that their
synthesis will require a careful protecting group strategy.
Since two key steps in the planned syntheses rely on the steric bulk of the axial
oxazoline, it was deemed necessary to gauge how strong an influence it could have on
the stereochemistry of the adjacent ring.
4.2.2 Influence axial oxazoline on reactivity
The axial oxazoline is key to the stereoselectivity proposed in the above synthesis.
Whilst an axial conformation has been confirmed by vicinal coupling constants, it
remains to be seen if this will affect its reactivity and how rigid the system is.
4.2.2.a Model study
It was felt that dihydroxylation of enone 201 would provide a good indication of the
facial selectivity that could be expected in the synthesis. This olefin was ideally suited
as the oxazoline is the predominant encumbering group, whilst the dihydroxylation
reaction was chosen since the formation of the bulky osmate ester 282 164 would be
very sensitive to the surrounding environment, and is a key reaction in the proposed
synthesis.
Ox*
Ox*
Ox*
HO
HO
OsO 4 (1%), NMO.H 2 O
O
CH 2 Cl 2 , 8 d
HO
O
HO
55% O 2%
201
axial
280 281
Ox*
O O
Os
O O
O
282
Scheme 4.12 – facial selectivity imparted by the axial oxazoline
The dihydroxylation of the enone under modified Upjohn conditions 165 proceeded
slowly, giving good diastereomeric ratio of 27:1, and relative stereochemistry was
140

Chapter 4 – Synthesis of carbasugars
assigned by nOe (vide infra). This result is consistent with the results of Figueredo et
al. in the diversity-orientated synthesis of gabosines (Scheme 4.13). 166 With matched
bulky groups they observed only one diastereomer, but found that inversion of the α’
centre reversed the stereochemical preference for the reaction. In light of this it is
likely that the presence of the isopropyl group is also important.
OTBS
OTBS
HO
OsO 4 (cat.), NMO
O
SPh
acetone/H 2 O
HO
O
SPh
70%
OTBS
O
SPh
OsO 4 (cat.), NMO
acetone/H 2 O
HO
HO
OTBS
O
SPh
62%
dr: 2.8 : 1
166
Scheme 4.13 – matched and mismatched steric encumbrance
A more rapid dihydroxylation of the electron deficient olefin might have been possible
under other conditions, but optimisation of this reaction was not deemed necessary
since it would not significantly affect the stereochemical outcome.
4.2.2.b nOe studies of oxazoline 280
Scheme 4.14 –nOe interactions superposed on structure of 280 (MM2-minimised)
The relative stereochemistry of diol 280 was assigned by nOe experiments showing
that the axial H3 proton (shown) interacts with H5. These experiments revealed very
strong interactions between the individual methyl groups and the protons on either face
141

4.2 – Carbasugar synthesis
of the oxazoline as depicted, with none to the other face; showing that the cyclic
system is very rigid in solution. The oxazoline group remained axial throughout the
synthesis (identified by J H2–H3 ), presumably since the cumulative equatorial preference
of the isopropyl and methyl groups (c. 3.5 kcal mol -1 ) was greater than the oxazoline
(methyl ester c. 1.5 kcal mol -1 ). The crystal structure of a later product is consistent
with the energy minimised structure presented (Scheme 4.17). With this result in hand
we were confident that the proposed synthesis would proceed with high levels of
substrate control.
4.2.3 Oxidation of the dienyl ether
The regioselective oxidation of conjugated silyl enol ethers was developed by
Rubottom to give α-hydroxy enones. 167 This was achieved by using the electrophilic
oxidant mCPBA which oxidises the electron rich olefin more rapidly and has since
been applied to enol ethers. 168 Unfortunately, when diene 102b was subjected to
modified Rubottom conditions, enone 276 was isolated in very low quantities with
many unidentified by-products, including significant amounts of enone 201.
Ox*
Ox*
T n 276 /%
OMe
102b
mCPBA (n eq)
CH 2 Cl 2 , T °C
O
276
OH
20 3.0 7
– 40 1.2 3
– 78 1.2 n.r.
Table 4.1 – attempted Rubottom oxidation of the dienyl ether
In a similar manner to Rubottom, McCormick used osmium tetroxide to oxidise
unconjugated silyl enol ethers to α-hydroxy ketones. 169 Since dihydroxylation is a
pericyclic process 170 involving the HOMO of the olefin, the more electron rich alkene
will again react first. Enol ether 102b was subject to the conditions of Upjohn 171
(entries a-d, Table 4.2) and Poli 172 (entries e, f).
142

Chapter 4 – Synthesis of carbasugars
Ox*
Ox*
i) OsO 4 , NMO, solvent
ii) reducing agent (aq)
OMe
O
102b 276
OH
Ox*
OH
O
283
Entry Solvent Reductant (pH) Workup ratio 276 : 283 * 276 / %
a t-BuOH / H 2 O Na 2 SO 3 (8) Aq 86 : 14 47
b t-BuOH / H 2 O Na 2 S 2 O 5 (4) Aq 95 : 5 68
c Acetone / H 2 O Na 2 S 2 O 5 (4) Aq 87 : 13 50
d t-BuOH / H 2 O Na 2 S 2 O 5 (4) SiO 2
‡
e CH 2 Cl 2 / H 2 O Na 2 S 2 O 5 (4) SiO 2
‡
f CH 2 Cl 2 Na 2 S 2 O 5 (4) SiO 2
‡
97 : 3 93
73 : 5 ** –
78 : 22 73
* determined by 1 H NMR of crude material; ** + 22% 201 ‡ passed thorough silica plug
Table 4.2 – dihydroxylation of the dienyl ether
The oxidation was completely regioselective giving α-hydroxyenone 276 in high yield,
although surprisingly accompanied by dienone 283. The presence of greater amounts
of the dienone under moderately alkaline quench for a short period of time (c. 1 hr,
entry a) implies that enone 276 is highly base sensitive. This was confirmed during
the attempted benzylation of enone 276 under the conditions employed by Lockwood
in the modification of carotenoids which returned dienone 283 (Scheme 4.15). 173
Ox*
O
276
OH
pKa in DMSO
i) LiHMDS (1.2 eq)
CH 2 Cl 2 , -20 °C
ii) BnBr (1.3 eq)
O
OMe
Ox*
O
283
Ph
O
OH
24.6 174 22.9 174
50%
80% conv
OMe
HO
Ox*
O
O H
284
30.3 175
Scheme 4.15 – autoxidation of 276
Under the strongly basic conditions, it is unclear whether this oxidation of 276
occurred during the reaction – solvents were not degassed – or upon workup.
However, a small excess of base returning a relatively high yield of dienone lends
143

4.2 – Carbasugar synthesis
support to the formation of diene 284 – (Scheme 4.15) via a single deprotonation. Even
though this seems unlikely as the secondary alcohol might be expected to be both
kinetically and thermodynamically more acidic, it is consistent with the pKas of related
compounds in DMSO, and with the observation of the dienone in relatively neutral
condition (Table 4.2). Anion 284 – would receive additional stabilisation from
delocalisation of its charge; consistent with the strong hydrogen bonding seen in the IR
and 1 H NMR spectra of 276.
The formation of dienone 283 in the oxidation of the enol ether even under weakly
acidic conditions (entry b, Table 4.2), makes the absence of the diastereomeric epi-276
conspicuous; raising the possibility that the dienone formed under these conditions
comes from oxidation of the opposite face (285, Scheme 4.16). Further oxidation
might then take place under the reaction conditions or upon workup; below are the
equilibria present in the reaction, again intermediate 284 would be susceptible to
further oxidation.
Ox*
Ox*
[O]
Ox*
−H +
Ox*
+H +
OH
284
OH
O
283
OH
MeO
OH
OH
285
H
O
OH
−H +
Ox*
OH
O
epi-276
Scheme 4.16 – proposed in-situ oxidation of epi-276
Oxidation of olefins to α-diketones is known to occur under Upjohn conditions 176
although hemiacetal 285 – the product of disfavoured syn oxidation – would not be
amenable to further oxidation. Rapid hydrolysis of 285 would give epi-276, which is
not isolated, but might be even more sensitive to base than 276 (vide supra) and
readily tautomerise to diene 284, which might oxidise to the dienone under the reaction
conditions.
144

Chapter 4 – Synthesis of carbasugars
4.2.4 Enone reduction
Reduction of enone 276 with a small nucleophile is expected to proceed from the axial
face to give equatorial alcohol 213. The 1,2-reduction of cyclic enones is normally
achieved with high degrees of regioselectivity 177 and stereoselectivity 178 by the use of
Luche conditions, which employ stoichiometric cerium trichloride and sodium
borohydride. However, the stereoselective reduction has also been achieved using 9-
BBN, 179 DIBAlH 180 and sodium borohydride without any additive. 181
In the Luche reduction, it is postulated 178 that the lanthanide additive promotes direct
1,2-addition to the unsaturated system by promoting the rapid methanolysis of the
borohydride to generate what are termed mixed methoxyborohydrides. The
regioselectivity is in turn attributed to the hard nature of these species, rather than any
complexation of the carbonyl by the lanthanide.
Whilst this is not supported by experiments with trimethoxyborohydride – which
shows identical regioselectivity to borohydride and improves with addition of
lanthanide – it is consistent with a number of other observations. Firstly,
regioselectivity increases with dilution in methanol and ethanol. Secondly, when
exploring possible catalysis, it was observed that just 25 mol% of cerium returns
regioselectivities above 95:5, and although not commented on, this would strongly
support the role of cerium as catalysing the first methanolysis, rather than as
complexing the enone.
The nature of the reducing species still remains unclear however as
alkoxyborohydrides are prone to further disproportionation, 182 which cerium
trichloride may also catalyse. It is of interest that Luche’s investigations were almost
exclusively conducted in alcoholic solvents due to poor solubility of cerium
trichloride, however, unoptimised studies of Sm and Eu salts in THF were also
promising. 178 Whilst it is clear is that under the Luche conditions cerium coordination
to the enone plays no role, this may not be true for other solvent systems.
The application of these conditions is shown below (Table 4.3, entries a-c), alongside
reduction in the absence of cerium trichloride.
145

4.2 – Carbasugar synthesis
Ox*
Ox*
Ox*
NaBH 4
O
OH
T °C
OH
OH
OH
OH
quant.
276 213
287
Entry T Conditions Reaction time 213 : 287
a rt + CeCl 3 .7H 2 O 10 min 8 : 1
b 0 + CeCl 3 .7H 2 O 20 min 10 : 1
c –60 + CeCl 3 .7H 2 O 60 min 5 : 1
d 0 – 30 min 10 : 1
e 0 – 6 hr > 20 : 1
Table 4.3 – borohydride reduction of the hydroxyenone
The stereoselectivity of the reductions do not correlate with either reagent or
temperature, but instead correlate strongly with the time of the reaction. Whilst this
was initially puzzling, it was found that enone 276 does not visualise well under either
UV irradiation or permanganate stain, but only under the molybdenate-based PMA
stain. When reactions were monitored using PMA stain, it was found that the reaction
was considerably slower than previously believed. Since sodium borohydride only
decomposes slowly in aqueous ammonium chloride, 183 which had been used to quench
the reactions, it is believed that unreacted borohydride species were responsible for the
loss of diastereoselectivity upon warming in entries a-d. When appropriate, future
reductions were quenched with acetic acid.
Under the mildly basic Luche conditions (entries a-c) it was found that the enone was
prone to oxidation to small amounts of dienone 283 (Scheme 4.15). This could be
countered by conducting the reaction at lower pH, which has been shown have little
effect on the regioselectivity. 178
The structure of 213 was confirmed by x-ray
diffraction.
146

Chapter 4 – Synthesis of carbasugars
Scheme 4.17 – crystal structure of allylic alcohol 213
Diol 213 is highly crystalline but inseparable from the syn-diol 287 by flash column
chromatography. Whilst the majority could be isolated by recrystallisation, it could
also be separated by the formation of the acetonide of the syn-diol, and subsequent
chromatography.
DIBAlH has also been used to effect the stereoselective 1,2-reduction of similar
enones. 180 Unfortunately only 1,4-reduction was observed (288), with mainly starting
material isolated from the reaction.
Ox*
Ox*
DIBAlH, CH 2 Cl 2
OH
-78 °C
O
O
276 288
OH
15%
40% conv
Scheme 4.18 – DIBAlH reduction
4.2.5 Protecting group strategy
It was anticipated that as the number of polar groups increased in the synthesis
isolation and purification would become more difficult and protecting groups would be
needed to mask some of the free alcohols. The protecting group would have to
withstand strongly alkylating, moderately reducing and moderately acidic reaction
conditions; it also should be removed without the need for aqueous workup. In light of
these requirements, the benzyl ether protecting group is ideally suited, and there is
significant precedent its use in sugar chemistry.
147

4.2 – Carbasugar synthesis
Ox*
Ox*
NaH (4 eq), BnBr (5 eq)
OH
213
OH
Bu 4 NI (cat), DMF
OBn
289
OBn
72%
Scheme 4.19 – benzylation
The benzylation conditions were adapted from those of Provelenghiou 184
using
catalytic tetrabutylammonium iodide, generating benzyl iodide in situ, to assist
functionalisation of the secondary alcohols. Dimethylformamide was chosen as
solvent as it promotes the nucleophilicity of anionic species through solubilisation of
the counter ion. 185
This yield was sufficient to continue the synthesis, however it
might be improved by benzylation with benzyltrichloroacetimidate, developed by
Bundle for use in sugar chemistry. 186
4.2.6 Oxidation of the allylic alcohol
Allylic alcohol 213 is the point of divergence in this synthesis since two
complementary stereoselective oxidations exist.
4.2.6.a Epoxidation
In 1957 Henbest demonstrated that stereoselective epoxidation of allylic alcohols may
be effected through association with the alcohol with an organic peracid. 187 A number
of other stereoselective methods exist for the epoxidation of allylic alcohols, the most
noteworthy being the seminal work by Sharpless and Katsuki; 188 an entirely reagentcontrolled
method using (+) or (–) diethyl tartrate as the source of chirality.
Whilst the original studies of Henbest were performed using peracids, these are not
always the best reagents. An insightful study into the selectivity of such oxidations
was recently authored by Adam 168 comparing both regio and chemo selectivity of
different reagents with acyclic allylic alcohols, and making mechanistic inferences
from the results. He divided oxidants into two broad groups; hydrogen bonding
reagents (such as peracids) and metal-alcoholate binding reagents (typified by the
vanadyl acetyl acetoacetonate, VO(acac) 2 system). Prior studies found these reagents
to differ in their optimal reaction geometry, specifically the angle, α, between the
148

Chapter 4 – Synthesis of carbasugars
plane of the olefin and the allylic C–O bond. Hydrogen-bonding reagents generally
proceed through a transition state with α ~120° whilst metal-alcoholate reagents prefer
α ~ 40°.
Adam applied this analysis to cyclohexenols, concluding that since α for equatorial
cyclohexenols is approximately 140°, hydrogen bonding reagents are more suited to
their epoxidation. This is somewhat borne out when such reagents are considered in a
rigid system such as allylic alcohols 290 (Table 4.4).
t-Bu
290a
pseudoaxial OH
OH
H
α
t-Bu
H
α
OH
α = +110° α = +140°
290b
pseudoequatorial OH
Me
R
Ox*
213
OH OH
α = +134°
syn : anti ratio
Entry oxidant solvent axial 290a equatorial 290b
a 168 mCPBA CH 2 Cl 2 90:10 98:2
b 189 CF 3 CO 3 H CH 2 Cl 2 99:1 99:1
c 168 DMDO CCl 4 58:42 82:18
d 168 DMDO acetone 30:70 60:40
Table 4.4 – epoxidation of allylic alcohols 290 by different reagents
However it should be noted that epoxidation of cyclohexen-3-ol (α = 110° or 140°)
with VO(acac) 2 proceeds with 98:2 syn-selectivity 190 despite the apparent unoptimal α-
values. This casts some doubt upon the validity of Adam’s argument, but with many
examples demonstrating their use, peracids are clearly the reagents of choice since they
are cheap, readily available and easily handled.
The crystal structure of 213 shows the allylic C6–C5=C4–O torsional angle to be 134°;
well-suited to the conditions suggested by Adam. To direct the mCPBA to the synface
the free alcohol 213 would be used for the epoxidation. The slightly more polar
epoxide is not expected to present any isolation problems since it has the same number
of hydrogen bonding sites as the diol which showed no hydrophilicity.
149

4.2 – Carbasugar synthesis
Ox*
Ox*
mCPBA, CH 2 Cl 2
O
OH 0 °C
OH
OH
213 216
OH
quant.
Scheme 4.20 – epoxidation of allylic alcohol
Pleasingly, complete facial selectivity was observed without the need for optimisation;
the epoxide is isolated cleanly from the reductive workup without the need for further
purification. In keeping with the protecting group strategy, epoxide 216 was
benzylated.
Ox*
Ox*
Ox*
O
OH
216
OH
NaH (2.4 eq), BnBr
Bu 4 NI (cat), DMF
O
OBn
291
O
OH
OBn
68%
OBn
10%
292
NaH, BnBr, Bu 4 NI
DMF
35% (55% conv)
Scheme 4.21 – benzylation
When using a slight excess of sodium hydride, monobenzyl ether 291 – identified by
1 H- 1 H correlation spectroscopy – was isolated with moderate selectivity. With no clear
use for this alcohol it was re-subjected to the reaction conditions, returning mainly the
desired dibenzyl ether 292, with some mono-benzylated starting material recovered.
4.2.6.b Dihydroxylation of the allylic alcohol
The anti-selectivity in the osmylation of cyclic and acyclic allylic alcohols was
discovered in the laboratories of Kishi 191 and has been borne out by the research of a
number of other groups. 192 The Kishi model to rationalise the stereochemical outcome
assumes a transition state resembling the ground state of the alkene which is governed
by allylic (1,3) strain.
150

Chapter 4 – Synthesis of carbasugars
OsO 4
L
R 2 O
R 1
H
R c
R t
Kishi model:
ground state-like transition state
governed by A(1,3) strain
Scheme 4.22 – Kishi model for dihydroxylation of allylic alcohols
It was later found by Evans 193 that for 1,1-disubstituted olefins (R t = R c = H), that
decreasing the size of R 2 or increasing L enhanced facial selectivity, despite reducing
the conformational preference for the ground state. These observations lent support to
reacting conformer models of Houk and Vedejs. 192 Interestingly, these models all
assume a single [3+2] cycloaddition to form the osmate ester, even though this was not
shown until computational and kinetic studies were performed almost 10 years later. 170
Subsequent computational modelling by Houk 164 showed that whilst for 1,2-cissubstituted
alkenes the dominant factor in the transition state conformation was in fact
A(1,3) strain, in all other cases, the transition state was determined primarily by the
inside alkoxy effect, with a further contribution to minimise σ* C-O -π interactions which
withdraw electron density from the nucleophilic olefin.
E +
OsO 4
(Outside) (Inside)
H OR 2
R 1
L (Anti)
H
L
R 1 R t
H
OR 2
Houk model:
transition state determined by
inside alkoxy effect
Scheme 4.23 – Houk model for dihydroxylation of allylic alcohols
Although many studies have investigated the origin of the asymmetry of
dihydroxylation in acyclic systems, little attention has been given to cyclic systems. 194
The stereochemical outcome of the reaction is attributed to a minimisation of the
dipole in the transition state, consistent with the increased diastereoselectivity observed
for oxidation of pseudo-axial allylic alcohol 295 by Donohoe (Scheme 4.24).
151

4.2 – Carbasugar synthesis
OsO 4 (cat.), NMO
OH
OH
t-Bu OH
OH equatorial
acetone/H 2 O
OsO 4 (cat.), NMO
t-Bu
OH
OH
91%
85:15 dr
OH
t-Bu
OH
OH axial
295
acetone/H 2 O
t-Bu
OH
90%
94:6 dr
Scheme 4.24 – dihydroxylation of axial and equatorial alcohols 195
Kishi showed that etherification does not affect facial selectivity significantly, whilst
esterification does, shown particularly well by Arjona et al. (Scheme 4.25). 196
OR 1
OR 2
OR 1
OR 2
OR 1
OR 2
OsO 4 (cat.), Me 3 NO
acetone/H 2 O
OH
OH
296 297
OH
OH
R1 R2 296 : 297
TBS Me 50:50
TBS Bz 80:20
Bn Bz 76:24
196
Scheme 4.25 – effect of etherification vs esterification on dihydroxyation
This shows that dihydroxylation of the olefin may employ either the free diol or the
benzyl ether. In our synthesis, if the free diol is used, the resulting tetraol would at
best be very polar, and at worst be amphiphilic, causing problems with isolation by
normal methods. As such, benzyl ether 289 was subject to a range of standard
dihydroxylation conditions.
Ox*
OBn
289
OBn
OsO 4 , NMO
solvent
HO
HO
Ox*
OBn
300
OBn
Solvent Yield / %
t-BuOH / H 2 O n.r.
acetone / H 2 O n.r.
CH 2 Cl 2 96
Scheme 4.26 – dihydroxylation of allyl ether
Under the conditions of Poli 172 only the expected anti-diol was observed, although
once again the reaction was slow, taking six days to complete. The relative
stereochemistry was assigned by vicinal coupling constants, and later confirmed by
crystal structure. The failure of the standard Upjohn conditions is surprising, although
152

Chapter 4 – Synthesis of carbasugars
during the course of the reactions black deposits were observed at the neck of the
reaction vessel. This is presumed to be osmium dioxide, indicating a lack of available
re-oxidant, even though two equivalents of NMO were used, and the oxidant is stable
under the conditions.
Benzylation of the resulting diol gave a mixture of mono- and dibenzylation products.
Tribenzyl ether 301 was isolated as a single compound and characterised by COSY
NMR, implying that benzylation first occurs at the more encumbered neopentylic
alcohol. This alcohol was re-subjected to the reaction conditions to give perbenzyl
ether 302 in good yield, ready for onward reaction.
Ox*
Ox*
Ox*
HO
BnO
NaH (2.4 eq), BnBr
BnO
HO
OBn
300
OBn
Bu 4 NI (cat), DMF
HO
OBn BnO OBn
OBn
54 %
OBn
33%
301 302
NaH, BnBr, Bu 4 NI
DMF
70%
Scheme 4.27 – benzylation of diol
4.2.7 Synthesis of an altrose analogue
Oxazoline 302 has all the stereocentres of α-L-altrose (Scheme 4.11). Employing the
alkylation-reduction-hydrolysis-reduction procedure (section 3.2), would reveal the
primary alcohol, and debenzylation would yield the desired carbasugar analogue.
302
MeOTf
then NaBH 4
BnO
BnO
Ph
O
Ph
NMe
i) (CO 2 H) 2 , THF/water
7 d, 60 °C
ii) NaBH 4 , MeOH
OBn
OBn
70%
225
Scheme 4.28 – removal of oxazoline auxiliary
The alkylation-reduction step proceeded well; however as previously discussed the
hydrolysis was much slower than for other related oxazolidines, which had typically
BnO
BnO
OH
OBn
304
OBn
85%
153

4.2 – Carbasugar synthesis
taken one to three days at ambient temperature. In the next section, this is shown to be
due to neighbouring group participation of a cis hydroxyl group at the 4 position.
OH
OH
OH
BnO
Pd(OH) 2
HO
HO
H
O
BnO
OBn
304
OBn
85%
H 2 , 20 bar
HO
OH
278
OH
quant.
HO OH
OH
α-L-Altrose
Scheme 4.29 – final step in synthesis of α-L-altrose analogue
Pleasingly, hydrogenolysis using Pearlman’s catalyst 197 proceeded cleanly without the
need for purification, and the relative stereochemistry was confirmed by crystal
structure.
water molecule
Scheme 4.30 – crystal structure confirming relative stereochemistry of 278
Somewhat surprisingly, pentaol 278 was apolar enough to be purified on normal phase
silica, eluting with just ethyl acetate (R f ~0.1). This was unexpected and led to the
review of the protecting group strategy (vide infra).
154

Chapter 4 – Synthesis of carbasugars
Ox*
Ox*
Ox*
Ox*
a
b
c,d
OMe
101b
OMe
102b
Ox*
O
276
OH
OH
OBn
289
OBn
e,f
BnO
g
BnO
BnO
OBn
OBn
BnO
OBn
OBn
302
304
OH
h
HO
HO
OH
278
OH
α-L-altrose
analogue
18.8% overall yield in
10 steps from arene 101b
a) i-PrLi, THF, DMPU, 20 min, –78 °C, then MeI, 70%; b) OsO 4 , NMO, t-BuOH then Na 2 S 2 O 5 ,
93%; c) NaBH 4 , MeOH, 0 °C, 6 hr, 98%; d) BnBr, NaH, Bu 4 NI, DMF, 72%; e) OsO 4 , NMO,
CH 2 Cl 2 , 96%; f) BnBr, NaH, Bu 4 NI, DMF, 71%; g) MeOTf, CH 2 Cl 2 , then NaBH 4 , 0 °C,
MeOH/THF, 70%; ii) (CO 2 H) 2 , THF/H 2 O, 50 °C 24 hr, iii) NaBH 4 , MeOH, 85% (2 steps); h)
Pd(OH) 2 , H 2 (20 bar), quant.
Scheme 4.31 – first synthesis of the α-L-altrose analogue
4.2.8 Synthesis of an epoxycarbasugar
The successful synthesis of the altrose analogue 278 indicated that protecting groups
may not be necessary, as such oxazoline removal was attempted with diol 216 without
benzylation.
O
Ph
O
OH
N
Ph
OH
MeOTf
t hr
then NaBH 4
Ph
O
OH
216 306
O
H
H
Ph
NMe
OH
O
O
O
307
OH
t 306 / % 307 / %
16 40 30
4 79

4.2 – Carbasugar synthesis
As well as the expected oxazolidine, an almost equivalent amount of lactone 307 was
seen when the alkylation reaction was left overnight before reduction. This
unexpected product is clearly produced by base catalysed hydrolysis of the ammonium
salt 308 before reduction (Scheme 4.33) and is only possible due to the 1,4-cis
relationship between the oxazoline and the free alcohol. The bicyclic structure of 307
is corroborated by a 1 Hz 4 J H4-H6 “W-coupling”.
Ph
Ph
O
O
N
OH
216
OH
Ph
O
Ph
OH
H N O
O
OH
308
Scheme 4.33 – lactonisation of oxazoline 216
O
O
O
307
OH
The increase of lactone 307 with time shows that hydrolysis occurs under the
alkylation conditions rather than the mildly basic reduction. The hydrolysis is likely
catalysed by trace water which would facilitate proton transfers and is basic enough to
deprotonate the final protonated lactone. Hydrolysis of oxazolidine 306 proceeded
smoothly returning epoxycabasugar 309 in excellent yield over three steps. The rate of
reaction was consistent with the hydrolysis of earlier oxazolidines with the cis-1,4
pattern discussed.
O
Ph
O
N
OH
216
Ph
OH
MeOTf, 2 hr
then NaBH 4
O
Ph
H
H
O
OH
306
Ph
NMe
OH
i) (CO 2 H) 2 , THF/water
17 hr, 50 °C
ii) NaBH 4 , MeOH
O
HO
OH
OH 83%
3 steps
309
Scheme 4.34 – oxazolidine hydrolysis facilitated by 1,4-cis-hydroxyl group
156

Chapter 4 – Synthesis of carbasugars
4.2.9 The 1,4 transannular relationship for oxazolidine hydrolysis
Whilst lactonisation of the quaternised oxazoline showed that the 1,4-cis-transannular
interaction was possible, material was already in hand which could show that
neighbouring group participation was indeed important. Alkylation of the monobenzylated
oxazoline 291 proceeded, on small scale, to give oxazolidine 299 in
comparable yield to previous reactions. Hydrolysis of this oxazolidine was determined
by 1 H NMR to be approximately 10% complete after 24 hours at 50 °C. This decrease
in rate by an order of magnitude is consistent with the observations in the previous
section, showing that when available, neighbouring group participation is the dominant
mechanism for oxazolidine hydrolysis.
Ph
Ph
Ph
Ph
O
O
N
OBn
OH
MeOTf, 18 hr
then NaBH 4
O
H
H
O
OBn
291 299
NMe
OH
75%
(CO 2 H) 2 , THF/water
24 hr, 50 °C
Scheme 4.35 – oxazolidine hydrolysis without cis-hydroxyl
c. 10%
hydrolysed
4.3 Revised Synthetic Strategy
The above section described the successful application of the dearomatising chemistry
to the synthesis of an analogue of altrose. In the process, it raised a number of areas of
synthetic importance which might expedite a revised synthesis. It is clear that a
hydroxyl group is necessary to facilitate oxazolidine hydrolysis, which would normally
have a profound impact on a protecting group strategy; however the functional
simplicity and surprising hydrophobicity mean no such strategy is necessary.
Whilst the lactonisation of the cis-hydroxyoxazoline should not have been so
surprising, it opens new synthetic possibilities for oxazoline removal and controlling
stereochemistry around the carbocycle. This will be explored in the synthesis of a
mannose analogue in section 4.5.
157

4.4 – Revised altrose synthesis
4.4 The Protecting Group-Free Synthesis of an Altrose Analogue
The revised synthetic strategy of the altrose analogue (Scheme 4.36) will build upon
the key steps of the previous synthesis but remove the protecting group steps. It is also
anticipated that a step can be saved in routes B and C by simultaneous 1,2-reduction of
the enone and the quaternised oxazoline.
Ox*
Ox*
i) H - HO
A
OH ii) [O]
HO OH
O
OH
276
309
Ph
Ph
Ph
Ph
O
N
O
N
B
OH
310
OH
[O]
HO
HO
OH
311
OH
HO
HO
[O]
HO
C
OH
312
OH
HO
OH
278
OH
Scheme 4.36 – proposed protecting group-free syntheses of altrose analogue
158

Chapter 4 – Synthesis of carbasugars
4.4.1 Route A
Route A is the same as the first synthesis but excludes the two protecting groups steps.
Intermediate 213 had been previously synthesised in 64% in three steps from the
anisole derivative.
Entry Conditions
Ox*
OH
213
OH
OsO 4 , conditions
no
reaction
a CH 2 Cl 2, NMO.H 2 O nr
b t-BuOH/H 2 O, NMO nr
c
quinuclidine,
K 3 Fe(CN) 6 , K 2 CO 3
nr
Table 4.5 – dihydroxylation of allylic alcohol (route A)
Surprisingly, no reaction was seen for this dihydroxylation under a range of conditions.
No reaction had occurred after 4 weeks under the Poli conditions (entry a, Table 4.5),
whilst standard Upjohn conditions failed, as did the modified AD conditions of
Warren, 176 the racemic dihydroxylation, RD (entry c). In light of the close precedent
in the previous synthesis this is especially disappointing, however the remaining routes
are both one step shorter than route A.
4.4.2 Route B or C: a model dihydroxylation
Routes B and C involve the same number of synthetic steps, but differ in the execution
of the key dihydroxylation step. In the previous synthesis it was assumed that the
matched “Kishi” stereoelectronics and the encumbrance afforded by the axial
oxazoline were responsible for the high diastereoselectivity. However this was not
tested, and is only now important since two different routes are being considered.
Whilst it may seem clear that route B would afford greater stereoselectivity, it is also
possible that the internal amine will complex osmium, shutting down the catalytic
cycle; dihydroxylation in route C would not face this problem.
In a model study, the dihydroxylation of allylic alcohol 225 was undertaken, also
serving to assign the relative stereochemistry of C4 (Scheme 4.37). As expected, the
anti-diol was favoured by Kishi selectivity (vide supra), however the selectivity was
significantly worse than in the previous synthesis, when it was matched by the
encumbrance of the oxazoline. In light of this, it seemed likely that route C would
159

4.4 – Revised altrose synthesis
suffer from poor facial selectivity and route B was favoured. Debenzylation of the
resulting diol gave tetraol 315, which was apolar enough to elute on silica gel.
HO
BnO
BnO
BnBr, NaH
OsO 4 , NMO
HO
6
Bu 4 NI, DMF
CH 2 Cl 2 HO
OH
OBn
93%
OBn
225 313 314
3
60% (80% conv.)
5:1 dr
BnO
HO
HO
OBn
314
Pd/C, H 2
10 bar, MeOH
HO
HO
HO
OH
315
quant.
3 J H2-H3ax = 13.5
3 J H3ax-H4 = 11.0
3 J H3eq-H4 = 5.0
3 J H4-H5 = 11.0
3 J H5-H6 = 3.0
Scheme 4.37 – model dihydroxylation and assignment of relative stereochemistry
4.4.3 Route B
This route would be four steps shorter than the previous altrose synthesis; three
protecting group manipulations, and the simultaneous reduction of the enone and
oxazoline. Furthermore, since there is no available hydroxyl group during the
alkylation step, lactonisation is not possible.
Ph Ph Ph Ph
Ox*
O
NMe
O
NMe
MeOTf, 7 hr
O
276
OH
then NaBH 4
0 °C
OH
310
OH
OH
78%
OH
1%
316
Scheme 4.38 – synthesis of the allylic alcohol (Route B)
The alkylation-reduction sequence proceeded in good yield and with excellent
diastereoselectivity, consistent with the previous enone reduction with sodium
borohydride (Table 4.3). The resulting oxazolidine was treated under a range of
dihydroxylation conditions.
160

Chapter 4 – Synthesis of carbasugars
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
NMe
O
NMe
O
NMe
O
NMe
OsO 4 HO
HO
Conditions
OH
HO OH
OH HO
OH
OH
O
O
310 311 318 319
OH
Time Ratio † (isolated yield / %)
Entry Conditions / d 311 318 319 Conv.*
a CH 2 Cl 2, Me 3 NO.H 2 O 5 39 21 15 -
b CH 2 Cl 2, Me 3 NO.H 2 O 7 30 (25) 28 (25) 19 (19) 81%
c CH 2 Cl 2, NMO.H 2 O 5 21 45 18 -
d CH 2 Cl 2, NMO.H 2 O 7 18 (21) 18 (11) 59 (42) 100%
e t-BuOH / H 2 O 9 11 (10) 14 (15) 4 (0) 40%
f Acetone / H 2 O 9 5 (5) 38 (32) 3 (0) 58%
g RD 2 8 31 40 -
h Donohoe 2 hr – ‡ – – 100%
* conversion given when products isolated † ratio in crude 1 H NMR, remainder is starting material
‡ no product isolated, see text
Table 4.6 – dihydroxylations of allylic alcohol (route B)
The dihydroxylation of the allylic alcohol was generally slow and unselective (Table
4.6). The most promising result was under the original conditions of Poli, using
trimethylamine N-oxide as reoxidant (entries a,b), indicating almost 40% of the desired
tetraol 311 by crude 1 H NMR. Unfortunately leaving the reaction for longer did not
improve conversion, and the isolated yield was poor with almost equal amounts of
each by-product seen. Under other dihydroxylation conditions enone 318 was the
major product, which under prolonged reaction oxidised to triol 319 (entries c, d). The
relative stereochemistry of 319 was assigned by analogy to the dihydroxylation of the
related enone 201 (section 4.2.2).
Whilst unexpected, the oxidation of allylic alcohols to enones under stoichiometric
osmium tetroxide has been previously observed by Donohoe 195 who proposed it to be
161

4.4 – Revised altrose synthesis
indicative of a strong interaction between the allylic alcohol and osmium tetroxide.
The substrate-metal interaction might be further strengthened by the presence of an
internal amine which would compete with the amine ligands of the catalytic systems
(N-methylmorpholine, trimethylamine or quinuclidine). Sharpless has previously
shown that osmate esters are unreactive to NMO when coordinatively saturated with
amines. 198
Since it is postulated that it is the catalytic cycle that is being inhibited, the problem
might be overcome under stoichiometric conditions. The most notable such reaction is
the application of the stoichiometric TMEDA/osmium tetroxide by Donohoe. 199 A
further advantage of this system is that it has been estimated to be 100 times more
reactive than the monodentate catalytic systems previously used, although conducting
the reaction at –78 °C to enhance selectivity might be expected to negate this. We
would not expect to obtain tetraol 311 as the major product from this reaction as
Donohoe conditions generally prefer syn-dihydroxylation.
Despite rapid consumption of starting material, no products could be identified either
before or after purification (Table 4.6, entry h). The reaction mixture remained rust
brown after all recommended hydrolysis conditions were employed, making analysis
of the reaction difficult. It is noted that osmate esters are normally detectable by 1 H
NMR and TLC, and no compounds could be identified by either method. Meanwhile,
enough of tetraol 311 had been isolated to investigate the forward reaction.
4.4.3.a Route B: oxazolidine hydrolysis
The isolated tetraol 311 and ketone 319 were subject to the hydrolysis conditions
previously developed (Scheme 4.39). The tetraol could be seen to go to a UV-inactive
product by TLC at both ambient and elevated temperatures, but upon workup no
aldehyde could be seen in the crude NMR. Reaction of ketone 319 was slow,
presumably since it lacked an available hydroxyl group to facilitate hydrolysis (section
4.2.9).
162

Chapter 4 – Synthesis of carbasugars
Ph
Ph
Ph
Ph
O
NMe
O
NMe
HO
HO
OH
311
OH
(CO 2 H) 2
THF/H 2 O
rt or
50 °C
no isolable
products
HO
HO
O
319
OH
(CO 2 H) 2
THF/H 2 O
50 °C
95:5 dr
α-L-Altrose
analogue
Scheme 4.40 – dihydroxylation of allylic alcohol (route C)
Pleasingly, the dihydroxylation proceeded cleanly with no other diastereomers
observed in the crude NMR or upon purification. Optimisation of this step was
deemed unnecessary since it completed the five step synthesis from diene 102b in
45.3% yield. An overview of the synthesis is given in Scheme 4.58 at the end of the
chapter.
163

4.5 – Mannose synthesis
4.5 Synthesis of a Mannose Analogue
Hydrolysis of the known epoxide 309 (section 4.2.8) would give an epimer of the
altrose analogue synthesised above. Regioselectivity of nucleophilic attack on
oxiranes can often be predicted by considering stabilisation of a developing charge and
torsional strain in the transition state.
If we consider the opening of epoxide 309 (Scheme 4.41) there is little stabilisation of
a developing charge at either juncture but clear differences when we consider torsional
strain in the transition states. Nucleophilic attack of cyclohexene oxides generally
proceeds through a chair-like trans-diaxial transition state, 200 whereas the regiomeric
opening requires the carbocycle to go through a strained twist-boat.
HO
HO
O
H 2 O
Me
HO
R
O
OH 2
321
twist-boat
OH OH
HO
HO OH
OH
α-L-Idose
analogue
322
OH
OH
309
H 2 O
R = i-Pr
Me
HO
R
OH 2
O
OH
323
trans-diaxial &
neopentyllic
OH
HO
HO
HO OH
OH
α-L-Mannose
analogue
324
Scheme 4.41 – hydrolysis of cyclohexane epoxide 309
However, the example above is complicated by the presence of a quaternary centre
hindering the approach of the nucleophile in the diaxial transition state 323. These
conflicting strains make it hard to predict the preferred product, and the likely result
would be poor regioselectivity, as was seen in the work of Gonzalez in the synthesis of
cyclitols from (–)-quinic acid. 201
164

Chapter 4 – Synthesis of carbasugars
TBSO
HO
HO
OH
OH
OH
TFA/H 2 O HO
HO
O
80 °C, 11 hr
OH
HO OH HO OH
OH
OH
OH
42% 58%
325 326
Scheme 4.42 – hydrolysis of an epoxycyclohexane similar to 309 201
Assuming that the ground state conformation of epoxide 325 is the same as that of 309,
the same choice of transition states exists; clearly these were very close in energy, with
a 3:2 preference for neopentylic, trans-diaxial opening (326). The elevated
temperature and prolonged time of the reaction may be indicative of the strain that had
to be overcome in both transition states.
This conflict of high torsional strain in the regioisomeric transition states may be
overcome if we consider the opening of the diastereomeric epoxide 327 (Scheme
4.43). trans-Diaxial hydrolysis of this epoxide would instead proceed by attack at the
distal centre; presenting a strong preference for the isomer with the stereocentres of α-
L-mannose.
O
HO
OH
327
OH
H 2 O
H 2 O
R = i-Pr
Me
HO
Me
HO
R
R
O
trans-diaxial
OH 2
OH 2
O
OH
Twist boat
& neopentyllic
OH
OH OH
HO
HO OH
OH
α-L-Mannose
analogue
324
HO
HO
HO
FAVOURED
HO
OH
α-L-Idose
analogue
322
OH
DISFAVOURED
Scheme 4.43 – possible hydrolysis of a diastereomer of epoxide 309
165

4.5 – Mannose synthesis
It is clear that if such an epoxide could be synthesised, selective hydrolysis would be
expected to yield an analogue of mannose with good regioselectivity. The next section
will discuss the synthesis of the diastereomeric epoxide by employing the lactonisation
previously discovered (section 4.2.8). This approach was chosen since it explores a
new method of oxazoline removal, and would complement the previous synthesis. It
should be noted that it would also possible to favour anti epoxidation by making the
silyl ether, 189 or by employing the Sharpless-Katsuki asymmetric epoxidation. 188
4.5.1 Strategy I: Lactonisation
It was recognised that lactonisation of diol 213 would leave only one hydrogen bond
donor to direct epoxidation in the newly formed bicycle 328 (Scheme 4.44). Simple
MM2 modelling indicates that whilst there is little to encumber the approach of the
oxidant to either face of the alkene, the pseudo-equatorial alcohol is well placed to
direct a hydrogen bonding reagent.
Ox*
MeOTf O
[O] O
O
OH
O
O
OH
OH
213 328 329
OH
Scheme 4.44 – proposed lactonisation-epoxidation & molecular model (MM2)
If successful, the resulting epoxide 329 should undergo diaxial hydrolysis to give an
analogue of mannose (Scheme 4.45). Whilst it might be possible to hydrolyse both the
epoxide and lactone in a single reaction, the resulting carboxylic acid would be
extremely polar and hard to isolate, instead a reduction-hydrolysis strategy is preferred.
166

Chapter 4 – Synthesis of carbasugars
O
Me
Me
i) H -
HO
HO
O
O
O CO 2
OH
213 328
OH
ii) H 2 O
HO
OH
α-L-Mannose
analogue
329
OH
Scheme 4.45 – proposed reduction-hydrolysis of lactone 213
4.5.1.a Initial studies of lactonisation-epoxidation strategy
It was anticipated that lactonisation could be induced under similar conditions to those
found before (section 4.2.8), but that replacing the reductive quench with an aqueous
one might increase yield of lactone and return some starting material. As before, the
alkylation was left overnight, but instead of the standard methanol/THF-borohydrdride
quench, aqueous ammonium chloride was added to the reagents in dichloromethane
with vigorous stirring.
Ox*
i) MeOTf, CH 2 Cl 2
16 hr
O
OH ii) NH 4 Cl (aq) O
8 hr
OH
213 328
OH
36 %
97% conv.
Scheme 4.46 – lactonisation
Lactone 328 was isolated in a similar quantity to the previous conditions, and despite
complete conversion of the oxazoline, no other products could be identified before or
after purification. That similar amounts of lactonisation were seen under reductive and
aqueous quenches lends support to the conclusion that lactonisation occurs during
alkylation.
Epoxidation of the resulting olefin went cleanly with no other products visible in the
crude NMR (Scheme 4.47). There was, however, a striking difference between the
carbon NMR of this compound and its diastereomer 307; the carbonyl of the latter was
only observable with a relaxation time of 25 seconds, whilst the carbonyl of 329 was
observable with a standard relaxation time of 1 second. Since spin relaxation of 13 C
nuclei is assisted by nearby protons in a through-space interaction, this is explained by
167

4.5 – Mannose synthesis
considering the local environment in the two compounds. In lactone 329 methine H6
is close to the carbonyl, whilst the diastereomeric lactone has no such available proton
to assist relaxation; further confirming the stereochemistry of the two compounds.
5s< T 1

Chapter 4 – Synthesis of carbasugars
4.5.1.b Lactonisation of cis-hydroxy oxazolines
Initial experimentation had shown that the stereoselective epoxidation works well but
that the lactonisation and reduction steps need improvement. Since lactonisation
occurred in the presence of excess alkylating agent and only trace amounts of water,
the rate determining step appears not to be the hydrolysis but the formation of the
ortho-amide (section 4.2.8). Under these conditions lactonisation might be improved
through longer reaction times, heating, or the use of bench dichloromethane rather than
that distilled over calcium hydride. However it is likely that such a method would be
limited to small scale reactions, and the use of methyl trifluoromethylsulfonate at
elevated temperature would increase the risk of exposure to the deadly reagent. 135,136
Instead a number of alternative conditions were explored (Table 4.7).
Ox*
Conditions
O
OH
O
OH
213 328
OH
Reagent Solvent Conditions 328
a MeI (3 eq) CH 2 Cl 2 Δ 6 hr nr
b HCl THF/H 2 O Δ 16 hr ester
c Cu(OTf) 2 (1.2 eq) CH 2 Cl 2 rt 16 hr nr
d Sc(OTf) 3 (1.2 eq), THF/H 2 O rt (16 hr) nr
e Sc(OTf) 3 (1.2 eq), THF/H 2 O 50 °C (4 hr) 20% *
* crude 1 H NMR SM:328:unknown = 2.5:1:1
Table 4.7 – attempted lactonisations
Methyl iodide had previously been used to quaternise oxazolines in a similar manner to
methyl triflate, 202 but would be more amenable to use at elevated temperature and not
as sensitive to water. Unfortunately, after prolonged reaction (entry a), only starting
material was recovered.
Likewise, it had previously been found that the oxazolines are quickly protonated in
aqueous hydrochloric acid in THF to give esters (section 3.2.4), it was possible that
this process might be catalysed by the formation of an ortho-amide, if not, the ester
169

4.5 – Mannose synthesis
which would result from oxazoline hydrolysis may itself undergo lactonisation. When
heated under these conditions (entry b) there was no sign of lactonisation, instead only
the ester was isolated. Treatment of this ester under mildly basic conditions (t-
BuOH/t-BuONa) yielded trace amounts of lactone along with a number of unidentified
products. Perchloric acid and sulfuric acid were also unsuccessful in catalysing the
lactonisation of the closely related epoxyoxazoline 216. Similarly trifluoroacetic acid
has been found to catalyse the lactonisation of oxazoline 331 at room temperature and
would be worth attempting since the bisphenyl oxazolines hydrolyse to amides when
treated with TFA (section 3.2.5).
O
N
TFA, THF/H 2 O
O
O
Ph
Ph
rt, 2 d
OH
331
203
Scheme 4.50 – lactonisation of oxazolines
Since the alkylating agent seemed to promote cyclisation by removing electron density
from the oxazoline π-system, it was anticipated that a Lewis acid might also work.
Oxazolines have been used to make copper (II) complexes which have proven to be of
enormous value in asymmetric synthesis, exemplified by the Evans Copper BOX. 204
In light of this, and that excess water did not seem necessary, copper (II) triflate was
employed, but no reaction observed (entry c, Table 4.7). Since previous lactonisations
worked in similarly anhydrous conditions it is unlikely that the reaction failed for a
lack of water, more likely is that the presence of trace water inhibited the sensitive
Lewis acid.
There has been much interest in the use of lanthanide (III) triflates as water soluble,
even water-activated, Lewis acids in catalytic synthesis. 205,206 In light of the above
problems, these rare earth metal salts seemed like perfect reagents to catalyse the
hydrolysis. Promisingly, excess scandium triflate returned a significant amount of the
lactone, with the remaining crude material comprising mostly oxazoline starting
material (entry e, Table 4.7); whilst only a small scale reaction, this result is indicative
170

Chapter 4 – Synthesis of carbasugars
that this strategy for hydrolysis could work. Whilst this was being pursued, another
strategy was providing promising results.
4.5.2 Strategy II: Cyclohexene oxides
The lactonisation strategy was appealing since hydrolysis of the resulting epoxide was
expected to give good regioselectivity (Scheme 4.43). Whilst it would be possible to
make this diastereomeric epoxide (vide supra) initial experiments would focus on
opening epoxides already in hand. A similar strategy to the final altrose synthesis may
be envisaged (Scheme 4.51). The main difference being that oxidation of the allylic
alcohol is directed by hydrogen bonding, and that steric encumbrance at C1 is
unimportant.
Ox*
Ox*
HO
D
O
276
a
OH 97%
b, 78%
O
OH
216
OH
H 2 O
d (i)
HO
HO OH
OH
α-L-Mannose
analogue
324
Ph
Ph
Ph
Ph
HO
O
N
O
N
HO
E
OH
310
OH
[O]
c, 79%
O
OH
306
OH
HO OH
OH
α-L-Idose
analogue
322
d (ii, iii)
83% 3 steps
HO
HO
F
OH
312
OH
[O]
O
OH
309
OH
H 2 O
a) i) NaBH 4 , MeOH, 0 °C, 6 hr, 98% ii) mCPBA, CH 2 Cl 2 , 0 °C, 6 hr, 99%; b) MeOTf, CH 2 Cl 2 , then
NaBH 4 , 0 °C, MeOH/THF, 78%; c) i) (CO 2 H) 2 , THF/H 2 O, 50 °C, 24 hr, ii) NaBH 4 , MeOH, 79% (2
steps); d) i) MeOTf, CH 2 Cl 2 , then NaBH 4 , 0 °C, MeOH/THF, ii) (CO 2 H) 2 , THF/H 2 O, 50 °C 17 hr, iii)
NaBH 4 , MeOH, 83% (3 steps).
Scheme 4.51 – proposed synthesis of diastereomeric carbasugar
171

4.5 – Mannose synthesis
One clear advantage of this synthetic plan is that much of the chemistry has already
been completed; the only query that remains is at which stage the oxidation and
hydrolysis will prove most selective. Hydrolysis of epoxyoxazolidine 306 is not
included in this synthetic plan since oxazolidine hydrolysis has proven problematic and
reactions would likely be very complicated.
4.5.2.a Epoxidations
Epoxidation D has been shown to work very well (section 4.2.6), but requires an extra
synthetic step than oxidations E and F. Furthermore, unlike the altrose synthesis,
hindrance of one side of the olefin should not affect the facial selectivity, whilst having
late stage intermediates in common would make the two syntheses less divergent and
more amenable to future scale-up. The oxidant would again be mCPBA since it had
performed excellently in the epoxidation of alkene 216.
Oxidation E of oxazolidine 310 was conducted at low temperature since it was hoped
that reduced temperature would favour stereoselective epoxidation whilst minimising
oxidation of the tertiary amine, which often requires elevated temperatures. 171
However epoxidation was accompanied by oxidation of the amine and only N-oxide
332 (Scheme 4.52) was isolated. This is consistent with the observations of Ganem
(Scheme 4.53). 207
Ph
O
OH
N
310
Ph
OH
mCPBA (2 eq)
CH 2 Cl 2
−40 °C
O
Ph
O
OH
332
Ph
O
N
OH
53%
(CO 2 H) 2 , rt
THF/H 2 O, 5 d
Scheme 4.52 – epoxidation (route E)
no isolable
products
It was thought that oxazolidine N-oxides might hydrolyse more rapidly to the aldehyde
than the parent oxazolidine. Initial results were promising since after two days of mild
hydrolytic conditions, an aldehyde was observed in the 1 H NMR spectrum of the crude
mixture in a 1:2 ratio with starting material 332. Unfortunately, upon consumption of
the oxazolidine, no aldehyde was present in the final reaction mixture (Scheme 4.52),
172

Chapter 4 – Synthesis of carbasugars
nor was any the desired triol 309 isolated upon reduction of this mixture with sodium
borohydride.
OH
OH
BnO
NBn
mCPBA (3.5 eq)
CH 2 Cl 2
BnO
O
NBn
BnO
OBn
0 °C to rt
BnO
OBn
O
207
Scheme 4.53 – N-oxidation of tertiary amines at ambient temperature
Oxidation F of allylic alcohol 312, the final intermediate in the final altrose synthesis,
was problematic due to its low solubility. The triol was only sparingly soluble in most
non-alcoholic solvents, and although small amounts of alcohol made the triol
completely soluble it was believed it would saturate the peracid with hydrogen bond
donors and prevent facial discrimination. Under high dilution conditions at ambient
temperature, the allylic alcohol was sparingly soluble in chloroform, but under these
conditions oxidation gave no discernable products by TLC or upon workup. It was
later found that whilst alcoholic solvents do destroy selectivity for the majority of
hydrogen bond oxidants, they have little effect on mCPBA. 168
HO
HO
OH
OH
mCPBA
CHCl 3
rt, 8 hr
no isolable
products
O
OH
312 312
OH
Scheme 4.54 – epoxidation (route F)
Although only single reactions had been performed, there were clear problems in both
instances; oxidation E would suffer with competing oxidation of the amine, and
oxidation F presented a significant practical challenge to which no solution was
immediately clear. Before returning to these problems, it seemed prudent to attempt
the hydrolysis of the respective epoxides which could be synthesised from
epoxyoxazoline 216.
173

4.5 – Mannose synthesis
4.5.2.b Epoxide hydrolysis
Following conditions employed in similar carbasugar syntheses, 165 epoxyoxazoline
216 was heated under alkaline conditions. Whilst the reaction did not go to
completion, the crude mixture showed hydrolysis was occurring to give a 2:1 mixture
of acylated starting material to oxazoline 333-Ac with the all trans stereochemistry of
the unnatural sugar idose.
O
Ox*
OH
216
OH
i) THF, KOH
(1M), Δ 22 hr
ii) Ac 2 O,
pyr., DMAP
AcO
AcO
Ox*
OAc
333-Ac
OAc
30% conversion
by 1 H NMR
HO
H
HO
O
HO OH
OH
α-L-Idose
3 J H3-H4 = 9.0
3 J H4-H5 = 10.0
3 J H5-H6 = 9.5
Scheme 4.55 – base catalysed epoxide hydrolysis (route D)
Such high regioselectivity was unexpected, especially since it requires a strained twistboat
transition state. The regioselectivity suggests severe congestion around C6, and
that forcing conditions will continue to be needed to promote reaction. Unfortunately
the mixed acetates could not be separated, and 333-Ac was not fully characterised.
Furthermore, this reaction could not be reproduced under the same or different
conditions (Table 4.8).
174

Chapter 4 – Synthesis of carbasugars
O
Ox*
OH
216
OH
Conditions
X
HO
HO
Ox*
OH
333
OH
Entry Conditions Result
a KOH (1M, aq) THF, Δ 22 hr nr
b KOH (3M, aq) THF, Δ 36 hr nr
c KOH (3M, aq) dioxane, Δ 36 hr nr
d KOH, d 6 -DMSO, rt, 2 hr nr
e KOH, d 6 -DMSO, 50 °C, 1 hr no isolable product
f KOH, d 6 -DMSO, 18-crown-6, rt, 2 hr no isolable product
g HCl (3M) THF, Δ 24 hr polymerised
h HCl (1M) THF, rt, 1 hr nr
i HCl (1M) THF, rt, 18 hr polymerised
j H 2 SO 4 (1M), THF, rt, 5 hr nr
k H 2 SO 4 (1M), THF, rt, 28 hr polymerised
m HClO 4 (1M), dioxane, rt, 28 hr 20% ester *
* rest SM, see section 3.2.4
Table 4.8 – attempted epoxide hydrolysis (route D)
Initial work attempted to repeat the above hydrolysis using the original and more
forcing conditions (entries a-c). The nucleophilicity of potassium hydroxide is
enhanced by the use of DMSO 208 which solvates potassium 185 making the counter ion
more reactive. At ambient temperature (entries d-f), no reaction was observed when
followed by 1 H NMR, however raising the temperature caused rapid decomposition of
the oxazoline ring. Similar degradation occurred when 18-crown-6 was added to the
reaction at ambient temperature.
Upon treatment with acid, the epoxyoxazoline rapidly turned to baseline salts (c. 10
min), and reverted back to starting material upon workup. This is most likely due to
protonation of the oxazoline which has previously been shown to be susceptible to acid
175

4.5 – Mannose synthesis
hydrolysis (section 3.2.4). Extended reaction with aqueous sulfuric and hydrochloric
acids led to polymerisation, with greater than ten times the mass of the reaction being
isolated as a globular oil. Treatment with perchloric acid (entry m) caused incomplete
hydrolysis to the ester, which could not be further hydrolysed.
Despite the initially promising result, the reactivity of the oxazoline was dominating
the reaction of 216. In light of this, the hydrolysis of the free epoxide 309 was
attempted (Table 4.9).
HO
HO
HO
O
OH
309
OH
Conditions
HO
HO
OH
324
OH
+
HO
HO
OH
322
OH
Entry Conditions Result
a KOH (1M, aq) THF, Δ 16 hr no isolable product
b KOH, d 6 -DMSO, 50 °C, 1 hr elimination
c TFA:H 2 O 1:3, rt, 16 hr nr
d H 2 SO 4 (3M), THF, rt, 5 hr polymerised
e HClO 4 (3M), dioxane, rt, 1 hr polymerised
f HCl (3M) THF, rt, 3 hr 50% 5:1 (324:322)
g HCl (3M) THF, 0 °C to rt, 8 hr 81% (324) *
* no crude NMR ratio obtainable
Table 4.9 – epoxide hydrolysis (route F)
Hydroxide opening of the epoxide was again unsuccessful (entries a-b). The KOH-
DMSO system again gave mixed oxirane products which were inseparable by
chromatography and only identified by similar chemical shift and couplings in the
crude 1 H NMR. Further analysis of the crude mixture indicates the product of
elimination at C3-C4. A range of acid conditions were also employed (entries c-g); the
epoxide was unreactive under TFA-H 2 O conditions despite good precedent. 201 It is
likely this is due to the poor solubility of the epoxide in water. Treatment with
perchloric acid and sulfuric acid returned crude reaction mixtures with UV active
products, and significant mass increase; this is again attributed to polymerisation.
176

Chapter 4 – Synthesis of carbasugars
Pleasingly, the epoxide reacted with hydrochloric acid at ambient temperature (Table
4.9, entry f) in a clean and rapid reaction with 5:1 regioselectivity favouring the
product of neopentylic, trans-diaxial opening. The relative stereochemistries of the
products were assigned by vicinal couplings, but their identities were initially
uncertain since their polarities were similar to that of the starting material.
-
Furthermore, EI mass spectroscopy showed a C 11 H 22 ClO 5 ion which was taken to
indicate the oxirane had undergone chloride opening to give carbocycle 335.
HO
HO
HO
O
OH
309
OH
HCl (aq), THF
0 °C - rt
8 hr
HO
HO
OH
324
OH
81%
Cl
HO OH
OH
335
C 11 H 21 ClO 4
13C δ/ppm
CH: 75.5, 73.7
70.8, 69.1
CH 2 : 67.1
Scheme 4.56 – final hydrolysis of epoxide
δ C 51.0
Cl
OH
Repetition of the reaction at low temperature (entry g) gave enough product for 13 C
NMR showing four methine carbons above 69 ppm, significantly downfield of that
expected for chloride 335 (51 ppm for 2-chloro-1-propanol 209 ). The EI+ mass
spectrum confirmed that chloride had been the ionising species, and revealed that a
tightly bound molecule of water might be responsible for the unexpected
hydrophobicity. Unfortunately, the crystals grown from methanol-water were not of
high enough quality for x-ray diffraction.
4.5.2.c Discussion of epoxide hydrolysis
The outcome of this final hydrolysis was surprising for three reasons. Firstly the
reaction proceeded rapidly at ambient temperature, which whilst common for epoxides
that develop no torsional strain, is surprising in light of the encumbrance present (vide
supra).
177

4.5 – Mannose synthesis
The second interesting feature is the high regioselectivity of the reaction. Whilst a
diastereomeric ratio was not obtained for the final conditions, it should be greater than
5:1, as none of the diastereomer was isolated. This is much more selective than the
similar example from Gonzalez presented earlier (Scheme 4.42) which showed
approximately 3:2 preference for a similar hydrolysis. It is possible that some of this
reduced selectivity reflects the elevated temperature of the Gonzalez reaction, skewing
the Bolzmann distribution. A literature survey of the hydrolysis of epoxides with
adjacent quaternary centres shows that in contrast to the results above, the vast
majority favour opening at the distal centre. 210
The third surprise was that the regioselectivity apparently switched when changing
from alkali to acid conditions (Scheme 4.57). Whilst it is often possible to change the
regioselectivity of epoxide hydrolysis by changing the pH of the reaction, this requires
an adjacent system to stabilise a developing positive charge. No such system exists in
these two instances, yet basic hydrolysis of epoxyoxazoline 216 occurred at the distal
centre (albeit as an isolated case), whilst acid hydrolysis of epoxide 309 took place at
the proximal one. In principle, the primary alcohol of 309 might participate in the
oxirane opening, but this would require a 6,5 trans-fused intermediate and result in
retention of stereochemistry at C5. Since the epoxides are very similar and are
expected to have similar stereoelectronic characteristics – corroborated by 13 C NMR
data – the only significant change in the reaction seem to be the conditions of
hydrolysis.
δ C6 61.0
δ C5 56.0
O
Ox*
OH
216
OH
THF, KOH
(1M, aq),
Δ 22 hr
HO
HO
Ox*
OH
333
OH
dr: high
irreproducible
δ C6 61.9
δ c5 58.8
HO
O
OH
309
OH
HCl (aq), THF
0 °C - rt
8 hr
HO
HO
HO
OH
324
OH
dr >5:1
Scheme 4.57– chemical shift and reactivity of the two epoxides
178

Chapter 4 – Synthesis of carbasugars
Acidic conditions favour epoxide attack at the centre with nearby orbitals available to
stabilise a developing positive charge. In these examples the only difference in
available orbitals are the adjacent σ bonds which could in principle stabilise
developing p-character at either C5 or C6 through hyperconjugation. However, for
this to be responsible for the high selectivity, the two σ C1-C orbitals would have to be
significantly more stabilising for C6 than the σ C4-H and σ C4-O are for C5. This is
211
unlikely since the pseudo-axial σ C4-H should equivalent to the pseudo-axial σ C6-C
whilst the remaining two pseudo-equatorial orbitals would have little overlap with an
empty p-orbital.
In light of this, it seems that there is no reason for such a stark, and irreproducible,
change in reactivity, other than to assume that the alkaline hydrolysis of the
epoxyoxazoline was spurious. Subsequent studies by Karlubíková have shown that
azide opening occurs at the neopentylic position, consistent with these latter results. 66
179

4.6 – Summary
4.6 Summary & Future Work
The synthesis of two carbasugar analogues is summarised below. The overall yields
compare extremely well to the literature syntheses summarised in section 4.1, of which
only six of the 104 routes had overall yields – taken from advanced intermediates or
chiral pool materials – above 40%. Using a similar measure, altrose analogue 278 has
been synthesised in 45% overall yield and mannose analogue 324 in 60% yield.
Ox*
Ox*
Ox*
a
b
OH
OMe
OMe
O
101b
102b
276
HO
HO
HO
d
HO
HO
H
O
OH
HO
OH
HO
OH
c
OH
OH
OH
312
278
α-L-Altrose
276
45.3%, 5 steps from 102b
32.7%, 6 steps from 101b
e, f
O
Ox
g, h
HO
HO
HO
HO
H
O
OH
OH
HO
OH
OH
HO
OH
OH
309
324
α-L-Mannose
60.6%, 7 steps from 102b
42.5%, 8 steps from 101b
a) i-PrLi, THF, 20 min, –78 °C, then MeI, 70%; b) OsO 4 , NMO, t-BuOH then Na 2 S 2 O 5 , 93%; c)
MeOTf, CH 2 Cl 2 , then NaBH 4 , 0 °C, MeOH/THF, 78%; ii) (CO 2 H) 2 , THF/H 2 O, 50 °C 24 hr, iii) NaBH 4 ,
MeOH, 79% (2 steps); d) OsO 4 , quinuclidine, MeSO 2 NH 2 , K 2 CO 3 , K 3 Fe(CN) 6 , t-BuOH/H 2 O, 3 d, 79%.
e) NaBH 4 , MeOH, 0 °C, 6 hr, 98%; f) mCPBA, CH 2 Cl 2 , 0 °C, 6 hr, 99%; g) i) MeOTf, CH 2 Cl 2 , then
NaBH 4 , 0 °C, MeOH/THF, ii) (CO 2 H) 2 , THF/H 2 O, 50 °C 17 hr, iii) NaBH 4 , MeOH, 83% (3 steps); h)
THF, HCl (aq), 0 °C rt, 8 hr, 81%.
Scheme 4.58 – divergent synthesis of α-L-mannose and α-L-altrose analogues
180

Chapter 4 – Synthesis of carbasugars
Despite being the shorter synthesis, the mannose analogue was obtained in a
significantly lower yield than the altrose analogue, largely because of two unoptimised
steps; the final dihydroxylation (step d) and the oxazoline removal in which the
oxazolidine was chromatographed which is believed have diminished the yield (step
c). It might be possible to access epoxide 309 by the other routes briefly explored in
section 4.5.2.a, but this is unlikely to give a significant improvement in the overall
yield.
4.6.1 Future work
Since aminocarbasugars are more common in nature and in medicinal compounds than
cyclitols (section 4.1), this would be an interesting synthetic avenue to explore. The
most obvious way to adapt the current syntheses would be the azide opening of either
epoxide 216 or 309 to which would be expected to proceed with the same
regioselectivity as hydrolysis (vide supra) to give azidosugar 340. Hydrogenation
would be preferred to Staudinger reduction since separation of triphenylphosphine
oxide from aminocarbasugar 341 would prove challenging, indeed isolation of
aminocarbasugars might prove significantly more challenging.
HO
HO
HO
O
OH
OH
NaN 3 , DMF
N 3
HO
OH
OH
H2 , Pd/C
or PPh 3 , H 2 O
H 2 N
HO
OH
OH
309
340
341
Scheme 4.59 – divergent synthesis of α-L-mannose and α-L-altrose analogues
Complete regioselectivity could be achieved by application of the Donohoe tethered
aminohydroxylation (TA) reaction, which overcomes the regioselectivity problems that
plague the Sharpless aminohydroxylation 212 by tethering the amine source, the
carbamate. 213 The TA conditions have recently been optimised, improving the scope
and yield of the reaction (Scheme 4.60). 214
181

4.6 – Summary
OH
CDI, NH 2 OH.HCl,
C 6 F 5 COCl, pyr.
Et 2 O, Et 3 N
O
O
O
O C 6 F 5
N
O
H
O 1% K 2 OsO 2 (OH)
NH
4
t-BuOH/H 2 O
OH
78% 98%
2-
HO O OH
Os
HO
O
OH
VI
O
O
H 2 O
O O
O
Os
O
N
O
N
VIII
O
Os
O
O
VI
214
Scheme 4.60 – Donohoe tethered aminohydroxylation (TA)
Attaching pentafluorobenzoate to the carbamate removes the need for the
stoichiometric t-butyl hyperchlorite re-oxidant which had caused chlorination under
the previous conditions. The tethered oxidant acts as a nitrene equivalent, oxidising
Os VI to form a complex that is able to stereoselectively oxidise the syn face of the
allylic olefin. This could be used with allylic alcohol 213 to give carbamate 343 as
shown, which should tolerate the existing conditions for oxazoline removal. 117
213
Ox*
R
O OP
HN O
O
342
OsO 4
HO
HN
O
Ox*
O
343
OP
R =
O
312
O
O
O
NH
R
OP
344
OP
OsO 4
O
HN
HO
O
H
OH
345
OP
C 6 F 5
Scheme 4.61 – possible application of the TA to make aminocarbasugars
Donohoe has shown this new protocol to be effective for homoallylic alcohols,
although it has only been demonstrated for acyclic terminal olefins thus far. Oxidation
182

Chapter 4 – Synthesis of carbasugars
of cyclic homoallylic alcohols such as 344 is unlikely to occur since it would form syn
6,6 bicycle 345.
Other interesting cyclitols might be made by using different organolithium
nucleophiles to introduce more interesting functional groups. Cyclohexyllithium
would be expected to work similarly to isopropyllithium, allowing the synthesis of
disaccharide mimics such as 346. Use of THP-Li 215 would allow access to more
oxygenated analogues such as 347, whilst silicon nucleophiles could be oxidised to
give compounds such as 348 which resembles the inositol family. Fluorinated dienes
102d and 102e have been synthesised in modest yield; these could offer an alternative
method of synthesising alkyl fluorides from a range of commercially available aryl
fluorides.
HO
HO
HO
HO
HO
O
HO
OH
HO
OH
HO
OH
HO
OH
OH
OH
OH
Nu = c-Hex
346
Nu = THP
347
Nu = SiMe 2 Ph
348
Ox*
Ox*
102d
F
F
102e
Scheme 4.62 – possible synthetic targets and starting materials
183

184

References
References for Chapters 1-4
(1) Ortiz, F. L.; Iglesias, M. J.; Fernandez, I.; Andujar-Sanchez, C. M.; Ruiz-
Gomez, G. Chem. Rev. 2007, 107, 1580-1691.
(2) Reimer, K.; Tiemann, F. Ber. Dtsch. Chem. Ges. 1876, 9, 1268.
(3) Auwers, K. V.; Winternitz, F. Ber. Dtsch. Chem. Ges. 1902, 465-471.
(4) Woodward, R. B. J. Am. Chem. Soc. 1940, 62, 1208-11.
(5) Birch, A. J. J. Chem. Soc. 1944, 430 - 436.
(6) March, J. Advanced Organic Chemistry. Reaction, mechanisms and structure;
Fourth ed.; Wiley, 1992.
(7) Zimmerman, H. E.; Wang, P. A. J. Am. Chem. Soc. 1993, 115, 2205-2216.
(8) Birch, A. J.; Chamberlain, K. B. Org. Synth. 1977, 57, 107.
(9) Schultz, A. G. Chem. Commun. 1999, 1263-1271.
(10) House, H. O.; Strickland, R. C.; Zaiko, E. J. J. Org. Chem. 1976, 41, 2401-8.
(11) Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras, A. G.; Welch, M. J.
Am. Chem. Soc. 1988, 110, 7828-41.
(12) Donohoe, T. J.; Guyo, P. M.; Beddoes, R. L.; Helliwell, M. J. Chem. Soc.,
Perkin Trans. 1 1998, 667.
(13) Bartoli, G.; Dalpozzo, R.; Grossi, L. J. Chem. Soc., Perkin Trans. 2 1989, 573-
578.
(14) Clayden, J. Organolithiums: Selectivity for Synthesis; Pergamon, 2002.
(15) Andujar-Sanchez, C. M.; Iglesias, M. J.; Ortiz, F. L. Tetrahedron Lett. 2002,
43, 2565.
(16) Andujar-Sanchez, C. M.; Iglesias, M. J.; Ortiz, F. L. Tetrahedron Lett. 2002,
43, 9611.
(17) Clayden, J.; Foricher, Y. J. Y.; Lam, H. K. Chem. Commun. 2002, 2138-2139.
(18) Clayden, J.; Foricher, Y. J. Y.; Lam, H. K. Eur. J. Org. Chem. 2002, 3558-
3565.
(19) Hattori, T.; Koike, N.; Satoh, T.; Miyano, S. Tetrahedron Lett. 1995, 36, 4821.
(20) Bartoli, G.; Bosco, M.; Cantagalli, G.; Dalporzo, R. J. Chem. Soc., Perkin
Trans. 2 1985, 773-780.
(21) Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H. J. Am. Chem.
Soc. 1992, 114, 7652-7660.
(22) Meyers, A. I.; Gabel, R. A. Heterocycles 1978, 11, 133-8.
(23) Meyers, A. I.; Natale, N. R.; Wettlaufer, D. G.; Rafii, S.; Clardy, J.
Tetrahedron Lett. 1981, 22, 5123-6.
(24) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297-360.
(25) Barner, B. A.; Meyers, A. I. J. Am. Chem. Soc. 1984, 106, 1865-6.
(26) Meyers, A. I.; Lutomski, K. A.; Laucher, D. Tetrahedron 1988, 44, 3107-18.
(27) James, B.; Meyers, A. I. Tetrahedron Lett. 1998, 39, 5301.
(28) Rawson, D. J.; Meyers, A. I. Tetrahedron Lett. 1991, 32, 2095.
(29) Meyers, A. I.; Gabel, R.; Mihelich, E. D. J. Org. Chem. 1978, 43, 1372.
(30) Meyers, A. I., Personal communication with J. Clayden.
(31) Meyers, A. I.; Roth, G. P.; Hoyer, D.; Barner, B. A.; Laucher, D. J. Am. Chem.
Soc. 1988, 110, 4611-24.
(32) Meyers, A. I.; Higashiyama, K. J. Org. Chem. 1987, 52, 4592-7.
(33) Meyers, A. I.; Licini, G. Tetrahedron Lett. 1989, 30, 4049-52.
(34) Meyers, A. I.; Barner, B. A. J. Org. Chem. 1986, 51, 120-2.
(35) Bickelhaupt, F.; Solà, M.; Fonseca Guerra, C. J. Mol. Model. 2006, 12, 563.
(36) Meyers, A. I. J. Org. Chem. 2005, 70, 6137-6151.
185

References
(37) Rawson, D. J.; Meyers, A. I. J. Org. Chem. 1991, 56, 2292-4.
(38) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356-363.
(39) Hulme, A. N.; Meyers, A. I. J. Org. Chem. 1994, 59, 952-953.
(40) Shimano, M.; Meyers, A. I. J. Org. Chem. 1995, 60, 7445-55.
(41) Shimano, M.; Meyers, A. I. J. Org. Chem. 1996, 61, 5714-5715.
(42) Maruoka, K.; Ito, M.; Yamamoto, H. J. Am. Chem. Soc. 1995, 117, 9091-2.
(43) Saito, S.; Sone, T.; Murase, M.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122,
10216-10217.
(44) Saito, S.; Shimada, K.; Yamamoto, H.; Marigorta, E. M.; Fleming, I. Chem.
Commun. 1997, 1299-1300.
(45) Saito, S.; Sone, T.; Shimada, K.; Yamamoto, H. Synlett 1999, 81.
(46) Tomioka, K.; Shindo, M.; Koga, K. J. Am. Chem. Soc. 1989, 111, 8266-8.
(47) Tomioka, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1990, 31, 1739-40.
(48) Tomioka, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1993, 34, 681-2.
(49) Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic
Molecules; Second ed.; University Science Books, 1999.
(50) Semmelhack, M. F.; Hall, H. T., Jr.; Farina, R.; Yoshifuji, M.; Clark, G.;
Bargar, T.; Hirotsu, K.; Clardy, J. J. Am. Chem. Soc. 1979, 101, 3535-44.
(51) Pape, A. R.; Kaliappan, K. P.; Künding, E. P. Chem. Rev. 2000, 100, 2917.
(52) Kündig, E. P.; Quattropani, A.; Inage, M.; Ripa, A.; Dupre, C.; Cunningham,
A. F., Jr.; Bourdin, B. Pure Appl. Chem. 1996, 68, 97-104.
(53) Kündig, E. P.; Ripa, A.; Bernardinelli, G. Angew. Chem., Int. Ed. 1992, 31,
1071-3.
(54) Amurrio, D.; Khan, K.; Kündig, E. P. J. Org. Chem. 1996, 61, 2258-9.
(55) Kündig, E. P.; Cannas, R.; Laxmisha, M.; Liu, R.; Tchertchian, S. J. Am. Chem.
Soc. 2003, 125, 5642-5643.
(56) Chung, Y. K.; Choi, H. S.; Sweigart, D. A.; Connelly, N. G. J. Am. Chem. Soc.
1982, 104, 4245-7.
(57) Miles, W. H.; Smiley, P. M.; Brinkman, H. R. J. Chem. Soc., Chem. Commun.
1989, 1897-9.
(58) Miles, W. H.; Brinkman, H. R. Tetrahedron Lett. 1992, 33, 589.
(60) Smith, P. L.; Chordia, M. D.; Dean Harman, W. Tetrahedron 2001, 57, 8203.
(61) Bao, M.; Nakamura, H.; Yamamoto, Y. J. Am. Chem. Soc. 2001, 123, 759-760.
(62) Clayden, J.; Purewal, S.; Helliwell, M.; Mantell, S. J. Angew. Chem., Int. Ed.
2002, 41, 1049-51.
(63) Purewal, S. PhD Thesis, University of Manchester, 2003.
(64) Cabedo, N. C.; University of Manchester: 2004-5.
(65) Mukhopadhyay, T.; Seebach, D. Helv. Chim. Acta 1982, 65, 385-391.
(66) Karlubíková, O.; University of Manchester: 2007-2008.
(67) Collum, D. B.; McNeil, A. J.; Ramirez, A. Angew. Chem., Int. Ed. 2007, 46,
3002-3017.
(68) Stent, M. SyntheticPages 2002, http://www.syntheticpages.org/pages/195.
(69) a 5 °C temperature increase was observed as 26 cm 3 i-PrLi at 0 °C was added to
the reaction (120 cm3) at –78 °C, but this was deemed to be in proportion to the
expected warming
(70) Clayden, J.; Parris, S.; Cabedo, N.; Payne, A. H. Angew. Chem., Int. Ed. 2008,
accepted for publication.
(71) Jaun, B.; Schwarz, J.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 5741-5748.
(72) Baker, T., Undergraduate project, University of Manchester, 2006.
186

References
(73) Betson, M. S.; Clayden, J.; Worrall, C. P.; Peace, S. Angew. Chem., Int. Ed.
2006, 45, 5803-5807.
(74) Köbrich, G.; Buck, P. Chem. Ber. 1970, 103, 1412-1419.
(75) Kolotuchin, S. V.; Meyers, A. I. J. Org. Chem. 2000, 65, 3018-3026.
(76) Rathke, M. W.; Sullivan, D. Tetrahedron Lett. 1972, 13, 4249.
(77) Pross, A. Acc. Chem. Res. 1985, 18, 212-219.
(78) Eberson, L.; Shaik, S. S. J. Am. Chem. Soc. 1990, 112, 4484-4489.
(79) Ashby, E. C. Acc. Chem. Res. 1988, 21, 414-421.
(80) Ashby, E. C.; Pham, T. N. J. Org. Chem. 1987, 52, 1291-1300.
(81) Newcomb, M.; Williams, W. G.; Crumpacker, E. L. Tetrahedron Lett. 1985,
26, 1183.
(82) Bailey, W. F.; Patricia, J. J.; Nurmi, T. T.; Wang, W. Tetrahedron Lett. 1986,
27, 1861.
(83) Meites, L.; Zuman, P. Electrochemical data; J. Wiley: New York, 1974.
(84) Ashby, E. C.; Goel, A. B.; DePriest, R. N. J. Am. Chem. Soc. 1980, 102, 7779-
7780.
(85) Gawley, R. E.; Low, E.; Zhang, Q.; Harris, R. J. Am. Chem. Soc. 2000, 122,
3344-3350.
(86) Hoffmann, R. W. Chem. Soc. Rev. 2003, 32, 225-230.
(87) Yamataka, H.; Sasaki, D.; Kuwatani, Y.; Mishima, M.; Shimizu, M.; Tsuno, Y.
J. Org. Chem. 2001, 66, 2131-2135.
(88) Clayden, J.; Knowles, F. E.; Baldwin, I. R. J. Am. Chem. Soc. 2005, 127, 2412-
2413.
(89) Köhnlein, W.; Böddeker, K. W.; Schindewolf, U. Angew. Chem., Int. Ed. 1967,
6, 360-361.
(90) X-band refers to the wavelength of the microwaves used to split the spin states
(30 mm)
(91) the modulation amplitude was too large to be able to observe the hyperfine
couplings
(92) Newcomb, M.; Curran, D. P. Acc. Chem. Res. 1988, 21, 206-214.
(93) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry Part A: Structure &
Mechanism; Fourth ed.; Kluwer Academic, 2000.
(94) Johnston, L. J.; Lusztyk, J.; Wayner, D. D. M.; Abeywickreyma, A. N.;
Beckwith, A. L. J.; Scaiano, J. C.; Ingold, K. U. J. Am. Chem. Soc. 1985, 107,
4594-4596.
(95) Goodman, J. M.; Kirby, P. D.; Haustedt, L. O. Tetrahedron Lett. 2000, 41,
9879.
(96) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317-323.
(97) Bailey, W. F.; Punzalan, E. R. Tetrahedron Lett. 1996, 37, 5435.
(98) Still, W. C.; Macdonald, T. L. J. Am. Chem. Soc. 1974, 96, 5561-5563.
(99) Clayden, J.; Kenworthy, M. N. Org. Lett. 2002, 4, 787-790.
(100) Yamataka, H.; Fujimura, N.; Kawafuji, Y.; Hanafusa, T. J. Am. Chem. Soc.
1987, 109, 4305-4308.
(101) Ashby, E. C.; Wiesemann, T. L. J. Am. Chem. Soc. 1978, 100, 3101-3110.
(102) Yamataka, H.; Kawafuji, Y.; Nagareda, K.; Miyano, N.; Hanafusa, T. J. Org.
Chem. 1989, 54, 4706-4708.
(103) Yamataka, H.; Sasaki, D.; Kuwatani, Y.; Mishima, M.; Tsuno, Y. J. Am. Chem.
Soc. 1997, 119, 9975-9979.
(104) Yamataka, H.; Matsuyama, T.; Hanafusa, T. J. Am. Chem. Soc. 1989, 111,
4912-4918.
187

References
(105) Gajewski, J. J.; Bocian, W.; Harris, N. J.; Olson, L. P.; Gajewski, J. P. J. Am.
Chem. Soc. 1999, 121, 326-334.
(106) Meyers, A. I.; Mihelich, E. D. J. Org. Chem. 1975, 40, 3158.
(107) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165-195.
(108) Hoffmann, R. W.; Holzer, B. Chem. Commun. 2001, 491-492.
(109) Collum, D. B. Acc. Chem. Res. 1992, 25, 448-454.
(110) Leung, S. S. W.; Streitwieser, A. J. Org. Chem. 1999, 64, 3390-3391.
(111) Sikorski, W. H.; Reich, H. J. J. Am. Chem. Soc. 2001, 123, 6527-6535.
(112) Reich, H. J.; Sikorski, W. H.; Gudmundsson, B. O.; Dykstra, R. R. J. Am.
Chem. Soc. 1998, 120, 4035-4036.
(113) Siemeling, U.; Redecker, T.; Neumann, B.; Stammler, H.-G. J. Am. Chem. Soc.
1994, 116, 5507-5508.
(114) Minakata, S.; Nishimura, M.; Takahashi, T.; Oderaotoshi, Y.; Komatsu, M.
Tetrahedron Lett. 2001, 42, 9019.
(115) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835-876.
(116) Frump, J. A. Chem. Rev. 1971, 71, 483-505.
(117) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; Third
ed.; Wiley, 1999.
(118) Crosignani, S.; Young, A. C.; Linclau, B. Tetrahedron Lett. 2004, 45, 9611-
9615.
(119) Liu, H.; Xu, J.; Du, D. M. Org. Lett. 2007, 9, 4725-4728.
(120) Heine, H. W.; Kaplin, M. S. J. Org. Chem. 1967, 36, 3069-74.
(121) Ferraris, D.; Drury, W. J.; Cox, C.; Lectka, T. J. Org. Chem. 1998, 63, 4568-
4569.
(122) Haidukewych, D.; Meyers, A. I. Tetrahedron Lett. 1972, 13, 3031.
(123) Aggarwal, V. K.; Vasse, J.-L. Org. Lett. 2003, 5, 3987.
(124) Kamata, K.; Agata, I.; Meyers, A. I. J. Org. Chem. 1998, 63, 3113-3116.
(125) Witte, H.; Seeliger, W. Liebigs Ann. Chem. 1974, 1974, 996-1009.
(126) Chang, H.-T.; Sharpless, K. B. Tetrahedron Lett. 1996, 37, 3219.
(127) Lipshutz, B. H.; Miller, T. A. Tetrahedron Lett. 1990, 31, 5253.
(128) Murray, R. W.; Singh, M. Org. Synth. 1998, Coll. Vol. 9, 288.
(129) Lygo, B., Suggestion to use diethyl ether-petrol solvent at low temperature to
encourage precipitation of Et 3 N.HCl salt, reducing free chloride ions which
would otherwise attack the aziridine ring.
(130) Harvey, R. A.; University of Manchester: 2006-2008.
(131) Sigma-Aldrich, As of Apr 2008: both (1R,2R)-(+)-2-Amino-1,2-
diphenylethanol (CAS 88082-66-0, catalogue no. 671126), and (1S,2S)-(−)-2-
Amino-1,2-diphenylethanol (CAS 23190-16-1, catalogue no. 671223) are
available at £43.50 / 0.5g.
(132) Meyers, A. I.; Temple, D. L.; Haidukewych, D.; Mihelich, E. D. J. Org. Chem.
1974, 39, 2787-2793.
(133) Meyers, A. I.; Knaus, G.; Kamata, K. J. Am. Chem. Soc. 1974, 96, 268-270.
(134) Meyers, A. I.; Slade, J. J. Org. Chem. 1980, 45, 2785-2791.
(135) Toxicitiy of methyl triflate is comparable with "Magic Methyl" (methyl
fluorosulfonate) whose vapours have proven deadly. See next reference.
(136) Stiles, D. In Chemistry World 2007; Vol. 4.
(137) Meyers, A. I.; Himmelsbach, R. J.; Reuman, M. J. Org. Chem. 1983, 48, 4053-
4058.
(138) Pridgen, L. N.; Killmer, L. B.; Webb, R. L. J. Org. Chem. 1982, 47, 1985-
1989.
188

References
(139) Yoon, Y.-J.; Joo, J.-E.; Lee, K.-Y.; Kim, Y.-H.; Oh, C.-Y.; Ham, W.-H.
Tetrahedron Lett. 2005, 46, 739.
(140) Chen, Y.-J.; Lei, F.; Liu, L.; Wang, D. Tetrahedron 2003, 59, 7609.
(141) Li, Y.; Manickam, G.; Ghoshal, A.; Subramaniam, P. Synth. Commun. 2006,
36, 925 - 928.
(142) Clayden, J.; Dufour, J.; Grainger, D. M.; Helliwell, M. J. Am. Chem. Soc. 2007,
129, 7488-7489.
(143) Kiessling, A. J.; McClure, C. K. Synth. Commun. 1997, 27, 923-937.
(144) Johansen, M.; Bundgaard, H. J. Pharm. Sci. 1983, 72, 1294-1298.
(145) Buur, A.; Bundgaard, H. Int. J. Pharm. 1984, 18, 325.
(146) estimated as 6 x half-life of oxazolidine derived from pivalaldehyde and
ephedrine, adjusted for ambient temperature (20 ºC drop in temperature gives
c. four-fold decrease in reaction rate
(147) Fife, T. H.; Hutchins, J. E. C. J. Org. Chem. 1980, 45, 2099-2104.
(148) Walker, R. B.; Huang, M.-J.; Leszczynski, J. J. Mol. Struct. Theochem 2001,
549, 137.
(149) Sigma-Aldrich, As of Apr 2008: (1S,2R)-(+)-2-Amino-1,2-diphenylethanol
(CAS 23364-44-5) Sigma-Aldrich 331880, £21.50 / 1g; (1R,2S)-(−)-2-Amino-
1,2-diphenylethanol (CAS 23190-16-1) Sigma-Aldrich 331899 £36 for 1g.
(150) McCasland, G. E.; Furuta, S.; Durham, L. J. J. Org. Chem. 1966, 31, 1516-
1521.
(151) McCasland, G. E.; Furuta, S.; Durham, L. J. J. Org. Chem. 1968, 33, 2841-
2844.
(152) Miwa, I.; Hara, H.; Okuda, J.; Suami, T.; Ogawa, S. Biochem. Int. 1985, 11,
809-16.
(153) Miller, T. W.; Arison, B. H.; Albers-Schonberg, G. Biotechnol. Bioeng. 1973,
15, 1075-1080.
(154) Marco-Contelles, J. Eur. J. Org. Chem. 2001, 2001, 1607-1618.
(155) Chen, X.; Fan, Y.; Zheng, Y.; Shen, Y. Chem. Rev. 2003, 103, 1955-1978.
(156) Arjona, O.; Gomez, A. M.; Lopez, J. C.; Plumet, J. Chem. Rev. 2007, 107,
1919-2036.
(157) Johansson, L.; Lindskog, A.; Silfversparre, G.; Cimander, C.; Nielsen, K. F.;
Lidén, G. Biotech. Bioeng. 2005, 92, 541-552.
(158) Bradley, D. Nat. Rev. Drug Discov. 2005, 4, 945.
(159) Acros Organics quote £31 for 100 mg, vs. £14 for 100 g for myo-inositol (Feb
2008)
(160) Ogawa, S.; Ara, M.; Kondoh, T.; Saitoh, M.; Masuda, R.; Toyokami, T.;
Suami, T. Bull. Chem. Soc. Jpn. 1980, 53, 1121.
(161) Angelaud, R.; Landais, Y. Tetrahedron Lett. 1997, 38, 8841.
(162) Ley, S. V.; Sternfeld, F.; Taylor, S. Tetrahedron Lett. 1987, 28, 225.
(163) Carless, H. A. J.; Malik, S. S. J. Chem. Soc., Chem. Commun. 1995, 2447-
2448.
(164) Haller, J.; Strassner, T.; Houk, K. N. J. Am. Chem. Soc. 1997, 119, 8031-8034.
(165) Hodgson, R.; Majid, T.; Nelson, A. J. Chem. Soc., Perkin Trans. 1 2002, 1444 -
1454.
(166) Alibes, R.; Bayon, P.; deMarch, P.; Figueredo, M.; Font, J.; Marjanet, G. Org.
Lett. 2006, 8, 1617-1620.
(167) Rubottom, G. M.; Gruber, J. M.; Juve, H. D.; Charleson, D. Org. Synth. 1990,
Coll. Vol 7, 282.
(168) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703-710.
189

References
(169) McCormick, J. P.; Tomasik, W.; Johnson, M. W. Tetrahedron Lett. 1981, 22,
607.
(170) Deubel, D. V.; Frenking, G. Acc. Chem. Res. 2003, 36, 645-651.
(171) VanRheenen, V.; Cha, D. Y.; Hartley, W. M. Org. Synth. 1978, 58, 43.
(172) Poli, G. Tetrahedron Lett. 1989, 30, 7385.
(173) Lockwood, S. F.; O'Malley, S.; Watumull, D. G.; Hix, L. M.; Jackson, H.;
Nadolski, G.; (USA): 2005, p 130 pp, Cont -in-part of U S Ser No 629,538.
(174) Bordwell, F. G.; Fried, H. E.; Hughes, D. L.; Lynch, T. Y.; Satish, A. V.;
Whang, Y. E. J. Org. Chem. 1990, 55, 3330-3336.
(175) Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J. Org. Chem. 1980, 45, 3295-
3299.
(176) Eames, J.; Mitchell, H. J.; Nelson, A.; O'Brien, P.; Warren, S.; Wyatt, P. J.
Chem. Soc., Perkin Trans. 1 1999, 1095-1103.
(177) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226-2227.
(178) Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454-5459.
(179) Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1977, 42, 1197-201.
(180) Kumamoto, T.; Tabe, N.; Yamaguchi, K.; Yagishita, H.; Iwasa, H.; Ishikawa,
T. Tetrahedron 2001, 57, 2717.
(181) D. J. Dixon, personal communication
(182) Wigfield, D. C. Tetrahedron 1979, 35, 449.
(183) Leo A. Paquette, D. C., Philip L. Fuchs and Gary Molander e-EROS
Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons, Ltd.,
2006.
(184) Czernecki, S.; Georgoulis, C.; Provelenghiou, C. Tetrahedron Lett. 1976, 17,
3535.
(185) Owensby, D. A.; Parker, A. J.; Diggle, J. W. J. Am. Chem. Soc. 1974, 96, 2682-
2688.
(186) Wessel, H. P.; Iversen, T.; Bundle, D. R. J. Chem. Soc., Perkin Trans. 1 1985,
2247-2250.
(187) Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1957, 1958 - 1965.
(188) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-5976.
(189) McKittrick, B. A.; Ganem, B. Tetrahedron Lett. 1985, 26, 4895.
(190) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95, 6136-6137.
(191) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247.
(192) Cha, J. K.; Kim, N.-S. Chem. Rev. 1995, 95, 1761-1795.
(193) Evans, D. A.; Kaldor, S. W. J. Org. Chem. 1990, 55, 1698-1700.
(194) In Haller & Houk, 1997, the final sentence of the results and discussion reads
"The Kishi model is also valid in cyclic alkenes where the stereogenic centre is
fixed in a position resembling that dictated by the 1,3-allylic strain."
(195) Donohoe, T. J.; Garg, R.; Moore, P. R. Tetrahedron Lett. 1996, 37, 3407.
(196) Arjona, O.; de Dios, A.; Plumet, J.; Saez, B. J. Org. Chem. 1995, 60, 4932-
4935.
(197) Pearlman, W. M. Tetrahedron Lett. 1967, 8, 1663.
(198) Jacobsen, E. N.; Marko, I.; France, M. B.; Svendsen, J. S.; Sharpless, K. B. J.
Am. Chem. Soc. 1989, 111, 737-739.
(199) Donohoe, T. J.; Blades, K.; Moore, P. R.; Waring, M. J.; Winter, J. J. G.;
Helliwell, M.; Newcombe, N. J.; Stemp, G. J. Org. Chem. 2002, 67, 7946-
7956.
(200) Fürst, A.; Plattner, P. A. Helv. Chim. Acta 1949, 32, 275-283.
(201) Gonzalez, C.; Carballido, M.; Castedo, L. J. Org. Chem. 2003, 68, 2248-2255.
190

References
(202) Meyers, A. I.; Temple, D. L.; Nolen, R. L.; Mihelich, E. D. J. Org. Chem.
1974, 39, 2778-2783.
(203) Kurosaki, Y.; Fukuda, T.; Iwao, M. Tetrahedron 2005, 61, 3289.
(204) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.;
Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669-685.
(205) Xie, W.; Jin, Y.; Wang, P. ChemTech 1999, 23-29.
(206) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209-217.
(207) Liotta, L. J.; Lee, J.; Ganem, B. Tetrahedron 1991, 47, 2433.
(208) Berti, G.; Macchia, B.; Macchia, F. Tetrahedron Lett. 1965, 6, 3421.
(209) (AIST), N. I. A. I. S. a. T.; Vol. 2008.
(210) Scifinder 2006 search of carbocyclic epoxides without adjacent π-systems
returned 50 reactions, of which 2 showed preference for opening at the
neopentylic centre. This survey did not consider the nature of the ground or
transition states, but it is assumed that a significant proportion will have
required a twist boat transition state to avoid neopentylic attack
(211) Alabugin, I. V.; Manoharan, M. J. Org. Chem. 2004, 69, 9011-9024.
(212) Bodkin, J. A.; McLeod, M. D. J. Chem. Soc., Perkin Trans. 1 2002, 2733-2746.
(213) Donohoe, T. J.; Johnson, P. D.; Cowley, A.; Keenan, M. J. Am. Chem. Soc.
2002, 124, 12934-12935.
(214) Donohoe, T. J.; Bataille, C. J. R.; Gattrell, W.; Kloesges, J.; Rossignol, E. Org.
Lett. 2007, 9, 1725-1728.
(215) Cohen, T.; Matz, J. R. J. Am. Chem. Soc. 1980, 102, 6900-2.
191

References
192

Experimental section
Chapter 5 – Experimental Section
5.1 General
NMR spectra were recorded on a Varian XL 300 or Bruker Ultrashield 500
spectrometers. The chemical shifts (δ) are reported in ppm downfield of
trimethylsilane and coupling constants (J) reported in hertz and rounded to 0.5 Hz.
Splitting patterns are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet
(q), quintet (qn), septet (p), octet (oct), mulitiplet (m), broad (br), or a combination of
these. An asterisk, * denotes the signal disappears upon a mixture with D 2 O or
CD 3 OD. Solvents were used as internal standard when assigning NMR spectra (δ H :
CDCl 3 7.27 ppm;δ C : CDCl 3 77.0 ppm; δ H : DMSO-d 6 2.50 ppm; δ C : DMSO-d 6 39.4
ppm; δ H : CD 3 OD 3.31 ppm; δ C : CD 3 OD 49.0 ppm; δ H : C 6 D 6 7.15 ppm; δ H : D 2 O 4.79
ppm). Coupling constants were calculated using Mestre-C 4.8.6 software, 1 and
complicated couplings simulated. 2 Structural assignment of NMR signals is based on
chemical shift, integration, coupling pattern and COSY, DEPT and HMQC NMR
experiments when necessary.
Low and high resolution mass spectra were recorded by staff at the University of
Manchester. EI and CI spectra were recorded on a Fisons VG Trio 2000; and high
resolution mass spectra (HRMS) were recorded on a Kratos Concept-IS mass
spectrometer, and are accurate to ± 0.001. Infrared spectra were recorded as on a Ati
Matson Genesis Series FTIR spectrometer as a film on a sodium chloride plate.
Absorptions reported are sharp and strong unless otherwise stated as broad (br),
medium (m), or weak (w), only absorption maxima of interest are reported.
Microanalysis was carried out using Carlo-Erba automatic analyser by members of
staff of the University of Manchester. Melting points (Mpt) were determined on a
GallenKamp apparatus and are uncorrected. Optical rotation measurements were taken
on a AA-100 polarimeter with the solvent, concentration and sample temperature as
stated.
Thin layer chromatography (TLC) was performed using commercially available precoated
plates (Macherey-Nagel alugram. Sil G/ UV254 ) and visualised with UV light at
193

Experimental section
254nm, dodecamolybdophosphoric acid (PMA) dip, or over iodine.
chromatography was carried out using Fluorochem Davilsil 40-63u 60 Å.
Flash
All reactions were conducted under atmospheric conditions unless otherwise stated.
Where a nitrogen atmosphere is employed, oven-dried glassware was used, and
immediately purged under vacuum before being backfilled with nitrogen whilst still
hot. Microwave reactions were conducted in a Biotage Initiator synthesis system.
Tetrahydrofuran (THF) and diethylether were distilled under nitrogen from sodium,
using a benzophenone indicator. Dichloromethane and toluene were obtained by
distillation from calcium hydride under nitrogen. Triethylamine was distilled from and
stored over potassium hydroxide. Anhydrous dioxane, methanol and
dimethylformamide were used as purchased from Sigma-Aldrich. Water was used as
supplied by United Utilities. Anhydrous dimethylhexahydro-2-pyrimidinone (DMPU)
was used as supplied by Fluka over molecular sieves (product number 41661); methyl
trifluoromethanesulfonate was used as supplied from Fluka (product number 91736).
Petrol refers to the fraction of light petroleum ether boiling between 40-65 °C. All
other solvents and commercially obtained reagents were used as received or purified
using standard procedures. Isopropyllithium was obtained as a solution (c. 0.7 M) in
pentane, s-butyllithium was obtained as a solution (c. 1.3 M) in cyclohexane and n-
butyllithium was obtained as a solution (c. 2.5 M) in cyclohexane. All organolithium
solutions were titrated prior to use against a stirred solution of diphenylacetic acid in
THF at 0 °C.
Numbering conventions in the main body and experimental sections are:
General Procedure 1: Amide synthesis
The acyl chloride (1.0 eq) in CH 2 Cl 2 (2 cm 3 /mmol) was added drop wise over a period
of 2 hr to a stirred solution of the commercially available amine (1.2 eq) in CH 2 Cl 2 (5
cm 3 /mmol) and Et 3 N (2 eq) at 0 °C under a nitrogen atmosphere. The white emulsion
194

Experimental section
was triturated with water (2 x reaction volume), filtered, triturated with acetone (2 x
reaction volume), filtered and triturated with EtOAc (1 x reaction volume). The
combined washes were reduced under vacuum, transferred to a separating funnel, the
aqueous phase acidified, washed with EtOAc (3 washes, each 2 x reaction volume) and
the organic washes reduced under vacuum to give the amide as a white powder which
was combined with the residue from the filtration.
General Procedure 2: Oxazoline synthesis from aryl amide
Adapted from the method of Linclau, 3 diisopropylcarbodiimide (DIC, 1.0 eq) was
added to a solution of the amide (1.0 eq) and Cu(OTf) 2 (0.06 eq) in cyclic ether (3
cm 3 /mmol) under a nitrogen atmosphere. When heated under reflux, dioxane was used
as solvent, and refluxed for the stated time. When heated under microwave irradiation,
THF was used and the reaction conducted in a closed vial at the stated temperature for
the stated time. Crude reaction mixture was filtered with EtOAc, concentrated under
vacuum, and purified by flash chromatography.
General Procedure 3: Preparation of oxazolines from aryl amide and α-amino
alcohol
Adapted from the method of Meyers 4 to a stirred solution of benzamide (1 eq)
dissolved in anhydrous CH 2 Cl 2 (10 cm 3 /mmol) was added triethyloxonium
tetrafluoroborate (1.2 eq) under an atmosphere of nitrogen. After being stirred at room
temperature for 16 hr, amino alcohol was added (1.3 eq), and solution brought to reflux
for 16 hr. Upon cooling the mixture was washed with water, extracted with CH 2 Cl 2 ,
dried over anhydrous Na 2 SO 4 , and concentrated under vacuum to give a residue which
was purified by flash chromatography.
General Procedure 4: Nucleophilic Addition to Aryl Oxazolines
The organolithium was added drop wise to a stirred solution of oxazoline in the stated
dry solvent (0.05 mmol/cm 3 ) and co-solvent at –78 °C under a nitrogen atmosphere.
After the stated time, the electrophile was added and the reaction mixture allowed to
warm to ambient temperature before addition of excess methanol. The reaction
mixture was reduced under vacuum and passed through a silica plug (1:1 EtOAc:
petrol) and solvent removed before purification by flash chromatography.
195

Experimental section
General Procedure 5: Modified Upjohn Dihydroxylation
Adapted from the methods of the Upjohn Company 5 and Nelson 6 , osmium tetroxide
(0.01 eq, 2.5% solution w/w in t-BuOH) was added to a vigorously stirred solution of
the olefin (1 eq) and N-methylmorpholine N-oxide (2 eq, NMO) in the stated solvent,
and the reaction monitored by TLC. When judged complete, an aqueous solution of
sodium sulfite or sodium metabisulfite (c. 5 eq) was added to the solution and stirred
for 2 hr, all solvent removed under vacuum, and the resulting emulsion dried onto
celite before being passed through a silica plug (EtOAc), and solvent again removed
under vacuum, before final purification by flash chromatography.
General Procedure 6: Oxazoline alkylation-reduction
Adapted from the method of Meyers 7 methyl trifluoromethanesulfonate (2.0 eq) was
added drop wise to a stirred solution of oxazoline in CH 2 Cl 2 (0.1M) under a nitrogen
atmosphere at room temperature. After the stated time, the reaction was cooled to 0 °C
and a cooled solution of sodium borohydride (2 eq) in dry THF-methanol (4:1) was
added over 10 min, resulting in a white foam. The reaction was warmed to room
temperature, and ammonium chloride (1 x reaction volume) was added and solvent
removed under vacuum. The reaction mixture was extracted with CH 2 Cl 2, dried over
anhydrous Na 2 SO 4 and concentrated under vacuum to give the crude oxazolidine.
General Procedure 7: Oxazolidine hydrolysis-reduction
Adapted from the method of Meyers 7 oxalic acid (5 eq) was added to a solution of
oxazolidine in 4:1 THF:water (0.1M) and stirred at the stated temperature. When
judged complete by TLC, the solvent was removed, the aqueous layer washed with
EtOAc and the combined organic phases dried over anhydrous MgSO 4 . The resulting
aldehyde was dissolved in methanol (0.1M), cooled to 0 °C and sodium borohydride (2
eq) added in a single portion. When judged complete by TLC, acetic acid was added
until effervescence ceased and the solvent removed under vacuum. The resultant oil
was partitioned between water and EtOAc, and the aqueous layer washed with EtOAc
until no further organic compound was extracted (TLC). The combined organic
washes were dried over anhydrous MgSO 4 and solvent removed under vacuum to give
the crude alcohol.
196

Experimental for chapter 2
5.2 Experimental Procedures for Chapter 2
Synthesis of (4R,5R)-2-((1S,6R)-6-isopropyl-1-methylcyclohexa-2,4-dienyl)-4,5-
diphenyloxazoline (102a)
Ph
O
N
Ph
i) i-PrLi (1.5 eq), DMPU (6 eq)
-78 °C, 30 min
ii) MeI
Ph
6
5
O
1
4
N
Ph
Me
2
3
+
Ph
6
5
O
4
1
N
102a 103a
General procedure 4 was used employing oxazoline 101a (130 mg, 0.43 mmol) i-PrLi
(0.65 mmol in pentane), DMPU (0.31 cm 3 , 6 eq) and methyl iodide (0.1 cm 3 ) quench
after 30 min. Flash chromatography (19:1 petrol:EtOAc) yielded, diene 102a (109 mg,
70%) as clear needles, and inseparable oxazolines 101a and 103a (24 mg, 2:1 ratio).
Ph
2
3
102a R f : 0.41 (4:1 petrol:EtOAc); Mpt: 108-110 ºC (EtOAc); [α] 23 D : –296 (c = 1.0,
EtOH); MS m/z (CI+): 358 (100%, MH + ), 359 (19%, (M+1)H + ); IR ν max (film)/cm -1 :
2958 (m, C–H), 1660 (C=N), 1495, 1453, 1257; Microanalysis: % found (% calc’d for
C 25 H 27 NO) C, 83.52 (83.99); H, 7.59 (7.61); N, 3.90 (3.92); 1 H-NMR (CDCl 3 , 300
MHz) δ 7.48-7.20 (m, 10H, Ph), 6.34 (d, 1H, J 10.0, H6), 6.14 (dd, 1H, J 5.0, 9.5, H4),
5.91 (dd, 1H, J 10.0, 5.0, 1.0, H5), 5.74 (dd, 1H, J 9.5, 6.0, H3), 5.22 (d, 1H, J 9.0,
OCHPh), 5.06 (d, 1H, J 9.0, NCHPh), 2.53-2.51 (m, 1H, H2), 2.08-2.04 (m, 1H,
CHMe 2 ), 1.55 (s, 3H, Me), 1.06 (d, 3H, J 7.0, CHMe A Me B ), 0.98 (d, 3H, J 7.0,
CHMe A Me B ); 13 C-NMR (CDCl 3 , 75 MHz) δ 171.4 (C=N), 141.9 (ipso-Ph), 140.4
(ipso-Ph), 132.5 (C6), 128.8, 128.7, 128.3, 127.5, 126.7, 125.7 (Ph), 124.4, 123.8,
121.5 (C3-C5), 88.9 (CHOPh), 78.8 (CHNPh), 47.2 (C2), 41.3 (C1), 31.5 (CHMe 2 ),
25.6 (CHMe A Me B ), 21.1 (CHMe A Me B ), 17.0 (Me).
103a R f : 0.45 (4:1 petrol:EtOAc); MS m/z (CI+): 314 (100%, MH + ), 315 (22%,
(M+1)H + ) 1 H-NMR (CDCl 3 , 300 MHz) δ 8.01 (d, 1H, J 7.5, H6), 7.45-7.22 (m, 10H,
Ar), 5.34 (d, 1H, J 7.5, OCHPh), 5.28 (d, 1H, J 7.5, NCHPh), 2.73 (s, 3H, Me).
197

Experimental for chapter 2
Synthesis of (4R,5R)-2-((1S,6R)-6-sec-butyl-1-methylcyclohexa-2,4-dienyl)-4,5-
diphenyloxazoline (102a’)
Ph
O
N
Ph
i) s-BuLi (1.5 eq), DMPU (15 eq)
-78 °C, 30 min
ii) MeI
Ph
O
6
5
N
Ph
7
1
2
3
4
102a'
8
9
11
10
Ph
O
6
5
4
1
N
103a
General procedure 4 was used employing oxazoline 101a (128 mg, 0.43 mmol) s-BuLi
(0.64 mmol in hexane), DMPU (1.00 cm 3 , 13 eq) and methyl iodide quench after 30
min. Flash chromatography (19:1 petrol:EtOAc) yielded, dienes 102a’ (128 mg, 81%,
inseparable) as white needles, and oxazolines 103a and starting material (11 mg, 10:1
ratio, inseparable) as a clear oil.
Ph
2
3
102a’ R f : 0.58 (4:1 petrol:EtOAc); MS: m/z (CI+): 372 (100%, MH + ), 373 (29%,
(M+1)H + ); IR: ν max (film)/cm -1 : 2958, 1737, 1659 (C=N), 1494, 1267; Microanalysis:
% found (% calc’d for C 26 H 29 NO) C, 83.27 (84.06); H, 7.90 (7.87); N, 3.78 (3.77); 1 H-
NMR (major diastereomer): (CDCl 3 , 300 MHz) δ 7.45-7.22 (m, 10H, Ar), 6.35 (dd,
1H, J 10.0, 1.0, H6), 6.10-6.05 (m, 1H, H4), 5.86 (ddd, 1H, J 10.5, 5.0, 1.0, H5), 5.67-
5.61 (m, 1H, H3), 5.22 (d, 1H, J 6.0, OCHPh), 5.06 (d, 1H, J 6.0, NCHPh), 2.65-2.61
(m, 1H, H2), 1.76-1.67 (m, 1H, H9), 1.55 (s, 3H, H7), 1.46-1.18 (m, 2H, H10), 1.05 (d,
3H, J 7.0, H8), 0.93 (m, 3H, H11); 13 C-NMR: (CDCl 3 , 75 MHz) δ 171.5 (C=N), 141.9
(ipso-Ph), 140.5 (ipso-Ph), 132.7, 128.8, 128.7, 128.3, 127.6, 126.7, 125.1, 125.7,
124.3, 123.9, 121.6 (Ph and C3 to C6), 88.9 (OCHPh), 78.9 (NCHPh), 45.3 (C2), 41.1
(C1), 38.8 (C9), 27.5 (C10), 25.6 (C8), 14.7 (C7), 12.5 (C11).
103a see previous page
198

Experimental for chapter 2
Synthesis of (4R,5R)-2-((1S,6R)-6-isopropyl-4-methoxy-1-methylcyclohexa-2,4-
dienyl)-4,5-diphenyloxazoline (102b)
Ph Ph
O N
i) i-PrLi (1.5 eq), DMPU (6 eq)
ii) MeI
OMe
Ph Ph Ph Ph
O N O N
1
6
2
5 3
4
+
1
6
2
5
3
4
OMe
OMe
102b 103b
General procedure 4 was used employing oxazoline 101b (2.00 g, 6.08 mmol) i-PrLi
(18.2 mmol in pentane), DMPU (4.41 cm 3 , 36.4 mmol) and methyl iodide (0.76 cm 3 ,
12.1 mmol) quench after 10 min. Flash chromatography (19:1 to 4:1 petrol:EtOAc)
yielded starting material (110 mg, 6%), oxazoline 103b (370 mg, 18%) as a clear oil
and, after recrystallisation from diethyl ether, diene 102b (1.64 g, 70%) as colourless
clear cubes.
102b R f : 0.60 (4:1 petrol:EtOAc); Mpt: 113-117 °C (toluene/hexane), 108-110 °C
(Et 2 O); [α] 24 D : –115 (c = 0.5, MeOH); MS m/z (CI+): 388 (100%, MH + ), 389 (29%,
(M+1)H + ); HRMS (ESI+) m/z found 388.2270 (MH calcd. 388.2271); Microanalysis:
% found (% calc’d for C 26 H 29 NO 2 ) C 80.42, (80.59); H, 7.76 (7.54); N, 3.56 (3.61); IR
ν max (film)/cm -1 : 2957 (CH), 1661 (C=N), 1453, 1220, 1087; 1 H-NMR (CDCl 3 , 300
MHz) δ 7.46-7.18 (m, 10H, Ph), 6.43 (d, 1H, J 10.0, H5), 5.74 (dd, 1H, J 10.0, 2.0,
H6), 5.22 (d, 1H, J 5.0, HCO), 5.06 (d, 1H, J 5.0, HCN), 4.53 (dd, 1H, J 6.5, 2.0, H3),
3.62 (s, 3H, OMe), 2.59 (ddd, 1H, J 6.5, 3.5, 1.0, H2), 2.08-1.96 (m, 1H, CHMe 2 ), 1.57
(s, 3H, Me), 1.00 (d, 3H, J 6.5, CHMe a Me b ), 0.96 (d, 3H, J 6.5, CHMe a Me b ); 13 C-
NMR (CDCl 3 , 125 MHz) δ 171.2 (C=N), 153.1 (C4), 141.9, 140.3 (ipso-Ph), 135.0
(C5), 128.9 (meta-Ph), 128.7 (meta-Ph), 128.3 (para-Ph), 127.6 (para-Ph), 126.7
(ortho-Ph), 125.7 (ortho-Ph), 121.6 (C6), 89.0 (COPh), 88.4 (C3), 78.8 (HCN), 54.2
(OMe), 46.8 (C2), 41.9 (C1), 31.7 (CMe 2 ), 25.8 (CMe), 21.2 (CMe a Me b ), 17.0
(CMe a Me b ).
103b R f : 0.50 (4:1 petrol:EtOAc); [α] D 22 : –44 (c = 1.0, EtOH); MS m/z (CI+): 344
(100%, MH + ), 345 (22%, (M+1)H + ); HRMS (ESI+) m/z found 344.1645 (MH calcd.
344.1645); IR ν max (film)/cm -1 : 2927 (m, C-H), 1637 (C=N), 1605, 1247; 1 H-NMR
199

Experimental for chapter 2
(CDCl 3 , 300 MHz) δ 8.00 (d, 1H, J 8.5, H6), 7.46-7.28 (m, 10H, Ph), 6.86-6.78 (m,
2H, H3, H5), 5.31 (d, 1H, J 7.5, CHO), 5.26 (d, 1H, J 7.5, CHN), 3.86 (s, 3H, OMe),
2.73 (s, 3H, CMe); 13 C-NMR (CDCl 3 , 125 MHz) δ 164.7 (C=N), 161.3 (C4), 142.5
(C2), 141.7 (ipso-Ph), 140.9 (ipso-Ph), 132.0, 128.9, 128.8, 128.3, 127.6, 126.6, 125.7,
119.2, 116.8, 110.9 (Ar), 87.8 (COPh), 79.3 (CNPh), 55.3 (OMe), 22.7 (Me).
Synthesis of (4R,5R)-2-((1S,6R)-6-sec-butyl-4-methoxy-1-methylcyclohexa-2,4-
dienyl)-4,5-diphenyloxazoline (102b’)
Ph
Ph
Ph
Ph
Ph
Ph
O
N
i) s-BuLi (3 eq), DMPU (6 eq)
-78 °C, 10 min
ii) MeI
O
1
6
5
N
7
2
3
4
8
9
10
11
+
O
N
OMe
OMe
dr 7:2
OMe
102b'
103b'
General procedure 2 was used employing oxazoline 101b (100 mg, 0.30 mmol) s-BuLi
(0.90 mmol in hexanes), DMPU (0.22 cm 3 , 36.4 mmol) and methyl iodide (0.1 cm 3 )
quench after 10 min. Flash chromatography (49:1 to 4:1 petrol:EtOAc) yielded
starting material (5 mg, 5%) and oxazolines 102b’ and 103b’ (94 mg, 78%, 9:1
mixture) as a clear oil.
R f : 0.29 (9:1, petrol:EtOAc); [α] 22 D : –104 (c = 1.0, CHCl 3 ); MS m/z (CI+) 402 (100%,
MH + ), 403 (27%, [(M+1)H] + ); HRMS: found 402.2431, MH requires 402.2428; IR
ν max (film)/cm⎯¹ 2959 (m), 1661 (C=N), 1452 (m), 1215, 1173 (m), 1086; ¹H-NMR
(major compound) (CDCl 3 , 500 MHz) δ 7.42-7.28 (m, 8H, Ph), 7.24-7.20 (m, 2H, Ph),
6.43 (d, 1H, J 10.0, H6), 5.74 (dd, 1H, J 10.0, 2.0, H5), 5.22 (d, 1H, J 8.5, CHOPh),
5.05 (d, 1H, J 8.5, CHNPh), 4.47 (dd, 1H, J 6.5, 2.0, H3), 3.61 (s, 3H, OMe), 2.73-
2.68 (m, 1H, H2), 1.71-1.64 (m, 1H, H9), 1.57 (s, 3H, H7), 1.42-1.32 (m, 1H, H10),
1.28-1.20 (m, 1H, H10’), 0.99 (d, 3H, J 6.5, H8), 0.95-0.90 (m, 3H, H11); ¹³C-NMR
(CDCl 3 , 125 MHz) δ 171.2 (C=N), 153.0 (C4), 141.9 (ipso-Ph), 140.4 (ipso-Ph), 135.1
(C5), 128.7, 128.7, 127.6, 126.7, 125.7 (Ph), 121.7 (C6), 89.0, 88.6 (CHOPh, C3), 78.9
(CHNPh), 54.2 (OMe), 44.8 (C2), 41.7 (C1), 39.0 (C9), 27.6 (C10), 25.8 (C7), 14.8,
12.4 (C8, C11).
200

Experimental for chapter 2
Synthesis of (4R*,5R*)-2-((R*)-6-isopropyl-4-methoxycyclohexa-1,4-dienyl)-4,5-
diphenyloxazoline (102γ) & (4R*,5R*)-2-((R*)-6-isopropyl-4-methoxycyclohexa-
1,3-dienyl)-4,5-diphenyloxazoline (102ε)
Ph
O
N
OMe
Ph
i) i-PrLi (3 eq), DMPU (6eq)
PhMe, −78°C, 20 min
ii) MeOH
Ph
6
5
O
1
4
N
Ph
2
3
Ph
E
O
F
A
D
OMe
OMe
OMe
102γ 102ε 116b
General procedure 4 was used employing oxazoline 101b (200 mg, 0.61 mmol) i-PrLi
(1.82 mmol in pentane), DMPU (0.44 cm 3 , 3.66 mmol) in toluene, and a methanol
(0.12 cm 3 3.04 mmol) quench after 5 min. Flash chromatography (19:1 petrol:EtOAc)
yielded diene 102γ (68 mg, 32%), as a colourless oil, diene 102ε and rearomatised
adduct 116b (50 mg, 5:1 ratio), and starting material (58 mg, 29%) as colourless oils.
N
Ph
B
C
Ph
O
Z
Y
U
X
N
Ph
V
W
102γ R f : 0.26 (9:1 petrol:EtOAc); MS m/z (CI+): 374 (100%, MH + ), 375 (26%,
(M+1)H + ); HRMS (ESI+) m/z found 374.2123 (MH calcd. 374.2215); IR
ν max (film)/cm -1 : 2950 (C-H), 1688 (C=N), 1618 (C=C), 1453 (m), 1217, 1168; 1 H-
NMR (CDCl 3 , 300 MHz) δ 7.44-7.20 (m, 10H, Ph), 6.89 (dd, 1H, J 5.0, 3.0, H6), 5.22
(d, 1H, J 7.0, CHO), 5.11 (d, 1H, J 7.0, CHN), 4.73 (dd, 1H, J 5.0, 2.0, H3), 3.63 (s,
3H, OMe), 3.57 (m, 1H, H2), 2.99 (dm, 1H, J 22.5, H5 a ), 2.85 (dt, 1H, J 22.5, 5.0,
H5 b ), 2.41 (pd, 1H, J 7.0, 2.5, CHMe 2 ), 1.03 (d, 3H, J 7.0, CHMe a Me b ), 0.76 (d, 3H, J
7.0, CHMe a Me b ); 13 C-NMR (CDCl 3 , 125 MHz) δ 163.8 (C=N), 153.3 (C4), 142.1
(ipso-Ph), 140.8 (ipso-Ph), 132.6 (C6), 129.0 (C1), 128.8 (meta-Ph), 128.7 (meta-Ph),
128.2 (para-Ph), 127.6 (para-Ph), 126.6 (ortho-Ph), 125.4 (ortho-Ph), 91.1 (C3), 88.0
(CHO), 79.0 (CHN), 54.2 (OMe), 42.0 (C2), 31.5 (CHMe 2 ), 30.0 (C5), 20.8
(CHMe a Me b ), 16.1 (CHMe a Me b ).
5:1 mixture 102ε:116b R f : 0.44 (4:1 petrol:EtOAc); HRMS: found 374.2115, MH
requires 374.2115; ¹H-NMR (CDCl 3 , 400 MHz) δ 7.91 (d, 1H, J 9.0, Hz), 7.42-7.22
(m, 10H, Ph), 7.04 (d, 1H, J 6, H f ), 6.97 (d, 1H, J 3.0, H w ), 6.77 (dd, 1H, J 9.0, 3.0,
H y ), 5.30 (d, 1H, J 8.0, CHOPh Min ), 5.25 (d, 1H, J 8.0, CHNPh Min ), 5.20 (d, 1H, J 8.0,
CHOPh Maj ), 5.07-5.02 (m, 2H, CHNPh Maj , H e ), 4.22 (p, 1H, J 7.0, CHMe 2Min ), 3.86 (s,
201

Experimental for chapter 2
3H, OMe Min ), 3.65 (s, 3H, OMe Maj ), 2.90-2.85 (m, 1H, H b ), 2.76 (ddd, 1H, J 17.0, 9.0,
2.0, H cax ), 2.35 (d, 1H, J 17.0, H ceq ), 2.07 (p, 1H, J 7.5, CHMe 2Maj ), 1.28 (d, 6H, J 7.0,
CHMe 2Min ), 0.99 (d, 3H, J 7.5, CHMe 2Maj ), 0.92 (d, 3H, J 7.5, CHMe 2Maj ).
Synthesis of (4R,5R)- 2-((1S,6S)-6-isopropyl-5-methoxy-1-methylcyclohexa-2,4-
dienyl)-4,5-diphenyloxazoline (102c)
Ph
O
N
Ph
i) i-PrLi (1.5 eq.), DMPU (6eq)
-78 °C, 20 min
ii) MeI
Ph
6
O
1
N
Ph
2
Ph
6
O
1
N
Ph
2
Me
OMe
5
4
3
OMe
5
4
102c 103c
3
OMe
General procedure 4 was used employing oxazoline 101c (122 mg, 0.37 mmol) i-PrLi
(0.55 mmol in pentanes), DMPU (0.27 cm 3 , 6 eq) and methyl iodide (0.1 cm 3 ) quench
after 10 min. Flash chromatography (99:1 to 95:1 petrol:EtOAc) yielded oxazoline
102c (77 mg, 54%) as colourless flowers, 103c (11 mg, 9%) as a colourless oil, and
starting material (24 mg, 20%).
102c R f : 0.55 (4:1 petrol:EtOAc); Mpt: 135-7 °C (PhMe); [α] 19 D : –105 (c = 0.25,
CH 2 Cl 2 ); MS m/z (CI+): 388 (100%, MH + ); HRMS (ESI+) m/z found 388.2281 (MH
calcd. 388.2271); Microanalysis: % found (% calc’d for C 26 H 29 NO 2 ) C, 78.36 (80.59),
H, 7.45 (7.54), N 3.37 (3.61); IR ν max (film)/cm -1 : 2961 (m), 1659 (C=N), 1590, 1453,
1269, 1209, 1083; 1 H NMR: (CDCl 3 , 300 MHz) δ 7.47-7.21 (m, 10H, Ph), 6.04 (d,
1H, J 9.5, H6), 5.85 (dd, 1H, J 9.5, 6.0, H5), 5.23 (d, 1H, J 8.5, CHOPh), 5.13-5.06
(m, 2H, H4, CHNPh), 3.63 (s, 3H, OMe), 2.38 (d, 1H, J 3.0, H2), 2.08 (pd, 1H, J 7.0,
3.0, CHMe 2 ), 1.56 (s, 3H, Me), 1.10 (d, 3H, J 7.0, CHMe A Me B ), 1.10 (d, 3H, J 7.0,
CHMe A Me B ); 13 C NMR: (CDCl 3 , 75 MHz) δ 171.3 (C=N), 157.2 (C3), 141.9 (ipso-
Ph), 140.4 (ipso-Ph), 128.8 (Ph), 128.7 (Ph), 128.2 (para-Ph), 127.5 (para-Ph), 126.6
(Ph), 125.6 (Ph), 125.0 (C6), 122.0 (C5), 93.0 (C4), 88.8 (CHO), 78.7 (CHN), 54.2
(OMe), 51.4 (C2), 43.6 (C1), 30.7 (CHMe 2 ) , 25.0 (Me), 23.6 (CHMe A Me B ), 17.9
(CHMe A Me B ).
202

Experimental for chapter 2
103c R f : 0.45 (4:1, petrol:EtOAc); MS m/z (CI) 344 (100%, MH + ), 345 (25%,
(M+1)H + ); HRMS: found 344.1650, MH requires 344.1645; IR ν max (film)/cm⎯¹ 2930
(m), 1644, 1461 (m, C-Me), 1259, 1046; ¹H-NMR (CDCl 3 , 300 MHz) δ 7.56 (d, 1H, J
8.0, H6), 7.50-7.22 (m, 11H, Ph, H5), 7.01 (d, 1H, J 8.0, H4), 5.37 (d, 1H, J 8.0,
CHOPh), 5.29 (d, 1H, J 8.0, CHNPh), 3.89 (s, 3H, OMe), 2.59 (s, 3H, Me); ¹³C-NMR
(CDCl3, 75.5 MHz) δ 164.8 (C3), 158.1 (C=N), 142.1 (ipso-Ph), 140.6 (ipso-Ph),
128.9, 128.8, 128.4, 127.7, 126.7, 126.1, 125.8 (Ph, C6), 122.1 (C5), 112.6 (C4), 88.4
(CHOPh), 79.3 (CHNPh), 55.8 (OMe), 13.4 (Me).
Synthesis of (4R*,5R*)-2-((1S*,6R*)-6-isopropyl-1-methyl-4-phenylcyclohexa-2,4-
dienyl)-4,5-diphenyloxazoline (102g) & (4R*,5R*)-2-(4-methoxy-2-methylphenyl)-
4,5-diphenyloxazoline (116g)
Ph
Ph
Ph
Ph
Ph
Ph
O
N
i) i-PrLi (1.5 eq), DMPU (6 eq)
-78°C
ii) MeI
O
1
6
N
2
O
1
6
N
2
Ph (±)
5
4
Ph
3
5
4
Ph
3
102g
116g
General procedure 4 was used employing oxazoline 101g (70 mg, 0.19 mmol) i-PrLi
(0.56 mmol in pentane), DMPU (0.14 cm 3 , 6 eq) in THF, and a methyl iodide (0.1
cm 3 ) quench after 30 min. Flash chromatography (19:1 petrol:EtOAc) and reverse
phase mass directed auto purification (MDAP) yielded diene 102g (27 mg, 32%),
oxazoline 116g (24 mg, 30%) and starting material (10 mg, 14%) all as clear
colourless oils.
102g R f : 0.51 (4:1 petrol:EtOAc); MS m/z (CI+): 434 (100%, MH + ), 435 (31%,
(M+1)H + ); HRMS (ESI+): m/z found 434.2484 (MH calcd. 434.2478); IR
ν max (film)/cm -1 : 2958 (m, C-H), 2360 (m), 1659 (C=N), 1453 (m), 1087; 1 H-NMR
(CDCl 3 , 400 MHz) δ 7.41-7.26 (m, 8H, Ph), 7.25-7.14 (m, 6H, Ph), 7.11-7.07 (m, 1H,
Ph), 6.46 (d, 1H, J 10.0, H6), 6.20 (dd, 1H, J 10.0, 1.5, H5), 5.92 (d, 1H, J 6.0, H3),
5.17 (d, 1H, J 9.0, CHO), 5.01 (d, 1H, J 9.0, CHN), 2.63 (dd, 1H, J 6.0, 3.0, H2), 2.03
(pd, 1H, J 7.0, 3.0, CHMe 2 ), 0.99 (d, 3H, J 7.0, CHMe A Me B ), 0.97 (d, 3H, J 7.0,
CHMe A Me B ); 13 C-NMR (CDCl 3 , 125 MHz) δ 170.3 (C=N), 140.9 (C4), 139.4 (ipso-
203

Experimental for chapter 2
Ph), 139.3 (ipso-Ph), 135.1 (ipso-Ph), 132.8 (C5), 127.9, 127.8, 127.4 (Ph), 127.4
(para-Ph), 126.6 (para-Ph), 126.1 (para-Ph), 125.7, 124.8, 124.6, 122.1, 88.0 (CHO),
77.8 (CHN), 46.9 (C2), 40.2 (C1), 31.1 (CHMe 2 ), 24.8 (CMe), 20.4 (CHMe a Me b ), 16.5
(CHMe a Me b ).
116g R f : 0.44 (4:1 petrol:EtOAc); MS m/z (CI+): 418 (100%, MH + ), 419 (28%,
(M+1)H + ); HRMS (ESI+): m/z found 418.2166 (MH calcd. 418.2165); IR
ν max (film)/cm -1 : 2963 (C-H), 1640 (C=N), 1260, 1040; 1 H-NMR (CDCl 3 , 400 MHz) δ
8.03 (d, 1H, J 8.5, H6), 7.72-7.66 (m, 3H, Ar) 7.55-7.34 (m, 15H, Ar), 5.41 (d, 1H, J
8.0, CHO), 5.34 (d, 1H, J 8.0, CHN), 4.24 (p, 1H, J 7.0, CHMe 2 ), 1.40 (d, 6H, J 7.0,
CHMe 2 ); 13 C-NMR (CDCl 3 , 100 MHz) δ 164.6 (C=N), 150.1 (C1), 143.8 (C4), 142.1
(ipso-Ph), 140.7 (ipso-Ph), 140.6 (ipso-Ph), 130.8 (C6), 128.9 (meta-Ph), 128.8 (meta-
Ph), 128.4, 127.7, 127.7 (C2, para-Ph), 127.3, 126.6, 125.8 (Ph), 125.2, 124.9, 124.3.
88.3 (CHO), 79.4 (CHN), 29.6 (CHMe 2 ), 24.1 (CHMe a Me b ), 23.9 (CHMe a Me b ).
Synthesis of (4R,5R)-2-((1S,6S)-5-allyloxy-6-isopropyl-1-methylcyclohexa-2,4-
dienyl)-4,5-diphenyloxazoline (101j) & (4R,5R)-2-(4a,5-dihydro-5-methyl-4Hchromen-5-yl)-4,5-diphenyloxazoline
(142)
Ph Ph
Ph Ph Ph Ph Ph Ph
O
N
O
N
O
N
O
N
O
i) i-PrLi, DMPU
ii) MeI
6
5
1
4
2
3
O
102j
7
8
9
6
5
1
4
2
3 7
O
102j*
8
9
6
5
1
4
2
3
9
O
142
8
7
General procedure 4 was used employing oxazoline 101j (73 mg, 0.21 mmol) i-PrLi
(0.42 mmol in pentane), DMPU (0.15 cm 3 , 1.26 mmol) and methyl iodide (0.05 cm 3 )
quench after 11 min. Flash chromatography (99:1 to 1:4 petrol:EtOAc) yielded
oxazoline 102j (8 mg, 10%), 102j* (4 mg, 5%) and 142 (15 mg, 20% 2:3 ratio) as
colourless oils.
204

Experimental for chapter 2
102j R f : 0.32 (9:1, petrol:EtOAc); [α] 22 D : –105 (c = 1, CHCl 3 ); MS m/z (ES+) 414
(100%, MH + ), 415 (32%, (M+1)H + ); HRMS: found 414.2421, MH requires 414.2428;
IR ν max (film)/cm⎯¹ 2918 (m), 1658 (C=N), 1588, 1453 (m), 1268 (m), 1189 (m), 1083;
¹H-NMR (CDCl 3 , 500 MHz) δ 7.43-7.34 (m, 5H, Ph), 7.33-7.28 (m, 3H, Ph), 7.25-
7.21 (m, 2H, Ph), 6.06-5.96 (m, 2H, H6, H8), 5.82 (dd, 1H, J 9.5, 6.0, H5), 5.38 (dq,
1H, J 17.5, 1.5, H9-trans), 5.25 (dq, 1H, J 10.5, 1.5, H9-cis), 5.21 (d, 1H, J 8.5,
CHOPh), 5.09 (d, 1H, J 6.0, H4), 5.07 (d, 1H, J 8.5, CHNPh), 4.35 (ddt, 1H, J 13.0,
5.5, 1.5, H7 a ), 4.29 (ddt, 1H, J 13.0, 5.0, 1.5, H7 b ), 2.41 (d, 1H, J 3.0, H2), 2.07 (pd,
1H, J 7.0, 3.0, CHMe 2 ), 1.55 (s, 3H, Me), 1.09 (d, 3H, J 7.0, i-Pr), 1.03 (d, 3H, J 7.0, i-
Pr); ¹³C-NMR (CDCl 3 , 125 MHz) δ 171.4 (C=N), 156.0 (C3), 142.0 (ipso-Ph), 140.5
(ipso-Ph), 133.2 (C8), 128.9, 128.8, 128.3, 127.6, 126.7, 125.7 (Ph), 125.2 (C6), 122.0
(C5), 116.9 (C9), 94.1 (C4), 88.8 (CHOPh), 78.8 (CHNPh), 67.7 (C7), 51.4 (C2), 43.7
(C1), 30.9 (CHMe 2 ), 25.2 (Me), 23.8 (i-Pr), 17.9 (i-Pr).
102j* R f : 0.32 (9:1, petrol:EtOAc); [α] 23 D : –56 (c = 0.5, CHCl 3 ); MS m/z (ES+) 414
(100%, MH + ), 415 (34%, (M+1)H + ); HRMS: found 414.2423, MH requires 414.2428;
IR ν max (film)/cm⎯¹ 2918 (m), 2362, 1995, 1661 (C=N), 1456 (m); ¹H-NMR (CDCl 3 ,
500 MHz) δ 7.44-7.34 (m, 6H, Ph), 7.34-7.28 (m, 2H, Ph), 7.24-7.20 (m, 2H, Ph), 6.29
(dd, 1H, J 6.0, 1.5, H7), 6.08 (d, 1H, J 9.5, H6), 5.81 (dd, 1H, J 9.5, 6.0, H5), 5.27 (d,
1H, J 6.0, H4), 5.23 (d, 1H, J 8.5, CHOPh), 5.08 (d, 1H, J 8.5, CHNPh), 4.85 (quin,
1H, J 6.5, H8), 2.48 (d, 1H, J 3.0, H2), 2.09 (pd, 1H, J 7.0, 3.0, CHMe 2 ), 1.66 (dd, 3H,
J 7.0, 1.5, H9), 1.57 (s, 3H, Me), 1.11 (d, 3H, J 7.0, CHMe A Me b ), 1.07 (d, 3H, J 7.0,
CHMe a Me B ); ¹³C-NMR (CDCl 3 , 125 MHz) δ 171.1 (C=N), 154.5 (C3), 141.9 (ipso-
Ph), 140.4 (ipso-Ph), 139.3 (C7), 128.9, 128.8, 128.4, 127.6, 126.7, 126.5, 125.7 (Ph),
121.5 (C5), 107.5 (C8), 97.5 (C4), 88.9 (CHOPh), 78.8 (CHNPh), 50.8 (C2), 43.8
(C1), 31.0 (CHMe 2 ), 25.2 (Me), 23.5 (CHMe a Me B ), 17.9 (CHMe A Me b ), 9.6 (C9).
142 (major diastereoisomer) R f : 0.16 (9:1, petrol:EtOAc); [α] 22 D : +52 (c = 1, CHCl 3 );
MS m/z (ES+) 370 (100%, MH + ), 371 (74%, (M+1)H + ), 392 (30%, MNa + ), 761 (56%,
2MNa + ); HRMS: found 370.1800, MH requires 370.1802; IR ν max (film)/cm⎯¹ 2918
(w), 1649 (C=N), 1451 (m), 1243, 1078; ¹H-NMR (CDCl 3 , 500 MHz) δ 7.41-7.34 (m,
6H, Ph), 7.33-7.29 (m, 2H, Ph), 7.23-7.18 (m, 2H, Ph), 6.38 (dd, 1H, J 6.0, 2.5, H7),
6.00 (dq, 1H, J 10.0, 2.0, H5), 5.79 (dt, 1H, J 10.0, 3.0, H6), 5.50 (dt, 1H, J 16.0, 1.5,
205

Experimental for chapter 2
H4), 5.23 (dd, 1H, J 7.5, 1.5, CHOPh), 4.99 (dd, 1H, J 7.0, 2.0, CHNPh), 4.89 (td, 1H,
J 6.0, 2.0, H8), 3.13-3.06 (m, 1H, H2), 2.28 (dtd, 1H, J 16.0, 6.0, 2.5, H9), 2.01-1.99
(tm, 1H, J 16.0, H9'), 1.58 (d, 1H, J 1.5, Me); ¹³C-NMR (CDCl 3 , 125 MHz) δ (all
peaks) 171.3, 171.3, 150.1, 150.0, 142.1, 141.8, 140.7, 129.1, 129.0, 128.8, 128.7,
128.3, 127.6, 126.5, 126.4, 125.4, 105.3, 105.1, 101.1, 101.1, 88.9, 78.4, 78.4, 40.7,
31.1, 31.1, 28.2, 28.2, 26.9, 26.9; ¹³C-NMR (CDCl 3 , 125 MHz) δ (assigned, ignoring
apparent doublets) 171.3 (C=N), 150.1 (C3); 142.1, 141.8, 140.7 (ipso-Ph, C7), 129.1,
129.0, 128.8, 128.7, 128.3, 127.6, 126.5, 126.4, 125.4 (Ph, C6, C5), 105.3, 101.1 (C8,
C4), 88.9 (CHOPh), 78.4 (CHNPh), 40.7 (C2), 31.1 (C1), 28.2 (C9), 26.9 (Me).
Synthesis of (4S,5S)-2-((1R,6R)-6-isopropyl-4-methoxy-1-methylcyclohexa-2,4-
dienyl)-4-(methoxymethyl)-5-phenyloxazoline (105)
Ph OMe
O N
i) i-PrLi, DMPU
ii) MeI
OMe
104b
Ph OMe
O N
OMe
OMe
107 108
22% 4%
General procedure 4 was used employing oxazoline 104b (180 mg, 0.60 mmol) i-PrLi
(0.96 mmol), DMPU (1.0 cm 3 , 13 eq) and methyl iodide (0.1 cm 3 ) quench after 30
min. Flash chromatography (9:1 petrol:EtOAc) yielded diene 105 (50 mg, 24%),
oxazoline 107 (46 mg, 22%), oxazoline 106 (14 mg, 7%) diene 108 (8 mg, 4%) and
starting material (18 mg, 10%) as colourless oils.
1
6
5
Me
2
3
4
Ph OMe
O N
OMe
OMe
105
106
24% 7%
Ph Me OMe Ph Me OMe
O N
O N
Me
1
Me
1
6
2
5
3
5
4
1
6
5
4
6
2
3
2
3
4
Me
206

Experimental for chapter 2
105 R f : 0.60 (4:1 petrol:EtOAc); [α] 22 D : +268 (c = 1.6, CH 2 Cl 2 ); MS m/z (CI+): 356
(100%, MH + ), 357 (19%, (M+1)H + ); HRMS (ESI+) m/z found 356.2217 (MH calcd.
356.2220); IR ν max (film)/cm -1 : 2955, 2928 (m, C-H), 1662 (C=N), 1451 (m), 1217; 1 H-
NMR (CDCl 3 , 300 MHz) δ 7.45-7.21 (m, 5H, Ph), 6.29 (d, 1H, J 9.5, H6), 5.70 (dd,
1H, 9.5, 2.0, H5), 5.36 (d, 1H, J 6.5, CHPh), 4.49 (dd, 1H, J 6.5, 2.0, H3), 4.15 (td, 1H,
J 6.5, 4.5, CHN), 3.67 (dd, 1H, J 9.5, 4.5, CH a H b ), 3.60 (s, 3H, OMe), 3.49-3.43 (m,
1H, CH a H b ), 3.40 (s, 3H, OMe), 2.51 (dd, 1H, J 6.5, 3.5, H2), 1.95-1.83 (m, 1H,
CHMe 2 ), 1.48 (s, 3H, Me), 0.91 (d, 3H, J 6.5, CHMe a Me b ) 0.82 (d, 3H, J 6.5
CHMe a Me b ); 13 C-NMR (CDCl 3 , 75 MHz) δ 171.4 (CNO), 153.2 (C4), 141.5 (ipso-
Ph), 135.2 (C5), 129.0 (meta-Ph), 128.3 (para-Ph), 125.7 (ortho-Ph), 121.8 (C4), 88.8
(C3), 83.6 (CHPh), 74.7 (CH 2 OMe), 74.7 (CHN), 59.5 (OMe), 54.5 (OMe), 47.3 (C2),
41.9 (C1), 31.6 (CHMe 2 ), 25.8 (C1-Me), 21.6 (CHMe a Me b ), 17.0 (CHMe a Me b ).
106 R f : 0.30 (4:1 petrol:EtOAc); MS m/z (CI+): 312 (100%, MH + ), 313 (17%,
(M+1)H + ); HRMS (ESI+) m/z found 312.1584 (MH calcd. 312.1594); IR
ν max (film)/cm -1 : 2932 (m, C-H), 1639 (C=N), 1608, 1505, 1249; 1 H-NMR (CDCl 3 , 300
MHz) δ 7.99 (d, 2H, J 9.0, ortho-H), 7.39-7.30 (m, 5H, Ph), 6.94 (d, 2H, J 9.0, meta-
H), 5.46 (d, 1H, J 7.0, CHPh), 4.30 (td, 1H, J 6.5, 4.5, CHN), 3.86 (s, 3H, ArOMe),
3.73 (dd, 1H, J 9.5, 3.5, CH a H b ), 3.61 (dd, 1H, J 9.5, 6.5, CH a H b ), 3.44 (s, 3H,
CH 2 OMe); 13 C-NMR (CDCl 3 , 75 MHz) δ 164.2 (CNO), 162.5 (C4), 141.3 (ipso-Ph),
130.5, 129.0, 128.4, 125.8 (Ar CH), 120.3 (C1), 114.0 (meta-CH), 83.8 (CHPh), 75.2
(CH 2 ), 74.8 (HCN), 59.6, 55.6 (OMe), 22.8 (Me).
107 R f : 0.40 (4:1 petrol:EtOAc); [α] 22 D : +106 (c = 1.4, CH 2 Cl 2 ) MS m/z (CI+): 326
(100%, MH + ), 327 (20%, (M+1)H + ); HRMS (ESI+) m/z found 326.1745 (MH calcd.
326.1751); IR ν max (film)/cm -1 : 2927 (m, C-H), 1641 (C=N), 1607,1503, 1248; 1 H-
NMR (CDCl 3 , 300 MHz) δ 7.99 (d, 2H, J 9.0, ortho-H), 7.39-7.30 (m, 5H, Ph), 6.94-
6.91 (m, 1H, meta-H), 4.30 (dd, 1H, J 6.5, 4.5, CHN), 3.86 (s, 3H, ArOMe), 3.73 (dd,
1H, J 9.5, 3.5, CH a H b ), 3.61 (dd, 1H, J 9.5, 6.5, CH a H b ), 3.44 (s, 3H, CH 2 OMe), 2.62
(s, 3H, BnMe), 1.79 (s, 3H, ArMe); 13 C-NMR (CDCl 3 , 75 MHz) δ 163.6 (CNO), 161.5
(C4), 147.3, 141.3 (ipso-Ph), 132.1, 128.7, 127.4 (C2), 124.8, 120.1 (C1), 116.9,
111.2, 88.3 (COPh), 75.3 (CH 2 ), 72.8 (HCN), 59.4 (OMe), 55.5 (OMe), 23.0 (Me),
22.6 (Me).
207

Experimental for chapter 2
108 R f = 0.62 (4:1 petrol:EtOAc); [α] 22 D : +269 (c = 0.4); MS m/z (CI+): 370 (100%,
MH + ), 371 (22%, (M+1)H + ); HRMS (ESI+) m/z found 370.2373 (MH calcd.
370.2377); IR ν max (film)/cm -1 : 2929 (m), 1660, 1651, 1450, 1217; 1 H-NMR (CDCl 3 ,
300 MHz) δ 7.44-7.19 (m, 5H, Ph), 6.21 (d, 1H, J 10.0, H6), 5.67 (dd, 1H, J 10.0, 2.0,
H5), 5.36 (d, 1H, J 6.5, CHPh), 4.48 (dd, 1H, J 6.5, 2.0, H3), 4.28 (dd, 1H, J 9.0, 4.5,
CHN), 3.72 (dd, 1H, J 9.5, 4.5, CH a H b ), 3.61 (s, 3H, OMe), 3.53 (dd, 1H, J 9.5, 9.0
CH a H b ), 3.41 (s, 3H, OMe), 2.54 (ddd, 1H, J 6.5, 3.5, 1.0, H2), 1.90 (pd, 1H, J 7.0, 3.5
CHMe 2 ), 1.47 (s, 3H, Me), 0.90 (d, 3H, J 6.5, CHMe a Me b ) 0.83 (d, 3H, J 6.5
CHMe a Me b ); 13 C-NMR (CDCl 3 , 125 MHz) δ 169.7 (CNO), 153.0 (C4), 147.7 (ipso-
Ph), 135.0 (C5), 128.8 (meta-Ph), 127.0 (para-Ph), 124.2 (ortho-Ph), 121.5 (C4), 88.5
(C3), 83.6 (CHPh), 74.6 (CH 2 OMe), 72.3 (CHN), 59.0 (OMe), 54.3 (OMe), 47.0 (C2),
41.6 (C1), 31.2 (CHMe 2 ), 25.8 (C1-Me), 23.2 (Bn-Me) 21.3 (CHMe a Me b ), 16.7
(CHMe a Me b ).
Synthesis of (4S,5S)-2-((1R,6S)-6-isopropyl-1-methylcyclohexa-2,4-dienyl)-4-
methyl-5-phenyloxazoline (112)
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Me
O
N
i) i-PrLi (1.5 eq), DMPU (6 eq)
−78 °C, 30 min
ii) MeI
O
N
Me
+
O
N
Me
+
O
N
Me
40% 12% 5%
112 113 114
General procedure 4 was used employing oxazoline 110 (100 mg, 0.42 mmol) i-PrLi
(0.63 mmol in pentane), DMPU (0.34 cm 3 , 6 eq) and methyl iodide (0.1 cm 3 ) quench
after 30 min. Flash chromatography (9:1 petrol:EtOAc) yielded, diene 112 (41 mg,
40%) as clear needles, oxazoline 113 (28 mg, 12%) as a clear oil and oxazoline 114
(12 mg, 6%) as a clear oil.
112 R f : 0.45 (4:1 petrol:EtOAc); Mpt: 72-73 °C (EtOAc); [α] 23 D : +388 (c = 0.3,
EtOH); MS m/z (CI+): 296 (100%, MH + ), 297 (21%, (M+1)H + ); HRMS (ESI+) m/z
found 296.2011 (MH calcd. 296.2009); IR ν max (film)/cm -1 : 2960 (C-H), 1663 (C=N),
1453, 1109, 1077; 1 H-NMR (CDCl 3 , 300 MHz) δ 7.34-7.18 (m, 5H, Ph), 6.10 (dd, 1H,
J 10.0, 1.0, H6), 5.97 (dd, 1H, J 10.0, 5.0, H4), 5.74 (ddd, 1H, J 10.0, 5.0, 1.0, H5),
208

Experimental for chapter 2
5.55 (dd, 1H, J 6.0, 10.0, H3), 4.87 (d, 1H, J 7.5, CHPh), 3.95 (quin, 1H, J 6.5, NCH),
2.39-2.33 (m, 1H, H2), 1.85-1.72 (m, 1H, CHMe 2 ), 1.36 (s, 3H, H7), 1.31 (d, 3H, J
6.5, CHMe), 0.85 (d, 3H, J 7.0, CHMe A Me b ), 0.82 (d, 3H, J 7.0, CHMe a Me B ); 13 C-
NMR (CDCl 3 , 75 MHz) δ 169.8 (C=N), 140.8 (ipso-Ph), 132.4, 128.7, 128.1, 125.4,
124.2, 123.8, 121.4, (C3, C4, C5, C6 & Ph), 87.6 (COPh), 70.5 (CN), 47.5 (C2), 31.2
(CMe 2 ), 25.2 (C7), 21.6 (CNMe), 21.2 (CMe A Me b ), 16.7 (CHMe a Me B ).
113 R f : 0.42 (4:1 petrol:EtOAc); [α] 23 D : +122 (c = 0.2, EtOH); MS m/z (CI+): 252
(100%, MH + ), 253 (17%, (M+1)H + ); HRMS (ESI+) m/z found 252.1382 (MH calcd.
252.1383); IR ν max (film)/cm -1 : 2964 (C–H), 1643 (C=N), 1453 (m), 1317 (m), 1039;
1 H-NMR (CDCl 3 , 300 MHz) δ 7.79-7.76 (m, 1H, H6), 7.31-7.20 (m, 6H, Ar), 7.17-
7.11 (m, 2H, Ar), 4.96 (d, 1H, J 7.5, CHPh), 4.13 (quin, 1H, J 6.5, CHMe), 2.53 (s,
3H, ortho-Me), 1.39 (d, 3H, J 6.5, Me); 13 C-NMR (CDCl 3 , 75 MHz) δ 163.2 (C=N),
140.7 (C), 138.8 (C), 131.2, 130.6, 129.9, 128.8, 128.2, 125.6 (Ar) 87.4 (PhCO), 71.2
(MeCN), 21.8 (NCMe), 21.7 (ortho-Me).
114 R f : 0.38 (4:1 petrol:EtOAc); [α] 23 D : +97 (c = 0.2, EtOH); MS m/z (CI+): 266
(100%, MH + ), 253 (18%, (M+1)H + ); HRMS (ESI+) m/z found 266.1538 (MH calcd.
266.1539); IR ν max (film)/cm -1 : 2975 (C-H), 1643 (C=N), 1448, 1319, 1266, 1037; 1 H-
NMR (CDCl 3 , 300 MHz) δ 7.89-7.86 (m, 1H, H6), 7.44-7.23 (m, 9H, Ar), 4.34 (q, 1H,
J 7.0, CHMe), 2.63 (s, 3H, ortho-Me), 1.65 (s, 3H, CMePh), 1.47 (d, 3H, J 7.0,
CHMe); 13 C-NMR (CDCl 3 , 75 MHz) δ 162.4 (C=N), 149.3 (C), 146.6 (C), 138.6,
131.2, 130.5 129.9, 128.8, 128.5, 127.2, 125.6, 124.0 (Ar), 88.5 (OCPh), 71.7
(NCMe); 22.4 (OCMe) 21.7 (NCMe), 16.8 (ortho-Me).
209

Experimental for chapter 2
Synthesis of (4R*,5R*)-2-(2-ethyl-4-methoxyphenyl)-4,5-diphenyloxazoline (120)
Ph
Ph
Ph
Ph
O
N
i) i-PrLi (3 eq.), DMPU (6 eq)
−78 °C
O
1
N
ii) MeI
6
2
OMe
5
4
OMe
3
General procedure 4 was used employing oxazoline 103b (250 mg, 0.73 mmol) i-PrLi
(2.19 mmol in pentane), DMPU (0.52 cm 3 , 6 eq) in THF to give a wine red solution,
and a methyl iodide (0.27 cm 3 ) quench after 5 min. Flash chromatography (19:1 to 9:1
petrol:EtOAc) yielded oxazoline 120 (170 mg, 65%) as a colourless oil.
R f : 0.39 (4:1, petrol:EtOAc); MS m/z (ES+) 358 (100%, MH + ), 359 (30%, (M+1)H + );
HRMS: found 358.1802, MH requires 358.1802; ¹H-NMR (CDCl 3 , 500 MHz) δ 7.89
(d, 1H, J 8.5, H6), 7.31-7.16 (m, 10H, Ph), 6.75 (d, 1H, J 2.5, H3), 6.67 (dd, 1H, J 8.5,
2.5, H5), 5.19 (d, 1H, J 7.5, CHOPh), 5.14 (d, 1H, J 7.5, CHNPh), 3.70 (s, 3H, OMe),
3.11-3.05 (m, 2H, CH 3 ), 1.18 (t, 3H, J 7.5, CH 2 Me); ¹³C-NMR (CDCl 3 , 125 MHz) δ
164.0 (C=N), 161.5 (C4), 147.6 (C2), 142.4 (ipso-Ph), 140.7 (ipso-Ph), 132.3 (C6),
128.8 (meta-Ph), 128.7 (meta-Ph), 128.2 (para-Ph), 127.5 (para-Ph), 126.5 (ortho-Ph),
125.6 (ortho-Ph), 115.3 (C3), 110.6 (C5), 87.8 (CHO), 79.2 (CHN), 55.1 (OMe), 27.8
(CH 2 ), 15.6 (Me).
210

Experimental for chapter 3.1
5.3 Experimental Procedures for Chapter 3.1
Synthesis of (S,S)-hydrobenzoin (176)
OH
Ph AD mix α, Me 2 SO 2 NH 2
HO
Ph
Ph
t-BuOH/H 2 O
Ph
By the Method of Sharpless 8 AD mix-α (45.93 g) and methylsulfonamide (4.70 g, 42.3
mmol) were dissolved in t-BuOH (255 cm 3 ) and water (255 cm 3 ) with vigorous stirring
and cooled to 0 °C. trans-Stilbene (6.00 g, 33.3 mmol) was added to the solution and
stirred for 48 hr. Sodium sulfite (50 g) was added with stirring and allowed to warm to
ambient temperature before being partitioned in a separating funnel. The organic
phase was concentrated under vacuum and recombined with the aqueous phase,
washed with CH 2 Cl 2 (3 x 150 cm 3 ), brine (3 x 200 cm 3 ), and the combined organic
phases dried over Na 2 SO 4 , and solvent concentrated under vacuum. The residue was
purified by flash chromatography (2:1 EtOAc:petrol) to give hydrobenzoin 176 (7.01
g, 98%) as colourless needles.
R f : 0.36 (1:2 petrol:EtOAc); Mpt: 146-147 ºC (petrol/EtOAc), lit. 9 148-150 ºC; [α] 23 D :
–94 (c = 1.0, EtOH), lit. 9 –94.1 (c = 1, EtOH); MS m/z (CI + ): 232 (MNH + 4 , 100%),
215 (MH + , 32%); IR ν max /cm -1 : 3498 (br, O–H), 2921, 2896, 1451, 1199, 1045;
Microanalysis: % found (% calc’d for C 14 H 14 O 2 ) C, 78.73 (78.48); H, 6.73 (6.59); 1 H-
NMR (DMSO, 300 MHz) δ 7.21-7.15 (m, 6H, Ph); 7.11-7.08 (m, 4H, Ph); 5.38* (s,
2H, OH); 4.59 (s, 2H, CH); 13 C-NMR (DMSO, 75 MHz) δ 143.1 (ipso-Ph); 128.0,
127.9, 127.4 (Ph); 78.4 (CH).
Synthesis of (4S,5S)-4,5-diphenyl-1,3-dioxolan-2-one (177)
O
OH
HO
CDI
O O
Ph
Ph
Ph Ph
To a stirred solution of (S,S)-hydrobenzoin (3.27 g, 15.2 mmol) in CH 2 Cl 2 (25 cm 3 )
was added CDI (3.71 g, 22.9 mmol). Aqueous hydrochloric acid (50 cm 3 , 1N) was
added after 6 hr and the mixture washed with CH 2 Cl 2 (2 x 50 cm 3 ), EtOAc (50 cm 3 ),
211

Experimental for chapter 3.1
saturated aqueous NaHCO 3 (2 x 40 cm 3 ) dried over Na 2 SO 4 and concentrated under
vacuum to give cyclic carbonate 177 (3.65 g, 100%) as clear colourless prisms.
20
R f : 0.41 (9:1 petrol:EtOAc); Mpt: 106-108 ºC (CH 2 Cl 2 ); [α] D : –122 (c = 0.5,
CH 2 Cl 2 ); MS m/z (CI+): 258 (100%, MNH + 4 ) 259 (18%, (M+1)NH + ), 241 (13%,
MH + ); Microanalysis: % found (% calc’d for C 15 H 12 O 3 ) C, 75.22 (74.99); H, 5.06
(5.03); IR ν max /cm -1 : 1822 (C=O), 1458, 1187, 1044; 1 H-NMR (CDCl 3 , 500 MHz) δ
7.46-7.42 (m, 6H, ortho/para-Ph), 7.34-7.30 (m, 4H, meta-Ph), 5.43 (s, 2H, PhCH);
13 C-NMR (CDCl 3 , 125 MHz) δ 154.1 (C=O), 134.8 (ipso-Ph), 129.8, 129.3, 126.1,
85.4 (PhCH).
Synthesis of (1S,2R)-2-azido-1,2-diphenylethanol (178) & (2R,3R)-2,3-
diphenylaziridine (173)
Ph
O
O
O
Ph
H
N
i) NaN 3 HO N 3
ii) PPh 3
Ph Ph
Ph Ph
178 173
Adapted from the methods of Sharpless 10 sodium azide (894 mg, 13.7 mmol) was
added to a stirred solution of cyclic carbonate (3.0 g, 12.5 mmol) in DMF (12 cm 3 ) and
water (0.20 cm 3 , 11 mmol) and heated to 110 °C for 48 hr under a nitrogen
atmosphere. Upon cooling, the resulting slurry was triturated with Et 2 O (3 x 50 cm 3 ),
filtered through Celite, and solvent removed under vacuum distillation to give crude
azide 178 as an orange oil. 11
By the method of Blum, 12 crude azide 178 was dissolved in Et 2 O (175 cm 3 ),
triphenylphosphine (3.28 g, 12.5 mmol) added and the solution brought to reflux for 2
hr. Et 2 O was added until precipitation stopped, the mixture filtered and the filtrate
concentrated under vacuum. Flash chromatography (90:9:1 petrol:EtOAc:Et 3 N) gave
aziridine 173 (1.57 g, 64%) as clear needles.
R f : 0.16 (9:1 petrol:EtOAc); Mpt: 44-46 ºC (EtOAc), lit. 13 45-46 ºC; [α] D 20 : +350 (c =
0.4, EtOH), lit +328.8 (c = 1.25, CHCl 3 ) 14 ; MS m/z (CI+): 196 (100%, MH + ), (19%,
(M+1)H + ); HRMS (ESI+) m/z found 194.0959 (MH calcd. 194.0964); IR
212

Experimental for chapter 3.1
ν max (film)/cm -1 : 3030 (NH), 1602, 1496; 1 H-NMR (CDCl 3 , 300 MHz) δ 7.45-7.22 (m,
10H, H-Ar), 3.18 (s, 2H, CHPh), 1.50 (br, 1H, NH); 13 C-NMR (CDCl 3 , 75 MHz) δ
139.9 (ipso-Ph), 128.9, 127.6, 125.8 (Ph), 44.0 (CHPh).
Synthesis of (1S, 2R)-2-amino-1,2-diphenylethanol (174)
HO
N 3
H 2 , Pd/C, HCl HO NH 2
Ph Ph
Ph Ph
By method of Sharpless 10 hydrochloric acid (0.56 cm 3 in 0.5 cm 3 water, 6.3 mmol) was
added drop wise to a stirred solution of crude azide 178 (1.25 g, 5.23 mmol) and
palladium on charcoal (10%, 60 mg) in EtOH (9 cm 3 ). The mixture was placed under
atmospheric pressure of hydrogen, and stirred vigorously for 48 hr. Water (20 cm 3 )
was added and the mixture concentrated under vacuum before filtration and acid-base
extraction into CH 2 Cl 2 (3 x 20 cm 3 ), dried over Na 2 SO 4 and solvent evaporated.
Amino alcohol 174 (1.09 g, 97%) was isolated as clear colourless needles by
recrystallisation from CH 2 Cl 2 .
R f : 0.22 (19:1 EtOAc:MeOH); Mpt: 143-144 °C (CH 2 Cl 2 ), lit. 143-144 °C (no solvent
stated) 10 ; [α] 22 D : +8.0 (c = 0.6, EtOH) lit. 10 for enantiomer –7.0 (c = 0.6, EtOH, no
temp stated), MS m/z (CI+): 214 (100%, MH + ), 216 (6%, (M+1)H + ); IR ν max (film)/cm -
1 : 3064, 1604, 1595; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.36-7.21 (m, 10H, Ph), 4.77 (d,
1H, J 6.5, CHOH), 4.19 (d, 1H, J 6.5, CHNH 2 ), 1.67 (br s, 3H, OH, NH 2 ); 13 C-NMR
(CDCl 3 , 125 MHz) δ 141.5 (ipso-Ph), 140.5 (ipso-Ph), 128.5 (meta-Ph), 128.0 (meta-
Ph), 127.7 (para-Ph), 127.6 (para-Ph), 127.1 (ortho-Ph), 126.6 (ortho-Ph), 78.3
(CHOH), 61.7 (CHNH 2 ).
Synthesis of cis-stilbene oxide (179)
O
mCPBA
Ph Ph
Ph Ph
mCPBA (1.58 g, 70% purity, 6.4 mmol) was added portion wise to a solution of cisstilbene
(1.011 cm 3 , 5.3 mmol) in CH 2 Cl 2 (50 cm 3 ) and stirred for 6 hr, before addition
of aqueous sodium sulfite (saturated, 10 cm 3 ). The solution was washed with saturated
aqueous NaHCO 3 (2 x 50 cm 3 ), CH 2 Cl 2 (2 x 50 cm 3 ), EtOAc (50 cm 3 ), dried over
213

Experimental for chapter 3.1
Na 2 SO 4 and solvent evaporated. cis-Stilbene oxide (935 mg, 90%) was obtained as
clear colourless needles after flash chromatography (20:1 to 4:1 petrol:EtOAc).
R f : 0.35 (9:1 petrol:EtOAc); Mpt: 38 °C (CH 2 Cl 2 ), lit. 21 38-40 °C; MS m/z (CI+): 197
(100%, MH + ), 189 (9%, (M+1)H + ), 214 (MNH + 4 ,57%); IR ν max (film)/cm -1 : 3163,
2994, 1603, 1005; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.72-7.16 (m, 10H, Ph), 4.40 (s, 2H,
CH); 13 C-NMR (CDCl 3 , 125 MHz) δ 134.3 (ipso-Ph), 127.7, 127.5, 126.8 (Ph), 29.7
(CH).
Synthesis of (R*,R*)-2-amino-1,2-diphenylethanol (175)
Ph
O
Ph
NH3 (aq.)
HO
Ph
(±)
NH 2
Ph
Microwave: cis-Stilbene oxide (700 mg, 3.57 mmol) was fully dissolved in MeOH (2.5
cm 3 ) before addition of saturated aqueous ammonia (7.5 cm 3 ) caused a fine precipitate.
The resulting solution was heated at 140 °C under microwave irradiation for 20 min
(pressure peaked at 11 bar) giving a clear yellow solution, which upon standing
overnight gave colourless cubes. Filtration and two further recrystallisations from
diethyl ether gave racemic amino alcohol 175 (710 mg, 93%).
Reflux: cis-Stilbene oxide (500 mg, 2.55 mmol) was dissolved in MeOH (19 cm 3 ) with
saturated aqueous ammonia (19 cm 3 ) and brought to gentle reflux (c. 70 °C, raising to
80 °C) for 24 hr. The clear solution was concentrated under vacuum, transferred to a
separatory funnel with aqueous NaOH (2 cm 3 NaOH 2N in 50 cm 3 water), washed
with CH 2 Cl 2 (2 x 50 cm 3 ) and EtOAc (50 cm 3 ), dried over Na 2 SO 4 , and concentrated
under vacuum to give a white solid. Purification by flash chromatography (1:1
petrol:EtOAc to 19:1 EtOAc:MeOH) isolated stilbene oxide (125 mg) and a white
solid, which was recrystallised from CH 2 Cl 2 to give clear colourless cubic crystals of
racemic amino alcohol 175 (295 mg, 55%).
R f : 0.24 (19:1 EtOAc:MeOH); Mpt: 127-128 °C (CH 2 Cl 2 ), lit: 116-119 °C; MS m/z
(CI+): 214 (39%, MH + ), 106 (100%, CHPhNH 2 + ); IR ν max (film)/cm -1 : 3066 (br, OH),
1604, 1595; 1 H-NMR (CDCl 3 , 300 MHz) δ 7.41-7.21 (m, 10H, Ph), 4.70 (d, 1H, J 6.5,
214

Experimental for chapter 3.1
CHOH), 4.04 (d, 1H, J 6.5, CHNH 2 ), 2.44 (br, 2H, NH 2 ); 13 C-NMR (CDCl 3 , 75 MHz)
δ 142.3 (Ph CCOH), 141.6 (Ph CCNH 2 ), 128.6, 127.9, 127.4, 127.4, 127.0, 126.4 (Ph),
78.0 (COH), 62.5 (CNH 2 ).
Synthesis of (2R,3R)-1-benzoyl-2,3-diphenylaziridine (100a)
O
Cl
H
N
Et 3 N, petrol/Et 2 O
O
N
Ph
Ph
Ph
Ph
Adapted from the method of Lygo, 15 benzoyl chloride (0.084 cm 3 , 0.73 mg) was
dissolved in petrol (2 cm 3 ) and added drop wise to a solution of aziridine 173 (150 mg,
0.77 mmol) in petrol (5 cm 3 ), Et 2 O (2 cm 3 ) and Et 3 N (0.01 cm 3 , 0.80 mmol) at –10 °C
and stirred until complete (IR). The resulting suspension was allowed to warm to
room temperature before trituration with Et 2 O (30 cm 3 ), filtration over celite and
evaporation, yielding aroyl aziridine 100a (c. 185 mg, 84%) as a clear oil which was
used without purification.
R f : 0.37 (9:1 petrol:EtOAc); MS m/z (CI+): 300 (100%, MH + ), 301 (13%, (M+1)H + );
IR ν max (film)/cm -1 : 3033 (CH), 1668 (CO), 1602, 1497; 1 H-NMR (CDCl 3 , 300 MHz)
δ 7.96 (d, 2H, J 8.5, ortho-Ph), 7.45-7.30 (m, 13H, Ar), 4.04 (s, 2H, CHPh); 13 C-
NMR (CDCl 3 , 75 MHz) δ 175.7 (CO), 135.5, 133.5, 132.3, 128.7, 128.5, 128.0, 127.9,
126.4 (Ph), 49.0 (CHPh).
215

Experimental for chapter 3.1
Synthesis of (2R,3R)-1-(4-methoxybenzoyl)-2,3-diphenylaziridine (100b)
O Cl
OMe
H
N
Ph Ph
Et 3 N, petrol/Et 2 O
+ 1
Ph
O N
Ph
OMe
Adapted from the method of Lygo, 15 p-anisoyl chloride (800mg, 4.71mmol) was
dissolved in petrol (10 cm 3 ) and added drop wise to a solution of aziridine (1.00g, 5.12
mmol) in petrol (25 cm 3 ), Et 2 O (10 cm 3 ) and Et 3 N (0.71 cm 3 , 5.12 mmol) at –10 °C
and stirred until complete (IR). The resulting suspension was allowed to warm to
room temperature before trituration with Et 2 O (200 cm 3 ), filtration over celite and
evaporation, yielding aroyl aziridine 100b (1.38 g, 89%) as colourless clear needles.
2
3
4
R f : 0.29 (4:1 petrol:EtOAc); Mpt: 72 °C (Et 2 O); [α] 23 D +72 (c = 1.4, CH 2 Cl 2 ); MS m/z
(CI+): 330 (100%, MH + ), 331 (22%, (M+1)H + ); HRMS (ESI+) m/z found 330.1493
(MH calcd. 330.1489); IR ν max (film)/cm -1 : 1660 (C=O), 1604, 1510, 1321 (m), 1257
(m); 1 H-NMR (CDCl 3 , 500 MHz) δ 7.86 (d, 2H, J 9.0, H2), 7.90-6.71 (m, 10H, Ph H),
6.74 (d, 2H, J 9.0, H3), 3.93 (s, 2H, CH), 3.75 (s, 3H, OMe); 13 C-NMR (CDCl 3 , 125
MHz) δ 175.0 (C=O), 162.8 (C4), 135.8 (ipso-Ph), 130.8, 128.6, 128.5, 127.9, 127.3,
126.4, 126.2, 125.4 (Ar), 113.3 (C3), 55.2 (OMe), 49.1 (CN).
Synthesis of (2R,3R)-1-(3-methoxybenzoyl)-2,3-diphenylaziridine (100c)
O
Cl
Ph
OMe
Ph
H
N
Ph
i-Pr 2 EtN, petrol/Et 2 O
6
O
5
4
N
Ph
1
2
3
OMe
Adapted from the method of Lygo, 15 m-anisoyl chloride (145 mg, 0.12 cm 3 , 0.85
mmol) was dissolved in pentane (2 cm 3 ) and added drop wise to a solution of aziridine
173 (200 mg, 1.02 mmol) in petrol (5 cm 3 ), Et 2 O (2 cm 3 ) and i-Pr 2 EtN (0.18 cm 3 , 1.02
mmol) at –10 °C and stirred until complete (IR). The resulting suspension was
allowed to warm to room temperature before tritriation with Et 2 O (30 cm 3 ), filtration
216

Experimental for chapter 3.1
over celite and evaporation, yielding aroyl aziridine 100c (244 mg, 87%) as a
colourless oil.
R f : 0.38 (4:1 petrol:EtOAc); IR ν max (film)/cm -1 : 1668 (C=O), 1601, 1510, 1321; 1 H-
NMR (CDCl 3 , 400 MHz) δ 7.51 (d, 1H, J 8.0, Ph, H6), 7.71-7.69 (m, 1H, Ph), 7.17-
7.06 (m, 11H, Ph, H5), 6.92 (ddd, 1H, J 8.5, 4.5, 1, H4), 3.95 (s, 2H, CHPh), 3.66 (s,
3H, OMe); 13 C-NMR (CDCl 3 , 100 MHz) δ 175.4 (C=O), 159.3 (C3), 135.7 (ipso-Ph),
140.3 (C1), 129.2 (para-Ph), 128.7 (meta-Ph), 128.2 (ortho-Ph), 121.4 (C4), 119.2
(C6), 113.1 (C2), 55.3 (OMe), 49.4 (CPh).
Synthesis of N-((1R,2S)-2-hydroxy-1,2-diphenylethanol)benzamide (165a)
Ph
O
Cl
Ph
Ph
NH 2
HO
O
NH
Ph
OH
Et 3 N
General procedure 1 was used mixing benzoyl chloride (0.23 cm 3 , 1.95 mmol) with
amino alcohol 174 (500 mg, 2.34 mmol) and triethylamine (5 cm 3 ) to give the title
amide (615 mg, 99%) as a colourless powder.
R f : 0.05 (EtOAc); Mpt: 243-246 °C (EtOAc); [α] 25 D : +89 (c = 0.4, DMSO); MS m/z
(CI+): 318 (100%, MH + ), 319 (10%, (M+1)H + ); HRMS (ESI+) m/z found 318.1490
(MH calcd. 318.1489); IR ν max (film)/cm -1 : 3337 (s, OH), 1630 (C=O), 1526; 1 H-NMR
(DMSO, 300 MHz) δ 8.83 (d, 1H, J 9.0, NH), 7.74-7.67 (m, 2H, ortho-Ph), 7.50-7.34
(m, 7H, Ph), 7.31-7.14 (m, 6H, Ph), 5.10 (d, 1H, J 5.0, OH), 5.13 (t, 1H, J 8.5,
CHNH), 4.98 (dd, 1H, J 8.0, 5.0, CHOH); 13 C-NMR (DMSO, 125 MHz) δ 165.2
(CO), 143.6, 141.3, 134.5 (ipso-Ph), 131.0, 128.5, 128.1, 127.6, 127.5, 127.3, 127.0,
126.9, 126.6 (Ph), 74.4 (COH), 59.3 (CH 2 N).
217

Experimental for chapter 3.1
Synthesis of N-((1R,2S)-2-hydroxy-1,2-diphenylethyl)-4-methoxybenzamide
(165b)
Ph
O Cl
Ph HO
Ph
Ph
NH 2
O NH
1
OH
2
Et 3 N
3
OMe
4
OMe
General procedure 1 was used mixing para-anisoyl chloride (13.9 g, 81.5 mmol) with
(1R,2S)-(−)-2-amino-1,2-diphenylethanol 174 (20.0 g, 93.8 mmol) and triethylamine
(22.5 cm 3 , 163 mmol) to give the title amide (25.3 g, 98%) as a colourless powder.
R f : 0.42 (2:1 petrol:EtOAc); Mpt: 240-244 °C (EtOAc); [α] 25 D : +41 (c = 0.4, DMSO);
MS m/z (CI+): 348 (100%, MH + ), 349 (27%, (M+1)H + ), 330 (57%, [M-H 2 O] + ), 96
(61%); HRMS (ESI+) m/z found 348.1586 (MH calcd. 348.1594); IR ν max (film)/cm -1 :
3334 (s, OH), 1632 (C=O), 1526; 1 H-NMR (MeOD, 300 MHz) δ 7.58 (d, 2H, J 9.0,
ortho-Ph), 7.44-7.17 (m, 10H, Ph), 6.92 (d, 2H, J 9.0, meta-Ph), 5.32 (d, 1H, J 8.0,
CHOH), 5.05 (d, 1H, J 8.0, CHN), 3.81 (s, 3H, OMe); 13 C-NMR (DMSO, 125 MHz) δ
164.9 (CO), 161.8 (ipso-Ph), 144.1 (ipso-Ph), 142.0, 129.3, 128.7, 128.0, 127.9, 127.3,
127.2, 127.1, 127.0 (Ar), 113.7 (C3), 74.9 (COH), 59.3 (CNH), 55.7 (OMe).
Synthesis of N-((1R,2S)-2-hydroxy-1,2-diphenylethyl)-3-methoxybenzamide
(165c)
Ph
O Cl
Ph
Ph
NH 2
OH
OMe Et 3 N
Ph
HO
O NH
6
5
4
1
2
3
OMe
General procedure 1 was used mixing meta-anisoyl chloride (0.30 cm 3 , 2.12 mmol)
with the amino alcohol 174 (500 mg, 2.34 mmol) and triethylamine (0.6 cm 3 , 4.25
mmol) to give amide 165c (710 mg, 96%) as colourless needles.
218

Experimental for chapter 3.1
R f : 0.45 (1:1 petrol:EtOAc); Mpt: 193-194 °C (acetone); [α] 24 D : –2.5 (c = 1.1,
DMSO); MS m/z (CI+): 348 (100%, MH + ), 349 (22%, (M+1)H + ), 330 (16%, [M-
H 2 O]H + ); HRMS (ESI+) m/z found 348.1591 (MH calcd. 348.1594); IR ν max /cm -1 :
3321 (sharp, OH), 1633 (C=O), 1537, 1244; 1 H-NMR (DMSO, 500 MHz) δ 8.63 (d,
1H, J 9.0, NH), 7.46 (d, 4H, J 7.5, Ph), 7.36-7.27 (m, 5H, Ar), 7.27-7.18 (m, 3H, Ar),
7.15-7.11 (m, 1H, H2), 7.04 (dd, 1H, J 8.0, 2.0, H4), 5.47 (d, 1H, J 5.0, OH), 5.12 (t,
1H, J 9.0, CHNH), 4.92 (dd, 1H, J 8.5, 5.0, CHOH); 13 C-NMR (DMSO, 125 MHz) δ
165.4 (CO), 159.3 (C3), 144.1 (ipso-Ph), 141.9 (ipso-Ph), 136.5, 128.7, 127.3, 127.9,
119.6, 117.0, 112.9, 112.7 (Ar), 74.9 (COH), 55.6 (CNH), 55.4 (OMe).
Synthesis of N-((1R*,2S*)-2-hydroxy-1,2-diphenylethyl)-4-phenylbenzamide
(165f)
Ph
O OH
Ph
i) DMF, (COCl) 2
ii) Ph
Ph
OH
NH 2
(±)
Et 3 N
Ph
HO
O NH
Ph
One drop of DMF was added to a stirred solution of para-biphenyl carboxylic acid
(397 mg, 2.0 mmol) and oxalyl chloride (0.19 cm 3 , 2.2 mmol) in CH 2 Cl 2 (4 cm 3 ).
Once effervescence had stopped, the solution was allowed to stir for 2 hr, the solvent
was removed under reduced pressure, and the crude acid chloride reacted on. General
procedure 1 was used mixing the acid chloride with the amino alcohol 174 (511 mg,
2.40 mmol) and triethylamine (0.56 cm 3 , 4.0 mmol) to give amide 165f (650 mg, 83%)
as a colourless powder.
1
2
3
4
R f : 0.27 (1:1 petrol:EtOAc); Mpt: 222-224 °C (acetone); MS m/z (CI+): 394 (100%,
MH + ), 395 (30%, (M+1)H + ), 376 (100%, [(M-H 2 O)H] + ); HRMS (ESI+) m/z found
394.1803 (MH calcd. 394.1802); IR ν max (film)/cm -1 : 3320 (m), 1635 (C=O), 1540 (m);
1 H-NMR (DMSO, 300 MHz) δ 8.69 (d, 1H, J 9.0, NH), 7.79-7.65 (m, 6H, Ar), 7.52-
7.35 (m, 7H, Ar), 7.34-7.15 (m, 6H, Ar), 5.47 (d, 1H, J 5.0, OH), 5.16 (t, 1H, J 9.0,
CHNH), 4.94 (dd, 1H, J 8.5, 5.0, CHOH); 13 C-NMR (DMSO, 75 MHz) δ 164.7
(C=O), 143.6 (C1), 142.5 (ipso-Ph), 141.4 (ipso-Ph), 139.1 (ipso-Ph), 133.3 (ipso-Ph),
219

Experimental for chapter 3.1
128.9, 128.3, 127.9 (para-Ph), 127.7, 127.6, 127.5, 127.0 (para-Ph), 126.8, 126.7,
126.6 (para-Ph), 126.3, 74.5 (CHO), 58.9 (CHN).
Synthesis of 4-cyano-N-((1R*,2S*)-2-hydroxy-1,2-diphenylethyl)benzamide (165g)
Ph
O OH
Ph
i) DMF, (COCl) 2 HO
ii)
O NH
Ph
1
Ph
NH 2
2
CN
OH
3
(±)
4
CN (±)
One drop of DMF was added to a stirred solution of para-cyanobenzoic acid (500 mg,
3.4 mmol) and oxalyl chloride (0.33 cm 3 , 3.74 mmol) in CH 2 Cl 2 (5 cm 3 ). Once
effervescence had stopped the solution was allowed to stir for 1 hr and the solvent was
removed under reduced pressure. The crude acyl chloride in CH 2 Cl 2 (5 cm 3 ) was
added drop wise over a period of 1 hr to a stirred solution of amine 174 (586 mg, 2.75
mmol) in CH 2 Cl 2 (20 cm 3 ) and Et 3 N (0.69 cm 3 , 5 mmol) at 0 °C. After warming to
room temperature, the solution was diluted in CH 2 Cl 2 (10 cm 3 ) and washed with
saturated aqueous sodium bicarbonate (20 cm 3 ), the aqueous extract washed with
further CH 2 Cl 2 (2 x 20 cm 3 ) and the combined organic extracts dried over sodium
sulphate and concentrated under vacuum. The resulting orange oil was purified by
flash chromatography (4:1 to 2:1 petrol:EtOAc) to yield amide 165g (480 mg, 41%) as
colourless cubes.
R f : 0.39 (1:1 petrol:EtOAc); Mpt: 199-200 °C (EtOAc); MS m/z (CI+): 343 (90%,
MH + ), 344 (26%, (M+1)H + ), 325 (100%, [M - H 2 O]H + ); HRMS (ESI+) m/z found
343.1434 (MH calcd. 343.1441); IR ν max (film)/cm -1 : 3324 (br, OH), 2232 (m, CH),
1638 (C=O), 1539, 699; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.85 (d, 2H, J 8.0, H2), 7.73
(d, 2H, J 8.0, H3), 7.30-7.22 (m, 6H, Ph), 7.13-7.03 (m, 5H, Ph, NH), 5.45 (dd, 1H, J
8.0, 4.0, CHNH), 5.23 (d, 1H, J 4.0, CHOH); 13 C-NMR (CDCl 3 , 125 MHz) δ 165.2
(C=O), 139.5 (ipso-Ph), 138.2 (ipso-Ph), 136.5 (C1), 132.5 (C2), 128.3, 128.2 (Ph),
128.2 (para-Ph), 128.0 (para-Ph), 127.9, 127.7 (Ph), 126.3 (C3), 117.9 (C4), 115.2
(CN), 76.7 (COH), 59.6 (CNH).
220

Experimental for chapter 3.1
Synthesis of N-((1R,2S)-2-hydroxy-1,2-diphenylethyl)-2-methoxybenzamide (165i)
Ph
O
Cl
OMe
Ph
Ph
NH 2
OH
Et 3 N
HO
O
1
6
5
Ph
NH
OMe
2
3
4
General procedure 1 was used mixing o-anisoyl chloride (0.38 cm 3 , 2.54 mmol) with
the amino alcohol yy (600 mg, 2.80 mmol) and triethylamine (0.71 cm 3 ) to give the
amide 165i (880 mg, 99%) as colourless needles.
R f : 0.65 (EtOAc); Mpt: 172-3 °C (EtOAc); [α] 22 D : 100.7 (c = 0.6, EtOH); MS m/z
(CI+): 348 (100%, MH + ), 349 (20%, (M+1)H + ), 330 (22%, [M-H 2 O]H + ); HRMS
(ESI+) m/z found 348.1596 (MH calcd. 348.1594); IR ν max (film)/cm -1 : 3330, 1629
(C=O), 1527; 1 H-NMR (CDCl 3 , 500 MHz) δ 8.75 (d, 1H, J 7.5, NH), 8.21 (dd, 1H, J
8.0, 2.0, H6), 7.46 (ddd, 1H, J 8.0, 7.5, 2.0, H4), 7.28-7.21 (m, 6H, Ar), 7.10-7.02 (m,
5H, Ar), 7.0 (d, 1H, J 8.5, 5.65 (dd, 1H, J 4.0, 7.5, CHNH), 5.17 (d, 1H, J 4.0, CHOH),
3.91 (s, 3H, OMe); 13 C-NMR (CDCl 3 , 125 MHz) δ 165.6 (C=O), 157.6 (C1), 139.5
(ipso-Ph), 137.7 (ipso-Ph), 133.0, 132.4, 132.3, 128.2, 127.6, 127.5, 126.9, 126.7,
121.4, 121.2, 120.9, 111.2, 60.1 (COH), 56.0 (CNH).
Synthesis of (4R,5R)-2,4,5-triphenyloxazoline (101a)
HO
O
Ph
NH
Ph
DIC, Cu(OTf) 2
Ph
O
N
Ph
Δ
Reflux: General procedure 2 was used with benzamide (317 mg, 1.0 mmol), DIC (0.15
cm 3 , 1.0 mmol), Cu(OTf) 2 (22 mg, 0.06 mmol), dioxane (3 cm 3 ) and heated under
reflux for 7 hr at 105 °C. Flash chromatography (19:1 petrol:EtOAc) yielded
oxazoline 101a (195 mg, 65%) as colourless needles.
221

Experimental for chapter 3.1
Microwave: General procedure 2 was used with benzamide (160 mg, 0.50 mmol), DIC
(0.08 cm 3 , 0.38 mmol), Cu(OTf) 2 (11 mg, 0.03 mmol), THF (3 cm 3 ) and heated under
microwave irradiation for 20 min at 150 °C. Flash chromatography (19:1
petrol:EtOAc) yielded oxazoline 101a (86 mg, 58%) as colourless needles.
R f : 0.51 (4:1 petrol:EtOAc); Mpt: 106-108 ºC (toluene) lit. 16 93-95 ºC; [α] 25 D : –11 (c
= 3.0, EtOH); MS m/z (CI+): 300 (100%, MH + ), 301 (21%, (M+1)H + ), 193 (12%, [M-
PhCO] + ); IR ν max (film)/cm -1 : 1650 (C=N), 1602, 1494, 1325; 1 H-NMR (300 MHz,
CDCl 3 ) δ 8.17 (d, 2H, J 7.0, ortho-Ph), 7.60-7.27 (m, 13H, Ph), 5.44 (d, 1H, J 7.5,
OCHPh), 5.26 (d, 1H, J 7.5, NCHPh); 13 C-NMR (75 MHz, CDCl 3 ) δ 164.0 (C=N),
141.9 (ipso-Ph), 140.4 (ipso-Ph), 131.7, 128.9, 128.8, 128.6, 128.4, 128.4, 127.7 (Ph)
127.4 (ipso-Ph), 126.7, 125.7 (Ph), 88.9 (COPh), 79.0 (CNPh); chiral HPLC: Pirkle
Covalent (R,R) Whelk-O1 column, 10% IPA in hexane, 1 cm 3 min -1 , 100%, 6.7 min;
racemic sample: 50% - 6.8 min, 50% - 10.5 min.
Synthesis of (4R*, 5R*)-2,4,5-triphenyloxazoline (101a) and (4R*, 5R*)-2-(4-
methoxyphenyl)-4,5-diphenyloxazoline (101b)
O NH 2
Ph Ph
O
N
Ph Ph
O N
O NH 2
i) (Et 3 O)BF 4
1
Ph
ii)
HO Ph
4
OMe
H 2 N (±)
OMe
±101a ±101b
General procedure 3 was used mixing benzamide (67 mg, 0.55 mmol), para-anisamide
(84 mg, 0.55 mmol) with the triethyloxonium salt (228 mg, 1.20 mmol) before
addition of the α-amino alcohol (280 mg, 1.35 mmol). Purification by flash
chromatography (9:1 petrol:EtOAc), and recrystallisation from toluene/hexane yielded
oxazoline 101a (140 mg, 85%) as colourless needles and oxazoline 101b (155 mg,
86%) as colourless needles.
101a data as enantiopure (previous page) Chiral HPLC: Pirkle Covalent (R,R) Whelk-
O1 column, 10% IPA in hexane, 1mL/ min: 50% - 6.8 min, 50% - 10.5 min.
2
3
222

Experimental for chapter 3.1
101b data as enantiopure (vide infra) Chiral HPLC: Pircle Covalent (R,R) Whelk-O1
column, 10% IPA in hexane, 1ml/ min: 50% - 11.3 min, 50% - 20.0 min.
Synthesis of (4R, 5R)-2-(4-methoxyphenyl)-4,5-diphenyloxazoline (101b)
HO
O
Ph
NH
Ph
DIC, Cu(OTf) 2
Ph
O
N
Ph
Δ
OMe OMe
Reflux:General procedure 2 was used with benzamide (20.0 mg, 57.6 mmol), DIC
(8.96 cm 3 , 57.6 mmol), Cu(OTf) 2 (1.25 g, 3.50 mmol), dioxane (175 cm 3 ) and heated
under reflux for 12 hr at 120 °C. Flash chromatography (9:1 to 4:1 petrol:EtOAc)
yielded oxazoline 101b (8.67 g, 46%) as colourless needles.
Microwave:General procedure 2 was used with benzamide (700 mg, 2.01 mmol), DIC
(0.31 cm 3 , 2.01 mmol), Cu(OTf) 2 (44 mg, 0.12 mmol), THF (7 cm 3 ) and heated under
microwave irradiation for 30 min. at 140 °C. Flash chromatography (9:1 to 4:1
petrol:EtOAc) yielded oxazoline 101b (661 mg, 72%) as colourless needles.
Ph
Ph
Ph
Ph
Ph
O
N
Ph
SiO 2 slurry, CH 2 Cl 2
O
1
N
O
N
2
OMe
3
4
OMe
OMe
101b 109b
An excess of silica was added to a stirred solution of aziridine 100b (1.38 g, 4.2 mmol)
in CH 2 Cl 2 (20 cm 3 ) and stirred for 8 days. The mixture was filtered, concentrated
under vacuum and purified by flash chromatography (9:1 to 3:1 petrol:EtOAc) to yield
oxazoline 101b (800 mg, 58%) as clear cubic crystals, and its diastereomeric oxazoline
109b (7 mg, 1%).
223

Experimental for chapter 3.1
R f : 0.38 (4:1 petrol:EtOAc); Mpt: 98-99 °C (toluene); [α] 32 D : –40.8 (c = 1.0, CHCl 3 );
[α] 20 D : –38 (c = 0.5, EtOH); MS m/z (CI+): 330 (100%, MH + ), 331 (21%, (M+1)H + );
HRMS (ESI+) m/z found 330.1488 (MH calcd. 330.1489); Microanalysis: % found
(% calc’d for C 22 H 19 NO 2 ) C, 80.22 (80.00), H, 5.81 (5.81), N 4.25 (4.23); IR
ν max (film)/cm -1 : 1641 (C=N), 1608, 1510, 1254; 1 H-NMR (CD 3 OD, 300 MHz) δ 8.06
(d, 2H, J 9.0, H2), 7.51-7.29 (m, 10H), 7.09 (d, 2H, J 9.0, H3), 5.49 (d, 1H, J 7.5,
CHO), 5.18 (d, 1H, J 7.5, CHN), 3.92 (s, 3H, OMe); 1 H-NMR (CDCl 3 , 300 MHz) δ
8.10 (d, 2H, J 9.0, H2), 7.45-7.31 (m, 10H), 6.99 (d, 2H, J 9.0, H3), 5.40 (d, 1H, J 7.5,
CHO), 5.21 (d, 1H, J 7.5, CHN), 3.89 (s, 3H, OMe); 13 C-NMR (CD 3 OD, 125 MHz) δ
165.4 (C=N) 163.3 (C4), 141.8 (ipso-Ph), 140.2 (ipso-Ph), 130.3, 128.9, 128.8, 128.5,
127.9, 126.7, 125.6 (Ph), 119.0 (C1), 114.0 (C3), 89.5 (CHOPh), 78.5 (CHNPh), 54.8
(OMe); chiral HPLC: Pirkle Covalent (R,R) Whelk-O1 column, 10% IPA in hexane,
1ml min -1 , 100%, 11.7 min; racemic sample: 50% - 11.3 min, 50% - 20.0 min. See
appendix for crystallographic information.
109b characterised separately (vide infra)
Synthesis of (4R,5R)-2-(3-methoxyphenyl)-4,5-diphenyloxazoline (101c)
HO
Ph
Ph
Ph
Ph
O
NH
DIC, Cu(OTf) 2
O
N
Δ
6
1
2
OMe
5
4
3
OMe
General procedure 2 was used with benzamide 165c (195 mg, 0.56 mmol), DIC (0.09
cm 3 , 0.56 mmol), Cu(OTf) 2 (12 mg, 0.03 mmol), dioxane (2 cm 3 ) and heated under
reflux for 17 hr. Flash chromatography (4:1 petrol:EtOAc) yielded oxazoline 101c (71
mg, 39%) as colourless needles.
R f : 0.38 (4:1 petrol:EtOAc); Mpt: 92-93 °C (PhMe); [α] 21 D : –25.0 (c = 0.4, EtOH);
MS m/z (CI+): 330 (100%, MH + ), 331 (23%, (M+1)H + ), 223 (23%); HRMS (ESI+)
m/z found 330.1495 (MH calcd. 330.1489); IR ν max (film)/cm -1 : 1646 (C=N), 1582,
1452, 1321, 1039; 1 H-NMR (CDCl 3 , 300 MHz) δ 7.75 (dt, 1H, J 8.0, 1.0, H6), 7.71-
7.69 (m, 1H, H2), 7.17-7.06 (m, 11H, Ph, H5), 7.11 (ddd, 1H, J 8.0, 2.5, 1.0, H4), 5.43
224

Experimental for chapter 3.1
(d, 1H, J 7.5, CHO), 5.25 (d, 1H, J 7.5, CHN), 3.88 (s, 3H, OMe); 13 C-NMR (CDCl 3 ,
75 MHz) δ 163.9 (C=N), 159.5 (C3), 141.8 (ipso-Ph), 140.3 (ipso-Ph), 129.4, 128.9,
128.8 (Ar), 128.6 (C1), 128.4, 127.7, 126.7, 125.6 (Ar), 121.0 (C4), 118.5 (C6), 112.7
(C2), 88.9 (CHO), 78.9 (CHN), 55.4 (OMe).
Synthesis of (4R*,5R*)-2-(3-fluorophenyl)-4,5-diphenyloxazoline (101d)
Ph
Ph
O NH 2
Ph
F
i) (Et 3 O)BF 4
ii)
Ph
NH 2
OH (±)
6
5
O
4
N
1
2
3
F
(±)
General procedure 3 was used mixing meta-fluorobenzamide (266 mg, 1.91 mmol)
with the triethyloxonium salt (400 mg, 2.10 mmol) stirring for 14 hr, before addition of
the α-amino alcohol (490 mg, 2.30 mmol) and reflux for 24 hr. Purification by flash
chromatography (9:1 petrol:EtOAc), yielded oxazoline 101d (510 mg, 82%) as clear
needles.
R f : 0.29 (9:1 petrol:EtOAc); Mpt: 63-64 °C (PhMe); MS m/z (CI+): 318 (100%,
MH + ), 319 (19%, (M+1)H + ), 211 (63%, [M-PhCHO]H + ); HRMS (ESI+) m/z found
318.1290 (MH calcd. 318.1289); IR ν max (film)/cm -1 : 3031 (w), 1651 (C=N), 1588,
1490 (m), 1453, 1321 (m), 1271 (m), 1185; 1 H-NMR (CDCl 3 , 500 MHz) δ 7.93 (d,
1H, J 8.0, H2), 7.83 (dd, 1H, J 9.5, 1.5, H4), 7.49-7.28 (m, 11H, Ar), 7.27-7.22 (m,
1H, Ar), 5.44 (d, 1H, J 7.5, CHO), 5.25 (d, 1H, J 7.5, CHN); 13 C-NMR (CDCl 3 , 125
MHz) δ 163.0 (C=N), 162.6 (d, J 245, C-F), 141.6 (ipso-Ph), 140.1 (ipso-Ph), 130.2 (d,
J 8, C1 or C5), 129.6 (d, J 8, C1 or C5), 129.1, 128.9, 128.0, 127.8, 126.8, 125.9,
125.6, 124.6, 124.1, 118.9, 115.8 (d, J 24, C2 or C4), 115.3 (d, J 24, C2 or C4), 89.2
(CHO), 78.9 (CHN).
225

Experimental for chapter 3.1
Synthesis of (4R*,5R*)-2-(4-cyanophenyl)-4,5-diphenyloxazoline (101g)
HO
O
Ph
NH
Ph
DIC, Cu(OTf) 2
Δ
Ph
O
Ph
N
1
2
CN
(±)
4
CN
3
(±)
General procedure 2 was used with benzamide (340 mg, 1.0 mmol), DIC (0.16 cm 3 ,
1.0 mmol), Cu(OTf) 2 (21 mg, 0.06 mmol), THF (3 cm 3 ) and heated under microwave
irradiation for 20 min. at 150 °C. Flash chromatography (9:1 petrol:EtOAc) yielded
oxazoline 101g (170 mg, 53%) as colourless needles.
R f : 0.30 (4:1 petrol:EtOAc); Mpt: 134 °C (PhMe); MS m/z (CI+): 325 (100%, MH + ),
326 (38%, (M+1)H + ), 130 (14%); IR ν max /cm -1 : 2934 (m), 2229 (w, CN), 1628 (C=N),
1527, 1317 (m); 1 H-NMR (CDCl 3 , 400 MHz) δ 8.23 (d, 2H, J 7.0, H2), 7.76 (d, 2H, J
7.0, H3), 7.44-7.25 (m, 10H, Ph), 5.46 (d, 1H, J 8.0, OCH), 5.27 (d, 1H, J 8.0, NCH);
13 C-NMR (CDCl 3 , 100 MHz) δ 162.5 (C=N), 141.3 (ipso-Ph), 139.8 (ipso-Ph), 132.3
(C3) 131.6 (C1), 129.2 (C2), 129.1, 129.0 (Ph), 128.8 (para-Ph), 128.1 (para-Ph),
126.7, 125.8 (Ph), 118.3 (C4), 115.1 (C≡N), 89.6 (HCO), 79.1 (HCN).
Synthesis of (4R*,5R*)-2-(4-nitrophenyl)-4,5-diphenyloxazoline (101h)
Ph
Ph
O NH 2
i) (Et 3 O)BF 4
O N
ii)
Ph
1
2
Ph
NH
NO 2
2
3
OH (±)
4
NO 2 (±)
General procedure 3 was used mixing para-nitrobenzamide (300 mg, 1.81 mmol) with
the triethyloxonium salt (378 mg, 2.00 mmol) stirring for 19 hr, before addition of the
amino alcohol (462 mg, 2.17 mmol) and reflux for 21 hr. Purification by flash
chromatography (19:1 to 9:1 petrol:EtOAc), yielded oxazoline 101h (340 mg, 55%) as
colourless flowers.
226

Experimental for chapter 3.1
R f : 0.41 (4:1 petrol:EtOAc); Mpt: 121-122 °C (EtOAc), 118-120 °C (PhMe); MS m/z
(CI+): 345 (100%, MH + ), 346 (20%, (M+1)H + ), 238 (6%); HRMS (ESI+) m/z found
345.1237 (MH calcd. 345.1234); IR ν max (film)/cm -1 : 1648 (C=N), 1598, 1527, 1494
(NO 2 ), 1347 (NO 2 ); 1 H-NMR (CDCl 3 , 300 MHz) δ 8.32 (d, 2H, J 3.0, H2), 8.30 (d,
2H, J 3.0, H3), 7.44-7.33 (m, 8H, Ar), 7.31 (d, 1H, J 2.0, ortho-Ph), 7.28 (t, 1H, J 1.5,
para-Ph), 5.49 (d, 1H, J 8.0, HCO), 5.30 (d, 1H, J 8.0, HCN); 13 C-NMR (CDCl 3 , 75
MHz) δ 162.1 (C=N), 149.7 (C4), 141.1 (ipso-Ph), 139.6 (ipso-Ph), 133.2 (C1), 129.6,
129.0, 129.0, 128.9 (Ph), 128.7 (para-Ph), 128.0 (para-Ph), 126.6, 125.7 (Ph), 123.6
(Ph), 89.6 (CHO), 79.0 (CHN).
Synthesis of (4R,5R)-2-(2-methoxyphenyl)-4,5-diphenyloxazoline (101i)
HO
O
Ph
NH
Ph
DIC, Cu(OTf) 2
Ph
O
N
Ph
OMe Δ
1
6
5
4
2
3
OMe
General procedure 2 was used with benzamide (890 mg, 2.56 mmol), DIC (0.40 cm 3 ,
2.56 mmol), Cu(OTf) 2 (56 mg, 0.15 mmol), dioxane (9 cm 3 ) and heated under reflux
for 18 hr at 120 °C. Flash chromatography (4:1 petrol:EtOAc) yielded oxazoline 101i
(420 mg, 50%) as colourless needles.
R f : 0.36 (3:1 petrol:EtOAc); Mpt: 79-81 °C (PhMe); [α] 21 D : –13 (c = 0.3, EtOH); MS
m/z (CI+): 330 (100%, MH + ), 331 (23%, (M+1)H + ), 223 (14%, [M-PhCHO]H + );
HRMS (ESI+) m/z found 330.1488 (MH calcd. 330.1489); IR ν max (film)/cm -1 : 1654
(C=O), 1595, 1060; 1 H-NMR (CDCl 3 , 300 MHz) δ 7.95 (dd, 1H, J 8.0, 2.0, H6), 7.49
(td, 1H, J 8.5, 2.0, H4), 7.44-7.39 (m, 5H, Ph), 7.39-7.36 (m, 3H, Ph), 7.35-731 (m,
2H, Ph), 7.08-7.01 (m, 2H, H3, H5), 5.40 (d, 1H, J 7.0, CHO), 5.28 (d, 1H, J 7.0,
CHN), 3.95 (s, 3H, OMe); 13 C-NMR (CDCl 3 , 75 MHz) δ 162.9 (C=N), 158.7 (C2),
142.2 (ipso-Ph), 140.7 (ipso-Ph), 132.4 (C4), 131.3 (C6), 128.7, 128.6, 128.1, 127.5,
126.6, 125.5 (Ar), 120.2 (C5), 116.9 (C1), 111.7 (C3), 88.1 (CHO), 79.0 (CHN), 55.9
(OMe).
227

Experimental for chapter 3.1
Synthesis of (4R,5R)-2-(3-hydroxylphenyl)-4,5-diphenyloxazoline (101k) &
(4R,5R)-2-(3-(allyloxy)phenyl)-4,5-diphenyloxazoline (101j)
Ph Ph
Ph Ph
O
OH
OH
HN
Ph
Ph
EDC.HCl
SiO 2 , CH 2 Cl 2
rt, 30 hr
O
N
OH
AllylBr, K 2 CO 3
DMF, NaI
O
1
6
5
4
N
2
3
O
101k
101j
EDC.HCl (382 mg, 2 mmol) was added to a stirred solution of aziridine (195 mg, 1
mmol), silica (2 g) and 3-hydroxybenzoic acid (207 mg, 1.5 mmol) in CH 2 Cl 2 (10
cm 3 ). The solvent was removed after 32 hr and the resulting residue partitioned
between water (10 cm 3 ) and CH 2 Cl 2 (30 cm 3 ). The aqueous phase was washed with
further CH 2 Cl 2 (3 x 30 cm 3 ) and the combined organic phases dried over sodium
sulphate, before purification by flash chromatography (4:1 petrol:EtOAc) to give
phenol 101k (180 mg, 57%) and starting materials (20%).
Adapted from the method of Ishizaki, 17 allyl bromide (83 µl, 0.95 mmol) was added to
a solution of phenol 101k (200 mg, 0.63 mmol), sodium iodide (9 mg, 0.06 mmol),
potassium carbonate (173 mg, 1.26 mmol) in DMF (7 cm3) and stirred for 16 hr.
Water (2 cm 3 , mild exotherm) was added and air blown of the stirred reaction mixture
for a further 2 hr before the mixture was concentrated, partitioned between water (10
cm 3 ) and EtOAc (40 cm 3 ) and the aqueous phase washed with CH 2 Cl 2 (3 x 30 cm 3 )
and the combined organic phases dried over sodium sulphate. Purification by flash
chromatography (70% toluene in petrol) to give oxazoline 101j (75 mg, 38%).
101k R f : 0.12 (4:1, petrol:EtOAc); MS m/z (ES-) 314 (100%, [M-H] - ), 315 (20%,
[(M+1)-H] - ); HRMS: found 338.1143, MNa requires 338.1138; ¹H-NMR (CDCl 3 , 500
MHz) δ 7.63-7.60 (m, 2H, H2, H6), 7.42-7.25 (m, 11H, Ar), 7.00-6.97 (m, 1H, H4),
5.42 (d, 1H, J 7.5, CHOPh), 5.23 (d, 1H, J 7.5, CHNPh); ¹³C-NMR (CDCl 3 , 75.5
MHz) δ 164.6 (C=N), 156.3 (C-OH), 141.6 (ipso-Ph), 140.1 (ipso-Ph), 129.8, 128.9,
128.9, 128.5, 128.2, 127.9, 126.7, 125.6 (Ar), 120.6 (C2 or C6), 119.4 (C4), 115.5 (C2
or C6), 89 (CHOPh), 78.4 (CHNPh).
228

Experimental for chapter 3.1
101j R f : 0.20 (9:1, petrol:EtOAc); [α] 24 D : –22.3 (c = 1.7, CHCl 3 ); MS m/z (ES+) 356
(27%), 378 (100%), 379 (29%); HRMS: found 378.1453, MNa requires 378.1465; IR
ν max (film)/cm⎯¹ 1992 (w), 1649 (C=N), 1582 (m, C=C), 1448 (m); ¹H-NMR (CDCl 3 ,
500 MHz) δ 7.74 (d, 1H, J 8.0, Ar), 7.71-7.69 (m, 1H, H2), 7.44-7.31 (m, 11H, Ar),
7.13 (dd, 1H, J 8.0, 2.0, H5), 6.13-6.04 (m, 1H, H8), 5.48-5.41 (m, 2H, CHOPh, H9),
5.31 (d, 1H, J 9.5, H9), 5.24 (d, 1H, J 7.5, CHNPh), 4.61 (d, 2H, J 5.0, H7); ¹³C-NMR
(CD 3 OD, 75.5 MHz) δ 166.3 (C=N), 160.2 (C3), 142.6 (ipso-Ph), 141.1 (ipso-Ph),
134.5, 131.0, 130.1, 130.0, 129.8, 129.3, 129.2, 127.9, 126.8 (Ar), 122.1 (CH), 120.3
(CH), 117.8 (CH 2 ), 115.2 (CH), 90.8 (CHOPh), 79.7 (CHNPh), 69.9 (CH 2 ).
Synthesis of (4R*,5R*)-2-cyclohexyl-4,5-diphenyloxazoline (101m)
Ph
Ph
i) (Et 3 O)BF 4
(±)
O NH 2
HO Ph
ii)
Ph
O
N
H 2 N
(±)
General procedure 3 was used mixing cyclohexanecarboxamide (500 mg, 3.92 mmol)
with the triethyloxonium salt (860 mg, 4.5 mmol) stirring for 20 hr, before addition of
the α-amino alcohol (500 mg, 2.35 mmol) and reflux for 16 hr. Purification by flash
chromatography (9:1 to 4:1 petrol:EtOAc), yielded oxazoline 101m (1.12 g, 93%) as a
white wax.
R f : 0.44 (4:1, petrol:EtOAc); MS m/z (CI+) 306 (100%, MH + ), 307 (22%, (M+1)H + );
HRMS: found 306.1855, MH requires 306.1852; IR ν max (film)/cm⎯¹ 2930 (C-H),
1663 (C=N), 1450 (m); ¹H-NMR (CDCl 3 , 500 MHz) δ 7.43-7.35 (m, 5H, Ph), 7.34-
7.26 (m, 3H, Ph), 7.25-7.21 (m, 2H, Ph), 5.23 (d, 1H, J 7.0, CHOPh), 5.03 (d, 1H, J
7.0, CHNPh), 2.67-2.56 (m, 1H, CH), 2.19-2.07 (m, 2H), 1.90-1.82 (m, 2H), 1.80-1.59
(m, 3H), 1.46-1.18 (m, 3H); ¹³C-NMR (CDCl 3 , 125 MHz) δ 171.5 (C=N), 142.4 (ipso-
Ph), 140.1 (ipso-Ph), 128.9 (meta-Ph), 128.8 (meta-Ph), 128.4 (para-Ph), 127.7 (para-
Ph), 126.5 (ortho-Ph), 125.5 (ortho-Ph), 88.3 (CHOPh), 78.3 (CHNPh), 37.5 (CH),
30.0, 29.9, 25.8, 25.6.
229

Experimental for chapter 3.1
Synthesis of (4S,5S)-4-(methoxymethyl)-2-(4-methoxyphenyl)-5-phenyloxazoline
(104b)
Ph OMe
O NH 2
i) (Et 3 O)BF 4
O N
ii) Ph
1
HO
2
OMe
H 2 N
OMe
3
4
OMe
General procedure 3 was used mixing p-anisamide (348 mg, 2.30 mmol) with the
triethyloxonium salt (524 mg, 2.76 mmol) before addition of the α-amino alcohol (542
mg, 2.99 mmol). Purification by flash chromatography (9:1 petrol:EtOAc) yielded
oxazoline 104b (493 mg, 72%) as colourless flowers.
R f : 0.18 (4:1 petrol:EtOAc); Mpt: 60-61 °C from (CH 2 Cl 2 ); [α] 23 D : –94 (c = 0.4,
EtOH); MS m/z (CI+): 298 (100%, MH + ), 299 (17%, (M+1)H + ); HRMS (ESI+) m/z
found 298.1439 (MH calcd. 298.1438); IR ν max (film)/cm -1 : 1648 (s, C=N), 1609 (s),
1512 (s), 1252 (s); 1 H-NMR (CDCl 3 , 300 MHz) δ 7.99 (d, 2H, J 9.0, ortho-Ph), 7.39-
7.30 (m, 5H, Ph), 6.94 (d, 2H, J 9.0, meta-Ph), 5.46 (d, 1H, J 7.0, CHPh), 4.30 (td, 1H,
J 6.5, 4.5, CHN), 3.86 (s, 3H, ArOMe), 3.73 (dd, 1H, J 9.5, 3.5, CH a H b ), 3.61 (dd, 1H,
J 9.5, 6.5, CH a H b ), 3.44 (s, 3H, CH 2 OMe); 13 C-NMR (CDCl 3 , 75 MHz) δ 164.2
(CNO), 162.5 (C4), 141.3 (ipso-Ph), 130.5, 129.0, 128.4, 125.8 (Ar CH), 120.3 (C1),
114.0 (meta-CH), 83.8 (CHPh), 75.2 (CH 2 ), 74.8 (CHN), 59.6, 55.6 (OMe).
230

Experimental for chapter 3.1
Synthesis of (4R,5S)-2,4,5-triphenyloxazoline (109a) and (4R, 5S)-2-(4-
methoxyphenyl)-4,5-diphenyloxazoline (109b)
Ph Ph
O NH 2
O N
Ph Ph
O N
i) (Et 3 O)BF 4
109b
OMe
ii)
O NH 2
OMe
HO
Ph
H 2 N
Ph
109a
1
4
2
3
General procedure 3 was used mixing benzamide (89 mg, 0.74 mmol) para-anisamide
(112 mg, 0.74 mmol) with the triethyloxonium salt (265 mg, 1.39 mmol), stirring for
27 hr, before addition of the α-amino alcohol (350 mg, 1.5 mmol) and reflux for 24 hr.
Purification by flash chromatography (9:1 petrol:EtOAc), and recrystallisation from
toluene/hexane yielded oxazoline 109a (155 mg, 70%) as clear colourless flowers and
anisole 109b (160 mg, 66%) as colourless needles.
109a R f : 0.41 (4:1 petrol:EtOAc); Mpt: 134-135 °C (toluene); [α] 25 D : +159 (c = 0.2,
EtOH); MS m/z (CI+): 300 (100%, MH + ), 301 (20%, (M+1)H + ); HRMS (ESI+) m/z
found 300.1387 (MH calcd. 300.1383); IR ν max (film)/cm -1 : 1643 (C=N), 1451, 1269;
1 H-NMR (CDCl 3 , 500 MHz) δ 8.21 (d, 2H, J 7.0, ortho-Ph), 7.60 (tt, 1H, J 8.5, 2.0,
para-Ph), 7.55-7.51 (m, 2H, Ph), 7.11-7.02 (m, 6H, Ph), 7.00-6.95 (m, 4H, Ph), 6.0 (d,
1H, J 10.0, CHO), 5.79 (d, 1H, J 10.0, CHN); 13 C-NMR (CDCl 3 , 75 MHz) δ 164.9
(CNO), 137.7 (ipso-Ph), 136.6 (ipso-Ph), 131.8, 128.6, 128.6, 127.9, 127.7, 127.6,
127.5 (ipso-Ph), 127.4, 127.0, 126.3 (Ph), 85.3 (COPh), 74.5 (CNPh).
109b R f : 0.23 (4:1 petrol:EtOAc); Mpt: 126 °C (tolene/petrol); [α] 20 D : +162 (c = 0.45
EtOH); MS m/z (CI+): 330 (100%, MH + ), 331 (23%, (M+1)H + ); HRMS (ESI+) m/z
found 330.1492 (MH calcd. 330.1489); IR ν max (film)/cm -1 : 1644 (C=N), 1608, 1511,
1255; 1 H-NMR (MeOD, 300 MHz) δ 8.07 (d, 2H, J 9.0, H2), 7.12-6.92 (m, 12H, Ph),
6.12 (d, 1H, J 10.0, CHO), 5.75 (d, 1H, J 10.0, CHN), 3.90 (s, 3H, OMe); 13 C-NMR
(CDCl 3 , 125 MHz) δ 164.7 (CO), 162.5 (C4), 137.9 (ipso-Ph), 136.7 (ipso-Ph), 130.3,
127.9, 127.6, 127.6, 126.3, 127.3, 126.9, 119.9 (C1), 113.9, 85.1 (COPh), 74.3
(CNPh), 55.4 (OMe).
231

Experimental for chapter 3.1
Synthesis of (S)-4-isopropyl-2-phenyloxazoline (111a)
O NH 2 i) (Et 3 O)BF 4
ii)
HO
H 2 N
O
N
General procedure 3 was used mixing benzamide (400 mg, 3.30 mmol) with the
triethyloxonium salt (690 mg, 3.63 mmol) stirring for 24 hr, before addition of the
amino alcohol (0.44 cm 3 , 3.96 mmol) and reflux for 21 hr. Purification by flash
chromatography (9:1 petrol:EtOAc), yielded oxazoline 111a (510 mg, 82%) as a clear
oil.
R f : 0.44 (4:1 petrol:EtOAc); [α] 24 D : –46 (c = 0.6, EtOH); MS m/z (CI+): 190 (100%,
MH + ), 191 (9%, (M+1)H + ); HRMS (ESI+) m/z found 190.1227 (MH calcd. 190.1226);
IR ν max (film)/cm -1 : 2960 (C-H), 1649 (C=N), 1450 (w), 1353 (m); 1 H-NMR (CDCl 3 ,
300 MHz) δ 7.99-7.92 (m, 2H, ortho-Ph), 7.50-7.35 (m, 3H, Ph), 4.45-4.35 (m, 1H,
CHN), 4.17-4.04 (m, 2H, CH 2 ), 1.93-1.79 (m, 1H, CHMe 2 ), 1.03 (d, 3H, J 7.0,
CHMe a Me b ), 0.92 (d, 3H, J 7.0, CHMe a Me b ); 13 C-NMR (CDCl 3 , 75 MHz) δ 163.3
(C=O), 131.1, 128.2, 128.2 (Ar), 127.8 (ipso-Ph), 72.5 (CO), 70.0 (CN), 32.8
(CHMe 2 ), 18.9 (CHMe a Me b ), 18.0 (CHMe a Me b ).
Synthesis of (S)-4-isopropyl-2-(4-methoxyphenyl)oxazoline (111b)
O NH 2
i) (EtO) 3 BF 4
O
N
OMe
1
ii)
HO
4
H 2 N
OMe
2
3
General procedure 3 was used mixing p-anisamide (451 mg, 2.98 mmol) with the
triethyloxonium salt (651 mg, 3.43 mmol) and stirred for 26 hr before addition of the
α-amino alcohol (400 mg, 3.88 mmol) and refluxed for 16 hr. Purification by flash
chromatography (4:1 petrol:EtOAc) yielded oxazoline 111b (382 mg, 58%) as a clear
oil.
232

Experimental for chapter 3.1
R f : 0.52 (2:1 petrol:EtOAc); [α] 22 D : –40.8 (c = 1.5); MS m/z (CI+): 220 (100%, MH + ),
221 (10%, (M+1)H + ); HRMS (ESI+) m/z found 220.1330 (MH calcd. 220.1332); IR
ν max (film)/cm -1 : 2961 (m, C–H), 1645 (C=N), 1610, 1512, 1258 (C–Me); 1 H-NMR
(CDCl 3 , 500 MHz) δ 7.87 (d, 2H, J 9.0, H2), 6.88 (d, 2H, J, 9.0, H3), 4.39-4.29 (m,
1H, CH A H B ), 4.10-4.01 (m, 2H, CH A H B & CHN), 3.80 (s, 3H, OMe), 1.82 (oct, 1H, J
6.5, CHMe 2 ), 1.00 (d, 3H, J 7.0, CHMe A Me b ), 0.89 (d, 3H, J 7.0, CHMe a Me B ); 13 C-
NMR (CDCl 3 , 125 MHz) δ 163.0 (C=O), 161.8 (C1, 129.8 (C2), 120.4 (C4), 113.5
(C3), 72.4 (CHN), 69.9 (OCH 2 ), 55.2 (OMe), 32.8 (CHMe 2 ), 18.9 (CHMe A Me b ), 18.0
(CHMe a Me B );
Synthesis of N-((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)benzamide (166)
Ph
O
Cl
Ph
Me
NH 2
HO
O
Me
NH
OH
Et 3 N
1
2
3
4
General procedure 3 was used mixing benzoyl chloride (0.32 cm 3 , 2.76 mmol), (–)-
norepedrine (500 mg, 3.31 mmol) and triethylamine (10 cm 3 ) to give the amide 166
(700 mg, 99%) as clear colourless cubes.
R f : 0.21 (2:1 petrol:EtOAc); Mpt: 164-165 °C (acetone); [α] 22 D : +32 (c = 0.2, EtOH);
MS m/z (CI+): 256 (100%, MH + ) 257 (14%, (M+1)H + ); HRMS (ESI+) m/z found
256.1336 (MH + , calcd. 256.1332); IR ν max (film)/cm -1 : 3286 (OH), 1635 (C=N), 1543
(C–Me); 1 H-NMR (CDCl 3 , 300 MHz) δ 7.84-7.76 (m, 2H, H2), 7.60-7.32 (m, 8H, Ph),
6.33 (d, 1H, J 7.5, NH), 5.30 (d, 1H, J 3.0, CHPh), 4.60 (dqd, 1H, J 7.5, 7.0, 3.0
CHMe), 1.17 (d, 3H, J 7.0, Me); 13 C-NMR (CDCl 3 , 125 MHz) δ 168.5 (CO), 141.0
(ipso-Ph), 134.6 (ipso-Ph), 132.1, 129.1, 129.0, 128.7, 128.0, 127.4, 126.8, 126.8,
126.7 (Ph), 51.8 (CNH), 12.2 (Me). COH under solvent peak by HMQC.
233

Experimental for chapter 3.1
Synthesis of (4S,5S)-4-methyl-2,5-diphenyloxazoline (110)
HO
O
Ph
NH
Me
DIC, Cu(OTf) 2
Ph
O
Me
N
Δ
General procedure 3 was used with benzamide (200 mg, 0.78 mmol), DIC (0.12 cm 3 ,
0.78 mmol), Cu(OTf) 2 (18 mg, 0.05 mmol), THF (3 cm 3 ) and heated under microwave
irradiation for 5 min at 150 °C. Flash chromatography (4:1 petrol:EtOAc) yielded an
inseparable mixture of oxazoline 110 and its diastereomer (195 mg, 65%, 95:5) as
colourless needles.
R f : 0.59 (2:1 petrol:EtOAc); MS m/z (CI+): 238 (100%, MH + ), 239 (18%, (M+1)H + ),
131 (51%, [M-PhCHO] + ); HRMS (ESI+) m/z found 238.1224 (MH calcd. 238.1226);
IR ν max (film)/cm -1 : 2926 (C-H), 1648 (C=N), 1450, 1269; 1 H-NMR data for major
compound (CDCl 3 , 300 MHz) δ 8.07-8.00 (m, 2H, ortho-Ph), 7.54-7.25 (m, 8H, Ph),
5.11 (d, 1H, J 8.0, CHPh), 4.22 (quin, 1H, J 7.0, CHMe), 1.50 (d, 3H, J 6.5, Me); 13 C-
NMR (75 MHz, CDCl 3 ) δ 164.2 (C=N), 140.2 (ipso-Ph), 131.7, 128.9, 128.8, 128.6,
128.4, 127.7 (Ph) 127.4 (ipso-Ph), 126.7, 125.7 (Ph), 86.2 (CHOPh), 63.3 (CHNMe),
22.7 (Me).
234

Experimental for chapter 3.2
5.4 Experimental Procedures for Chapter 3.2
(4S,5S)-4-((4R,5R)-4,5-diphenyloxazolinyl)-5-isopropyl-4-methylcyclohex-2-enone
(201)
Ph Ph
Ph Ph
O
N
O
N
SiO 2 , CH 2 Cl 2
6
1
2
5
3
4
OMe
O
Silica (7.00 g) was added to a stirred solution of enol ether 102a (0.70 g, 1.81 mmol) in
CH 2 Cl 2 (20 cm 3 ). Upon completion (36 hr) the mixture was filtered with EtOAc and
the filtrate concentrated under vacuum to give enone 201 (0.67 mg, 100%) as a yellow
oil.
R f : 0.21 (4:1 petrol:EtOAc); [α] 22 D : +118 (c = 1.3, CHCl 3 ); MS m/z (CI+): 374 (100%,
MH + ), 375 (27%, (M+1)H + ); HRMS (ESI+) m/z found 374.2110 (MH calcd.
374.2115); IR ν max (film)/cm -1 : 2960, 1682 (C=O), 1659 (C=N), 1091 (m); ¹H NMR
(CDCl 3 , 400 MHz) δ 7.43-7.15 (m, 10H, Ph), 7.11 (d, 1H, J 10.5, H6), 6.06 (d, 1H, J
10.5, H5), 5.21 (d, 1H, J 9.5, CHO), 5.09 (d, 1H, J 9.5, CHN), 2.73 (dd, 1H, J 17.0,
8.0, H3 A ), 2.58 (dd, 1H, J 17.0, 5.0, H3 B ), 2.27-2.20 (m, 2H, H2, CHMe 2 ), 1.67 (s, 3H,
Me), 1.02 (d, 3H, J 7.0, CHMe A Me B ), 0.90 (d, 3H, J 7.0, CHMe A Me B ); ¹³C NMR
(CDCl 3 , 100 MHz) δ 199.5 (C=O), 168.5 (C=N), 153.0 (C6), 141.0 (ipso-Ph), 139.2
(ipso-Ph), 128.9, 128.7, 128.5 (C5), 128.0 (para-Ph), 127.7 (para-Ph), 126.5, 125.8,
89.5 (CHO), 78.1 (CHN), 48.3 (C2), 42.3 (C1), 34.5 (C3), 28.4 (CHMe 2 ), 25.6 (Me),
23.0 (CHMe A Me B ), 18.4 (CHMe A Me B ).
235

Experimental for chapter 3.2
Synthesis of N-(1,2-diphenylethyl)cyclohexanecarboxamide (204) and N-
((1R*,2R*)-2-hydroxy-1,2-diphenylethyl)cyclohexanecarboxamide (205)
Ph
O
N
Ph
O
H
N
Ph
Ph
+
O
H
N
Ph
OH
Ph
H 2
204 205
H-cube: A solution of oxazoline 101m (10 mg) in the stated solvent (1 cm 3 ) was
passed thorough the H-cube (1 cm 3 /min, temperature & cartridge as stated) and the
eluent collected for 15 min. The solvent was removed by rotary evaporation and
products purified by flash chromatography (9:1 to 4:1 EtOAc:petrol) to give amide 204
as colourless needles and hydroxyamide 205 as a colourless oil (see text).
Bomb: The bomb was charge with a solution of oxazoline 101m (20 mg) and catalyst
(2 mg) in the stated solvent (2 cm 3 ), backfilled with hydrogen to the stated pressure
and stirred overnight (c. 14 hr). The pressure was released, catalyst filtered under
nitrogen, the solvent was removed by rotary evaporation and products purified by flash
chromatography (9:1 to 4:1 EtOAc:petrol) to give amide 204 as colourless needles and
hydroxyamide 205 as a colourless oil (see text).
204 R f : 0.22 (4:1, petrol:EtOAc); Mpt: 155-156 ºC (CH 2 Cl 2 ); MS m/z (CI+) 308
(100%, MH + ), 309 (19%, (M+1)H + ), 216 (15%, [M-Bn] + ); HRMS: found 308.2018,
MH requires 308.2009; IR ν max (film)/cm⎯¹ 2929 (C-H), 1639 (C=O), 1534 (N-H); ¹H-
NMR (CDCl 3 , 500 MHz) δ 7.33-7.29 (m, 2H, Ph), 7.27-7.19 (m, 6H, Ph), 7.07-7.05
(m, 2H, Ph), 5.69 (d, 1H, J 7.5, NH), 5.29 (q, 1H, J 7.5, CHPh), 3.13 (dd, 1H, J 14.0,
7.5, CH 2 Ph), 3.08 (dd, 1H, J 14.0, 7.5, CH 2 Ph), 2.02 (tt, 1H, J 11.5, 3.0, CH), 1.81-
1.69 (m, 4H), 1.67-1.57 (m, 1H), 1.41-1.27 (m, 2H), 1.28-1.12 (m, 3H); ¹³C-NMR
(CDCl 3 , 125 MHz) δ 175.2 (C=N), 141.7 (ipso-Ph), 137.3 (ipso-Ph), 129.3, 128.5 (Ph),
128.3 (para-Ph), 127.3 (para-Ph), 127.3, 126.5 (Ph), 53.8 (CHPh), 45.5 (CH 2 Ph), 42.6
(CH), 29.6, 29.5, 25.7, 25.6 (CH 2 ).
205 R f : 0.17 (2:1, petrol:EtOAc); MS m/z (CI) 324 (100%, MH + ), 325 (22%,
(M+1)H + ), 217 (74%, [M-PhCH 2 OH] + ); HRMS: found 324.1963, MH requires
236

Experimental for chapter 3.2
324.1958; IR ν max (film)/cm⎯¹ 3315 (br, O-H), 2931 (C-H), 1641 (C=O), 1534 (N-H);
¹H-NMR (CDCl 3 , 500 MHz) δ 7.25-7.23 (m, 10H, Ph), 6.32 (d, 1H, J 7.5, NH), 5.23
(dd, 1H, J 8.0, 4.5, CHNPh), 4.30 (d, 1H, J 4.5, CHOPh), 2.09 (tt, 1H, J 11.5, 3.0,
CH), 1.81-1.71 (m, 4H), 1.67-1.61 (m, 1H), 1.36-1.15 (m, 5H); ¹³C-NMR (CDCl 3 , 125
MHz) δ 176.4 (C=N), 140.7 (ipso-Ph), 139.6 (ipso-Ph), 128.7, 128.2 (Ph), 127.7 (para-
Ph), 127.7 (para-Ph), 126.8, 126 (Ph), 77.2 (CHOPh), 59 (CHNPh), 45.4 (CH), 29.6,
29.4, 25.6, 25.6 (CH 2 ).
Synthesis of (3S*,4S*)-N-((S*)-1,2-diphenylethyl)-3-isopropyl-4-methylcyclohexanone-4-carboxamide
(206)
Ph
O
N
Ph
H 2 Pd/C 20 bar
Ph
Ph
H
N
O
O
O
A solution of oxazoline 201 (90 mg, 0.24 mmol) in methanol (6 cm 3 ) was passed
thorough the H-cube (1 cm 3 /min, 20 bar, Pd/C) and the eluent collected for 30 min.
The solvent was removed by rotary evaporation to give amide 206 (93 mg, 96%) as a
colourless oil.
R f : 0.10 (4:1, petrol:EtOAc); MS m/z (CI+) 378 (100%, MH + ), 379 (24%, (M+1)H + );
HRMS: found 378.2425, MH requires 378.2428; IR ν max (film)/cm⎯¹ 2932 (m, C-H),
1714 (ketone), 1639 (amide), 1531 (m, N-H), 1453 (m); ¹H-NMR (CDCl 3 , 500 MHz)
δ 7.37-7.18 (m, 8H, Ph), 7.11-7.16 (m, 2H, Ph), 5.93 (br d, 1H, J 8.0, NH), 5.39-5.29
(m, 1H, CHNPh), 3.23 (dd, 1H, J 14.0, 6.0, CH 2 Ph), 3.02 (dd, 1H, J 14.0, 9.0, CH 2 Ph),
2.96-2.85 (m, 1H), 2.93 (dd, 1H, J 14.5, 12.0), 2.74 (ddd, 1H, J 15.5, 11.5, 6.5), 2.17-
2.11 (m, 2H), 1.82-1.75 (m, 2H, CHMe 2 , CH), 1.59-1.53 (m, 2H), 1.20 (s, 3H, J 6.5,
Me), 0.81 (d, 3H, J 6.5, i-Pr), 0.52 (d, 3H, i-Pr); ¹³C-NMR (CDCl 3 , 75.5 MHz) δ
213.4, 174.5, 141.5, 137.3, 129.2, 128.6, 128.4, 127.5, 126.7, 126.5, 53.7, 51.8, 43.2,
42.7, 38.3, 38.1, 37.0, 27.7, 24.5, 23.7, 17.2.
237

Experimental for chapter 3.2
Synthesis of (1R*,2R*)-2-(cyclohexylmethylamino)-1,2-diphenylethanol (210)
Ph
O
N
Ph
DIBALH (3 eq)
0 °C
H
N
Ph
OH
Ph
O
H
N
Ph
OH
Ph
210 205
A solution of DIBAlH (0.24 cm 3 , 1M in PhMe, 3 eq) was added drop wise to a stirred
solution of oxazoline 101m (22 mg, 0.07 mmol) in toluene (1 cm 3 ) under a nitrogen
atmosphere, maintained at 0 °C for 4 hr before warming to rt and stirred for 16 hr.
Ammonium chloride (sat. aq. 2 cm 3 ) was added and stirred for 2 hr before being
partitioned between water (2 cm 3 ) and CH 2 Cl 2 (10 cm 3 ) and the aqueous layer was
extracted with CH 2 Cl 2 (3 x 10 cm 3 ) and the combined organic layers dried with sodium
sulfate and reduced under vacuum. Flash chromatography (9:1 petrol:EtOAc) yielded
amine 210 (17 mg, 80%) as a colourless oil and hydroxyamide 205 (2 mg, 10%).
210 R f : 0.26 (4:1, petrol:EtOAc+Et 3 N); MS m/z (CI+) 310 (100%, MH + ), 311 (19%,
(M+1)H + ), 202 (68%, [M-PhCH 2 OH] + ); HRMS: found 310.2176, MH requires
310.2165; IR ν max (film)/cm⎯¹ 3400 (br, N-H, O-H), 2922 (C-H), 1451 (m, C-H); ¹H-
NMR (CDCl 3 , 500 MHz) δ 7.24-7.16 (m, 6H, Ph), 7.09-7.07 (m, 2H, Ph), 7.02-6.98
(m, 2H, Ph), 4.55 (d, 1H, J 9.0 CHOPh), 3.53 (d, 1H, J 9.0 CHNPh), 2.77 (br s, 2H,
OH, NH), 2.38 (dd, 1H, J 11.5, 6.5, H5), 2.27 (dd, 1H, J 11.5, 6.5 H5’), 1.79-1.62 (m,
5H), 1.46-1.38 (m, 1H), 1.26-1.10 (m, 3H), 0.95-0.82 (m, 2H); ¹³C-NMR (CDCl 3 , 125
MHz) δ 141.2 (ipso-Ph), 140.0 (ipso-Ph), 128.2, 127.8, 127.6, 127.3, 126.8 (Ph), 77.6
(CHOPh), 70.8 (CHNPh), 54.2 (CH 2 N), 38.2 (CH), 31.4, 31.2, 26.6, 26.0, 26.0 (CH 2 ).
205: see page 236
238

Experimental for chapter 3.2
Synthesis of (1R*,2R*)-2-amino-1,2-diphenylethyl cyclohexanecarboxylate
hydrochloride (211.HCl)
Ph Ph
NH 3 Cl
O N HCl (aq), THF, Δ
O O
Ph
Ph
Oxazoline 101m (44 mg, 0.14 mmol) was dissolved in a THF/HCl (aq) mixture (1 cm 3 ,
3:1 HCl (6M):THF) and gently heated such that a white precipitate slowly forms.
Once precipitate has stopped forming (c. 2 min) the solution was triturated with THF
(2 cm 3 ) and filtered, the residue was transferred to another flask (CH 2 Cl 2 ) and the
filtrate concentrated under vacuum and triturated with diethyl ether and again filtered.
The residues were combined (CH 2 Cl 2 ) dried over sodium sulfate and concentrated to
give ester 211.HCl (47 mg, 91%) as colourless needles.
R f : 0.12 (2:1, petrol:EtOAc); Mpt: 134 ºC (CH 2 Cl 2 ); MS m/z (CI+) 324 (52%, [M-
Cl] + ), 306 (100%, [M-NH 3 Cl] + ), 307 (20%, [(M+1)-NH 3 Cl] + ); HRMS: found
324.1964, M-Cl requires 324.1958; IR ν max (film)/cm⎯¹ 2925 (N-H), 2853 (N-H), 2365
(w), 1731 (C=O), 1162 (m), 1027 (w, C-N); ¹H-NMR (CD 3 OD, 500 MHz) δ 7.36-7.32
(m, 3H, Ph), 7.28-7.22 (m, 5H, Ph), 7.19-7.14 (m, 2H, Ph), 5.98 (d, 1H, J 7.0,
CHOPh), 4.76 (d, 1H, J 7.0, CHNPh), 2.58-2.51 (m, 1H, CH), 1.96-1.87 (m, 2H),
1.79-1.62 (m, 3H), 1.50-1.41 (m, 1H), 1.39-1.18 (m, 4H); ¹³C-NMR (CD 3 OD, 75.5
MHz) δ 175.8 (C=O), 137.1 (ipso-Ph), 134.5 (ipso-Ph), 130.6 (para-Ph), 130.1 (Ph),
129.9 (para-Ph), 129.5, 129.1, 128.4 (Ph), 77.9 (CHOPh), 60.1 (CHNPh), 43.9 (CH),
30.2, 29.5, 26.7, 26.5, 26.1 (CH 2 ).
239

Experimental for chapter 3.2
Synthesis of 1,2-diphenylethanamine (212)
NH 3 Cl
O
O
Ph
Ph
H 2 , Pd/C
H 2 N
Ph
Ph
A stirred solution of ester 211.HCl (20 mg) and palladium on carbon (5%, 2 mg) in
ethanol (2 cm 3 ), was backfilled with hydrogen and maintained under a positive
pressure until complete by TLC (1.5 hr). The pressure was released, catalyst filtered
under nitrogen, the solvent was removed by rotary evaporation and the resulting
residue partitioned between water (2 cm 3 ) and CH 2 Cl 2 (6 cm 3 ). The aqueous phase
was washed with further CH 2 Cl 2 (2 x 5 cm 3 ) and the combined organic phases dried
over sodium sulphate and concentrated to give amine 212 (11 mg, 100%) as a white
powder.
Analytical data consistent with literature. 18
Synthesis of (1S*,4R*,5R*,6S*)-(1R,2R)-2-amino-1,2-diphenylethyl 4,5-dihydroxy-
6-isopropyl-1-methylcyclohex-2-enecarboxylate.hydrochloride (214)
Ph Ph
NH 3 Cl
O N
Ph O O
HCl (aq), THF
Ph
Δ
OH
OH
OH
OH
A solution of oxazoline 213 (11 mg) in THF (0.4 cm 3 ) and HCl (3M, 0.2 cm 3 ) was
heated at 90 °C for 13 hr, and partitioned between CH 2 Cl 2 (5 cm 3 ) and water (2 cm 3 ).
The aqueous layer was washed with CH 2 Cl 2 (2 x 5 cm 3 ), the combined organic extracts
dried over anhydrous sodium sulfate and solvent removed to yield ester 214 (10 mg,
70%) as a colourless oil.
R f : 0.25 (EtOAc); MS m/z (ES+) 410 (100%, [M-Cl] + ), 411 (27%, [(M+1)-Cl] + ), 432
(34%, [M-HCl]Na + ); HRMS: found 426.2275, MH requires 426.2275; IR ν max
(film)/cm⎯¹ 3340 (br, O-H), 2942 (m), 1733 (C=O), 1452 (m); ¹H-NMR (CDCl 3 , 500
MHz) δ 7.22-7.15 (m, 7H, Ph), 7.12-7.10 (m, 3H, Ph), 5.81 (d, 1H, J 8.5, CHOPh),
240

Experimental for chapter 3.2
5.56 (d, 1H, J 10.0, H6), 5.41 (d, 1H, J 10.0, H5), 4.31 (d, 1H, J 8.5, CHNPh), 3.93-
3.87 (m, 2H, H4, H3), 3.32 (br s, 1H, OH), 2.44 (br s, 1H, OH), 2.23 (pd, 1H, J 7.0,
1.0, CHMe 2 ), 1.40 (d, 1H, J 10.5, 1.0, H2), 1.36 (s, 3H, Me), 1.11 (d, 3H, J 7.0, i-Pr),
1.02 (d, 3H, J 7.0, i-Pr); ¹³C-NMR (CDCl 3 , 125 MHz) δ 194.9 (C=O), 138.3 (ipso-Ph),
137.9 (ipso-Ph), 127.0, 126.2 (Ph), 132.5 (C5), 129.2 (C6), 128.7, 127.9, 126.3, 80.6
(CHOPh), 74.7 (CHOH), 72.7 (CHOH), 63.1 (CHNPh), 53.9 (C2), 33.6 (C1), 26.9
(CHMe 2 ), 22.7 (i-Pr), 20.5 (Me) , 18.2 (i-Pr).
Synthesis of (1S*,6S*)-(1R*,2R*)-2-amino-1,2-diphenylethyl 6-isopropyl-1-
methyl-4-oxocyclohex-2-enecarboxylate. hydrochlorate (215)
Ph Ph
O N
Ph
HCl (aq), THF, Δ
O
NH 2
O O
Ph
6
5
1
2
3
4
A solution of oxazoline 201 (30 mg, 0.08 mmol) in THF (1.5 cm 3 ) and HCl (3 cm 3 ,
6M) was heated at reflux for 12 hr, cooled, and the solvent removed under vacuum to
give a white solid. The white solid was triturated with Et 2 O (5 cm 3 ) and filtered,
giving ester 215 (15 mg, 45%) as a white amorphous solid.
O
Mpt: 156 ºC (Et 2 O); MS m/z (ES+) 414 (100%, [M-HCl]Na + ), 415 (26%, [(M+1)-
HCl]Na + ); HRMS: found 392.2218, [M-Cl] + requires 392.2220; IR ν max (film)/cm⎯¹
3325 (br, NH), 2873 (m, C-H), 1737 (COOR), 1674 (C=C=O), 1458 (s), 1103 (m); ¹H-
NMR (CD 3 OD, 300 MHz) δ 7.36-7.23 (m, 10H, Ph), 7.12 (d, 1H, J 10.0, H6), 6.18 (d,
1H, J 9.0, CHOPh), 5.97 (d, 1H, J 10.0, H5), 4.99-4.95 (m, 1H, CHNPh), 2.56-2.48
(m, 2H, H3), 2.27-2.19 (m, 1H, H2), 1.67 (s, 3H, Me), 1.47 (m, 1H, CHMe 2 ), 0.75 (d,
3H, J 7.0, i-Pr), 0.28 (d, 3H, J 7.0, i-Pr); ¹³C-NMR (CDCl 3 , 125 MHz) δ 199.9
(ketone), 172.0 (ester C=O), 152.1 (C6), 138.2 (ipso-Ph), 137.1 (ipso-Ph), 128.8,
128.3, 128.5, 128.0, 127.9, 127.6, 127.1 (Ph, C5), 80.7 (CHOPh), 69.1 (CHNPh), 48.7
(C2), 47.8 (C1), 34.6 (C3), 27.8 (CHMe 2 ), 25.2, 23.1, 18.5 (Me).
241

Experimental for chapter 3.2
Synthesis of (1R,2R,3S,4S,5R,6S)-(1R,2R)-2-amino-1,2-diphenylethyl 4,5-
dihydroxy-2,3-epoxy-6-isopropyl-1-methylcyclohexanecarboxylate (217)
Ph Ph
O N
HClO 4 (aq), dioxane
O
rt
OH
OH
O
Ph
Ph
NH 2
O O
6
5
1
2
3
4 OH
OH
A solution of oxazoline 216 (9 mg) in dioxane (1.0 cm 3 ) and perchloric acid (1M, 0.1
cm 3 ) was stirred at rt for 28 hr, and partitioned between CH 2 Cl 2 (5 cm 3 ) and sodium
bicarbonate (sat. 2 cm 3 ). The aqueous layer was washed with CH 2 Cl 2 (2 x 5 cm 3 ), the
combined organic extracts dried over anhydrous sodium sulfate and purified by flash
column chromatography to give ester 217 (4 mg, 40%) as a colourless oil and starting
material (4 mg, 45%).
Rf: 0.25 (10%, MeOH in EtOAc); [α] 22 D : –2.4 (c = 0.5, CHCl 3 ); MS m/z (ES+) 426
(100%, MH + ), 427 (32%, (M+1)H + ), 448 (29%, MNa + ); HRMS: found 426.2275, MH
requires 426.2275; IR ν max (film)/cm⎯¹ 3360 (br, O-H), 2963 (m), 1720, 1453 (m),
1259 (m); ¹H-NMR (CD 3 OD, 500 MHz) δ 7.22-7.18 (m, 7H, Ph), 7.17-7.14 (m, 3H,
Ph), 5.83 (d, 1H, J 8.5, CHOPh), 4.36 (d, 1H, J 8.5, CHNPh), 3.85 (dd, 1H, J 11.0, 8.0,
H3), 3.69 (dd, 1H, J 8.0, 1.5, H4), 3.39 (dd, 1H, J 4.0, 1.5, H5), 3.29 (d, 1H, J 4.0,
H6), 1.54 (p, 1H, J 7.0, CHMe 2 ), 1.47 (s, 3H, Me), 1.23 (d, 1H, J 11.0, H2), 0.92 (d,
3H, J 7.0, CHMe A Me b ), 0.72 (d, 3H, J 7.0, CHMe a Me B ); ¹³C-NMR (CD 3 OD, 75.5
MHz) δ 194.9 (C=O), 137.9 (ipso-Ph), 138.3 (ipso-Ph), 128.7, 128.2, 127.9, 127.8,
127.3 (Ph), 80.6 (CHOPh), 75.2, 70.9 (C3, C4), 63.1 (CHNPh), 62.1, 57.2 (C5, C6),
54.5 (C2), 32.4 (C1), 28.1 (CHMe 2 ), 26.2 (CHMe A Me b ), 23.4 (Me), 17.1 (CHMe a Me B ).
242

Experimental for chapter 3.2
Synthesis of (1S,6S)-(1R,2R)-2-(methylamino)-1,2-diphenylethyl 6-isopropyl-1-
methyl-4-oxocyclohex-2-enecarboxylate (218)
Ph
O
N
Ph
MeOTf, then NH 4 Cl
Ph
O
1
6
O
2
HN
Ph
O
General procedure 6 was used employing oxazoline 201 (55 mg, 0.15 mmol) and
methyl triflate (34 µl, 0.29 mmol) for 16 hr and an ammonium chloride (sat. aq., 0.5
cm 3 ) quench. The layers were partitioned, the aqueous layer washed with CH 2 Cl 2 (2 x
5 cm 3 ) and the combined organic phases dried over anhydrous sodium sulfate. Flash
chromatography (9:1 to 2:1 petrol:EtOAc) gave ester 218 (35 mg, 60%) and starting
material (3 mg, 5%).
5
4
O
3
R f : 0.20 (4:1, petrol:EtOAc); [α] 25 D : +77 (c = 1.4, CHCl 3 ); MS m/z (CI) 406 (100%,
MH + ), 407%, (M+1)H + , 428 (5%, MNa + ); HRMS: found 406.2375, MH requires
406.2377; IR ν max (film)/cm⎯¹ 2959 (m), 1730 (C=O), 1683 (C=C–C=O), 1453 (m),
1225 (m), 1107 (m); ¹H-NMR (CDCl 3 , 500 MHz) δ 7.21-7.16 (m, 6H, Ph), 7.05-7.01
(m, 4H, Ph), 6.83 (d, 1H, J 10.0, H6), 6.05 (d, 1H, J 10.0, H5), 5.86 (d, 1H, J 8.0,
CHOPh), 3.91 (d, 1H, J 8.0, CHNPh), 2.70 (dd, 1H, J 17.5, 9.0, H3 ax ), 2.48 (dd, 1H, J
17.5, 5.0, H3 eq ), 2.26 (s, 3H, NMe), 2.12 (ddd, 1H, J 9.0, 5.0, 2.0, H2), 1.82 (pd, 1H, J
7.0, 2.0, CHMe 2 ), 1.48 (s, 3H, Me), 0.85 (d, 3H, J 7.0, CHMe A Me b ), 0.57 (d, 3H, J 7.0,
CHMe a Me B ); ¹³C-NMR (CDCl 3 , 125 MHz) δ 199.7 (C=C=O), 172.1 (CO2), 152.0
(C6), 138.2 (ipso-Ph), 137.1 (ipso-Ph), 128.6, 128.3, 128.1, 128.0, 127.9, 127.6, 127.2
(Ph, C5), 80.7 (CHOPh), 69.1 (CHNPh), 49.1 (C2), 47.8 (C1), 34.6 (C3), 34.3 (NMe),
27.8 (CHMe 2 ), 25.0 (Me), 23.1 (CHMe A Me b ), 17.7 (CHMe a Me B ).
243

Experimental for chapter 3.2
Synthesis of (1S*,4S*,5S*)-5-isopropyl-4-methyl-4-(N-methyl- (4R*,5R*)-4,5-
diphenyloxazolidin-2-yl)cyclohex-2-enol (222) & (1S*,4S*,6S*)-4-hydroxy-6-
isopropyl-1-methylcyclohex-2-enecarbaldehyde (223)
Ph Ph
Ph Ph
O
N
O N
i) MeOTf, then NaBH 4
6
1
2
O
H
ii) H 3 O + 223
O
5
4
OH
222
3
(±)
OH
(±)
General procedure 6 was used employing oxazoline 201 (72 mg, 0.19 mmol) and
methyl triflate (50 µl, 0.40 mmol) for 19 hr. The crude oxazolidine was dissolved in
4:1 THF:water (2 cm 3 ) and oxalic acid (125 mg) was added and stirred at rt for 40 hr,
the solvent was removed, the aqueous layer washed with EtOAc and the combined
organic phases dried over anhydrous MgSO 4 . Flash chromatography (5% to 10%
EtOAc in petrol) gave aldehyde 223 (16 mg, 45%) and oxazolidine 222 (8 mg, 11%) as
colourless oils.
222 R f : 0.29 (4:1, petrol:EtOAc); MS m/z (CI+) 392 (100%, MH + ), 238 (38%);
HRMS: found 392.2594, MH requires 392.2584; IR ν max (film)/cm⎯¹ 3583 (O-H),
2955 (C-H), 1453 (C-Me); ¹H-NMR (CDCl 3 , 500 MHz) δ 7.32-7.28 (m, 3H, Ph), 7.26-
7.21 (m, 5H, Ph), 7.09-7.02 (m, 2H, Ph), 6.13 (dd, 1H, J 10.0, 2.0, H5), 5.83 (dm, 1H,
J 10.0, H6), 4.82 (d, 1H, J 9.5, CHOPh), 4.58 (s, 1H, CHON), 4.21-4.15 (m, 1H, H4),
3.31 (d, 1H, J 9.5, CHNPh), 2.40 (s, 3H, NMe), 2.19 (p, 1H, CHMe 2 ), 1.95-1.86 (m,
1H, H3), 1.84-1.76 (m, 1H, H3’), 1.61 (br s, 1H, OH), 1.39-1.34 (m, 1H, H2), 1.16 (s,
3H, Me), 1.08 (d, 3H, J 7.0, i-Pr), 1.02 (d, 3H, J 7.0, i-Pr); ¹³C-NMR (CDCl 3 , 125
MHz) δ 138.7 (ipso-Ph), 137.9 (ipso-Ph), 135.2 (C5), 132.4 (C6), 128.3, 128.2, 128.0
(Ph), 127.7 (para-Ph), 127.6 (para-Ph), 126.3 (Ph), 100.6 (CHON), 85.4 (CHOPh),
79.5 (CHNPh), 69.5 (C4), 49.6 (C2), 45.2 (NMe), 42.0 (C1), 34.3 (C3), 25.2 (i-Pr),
25.0 (CHMe 2, i-Pr), 18.3 (Me).
223 R f : 0.23 (2:1, petrol:EtOAc); MS m/z (CI+) 200 (100%, MNH + 4 ); HRMS: found
200.1641, MNH 4 requires 200.1645; IR ν max (film)/cm⎯¹ 3405 (br, O-H), 2960 (m, C-
H), 1716 (C=O); ¹H-NMR (CDCl 3 , 500 MHz) δ 9.80 (s, 1H, CHO), 5.99 (dm, 1H, J
244

Experimental for chapter 3.2
10.0, H5), 5.17 (dd, 1H, J 10.0, 2.0, H6), 4.39-4.33 (m, 1H, H4), 2.10-1.99 (m, 2H,
H3), 1.63-1.58 (m, 2H, H2,CHMe 2 ), 1.20 (s, 3H, Me), 0.96 (d, 3H, J 7.0, CHMe A Me b ),
0.78 (d, 3H, J 7.0, CHMe a Me B ); ¹³C-NMR (CDCl 3 , 125 MHz) δ 202.7 (CHO), 135.5
(C5), 130.7 (C6), 68.5 (C4), 52.3 (C1), 49.2 (C2), 29.5 (C3), 25.8 (CHMe 2 ), 23.5
(CHMe A Me b ), 20.5 (Me), 18.3 (CHMe a Me B ).
Synthesis of (1S,4S,5S)-4-(hydroxymethyl)-5-isopropyl-4-methylcyclohex-2-enol
(225)
Ph
O
N
Ph
i) MeOTf, then NaBH 4
ii) H 3 O +
iii) NaBH 4 , MeOH
HO
OH
O
General procedure 6 was used employing oxazoline 201 (66 mg, 0.18 mmol) and
methyl triflate (40 µl, 0.35 mmol) for 18 hr. The crude oxazolidine was subjected to
general procedure 7, the room temperature hydrolysis taking 3 days. The resulting
crude alcohol was purified by flash column chromatography (2:1 to 1:1 petrol:EtOAc)
to give diol 225 (31 mg, 94%) as a colourless oil.
R f : 0.12 (1:1, petrol:EtOAc); [α] 22 D : +49.5 (c = 1.1, CHCl 3 ); MS m/z (CI+) 185
(100%, MH + ), 202 (44%, MNH + 4 ), 137 (62%); HRMS: found 202.1808, MNH 4
requires 202.1802; IR ν max (film)/cm⎯¹ 3330 (br, O-H), 2955 (C-H), 2869 (m, C-H),
1462, 1042 (m); ¹H-NMR (CDCl 3 , 500 MHz) δ 5.84-5.81 (m, 1H, H5), 5.41 (dd, 1H, J
10.0, 2.0, H6), 4.26-4.21 (m, 1H, H4), 3.65 (d, 1H, J 11.0, H7 a ), 3.36 (d, 1H, J 11.0,
H7 b ), 2.12 (br s, 1H, OH), 1.99 (p, 1H, J 7.0, CHMe 2 ), 1.89-1.83 (m, 1H, H3 a ), 1.77
(br s, 1H, OH), 1.61-1.52 (m, 1H, H3 b ), 1.33 (d, 1H, J 12.5, H2), 0.96 (d, 3H, J 7.0, i-
Pr), 0.94 (s, 3H, Me), 0.90 (d, 3H, J 7.0, i-Pr); ¹³C-NMR (CDCl 3 , 125 MHz) δ 136.0
(C5), 133.2 (C6), 69.0 (C4), 67.4 (C7), 47.0, 40.9 (C2, C1), 29.9, 25.3 (C3, CHMe 2 ),
24.5, 24.3, 18.0 (Me).
245

Experimental for chapter 3.2
Synthesis of ((1S,4S,5S)-4-(hydroxymethyl)-5-isopropyl-4-methylcyclohex-2-enol)
bis para-bromobenzoate (115)
O
HO
Cl
Br Br
DMAP
Et
OH
3 N, CH 2 Cl 2
8
9
O
O
7
1 2
3
6
4
5
O
O
Br
4-bromobenzoyl chloride (120 mg, 0.55 mmol) was added to a solution of diol 225 (20
mg, 0.1 mmol), DMAP (2 mg, 0.02 mmol), triethylamine (1 cm 3 ) in CH 2 Cl 2 (5 cm 3 )
under a nitrogen atmosphere. After 12 hr sodium hydroxide (2.5 cm 3 , 3M aq.) was
added to the reaction and stirred for 1 hr before being partitioned in EtOAc (1 cm 3 ) and
the organic layer washed sequentially with HCl (3M aq.), sodium bicarbonate, and
brine. The organic layer was dried over anhydrous sodium sulphate and solvent
evaporated to give a clear yellow oil, which was purified by flash column
chromatography (99:1 petrol:EtOAc) to give benzoyl ester 115 (34 mg, 62%) as a
white oil.
R f : 0.46 (9:1, petrol:EtOAc); [α] 21 D : –15 (c = 1.0, CHCl 3 ); IR ν max (film)/cm⎯¹ 2960
(m), 1717 (C=O), 1590 (m), 1266, 1101 (m); ¹H-NMR (CDCl 3 , 500 MHz) δ 7.92 (d,
2H, J 8.5, H8 or H8'), 7.82 (d, 2H, J 8.5, H8 or H8'), 7.61-7.55 (m, 4H, H9, H9'), 5.78-
5.72 (m, 1H, H5), 5.66 (dd, 1H, J 10.0, 2.0, H6), 5.64-5.59 (m, 1H, H4), 4.34 (d, 1H, J
11.0, H7 a ), 4.26 (d, 1H, J 11.0, H7 b ), 2.19-2.07 (m, 2H, H3, CHMe2), 1.85-1.76 (m,
1H, H3), 1.58 (d, 1H, J 14.0, H2), 1.16 (s, 3H, Me), 1.04 (d, 3H, J 7.0, i-Pr), 0.90 (d,
3H, J 7.0, i-Pr); ¹³C-NMR (CDCl 3 , 75.5 MHz) δ 165.6 (C=O), 165.5 (C=O), 137.7 (C6
or C5), 131.8, 131.7, 131.1, 129.3, 129.1, 128.1, 128.1 (Ar), 127.4 (C6 or C5), 72.2
(C4), 68.6 (C7), 46.9, 39.5 (C2, C1), 25.7, 25.5 (C3, CHMe 2 ), 24.5 (CHMe a Me b ), 24.4
(Me), 18.0 (CHMe a Me b ); Chiral HPLC: DAICEL Chiralcel OD-H, 2.5% IPA in
hexane, 0.5 ml/min, 11.3 min (0.2%), 12.7 min (99.8%); racemic sample: 11.3 min
(49.6%), 12.9 min (50.4%).
246

Experimental for chapter 4.1
5.5 Experimental Procedures for Chapter 4.1
Synthesis of (2S,3S,4R,5S)-4-((4R,5R)-4,5-diphenyloxazolin-2-yl)-2,3-dihydroxy-5-
isopropyl-4-methylcyclohexanone (280)
Ph Ph
Ph Ph
Ph Ph
O
N
O
N
O
N
OsO 4 , NMO, CH 2 Cl 2
280 281
HO
6
1
2
HO
6
1
2
O
HO
5
O
4
3
HO
5
O
4
3
General procedure 5 was employed using enone (100 mg, 0.27 mmol), OsO 4 (0.6 mg,
0.003 mmol), NMO monohydrate (73 mg, 0.54 mmol), in CH 2 Cl 2 (5 cm 3 ). Upon
completion, sodium sulfite (0.5 cm 3 , sat. aq.) was added. Purification by flash
chromatography (9:1 to 2:1 petrol:EtOAc) yielded diol 280 (57 mg, 55%) as a
colourless foam, and diol 281 (3 mg, 2%) and starting material (11 mg, 11%) as a
colourless oil.
280 R f : 0.39 (1:1 petrol:EtOAc); [α] 25 D : +36 (c = 1.0, CH 2 Cl 2 ); MS m/z (CI+): 408
(100%, MH + ), 409 (24%, (M+1)H + ); HRMS (ESI+) m/z found 408.2170 (MH calcd.
408.2169); IR ν max (film)/cm -1 : 3470 (br, O-H), 2952 (m, C-H), 1719 (C=O), 1453 (m);
1 H-NMR (DMSO, 500 MHz) δ 7.36 (m, 2H, ortho-Ph), 7.45 (t, 2H, J 7.5, meta-Ph),
7.40-7.38 (m, 3H, Ph), 7.32 (tt, 1H, J 7.5, 2.0, para-Ph), 7.32 (d, 2H, J 7.5, ortho-Ph),
5.49 (d, 1H, J 4.5, C6OH), 5.25 (d, 1H, J 9.0, CHO), 5.14 (d, 1H, J 9.0, CHN), 5.00
(dd, 1H, J 7.0, 3.5, H5), 4.72 (d, 1H, J 7.0, C5OH), 4.04 (t. 1H, J 4.0, H6), 2.76 (t, 1H,
J 13.5, H3 axial ), 2.18 (dd, 1H, J 13.5, 4.0, H3 eq ), 2.12 (pd, 1H, J 7.0, 2.5, CHMe 2 ), 2.01
(ddd, 1H, J 14.0, 4.0, 2.5, H2), 1.42 (s, 3H, Me), 0.94 (d, 3H, J 7.0, CHMe a Me b ), 0.83
(d, 3H, J 7.0, CHMe a Me b ); 13 C-NMR (DMSO, 125 MHz) δ 209.9 (C=O), 168.6
(C=N), 141.5 (ipso-Ph), 139.7 (ipso-Ph), 129.1 (meta-Ph), 128.8 (meta-Ph), 128.7
(para-Ph), 127.3 (para-Ph), 126.6 (ortho-Ph), 126.4 (ortho-Ph), 126.3 (ortho-Ph), 87.3
(CHO), 79.3 (C6), 77.4 (CHN), 75.5 (C5), 46.2 (C1), 45.4 (C2), 37.8 (C3), 26.6
(CHMe 2 ), 24.6 (CHMe a Me b ), 21.6 (Me), 18.5 (CHMe a Me b ).
247

Experimental for chapter 4.1
281 R f : 0.30 (1:1 petrol:EtOAc); [α] 25 D : +58 (c = 0.8, DMSO); MS m/z (CI+): 408
(100%, MH + ), 409 (28%, (M+1)H + ), 390 (20%, [M–H 2 O]H + ); HRMS (ESI+) m/z
found 408.2168 (MH calcd. 408.2169); IR ν max (film)/cm -1 : 3468 (br, O-H), 2944 (m,
C-H), 1712 (C=O), 1452 (m, C-Me); 1 H-NMR (DMSO, 500 MHz) δ 7.47-7.3 (m, 7H,
Ph), 7.24-7.20 (m, 3H, Ph), 5.70 (d, 1H, J 4.5, C6OH), 5.28 (d, 1H, J 11.0, CHO), 5.12
(d, 1H, J 11.0, CHN), 4.80 (d, 1H, J 8.5, C5OH), 4.77 (dd, 1H, J 8.5, 5.5, H5), 4.03
(dd. 1H, J 5.5, 3.5, H6), 2.87 (t, 1H, J 17.0, H3 axial ), 2.18 (dd, 1H, J 17.0, 5.0, H3 eq ),
216.-2.07 (m, 1H, J 7.0, 2.5, CHMe 2 ), 2.01 (dt, 1H, J 17.0, 5.0, H2), 1.43 (s, 3H, Me),
0.93 (d, 3H, J 8.5, CHMe a Me b ), 0.84 (d, 3H, J 8.5, CHMe a Me b ); 13 C-NMR (DMSO,
125 MHz) δ 209.9 (C=O), 168.6 (C=N), 141.5 (ipso-Ph), 139.4 (ipso-Ph), 128.8 (meta-
Ph), 128.7 (meta-Ph), 128.5 (para-Ph), 127.5 (para-Ph), 126.5 (ortho-Ph), 126.2
(ortho-Ph), 87.4 (CHO), 79.3 (C6), 77.1 (CHN), 75.5 (C5), 46.1 (C1), 45.1 (C2), 38.0
(C3), 26.3 (CHMe 2 ), 24.6 (CHMe a Me b ), 21.8 (Me), 18.4 (CHMe a Me b ).
Synthesis of (4S,5S,6R)-4-((4R,5R)-4,5-diphenyloxazolinyl)-6-hydroxy-5-
isopropyl-4-methylcyclohex-2-enone (276)
Ph Ph
Ph Ph Ph Ph
O
N
O
N
O
N
OMe
OsO 4 , NMO, t-BuOH/H 2 O 1
6
5
2
3
4 OH
O
6
5
1
2
3
276 283
4 OH
O
General procedure 5 was employed using enol ether 102b (700 mg, 1.80 mmol), OsO 4
(4.5 mg, 0.018 mmol), NMO (458 mg, 3.6 mmol), in t-BuOH (15 cm 3 ) and water (3.7
cm 3 ). Upon complete reaction of starting material (c. 40 hr), sodium metabisulfite (1.0
cm 3 , 5% w/w aq. solution) was added. Purification by flash chromatography (8%
EtOAc in petrol) yielded enone 276 (651 mg, 93%) as a yellow oil and dienone 283
(28 mg, 4%) as a colourless oil.
276 R f : 0.14 (4:1 petrol:EtOAc); [α] 25 D : +256 (c = 1.2, CH 2 Cl 2 ); MS m/z (CI+): 390
(100%, MH + ), 391 (27%, (M+1)H + ), 196 (5%, [M-Ph 2 CHO]H + ); HRMS (ESI+) m/z
found 390.2074 (MH calcd. 390.2064); IR ν max (film)/cm -1 : 3474 (m, O-H), 2971 (w,
C-H), 1686 (C=O), 1647 (C=N); 1 H-NMR (CDCl 3 , 400 MHz) δ 7.44-7.27 (m, 8H,
248

Experimental for chapter 4.1
Ph), 7.22-7.18 (m, 2H, Ph), 6.78 (d, 1H, J 10.0, H6), 6.18 (d, 1H, J 10.0, H5), 5.22 (d,
1H, J 10.5, CHO), 5.09 (d, 1H, J 10.5, CHN), 4.68 (dd, 1H, J 13.0, 2.0, H3), 3.62* (d,
1H, J 2.0, OH), 2.40 (p, 1H, J 7.5, CHMe 2 ), 1.99 (d, 1H, J 13.0, H2), 1.63 (s, 3H, Me),
1.70 (d, 3H, J 7.5, CHMe a Me b ), 1.15 (d, 3H, J 7.5, CHMe a Me b ); 13 C-NMR (CDCl 3 ,
100 MHz) δ 201.7 (C=O), 167.4 (C=N), 153.9 (C6), 140.5 (ipso-Ph), 138.5 (ipso-Ph),
129.0, 128.9, 128.8, 127.9, 126.7, 126.2, 124.7 (Ph), 90.1 (CHO), 77.9 (CNH), 55.2
(COH), 44.1 (C1), 27.1 (CHMe 2 ), 25.9 (CHMe a Me b ), 25.5 (CHMe a Me b ), 17.3 (Me).
283 R f : 0.18 (4:1 petrol:EtOAc); [α] 21 D : +197.5 (c = 2.1, CHCl 3 ); MS m/z (CI+): 388
(100%, MH + ), 389 (27%, (M+1)H + ), 194 (70%, [M-Ph 2 CHO]H + ); HRMS (ESI+) m/z
found 388.1911 (MH calcd. 388.1907); IR ν max (film)/cm -1 : 3391 (m, O-H), 2931 (w,
C-H), 1643 (C=O); 1 H-NMR (CDCl 3 , 300 MHz) δ 7.43-7.26 (m, 8H, Ph), 7.24-7.18
(m, 2H, Ph), 7.04 (d, 1H, J 10.0, H6), 6.64 (s, 1H, OH), 6.49 (d, 1H, J 10.0, H5), 5.23
(d, 1H, J 8.5, CHO), 5.18 (d, 1H, J 8.5, CHN), 2.61 (p, 1H, J 2.5, CHMe 2 ), 1.75 (s,
3H, Me), 1.34 (d, 3H, J 7.0, CHMe a Me b ), 1.28 (d, 3H, J 7.0, CHMe a Me b ); 13 C-NMR
(CDCl 3 , 75 MHz) δ 181.1 (C4), 167.1 (C=N), 152.8, 145.1 (C3, C6), 141.2 (ipso-Ph),
138.8 (ipso-Ph), 136.0 (C5), 128.9 (meta-Ph), 128.9 (meta-Ph), 127.9 (para-Ph), 126.6
(ortho-Ph), 126.5 (ortho-Ph), 125.6 (C2), 90.3 (CHO), 77.6 (CHN), 46.9 (CMe), 30.4
(CHMe 2 ), 22.9 (Me), 19.9 (CHMe a Me b ), 19.4 (CHMe a Me b ).
Synthesis of (1R,2R,5S,6S)-5-((4R,5R)-4,5-diphenyloxazolin-2-yl)-6-isopropyl-5-
methylcyclohex-3-ene-1,2-diol (213)
Ph Ph
Ph Ph
O
N
O
N
NaBH 4
EtOH, 0 °C
OH
O
6
5
1
2
3
4 OH
OH
Sodium borohydride (24 mg, 0.63 mmol) was added in a single portion to a stirred
solution of enone 276 (220 mg, 0.57 mmol) in ethanol (6 cm 3 ) at 0 °C. When judged
complete by TLC (PMA stain c. 6 hr) acetic acid was added to the cooled reaction
mixture until effervescence ceased and warmed to room temperature. The solvent was
removed from the reaction mixture, which was partitioned between water (10 cm 3 ) and
CH 2 Cl 2 (20 cm 3 ) and the aqueous layer further washed (2 x 20 cm 3 CH 2 Cl 2 ) and the
249

Experimental for chapter 4.1
combined organic layers washed with brine before being dried over sodium sulphate.
Removal of solvent gave a white crystalline solid which was purified by
recrystallisation from diethyl ether to give colourless cubes of allyl alcohol 213 (216
mg, 98%)
R f : 0.31 (1:1, petrol:EtOAc); Mpt: 155-156 ºC (Et 2 O); [α] 25 D : +174 (c = 1.0, CHCl 3 );
MS m/z (CI+) 392 (100%, MH + ), 393 (24%, (M+1)H + ), 303 (15%, [M-PhCH] + ), 285
(22%, [M-PhCHO] + ); HRMS: found 392.2228, MH requires 392.2220; Microanalysis
found (%): C 75.03, H 7.56, N 3.48, C 25 H 29 NO 3 requires (%): C 76.70, H 7.47, N 3.58;
IR ν max (film)/cm⎯¹ 3359 (br, OH), 2970 (m, C-H), 1638 (C=N), 1050 (C-OH); ¹H-
NMR (CDCl 3 , 500 MHz) δ 7.33-7.25 (m, 5H, Ph), 7.24-7.20 (m, 1H, Ph), 7.20-7.16
(m, 2H, Ph), 7.15-7.11 (m, 2H, Ph), 5.53 (d, 1H, J 10.0, H6), 5.44 (d, 1H, J 10.0, H5),
5.07 (d, 1H, J 10.5, CHOPh), 4.94 (d, 1H, J 10.5, CHNPh), 3.93-3.87 (m, 2H, H4, H3),
3.32 (br s, 1H, OH), 2.44 (br s, 1H, OH), 2.23 (p, 1H, J 7.0, CHMe 2 ), 1.51 (d, 1H, J
10.5, H2), 1.37 (s, 3H, Me), 1.09 (d, 3H, J 7.0, CHMe a Me b ), 1.00 (d, 3H, J 7.0,
CHMe a Me b ); ¹H-NMR (C 6 D 6 , 300 MHz) δ 7.28-7.22 (m, 2H, Ph), 7.20-7.03 (m, 8H,
Ph), 5.64 (d, 1H, J 10.0, H6), 5.45 (dd, 1H, J 10.0, 2.0, H5), 5.12 (s, 2H, CHPh), 4.21
(ddd, 1H, J 11.5, 7.5, 2.0, H3), 4.04 (br d, 1H, J 7.5, H4), 2.89 (br s, 2H, OH), 2.41 (p,
1H, J 7.0, CHMe 2 ), 1.64 (d, 1H, J 11.5, H2), 1.40 (s, 3H, Me), 1.36 (d, 3H, J 7.0,
CHMe a Me b ), 1.33 (d, 3H, J 7.0, CHMe a Me b ); ¹³C-NMR (CD 3 OD, 75.5 MHz) δ 171.8
(C=N), 140.8 (ipso-Ph), 138.4 (ipso-Ph), 132.5 (C5), 129.2 (C6), 128.7, 127.9, 127.0,
126.3 (Ph), 90.6 (CHOPh), 77.5 (CHNPh), 74.7 (CHOH), 72.7 (CHOH), 53.1 (C2),
44.3 (C1), 26.9 (CHMe 2 ), 25.7 (CHMe a Me b ), 25.5 (Me), 17.0 (CHMe a Me b ).
250

Experimental for chapter 4.1
Synthesis of (1R,2S,5S,6S)-5-((4R,5R)-4,5-diphenyloxazolin-2-yl)-6-isopropyl-5-
methylcyclohex-3-ene-1,2-diol (287)
Ph Ph
Ph Ph Ph Ph
O
N
O
N
O
N
O
OH
CeCl 3. 7H 2 O, NaBH 4
1
MeOH, 0 °C
OH
OH
213 287
6
5
2
3
4 OH
OH
Sodium borohydride (24 mg, 0.63 mmol) was added portion wise to a stirred solution
of enone 276 (100 mg, 0.26 mmol) and cerium trichloride heptahydrate (97 mg, 0.26
mmol) in methanol (0.6 cm 3 ) at 0 °C. When judged complete by TLC (PMA stain c.
20 min) ammonium chloride (sat. aqueous) was added to the cooled reaction mixture
until. The solvent was removed from the reaction mixture, which was partitioned
between water (3 cm 3 ) and CH 2 Cl 2 (10 cm 3 ) and the aqueous layer further washed (2 x
10 cm 3 CH 2 Cl 2 ) and the combined organic layers washed with brine before being dried
over sodium sulphate. Removal of solvent gave a mixture of diols 213 and 287 (100
mg, 99%, 10:1 mixture) which were separated by recrystallisation from Et 2 O and
forming the acetonide of 287.
213 – see page 250
287 R f : 0.23 (2:1, petrol:EtOAc); [α] 22 D : +216 (c = 0.5, CHCl 3 ); MS m/z (CI+) 410
(100%, MH + ), 411 (23%, (M+1)H + ); HRMS: found 432.2146, MNa requires
432.2145; IR ν max (film)/cm⎯¹ 3359 (br), 2923 (m), 1639, 1451 (m), 1382, 1258; ¹H-
NMR (CD 3 OD, 500 MHz) 7.43-7.30 (m, 8H, Ph), 7.27-7.23 (m, 2H, Ph), 5.92 (dd, 1H,
J 5.0, 10.0, H5), 5.72 (d, 1H, J 10.0, H6), 5.24 (d, 1H, J 10.5, CHOPh), 5.02 (d, 1H, J
10.5, CHNPh), 4.21 (dd, 1H, J 12.0, 4.5, H3), 4.06 (t, 1H, J 4.5, H4), 2.73 (sept, 1H, J
7.0, CHMe2), 1.84 (d, 1H, J 12.0, H2), 1.48 (s, 3H, Me), 1.19 (d, 3H, J 7.0,
CHMe A Me B ), 1.12 (d, 3H, J 7.0, CHMe A Me B ); ¹³C-NMR (CDCl 3 , 125 MHz) δ 169.5
(C=N), 140.9 (ipso-Ph), 138.9 (ipso-Ph), 137.5 (C5), 128.8 (C6), 128.7, 128.5, 127.7,
126.8 , 126.1, 125.7 (Ph), 90.0 (CHOPh), 78.0 (CHNPh), 69.0 (C3), 66.7 (C4), 48.7
(C2), 44.2 (C1), 26.7 (Me), 26.4 (CHMe 2 ), 26.0 (Me), 17.5 (CHMe a Me b ).
251

Experimental for chapter 4.1
Synthesis of (2R,3S,4S)-4-((4R,5R)-4,5-diphenyloxazolinyl)-2-hydroxy-3-
isopropyl-4-methylcyclohexanone (288)
Ph Ph
Ph Ph
O
N
DIBAlH, CH 2 Cl 2
O
N
−78 °C
OH
OH
O
O
A solution of DIBAlH (0.18 cm 3 , 1M in CH 2 Cl 2 ) was added drop wise to a stirred
solution of oxazoline 276 (60 mg, 0.15 mmol) in CH 2 Cl 2 (2 cm 3 ) at –78 °C under a
nitrogen atmosphere to give a clear yellow solution. After 90 min, methanol (0.5 cm 3 )
was added in a single portion to the cooled solution followed by ammonium chloride
(sat. aq. 2 cm 3 ) and the reaction warmed to rt. The resulting solution was partitioned
between water (2 cm 3 ) and EtOAc (10 cm 3 ) and the aqueous layer was extracted with
EtOAc (3 x 10 cm 3 ) and the combined organic layers dried with sodium sulfate and
reduced under vacuum. Flash chromatography (petrol to 4:1 petrol:EtOAc) yielded
ketone 288 (8 mg, 15%) as a colourless oil and starting material (35 mg, 58%).
R f : 0.49 (2:1, petrol:EtOAc); [α] 22 D : –132 (c = 0.8, CHCl 3 ); MS m/z (CI+) 392 (100%,
MH + ), 393 (25%, (M+1)H + ), 180 (53%), 305 (13%); HRMS: found 392.2227, MH
requires 392.2220; IR ν max (film)/cm⎯¹ 3414 (br, O-H), 2928 (m, C-H), 1710 (C=O),
1644 (C=N), 1451 (m), 1112 (m), 1085 (m), 1058 (m); ¹H-NMR (CDCl 3 , 500 MHz) δ
7.44-7.28 (m, 8H, Ph), 7.24-7.20 (m, 2H, Ph), 5.21 (d, 1H, J 9.5, CHOPh), 5.11 (d, 1H,
J 9.5, CHNPh), 4.68 (dd, 1H, J 12.0, 2.0, H3), 3.70 (d, 1H, J 2.0, OH), 3.39 (tdd, 1H, J
14.0, 6.5, 1.0, H5 ax ), 2.52 (ddd, 1H, J 14.0, 4.5, 2.5, H5 eq ), 2.42 (ddd, 1H, J 14.0, 6.5,
2.5, H6 eq ), 2.32 (p, 1H, J 7.0, CHMe 2 ), 1.79 (td, 1H, J 14.0, 4.5, H6 ax ), 1.57 (d, 1H, J
12.0, H2), 1.50 (s, 3H, Me), 1.18-1.12 (m, 6H, CHMe 2 ); ¹³C-NMR (CDCl 3 , 125 MHz)
δ 212.8 (C4), 170.0 (C=N), 141.3 (ipso-Ph), 139.5 (ipso-Ph), 129.0 (meta-Ph), 128.9
(meta-Ph), 128.6 (para-Ph), 127.8 (para-Ph), 126.6 (ortho-Ph), 126.0 (ortho-Ph), 88.8
(COPh), 78.2 (CNPh), 74.6 (C3), 59.8 (C2), 41.3 (C1), 39.3 (C5), 36.7 (C6), 28.2
(CHMe 2 ), 26.6, 26.2, 17.9 (Me).
252

Experimental for chapter 4.1
Synthesis of (1R,2R,5S,6S)-5-((4R,5R)-4,5-diphenyloxazolin-2-yl)-1,2-
bis(benzyloxy)-6-isopropyl-5-methylcyclohex-3-ene (289)
Ph Ph
Ph Ph
O
OH
N
OH
BnBr, DMF, NaH
n-Bu 4 NI
6
5
O
1
N
2
3
4 OBn
OBn
Adapted from the method of Provelenghi, 19 sodium hydride (25 mg, 0.62 mmol) was
added slowly to a solution of benzyl bromide (0.1 cm 3 , 0.84 mmol), diol 213 (52 mg,
0.13 mmol) and tetrabutylammonium iodide (4 mg, 0.01 mmol) in DMF (1.5 cm 3 )
whilst the reaction mixture was maintained at ambient temperature. When the reaction
was judged complete (c. 18 hr) aqueous ammonium chloride (saturated, 0.1 cm 3 ) was
added to the reaction, the solvent removed under vacuum and the resulting residue
partitioned between water (2 cm 3 ) and CH 2 Cl 2 (6 cm 3 ). The aqueous phase was
washed with further CH 2 Cl 2 (2 x 5 cm 3 ) and the combined organic phases dried over
sodium sulphate, before purification by flash chromatography (9:1 to 4:1
petrol:EtOAc) yielded benzyl ether 289 (54 mg, 72%) as a colourless oil.
R f : 0.45 (4:1, petrol:EtOAc); [α] 20 D : +85 (c = 2.0, CH 2 Cl 2 ); MS m/z (ES+) 572 (100%,
MH + ), 573 (40%, (M+1)H + ), 594 (7%, MNa + ), 465 (6%, [M-OBn]H + ); HRMS: found
572.3150, MH requires 572.3159; IR ν max (film)/cm⎯¹ 3030 (m, C-H), 1646 (C=N),
1453; ¹H-NMR (CDCl 3 , 500 MHz) δ 7.47-7.24 (m, 20H, Ph), 5.85 (dd, 1H, J 10.0,
1.5, H5, H6), 5.82 (dd, 1H, J 10.0, 1.5, H5, H6), 5.23 (d, 1H, J 10.0, CHOPh), 5.13 (d,
1H, J 11.5, OBn), 5.10 (d, 1H, J 10.0, CHNPh), 4.72 (d, 1H, J 11.5, OBn'), 4.65 ("t",
2H, J 11.5, OBn, OBn'), 4.35 (d, 1H, J 6.5, H4), 4.16 (dd, 1H, J 10.0, 6.5, H3), 2.28 (p,
1H, J 7.0, CHMe 2 ), 1.88 (d, 1H, J 10.0, H2), 1.52 (s, 3H, Me), 1.16 (d, 3H, J 7.0, i-Pr),
1.01 (d, 3H, J 7.0, i-Pr); ¹³C-NMR (CDCl 3 , 75.5 MHz) δ 170.1, 141.4, 139.2, 138.5,
134.0, 128.8, 128.7, 128.4, 128.3, 128.2, 127.8, 127.6, 127.5, 127.1, 126.7, 126.3,
126.0, 89.9, 82.8, 78.1, 77.8, 73.0, 70.4, 52.2, 43.9, 27.4, 26.4, 26.0, 18.2.
253

Experimental for chapter 4.1
Synthesis of (1S,2R,3S,4R,5R,6S)-5-((4R,5R)-4,5-diphenyloxazolin-2-yl)-3,4-epoxy-
6-isopropyl-5-methylcyclohexane-1,2-diol (216)
Ph Ph
Ph Ph
O
N
O
N
OH
OH
mCPBA, CH 2 Cl 2
−40 °C - rt
O
6
5
1
2
3
4 OH
OH
mCPBA (192 mg, 50%, 0.56 mmol) was added in a single portion to a vigorously
stirred solution of allyl alcohol 213 (110 mg, 0.28 mmol) at 0 °C in CH 2 Cl 2 (3 cm 3 ).
After 6 hr, aqueous sodium sulfite (1 cm 3 sat.) was added and the reaction warmed to
ambient temperature. The reaction mixture was washed with aqueous sodium
bicarbonate (2 cm 3 saturated) and the aqueous phase extracted with further CH 2 Cl 2 (3 x
10 cm 3 ). The combined organic layers dried over anhydrous sodium sulfate, and the
solvent removed under vacuum to yield epoxide 216 (113 mg, 99%) as a colourless oil.
R f : 0.14 (1:1, petrol:EtOAc); [α] 26 D : 109.3 (c = 1.8, CH 2 Cl 2 ); MS m/z (EI+) 408
(100%, MH + ), 409 (16%, (M+1)H + ), 430 (22%, MNa + ); HRMS: found 408.2179, MH
requires 408.2169; IR ν max (film)/cm⎯¹ 3389 (br, OH), 2928 (m, C-H), 1637 (C=N),
1454 (m), 1056; ¹H-NMR (CDCl 3 , 500 MHz) δ 7.41-7.33 (m, 7H, Ph), 7.32-7.28 (m,
1H, Ph), 7.26-7.23 (m, 1H, Ph), 5.26 (d, 1H, J 9.0, CHOPh), 5.14 (d, 1H, J 9.0,
CHNPh), 4.06 (dd, 1H, J 11.0, 8.0, H3), 3.81 (dd, 1H, J 8.0, 1.5, H4), 3.46 (dd, 1H, J
4.0, 1.5, H5), 3.30 (d, 1H, J 4.0, H6), 2.24 (br s, 1H, OH), 2.00 (pd, 1H, J 7.0, 1.0,
CHMe 2 ), 1.59 (s, 3H, Me), 1.39 (dd, 1H, J 11.0, 1.5, H2), 1.11 (d, 3H, J 7.0,
CHMe A Me B ), 1.04 (d, 3H, J 7.0, CHMe A Me B ); ¹³C-NMR (CDCl 3 , 125 MHz) δ 168.9
(C=N), 141.5 (ipso-Ph), 139.1 (ipso-Ph), 128.8 (Ph), 128.7 (Ph), 128.6 (Ph), 127.7
(para-Ph), 126.9 (Ph), 126.8 (Ph), 89.7 (CHOPh), 77.6 (CHNPh), 75.9 (CHOH), 71.4
(CHOH), 61.0 (C6), 56.0 (C5), 53.7 (C2), 42.9 (C1), 28.9 (CHMe 2 ), 27.1
(CHMe A Me B ), 25.4 (Me), 19.0 (CHMe A Me B ).
254

Experimental for chapter 4.1
Synthesis of (1S,2R,3S,4R,5R,6S)-1,2-bis(benzyloxy)-5-((4R,5R)-4,5-
diphenyloxazolin-2-yl)-3,4-epoxy-6-isopropyl-5-methylcyclohexane (292)
Ph
Ph
Ph
Ph
Ph
Ph
O
O
OH
N
OH
BnBr, DMF, NaH
n-Bu 4 NI
O
O N
O N
1
6 2
3
5
4
OBn
O
1
6 2
3
5
4
OBn
OBn
292 291
OH
Adapted from the method of Provelenghi, 19 sodium hydride (7 mg, 0.16 mmol) was
added slowly to a solution of benzyl bromide (40 µl, 0.29 mmol), diol 213 (30 mg,
0.07 mmol) and tetrabutylammonium iodide (1 mg, 0.003 mmol) in DMF (0.8 cm 3 )
whilst the reaction mixture was maintained at ambient temperature. When the reaction
was judged complete (c. 16 hr) aqueous ammonium chloride (sat. 0.1 cm 3 ) was added
to the reaction, the solvent removed under vacuum and the resulting residue partitioned
between water (2 cm 3 ) and CH 2 Cl 2 (6 cm 3 ). The aqueous phase was washed with
further CH 2 Cl 2 (2 x 5 cm 3 ) and the combined organic phases dried over sodium
sulphate, before purification by flash chromatography (19:1 to 3:1 petrol:EtOAc)
yielded alcohol 291 (24 mg, 68%) and dibenzyl ether 292 (4 mg, 10%) as colourless
oils.
292 R f : 0.23 (4:1, petrol:EtOAc); [α] 23 D : +85 (c = 2, CHCl 3 ); MS m/z (ES+) 588
(100%, MH + ), 610 (37%, (M+1)H + ), 610 (80%, MNa + ); HRMS: found 588.3106, MH
requires 588.3108; IR ν max (film)/cm⎯¹ 2924 (C-H), 1995 (m), 1640, 1454, 1078; ¹H-
NMR (CDCl 3 , 500 MHz) δ 7.41-7.24 (m, 20H, Ph), 5.29 (d, 1H, J 8.5, CHNPh), 5.14
(d, 1H, J 8.5, CHOPh), 5.05 (d, 1H, J 11.5, OBn), 4.81 (d, 1H, J 11.5, OBn'), 4.76 (d,
1H, J 11.5, OBn'), 4.59 (d, 1H, J 11.5, OBn), 4.07 (dd, 1H, J 9.0, 7.0, H3), 3.99 (d, 1H,
J 7.0, H4), 3.45 (d, 1H, J 4.0, H6), 3.36 (d, 1H, J 4.0, H5), 1.98 (p, 1H, J 7.0, CHMe 2 ),
1.63-1.57 (m, 4H, H2, Me), 1.11 (d, 3H, J 7.0, i-Pr), 1.03 (d, 3H, J 7.0, i-Pr); ¹³C-
NMR (CDCl 3 , 75.5 MHz) δ 169.5, 141.8, 139.5, 139.3, 138.1, 128.7, 128.7, 128.5,
128.4, 128.2, 128.0, 127.7, 127.6, 127.2, 127.1, 126.9, 126.8, 89.7, 83.8, 77.8, 73.2,
72.1, 60.5, 54.0, 53.3, 43.1, 29.7, 26.8, 25.5, 19.8.
255

Experimental for chapter 4.1
291 R f : 0.11 (4:1, petrol:EtOAc); [α] 27 D : +89 (c = 1.2, CHCl 3 ); MS m/z (ES+) 520
(100%, MNa + ), 521 (34%, (M+1)Na + ), 498 (75%, MH + ); HRMS: found 498.2632,
MH requires 498.2639; IR ν max (film)/cm⎯¹ 3333 (br, O-H), 2954 (C-H), 1638, 1453,
1076; ¹H-NMR (CDCl 3 , 500 MHz) δ 7.35-7.15 (m, 15H, Ph), 5.19 (d, 1H, J 9.0,
CHOPh), 5.05 (d, 1H, J 9.0, CHNPh), 4.78 (d, 1H, J 11.5, OBn), 4.63 (d, 1H, J 11.5,
OBn), 4.15-4.09 (m, 1H, H3), 3.63 (dd, 1H, J 8.0, 1.0, H4), 3.38 (dd, 1H, J 4.0, 1.0,
H5), 3.21 (d, 1H, J 4.0, H6), 2.28 (s, 1H), 2.17 (d, 1H, J 2.0, C3OH), 1.90 (pd, 1H, J
7.0, 1.0, CHMe 2 ), 1.50 (s, 3H), 1.36 (dd, 1H, J 11.0, 1, H2), 1.01 (d, 3H, J 7.0, i-Pr),
0.94 (d, 3H, J 7.0, i-Pr); ¹³C-NMR (CDCl 3 , 75.5 MHz) δ 169.3 (C=N), 141.7 (ipso-
Ph), 139.2 (ipso-Ph), 138.0 (ipso-Ph), 129.0, 128.7, 128.7, 128.6, 128.5, 128.2, 127.9,
127.6, 126.9 (Ph), 89.8 (CHOPh), 83.0, 77.5, 71.9, 69.1, 60.4, 53.4, 53.0, 42.7, 29.2,
26.9, 25.7, 18.7.
Synthesis of (1S,2S,3R,4S,5R,6R)-5,6-bis(benzyloxy)-3-((4R,5R)-4,5-
diphenyloxazolin-2-yl)-4-isopropyl-3-methylcyclohexane-1,2-diol (300)
Ph Ph
Ph Ph
O
N
O
N
OsO 4 , NMO, CH 2 Cl 2
HO
6
1
2
OBn
OBn
HO
5
3
4 OBn
OBn
General procedure 5 was employed using olefin 289 (26 mg, 0.04 mmol), OsO 4 (0.2
mg, 2 mol %), NMO (12 mg, 0.1 mmol), in CH 2 Cl 2 (0.5 cm 3 ). Upon complete
reaction of starting material (c. 9 d), sodium metabisulfite (0.1 cm 3 , 5% w/w aq.
solution) was added. Purification by flash chromatography (10% EtOAc in petrol)
yielded diol 300 (26 mg, 96 %) as a colourless oil.
R f : 0.09 (4:1, petrol:EtOAc); [α] 26 D : +35 (c = 1.2, CHCl 3 ); MS m/z (ES+) 606.4
(100%, MH + ), 607.4 (48%, (M+1)H + ), 628.4 (46%, MNa + ); HRMS: found 606.3222,
MH requires 606.3214; IR ν max (film)/cm⎯¹ 3441 (br, OH), 2948 (m, C-H), 1642
(C=N), 1453, 1069; ¹H-NMR (CDCl 3 , 500 MHz) δ 7.37-7.18 (m, 16H, Ph), 7.16-7.08
(m, 4H, Ph), 5.09-5.06 (m, CHOPh, OBn), 4.99 (d, J 9.0, CHNPh), 4.82 (d, J 11.5,
OBn'), 4.66 ("t", 2H, J 11.5, OBn, OBn'), 4.29 (dd, 1H, J 10.0, 3.0, H5), 4.09 (dd, 1H,
J 11.0, 9.0, H3), 4.00 (d, 1H, J 3, H6), 3.88-3.82 (m, 1H, H4), 2.62 (br s, 1H, OH),
256

Experimental for chapter 4.1
2.30 (br s, 1H, OH), 2.10 (pd, 1H, J 7.0, 1.0, CHMe 2 ), 1.99 (dd, 1H, J 11.0, 1.0, H2),
1.53 (s, 3H, Me), 1.11 (d, 3H, J 7.0, CHMe A Me b ), 1.01 (d, 3H, J 7.0, CHMe a Me B ); ¹³C-
NMR (CDCl 3 , 75.5 MHz) δ 169.4 (C=N), 141.4 (ipso-Ph), 139.5 (ipso-Ph), 139.2
(ipso-Ph), 138.5 (ipso-Ph), 129 (para-Ph), 128.9 (Ph), 128.8 (Ph), 128.7 (Ph), 128.5
(para-Ph), 128.2 (Ph), 128.2 (para-Ph), 127.9 (Ph), 127.7 (para-Ph), 127.1, 127,
126.6, 126.1 (Ph), 88.8 (CHOPh), 85.9 (CHOR), 80.1 (CHOR), 78.2 (CHNPh), 75.6
(OBn), 75.1 (CHOR), 72.8 (OBn), 71.9 (CHOR), 49.1 (C2), 45.7 (C1), 27.6 (CHMe 2 ),
26.7 (Me), 22.4 (CHMe A Me b ), 19.5 (CHMe a Me B ).
Synthesis of (1R,2S,3S,4S,5R,6S)-2,3,4,5-tetra(benzyloxy)-1-((4R,5R)-4,5-
diphenyloxazolin-2-yl)-6-isopropyl-1-methylcyclohexane (302)
HO
HO
Ph
O
N
OBn
Ph
OBn
BnBr, DMF, NaH
n-Bu 4 NI
BnO
BnO
Ph
5
O
6
1
N
Ph
2
OBn
3
4 OBn
BnO
HO
Ph
5
O
6
1
N
Ph
2
3
4 OBn
OBn
Adapted from the method of Provelenghi, 19 sodium hydride (5 mg, 0.12 mmol) was
added slowly to a solution of benzyl bromide (20 µl, 0.15 mmol), diol 300 (23 mg,
0.04 mmol) and tetrabutylammonium iodide (1 mg, 0.003 mmol) in DMF (0.8 cm 3 )
whilst the reaction mixture was maintained at ambient temperature. When the reaction
was judged complete (c. 16 hr) aqueous ammonium chloride (saturated, 0.1 cm 3 ) was
added to the reaction, the solvent removed under vacuum and the resulting residue
partitioned between water (2 cm 3 ) and CH 2 Cl 2 (6 cm 3 ). The aqueous phase was
washed with further CH 2 Cl 2 (2 x 5 cm 3 ) and the combined organic phases dried over
sodium sulphate, before purification by flash chromatography (19:1 to 9:1
petrol:EtOAc) yielded alcohol 301 (14 mg, 54%), perbenzyl ether 302 (10 mg, 33%)
and starting material (2 mg, 9%) as colourless oils.
302 R f : 0.45 (9:1, petrol:EtOAc); [α] 24 D : +21 (c = 1, CHCl 3 ); MS m/z (ES+) 786
(67%, MH + ), 808 (100%, MNa + ), 809 (52%, (M+1)Na + ); HRMS: found 786.4159,
MH requires 786.4153; IR ν max (film)/cm⎯¹ 2930 (m, C-H), 1453 (m, C-Me), 1069; ¹H-
NMR (CDCl 3 , 500 MHz) δ 7.36-7.10 (m, 30H, Ph), 5.20 (d, 1H, J 11.5, CHOPh), 5.12
(s, 2H, OBn), 5.09 (d, 1H, J 11.5, CHNPh), 5.01 (d, 1H, J 10.5, OBn), 4.79-4.71 (m,
257

Experimental for chapter 4.1
3H, OBn), 4.69 (d, 1H, J 11.0, OBn), 4.65 (d, 1H, J 11.5, OBn), 4.22 (dd, 1H, J 10.0,
8.5, H4), 4.18-4.10 (m, 2H, H5, H3), 4.02 (d, 1H, J 2.0, H6), 2.07 (pd, 1H, J 7.0, 1.5,
CHMe 2 ), 2.01 (dd, 1H, J 11.0, 1.5, H2), 1.57 (s, 3H, Me), 1.13 (d, 3H, J 7.0,
CHMe A Me b ), 1.08 (d, 3H, J 7.0, CHMe a Me B ); ¹³C-NMR (CDCl 3 , 75.5 MHz) δ 169.7
(C=N), 141.7 (ipso-Ph), 139.7 (ipso-Ph), 139.6 (ipso-Ph), 138.9 (ipso-Ph), 138.8 (ipso-
Ph), 138.7 (ipso-Ph), 128.9, 128.7, 128.7, 128.3, 128.3, 128.2, 128.1, 127.8, 127.7,
127.4, 127.4, 127.1, 126.9, 126.5, 126.3 (Ph), 88.6 (CHOPh), 85.5, 82.3, 81.8, 80.7
(C3, C4, C5, C6), 77.9 (CHNPh), 75.9 (OCH 2 Ph), 75.4 (OCH 2 Ph), 72.8 (OCH 2 Ph),
72.7 (OCH 2 Ph), 49.1, 47.0 (C1, C2), 28.2 (CHMe 2 ), 27.3 (CHMe A Me b ), 23.2 (Me),
19.4 (CHMe a Me B ).
301 R f : 0.24 (4:1, petrol:EtOAc); [α] 27 D : +24 (c = 1, CHCl 3 ); MS m/z (ES+) 696
(100%, MH + ), 697 (36%, (M+1)H + ), 718 (29%, MNa + ); HRMS: found 696.3681, MH
requires 696.3686; IR ν max (film)/cm⎯¹ 3582 (O-H), 2924 (C-H), 1641 (C=N), 1453 (C-
Me), 1069; ¹H-NMR (CDCl 3 , 500 MHz) δ 7.46-7.16 (m, 23H, Ph), 7.14-6.99 (m, 2H,
Ph), 5.15 (d, 1H, J 9.0, CHOPh), 5.13 (d, 1H, J 11.5, OBn), 5.08 (d, 1H, J 9.0,
CHNPh), 4.90 (d, 1H, J 11.0, OBn), 4.86 (d, 1H, J 11.0, OBn), 4.76 (dd, 2H, J 11.0,
2.0, OBn), 4.73-4.67 (m, 2H, OBn), 4.25 (ddd, 1H, J 10.0, 5.5, 3.0, H5), 4.19 (dd, 1H,
J 11.0, 8.5, H3), 4.00 (dd, 1H, J 10.0, 8.5, H4), 3.94 (d, 1H, J 3.0, H6), 2.11 (pd, 1H, J
7.0, 1.5, CHMe 2 ), 2.02 (d, 1H, J 5.5, C5-OH), 2.01 (dd, J 11.0, 1.5, H2), 1.62 (s, 3H,
Me), 1.16 (d, 3H, J 7.0, CHMe A Me b ), 1.11 (d, 3H, J 7.0, CHMe a Me B ); ¹³C-NMR
(CDCl 3 , 125 MHz) δ 169.6 (C=N), 141.6 (ipso-Ph), 139.6 (ipso-Ph), 138.7 (ipso-Ph),
138.5 (ipso-Ph), 128.9, 128.8, 128.6, 128.4, 128.2, 128.1, 127.9, 127.7, 127.1, 127.0,
126.5, 126.2 (Ph), 88.8 (CHOPh), 86.4 (C4), 84.8 (C3), 80.5 (C6), 78.3 (CHNPh), 76.5
(OCH 2 Ph), 75.1 (OCH 2 Ph), 72.8 (OCH 2 Ph), 72.7 (C5), 49.5 (C2), 47.3 (C1), 28.0,
28.0 (CHMe 2 , CHMe A Me b ), 27.2 (Me), 19.7 (CHMe a Me B ).
258

Experimental for chapter 4.1
Synthesis of (1R,2S,3S,4S,5S,6S)-tetrakis(benzyloxy)5-((benzyloxy)methyl)-6-
isopropyl-5-methylcyclohexane (304)
BnO
BnO
Ph
O
N
OBn
Ph
OBn
i) MeOTf, then NaBH 4
ii) H 3 O + 60 °C
iii) NaBH 4
BnO
BnO
HO
6
5
1
7
2
3
4 OBn
OBn
General procedure 6 was used employing oxazoline 302 (20 mg, 0.025 mmol) and
methyl triflate (6 µl, 0.05 mmol) for 20 hr. The crude oxazolidine was subjected to
general procedure 7, hydrolysis at 60 °C taking 7 days. The resulting crude alcohol
was purified by flash column chromatography (4:1 petrol:EtOAc) to give alcohol 304
(9 mg, 60%) as a colourless oil.
R f : 0.30 (40%, EtOAc in petrol); [α] 24 D : +135 (c = 1, CHCl 3 ); MS m/z (ES+) 430
(100%, MNa + ), 408 (27%, MH + ), 838 (39%, 2MNa + ); HRMS: found 430.2349, MNa
requires 430.2353; IR ν max (film)/cm⎯¹ 3364 (br, OH), 2947 (m), 2360 (w, C=C), 1453
(m); ¹H-NMR (CDCl 3 , 500 MHz) δ 7.31-7.25 (m, 3H, Ar), 7.23-7.16 (m, 5H, Ar),
7.05-7.00 (m, 2H, Ar), 6.06 (dd, 1H, J 10.0, 2.0, H5), 5.65 (dd, 1H, J 10.0, 2.0, H6),
4.74 (d, 1H, J 9.0, CHOPh), 4.54 (s, 1H, CHON), 4.24 (dd, 1H, J 11.5, 7.0, H3), 3.95
(br d, 1H, J 7.0, H4), 3.30 (d, 1H, J 9.0, CHNPh), 2.37 (s, 3H, NMe), 2.31-2.10 (m,
3H, CHMe 2 & OH), 1.48 (d, 1H, J 11.5, H2), 1.29 (d, 3H, J 7.0, CHMe A Meb), 1.21-
1.17 (m, 6H, Me & CHMeaMe B ); ¹³C-NMR (CDCl 3 , 75.5 MHz) δ 138.6 (ipso-Ph),
137.6 (ipso-Ph), 134.7 (C5), 128.3 (C6), 128.1, 128.0, 127.8, 127.7, 126.4 (Ph), 99.9
(CHON), 85.6 (CHOPh), 79.6 (CHNPh), 76.1 (C4), 74.1 (C3), 55.1 (C2), 48.6 (C1),
41.9 (NMe), 27.3 (CHMeaMe B ), 25.9 (CHMe 2 ), 24.7 (Me), 17.9 (CHMe A Meb).
259

Experimental for chapter 4.1
Synthesis of (1R,2S,3S,4S,5S,6S)-5-(hydroxymethyl)-6-isopropyl-5-
methylcyclohexane-1,2,3,4-tetraol (278)
BnO
BnO
HO
OBn
OBn
Pd(OH) 2 , MeOH
H 2 , 20 bar
Benzyl ether 304 (3 mg, 5 µmol) was dissolved in MeOH (0.5 cm 3 ) and passed
through a Pd(OH) 2 H-Cube cartridge at 20 bar H 2 , flow rate 0.5 cm 3 min -1 . The solvent
was removed from the resulting solution to yield pentaol 278 (1 mg, quant.) as
colourless needles.
HO
HO
OH
OH
OsO 4 , quinuclidine,
MeSO 2 NH 2 ,
K 2 CO 3 , K 3 Fe(CN) 6 ,
t-BuOH/H 2 O
HO
HO
HO
HO
5
HO
6
1
OH
7
2
3
OH
4 OH
OH
Adapted from the method of Warren 20 osmium tetroxide (20 µl of 2.5% solution in t-
BuOH) was added to a vigorously stirred orange solution of triol 312 (16 mg, 0.08
mmol) in t-BuOH (0.4 cm 3 ), H 2 O (0.4 cm 3 ) with potassium ferricyanide (79 mg,
ground, 0.24 mmol), potassium carbonate (33mg, 0.24 mmol), methyl sulfonamide (8
mg, 0.08 mmol) and quinuclidine (1 mg, 0.01 mmol). When complete my TLC
analysis (c. 72 hr) excess sodium sulfite was added, and the decolourised reaction
mixture partitioned between EtOAc (5 cm 3 ) and water (2 cm 3 ), the aqueous layer was
washed with EtOAc (5 x 5 cm 3 ), the combined organic extracts dried over anhydrous
sodium sulfate and solvent removed to yield a white solid (16 mg). Flash column
chromatography (EtOAc to 1% MeOH in EtOAc) yields pentaol 278 (15 mg, 79%) as
colourless needles.
R f : 0.09 (EtOAc); Mpt: 175 ºC (MeOH); [α] 22 D : +7.2 (c = 1.0, MeOH); MS m/z (ES–)
269 (100%, MCl 35- ), 271 (34%, MCl 37- ), 233 (32%, M – ), 467 (16%, 2M – ); HRMS:
found 269.1179, MCl requires 269.1161; IR ν max (film)/cm⎯¹ 3364 (br, OH), 2943 (m),
1021 (w); ¹H-NMR (D 2 O, 500 MHz) δ 3.81 (d, 1H, J 3.0, H6), 3.66 (dd, 1H, J 10.0,
3.0, H5), 3.62-3.56 (m, 1H), 3.56-3.49 (m, 3H), 1.93 (p, 1H, J 7.0, CHMe 2 ), 1.48 (d,
1H, J 11.5, H2), 1.06 (s, 3H, Me), 1.03 (d, 3H, J 7.0, i-Pr), 0.93 (d, 3H, J 7.0, i-Pr);
260

Experimental for chapter 4.1
¹³C-NMR (CD 3 OD, 75.5 MHz) δ 77.7 (CHOH), 76.3 (CHOH), 74.0 (CHOH), 72.6
(CHOH), 65.8 (C7), 49.4 (C2), 45.3 (C1), 27.5 (CHMe 2 ), 26.9, 21.8, 18.7 (Me).
Synthesis of (1S,2R,3S,4R,5R,6S)-5-(N-methyl-(4R,5R)-4,5-diphenyloxazolidin-2-
yl)-3,4-epoxy-6-isopropyl-5-methylcyclohexane-1,2-diol (306) and
(1S,2R,3S,4R,5R,6S)-2,3-epoxy-5-hydroxy-6-isopropyl-1-methylcyclohexane-δlactone
(307)
Ph Ph
Ph Ph
O
O
OH
N
OH
O NMe
MeOTf, then NaBH 4
Me
1
1
6 2 O
2
O
O
3
O
5 4 OH
4
OH
306 307
3
OH
General procedure 6 was used employing oxazoline 216 (101 mg, 0.25 mmol) and
methyl triflate (56 µl, 0.50 mmol) for 16 hr. The solvent was removed, the aqueous
layer washed with CH 2 Cl 2 (2 x 10 cm 3 ) and the combined organic phases dried over
anhydrous sodium sulfate. Flash chromatography (9:1 to 1:1 petrol:EtOAc) gave
oxazolidine 306 (39 mg, 40%) and oxazolidine 307 (15 mg, 30%) as colourless oils.
306 R f : 0.21 (2:1, petrol:EtOAc); [α] 23 D : +72 (c = 1.3, CHCl3); MS m/z (ES+) 424
(23%, MH + ), 446 (100%, MNa + ), 447 (32%, (M+1)Na + ), 869 (40%, M 2 Na + ); HRMS:
found 424.2483, MH requires 424.2482; IR ν max (film)/cm⎯¹ 3392 (br, O-H), 2928 (m,
C-H), 2357 (m), 1456 (m, C-Me), 1068 (C-O-C); ¹H-NMR (CDCl 3 , 500 MHz) δ 7.31-
7.28 (m, 5H, Ph), 7.26-7.22 (m, 2H, Ph), 7.21-7.16 (m, 1H, Ph), 7.11-7.07 (m, 2H, Ph),
5.36 (d, 1H, J 9.5, CHOPh), 4.71 (s, 1H, CHNO), 4.16 (dd, 1H, J 11.5, 8.0H3), 3.68
(dd, 1H, J 8.0, 1.5H4), 3.49 (d, 1H, J 4.0, H6), 3.43 (dd, 1H, J 4.0, 1.5, H5), 3.34 (d,
1H, J 9.5, CHNPh), 2.41 (s, 3H, NMe), 2.16 (m, 1H, CHMe 2 ), 1.34 (d, 3H, J 7.0,
CHMe A Me b ), 1.29-1.26 (m, 4H, Me, H2), 1.18 (d, 3H, J 7.0, CHMe a Me B ); ¹³C-NMR
(CDCl 3 , 75.5 MHz) δ 139.9 (ipso-Ph), 138.2 (ipso-Ph), 128.6, 128.3, 128.0, 127.8,
127.4, 126.1 (Ph), 101.5 (CHNO), 85.4 (CHOPh), 81.0 (CHNPh), 77.3 (C4), 72.0
(C3), 61.0 (C6), 56.6 (C2), 55.3 (C5), 43.6 (C1), 42.1 (NMe), 27.6 (CHMe a Me B ), 26.4
(CHMe 2 ), 24.9 (Me), 17.8 (CHMe A Me b ).
261

Experimental for chapter 4.1
307 R f : 0.24 (1:1, petrol:EtOAc); [α] 23 D : –72 (c = 0.5, CHCl 3 ); MS m/z (ES+) 213
(4%, MH + ), 235 (100%, MNa + ), 236 (5%, (M+1)Na + ), 447 (10%, M 2 Na + ); HRMS:
found 230.1389, MH requires 230.1387; IR ν max (film)/cm⎯¹ 3434 (br, O-H), 2928 (m,
C-H), 1745 (C=O), 1453 (m, R-Me), 1058 (C-O-C); ¹H-NMR (CDCl 3 , 500 MHz) δ
4.73 (t, 1H, J 3.5, H4), 4.35 (t, 1H, J 4.0, H3), 3.77 (dd, 1H, J 4.0, 3.0, H5), 3.36 (dd,
1H, J 4.0, 1.0, H6), 2.09 (pd, 1H, J 7.0, 3.5, CHMe 2 ), 1.97 (s, 1H, OH), 1.72 (t, 1H, J
4.0, H2), 1.43 (s, 3H, Me), 1.05 (d, 3H, J 7.0, i-Pr), 0.77 (d, 3H, J 7.0, i-Pr); ¹³C-NMR
(CDCl 3 , 75.5 MHz, relaxation time 25 s) δ, 172.3 (C=O), 71.1 (CHOH), 67.7 (CHO-),
53.9 (CHO-), 51.9 (CHO-), 48.1 (C2), 45.4 (C1), 26.1 (CH), 21.9, 16.4, 15.7 (Me).
Synthesis of (1S,2R,3S,4R,5R,6S)-5-(hydroxymethyl)-3,4-epoxy-6-isopropyl-5-
methylcyclohexane-1,2-diol (309)
O
Ph
O
OH
Ph
NMe
OH
HO
7
i) MeOTf, then NaBH 1
4
6 2
ii) H 3 O + 60 °C
O
3
iii) NaBH 4 5
OH
4 OH
General procedure 3 was employed using oxazoline 216 (55 mg, 0.13 mmol) and
methyl triflate (31 µl, 0.27 mmol) for 4 hr. The resulting crude oxazolidine was then
subject to general procedure 4 and heated at 50 °C for 17 hr. The resulting oil was
purified by flash chromatography (3:2 to 1:1 petrol:EtOAc) to give triol 309 (24 mg,
83%) as colourless needles.
R f : 0.28 (EtOAc); Mpt: 116-117 ºC (H 2 O/MeOH); [α] 24 D : +312 (c = 0.5, CHCl 3 ); MS
m/z (ES–) 431 (100%, [2M-H] – ), 251 (52%, [M+Cl] – ), 215 (27%, [M-H] – ); IR ν max
(film)/cm⎯¹ 3369 (br, OH), 2963 (m, C-H), 1039 (C-O-C); ¹H-NMR (CD 3 OD, 500
MHz) δ 3.80 (d, 1H, J 10.0, H7 a ), 3.67 (dd, 1H, J 8.0, 1.5, H4), 3.59 (dd, 1H, J 11.5,
8.0, H3), 3.46 (d, 1H, J 10.0, H7 b ), 3.35 (dd, 1H, J 4.0, 1.5, H5), 3.03 (d, 1H, J 4.0,
H6), 1.88 (p, 1H, J 7.0, CHMe 2 ), 1.20 (d, 1H, J 11.5, H2), 1.16 (s, 3H, Me), 1.09 (d,
3H, J 7.0, i-Pr), 1.01 (d, 3H, J 7.0, i-Pr); ¹³C-NMR (CD 3 OD, 75.5 MHz) δ 76.9
(CHOH), 71.0 (CHOH), 65.4 (C7), 61.9 (C6), 58.8 (C5), 54.5 (C2), 41.6 (C1), 28.1
(CHMe 2 ), 27.3 (i-Pr), 22.4 (Me), 18.4 (i-Pr).
262

Experimental for chapter 4.2
5.6 Experimental Procedures for Chapter 4.2
Synthesis of (1S*,4S*,5S*)-1-(benzyloxy)-4-((benzyloxy)methyl)-5-isopropyl-4-
methylcyclohex-2-ene (313)
HO
BnO
NaH, BnBr, DMF
(±)
OH
(±)
OBn
Sodium hydride (10 mg, 0.24 mmol) was added slowly to a solution of benzyl bromide
(40 µl, 0.35 mmol) and diol 225 (16 mg, 0.08 mmol) in DMF (1 cm 3 ) whilst the
reaction mixture was maintained at ambient temperature. When the reaction was
judged complete (c. 16 hr) methanol (0.1 cm 3 ) was added, the solvent removed under
vacuum and the resulting residue partitioned between water (2 cm 3 ) and CH 2 Cl 2 (6
cm 3 ). The aqueous phase was washed with further CH 2 Cl 2 (2 x 5 cm 3 ) and the
combined organic phases dried over sodium sulphate, before purification by flash
chromatography (petrol to 19:1 petrol:EtOAc) to give 313 (27 mg, 93%) as a
colourless oil.
R f : 0.48 (9:1, petrol:EtOAc); MS m/z (CI+) 382 (100%, MNH + 4 ), 383 (26%,
(M+1)NH + 4 ); HRMS: found 382.2740, MNH 4 requires 382.2741; IR ν max (film)/cm⎯¹
2950 (C-H), 2862 (m, C-H), 1461 (C-Me), 1062 (m); ¹H-NMR (CDCl 3 , 500 MHz) δ
7.39-7.31 (m, 8H, Ph), 7.30-7.25 (m, 2H, Ph), 5.79 (dd, 1H, J 10.0, 1.5, H6), 5.59 (dd,
1H, J 10.0, 2.5, H5), 4.63 (d, 1H, J 12.0, OBn), 4.59 (d, 1H, J 12.0, OBn), 4.49 (d, 1H,
J 12.0, OBn'), 4.45 (d, 1H, J 12.0, OBn'), 4.07 (ddt, 1H, J 10.0, 6.0, 2.0, H4), 3.42 (d,
1H, J 9.0, H7), 3.36 (d, 1H, J 9.0, H7'), 2.08 (p, 1H, J 7.0, CHMe 2 ), 1.93-1.87 (m, 1H,
H3), 1.66-1.57 (m, 1H, H3'), 1.31 (d, 1H, J 13.5, H2), 1.06 (s, 3H, Me), 0.95 (d, 3H, J
7.0, i-Pr), 0.82 (d, 3H, J 7.0, i-Pr); ¹³C-NMR (CDCl 3 , 75.5 MHz) δ 139.0, 138.7,
138.2, 138.0 (ipso-Ph, C5, C6), 128.4, 128.3, 128.2, 128.0, 127.8, 127.6, 127.4, 127.2
(Ph), 76.0, 75.2, 73.3, 72.1, 69.6, 47.4, 40.5, 26.0, 25.4, 24.7, 24.5, 18.2.
263

Experimental for chapter 4.2
(1S*,2S*,3S*,4S*,6S*)-6-(benzyloxy)-3-((benzyloxy)methyl)-4-isopropyl-3-
methylcyclohexane-1,2-diol (314)
BnO
BnO
7
OsO 4 , NMO
HO
6
1
2
OBn (±)
CH 2 Cl 2
HO
5
4
3
OBn (±)
General procedure 5 was employed using olefin 313 (26 mg, 0.07 mmol), OsO 4 (22 µl,
2.5 mol%), NMO (9 mg, 0.19 mmol), in CH 2 Cl 2 (1 cm 3 ). Upon complete reaction of
starting material (c. 14 d), sodium metabisulfite (0.2 cm 3 , 5% w/w aq. solution) was
added. Purification by flash chromatography (9:1 to 4:1 petrol:EtOAc) yielded diol
314 (17 mg, 60%, 5:1 mixture of diastereomers) and starting material (6 mg, 20%) as a
colourless oil.
R f : 0.25 (2:1, petrol:EtOAc); MS m/z (ES+) 421 (100%, MNa + ), 437 (53%, MK + );
HRMS: found 421.2342, MNa requires 421.2349; IR ν max (film)/cm⎯¹ 3434 (br, O-H),
2957 (m, C-H), 1456 (m), 1085; ¹H-NMR (CDCl 3 , 500 MHz) δ 7.29-7.17 (m, 10H,
Ph), 4.63 (d, 1H, J 11.5, OBn), 4.41 (d, 1H, J 11.5, OBn), 4.36 (s, 2H, OBn), 3.92 (d,
1H, J 3.0, H6), 3.79-3.75 (m, 1H, H5), 3.60 (td, 1H, J 11.0, 5.0, H4), 3.42 (d, 1H, J
9.5, H7), 3.21 (d, 1H, J 9.5, H7), 2.57 (br s, 1H, OH), 2.30 (br s, 1H, OH), 1.87-1.76
(m, 2H, H3 eq & CHMe 2 ), 1.58 (dd, 1H, J 13.5, 3.0, H2), 1.37-1.28 (m, 1H, H3 ax ), 1.05
(s, 3H, Me), 0.86 (d, 3H, J 7.0, i-Pr), 0.68 (d, 3H, J 7.0, i-Pr); ¹³C-NMR (CDCl 3 , 125
MHz) δ 138.6 (ipso-Ph), 138.3 (ipso-Ph), 128.5, 128.3, 127.8 (Ph), 127.7 (para-Ph),
127.3 (para-Ph), 79.1 (C4), 75.7 (C6), 73.8 (C7, OBn), 73.4 (C7, OBn), 73.0 (C7,
OBn), 71.1 (C5), 43.0, 42.8 (C2, C1), 25.5 (CHMe 2 ), 25.2 (C3), 24.8, 21.4, 18.9 (Me).
264

Experimental for chapter 4.2
Synthesis of (1S*,2R*,3S*,4S*,5S*)-4-(hydroxymethyl)-5-isopropyl-4-
methylcyclohexane-1,2,3-triol (315)
BnO
HO
HO
H 2 , Pd/C
HO
6
1
2
HO
OBn (±)
HO
5
4
OH
3
(±)
A solution of oxazoline 314 (12 mg, 0.03 mmol) in methanol (1.5 cm 3 ) was passed
thorough the H-cube (1 cm 3 /min, 10 bar, Pd/C) and the eluent collected for 15 min.
The solvent was removed by rotary evaporation to give amide 315 (6 mg, 93%) as a
colourless oil.
R f : 0.11 (EtOAc); MS m/z (ES+) 241 (100%, MNa + ), 459 (30%, 2MNa + ); HRMS:
found 241.1400, MNa requites 241.1410; IR ν max (film)/cm⎯¹ 3375 (br, O-H), 2958
(CH), 1030; ¹H-NMR (CD 3 OD, 500 MHz) δ 3.87 (d, 1H, J 3.0, H6), 3.70 (d, 1H, J
11.0, H7), 3.74-3.69 (m, 1H, H4), 3.58-3.53 (m, 1H, H5), 3.49 (d, 1H, J 11.0, H7'),
1.93 (p, 1H, J 7.0, CHMe 2 ), 1.70-1.63 (m, 2H, H3), 1.36-1.28 (m, 1H, H2), 1.09 (s,
3H, Me), 0.95 (d, 3H, J 7.0, i-Pr), 0.80 (d, 3H, J 7.0, i-Pr); ¹³C-NMR (CD 3 OD, 75.5
MHz) δ 76.5, 75.0, 72.0, 65.6, 45.6, 44.0, 30.2, 26.3, 25.4, 21.7, 19.6.
Synthesis of (1R,2R,5S,6S)-6-isopropyl-5-methyl-5-(N-methyl-(4R,5R)-4,5-
diphenyloxazolidin-2-yl)cyclohex-3-ene-1,2-diol (310)
Ph
Ph
Ph
Ph
Ph
Ph
O
N
O
NMe
O
NMe
MeOTf, then NaBH 4 1
6
2
6
1
2
OH
5
4
3
OH
5
4
3
OH
O
OH
OH
310
316
General procedure 3 was employed using oxazoline 276 (300 mg, 0.77 mmol) and
methyl triflate (150 µl, 1.54 mmol) for 7 hr. The resulting yellow oil was purified by
flash chromatography (4:1 to 2:1 petrol:EtOAc) to give oxazolidine 310 (245 mg,
78%) and oxazolidine 316 (4 mg, 1%) as colourless oils.
265

Experimental for chapter 4.2
310 R f : 0.30 (40%, EtOAc in petrol); [α] 24 D : +135 (c = 1.0, CHCl 3 ); MS m/z (ES + ) 430
(100%, MNa + ), 408 (27%, MH + ), 838 (39%, [2M]Na + ); HRMS: found 430.2349, MNa
requires 430.2353; IR ν max (film)/cm⎯¹ 3364 (br, O-H), 2947 (m), 2360 (w, C=C), 1453
(m); ¹H-NMR (CDCl 3 , 500 MHz) δ 7.31-7.25 (m, 3H, Ar), 7.23-7.16 (m, 5H, Ar),
7.05-7.00 (m, 2H, Ar), 6.06 (dd, 1H, J 10.0, 2.0, H5), 5.65 (dd, 1H, J 10.0, 2.0, H6),
4.74 (d, 1H, J 9.0, CHOPh), 4.54 (s, 1H, CHON), 4.24 (dd, 1H, J 11.5, 7.0, H3), 3.95
(br d, 1H, J 7.0, H4), 3.30 (d, 1H, J 9.0, CHNPh), 2.37 (s, 3H, NMe), 2.31-2.10 (m,
3H, CHMe 2 , OH), 1.48 (d, 1H, J 11.5, H2), 1.29 (d, 3H, J 7.0, CHMe A Me b ), 1.21-1.17
(m, 6H, Me & CHMe a Me B ); ¹³C-NMR (CDCl 3 , 75.5 MHz) δ 138.6 (ipso-Ph), 137.6
(ipso-Ph), 134.7 (C5), 128.3 (C6), 128.1, 128.0, 127.8, 127.7, 126.4 (Ph), 99.9
(CHON), 85.6 (CHOPh), 79.6 (CHNPh), 76.1 (C4), 74.1 (C3), 55.1 (C2), 48.6 (C1),
41.9 (NMe), 27.3 (CHMe a Me B ), 25.9 (CHMe 2 ), 24.7 (Me), 17.9 (CHMe A Me b ).
316 R f : 0.32 (2:1, petrol:EtOAc); [α] 24 D : +217 (c = 1.0, CHCl 3 ); MS m/z (ES + ) 430
(100%, MNa + ); HRMS: found 430.2348, MNa requires 430.2353; IR ν max (film)/cm⎯¹
3368 (br, O-H), 2957 (m, C-H), 1604 (m, C=C), 1453 (C-Me); ¹H-NMR (CDCl 3 , 500
MHz) δ 7.33-7.28 (m, 3H, Ph), 7.26-7.22 (m, 3H, Ph), 7.22-6.98 (m, 2H, Ph), 7.05-
7.01 (m, 2H, Ph), 6.29 (d, 1H, J 10.0, H6), 6.00 (dd, 1H, J 10.0, 5.0, H5), 4.67 (d, 1H,
J 9.5, CHOPh), 4.61 (s, 1H, CHON), 4.52 (dd, 1H, J 12.0, 5.0, H3), 3.99 (t, 1H, J 5.0,
H4), 3.31 (d, 1H, J 9.5, CHNPh), 2.39 (s, 3H, NMe), 2.21 (p, 1H, J 7.0, CHMe 2 ), 2.08
(br s, 1H, OH), 1.86 (br s, 1H, OH), 1.52 (d, 1H, J 12.0, H2), 1.35 (d, 3H, J 7.0, i-Pr),
1.23-1.20 (m, 6H, Me & i-Pr); ¹³C-NMR (CDCl 3 , 125 MHz) δ 138.7 (ipso-Ph), 138.5
(ipso-Ph), 137.6 (C5), 128.3 (C6), 128.1, 128.0, 127.8, 127.7, 126.5, 126.2 (Ph), 100.0
(CHON), 85.7 (CHOPh), 79.5 (CHNPh), 69.1, 66.7 (C3, C4), 50.4 (C2), 48.8 (C1),
41.8 (NMe), 27.6 (i-Pr), 25.8 (i-Pr), 24.7 (Me), 17.7 (i-Pr).
266

Experimental for chapter 4.2
Synthesis of (1R,2S,3S,4S,5R,6S)-6-isopropyl-5-methyl-5-(N-methyl-(4R,5R)-4,5-
diphenyloxazolidin-2-yl)cyclohexane-1,2,3,4-tetraol (311)
Ph Ph
Ph Ph Ph Ph Ph Ph
O
N
O
NMe
O
NMe
O
NMe
1
OsO 4
HO 6
HO
2
OH
CH 2 Cl 2 , NMO
5
HO
3
4 OH
OH HO OH
OH
OH
O
O
311 318 319
General procedure 5 was employed using olefin 310 (20 mg, 0.05 mmol), OsO 4 (12 µl,
2.0 mol%), NMO (12 mg, 0.10 mmol), in CH 2 Cl 2 (0.5 cm 3 ). Upon complete reaction
of starting material (7 days), sodium metabisulfite (0.2 cm 3 , 5% w/w aq. solution) was
added. Purification by flash chromatography (19:1 to 1:2 petrol:EtOAc) yielded
tetraol 311 (4 mg, 21%), enone 318 (2 mg, 11%) and triol 319 (8 mg, 42%) as
colourless oils.
311 R f : 0.23 (2:1, petrol:EtOAc); [α] 20 D : +14 (c = 1, CHCl 3 ); MS m/z (ES–) 442
(100%, MH + ), 443 (31%, (M+1)H + ); HRMS: found 442.2584, MH requires 442.2588;
IR ν max (film)/cm⎯¹ 3398 (br, O-H), 2927 (m, C-H), 2360 (w), 1457 (w), 1065; ¹H-
NMR (CDCl 3 , 500 MHz) δ 7.33-7.27 (m, 6H, Ph), 7.22-7.16 (m, 2H, Ph), 7.08-6.99
(m, 2H, Ph), 4.63 (d, 1H, J 9.0, CHOPh), 4.59 (d, 1H, J 3.0, H6), 4.51 (s, 1H, CHNO),
4.15 (dd, 1H, J 11.0, 9.0, H3), 3.95-3.90 (m, 1H, H5), 3.71 (t, 1H, J 9.0, H4), 3.35 (d,
1H, J 9.0, CHNPh), 2.29 (s, 3H, NMe), 2.13 (p, 1H, J 7.0, CHMe 2 ), 1.74 (d, 1H, J
11.0, H2), 1.29 (d, 3H, J 7.0, CHMe A Me b ), 1.28 (s, Me), 1.20 (d, 3H, J 7.0,
CHMe a Me B ); ¹³C-NMR (CDCl 3 , 75.5 MHz) δ 139.2 (ipso-Ph), 137.1 (ipso-Ph),
128.544, 128.3, 128.0, 127.7, 126.3 (Ph), 101.2 (CHNO), 85.2 (CHOPh), 79.7
(CHNPh), 76.8 (CHOH), 73.6 (CHOH), 73.5 (CHOH), 72.6 (CHOH), 52.2 (C2), 47.2
(C1), 39.7 (NMe), 27.7 (CHMe a Me B ), 25.3 (CHMe 2 ), 23.144 (Me), 18.2 (CHMe A Me b ).
318 R f : 0.20 (9:1, petrol:EtOAc); [α] 24 D : +268 (c = 1, CHCl3); MS m/z (ES+) 428
(100%, MNa + ), 429 (32%, (M+1)H + ); HRMS: found 428.2191, MNa requires
428.2196; IR ν max (film)/cm⎯¹ 3383 (m, O-H), 2947 (m, C-H), 2355 (m), 1675 (C=O),
1450 (w, C-Me), 1061 (m); ¹H-NMR (CDCl 3 , 500 MHz) δ 7.34-7.29 (m, 4H, Ph, H6),
7.27-7.23 (m, 3H, Ph), 7.18-7.15 (m, 2H, Ph), 7.03-6.99 (m, 2H, Ph), 6.22 (d, 1H, J
267

Experimental for chapter 4.2
10.0, H5), 4.86 (dd, 1H, J 13.0, 1.0, H3), 4.82 (s, 1H, CHON), 4.62 (d, 1H, J 9.5,
CHOPh), 3.42 (br d, 1H, J 1.0, OH), 3.38 (d, 1H, J 9.5, CHNPh), 2.45 (s, 3H, NMe),
2.26 (p, 1H, J 7.0, CHMe 2 ), 1.85 (d, 1H, J 13.0, H2); 1.39 (s, 3H, Me), 1.37 (d, 3H, J
7.0, CHMe A Me b ), 1.21 (d, 3H, J 7.0, CHMe a Me B ); ¹³C-NMR (CDCl 3 , 75.5 MHz) δ
202.9 (C=O), 157.6 (C6), 137.8 (ipso-Ph), 136.9 (ipso-Ph), 128.5, 128.1, 128.1, 128.0,
128.0, 126.4, 126.3 (Ph), 100.6 (CHNO), 86.6 (CHOPh), 79.6 (CHNPh), 72.2 (C3),
56.6 (C2), 49.4 (C1), 41.7 (NMe), 26.6 (CHMe a Me B ), 26.5 (CHMe 2 ), 24.2 (Me), 17.5
(CHMe A Me b ).
319 R f : 0.33 (0.4, EtOAc in petrol); [α] 22 D : +43 (c = 1.3, CHCl 3 ); MS m/z (ES+) 440
(100%, MH + ), 441 (29%, (M+1)H + ); HRMS: found 440.2434, MH requires 440.2431;
IR ν max (film)/cm⎯¹ 3474 (O-H), 2950 (m, C-H), 1717 (C=O), 1453 (m); ¹H-NMR
(CDCl 3 , 500 MHz) δ 7.37-7.25 (m, 6H, Ph), 7.23-7.18 (m, 2H, Ph), 7.10-7.04 (m, 2H,
Ph), 4.98 (br d, 1H, J 11.0, H3), 4.87 (d, 1H, J 3.0, H5 or H6), 4.80 (d, 1H, J 3.0, H5 or
H6), 4.69-4.64 (m, 2H, CHNO, CHOPh), 3.81 (br s, 1H, OH), 3.45 (d, 1H, J 9.0,
CHNPh), 3.23. (br d, 1H, J 3.0, C3-OH), 2.65 (br s, 1H, OH), 2.35 (s, 3H, NMe), 2.24
(p, 1H, J 7.0, CHMe 2 ), 2.01 (d, 1H, J 11.5, H2), 1.38 (s, 3H, Me), 1.35 (d, 3H, J 7.0, i-
Pr), 1.18 (d, 3H, J 7.0, i-Pr); ¹³C-NMR (CDCl 3 , 125 MHz) δ 138.6, 136.6, 128.7,
128.3, 128.2, 128.1, 126.4, 101.2, 86.2, 79.7, 74.7, 74.2, 57.0, 46.0, 39.4, 27.2, 25.9,
22.8, 18.1.
268

Experimental for chapter 4.2
Synthesis of (1R,2R,5S,6S)-5-(hydroxymethyl)-6-isopropyl-5-methylcyclohex-3-
ene-1,2-diol (312)
Ph
Ph
O
NMe
i) H 3 O + , 50 °C
HO
6
1
2
OH
OH
ii) NaBH 4
5
4
OH
3
OH
General procedure 7 was employed using oxazolidine 310 (50 mg, 0.12 mmol), and the
reaction heated at 50 °C for 24 hr. Flash chromatography (3:2 petrol:EtOAc) yielded
triol 312 (19 mg, 79%) as colourless needles.
R f : 0.34 (EtOAc); Mpt: 136-138 ºC (MeOH); [α] 22 D : +10.8 (c = 1.7, MeOH); MS m/z
(ES+) 223 (100%, MNa + ), 224 (15%, (M+1)Na + ); HRMS: found 223.1299, MNa
requires 223.1305; IR ν max (film)/cm⎯¹ 3348 (br, O-H), 2958 (m, C-H), 1651 (w, C=C);
¹H-NMR (CD 3 OD, 500 MHz) δ 5.60 (dd, 1H, J 10.0, 1.5, H5), 5.44 (dd, 1H, J 10.0,
2.0, H6), 4.00 (d, 1H, J 7.5, H4), 3.91 (dd, 1H, J 12.0, 7.5, H3), 3.59 (d, 1H, J 11.0,
H7), 3.39 (d, 1H, J 11.0, H7’), 2.03 (p, 1H, J 7.0, CHMe 2 ), 1.48 (d, 1H, J 12.0, H2),
1.19 (d, 6H, J 7.0, i-Pr), 1.01 (s, 3H, Me); ¹³C-NMR (CD 3 OD, 75.5 MHz) δ 136.8
(C5), 129.3 (C6), 76.3 (C4), 74.1 (C3), 67.7 (C7), 53.7 (C2), 44.9 (C1), 27.5 (CHMe 2 ),
27.5 (CHMe A Me B ), 24.7 (Me), 18.1 (CHMe A Me B ).
For dihydroxylation of 312 to give altrose analogue 278, see page 260
Synthesis of (1S,4R,5R,6S)-5-hydroxy-6-isopropyl-1-methylcyclohex-2-ene-δlactone
(328)
Ph
Ph
O
N
Me
MeOTf, then NH 4 Cl
O
1
2
OH
O
4
3
OH
OH
General procedure 6 was used employing oxazoline 213 (45 mg, 0.11 mmol) and
methyl triflate (27 µl, 0.23 mmol) for 16 hr and an ammonium chloride (sat. aq., 0.5
269

Experimental for chapter 4.2
cm 3 ) quench. The layers were partitioned, the aqueous layer washed with CH 2 Cl 2 (2 x
5 cm 3 ) and the combined organic phases dried over anhydrous sodium sulfate. Flash
chromatography (9:1 to 1:1 petrol:EtOAc) gave lactone 328 (8 mg, 36%) as a
colourless oil.
R f : 0.09 (4:1, petrol:EtOAc); [α] 24 D : +187 (c = 0.8, CHCl 3 ); MS m/z (ES-) 391 (100%,
[2M-H] – ), 195 (40%, [M-H] – ), 196 (4%, [(M+1)-H] – ); IR ν max (film)/cm⎯¹ 3432 (br,
OH), 2964 (m, C-H), 1758 (C=O); ¹H-NMR (CDCl 3 , 500 MHz) δ 5.93 (d, 1H, J 9.0,
H6), 5.79-5.74 (dm, 1H, J 9.0, H5), 4.54-4.50 (m, 1H, H4), 4.37-4.32 (m, 1H, H3),
2.16 (d, 1H, J 3.5, H2), 2.01 (pd, 1H, J 7.0, 3.5, CHMe 2 ), 1.91 (br d, 1H, J 6.0, H3),
1.32 (s, 3H, Me), 1.04 (d, 3H, J 7.0, i-Pr), 0.87 (d, 3H, J 7.0, i-Pr); ¹³C-NMR (CDCl 3 ,
125 MHz) δ 179.0 (C=O), 139.2, 128.2, 66.8, 50.8, 25.5, 21.5, 17.6, 14.9.
(1S,2S,3R,4R,5R,6S)-2,3-epoxy-5-hydroxy-6-isopropyl-1-methylcyclohexane-δlactone
(329)
O
O
Me
OH
mCPBA
O
Me
1
2
O
O
4
3
OH
mCPBA (17 mg, 50%, 0.05 mmol) was added in a single portion to a stirred solution
of allyl alcohol 328 (5 mg, 0.05 mmol) at –20 °C in CH 2 Cl 2 (0.3 cm 3 ) and maintained
at the temperature for 4 hr, after which period the reaction was allowed to warm to rt.
After 18 hr, aqueous sodium bicarbonate (1 cm 3 sat.) was added, the reaction
partitioned, and the aqueous phase extracted with further CH 2 Cl 2 (2 x 5 cm 3 ). The
combined organic layers were dried over anhydrous sodium sulfate, and the solvent
removed. The resulting mixture was purified by flash column chromatography (4:1
petrol:EtOAc) to give epoxide 329 (4 mg, 80%) as a colourless oil.
R f : 0.29 (2:1, petrol:EtOAc); [α] 24 D : +78 (c = 0.5, CHCl 3 ); MS m/z (ES–) 211 (100%,
(M-H) – ), 212 (9%, ([M+1]-H) – ), 423 (90%, (2M-H) – ); HRMS: found 212.1044, M
requires 212.1043; IR ν max (film)/cm⎯¹ 3431 (br, O-H), 2964 (m, C-H), 1779 (C=O),
1261 (m); ¹H-NMR (CDCl 3 , 500 MHz) δ 4.33-4.29 (m, 1H, H3 or H4), 4.10-4.04 (m,
1H, H3 or H4), 3.37-3.32 (m, 2H, H5, H6), 2.32 (d, 1H, J 3.5, H2), 2.19 (br s, 1H,
OH), 1.89 (pd, 1H, J 7.0, 3.5, CHMe 2 ), 1.41 (s, 3H, Me), 0.99 (d, 3H, J 7.0, i-Pr), 0.83
270

Experimental for chapter 4.2
(d, 3H, J 7.0, i-Pr); ¹³C-NMR (CDCl 3 , 125 MHz) δ 177.6, 64.9, 60.1, 51.1, 44.6, 43.3,
24.9, 21.4, 17.5, 14.0
Synthesis of (1S,2R,3S,4R,5R,6S)-5-(N-methyl-N-oxo-(4R,5R)-4,5-
diphenyloxazolidin-2-yl)-3,4-epoxy-6-isopropyl-5-methylcyclohexane-1,2-diol
(332)
Ph Ph
Ph Ph
O N
mCPBA, CH 2 Cl 2
O
OH
OH
O
O N
1
6 2
3
5
4
mCPBA (37 mg, 50%, 0.11 mmol) was added in a single portion to a stirred solution
of allyl alcohol 310 (22 mg, 0.05 mmol) at –40 °C in CH 2 Cl 2 (0.5 cm 3 ) and maintained
at the temperature for 4 hr, after which period the reaction was allowed to warm to rt.
After 18 hr, aqueous sodium sulfite (1 cm 3 sat.) was added, the reaction mixture was
washed with aqueous sodium bicarbonate (1 cm 3 sat.) and the aqueous phase extracted
with further CH 2 Cl 2 (3 x 5 cm 3 ). The combined organic layers were dried over
anhydrous sodium sulfate, and the solvent removed. The resulting mixture was
purified by flash column chromatography (9:1 petrol:EtOAc to 10% MeOH in EtOAc)
to give epoxide 332 (12 mg, 53%) as a white wax.
OH
OH
R f : 0.28 (9:1, EtOAc:MeOH); [α] 24 D : +125 (c = 1, CHCl 3 ); MS m/z (ES+) 440 (58%,
MH + ), 462 (100%, MNa + ); 901 (36%, M 2 Na + ); HRMS: found 440.2428, MH requires
440.2431; IR ν max (film)/cm⎯¹ 3435 (br, OH), 1187, 1121, 1040 (C-O-C), 1010 (m, N-
O); ¹H-NMR (CD 3 OD, 500 MHz) δ 7.66-7.62 (m, 2H, Ph), 7.44-7.35 (m, 3H, Ph),
7.34-7.28 (m, 2H, Ph), 7.23-7.19 (m, 3H, Ph), 6.04 (d, 1H, J 11.0, CHOPh), 5.50 (s,
1H, CHNO), 4.67 (d, 1H, J 11.0, CHNPh), 4.07 (dd, 1H, J 11.5, 7.5, H3), 3.86 (d, 1H,
J 3.5, H6), 3.61 (dd, 1H, J 7.5, 1.5, H4), 3.23-3.19 (m, 4H, NMe, H5), 2.10 (p, 1H, J
7.0, CHMe 2 ), 1.57 (s, 3H, Me), 1.33 (d, 3H, J 7.0, i-Pr), 1.29 (d, 1H, J 11.5, H2), 1.21
(d, 3H, J 7.0, i-Pr); ¹³C-NMR (CDCl 3 , 75.5 MHz) δ 136.6, 132.8, 130.1, 128.4, 128.3,
128.0, 127.1, 126.4 (Ph), 108.1 (CHNO), 87.8 (CHOPh), 81.5 (CHNPh), 77.3 (C4),
71.2 (C3), 61.4 (C6), 57.6 (C2), 54.8 (C5), 42.9 (NMe), 42.8 (C1), 27.5 (i-Pr), 27.2
(CHMe 2 ), 22.7 (Me), 17.4 (i-Pr).
271

Experimental for chapter 4.2
Synthesis of (1R,2S,3R,4S,5S,6S)-5-(hydroxymethyl)-6-isopropyl-5-
methylcyclohexane-1,2,3,4-tetraol (324)
HO
HCl (aq), THF
O
OH
0 °C - rt
OH
HO
HO
HO
1
6
5
4
Aqueous hydrochloric acid (0.3 cm 3 , 6M) was added to a solution of epoxide 309 in
THF (0.3 cm 3 ) an ice bath at 0 °C which was allowed to warm to ambient temperature.
Solvent was removed from the reaction after 8 hr, and the resulting oil was purified by
flash chromatography (2:1 to 2:3 petrol:EtOAc) to yield pentaol 324 (13 mg 81%) as
colourless needles.
OH
2
3
OH
R f : 0.30 (EtOAc); Mpt: 204-5 ºC (MeOH); [α] 23 D : –10.4 (c = 0.5, CHCl 3 ); MS m/z
(ES+) 275 (100%, [M+H 2 O]Na + ); HRMS: found 275.1445, [M+H 2 O]Na + requires
275.1465; IR ν max (film)/cm⎯¹ 3325 (br, O-H), 3161 (br, O-H), 2967 (m, C-H), 2913
(m, C-H), 1471 (w, C-Me), 1100, 1058; ¹H-NMR (CD 3 OD, 500 MHz) δ 4.36 (d, 1H, J
3.0, H6), 4.13 (t, 1H, J 3.0, H5), 4.08 (d, 1H, J 11.0, H7 a ), 3.90-3.86 (m, 2H, H3 or
H4), 3.48 (d, 1H, J 11.0, H7 b ), 1.94 (p, 1H, J 7.0, CHMe 2 ), 1.69-1.63 (m, 1H, H2),
1.16-1.12 (m, 6H, Me, i-Pr), 1.10 (d, 3H, J 7.0, i-Pr); ¹³C-NMR (CD 3 OD, 75.5 MHz) δ
75.5 (CHOH), 73.7 (CHOH), 70.8 (CHOH), 69.1 (CHOH), 67.1 (C7), 50.4 (C2), 46.2
(C1), 27.6, 27.0, 25.7, 18.6 (Me).
272

Experimental for chapter 4.2
Data for (1R,2S,3S,4R,5S,6S)-5-(hydroxymethyl)-6-isopropyl-5-
methylcyclohexane-1,2,3,4-tetraol (322)
HO
7
HO
6
1
2
HO
5
3
4 OH
OH
R f : 0.47 (EtOAc); [α] 22 D : –104 (c = 0.1, CHCl 3 ); MS m/z (ES+) 275 (100%,
[M+H 2 O]Na + ); IR ν max (film)/cm⎯¹ 3357 (br, O-H), 2909, 1993, 1458; ¹H-NMR
(CDCl 3 , 500 MHz) δ 4.34 (t, 1H, J 10.5, H5), 3.92 (dd, 1H, J 11.5, 9.0, H3), 3.72 (d,
2H, J 3.5, H7), 3.50-3.43 (m, 2H, H4, H6), 2.81 (d, 1H, J 3.0, OH), 2.64 (br s, 1H,
OH), 2.43 (br s, 1H, OH), 2.29 (t, 1H, J 3.5, C7-OH), 2.02 (p, 1H, J 7.0, CHMe 2 ), 1.19
(s, 3H, Me), 1.15 (d, 3H, J 7.0, i-Pr), 1.11 (d, 3H, J 7.0, i-Pr).
273

Experimental for chapter 4.2
5.7 References for Experimental Section
(1) Gomez, J. C. C.; Lopez, F. J. S.; 4.8.6 ed.; MestRe-C, Ed. 2005.
(2) Gomes, M.; 1.0 ed.; Paulo, U. d. S., Ed.; Universidade de Sao Paulo: 2004.
(3) Crosignani, S.; Young, A. C.; Linclau, B. Tetrahedron Lett. 2004, 45, 9611-
9615.
(4) Meyers, A. I.; Roth, G. P.; Hoyer, D.; Barner, B. A.; Laucher, D. J. Am. Chem.
Soc. 1988, 110, 4611-24.
(5) VanRheenen, V.; Cha, D. Y.; Hartley, W. M. Org. Synth. 1978, 58, 43.
(6) Hodgson, R.; Majid, T.; Nelson, A. J. Chem. Soc., Perkin Trans. 1 2002, 1444 -
1454.
(7) Barner, B. A.; Meyers, A. I. J. Am. Chem. Soc. 1984, 106, 1865-6.
(8) Kolb, H.; VanNieuwenhze, M.; Sharpless, K. B. Chem. Rev. 1994, 2483.
(9) Wang, Z. M.; Sharpless, K. B. J. Org. Chem. 1994, 8302.
(10) Chang, H.-T.; Sharpless, K. B. Tetrahedron Lett. 1996, 37, 3219.
(11) Cabedo, N. C.; University of Manchester: 2004-5.
(12) Ittah, Y.; Sasson, Y.; Shahak, I.; Tsaroom, S.; Blum, J. J. Org. Chem. 1978, 43,
4271-4273.
(13) Heine, H. W.; King, D. C.; Portland, L. A. J. Org. Chem. 1966, 31, 4271-4272.
(14) Reyes, A.; Juaristi, E. Chirality 1998, 10, 95-99.
(15) Lygo, B., Suggestion to use diethyl ether-petrol solvent at low temperature to
encourage precipitation of Et 3 .HCl salt, reducing free chloride ions which
would otherwise attack the aziridine ring.
(16) Groundwater, P. W.; Garnett, I.; Morton, A. J.; Sharif, T.; Coles, S. J.;
Hursthouse, M. B.; Nyerges, M.; Anderson, R. J.; Bendell, D.; McKillop, A.;
Zhang, W. J. Chem. Soc., Perkin Trans. 1 2001, 2781-2787.
(17) Hayashida, M.; Ishizaki, M.; Hara, H. Chem. Pharm. Bull. 2006, 54, 1299.
(18) Haak, E.; Siebeneicher, H.; Doye, S. Org. Lett. 2000, 2, 1935-1937.
(19) Czernecki, S.; Georgoulis, C.; Provelenghiou, C. Tetrahedron Lett. 1976, 17,
3535.
(20) Eames, J.; Mitchell, H. J.; Nelson, A.; O'Brien, P.; Warren, S.; Wyatt, P. J.
Chem. Soc., Perkin Trans. 1 1999, 1095-1103.
(21) Curtin, D. Y.; Kellom, D. B. J. Am. Chem. Soc. 1953, 75, 6011-6018
274

Appendix A: Selected NMR Spectra
275

276

277

278

279

280

281

282

283

284

Appendix B – Crystallographic Information Files (cif)
a. Compound 102b
Ph
O
N
Ph
Me
OMe
102b
Identification code s2170m
Empirical formula C26 H29 N O2
Formula weight 387.50
Temperature
100(2) K
Wavelength
0.71073 A
Crystal system, space group Orthorhombic, P2(1)2(1)2(1)
Unit cell dimensions a = 12.1398(11) A alpha = 90 deg.
b = 12.8480(11) A beta = 90 deg.
c = 13.5618(12) A gamma = 90 deg.
Volume
2115.3(3) A^3
Z, Calculated density 4, 1.217 Mg/m^3
Absorption coefficient 0.076 mm^-1
F(000) 832
Crystal size
0.40 x 0.20 x 0.15 mm
Theta range for data collection 2.18 to 28.29 deg.
Limiting indices -14

Absolute structure parameter 1.3(11)
Largest diff. peak and hole 0.175 and -0.143 e.A^-3
286

_audit_creation_method SHELXL-97
_chemical_name_systematic
_chemical_name_common ?
_chemical_melting_point ?
_chemical_formula_moiety ?
_chemical_formula_sum
'C26 H29 N O2'
_chemical_formula_weight 387.50
loop_
_atom_type_symbol
_atom_type_description
_atom_type_scat_dispersion_real
_atom_type_scat_dispersion_imag
_atom_type_scat_source
'C' 'C' 0.0033 0.0016
'International Tables Vol C Tables 4.2.6.8 and
6.1.1.4'
'H' 'H' 0.0000 0.0000
'International Tables Vol C Tables 4.2.6.8 and
6.1.1.4'
'N' 'N' 0.0061 0.0033
'International Tables Vol C Tables 4.2.6.8 and
6.1.1.4'
'O' 'O' 0.0106 0.0060
'International Tables Vol C Tables 4.2.6.8 and
6.1.1.4'
_symmetry_cell_setting Orthorhombic
_symmetry_space_group_name_H-M
P2(1)2(1)2(1)
loop_
_symmetry_equiv_pos_as_xyz
'x, y, z'
'-x+1/2, -y, z+1/2'
'-x, y+1/2, -z+1/2'
'x+1/2, -y+1/2, -z'
_cell_length_a 12.1398(11)
_cell_length_b 12.8480(11)
_cell_length_c 13.5618(12)
_cell_angle_alpha 90.00
_cell_angle_beta 90.00
_cell_angle_gamma 90.00
_cell_volume 2115.3(3)
_cell_formula_units_Z 4
_cell_measurement_temperature 100(2)
_cell_measurement_reflns_used input
_cell_measurement_theta_min 2.2475
_cell_measurement_theta_max 20.9675
_exptl_crystal_description prism
_exptl_crystal_colour white
_exptl_crystal_size_max 0.40
_exptl_crystal_size_mid 0.20
_exptl_crystal_size_min 0.15
_exptl_crystal_density_meas 0
_exptl_crystal_density_diffrn 1.217
_exptl_crystal_density_method 'not measured'
_exptl_crystal_F_000 832
_exptl_absorpt_coefficient_mu 0.076
_exptl_absorpt_correction_type none
_exptl_absorpt_correction_T_min 0.9703
_exptl_absorpt_correction_T_max 0.9887
_exptl_absorpt_process_details ?
_exptl_special_details
_diffrn_ambient_temperature 100(2)
_diffrn_radiation_wavelength 0.71073
_diffrn_radiation_type MoK\a
_diffrn_radiation_source 'fine-focus sealed
tube'
_diffrn_radiation_monochromator graphite
_diffrn_measurement_device_type 'CCD area
detector'
_diffrn_measurement_method 'phi and omega
scans'
_diffrn_detector_area_resol_mean ?
_diffrn_standards_number ?
_diffrn_standards_interval_count ?
287

_diffrn_standards_interval_time ?
_diffrn_standards_decay_% ?
_diffrn_reflns_number 13445
_diffrn_reflns_av_R_equivalents 0.0713
_diffrn_reflns_av_sigmaI/netI 0.1472
_diffrn_reflns_limit_h_min -14
_diffrn_reflns_limit_h_max 15
_diffrn_reflns_limit_k_min -16
_diffrn_reflns_limit_k_max 8
_diffrn_reflns_limit_l_min -17
_diffrn_reflns_limit_l_max 18
_diffrn_reflns_theta_min 2.18
_diffrn_reflns_theta_max 28.29
_reflns_number_total 4966
_reflns_number_gt 2771
_reflns_threshold_expression >2sigma(I)
_computing_data_collection
'Bruker
SMART'
_computing_cell_refinement
'Bruker
SMART'
_computing_data_reduction
'Bruker
SAINT'
_computing_structure_solution 'SHELXS-97
(Sheldrick, 1990)'
_computing_structure_refinement 'SHELXL-97
(Sheldrick, 1997)'
_computing_molecular_graphics 'Bruker
SHELXTL'
_computing_publication_material 'Bruker
SHELXTL'
_refine_special_details
Refinement of F^2^ against ALL reflections. The
weighted R-factor wR and
goodness of fit S are based on F^2^, conventional
R-factors R are based
on F, with F set to zero for negative F^2^. The
threshold expression of
F^2^ > 2sigma(F^2^) is used only for calculating
R-factors(gt) etc. and is
not relevant to the choice of reflections for
refinement. R-factors based
on F^2^ are statistically about twice as large as
those based on F, and R-
factors based on ALL data will be even larger.
_refine_ls_structure_factor_coef Fsqd
_refine_ls_matrix_type full
_refine_ls_weighting_scheme calc
_refine_ls_weighting_details
'calc w=1/[\s^2^(Fo^2^)+(0.0000P)^2^+0.0000P]
where P=(Fo^2^+2Fc^2^)/3'
_atom_sites_solution_primary direct
_atom_sites_solution_secondary difmap
_atom_sites_solution_hydrogens geom
_refine_ls_hydrogen_treatment mixed
_refine_ls_extinction_method none
_refine_ls_extinction_coef ?
_refine_ls_abs_structure_details
'Flack H D (1983), Acta Cryst. A39, 876-881'
_refine_ls_abs_structure_Flack 1.3(11)
_refine_ls_number_reflns 4966
_refine_ls_number_parameters 266
_refine_ls_number_restraints 0
_refine_ls_R_factor_all 0.0879
_refine_ls_R_factor_gt 0.0407
_refine_ls_wR_factor_ref 0.0598
_refine_ls_wR_factor_gt 0.0518
_refine_ls_goodness_of_fit_ref 0.675
_refine_ls_restrained_S_all 0.675
_refine_ls_shift/su_max 0.000
288

_refine_ls_shift/su_mean 0.000
loop_
_atom_site_label
_atom_site_type_symbol
_atom_site_fract_x
_atom_site_fract_y
_atom_site_fract_z
_atom_site_U_iso_or_equiv
_atom_site_adp_type
_atom_site_occupancy
_atom_site_symmetry_multiplicity
_atom_site_calc_flag
_atom_site_refinement_flags
_atom_site_disorder_assembly
_atom_site_disorder_group
C1 C 0.83045(16) 0.49054(15) 0.14451(14)
0.0204(5) Uani 1 1 d . . .
C2 C 0.92740(14) 0.41706(15) 0.17390(14)
0.0207(5) Uani 1 1 d . . .
H2 H 0.9720 0.4561 0.2236 0.025 Uiso 1 1 calc
R . .
C3 C 0.88510(15) 0.32101(14) 0.22610(14)
0.0220(5) Uani 1 1 d . . .
H3 H 0.9308 0.2867 0.2727 0.026 Uiso 1 1 calc
R . .
C4 C 0.78501(16) 0.28394(15) 0.20775(14)
0.0200(5) Uani 1 1 d . . .
C5 C 0.71032(15) 0.33576(15) 0.13987(14)
0.0233(5) Uani 1 1 d . . .
H5 H 0.6448 0.3015 0.1194 0.028 Uiso 1 1 calc
R . .
C6 C 0.73267(15) 0.43020(16) 0.10625(14)
0.0236(5) Uani 1 1 d . . .
H6 H 0.6866 0.4604 0.0574 0.028 Uiso 1 1 calc
R . .
C7 C 0.79109(16) 0.55021(14) 0.23711(14)
0.0300(6) Uani 1 1 d . . .
H7A H 0.8506 0.5951 0.2611 0.045 Uiso 1 1 calc R
. .
H7B H 0.7708 0.5004 0.2887 0.045 Uiso 1 1 calc R
. .
H7C H 0.7269 0.5929 0.2202 0.045 Uiso 1 1 calc R
. .
C8 C 1.00781(15) 0.38867(16) 0.08889(14)
0.0242(5) Uani 1 1 d . . .
H8 H 1.0342 0.4554 0.0592 0.029 Uiso 1 1 calc R .
.
C9 C 0.95494(15) 0.32482(14) 0.00635(15)
0.0298(6) Uani 1 1 d . . .
H9A H 0.9297 0.2580 0.0328 0.045 Uiso 1 1 calc R
. .
H9B H 1.0092 0.3125 -0.0459 0.045 Uiso 1 1 calc
R . .
H9C H 0.8920 0.3630 -0.0208 0.045 Uiso 1 1 calc
R . .
C10 C 1.10924(15) 0.33115(15) 0.12915(14)
0.0341(6) Uani 1 1 d . . .
H10A H 1.0870 0.2626 0.1538 0.051 Uiso 1 1 calc
R . .
H10B H 1.1419 0.3716 0.1830 0.051 Uiso 1 1 calc
R . .
H10C H 1.1635 0.3225 0.0763 0.051 Uiso 1 1 calc
R . .
C11 C 0.80696(15) 0.13795(15) 0.31431(14)
0.0286(6) Uani 1 1 d . . .
H11A H 0.8747 0.1166 0.2807 0.043 Uiso 1 1 calc
R . .
H11B H 0.7674 0.0761 0.3374 0.043 Uiso 1 1 calc
R . .
H11C H 0.8255 0.1822 0.3707 0.043 Uiso 1 1 calc
R . .
C12 C 0.86735(15) 0.56876(16) 0.06908(15)
0.0211(5) Uani 1 1 d . . .
C13 C 0.89699(15) 0.66286(15) -0.06504(13)
0.0215(5) Uani 1 1 d . . .
289

H13 H 0.8405 0.7136 -0.0889 0.026 Uiso 1 1
calc R . .
C14 C 0.96120(16) 0.71333(15) 0.02178(14)
0.0212(5) Uani 1 1 d . . .
H14 H 1.0419 0.7126 0.0069 0.025 Uiso 1 1 calc
R . .
C15 C 0.97123(15) 0.63387(16) -0.15098(14)
0.0198(5) Uani 1 1 d . . .
C16 C 0.97990(16) 0.53350(16) -0.18628(14)
0.0240(5) Uani 1 1 d . . .
H16 H 0.9404 0.4786 -0.1555 0.029 Uiso 1 1
calc R . .
C17 C 1.04686(16) 0.51316(16) -0.26732(15)
0.0291(5) Uani 1 1 d . . .
H17 H 1.0531 0.4439 -0.2911 0.035 Uiso 1 1
calc R . .
C18 C 1.10389(15) 0.59113(17) -0.31340(15)
0.0269(5) Uani 1 1 d . . .
H18 H 1.1475 0.5763 -0.3699 0.032 Uiso 1 1
calc R . .
C19 C 1.09767(16) 0.69211(16) -0.27715(15)
0.0278(5) Uani 1 1 d . . .
H19 H 1.1388 0.7465 -0.3072 0.033 Uiso 1 1
calc R . .
C20 C 1.03127(16) 0.71245(16) -0.19718(15)
0.0259(5) Uani 1 1 d . . .
H20 H 1.0262 0.7816 -0.1729 0.031 Uiso 1 1
calc R . .
C21 C 0.92576(16) 0.82249(16) 0.04727(13)
0.0210(5) Uani 1 1 d . . .
C22 C 0.99991(16) 0.90429(16) 0.04092(13)
0.0253(5) Uani 1 1 d . . .
H22 H 1.0746 0.8911 0.0241 0.030 Uiso 1 1 calc
R . .
C23 C 0.96523(19) 1.00542(17) 0.05915(14)
0.0325(6) Uani 1 1 d . . .
H23 H 1.0161 1.0614 0.0544 0.039 Uiso 1 1 calc
R . .
C24 C 0.85718(19) 1.02462(16) 0.08415(14)
0.0334(6) Uani 1 1 d . . .
H24 H 0.8334 1.0940 0.0959 0.040 Uiso 1 1 calc R
. .
C25 C 0.78323(18) 0.94337(16) 0.09222(15)
0.0321(6) Uani 1 1 d . . .
H25 H 0.7089 0.9567 0.1103 0.039 Uiso 1 1 calc R
. .
C26 C 0.81767(16) 0.84271(16) 0.07395(15)
0.0271(5) Uani 1 1 d . . .
H26 H 0.7668 0.7869 0.0797 0.033 Uiso 1 1 calc R
. .
N1 N 0.83959(12) 0.57312(12) -0.02097(12)
0.0220(4) Uani 1 1 d . . .
O1 O 0.73859(10) 0.19485(10) 0.24714(9)
0.0239(3) Uani 1 1 d . . .
O2 O 0.93834(10) 0.64334(10) 0.10419(10)
0.0244(4) Uani 1 1 d . . .
loop_
_atom_site_aniso_label
_atom_site_aniso_U_11
_atom_site_aniso_U_22
_atom_site_aniso_U_33
_atom_site_aniso_U_23
_atom_site_aniso_U_13
_atom_site_aniso_U_12
C1 0.0205(11) 0.0166(12) 0.0239(12) -0.0021(10) -
0.0007(10) 0.0000(10)
C2 0.0209(12) 0.0197(13) 0.0214(12) -0.0001(10) -
0.0059(9) -0.0029(11)
C3 0.0261(13) 0.0188(12) 0.0210(12) 0.0008(10) -
0.0036(9) 0.0032(10)
C4 0.0228(12) 0.0145(12) 0.0228(12) 0.0003(10)
0.0009(10) 0.0007(10)
C5 0.0181(11) 0.0252(14) 0.0265(13) -0.0045(11) -
0.0023(10) -0.0039(11)
C6 0.0210(11) 0.0244(13) 0.0254(12) -0.0003(11) -
0.0048(10) 0.0029(10)
290

C7 0.0311(13) 0.0244(13) 0.0347(13) -
0.0026(11) 0.0077(11) -0.0019(10)
C8 0.0229(12) 0.0225(13) 0.0271(13)
0.0038(11) 0.0025(10) 0.0019(10)
C9 0.0332(13) 0.0232(13) 0.0331(14) -
0.0042(11) 0.0054(11) 0.0026(11)
C10 0.0270(13) 0.0313(15) 0.0440(16)
0.0037(12) 0.0014(11) 0.0056(11)
C11 0.0319(13) 0.0226(13) 0.0313(13)
0.0061(11) -0.0029(11) -0.0009(11)
C12 0.0146(11) 0.0146(12) 0.0341(14) -
0.0031(10) 0.0008(10) 0.0039(9)
C13 0.0232(11) 0.0176(12) 0.0237(12) -
0.0006(9) -0.0026(10) 0.0033(10)
C14 0.0227(12) 0.0198(12) 0.0209(12)
0.0032(10) 0.0044(10) -0.0039(10)
C15 0.0175(11) 0.0216(13) 0.0205(12)
0.0014(10) -0.0018(9) 0.0047(10)
C16 0.0226(12) 0.0208(13) 0.0285(13) -
0.0013(11) -0.0013(10) -0.0010(10)
C17 0.0280(13) 0.0213(13) 0.0381(14) -
0.0138(12) 0.0023(11) -0.0013(11)
C18 0.0217(12) 0.0352(15) 0.0238(13) -
0.0064(11) 0.0010(10) 0.0021(12)
C19 0.0296(13) 0.0268(14) 0.0269(13)
0.0080(11) -0.0029(10) -0.0011(11)
C20 0.0326(13) 0.0180(13) 0.0271(13)
0.0015(11) -0.0012(10) 0.0038(11)
C21 0.0265(12) 0.0194(13) 0.0171(12)
0.0033(9) 0.0011(9) 0.0007(11)
C22 0.0306(13) 0.0204(13) 0.0249(13)
0.0013(10) 0.0045(10) -0.0001(11)
C23 0.0450(15) 0.0228(15) 0.0296(14)
0.0016(11) 0.0040(12) -0.0071(12)
C24 0.0567(17) 0.0179(13) 0.0255(13)
0.0010(11) 0.0079(13) 0.0102(13)
C25 0.0355(13) 0.0308(15) 0.0300(13)
0.0007(12) 0.0117(12) 0.0075(12)
C26 0.0279(13) 0.0211(14) 0.0324(14) 0.0002(10)
0.0037(10) -0.0027(11)
N1 0.0221(10) 0.0200(10) 0.0238(10) -0.0018(9)
0.0016(8) -0.0008(8)
O1 0.0251(8) 0.0176(8) 0.0290(9) 0.0025(7) -
0.0006(7) -0.0024(7)
O2 0.0290(8) 0.0191(9) 0.0251(8) 0.0025(7) -
0.0045(7) -0.0027(7)
_geom_special_details
All esds (except the esd in the dihedral angle
between two l.s. planes)
are estimated using the full covariance matrix. The
cell esds are taken
into account individually in the estimation of esds
in distances, angles
and torsion angles; correlations between esds in
cell parameters are only
used when they are defined by crystal symmetry.
An approximate (isotropic)
treatment of cell esds is used for estimating esds
involving l.s. planes.
loop_
_geom_bond_atom_site_label_1
_geom_bond_atom_site_label_2
_geom_bond_distance
_geom_bond_site_symmetry_2
_geom_bond_publ_flag
C1 C12 1.502(3) . ?
C1 C6 1.510(2) . ?
C1 C7 1.547(2) . ?
C1 C2 1.561(2) . ?
C2 C3 1.513(2) . ?
C2 C8 1.554(2) . ?
C2 H2 1.0000 . ?
C3 C4 1.329(2) . ?
C3 H3 0.9500 . ?
C4 O1 1.383(2) . ?
291

C4 C5 1.454(2) . ?
C5 C6 1.324(2) . ?
C5 H5 0.9500 . ?
C6 H6 0.9500 . ?
C7 H7A 0.9800 . ?
C7 H7B 0.9800 . ?
C7 H7C 0.9800 . ?
C8 C9 1.529(2) . ?
C8 C10 1.536(2) . ?
C8 H8 1.0000 . ?
C9 H9A 0.9800 . ?
C9 H9B 0.9800 . ?
C9 H9C 0.9800 . ?
C10 H10A 0.9800 . ?
C10 H10B 0.9800 . ?
C10 H10C 0.9800 . ?
C11 O1 1.4329(19) . ?
C11 H11A 0.9800 . ?
C11 H11B 0.9800 . ?
C11 H11C 0.9800 . ?
C12 N1 1.268(2) . ?
C12 O2 1.374(2) . ?
C13 N1 1.474(2) . ?
C13 C15 1.520(2) . ?
C13 C14 1.554(2) . ?
C13 H13 1.0000 . ?
C14 O2 1.461(2) . ?
C14 C21 1.507(3) . ?
C14 H14 1.0000 . ?
C15 C16 1.380(2) . ?
C15 C20 1.394(3) . ?
C16 C17 1.392(2) . ?
C16 H16 0.9500 . ?
C17 C18 1.369(3) . ?
C17 H17 0.9500 . ?
C18 C19 1.390(2) . ?
C18 H18 0.9500 . ?
C19 C20 1.376(3) . ?
C19 H19 0.9500 . ?
C20 H20 0.9500 . ?
C21 C26 1.386(2) . ?
C21 C22 1.386(3) . ?
C22 C23 1.388(3) . ?
C22 H22 0.9500 . ?
C23 C24 1.377(3) . ?
C23 H23 0.9500 . ?
C24 C25 1.381(3) . ?
C24 H24 0.9500 . ?
C25 C26 1.382(2) . ?
C25 H25 0.9500 . ?
C26 H26 0.9500 . ?
loop_
_geom_angle_atom_site_label_1
_geom_angle_atom_site_label_2
_geom_angle_atom_site_label_3
_geom_angle
_geom_angle_site_symmetry_1
_geom_angle_site_symmetry_3
_geom_angle_publ_flag
C12 C1 C6 110.12(16) . . ?
C12 C1 C7 108.26(16) . . ?
C6 C1 C7 106.90(15) . . ?
C12 C1 C2 110.71(16) . . ?
C6 C1 C2 111.73(16) . . ?
C7 C1 C2 108.99(16) . . ?
C3 C2 C8 111.65(16) . . ?
C3 C2 C1 110.92(15) . . ?
C8 C2 C1 115.23(15) . . ?
C3 C2 H2 106.1 . . ?
C8 C2 H2 106.1 . . ?
C1 C2 H2 106.1 . . ?
C4 C3 C2 121.02(18) . . ?
C4 C3 H3 119.5 . . ?
C2 C3 H3 119.5 . . ?
C3 C4 O1 126.65(18) . . ?
C3 C4 C5 121.66(19) . . ?
292

O1 C4 C5 111.68(17) . . ?
C6 C5 C4 120.66(19) . . ?
C6 C5 H5 119.7 . . ?
C4 C5 H5 119.7 . . ?
C5 C6 C1 120.88(19) . . ?
C5 C6 H6 119.6 . . ?
C1 C6 H6 119.6 . . ?
C1 C7 H7A 109.5 . . ?
C1 C7 H7B 109.5 . . ?
H7A C7 H7B 109.5 . . ?
C1 C7 H7C 109.5 . . ?
H7A C7 H7C 109.5 . . ?
H7B C7 H7C 109.5 . . ?
C9 C8 C10 109.79(16) . . ?
C9 C8 C2 113.91(16) . . ?
C10 C8 C2 110.66(15) . . ?
C9 C8 H8 107.4 . . ?
C10 C8 H8 107.4 . . ?
C2 C8 H8 107.4 . . ?
C8 C9 H9A 109.5 . . ?
C8 C9 H9B 109.5 . . ?
H9A C9 H9B 109.5 . . ?
C8 C9 H9C 109.5 . . ?
H9A C9 H9C 109.5 . . ?
H9B C9 H9C 109.5 . . ?
C8 C10 H10A 109.5 . . ?
C8 C10 H10B 109.5 . . ?
H10A C10 H10B 109.5 . . ?
C8 C10 H10C 109.5 . . ?
H10A C10 H10C 109.5 . . ?
H10B C10 H10C 109.5 . . ?
O1 C11 H11A 109.5 . . ?
O1 C11 H11B 109.5 . . ?
H11A C11 H11B 109.5 . . ?
O1 C11 H11C 109.5 . . ?
H11A C11 H11C 109.5 . . ?
H11B C11 H11C 109.5 . . ?
N1 C12 O2 118.01(19) . . ?
N1 C12 C1 127.31(19) . . ?
O2 C12 C1 114.68(17) . . ?
N1 C13 C15 113.56(17) . . ?
N1 C13 C14 104.86(15) . . ?
C15 C13 C14 112.70(15) . . ?
N1 C13 H13 108.5 . . ?
C15 C13 H13 108.5 . . ?
C14 C13 H13 108.5 . . ?
O2 C14 C21 110.07(16) . . ?
O2 C14 C13 103.15(14) . . ?
C21 C14 C13 114.77(16) . . ?
O2 C14 H14 109.5 . . ?
C21 C14 H14 109.5 . . ?
C13 C14 H14 109.5 . . ?
C16 C15 C20 118.76(19) . . ?
C16 C15 C13 122.72(18) . . ?
C20 C15 C13 118.51(19) . . ?
C15 C16 C17 119.6(2) . . ?
C15 C16 H16 120.2 . . ?
C17 C16 H16 120.2 . . ?
C18 C17 C16 121.2(2) . . ?
C18 C17 H17 119.4 . . ?
C16 C17 H17 119.4 . . ?
C17 C18 C19 119.62(19) . . ?
C17 C18 H18 120.2 . . ?
C19 C18 H18 120.2 . . ?
C20 C19 C18 119.2(2) . . ?
C20 C19 H19 120.4 . . ?
C18 C19 H19 120.4 . . ?
C19 C20 C15 121.5(2) . . ?
C19 C20 H20 119.2 . . ?
C15 C20 H20 119.2 . . ?
C26 C21 C22 119.3(2) . . ?
C26 C21 C14 120.31(18) . . ?
C22 C21 C14 120.39(17) . . ?
C21 C22 C23 120.11(19) . . ?
C21 C22 H22 119.9 . . ?
C23 C22 H22 119.9 . . ?
293

C24 C23 C22 120.0(2) . . ?
C24 C23 H23 120.0 . . ?
C22 C23 H23 120.0 . . ?
C23 C24 C25 120.2(2) . . ?
C23 C24 H24 119.9 . . ?
C25 C24 H24 119.9 . . ?
C24 C25 C26 119.8(2) . . ?
C24 C25 H25 120.1 . . ?
C26 C25 H25 120.1 . . ?
C25 C26 C21 120.6(2) . . ?
C25 C26 H26 119.7 . . ?
C21 C26 H26 119.7 . . ?
C12 N1 C13 107.43(17) . . ?
C4 O1 C11 115.58(15) . . ?
C12 O2 C14 106.46(14) . . ?
loop_
_geom_torsion_atom_site_label_1
_geom_torsion_atom_site_label_2
_geom_torsion_atom_site_label_3
_geom_torsion_atom_site_label_4
_geom_torsion
_geom_torsion_site_symmetry_1
_geom_torsion_site_symmetry_2
_geom_torsion_site_symmetry_3
_geom_torsion_site_symmetry_4
_geom_torsion_publ_flag
C12 C1 C2 C3 -163.89(16) . . . . ?
C6 C1 C2 C3 -40.8(2) . . . . ?
C7 C1 C2 C3 77.1(2) . . . . ?
C12 C1 C2 C8 -35.8(2) . . . . ?
C6 C1 C2 C8 87.3(2) . . . . ?
C7 C1 C2 C8 -154.78(16) . . . . ?
C8 C2 C3 C4 -101.69(19) . . . . ?
C1 C2 C3 C4 28.3(3) . . . . ?
C2 C3 C4 O1 177.08(16) . . . . ?
C2 C3 C4 C5 -2.3(3) . . . . ?
C3 C4 C5 C6 -10.9(3) . . . . ?
O1 C4 C5 C6 169.62(17) . . . . ?
C4 C5 C6 C1 -5.7(3) . . . . ?
C12 C1 C6 C5 155.26(18) . . . . ?
C7 C1 C6 C5 -87.4(2) . . . . ?
C2 C1 C6 C5 31.8(3) . . . . ?
C3 C2 C8 C9 62.9(2) . . . . ?
C1 C2 C8 C9 -64.8(2) . . . . ?
C3 C2 C8 C10 -61.4(2) . . . . ?
C1 C2 C8 C10 170.93(16) . . . . ?
C6 C1 C12 N1 -13.7(3) . . . . ?
C7 C1 C12 N1 -130.2(2) . . . . ?
C2 C1 C12 N1 110.4(2) . . . . ?
C6 C1 C12 O2 165.72(15) . . . . ?
C7 C1 C12 O2 49.2(2) . . . . ?
C2 C1 C12 O2 -70.2(2) . . . . ?
N1 C13 C14 O2 3.15(19) . . . . ?
C15 C13 C14 O2 -120.85(16) . . . . ?
N1 C13 C14 C21 -116.57(17) . . . . ?
C15 C13 C14 C21 119.43(18) . . . . ?
N1 C13 C15 C16 2.5(3) . . . . ?
C14 C13 C15 C16 121.6(2) . . . . ?
N1 C13 C15 C20 -178.81(17) . . . . ?
C14 C13 C15 C20 -59.8(2) . . . . ?
C20 C15 C16 C17 -0.7(3) . . . . ?
C13 C15 C16 C17 177.94(17) . . . . ?
C15 C16 C17 C18 -0.5(3) . . . . ?
C16 C17 C18 C19 1.9(3) . . . . ?
C17 C18 C19 C20 -2.0(3) . . . . ?
C18 C19 C20 C15 0.8(3) . . . . ?
C16 C15 C20 C19 0.6(3) . . . . ?
C13 C15 C20 C19 -178.16(17) . . . . ?
O2 C14 C21 C26 -57.4(2) . . . . ?
C13 C14 C21 C26 58.4(2) . . . . ?
O2 C14 C21 C22 124.92(17) . . . . ?
C13 C14 C21 C22 -119.28(19) . . . . ?
C26 C21 C22 C23 -1.3(3) . . . . ?
C14 C21 C22 C23 176.39(18) . . . . ?
294

C21 C22 C23 C24 0.4(3) . . . . ?
C22 C23 C24 C25 0.7(3) . . . . ?
C23 C24 C25 C26 -0.8(3) . . . . ?
C24 C25 C26 C21 -0.2(3) . . . . ?
C22 C21 C26 C25 1.3(3) . . . . ?
C14 C21 C26 C25 -176.48(19) . . . . ?
O2 C12 N1 C13 0.7(2) . . . . ?
C1 C12 N1 C13 -179.88(18) . . . . ?
C15 C13 N1 C12 121.00(17) . . . . ?
C14 C13 N1 C12 -2.4(2) . . . . ?
C3 C4 O1 C11 -0.1(3) . . . . ?
C5 C4 O1 C11 179.39(15) . . . . ?
N1 C12 O2 C14 1.5(2) . . . . ?
C1 C12 O2 C14 -178.00(15) . . . . ?
C21 C14 O2 C12 120.13(17) . . . . ?
C13 C14 O2 C12 -2.78(18) . . . . ?
_diffrn_measured_fraction_theta_max
0.970
_diffrn_reflns_theta_full 28.29
_diffrn_measured_fraction_theta_full
0.970
_refine_diff_density_max 0.175
_refine_diff_density_min -0.143
_refine_diff_density_rms 0.035
295

. Compound 102c
Ph
O
N
Ph
Me
102c
OMe
Identification code s2291abs
Empirical formula C26 H29 N O2
Formula weight 387.50
Temperature
100(2) K
Wavelength
0.71073 A
Crystal system, space group Orthorhombic, P2(1)2(1)2(1)
Unit cell dimensions a = 8.2463(6) A alpha = 90 deg.
b = 10.6095(7) A beta = 90 deg.
c = 24.6291(19) A gamma = 90 deg.
Volume
2154.8(3) A^3
Z, Calculated density 4, 1.194 Mg/m^3
Absorption coefficient 0.075 mm^-1
F(000) 832
Crystal size
0.70 x 0.50 x 0.50 mm
Theta range for data collection 1.65 to 26.37 deg.
Limiting indices -10

The structure was solved by the direct methods.
All non-H atoms were refined anisotropically.
H atoms were included in calculated positions.
_chemical_name_common ?
_chemical_melting_point ?
_chemical_formula_moiety ?
_chemical_formula_sum
'C26 H29 N O2'
_chemical_formula_weight 387.50
loop_
_atom_type_symbol
_atom_type_description
_atom_type_scat_dispersion_real
_atom_type_scat_dispersion_imag
_atom_type_scat_source
'C' 'C' 0.0033 0.0016
'International Tables Vol C Tables 4.2.6.8 and
6.1.1.4'
'H' 'H' 0.0000 0.0000
'International Tables Vol C Tables 4.2.6.8 and
6.1.1.4'
'N' 'N' 0.0061 0.0033
'International Tables Vol C Tables 4.2.6.8 and
6.1.1.4'
'O' 'O' 0.0106 0.0060
'International Tables Vol C Tables 4.2.6.8 and
6.1.1.4'
_symmetry_cell_setting Orthorhombic
_symmetry_space_group_name_H-M
P2(1)2(1)2(1)
loop_
_symmetry_equiv_pos_as_xyz
'x, y, z'
'-x+1/2, -y, z+1/2'
'-x, y+1/2, -z+1/2'
'x+1/2, -y+1/2, -z'
_cell_length_a 8.2463(6)
_cell_length_b 10.6095(7)
_cell_length_c 24.6291(19)
_cell_angle_alpha 90.00
_cell_angle_beta 90.00
_cell_angle_gamma 90.00
_cell_volume 2154.8(3)
_cell_formula_units_Z 4
_cell_measurement_temperature 100(2)
_cell_measurement_reflns_used 4494
_cell_measurement_theta_min 2.54
_cell_measurement_theta_max 26.37
_exptl_crystal_description irregular
_exptl_crystal_colour colourless
_exptl_crystal_size_max 0.70
_exptl_crystal_size_mid 0.50
_exptl_crystal_size_min 0.50
_exptl_crystal_density_meas ?
_exptl_crystal_density_diffrn 1.194
_exptl_crystal_density_method 'not measured'
_exptl_crystal_F_000 832
_exptl_absorpt_coefficient_mu 0.075
_exptl_absorpt_correction_type multi-scan
_exptl_absorpt_correction_T_min 0.9497
_exptl_absorpt_correction_T_max 0.9637
_exptl_absorpt_process_details 'SADABS'
_exptl_special_details
_diffrn_ambient_temperature 100(2)
_diffrn_radiation_wavelength 0.71073
_diffrn_radiation_type MoK\a
_diffrn_radiation_source 'fine-focus sealed
tube'
_diffrn_radiation_monochromator graphite
_diffrn_measurement_device_type 'CCD area
detector'
_diffrn_measurement_method 'phi and omega
scans'
_diffrn_detector_area_resol_mean ?
_diffrn_standards_number ?
_diffrn_standards_interval_count ?
297

_diffrn_standards_interval_time ?
_diffrn_standards_decay_% ?
_diffrn_reflns_number 8895
_diffrn_reflns_av_R_equivalents 0.0314
_diffrn_reflns_av_sigmaI/netI 0.0297
_diffrn_reflns_limit_h_min -10
_diffrn_reflns_limit_h_max 6
_diffrn_reflns_limit_k_min -7
_diffrn_reflns_limit_k_max 13
_diffrn_reflns_limit_l_min -30
_diffrn_reflns_limit_l_max 22
_diffrn_reflns_theta_min 1.65
_diffrn_reflns_theta_max 26.37
_reflns_number_total 2509
_reflns_number_gt 2370
_reflns_threshold_expression >2sigma(I)
_computing_data_collection 'Bruker SMART'
_computing_cell_refinement 'Bruker SMART'
_computing_data_reduction 'Bruker SAINT'
_computing_structure_solution 'SHELXS-97
(Sheldrick, 1990)'
_computing_structure_refinement 'SHELXL-97
(Sheldrick, 1997)'
_computing_molecular_graphics 'Bruker
SHELXTL'
_computing_publication_material 'Bruker
SHELXTL'
_refine_special_details
Refinement of F^2^ against ALL reflections. The
weighted R-factor wR and
goodness of fit S are based on F^2^, conventional
R-factors R are based
on F, with F set to zero for negative F^2^. The
threshold expression of
F^2^ > 2sigma(F^2^) is used only for calculating
R-factors(gt) etc. and is
not relevant to the choice of reflections for
refinement. R-factors based
on F^2^ are statistically about twice as large as
those based on F, and R-
factors based on ALL data will be even larger.
_refine_ls_structure_factor_coef Fsqd
_refine_ls_matrix_type full
_refine_ls_weighting_scheme calc
_refine_ls_weighting_details
'calc w=1/[\s^2^(Fo^2^)+(0.0405P)^2^+0.5305P]
where P=(Fo^2^+2Fc^2^)/3'
_atom_sites_solution_primary direct
_atom_sites_solution_secondary difmap
_atom_sites_solution_hydrogens geom
_refine_ls_hydrogen_treatment constr
_refine_ls_extinction_method none
298

_refine_ls_extinction_coef ?
_refine_ls_abs_structure_details
'Flack H D (1983), Acta Cryst. A39, 876-881'
_refine_ls_abs_structure_Flack -0.4(13)
_chemical_absolute_configuration syn
_refine_ls_number_reflns 2509
_refine_ls_number_parameters 266
_refine_ls_number_restraints 0
_refine_ls_R_factor_all 0.0350
_refine_ls_R_factor_gt 0.0326
_refine_ls_wR_factor_ref 0.0820
_refine_ls_wR_factor_gt 0.0802
_refine_ls_goodness_of_fit_ref 1.040
_refine_ls_restrained_S_all 1.040
_refine_ls_shift/su_max 0.001
_refine_ls_shift/su_mean 0.000
loop_
_atom_site_label
_atom_site_type_symbol
_atom_site_fract_x
_atom_site_fract_y
_atom_site_fract_z
_atom_site_U_iso_or_equiv
_atom_site_adp_type
_atom_site_occupancy
_atom_site_symmetry_multiplicity
_atom_site_calc_flag
_atom_site_refinement_flags
_atom_site_disorder_assembly
_atom_site_disorder_group
O1 O 0.74597(16) 1.07720(12) 0.59978(5)
0.0224(3) Uani 1 1 d . . .
O2 O 0.85316(16) 1.21137(12) 0.80110(5)
0.0207(3) Uani 1 1 d . . .
N1 N 0.55197(18) 0.93270(14) 0.61905(6)
0.0183(3) Uani 1 1 d . . .
C1 C 0.6322(2) 1.02851(17) 0.63416(7)
0.0195(4) Uani 1 1 d . . .
C2 C 0.6042(2) 0.90213(16) 0.56341(7) 0.0177(4)
Uani 1 1 d . . .
H2 H 0.5123 0.9197 0.5380 0.021 Uiso 1 1 calc R .
.
C3 C 0.7436(2) 0.99817(16) 0.55146(7) 0.0180(4)
Uani 1 1 d . . .
H3 H 0.8490 0.9522 0.5481 0.022 Uiso 1 1 calc R .
.
C4 C 0.6086(2) 1.10139(17) 0.68643(7) 0.0182(4)
Uani 1 1 d . . .
C5 C 0.7666(2) 1.10303(16) 0.72129(7) 0.0166(3)
Uani 1 1 d . . .
H5 H 0.8392 1.1682 0.7049 0.020 Uiso 1 1 calc R .
.
C6 C 0.7256(2) 1.14878(15) 0.77815(7) 0.0175(4)
Uani 1 1 d . . .
C7 C 0.5818(2) 1.12851(17) 0.80158(7) 0.0194(4)
Uani 1 1 d . . .
H7 H 0.5631 1.1548 0.8379 0.023 Uiso 1 1 calc R .
.
C8 C 0.4539(2) 1.06579(17) 0.77093(7) 0.0208(4)
Uani 1 1 d . . .
H8 H 0.3602 1.0365 0.7895 0.025 Uiso 1 1 calc R .
.
C9 C 0.4653(2) 1.04862(17) 0.71759(7) 0.0205(4)
Uani 1 1 d . . .
H9 H 0.3832 1.0031 0.6989 0.025 Uiso 1 1 calc R .
.
C10 C 0.5667(3) 1.23878(18) 0.67028(7) 0.0254(4)
Uani 1 1 d . . .
H10A H 0.4680 1.2393 0.6481 0.038 Uiso 1 1 calc
R . .
H10B H 0.6566 1.2749 0.6494 0.038 Uiso 1 1 calc
R . .
H10C H 0.5489 1.2891 0.7031 0.038 Uiso 1 1 calc
R . .
C11 C 0.8641(2) 0.97756(16) 0.72155(7) 0.0183(4)
Uani 1 1 d . . .
299

H11 H 0.8924 0.9592 0.6829 0.022 Uiso 1 1 calc
R . .
C12 C 0.7710(2) 0.86323(16) 0.74238(7)
0.0208(4) Uani 1 1 d . . .
H12A H 0.7395 0.8772 0.7803 0.031 Uiso 1 1
calc R . .
H12B H 0.8401 0.7883 0.7400 0.031 Uiso 1 1
calc R . .
H12C H 0.6736 0.8507 0.7202 0.031 Uiso 1 1
calc R . .
C13 C 1.0248(2) 0.99158(18) 0.75205(9)
0.0267(4) Uani 1 1 d . . .
H13A H 1.0905 0.9156 0.7468 0.040 Uiso 1 1
calc R . .
H13B H 1.0032 1.0032 0.7909 0.040 Uiso 1 1
calc R . .
H13C H 1.0837 1.0650 0.7381 0.040 Uiso 1 1
calc R . .
C14 C 0.8279(2) 1.25963(18) 0.85485(7)
0.0229(4) Uani 1 1 d . . .
H14A H 0.8102 1.1894 0.8800 0.034 Uiso 1 1
calc R . .
H14B H 0.7327 1.3149 0.8550 0.034 Uiso 1 1
calc R . .
H14C H 0.9236 1.3076 0.8663 0.034 Uiso 1 1
calc R . .
C15 C 0.6557(2) 0.76646(16) 0.55634(7)
0.0183(4) Uani 1 1 d . . .
C16 C 0.7354(2) 0.70087(18) 0.59737(7)
0.0229(4) Uani 1 1 d . . .
H16 H 0.7541 0.7404 0.6314 0.028 Uiso 1 1 calc
R . .
C17 C 0.7879(3) 0.57792(19) 0.58883(8)
0.0281(4) Uani 1 1 d . . .
H17 H 0.8419 0.5337 0.6171 0.034 Uiso 1 1 calc
R . .
C18 C 0.7618(3) 0.51959(18) 0.53929(9)
0.0292(4) Uani 1 1 d . . .
H18 H 0.7974 0.4355 0.5336 0.035 Uiso 1 1 calc R
. .
C19 C 0.6835(2) 0.58456(19) 0.49813(8) 0.0276(4)
Uani 1 1 d . . .
H19 H 0.6666 0.5452 0.4639 0.033 Uiso 1 1 calc R
. .
C20 C 0.6296(2) 0.70694(18) 0.50665(7) 0.0231(4)
Uani 1 1 d . . .
H20 H 0.5746 0.7504 0.4784 0.028 Uiso 1 1 calc R
. .
C21 C 0.7137(2) 1.07484(16) 0.50097(7) 0.0180(4)
Uani 1 1 d . . .
C22 C 0.7765(2) 1.03311(17) 0.45186(7) 0.0230(4)
Uani 1 1 d . . .
H22 H 0.8464 0.9620 0.4512 0.028 Uiso 1 1 calc R
. .
C23 C 0.7381(3) 1.09433(18) 0.40382(7) 0.0272(4)
Uani 1 1 d . . .
H23 H 0.7804 1.0643 0.3703 0.033 Uiso 1 1 calc R
. .
C24 C 0.6379(3) 1.19955(19) 0.40461(7) 0.0280(4)
Uani 1 1 d . . .
H24 H 0.6108 1.2415 0.3717 0.034 Uiso 1 1 calc R
. .
C25 C 0.5778(3) 1.24278(18) 0.45361(8) 0.0274(4)
Uani 1 1 d . . .
H25 H 0.5107 1.3156 0.4543 0.033 Uiso 1 1 calc R
. .
C26 C 0.6143(2) 1.18102(17) 0.50177(7) 0.0229(4)
Uani 1 1 d . . .
H26 H 0.5716 1.2111 0.5352 0.028 Uiso 1 1 calc R
. . loop_
_atom_site_aniso_label
_atom_site_aniso_U_11
_atom_site_aniso_U_22
_atom_site_aniso_U_33
_atom_site_aniso_U_23
_atom_site_aniso_U_13
300

_atom_site_aniso_U_12
O1 0.0253(7) 0.0262(6) 0.0156(6) -0.0021(5)
0.0016(5) -0.0058(6)
O2 0.0212(6) 0.0213(6) 0.0196(6) -0.0046(5)
0.0022(5) -0.0030(6)
N1 0.0203(7) 0.0189(7) 0.0157(7) -0.0002(6)
0.0029(6) 0.0017(7)
C1 0.0197(8) 0.0227(8) 0.0162(8) 0.0041(7) -
0.0015(7) 0.0051(8)
C2 0.0173(8) 0.0212(9) 0.0146(8) 0.0015(7) -
0.0006(7) -0.0005(7)
C3 0.0191(8) 0.0193(8) 0.0157(8) -0.0022(7) -
0.0003(7) -0.0009(7)
C4 0.0193(9) 0.0195(8) 0.0160(8) 0.0003(7)
0.0005(7) 0.0017(7)
C5 0.0174(8) 0.0161(8) 0.0163(8) 0.0009(7)
0.0019(7) -0.0016(7)
C6 0.0199(9) 0.0145(7) 0.0181(8) 0.0000(7)
0.0000(7) 0.0013(7)
C7 0.0233(9) 0.0205(9) 0.0145(8) -0.0018(7)
0.0027(7) 0.0023(8)
C8 0.0179(8) 0.0214(8) 0.0231(9) -0.0013(7)
0.0040(7) 0.0008(7)
C9 0.0158(8) 0.0226(9) 0.0233(9) -0.0037(7) -
0.0004(7) 0.0015(7)
C10 0.0311(10) 0.0241(9) 0.0210(9) 0.0002(8) -
0.0004(8) 0.0069(9)
C11 0.0179(8) 0.0196(8) 0.0172(8) -0.0039(7)
0.0018(7) 0.0023(7)
C12 0.0241(9) 0.0190(8) 0.0192(8) -0.0001(7)
0.0001(8) 0.0011(8)
C13 0.0197(10) 0.0258(10) 0.0345(10) -
0.0089(8) -0.0030(8) 0.0035(8)
C14 0.0278(10) 0.0228(9) 0.0180(8) -0.0040(7)
-0.0012(7) -0.0019(8)
C15 0.0158(8) 0.0198(9) 0.0193(8) 0.0010(7)
0.0054(7) -0.0039(7)
C16 0.0249(9) 0.0260(9) 0.0178(8) 0.0001(7)
0.0024(8) 0.0028(9)
C17 0.0282(10) 0.0253(9) 0.0306(10) 0.0064(8)
0.0046(8) 0.0046(9)
C18 0.0244(10) 0.0212(9) 0.0421(11) -0.0032(9)
0.0105(9) 0.0012(9)
C19 0.0260(10) 0.0285(10) 0.0282(10) -0.0099(8)
0.0056(8) -0.0048(9)
C20 0.0224(9) 0.0257(9) 0.0211(8) -0.0005(8) -
0.0001(8) -0.0026(8)
C21 0.0189(8) 0.0179(8) 0.0171(8) 0.0008(7) -
0.0006(7) -0.0048(7)
C22 0.0278(10) 0.0197(8) 0.0213(8) 0.0002(7)
0.0022(8) 0.0007(8)
C23 0.0381(11) 0.0268(10) 0.0166(8) 0.0002(7)
0.0036(8) -0.0027(10)
C24 0.0356(11) 0.0263(9) 0.0221(9) 0.0100(8) -
0.0019(8) -0.0037(9)
C25 0.0279(10) 0.0216(9) 0.0326(10) 0.0045(8)
0.0012(8) 0.0021(9)
C26 0.0246(10) 0.0225(9) 0.0217(9) -0.0013(7)
0.0046(8) 0.0000(8)
_geom_special_details
loop_
_geom_bond_atom_site_label_1
_geom_bond_atom_site_label_2
_geom_bond_distance
_geom_bond_site_symmetry_2
_geom_bond_publ_flag
O1 C1 1.365(2) . ?
O1 C3 1.456(2) . ?
O2 C6 1.366(2) . ?
O2 C14 1.434(2) . ?
N1 C1 1.269(2) . ?
N1 C2 1.473(2) . ?
C1 C4 1.514(2) . ?
C2 C15 1.511(2) . ?
C2 C3 1.564(2) . ?
301

C2 H2 1.0000 . ?
C3 C21 1.506(2) . ?
C3 H3 1.0000 . ?
C4 C9 1.516(2) . ?
C4 C10 1.550(3) . ?
C4 C5 1.560(2) . ?
C5 C6 1.520(2) . ?
C5 C11 1.555(2) . ?
C5 H5 1.0000 . ?
C6 C7 1.336(3) . ?
C7 C8 1.458(3) . ?
C7 H7 0.9500 . ?
C8 C9 1.330(3) . ?
C8 H8 0.9500 . ?
C9 H9 0.9500 . ?
C10 H10A 0.9800 . ?
C10 H10B 0.9800 . ?
C10 H10C 0.9800 . ?
C11 C12 1.524(2) . ?
C11 C13 1.531(3) . ?
C11 H11 1.0000 . ?
C12 H12A 0.9800 . ?
C12 H12B 0.9800 . ?
C12 H12C 0.9800 . ?
C13 H13A 0.9800 . ?
C13 H13B 0.9800 . ?
C13 H13C 0.9800 . ?
C14 H14A 0.9800 . ?
C14 H14B 0.9800 . ?
C14 H14C 0.9800 . ?
C15 C16 1.392(3) . ?
C15 C20 1.394(2) . ?
C16 C17 1.390(3) . ?
C16 H16 0.9500 . ?
C17 C18 1.385(3) . ?
C17 H17 0.9500 . ?
C18 C19 1.386(3) . ?
C18 H18 0.9500 . ?
C19 C20 1.388(3) . ?
C19 H19 0.9500 . ?
C20 H20 0.9500 . ?
C21 C22 1.388(2) . ?
C21 C26 1.393(3) . ?
C22 C23 1.386(3) . ?
C22 H22 0.9500 . ?
C23 C24 1.389(3) . ?
C23 H23 0.9500 . ?
C24 C25 1.383(3) . ?
C24 H24 0.9500 . ?
C25 C26 1.388(3) . ?
C25 H25 0.9500 . ?
C26 H26 0.9500 . ?
loop_
_geom_angle_atom_site_label_1
_geom_angle_atom_site_label_2
_geom_angle_atom_site_label_3
_geom_angle
_geom_angle_site_symmetry_1
_geom_angle_site_symmetry_3
_geom_angle_publ_flag
C1 O1 C3 106.24(13) . . ?
C6 O2 C14 116.32(14) . . ?
C1 N1 C2 107.28(14) . . ?
N1 C1 O1 118.65(15) . . ?
N1 C1 C4 126.28(16) . . ?
O1 C1 C4 114.97(15) . . ?
N1 C2 C15 113.53(13) . . ?
N1 C2 C3 104.28(13) . . ?
C15 C2 C3 113.13(14) . . ?
N1 C2 H2 108.6 . . ?
C15 C2 H2 108.6 . . ?
C3 C2 H2 108.6 . . ?
O1 C3 C21 111.48(14) . . ?
O1 C3 C2 103.38(13) . . ?
C21 C3 C2 112.77(14) . . ?
O1 C3 H3 109.7 . . ?
302

C21 C3 H3 109.7 . . ?
C2 C3 H3 109.7 . . ?
C1 C4 C9 109.98(15) . . ?
C1 C4 C10 106.90(14) . . ?
C9 C4 C10 107.64(15) . . ?
C1 C4 C5 111.49(14) . . ?
C9 C4 C5 112.12(14) . . ?
C10 C4 C5 108.48(15) . . ?
C6 C5 C11 112.60(14) . . ?
C6 C5 C4 108.95(14) . . ?
C11 C5 C4 115.11(14) . . ?
C6 C5 H5 106.5 . . ?
C11 C5 H5 106.5 . . ?
C4 C5 H5 106.5 . . ?
C7 C6 O2 125.65(15) . . ?
C7 C6 C5 122.94(16) . . ?
O2 C6 C5 111.41(15) . . ?
C6 C7 C8 119.48(15) . . ?
C6 C7 H7 120.3 . . ?
C8 C7 H7 120.3 . . ?
C9 C8 C7 121.53(17) . . ?
C9 C8 H8 119.2 . . ?
C7 C8 H8 119.2 . . ?
C8 C9 C4 120.30(17) . . ?
C8 C9 H9 119.9 . . ?
C4 C9 H9 119.9 . . ?
C4 C10 H10A 109.5 . . ?
C4 C10 H10B 109.5 . . ?
H10A C10 H10B 109.5 . . ?
C4 C10 H10C 109.5 . . ?
H10A C10 H10C 109.5 . . ?
H10B C10 H10C 109.5 . . ?
C12 C11 C13 110.37(15) . . ?
C12 C11 C5 115.00(14) . . ?
C13 C11 C5 111.50(14) . . ?
C12 C11 H11 106.5 . . ?
C13 C11 H11 106.5 . . ?
C5 C11 H11 106.5 . . ?
C11 C12 H12A 109.5 . . ?
C11 C12 H12B 109.5 . . ?
H12A C12 H12B 109.5 . . ?
C11 C12 H12C 109.5 . . ?
H12A C12 H12C 109.5 . . ?
H12B C12 H12C 109.5 . . ?
C11 C13 H13A 109.5 . . ?
C11 C13 H13B 109.5 . . ?
H13A C13 H13B 109.5 . . ?
C11 C13 H13C 109.5 . . ?
H13A C13 H13C 109.5 . . ?
H13B C13 H13C 109.5 . . ?
O2 C14 H14A 109.5 . . ?
O2 C14 H14B 109.5 . . ?
H14A C14 H14B 109.5 . . ?
O2 C14 H14C 109.5 . . ?
H14A C14 H14C 109.5 . . ?
H14B C14 H14C 109.5 . . ?
C16 C15 C20 118.93(16) . . ?
C16 C15 C2 121.70(15) . . ?
C20 C15 C2 119.29(16) . . ?
C17 C16 C15 120.42(17) . . ?
C17 C16 H16 119.8 . . ?
C15 C16 H16 119.8 . . ?
C18 C17 C16 120.28(19) . . ?
C18 C17 H17 119.9 . . ?
C16 C17 H17 119.9 . . ?
C17 C18 C19 119.65(18) . . ?
C17 C18 H18 120.2 . . ?
C19 C18 H18 120.2 . . ?
C18 C19 C20 120.25(18) . . ?
C18 C19 H19 119.9 . . ?
C20 C19 H19 119.9 . . ?
C19 C20 C15 120.46(18) . . ?
C19 C20 H20 119.8 . . ?
C15 C20 H20 119.8 . . ?
C22 C21 C26 119.32(16) . . ?
C22 C21 C3 119.08(16) . . ?
303

C26 C21 C3 121.41(15) . . ?
C23 C22 C21 120.59(17) . . ?
C23 C22 H22 119.7 . . ?
C21 C22 H22 119.7 . . ?
C22 C23 C24 120.03(17) . . ?
C22 C23 H23 120.0 . . ?
C24 C23 H23 120.0 . . ?
C25 C24 C23 119.47(17) . . ?
C25 C24 H24 120.3 . . ?
C23 C24 H24 120.3 . . ?
C24 C25 C26 120.76(18) . . ?
C24 C25 H25 119.6 . . ?
C26 C25 H25 119.6 . . ?
C25 C26 C21 119.81(17) . . ?
C25 C26 H26 120.1 . . ?
C21 C26 H26 120.1 . . ?
loop_
_geom_torsion_atom_site_label_1
_geom_torsion_atom_site_label_2
_geom_torsion_atom_site_label_3
_geom_torsion_atom_site_label_4
_geom_torsion
_geom_torsion_site_symmetry_1
_geom_torsion_site_symmetry_2
_geom_torsion_site_symmetry_3
_geom_torsion_site_symmetry_4
_geom_torsion_publ_flag
C2 N1 C1 O1 -2.4(2) . . . . ?
C2 N1 C1 C4 173.89(16) . . . . ?
C3 O1 C1 N1 -0.3(2) . . . . ?
C3 O1 C1 C4 -177.07(14) . . . . ?
C1 N1 C2 C15 127.44(16) . . . . ?
C1 N1 C2 C3 3.88(18) . . . . ?
C1 O1 C3 C21 124.14(15) . . . . ?
C1 O1 C3 C2 2.73(17) . . . . ?
N1 C2 C3 O1 -3.96(16) . . . . ?
C15 C2 C3 O1 -127.78(14) . . . . ?
N1 C2 C3 C21 -124.49(15) . . . . ?
C15 C2 C3 C21 111.69(16) . . . . ?
N1 C1 C4 C9 -3.8(2) . . . . ?
O1 C1 C4 C9 172.64(14) . . . . ?
N1 C1 C4 C10 -120.4(2) . . . . ?
O1 C1 C4 C10 56.1(2) . . . . ?
N1 C1 C4 C5 121.23(19) . . . . ?
O1 C1 C4 C5 -62.34(19) . . . . ?
C1 C4 C5 C6 -166.51(14) . . . . ?
C9 C4 C5 C6 -42.70(19) . . . . ?
C10 C4 C5 C6 76.04(17) . . . . ?
C1 C4 C5 C11 -38.9(2) . . . . ?
C9 C4 C5 C11 84.87(18) . . . . ?
C10 C4 C5 C11 -156.39(15) . . . . ?
C14 O2 C6 C7 -0.5(3) . . . . ?
C14 O2 C6 C5 179.64(14) . . . . ?
C11 C5 C6 C7 -98.17(19) . . . . ?
C4 C5 C6 C7 30.8(2) . . . . ?
C11 C5 C6 O2 81.72(18) . . . . ?
C4 C5 C6 O2 -149.32(14) . . . . ?
O2 C6 C7 C8 176.77(16) . . . . ?
C5 C6 C7 C8 -3.4(3) . . . . ?
C6 C7 C8 C9 -12.4(3) . . . . ?
C7 C8 C9 C4 -3.7(3) . . . . ?
C1 C4 C9 C8 156.95(17) . . . . ?
C10 C4 C9 C8 -86.9(2) . . . . ?
C5 C4 C9 C8 32.3(2) . . . . ?
C6 C5 C11 C12 66.75(19) . . . . ?
C4 C5 C11 C12 -58.95(19) . . . . ?
C6 C5 C11 C13 -59.9(2) . . . . ?
C4 C5 C11 C13 174.44(15) . . . . ?
N1 C2 C15 C16 -35.3(2) . . . . ?
C3 C2 C15 C16 83.3(2) . . . . ?
N1 C2 C15 C20 147.76(16) . . . . ?
C3 C2 C15 C20 -93.66(19) . . . . ?
C20 C15 C16 C17 -0.1(3) . . . . ?
C2 C15 C16 C17 -177.07(17) . . . . ?
C15 C16 C17 C18 0.2(3) . . . . ?
C16 C17 C18 C19 0.2(3) . . . . ?
304

C17 C18 C19 C20 -0.8(3) . . . . ?
C18 C19 C20 C15 1.0(3) . . . . ?
C16 C15 C20 C19 -0.5(3) . . . . ?
C2 C15 C20 C19 176.55(17) . . . . ?
O1 C3 C21 C22 151.21(16) . . . . ?
C2 C3 C21 C22 -93.0(2) . . . . ?
O1 C3 C21 C26 -33.8(2) . . . . ?
C2 C3 C21 C26 82.0(2) . . . . ?
C26 C21 C22 C23 -1.5(3) . . . . ?
C3 C21 C22 C23 173.60(18) . . . . ?
C21 C22 C23 C24 1.0(3) . . . . ?
C22 C23 C24 C25 0.3(3) . . . . ?
C23 C24 C25 C26 -1.1(3) . . . . ?
C24 C25 C26 C21 0.5(3) . . . . ?
C22 C21 C26 C25 0.8(3) . . . . ?
C3 C21 C26 C25 -174.24(17) . . . . ?
_diffrn_measured_fraction_theta_max 0.991
_diffrn_reflns_theta_full 26.37
_diffrn_measured_fraction_theta_full 0.991
_refine_diff_density_max 0.245
_refine_diff_density_min -0.155
_refine_diff_density_rms 0.035
305

c. Compound 213
Ph
O
N
Ph
Me
OH
213
OH
Identification code s2494m
Empirical formula C25 H29 N O3
Formula weight 391.49
Temperature
100(2) K
Wavelength
0.71073 A
Crystal system, space group Triclinic, P1
Unit cell dimensions a = 7.8190(18) A alpha = 88.315(4) deg.
b = 10.875(3) A beta = 83.873(5) deg.
c = 12.833(3) A gamma = 85.179(4) deg.
Volume
1080.9(4) A^3
Z, Calculated density 2, 1.203 Mg/m^3
Absorption coefficient 0.078 mm^-1
F(000) 420
Crystal size
0.40 x 0.20 x 0.06 mm
Theta range for data collection 1.60 to 28.26 deg.
Limiting indices -9

Final R indices [I>2sigma(I)] R1 = 0.0574, wR2 = 0.0998
R indices (all data) R1 = 0.1426, wR2 = 0.1223
Absolute structure parameter 0(10)
Largest diff. peak and hole 0.242 and -0.242 e.A^-3
_audit_creation_method SHELXL-97
_chemical_name_systematic
_chemical_name_common ?
_chemical_melting_point ?
_chemical_formula_moiety ?
_chemical_formula_sum
'C25 H29 N O3'
_chemical_formula_weight 391.49
loop_
_atom_type_symbol
_atom_type_description
_atom_type_scat_dispersion_real
_atom_type_scat_dispersion_imag
_atom_type_scat_source
'C' 'C' 0.0033 0.0000
'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4'
'H' 'H' 0.0000 0.0000
'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4'
'N' 'N' 0.0061 0.0000
'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4'
'O' 'O' 0.0106 0.0000
'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4'
_symmetry_cell_setting Triclinic
_symmetry_space_group_name_H-M P1
loop_
_symmetry_equiv_pos_as_xyz
'x, y, z'
_cell_length_a 7.8190(18)
_cell_length_b 10.875(3)
_cell_length_c 12.833(3)
_cell_angle_alpha 88.315(4)
_cell_angle_beta 83.873(5)
_cell_angle_gamma 85.179(4)
307

_cell_volume 1080.9(4)
_cell_formula_units_Z 2
_cell_measurement_temperature 100(2)
_cell_measurement_reflns_used 540
_cell_measurement_theta_min 2.4375
_cell_measurement_theta_max 19.2385
_exptl_crystal_description block
_exptl_crystal_colour white
_exptl_crystal_size_max 0.40
_exptl_crystal_size_mid 0.20
_exptl_crystal_size_min 0.06
_exptl_crystal_density_meas 0
_exptl_crystal_density_diffrn 1.203
_exptl_crystal_density_method 'not measured'
_exptl_crystal_F_000 420
_exptl_absorpt_coefficient_mu 0.078
_exptl_absorpt_correction_type none
_exptl_absorpt_correction_T_min 0.9694
_exptl_absorpt_correction_T_max 0.9953
_exptl_absorpt_process_details ?
_exptl_special_details
_diffrn_ambient_temperature 100(2)
_diffrn_radiation_wavelength 0.71073
_diffrn_radiation_type MoK\a
_diffrn_radiation_source 'fine-focus sealed tube'
_diffrn_radiation_monochromator graphite
_diffrn_measurement_device_type 'CCD area detector'
_diffrn_measurement_method 'phi and omega scans'
_diffrn_detector_area_resol_mean ?
_diffrn_standards_number ?
_diffrn_standards_interval_count ?
_diffrn_standards_interval_time ?
_diffrn_standards_decay_% ?
_diffrn_reflns_number 6697
_diffrn_reflns_av_R_equivalents 0.0699
_diffrn_reflns_av_sigmaI/netI 0.2619
_diffrn_reflns_limit_h_min -9
_diffrn_reflns_limit_h_max 10
308

_diffrn_reflns_limit_k_min -11
_diffrn_reflns_limit_k_max 14
_diffrn_reflns_limit_l_min -17
_diffrn_reflns_limit_l_max 15
_diffrn_reflns_theta_min 1.60
_diffrn_reflns_theta_max 28.26
_reflns_number_total 4736
_reflns_number_gt 1921
_reflns_threshold_expression >2sigma(I)
_computing_data_collection 'Bruker SMART'
_computing_cell_refinement 'Bruker SMART'
_computing_data_reduction 'Bruker SAINT'
_computing_structure_solution 'SIR2004 (Burla et al, 2005)'
_computing_structure_refinement 'SHELXL-97 (Sheldrick, 1997)'
_computing_molecular_graphics 'Bruker SHELXTL'
_computing_publication_material 'Bruker SHELXTL'
_refine_special_details
Refinement of F^2^ against ALL reflections. The weighted R-factor wR and
goodness of fit S are based on F^2^, conventional R-factors R are based
on F, with F set to zero for negative F^2^. The threshold expression of
F^2^ > 2sigma(F^2^) is used only for calculating R-factors(gt) etc. and is
not relevant to the choice of reflections for refinement. R-factors based
on F^2^ are statistically about twice as large as those based on F, and R-
factors based on ALL data will be even larger.
_refine_ls_structure_factor_coef Fsqd
_refine_ls_matrix_type full
_refine_ls_weighting_scheme calc
_refine_ls_weighting_details
'calc w=1/[\s^2^(Fo^2^)+(0.0289P)^2^+0.0000P] where P=(Fo^2^+2Fc^2^)/3'
_atom_sites_solution_primary direct
_atom_sites_solution_secondary difmap
_atom_sites_solution_hydrogens geom
_refine_ls_hydrogen_treatment constr
_refine_ls_extinction_method none
_refine_ls_extinction_coef ?
_refine_ls_abs_structure_details
'Flack H D (1983), Acta Cryst. A39, 876-881'
_refine_ls_abs_structure_Flack 0(10)
309

_refine_ls_number_reflns 4736
_refine_ls_number_parameters 533
_refine_ls_number_restraints 3
_refine_ls_R_factor_all 0.1426
_refine_ls_R_factor_gt 0.0574
_refine_ls_wR_factor_ref 0.1223
_refine_ls_wR_factor_gt 0.0998
_refine_ls_goodness_of_fit_ref 0.718
_refine_ls_restrained_S_all 0.718
_refine_ls_shift/su_max 0.000
_refine_ls_shift/su_mean 0.000
loop_
_atom_site_label
_atom_site_type_symbol
_atom_site_fract_x
_atom_site_fract_y
_atom_site_fract_z
_atom_site_U_iso_or_equiv
_atom_site_adp_type
_atom_site_occupancy
_atom_site_symmetry_multiplicity
_atom_site_calc_flag
_atom_site_refinement_flags
_atom_site_disorder_assembly
_atom_site_disorder_group
C1 C 0.8582(9) 0.1544(6) 0.0767(5) 0.0230(17) Uani 1 1 d . . .
C2 C 0.7980(9) 0.3587(6) 0.0652(5) 0.0245(17) Uani 1 1 d . . .
H2 H 0.6816 0.3882 0.0996 0.029 Uiso 1 1 calc R . .
C3 C 0.9199(9) 0.3238(6) 0.1490(5) 0.0191(16) Uani 1 1 d . . .
H3 H 1.0373 0.3467 0.1206 0.023 Uiso 1 1 calc R . .
C4 C 0.8559(8) 0.0209(6) 0.0415(5) 0.0206(17) Uani 1 1 d . . .
C5 C 0.6691(8) -0.0238(6) 0.0490(5) 0.0186(16) Uani 1 1 d . . .
H5 H 0.6867 -0.1098 0.0221 0.022 Uiso 1 1 calc R . .
C6 C 0.6003(8) -0.0398(6) 0.1629(5) 0.0160(15) Uani 1 1 d . . .
H6 H 0.6043 0.0394 0.1998 0.019 Uiso 1 1 calc R . .
C7 C 0.7098(8) -0.1406(6) 0.2145(5) 0.0184(16) Uani 1 1 d . . .
H7 H 0.6778 -0.2224 0.1926 0.022 Uiso 1 1 calc R . .
C8 C 0.8984(9) -0.1335(6) 0.1865(5) 0.0200(16) Uani 1 1 d . . .
310

H8 H 0.9757 -0.1848 0.2244 0.024 Uiso 1 1 calc R . .
C9 C 0.9635(9) -0.0603(6) 0.1125(5) 0.0229(17) Uani 1 1 d . . .
H9 H 1.0853 -0.0579 0.1025 0.027 Uiso 1 1 calc R . .
C10 C 0.9453(9) 0.0119(7) -0.0695(5) 0.0279(18) Uani 1 1 d . . .
H10A H 1.0618 0.0393 -0.0712 0.042 Uiso 1 1 calc R . .
H10B H 0.8791 0.0645 -0.1168 0.042 Uiso 1 1 calc R . .
H10C H 0.9525 -0.0739 -0.0920 0.042 Uiso 1 1 calc R . .
C11 C 0.5454(9) 0.0443(6) -0.0236(5) 0.0223(17) Uani 1 1 d . . .
H11 H 0.6190 0.0828 -0.0822 0.027 Uiso 1 1 calc R . .
C12 C 0.4243(9) 0.1496(6) 0.0289(5) 0.0264(18) Uani 1 1 d . . .
H12A H 0.3248 0.1149 0.0686 0.040 Uiso 1 1 calc R . .
H12B H 0.3842 0.2073 -0.0251 0.040 Uiso 1 1 calc R . .
H12C H 0.4870 0.1934 0.0765 0.040 Uiso 1 1 calc R . .
C13 C 0.4397(9) -0.0432(7) -0.0725(5) 0.0259(18) Uani 1 1 d . . .
H13A H 0.5167 -0.1032 -0.1143 0.039 Uiso 1 1 calc R . .
H13B H 0.3629 0.0033 -0.1178 0.039 Uiso 1 1 calc R . .
H13C H 0.3707 -0.0868 -0.0173 0.039 Uiso 1 1 calc R . .
C14 C 0.8597(9) 0.4533(6) -0.0172(5) 0.0249(17) Uani 1 1 d . . .
C15 C 0.7715(9) 0.5669(6) -0.0271(5) 0.0305(19) Uani 1 1 d . . .
H15 H 0.6688 0.5886 0.0173 0.037 Uiso 1 1 calc R . .
C16 C 0.8362(11) 0.6506(7) -0.1041(6) 0.042(2) Uani 1 1 d . . .
H16 H 0.7752 0.7291 -0.1119 0.051 Uiso 1 1 calc R . .
C17 C 0.9843(11) 0.6218(7) -0.1680(6) 0.042(2) Uani 1 1 d . . .
H17 H 1.0246 0.6798 -0.2198 0.051 Uiso 1 1 calc R . .
C18 C 1.0751(11) 0.5093(7) -0.1576(6) 0.046(2) Uani 1 1 d . . .
H18 H 1.1790 0.4889 -0.2012 0.055 Uiso 1 1 calc R . .
C19 C 1.0103(10) 0.4241(7) -0.0804(5) 0.035(2) Uani 1 1 d . . .
H19 H 1.0717 0.3459 -0.0722 0.042 Uiso 1 1 calc R . .
C20 C 0.8762(8) 0.3833(6) 0.2535(5) 0.0191(16) Uani 1 1 d . . .
C21 C 0.9035(8) 0.5081(6) 0.2635(5) 0.0257(18) Uani 1 1 d . . .
H21 H 0.9387 0.5557 0.2029 0.031 Uiso 1 1 calc R . .
C22 C 0.8799(9) 0.5617(6) 0.3595(5) 0.0262(18) Uani 1 1 d . . .
H22 H 0.8978 0.6465 0.3647 0.031 Uiso 1 1 calc R . .
C23 C 0.8302(9) 0.4941(7) 0.4495(6) 0.0283(19) Uani 1 1 d . . .
H23 H 0.8204 0.5310 0.5163 0.034 Uiso 1 1 calc R . .
C24 C 0.7947(9) 0.3712(6) 0.4406(5) 0.0270(18) Uani 1 1 d . . .
H24 H 0.7539 0.3250 0.5008 0.032 Uiso 1 1 calc R . .
C25 C 0.8199(8) 0.3175(6) 0.3424(5) 0.0234(17) Uani 1 1 d . . .
311

H25 H 0.7979 0.2335 0.3365 0.028 Uiso 1 1 calc R . .
C26 C 0.2928(9) 0.7886(6) 0.5233(5) 0.0224(17) Uani 1 1 d . . .
C27 C 0.2850(9) 0.5816(6) 0.5312(5) 0.0236(17) Uani 1 1 d . . .
H27 H 0.1826 0.5452 0.5079 0.028 Uiso 1 1 calc R . .
C28 C 0.4031(9) 0.6214(6) 0.4357(5) 0.0210(17) Uani 1 1 d . . .
H28 H 0.5243 0.5916 0.4473 0.025 Uiso 1 1 calc R . .
C29 C 0.2556(8) 0.9190(6) 0.5639(5) 0.0180(16) Uani 1 1 d . . .
C30 C 0.0682(8) 0.9745(6) 0.5535(5) 0.0140(14) Uani 1 1 d . . .
H30 H 0.0647 1.0600 0.5807 0.017 Uiso 1 1 calc R . .
C31 C 0.0448(9) 0.9934(6) 0.4366(5) 0.0225(17) Uani 1 1 d . . .
H31 H 0.0790 0.9140 0.3996 0.027 Uiso 1 1 calc R . .
C32 C 0.1555(9) 1.0903(6) 0.3893(5) 0.0225(17) Uani 1 1 d . . .
H32 H 0.1010 1.1732 0.4115 0.027 Uiso 1 1 calc R . .
C33 C 0.3330(9) 1.0742(6) 0.4230(5) 0.0201(16) Uani 1 1 d . . .
H33 H 0.4182 1.1217 0.3870 0.024 Uiso 1 1 calc R . .
C34 C 0.3810(8) 0.9986(6) 0.4995(5) 0.0198(16) Uani 1 1 d . . .
H34 H 0.4976 0.9939 0.5147 0.024 Uiso 1 1 calc R . .
C35 C 0.2973(9) 0.9194(6) 0.6791(5) 0.0254(18) Uani 1 1 d . . .
H35A H 0.2327 0.8579 0.7203 0.038 Uiso 1 1 calc R . .
H35B H 0.2642 1.0014 0.7081 0.038 Uiso 1 1 calc R . .
H35C H 0.4213 0.8992 0.6818 0.038 Uiso 1 1 calc R . .
C36 C -0.0775(8) 0.9141(6) 0.6224(5) 0.0227(17) Uani 1 1 d . . .
H36 H -0.0242 0.8779 0.6851 0.027 Uiso 1 1 calc R . .
C37 C -0.1550(9) 0.8070(6) 0.5732(6) 0.0305(19) Uani 1 1 d . . .
H37A H -0.2353 0.8402 0.5238 0.046 Uiso 1 1 calc R . .
H37B H -0.2169 0.7587 0.6285 0.046 Uiso 1 1 calc R . .
H37C H -0.0622 0.7539 0.5360 0.046 Uiso 1 1 calc R . .
C38 C -0.2183(8) 1.0112(6) 0.6644(5) 0.0266(18) Uani 1 1 d . . .
H38A H -0.1674 1.0721 0.7038 0.040 Uiso 1 1 calc R . .
H38B H -0.3062 0.9713 0.7106 0.040 Uiso 1 1 calc R . .
H38C H -0.2716 1.0526 0.6056 0.040 Uiso 1 1 calc R . .
C39 C 0.3716(9) 0.4925(6) 0.6067(5) 0.0237(18) Uani 1 1 d . . .
C40 C 0.4876(9) 0.5309(7) 0.6681(5) 0.0303(19) Uani 1 1 d . . .
H40 H 0.5105 0.6154 0.6660 0.036 Uiso 1 1 calc R . .
C41 C 0.5743(10) 0.4474(8) 0.7348(6) 0.043(2) Uani 1 1 d . . .
H41 H 0.6574 0.4743 0.7761 0.052 Uiso 1 1 calc R . .
C42 C 0.5353(12) 0.3248(8) 0.7387(7) 0.053(3) Uani 1 1 d . . .
H42 H 0.5905 0.2676 0.7842 0.064 Uiso 1 1 calc R . .
312

C43 C 0.4196(12) 0.2863(7) 0.6783(6) 0.044(2) Uani 1 1 d . . .
H43 H 0.3968 0.2018 0.6806 0.053 Uiso 1 1 calc R . .
C44 C 0.3335(11) 0.3685(7) 0.6129(6) 0.042(2) Uani 1 1 d . . .
H44 H 0.2495 0.3409 0.5726 0.050 Uiso 1 1 calc R . .
C45 C 0.3663(9) 0.5719(6) 0.3329(5) 0.0224(17) Uani 1 1 d . . .
C46 C 0.3683(8) 0.4458(6) 0.3219(6) 0.0251(18) Uani 1 1 d . . .
H46 H 0.3852 0.3919 0.3802 0.030 Uiso 1 1 calc R . .
C47 C 0.3459(9) 0.3984(7) 0.2269(6) 0.0287(19) Uani 1 1 d . . .
H47 H 0.3464 0.3115 0.2211 0.034 Uiso 1 1 calc R . .
C48 C 0.3228(9) 0.4721(7) 0.1401(6) 0.0309(19) Uani 1 1 d . . .
H48 H 0.3096 0.4371 0.0747 0.037 Uiso 1 1 calc R . .
C49 C 0.3193(9) 0.6005(7) 0.1504(5) 0.0275(18) Uani 1 1 d . . .
H49 H 0.3049 0.6541 0.0916 0.033 Uiso 1 1 calc R . .
C50 C 0.3370(8) 0.6482(6) 0.2479(5) 0.0248(17) Uani 1 1 d . . .
H50 H 0.3289 0.7352 0.2560 0.030 Uiso 1 1 calc R . .
N1 N 0.9268(7) 0.1878(5) 0.1565(4) 0.0210(14) Uani 1 1 d . . .
N2 N 0.3884(7) 0.7580(5) 0.4393(4) 0.0218(14) Uani 1 1 d . . .
O1 O 0.7871(6) 0.2416(4) 0.0124(3) 0.0259(12) Uani 1 1 d . . .
O2 O 0.4253(6) -0.0749(4) 0.1738(4) 0.0214(11) Uani 1 1 d . . .
H2A H 0.3566 -0.0113 0.1727 0.032 Uiso 1 1 calc R . .
O3 O 0.6828(5) -0.1355(4) 0.3286(3) 0.0199(11) Uani 1 1 d . . .
H3A H 0.5795 -0.1467 0.3490 0.030 Uiso 1 1 calc R . .
O4 O 0.2293(6) 0.6976(4) 0.5865(3) 0.0245(12) Uani 1 1 d . . .
O5 O -0.1323(5) 1.0327(4) 0.4216(3) 0.0223(12) Uani 1 1 d . . .
H5A H -0.1509 1.0172 0.3602 0.033 Uiso 1 1 calc R . .
O6 O 0.1779(5) 1.0876(4) 0.2767(3) 0.0213(11) Uani 1 1 d . . .
H6A H 0.2834 1.0747 0.2560 0.032 Uiso 1 1 calc R . .
loop_
_atom_site_aniso_label
_atom_site_aniso_U_11
_atom_site_aniso_U_22
_atom_site_aniso_U_33
_atom_site_aniso_U_23
_atom_site_aniso_U_13
_atom_site_aniso_U_12
C1 0.020(4) 0.026(4) 0.023(4) 0.013(3) -0.003(3) -0.003(3)
C2 0.027(4) 0.021(4) 0.027(4) 0.008(3) -0.007(3) -0.007(3)
C3 0.018(4) 0.021(4) 0.019(4) -0.001(3) -0.003(3) -0.007(3)
313

C4 0.025(4) 0.019(4) 0.018(4) 0.001(3) -0.004(3) -0.005(3)
C5 0.025(4) 0.010(4) 0.023(4) -0.001(3) -0.007(3) -0.005(3)
C6 0.018(4) 0.015(4) 0.015(4) -0.005(3) 0.000(3) -0.003(3)
C7 0.029(4) 0.006(3) 0.021(4) -0.003(3) -0.003(3) 0.000(3)
C8 0.022(4) 0.015(4) 0.024(4) -0.003(3) -0.008(3) 0.001(3)
C9 0.018(4) 0.016(4) 0.035(5) -0.004(3) -0.008(4) 0.006(3)
C10 0.024(4) 0.030(5) 0.029(4) 0.006(4) 0.000(3) -0.003(3)
C11 0.030(4) 0.016(4) 0.022(4) 0.008(3) -0.008(3) -0.002(3)
C12 0.031(4) 0.026(4) 0.021(4) 0.006(3) -0.003(3) 0.001(4)
C13 0.022(4) 0.034(5) 0.021(4) -0.006(3) -0.001(3) 0.002(3)
C14 0.032(5) 0.020(4) 0.024(4) 0.000(3) -0.003(4) -0.008(3)
C15 0.037(5) 0.022(4) 0.030(4) 0.004(4) -0.001(4) 0.005(4)
C16 0.067(7) 0.007(4) 0.050(6) 0.006(4) -0.006(5) 0.005(4)
C17 0.056(6) 0.028(5) 0.038(5) 0.014(4) 0.016(5) -0.009(4)
C18 0.048(6) 0.031(5) 0.054(6) 0.010(4) 0.012(5) -0.004(4)
C19 0.052(6) 0.019(4) 0.027(4) 0.011(3) 0.013(4) 0.012(4)
C20 0.017(4) 0.018(4) 0.023(4) 0.006(3) -0.006(3) -0.004(3)
C21 0.023(4) 0.025(5) 0.028(5) 0.003(4) 0.003(3) -0.002(3)
C22 0.028(5) 0.013(4) 0.036(5) 0.000(4) -0.002(4) 0.004(3)
C23 0.022(4) 0.029(5) 0.035(5) -0.004(4) -0.010(4) 0.001(4)
C24 0.028(5) 0.023(4) 0.027(4) 0.007(3) 0.002(4) 0.002(3)
C25 0.028(4) 0.018(4) 0.025(4) 0.007(3) -0.004(3) -0.002(3)
C26 0.025(4) 0.019(4) 0.023(4) 0.006(3) -0.002(3) -0.001(3)
C27 0.029(4) 0.015(4) 0.026(4) 0.000(3) 0.002(3) -0.002(3)
C28 0.027(4) 0.012(4) 0.023(4) 0.004(3) 0.000(3) 0.001(3)
C29 0.030(4) 0.010(4) 0.014(4) 0.006(3) 0.005(3) -0.008(3)
C30 0.015(4) 0.013(3) 0.015(4) 0.000(3) -0.005(3) -0.002(3)
C31 0.028(4) 0.012(4) 0.028(4) -0.008(3) -0.002(3) 0.000(3)
C32 0.025(4) 0.021(4) 0.022(4) -0.003(3) -0.002(3) -0.002(3)
C33 0.024(4) 0.020(4) 0.017(4) -0.004(3) 0.002(3) -0.009(3)
C34 0.021(4) 0.012(4) 0.028(4) -0.008(3) -0.013(3) 0.000(3)
C35 0.028(5) 0.020(4) 0.029(4) 0.001(3) -0.006(4) -0.002(3)
C36 0.025(4) 0.013(4) 0.030(4) 0.003(3) -0.004(3) 0.000(3)
C37 0.034(5) 0.022(4) 0.036(5) 0.013(4) -0.007(4) -0.004(4)
C38 0.019(4) 0.029(4) 0.034(4) -0.007(4) -0.006(3) -0.002(3)
C39 0.038(5) 0.008(4) 0.023(4) 0.008(3) 0.002(4) -0.003(3)
C40 0.037(5) 0.025(4) 0.030(5) 0.006(4) -0.011(4) 0.001(4)
C41 0.045(6) 0.051(6) 0.031(5) 0.015(4) -0.004(4) 0.004(5)
314

C42 0.072(7) 0.028(5) 0.057(6) 0.013(5) -0.011(5) 0.009(5)
C43 0.071(7) 0.010(4) 0.050(6) 0.002(4) 0.001(5) 0.000(4)
C44 0.065(6) 0.030(5) 0.031(5) 0.000(4) -0.003(4) -0.011(4)
C45 0.023(4) 0.018(4) 0.024(4) -0.001(3) 0.003(3) -0.002(3)
C46 0.021(4) 0.021(4) 0.033(5) 0.006(4) -0.004(4) -0.003(3)
C47 0.034(5) 0.016(4) 0.037(5) -0.008(4) -0.003(4) -0.001(3)
C48 0.020(4) 0.042(5) 0.031(5) -0.013(4) 0.003(4) -0.011(4)
C49 0.029(5) 0.033(5) 0.020(4) 0.003(4) 0.006(3) -0.011(4)
C50 0.018(4) 0.021(4) 0.034(4) 0.002(4) 0.004(3) -0.008(3)
N1 0.026(4) 0.018(3) 0.019(3) 0.005(3) 0.001(3) -0.003(3)
N2 0.029(4) 0.015(3) 0.021(3) 0.000(3) -0.003(3) -0.003(3)
O1 0.038(3) 0.015(3) 0.027(3) 0.007(2) -0.011(2) -0.007(2)
O2 0.020(3) 0.016(3) 0.029(3) -0.002(2) -0.004(2) -0.004(2)
O3 0.021(3) 0.019(3) 0.020(3) 0.006(2) 0.000(2) -0.008(2)
O4 0.026(3) 0.015(3) 0.031(3) 0.005(2) 0.003(2) 0.001(2)
O5 0.018(3) 0.021(3) 0.028(3) 0.001(2) -0.008(2) 0.001(2)
O6 0.018(3) 0.021(3) 0.024(3) 0.000(2) 0.002(2) -0.001(2) _geom_special_details
All esds (except the esd in the dihedral angle between two l.s. planes)
are estimated using the full covariance matrix. The cell esds are taken
into account individually in the estimation of esds in distances, angles
and torsion angles; correlations between esds in cell parameters are only
used when they are defined by crystal symmetry. An approximate (isotropic)
treatment of cell esds is used for estimating esds involving l.s. planes.
315

loop_
_geom_bond_atom_site_label_1
_geom_bond_atom_site_label_2
_geom_bond_distance
_geom_bond_site_symmetry_2
_geom_bond_publ_flag
C1 N1 1.281(8) . ?
C1 O1 1.361(7) . ?
C1 C4 1.535(9) . ?
C2 O1 1.474(7) . ?
C2 C14 1.523(9) . ?
C2 C3 1.530(8) . ?
C2 H2 1.0000 . ?
C3 N1 1.476(8) . ?
C3 C20 1.501(9) . ?
C3 H3 1.0000 . ?
C4 C9 1.519(8) . ?
C4 C10 1.521(9) . ?
C4 C5 1.570(9) . ?
C5 C6 1.513(8) . ?
C5 C11 1.544(8) . ?
C5 H5 1.0000 . ?
C6 O2 1.443(7) . ?
C6 C7 1.514(8) . ?
C6 H6 1.0000 . ?
C7 O3 1.459(6) . ?
C7 C8 1.488(9) . ?
C7 H7 1.0000 . ?
C8 C9 1.310(9) . ?
C8 H8 0.9500 . ?
C9 H9 0.9500 . ?
C10 H10A 0.9800 . ?
C10 H10B 0.9800 . ?
C10 H10C 0.9800 . ?
C11 C13 1.504(9) . ?
C11 C12 1.546(8) . ?
C11 H11 1.0000 . ?
C12 H12A 0.9800 . ?
C12 H12B 0.9800 . ?
C12 H12C 0.9800 . ?
C13 H13A 0.9800 . ?
C13 H13B 0.9800 . ?
C13 H13C 0.9800 . ?
C14 C15 1.373(9) . ?
C14 C19 1.376(9) . ?
C15 C16 1.407(10) . ?
C15 H15 0.9500 . ?
C16 C17 1.365(10) . ?
C16 H16 0.9500 . ?
C17 C18 1.372(10) . ?
C17 H17 0.9500 . ?
C18 C19 1.420(10) . ?
C18 H18 0.9500 . ?
C19 H19 0.9500 . ?
C20 C25 1.381(8) . ?
C20 C21 1.402(9) . ?
C21 C22 1.367(9) . ?
C21 H21 0.9500 . ?
C22 C23 1.388(9) . ?
C22 H22 0.9500 . ?
C23 C24 1.398(9) . ?
C23 H23 0.9500 . ?
C24 C25 1.393(9) . ?
C24 H24 0.9500 . ?
C25 H25 0.9500 . ?
C26 N2 1.280(8) . ?
C26 O4 1.353(8) . ?
C26 C29 1.520(9) . ?
C27 O4 1.477(7) . ?
C27 C39 1.519(9) . ?
C27 C28 1.529(9) . ?
C27 H27 1.0000 . ?
C28 N2 1.482(8) . ?
C28 C45 1.504(9) . ?
C28 H28 1.0000 . ?
C29 C34 1.523(9) . ?
316

C29 C35 1.548(8) . ?
C29 C30 1.554(8) . ?
C30 C31 1.537(8) . ?
C30 C36 1.546(9) . ?
C30 H30 1.0000 . ?
C31 O5 1.446(7) . ?
C31 C32 1.494(9) . ?
C31 H31 1.0000 . ?
C32 O6 1.438(7) . ?
C32 C33 1.493(9) . ?
C32 H32 1.0000 . ?
C33 C34 1.326(8) . ?
C33 H33 0.9500 . ?
C34 H34 0.9500 . ?
C35 H35A 0.9800 . ?
C35 H35B 0.9800 . ?
C35 H35C 0.9800 . ?
C36 C38 1.526(8) . ?
C36 C37 1.538(9) . ?
C36 H36 1.0000 . ?
C37 H37A 0.9800 . ?
C37 H37B 0.9800 . ?
C37 H37C 0.9800 . ?
C38 H38A 0.9800 . ?
C38 H38B 0.9800 . ?
C38 H38C 0.9800 . ?
C39 C40 1.361(9) . ?
C39 C44 1.404(10) . ?
C40 C41 1.412(9) . ?
C40 H40 0.9500 . ?
C41 C42 1.391(11) . ?
C41 H41 0.9500 . ?
C42 C43 1.351(11) . ?
C42 H42 0.9500 . ?
C43 C44 1.391(10) . ?
C43 H43 0.9500 . ?
C44 H44 0.9500 . ?
C45 C50 1.378(9) . ?
C45 C46 1.381(9) . ?
C46 C47 1.371(9) . ?
C46 H46 0.9500 . ?
C47 C48 1.372(10) . ?
C47 H47 0.9500 . ?
C48 C49 1.405(10) . ?
C48 H48 0.9500 . ?
C49 C50 1.394(9) . ?
C49 H49 0.9500 . ?
C50 H50 0.9500 . ?
O2 H2A 0.8400 . ?
O3 H3A 0.8400 . ?
O5 H5A 0.8400 . ?
O6 H6A 0.8400 . ?
loop_
_geom_angle_atom_site_label_1
_geom_angle_atom_site_label_2
_geom_angle_atom_site_label_3
_geom_angle
_geom_angle_site_symmetry_1
_geom_angle_site_symmetry_3
_geom_angle_publ_flag
N1 C1 O1 119.6(6) . . ?
N1 C1 C4 125.5(6) . . ?
O1 C1 C4 114.9(5) . . ?
O1 C2 C14 108.1(5) . . ?
O1 C2 C3 103.8(5) . . ?
C14 C2 C3 115.7(6) . . ?
O1 C2 H2 109.7 . . ?
C14 C2 H2 109.7 . . ?
C3 C2 H2 109.7 . . ?
N1 C3 C20 112.7(5) . . ?
N1 C3 C2 104.5(5) . . ?
C20 C3 C2 116.8(5) . . ?
N1 C3 H3 107.5 . . ?
C20 C3 H3 107.5 . . ?
C2 C3 H3 107.5 . . ?
C9 C4 C10 107.8(5) . . ?
317

C9 C4 C1 107.1(5) . . ?
C10 C4 C1 107.9(6) . . ?
C9 C4 C5 109.3(5) . . ?
C10 C4 C5 111.5(5) . . ?
C1 C4 C5 113.0(5) . . ?
C6 C5 C11 116.7(5) . . ?
C6 C5 C4 109.6(5) . . ?
C11 C5 C4 116.0(5) . . ?
C6 C5 H5 104.3 . . ?
C11 C5 H5 104.3 . . ?
C4 C5 H5 104.3 . . ?
O2 C6 C5 111.7(5) . . ?
O2 C6 C7 107.5(5) . . ?
C5 C6 C7 109.9(5) . . ?
O2 C6 H6 109.2 . . ?
C5 C6 H6 109.2 . . ?
C7 C6 H6 109.2 . . ?
O3 C7 C8 105.6(5) . . ?
O3 C7 C6 111.9(5) . . ?
C8 C7 C6 113.4(5) . . ?
O3 C7 H7 108.6 . . ?
C8 C7 H7 108.6 . . ?
C6 C7 H7 108.6 . . ?
C9 C8 C7 123.5(6) . . ?
C9 C8 H8 118.3 . . ?
C7 C8 H8 118.3 . . ?
C8 C9 C4 124.0(6) . . ?
C8 C9 H9 118.0 . . ?
C4 C9 H9 118.0 . . ?
C4 C10 H10A 109.5 . . ?
C4 C10 H10B 109.5 . . ?
H10A C10 H10B 109.5 . . ?
C4 C10 H10C 109.5 . . ?
H10A C10 H10C 109.5 . . ?
H10B C10 H10C 109.5 . . ?
C13 C11 C5 111.9(5) . . ?
C13 C11 C12 109.3(6) . . ?
C5 C11 C12 114.6(5) . . ?
C13 C11 H11 106.9 . . ?
C5 C11 H11 106.9 . . ?
C12 C11 H11 106.9 . . ?
C11 C12 H12A 109.5 . . ?
C11 C12 H12B 109.5 . . ?
H12A C12 H12B 109.5 . . ?
C11 C12 H12C 109.5 . . ?
H12A C12 H12C 109.5 . . ?
H12B C12 H12C 109.5 . . ?
C11 C13 H13A 109.5 . . ?
C11 C13 H13B 109.5 . . ?
H13A C13 H13B 109.5 . . ?
C11 C13 H13C 109.5 . . ?
H13A C13 H13C 109.5 . . ?
H13B C13 H13C 109.5 . . ?
C15 C14 C19 120.0(7) . . ?
C15 C14 C2 121.5(7) . . ?
C19 C14 C2 118.5(6) . . ?
C14 C15 C16 118.7(7) . . ?
C14 C15 H15 120.7 . . ?
C16 C15 H15 120.7 . . ?
C17 C16 C15 121.7(7) . . ?
C17 C16 H16 119.2 . . ?
C15 C16 H16 119.2 . . ?
C16 C17 C18 120.1(7) . . ?
C16 C17 H17 119.9 . . ?
C18 C17 H17 119.9 . . ?
C17 C18 C19 118.6(7) . . ?
C17 C18 H18 120.7 . . ?
C19 C18 H18 120.7 . . ?
C14 C19 C18 120.9(7) . . ?
C14 C19 H19 119.5 . . ?
C18 C19 H19 119.5 . . ?
C25 C20 C21 118.3(6) . . ?
C25 C20 C3 122.2(6) . . ?
C21 C20 C3 119.4(6) . . ?
C22 C21 C20 120.6(7) . . ?
C22 C21 H21 119.7 . . ?
318

C20 C21 H21 119.7 . . ?
C21 C22 C23 121.1(7) . . ?
C21 C22 H22 119.5 . . ?
C23 C22 H22 119.5 . . ?
C22 C23 C24 119.2(7) . . ?
C22 C23 H23 120.4 . . ?
C24 C23 H23 120.4 . . ?
C25 C24 C23 119.1(7) . . ?
C25 C24 H24 120.4 . . ?
C23 C24 H24 120.4 . . ?
C20 C25 C24 121.6(7) . . ?
C20 C25 H25 119.2 . . ?
C24 C25 H25 119.2 . . ?
N2 C26 O4 118.2(6) . . ?
N2 C26 C29 125.4(6) . . ?
O4 C26 C29 116.1(6) . . ?
O4 C27 C39 108.2(5) . . ?
O4 C27 C28 104.2(5) . . ?
C39 C27 C28 114.9(6) . . ?
O4 C27 H27 109.8 . . ?
C39 C27 H27 109.8 . . ?
C28 C27 H27 109.8 . . ?
N2 C28 C45 113.8(5) . . ?
N2 C28 C27 104.3(5) . . ?
C45 C28 C27 115.1(6) . . ?
N2 C28 H28 107.8 . . ?
C45 C28 H28 107.8 . . ?
C27 C28 H28 107.8 . . ?
C26 C29 C34 106.7(5) . . ?
C26 C29 C35 108.7(5) . . ?
C34 C29 C35 107.6(6) . . ?
C26 C29 C30 113.7(6) . . ?
C34 C29 C30 108.8(5) . . ?
C35 C29 C30 111.1(5) . . ?
C31 C30 C36 116.6(5) . . ?
C31 C30 C29 108.8(5) . . ?
C36 C30 C29 116.6(5) . . ?
C31 C30 H30 104.4 . . ?
C36 C30 H30 104.4 . . ?
C29 C30 H30 104.4 . . ?
O5 C31 C32 107.9(5) . . ?
O5 C31 C30 111.3(5) . . ?
C32 C31 C30 110.1(6) . . ?
O5 C31 H31 109.2 . . ?
C32 C31 H31 109.2 . . ?
C30 C31 H31 109.2 . . ?
O6 C32 C33 105.7(5) . . ?
O6 C32 C31 112.5(6) . . ?
C33 C32 C31 111.9(5) . . ?
O6 C32 H32 108.9 . . ?
C33 C32 H32 108.9 . . ?
C31 C32 H32 108.9 . . ?
C34 C33 C32 125.0(6) . . ?
C34 C33 H33 117.5 . . ?
C32 C33 H33 117.5 . . ?
C33 C34 C29 122.3(6) . . ?
C33 C34 H34 118.8 . . ?
C29 C34 H34 118.8 . . ?
C29 C35 H35A 109.5 . . ?
C29 C35 H35B 109.5 . . ?
H35A C35 H35B 109.5 . . ?
C29 C35 H35C 109.5 . . ?
H35A C35 H35C 109.5 . . ?
H35B C35 H35C 109.5 . . ?
C38 C36 C37 111.2(6) . . ?
C38 C36 C30 111.0(6) . . ?
C37 C36 C30 116.0(5) . . ?
C38 C36 H36 106.0 . . ?
C37 C36 H36 106.0 . . ?
C30 C36 H36 106.0 . . ?
C36 C37 H37A 109.5 . . ?
C36 C37 H37B 109.5 . . ?
H37A C37 H37B 109.5 . . ?
C36 C37 H37C 109.5 . . ?
H37A C37 H37C 109.5 . . ?
H37B C37 H37C 109.5 . . ?
319

C36 C38 H38A 109.5 . . ?
C36 C38 H38B 109.5 . . ?
H38A C38 H38B 109.5 . . ?
C36 C38 H38C 109.5 . . ?
H38A C38 H38C 109.5 . . ?
H38B C38 H38C 109.5 . . ?
C40 C39 C44 119.2(7) . . ?
C40 C39 C27 120.9(6) . . ?
C44 C39 C27 119.9(7) . . ?
C39 C40 C41 121.2(7) . . ?
C39 C40 H40 119.4 . . ?
C41 C40 H40 119.4 . . ?
C42 C41 C40 118.4(8) . . ?
C42 C41 H41 120.8 . . ?
C40 C41 H41 120.8 . . ?
C43 C42 C41 120.7(8) . . ?
C43 C42 H42 119.7 . . ?
C41 C42 H42 119.7 . . ?
C42 C43 C44 121.0(8) . . ?
C42 C43 H43 119.5 . . ?
C44 C43 H43 119.5 . . ?
C43 C44 C39 119.5(8) . . ?
C43 C44 H44 120.2 . . ?
C39 C44 H44 120.2 . . ?
C50 C45 C46 118.9(7) . . ?
C50 C45 C28 122.0(6) . . ?
C46 C45 C28 119.0(6) . . ?
C47 C46 C45 120.0(7) . . ?
C47 C46 H46 120.0 . . ?
C45 C46 H46 120.0 . . ?
C46 C47 C48 122.3(7) . . ?
C46 C47 H47 118.8 . . ?
C48 C47 H47 118.8 . . ?
C47 C48 C49 118.2(7) . . ?
C47 C48 H48 120.9 . . ?
C49 C48 H48 120.9 . . ?
C50 C49 C48 119.1(7) . . ?
C50 C49 H49 120.4 . . ?
C48 C49 H49 120.4 . . ?
C45 C50 C49 121.3(7) . . ?
C45 C50 H50 119.3 . . ?
C49 C50 H50 119.3 . . ?
C1 N1 C3 105.5(5) . . ?
C26 N2 C28 107.3(6) . . ?
C1 O1 C2 104.1(5) . . ?
C6 O2 H2A 109.5 . . ?
C7 O3 H3A 109.5 . . ?
C26 O4 C27 105.7(5) . . ?
C31 O5 H5A 109.5 . . ?
C32 O6 H6A 109.5 . . ?
loop_
_geom_torsion_atom_site_label_1
_geom_torsion_atom_site_label_2
_geom_torsion_atom_site_label_3
_geom_torsion_atom_site_label_4
_geom_torsion
_geom_torsion_site_symmetry_1
_geom_torsion_site_symmetry_2
_geom_torsion_site_symmetry_3
_geom_torsion_site_symmetry_4
_geom_torsion_publ_flag
O1 C2 C3 N1 -15.7(6) . . . . ?
C14 C2 C3 N1 -133.9(6) . . . . ?
O1 C2 C3 C20 -140.9(6) . . . . ?
C14 C2 C3 C20 100.9(7) . . . . ?
N1 C1 C4 C9 -5.2(9) . . . . ?
O1 C1 C4 C9 171.5(6) . . . . ?
N1 C1 C4 C10 -121.1(7) . . . . ?
O1 C1 C4 C10 55.7(7) . . . . ?
N1 C1 C4 C5 115.1(7) . . . . ?
O1 C1 C4 C5 -68.1(7) . . . . ?
C9 C4 C5 C6 48.6(7) . . . . ?
C10 C4 C5 C6 167.7(5) . . . . ?
C1 C4 C5 C6 -70.5(6) . . . . ?
C9 C4 C5 C11 -176.5(5) . . . . ?
C10 C4 C5 C11 -57.4(7) . . . . ?
320

C1 C4 C5 C11 64.4(7) . . . . ?
C11 C5 C6 O2 42.6(7) . . . . ?
C4 C5 C6 O2 177.1(5) . . . . ?
C11 C5 C6 C7 161.8(5) . . . . ?
C4 C5 C6 C7 -63.7(6) . . . . ?
O2 C6 C7 O3 -75.2(6) . . . . ?
C5 C6 C7 O3 163.1(5) . . . . ?
O2 C6 C7 C8 165.4(5) . . . . ?
C5 C6 C7 C8 43.7(7) . . . . ?
O3 C7 C8 C9 -133.1(7) . . . . ?
C6 C7 C8 C9 -10.2(9) . . . . ?
C7 C8 C9 C4 -3.8(10) . . . . ?
C10 C4 C9 C8 -137.2(7) . . . . ?
C1 C4 C9 C8 106.9(8) . . . . ?
C5 C4 C9 C8 -15.8(9) . . . . ?
C6 C5 C11 C13 -90.0(7) . . . . ?
C4 C5 C11 C13 138.3(6) . . . . ?
C6 C5 C11 C12 35.1(8) . . . . ?
C4 C5 C11 C12 -96.5(7) . . . . ?
O1 C2 C14 C15 127.8(7) . . . . ?
C3 C2 C14 C15 -116.5(7) . . . . ?
O1 C2 C14 C19 -54.2(8) . . . . ?
C3 C2 C14 C19 61.6(9) . . . . ?
C19 C14 C15 C16 1.4(11) . . . . ?
C2 C14 C15 C16 179.4(6) . . . . ?
C14 C15 C16 C17 -0.6(12) . . . . ?
C15 C16 C17 C18 -0.5(13) . . . . ?
C16 C17 C18 C19 0.8(13) . . . . ?
C15 C14 C19 C18 -1.1(12) . . . . ?
C2 C14 C19 C18 -179.2(7) . . . . ?
C17 C18 C19 C14 0.0(12) . . . . ?
N1 C3 C20 C25 -10.5(9) . . . . ?
C2 C3 C20 C25 110.5(7) . . . . ?
N1 C3 C20 C21 165.3(6) . . . . ?
C2 C3 C20 C21 -73.7(8) . . . . ?
C25 C20 C21 C22 2.0(10) . . . . ?
C3 C20 C21 C22 -174.0(6) . . . . ?
C20 C21 C22 C23 0.6(10) . . . . ?
C21 C22 C23 C24 -3.5(10) . . . . ?
C22 C23 C24 C25 3.7(10) . . . . ?
C21 C20 C25 C24 -1.7(10) . . . . ?
C3 C20 C25 C24 174.1(6) . . . . ?
C23 C24 C25 C20 -1.1(10) . . . . ?
O4 C27 C28 N2 -6.0(6) . . . . ?
C39 C27 C28 N2 -124.2(6) . . . . ?
O4 C27 C28 C45 -131.4(6) . . . . ?
C39 C27 C28 C45 110.4(7) . . . . ?
N2 C26 C29 C34 -11.6(9) . . . . ?
O4 C26 C29 C34 163.0(5) . . . . ?
N2 C26 C29 C35 -127.3(7) . . . . ?
O4 C26 C29 C35 47.3(8) . . . . ?
N2 C26 C29 C30 108.4(7) . . . . ?
O4 C26 C29 C30 -77.0(7) . . . . ?
C26 C29 C30 C31 -67.1(7) . . . . ?
C34 C29 C30 C31 51.7(7) . . . . ?
C35 C29 C30 C31 169.9(5) . . . . ?
C26 C29 C30 C36 67.2(7) . . . . ?
C34 C29 C30 C36 -174.0(5) . . . . ?
C35 C29 C30 C36 -55.8(7) . . . . ?
C36 C30 C31 O5 39.7(7) . . . . ?
C29 C30 C31 O5 174.0(5) . . . . ?
C36 C30 C31 C32 159.3(5) . . . . ?
C29 C30 C31 C32 -66.4(7) . . . . ?
O5 C31 C32 O6 -75.2(6) . . . . ?
C30 C31 C32 O6 163.2(5) . . . . ?
O5 C31 C32 C33 166.0(5) . . . . ?
C30 C31 C32 C33 44.4(7) . . . . ?
O6 C32 C33 C34 -134.3(6) . . . . ?
C31 C32 C33 C34 -11.6(9) . . . . ?
C32 C33 C34 C29 -0.8(10) . . . . ?
C26 C29 C34 C33 103.1(7) . . . . ?
C35 C29 C34 C33 -140.4(6) . . . . ?
C30 C29 C34 C33 -20.0(9) . . . . ?
C31 C30 C36 C38 -87.8(7) . . . . ?
C29 C30 C36 C38 141.4(6) . . . . ?
C31 C30 C36 C37 40.3(8) . . . . ?
321

C29 C30 C36 C37 -90.4(7) . . . . ?
O4 C27 C39 C40 -44.7(9) . . . . ?
C28 C27 C39 C40 71.2(8) . . . . ?
O4 C27 C39 C44 136.0(7) . . . . ?
C28 C27 C39 C44 -108.1(8) . . . . ?
C44 C39 C40 C41 2.3(11) . . . . ?
C27 C39 C40 C41 -177.1(7) . . . . ?
C39 C40 C41 C42 -1.7(11) . . . . ?
C40 C41 C42 C43 1.3(12) . . . . ?
C41 C42 C43 C44 -1.6(13) . . . . ?
C42 C43 C44 C39 2.2(13) . . . . ?
C40 C39 C44 C43 -2.5(12) . . . . ?
C27 C39 C44 C43 176.8(7) . . . . ?
N2 C28 C45 C50 5.5(10) . . . . ?
C27 C28 C45 C50 125.8(7) . . . . ?
N2 C28 C45 C46 -177.1(6) . . . . ?
C27 C28 C45 C46 -56.8(8) . . . . ?
C50 C45 C46 C47 1.7(11) . . . . ?
C28 C45 C46 C47 -175.9(6) . . . . ?
C45 C46 C47 C48 0.7(11) . . . . ?
C46 C47 C48 C49 -1.1(11) . . . . ?
C47 C48 C49 C50 -0.8(11) . . . . ?
C46 C45 C50 C49 -3.6(11) . . . . ?
C28 C45 C50 C49 173.8(6) . . . . ?
C48 C49 C50 C45 3.2(11) . . . . ?
O1 C1 N1 C3 -4.9(9) . . . . ?
C4 C1 N1 C3 171.7(6) . . . . ?
C20 C3 N1 C1 140.6(6) . . . . ?
C2 C3 N1 C1 12.8(7) . . . . ?
O4 C26 N2 C28 -0.2(8) . . . . ?
C29 C26 N2 C28 174.3(6) . . . . ?
C45 C28 N2 C26 130.2(6) . . . . ?
C27 C28 N2 C26 4.0(7) . . . . ?
N1 C1 O1 C2 -5.6(8) . . . . ?
C4 C1 O1 C2 177.5(5) . . . . ?
C14 C2 O1 C1 136.2(6) . . . . ?
C3 C2 O1 C1 12.9(6) . . . . ?
N2 C26 O4 C27 -3.9(8) . . . . ?
C29 C26 O4 C27 -178.9(5) . . . . ?
C39 C27 O4 C26 128.6(6) . . . . ?
C28 C27 O4 C26 5.9(6) . . . . ?
loop_
_geom_hbond_atom_site_label_D
_geom_hbond_atom_site_label_H
_geom_hbond_atom_site_label_A
_geom_hbond_distance_DH
_geom_hbond_distance_HA
_geom_hbond_distance_DA
_geom_hbond_angle_DHA
_geom_hbond_site_symmetry_A
O2 H2A O6 0.84 2.08 2.761(6) 137.9 1_545
O3 H3A N2 0.84 2.11 2.883(7) 152.0 1_545
O6 H6A O2 0.84 2.13 2.761(6) 131.7 1_565
O5 H5A O3 0.84 2.26 2.793(6) 121.1 1_465
_diffrn_measured_fraction_theta_max 0.884
_diffrn_reflns_theta_full 28.26
_diffrn_measured_fraction_theta_full 0.884
_refine_diff_density_max 0.242
_refine_diff_density_min -0.242
_refine_diff_density_rms 0.055
322

d. Compound 278
HO
OH
HO
OH
278
OH
Identification code s2760m
Empirical formula C11 H24 O6
Formula weight 252.30
Temperature
100(2) K
Wavelength
0.71073 A
Crystal system, space group Monoclinic, P21
Unit cell dimensions a = 11.603(2) A alpha = 90 deg.
b = 8.0007(16) A beta = 106.896(4) deg.
c = 14.488(3) A gamma = 90 deg.
Volume
1286.9(4) A^3
Z, Calculated density 4, 1.302 Mg/m^3
Absorption coefficient 0.105 mm^-1
F(000) 552
Crystal size
0.20 x 0.10 x 0.04 mm
Theta range for data collection 1.83 to 25.02 deg.
Limiting indices -13

The structure was solved by the direct methods
and there are two molecules in the asymmetric unit.
All non-H atoms were refined anisotropically.
H atoms were included in calculated positions.
The absolute configuration was input.
_chemical_formula_sum
'C11 H24 O6'
_chemical_formula_weight 252.30
loop_
_atom_type_symbol
_atom_type_description
_atom_type_scat_dispersion_real
_atom_type_scat_dispersion_imag
_atom_type_scat_source
'C' 'C' 0.0033 0.0016
'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4'
'H' 'H' 0.0000 0.0000
'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4'
'O' 'O' 0.0106 0.0060
'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4'
_symmetry_cell_setting Monoclinic
_symmetry_space_group_name_H-M P21
loop_
_symmetry_equiv_pos_as_xyz
'x, y, z'
'-x, y+1/2, -z'
_cell_length_a 11.603(2)
_cell_length_b 8.0007(16)
_cell_length_c 14.488(3)
_cell_angle_alpha 90.00
_cell_angle_beta 106.896(4)
_cell_angle_gamma 90.00
_cell_volume 1286.9(4)
_cell_formula_units_Z 4
_cell_measurement_temperature 100(2)
_cell_measurement_reflns_used 673
_cell_measurement_theta_min 2.94
_cell_measurement_theta_max 23.62
324

_exptl_crystal_description plate
_exptl_crystal_colour colourless
_exptl_crystal_size_max 0.20
_exptl_crystal_size_mid 0.10
_exptl_crystal_size_min 0.04
_exptl_crystal_density_meas ?
_exptl_crystal_density_diffrn 1.302
_exptl_crystal_density_method 'not measured'
_exptl_crystal_F_000 552
_exptl_absorpt_coefficient_mu 0.105
_exptl_absorpt_correction_type none
_exptl_absorpt_correction_T_min ?
_exptl_absorpt_correction_T_max ?
_exptl_absorpt_process_details ?
_exptl_special_details
_diffrn_ambient_temperature 100(2)
_diffrn_radiation_wavelength 0.71073
_diffrn_radiation_type MoK\a
_diffrn_radiation_source 'fine-focus sealed tube'
_diffrn_radiation_monochromator graphite
_diffrn_measurement_device_type 'CCD area detector'
_diffrn_measurement_method 'phi and omega scans'
_diffrn_detector_area_resol_mean ?
_diffrn_standards_number ?
_diffrn_standards_interval_count ?
_diffrn_standards_interval_time ?
_diffrn_standards_decay_% ?
_diffrn_reflns_number 8740
_diffrn_reflns_av_R_equivalents 0.0738
_diffrn_reflns_av_sigmaI/netI 0.0742
_diffrn_reflns_limit_h_min -13
_diffrn_reflns_limit_h_max 13
_diffrn_reflns_limit_k_min -9
_diffrn_reflns_limit_k_max 9
_diffrn_reflns_limit_l_min -17
_diffrn_reflns_limit_l_max 16
_diffrn_reflns_theta_min 1.83
_diffrn_reflns_theta_max 25.02
325

_reflns_number_total 2447
_reflns_number_gt 2122
_reflns_threshold_expression >2sigma(I)
_computing_data_collection 'Bruker SMART'
_computing_cell_refinement 'Bruker SMART'
_computing_data_reduction 'Bruker SAINT'
_computing_structure_solution 'SHELXS-97 (Sheldrick, 1990)'
_computing_structure_refinement 'SHELXL-97 (Sheldrick, 1997)'
_computing_molecular_graphics 'Bruker SHELXTL'
_computing_publication_material 'Bruker SHELXTL'
_refine_special_details
Refinement of F^2^ against ALL reflections. The weighted R-factor wR and
goodness of fit S are based on F^2^, conventional R-factors R are based
on F, with F set to zero for negative F^2^. The threshold expression of
F^2^ > 2sigma(F^2^) is used only for calculating R-factors(gt) etc. and is
not relevant to the choice of reflections for refinement. R-factors based
on F^2^ are statistically about twice as large as those based on F, and R-
factors based on ALL data will be even larger.
_refine_ls_structure_factor_coef Fsqd
_refine_ls_matrix_type full
_refine_ls_weighting_scheme calc
_refine_ls_weighting_details
'calc w=1/[\s^2^(Fo^2^)+(0.0259P)^2^+0.4529P] where P=(Fo^2^+2Fc^2^)/3'
_atom_sites_solution_primary direct
_atom_sites_solution_secondary difmap
_atom_sites_solution_hydrogens geom
_chemical_absolute_configuration syn
_refine_ls_hydrogen_treatment mixed
_refine_ls_extinction_method none
_refine_ls_extinction_coef ?
_refine_ls_number_reflns 2447
_refine_ls_number_parameters 339
_refine_ls_number_restraints 1
_refine_ls_R_factor_all 0.0721
_refine_ls_R_factor_gt 0.0592
_refine_ls_wR_factor_ref 0.1045
_refine_ls_wR_factor_gt 0.1006
_refine_ls_goodness_of_fit_ref 1.154
326

_refine_ls_restrained_S_all 1.154
_refine_ls_shift/su_max 0.000
_refine_ls_shift/su_mean 0.000
loop_
_atom_site_label
_atom_site_type_symbol
_atom_site_fract_x
_atom_site_fract_y
_atom_site_fract_z
_atom_site_U_iso_or_equiv
_atom_site_adp_type
_atom_site_occupancy
_atom_site_symmetry_multiplicity
_atom_site_calc_flag
_atom_site_refinement_flags
_atom_site_disorder_assembly
_atom_site_disorder_group
O1 O 1.2534(3) 0.8414(5) 1.1873(2) 0.0274(9) Uani 1 1 d . . .
H1 H 1.3159 0.8625 1.2323 0.041 Uiso 1 1 calc R . .
O2 O 0.7867(3) 0.6097(4) 1.2036(3) 0.0189(8) Uani 1 1 d . . .
H2 H 0.7921 0.5052 1.2085 0.028 Uiso 1 1 calc R . .
O3 O 0.7790(3) 0.6641(4) 1.0083(2) 0.0198(8) Uani 1 1 d . . .
H3 H 0.7053 0.6879 0.9927 0.030 Uiso 1 1 calc R . .
O4 O 0.8975(3) 0.9572(4) 0.9708(2) 0.0228(8) Uani 1 1 d . . .
H4 H 0.8385 0.9090 0.9325 0.034 Uiso 1 1 calc R . .
O5 O 0.9383(3) 1.1074(4) 1.1463(2) 0.0181(8) Uani 1 1 d . . .
H5 H 0.9076 1.1543 1.0930 0.027 Uiso 1 1 calc R . .
C1 C 1.0655(4) 0.8838(6) 1.2325(3) 0.0150(11) Uani 1 1 d . . .
C2 C 0.9646(4) 0.7839(6) 1.2604(3) 0.0169(11) Uani 1 1 d . . .
H2A H 0.9076 0.8709 1.2707 0.020 Uiso 1 1 calc R . .
C3 C 0.8888(4) 0.6744(6) 1.1774(3) 0.0160(11) Uani 1 1 d . . .
H3A H 0.9391 0.5790 1.1668 0.019 Uiso 1 1 calc R . .
C4 C 0.8435(4) 0.7719(6) 1.0851(3) 0.0152(11) Uani 1 1 d . . .
H4A H 0.7867 0.8598 1.0947 0.018 Uiso 1 1 calc R . .
C5 C 0.9429(4) 0.8564(6) 1.0555(3) 0.0189(12) Uani 1 1 d . . .
H5A H 0.9979 0.7692 1.0424 0.023 Uiso 1 1 calc R . .
C6 C 1.0152(4) 0.9726(6) 1.1341(3) 0.0159(10) Uani 1 1 d . . .
H6 H 1.0839 1.0201 1.1139 0.019 Uiso 1 1 calc R . .
327

C7 C 1.1671(4) 0.7629(7) 1.2254(4) 0.0242(12) Uani 1 1 d . . .
H7A H 1.2084 0.7187 1.2905 0.029 Uiso 1 1 calc R . .
H7B H 1.1309 0.6671 1.1838 0.029 Uiso 1 1 calc R . .
C8 C 1.1195(4) 1.0188(6) 1.3087(3) 0.0199(12) Uani 1 1 d . . .
H8A H 1.0544 1.0848 1.3210 0.030 Uiso 1 1 calc R . .
H8B H 1.1722 1.0922 1.2848 0.030 Uiso 1 1 calc R . .
H8C H 1.1664 0.9651 1.3686 0.030 Uiso 1 1 calc R . .
C9 C 1.0102(5) 0.6905(6) 1.3590(3) 0.0200(12) Uani 1 1 d . . .
H9 H 1.0862 0.7472 1.3965 0.024 Uiso 1 1 calc R . .
C10 C 1.0415(4) 0.5043(7) 1.3499(3) 0.0231(12) Uani 1 1 d . . .
H10A H 0.9672 0.4406 1.3230 0.035 Uiso 1 1 calc R . .
H10B H 1.0842 0.4602 1.4138 0.035 Uiso 1 1 calc R . .
H10C H 1.0930 0.4943 1.3072 0.035 Uiso 1 1 calc R . .
C11 C 0.9215(5) 0.7050(7) 1.4181(3) 0.0289(14) Uani 1 1 d . . .
H11A H 0.9549 0.6495 1.4805 0.043 Uiso 1 1 calc R . .
H11B H 0.8452 0.6517 1.3833 0.043 Uiso 1 1 calc R . .
H11C H 0.9073 0.8233 1.4287 0.043 Uiso 1 1 calc R . .
O6 O 0.5233(3) 0.4657(4) 0.7296(2) 0.0178(8) Uani 1 1 d . . .
H6A H 0.5004 0.3934 0.7625 0.027 Uiso 1 1 calc R . .
O7 O 0.6153(3) 0.9803(4) 0.8264(2) 0.0183(8) Uani 1 1 d . . .
H7 H 0.5740 1.0656 0.8285 0.027 Uiso 1 1 calc R . .
O8 O 0.5623(3) 0.8147(4) 0.9779(2) 0.0154(7) Uani 1 1 d . . .
H8 H 0.5943 0.9097 0.9890 0.023 Uiso 1 1 calc R . .
O9 O 0.3635(3) 0.6085(4) 0.9470(2) 0.0147(8) Uani 1 1 d . . .
H9A H 0.3120 0.6807 0.9497 0.022 Uiso 1 1 calc R . .
O10 O 0.2212(3) 0.7613(4) 0.7757(2) 0.0151(7) Uani 1 1 d . . .
H10 H 0.1677 0.7116 0.7937 0.023 Uiso 1 1 calc R . .
C12 C 0.3608(4) 0.6857(6) 0.6852(3) 0.0164(11) Uani 1 1 d . . .
C13 C 0.4427(4) 0.8464(6) 0.7063(3) 0.0152(11) Uani 1 1 d . . .
H13 H 0.3883 0.9411 0.7107 0.018 Uiso 1 1 calc R . .
C14 C 0.5389(4) 0.8370(6) 0.8059(3) 0.0172(11) Uani 1 1 d . . .
H14 H 0.5903 0.7365 0.8063 0.021 Uiso 1 1 calc R . .
C15 C 0.4759(4) 0.8137(6) 0.8835(3) 0.0130(10) Uani 1 1 d . . .
H15 H 0.4162 0.9058 0.8790 0.016 Uiso 1 1 calc R . .
C16 C 0.4122(4) 0.6481(6) 0.8703(3) 0.0148(11) Uani 1 1 d . . .
H16 H 0.4728 0.5601 0.8690 0.018 Uiso 1 1 calc R . .
C17 C 0.3148(4) 0.6441(6) 0.7724(3) 0.0132(11) Uani 1 1 d . . .
H17 H 0.2789 0.5295 0.7628 0.016 Uiso 1 1 calc R . .
328

C18 C 0.4218(4) 0.5303(6) 0.6578(3) 0.0154(11) Uani 1 1 d . . .
H18A H 0.3607 0.4405 0.6392 0.018 Uiso 1 1 calc R . .
H18B H 0.4474 0.5579 0.6001 0.018 Uiso 1 1 calc R . .
C19 C 0.2507(4) 0.7174(7) 0.5978(3) 0.0194(12) Uani 1 1 d . . .
H19A H 0.2749 0.7122 0.5385 0.029 Uiso 1 1 calc R . .
H19B H 0.2174 0.8282 0.6035 0.029 Uiso 1 1 calc R . .
H19C H 0.1894 0.6321 0.5957 0.029 Uiso 1 1 calc R . .
C20 C 0.4964(5) 0.8919(6) 0.6218(3) 0.0174(11) Uani 1 1 d . . .
H20 H 0.4419 0.8422 0.5615 0.021 Uiso 1 1 calc R . .
C21 C 0.6229(4) 0.8220(7) 0.6336(3) 0.0223(12) Uani 1 1 d . . .
H21A H 0.6798 0.8722 0.6905 0.033 Uiso 1 1 calc R . .
H21B H 0.6477 0.8486 0.5761 0.033 Uiso 1 1 calc R . .
H21C H 0.6222 0.7004 0.6418 0.033 Uiso 1 1 calc R . .
C22 C 0.4955(5) 1.0817(6) 0.6070(4) 0.0247(13) Uani 1 1 d . . .
H22A H 0.5219 1.1073 0.5501 0.037 Uiso 1 1 calc R . .
H22B H 0.5504 1.1346 0.6639 0.037 Uiso 1 1 calc R . .
H22C H 0.4138 1.1246 0.5974 0.037 Uiso 1 1 calc R . .
O1S O 0.7845(3) 0.3209(5) 1.0057(3) 0.0216(8) Uani 1 1 d . . .
H1S H 0.791(5) 0.416(7) 1.018(4) 0.03(2) Uiso 1 1 d . . .
H2S H 0.763(4) 0.316(7) 0.940(4) 0.029(15) Uiso 1 1 d . . .
O2S O 0.4449(3) 0.2330(4) 0.8381(2) 0.0173(8) Uani 1 1 d . . .
H3S H 0.468(5) 0.250(8) 0.905(4) 0.046(18) Uiso 1 1 d . . .
H4S H 0.365(7) 0.202(10) 0.827(5) 0.09(3) Uiso 1 1 d . . .
loop_
_atom_site_aniso_label
_atom_site_aniso_U_11
_atom_site_aniso_U_22
_atom_site_aniso_U_33
_atom_site_aniso_U_23
_atom_site_aniso_U_13
_atom_site_aniso_U_12
O1 0.0199(19) 0.039(2) 0.0234(19) -0.0002(19) 0.0067(16) -0.0021(19)
O2 0.0159(18) 0.0124(18) 0.029(2) 0.0049(17) 0.0068(15) 0.0012(16)
O3 0.0153(19) 0.020(2) 0.0212(19) -0.0045(15) 0.0004(16) 0.0009(16)
O4 0.028(2) 0.024(2) 0.0145(17) -0.0005(16) 0.0029(15) -0.0070(17)
O5 0.023(2) 0.0145(18) 0.0190(18) 0.0035(15) 0.0103(16) 0.0046(16)
C1 0.013(2) 0.013(3) 0.018(3) -0.002(2) 0.003(2) -0.002(2)
C2 0.014(3) 0.014(3) 0.021(3) 0.006(2) 0.004(2) 0.008(2)
329

C3 0.015(3) 0.016(3) 0.021(3) -0.002(2) 0.012(2) -0.002(2)
C4 0.015(2) 0.019(3) 0.011(2) -0.004(2) 0.003(2) 0.000(2)
C5 0.028(3) 0.016(3) 0.017(3) 0.002(2) 0.012(2) -0.001(2)
C6 0.017(3) 0.013(3) 0.020(3) -0.001(2) 0.009(2) -0.001(2)
C7 0.016(3) 0.027(3) 0.030(3) 0.009(3) 0.008(2) 0.001(2)
C8 0.022(3) 0.016(3) 0.021(3) -0.002(2) 0.006(2) -0.008(2)
C9 0.021(3) 0.024(3) 0.016(3) 0.004(2) 0.006(2) 0.001(2)
C10 0.019(3) 0.024(3) 0.024(3) 0.008(2) 0.002(2) 0.003(3)
C11 0.036(3) 0.033(3) 0.020(3) 0.002(3) 0.011(3) -0.002(3)
O6 0.0186(18) 0.0144(19) 0.0211(18) 0.0020(15) 0.0066(15) 0.0023(16)
O7 0.0205(18) 0.0133(18) 0.0220(18) -0.0025(17) 0.0080(15) -0.0063(16)
O8 0.0166(18) 0.0138(19) 0.0141(17) 0.0001(15) 0.0018(14) -0.0020(16)
O9 0.0151(19) 0.0129(18) 0.0177(17) 0.0047(15) 0.0074(15) 0.0050(15)
O10 0.0111(17) 0.0147(19) 0.0224(18) 0.0020(15) 0.0093(14) -0.0010(15)
C12 0.015(3) 0.016(3) 0.018(3) -0.003(2) 0.006(2) -0.001(2)
C13 0.023(3) 0.011(3) 0.013(2) -0.002(2) 0.008(2) 0.003(2)
C14 0.014(2) 0.018(3) 0.020(3) -0.002(2) 0.006(2) -0.003(2)
C15 0.013(2) 0.013(3) 0.011(2) 0.000(2) -0.0002(19) 0.007(2)
C16 0.023(3) 0.006(3) 0.020(3) 0.000(2) 0.014(2) 0.003(2)
C17 0.016(3) 0.003(2) 0.021(3) -0.001(2) 0.006(2) -0.001(2)
C18 0.014(3) 0.019(3) 0.014(2) 0.001(2) 0.004(2) -0.001(2)
C19 0.015(3) 0.022(3) 0.019(3) -0.004(2) 0.001(2) 0.000(2)
C20 0.026(3) 0.014(3) 0.014(3) -0.001(2) 0.010(2) -0.005(2)
C21 0.024(3) 0.024(3) 0.022(3) 0.002(2) 0.011(2) -0.002(3)
C22 0.038(3) 0.019(3) 0.025(3) 0.001(2) 0.020(3) -0.004(3)
O1S 0.033(2) 0.013(2) 0.022(2) -0.0036(17) 0.0114(17) -0.0030(19)
O2S 0.023(2) 0.0147(19) 0.0155(19) 0.0006(16) 0.0068(16) -0.0009(17)
_geom_special_details
All esds (except the esd in the dihedral angle between two l.s. planes)
are estimated using the full covariance matrix. The cell esds are taken
into account individually in the estimation of esds in distances, angles
and torsion angles; correlations between esds in cell parameters are only
used when they are defined by crystal symmetry. An approximate (isotropic)
treatment of cell esds is used for estimating esds involving l.s. planes.
330

loop_
_geom_bond_atom_site_label_1
_geom_bond_atom_site_label_2
_geom_bond_distance
_geom_bond_site_symmetry_2
_geom_bond_publ_flag
O1 C7 1.423(5) . ?
O1 H1 0.8400 . ?
O2 C3 1.441(5) . ?
O2 H2 0.8400 . ?
O3 C4 1.434(5) . ?
O3 H3 0.8400 . ?
O4 C5 1.435(5) . ?
O4 H4 0.8400 . ?
O5 C6 1.443(6) . ?
O5 H5 0.8400 . ?
C1 C8 1.541(6) . ?
C1 C6 1.547(6) . ?
C1 C7 1.551(7) . ?
C1 C2 1.564(6) . ?
C2 C3 1.540(6) . ?
C2 C9 1.562(6) . ?
C2 H2A 1.0000 . ?
C3 C4 1.505(6) . ?
C3 H3A 1.0000 . ?
C4 C5 1.503(6) . ?
C4 H4A 1.0000 . ?
C5 C6 1.520(6) . ?
C5 H5A 1.0000 . ?
C6 H6 1.0000 . ?
C7 H7A 0.9900 . ?
C7 H7B 0.9900 . ?
C8 H8A 0.9800 . ?
C8 H8B 0.9800 . ?
C8 H8C 0.9800 . ?
C9 C11 1.524(6) . ?
C9 C10 1.547(7) . ?
C9 H9 1.0000 . ?
C10 H10A 0.9800 . ?
C10 H10B 0.9800 . ?
C10 H10C 0.9800 . ?
C11 H11A 0.9800 . ?
C11 H11B 0.9800 . ?
C11 H11C 0.9800 . ?
O6 C18 1.423(5) . ?
O6 H6A 0.8400 . ?
O7 C14 1.427(6) . ?
O7 H7 0.8400 . ?
O8 C15 1.443(5) . ?
O8 H8 0.8400 . ?
O9 C16 1.420(5) . ?
O9 H9A 0.8400 . ?
O10 C17 1.446(5) . ?
O10 H10 0.8400 . ?
C12 C19 1.536(6) . ?
C12 C18 1.539(6) . ?
C12 C17 1.544(6) . ?
C12 C13 1.575(7) . ?
C13 C14 1.549(6) . ?
C13 C20 1.569(6) . ?
C13 H13 1.0000 . ?
C14 C15 1.520(6) . ?
C14 H14 1.0000 . ?
C15 C16 1.502(6) . ?
C15 H15 1.0000 . ?
C16 C17 1.535(6) . ?
C16 H16 1.0000 . ?
C17 H17 1.0000 . ?
C18 H18A 0.9900 . ?
C18 H18B 0.9900 . ?
C19 H19A 0.9800 . ?
C19 H19B 0.9800 . ?
C19 H19C 0.9800 . ?
C20 C21 1.533(7) . ?
C20 C22 1.534(7) . ?
C20 H20 1.0000 . ?
331

C21 H21A 0.9800 . ?
C21 H21B 0.9800 . ?
C21 H21C 0.9800 . ?
C22 H22A 0.9800 . ?
C22 H22B 0.9800 . ?
C22 H22C 0.9800 . ?
O1S H1S 0.78(6) . ?
O1S H2S 0.91(5) . ?
O2S H3S 0.93(6) . ?
O2S H4S 0.93(7) . ?
loop_
_geom_angle_atom_site_label_1
_geom_angle_atom_site_label_2
_geom_angle_atom_site_label_3
_geom_angle
_geom_angle_site_symmetry_1
_geom_angle_site_symmetry_3
_geom_angle_publ_flag
C7 O1 H1 109.5 . . ?
C3 O2 H2 109.5 . . ?
C4 O3 H3 109.5 . . ?
C5 O4 H4 109.5 . . ?
C6 O5 H5 109.5 . . ?
C8 C1 C6 107.7(4) . . ?
C8 C1 C7 109.0(4) . . ?
C6 C1 C7 108.4(4) . . ?
C8 C1 C2 110.7(4) . . ?
C6 C1 C2 111.3(4) . . ?
C7 C1 C2 109.8(4) . . ?
C3 C2 C9 114.0(4) . . ?
C3 C2 C1 112.9(4) . . ?
C9 C2 C1 113.6(4) . . ?
C3 C2 H2A 105.1 . . ?
C9 C2 H2A 105.1 . . ?
C1 C2 H2A 105.1 . . ?
O2 C3 C4 108.6(4) . . ?
O2 C3 C2 109.0(3) . . ?
C4 C3 C2 111.8(4) . . ?
O2 C3 H3A 109.1 . . ?
C4 C3 H3A 109.1 . . ?
C2 C3 H3A 109.1 . . ?
O3 C4 C5 108.7(4) . . ?
O3 C4 C3 110.3(4) . . ?
C5 C4 C3 112.8(4) . . ?
O3 C4 H4A 108.3 . . ?
C5 C4 H4A 108.3 . . ?
C3 C4 H4A 108.3 . . ?
O4 C5 C4 112.0(4) . . ?
O4 C5 C6 106.4(4) . . ?
C4 C5 C6 111.3(4) . . ?
O4 C5 H5A 109.0 . . ?
C4 C5 H5A 109.0 . . ?
C6 C5 H5A 109.0 . . ?
O5 C6 C5 108.8(4) . . ?
O5 C6 C1 108.1(4) . . ?
C5 C6 C1 112.8(4) . . ?
O5 C6 H6 109.0 . . ?
C5 C6 H6 109.0 . . ?
C1 C6 H6 109.0 . . ?
O1 C7 C1 112.6(4) . . ?
O1 C7 H7A 109.1 . . ?
C1 C7 H7A 109.1 . . ?
O1 C7 H7B 109.1 . . ?
C1 C7 H7B 109.1 . . ?
H7A C7 H7B 107.8 . . ?
C1 C8 H8A 109.5 . . ?
C1 C8 H8B 109.5 . . ?
H8A C8 H8B 109.5 . . ?
C1 C8 H8C 109.5 . . ?
H8A C8 H8C 109.5 . . ?
H8B C8 H8C 109.5 . . ?
C11 C9 C10 109.6(4) . . ?
C11 C9 C2 111.9(4) . . ?
C10 C9 C2 114.1(4) . . ?
C11 C9 H9 106.9 . . ?
C10 C9 H9 106.9 . . ?
332

C2 C9 H9 106.9 . . ?
C9 C10 H10A 109.5 . . ?
C9 C10 H10B 109.5 . . ?
H10A C10 H10B 109.5 . . ?
C9 C10 H10C 109.5 . . ?
H10A C10 H10C 109.5 . . ?
H10B C10 H10C 109.5 . . ?
C9 C11 H11A 109.5 . . ?
C9 C11 H11B 109.5 . . ?
H11A C11 H11B 109.5 . . ?
C9 C11 H11C 109.5 . . ?
H11A C11 H11C 109.5 . . ?
H11B C11 H11C 109.5 . . ?
C18 O6 H6A 109.5 . . ?
C14 O7 H7 109.5 . . ?
C15 O8 H8 109.5 . . ?
C16 O9 H9A 109.5 . . ?
C17 O10 H10 109.5 . . ?
C19 C12 C18 104.8(4) . . ?
C19 C12 C17 107.9(4) . . ?
C18 C12 C17 109.3(4) . . ?
C19 C12 C13 109.6(4) . . ?
C18 C12 C13 114.4(4) . . ?
C17 C12 C13 110.5(4) . . ?
C14 C13 C20 113.4(4) . . ?
C14 C13 C12 111.8(4) . . ?
C20 C13 C12 113.1(4) . . ?
C14 C13 H13 105.9 . . ?
C20 C13 H13 105.9 . . ?
C12 C13 H13 105.9 . . ?
O7 C14 C15 110.4(4) . . ?
O7 C14 C13 113.0(4) . . ?
C15 C14 C13 108.9(4) . . ?
O7 C14 H14 108.1 . . ?
C15 C14 H14 108.1 . . ?
C13 C14 H14 108.1 . . ?
O8 C15 C16 107.8(4) . . ?
O8 C15 C14 110.4(4) . . ?
C16 C15 C14 109.8(4) . . ?
O8 C15 H15 109.6 . . ?
C16 C15 H15 109.6 . . ?
C14 C15 H15 109.6 . . ?
O9 C16 C15 113.0(4) . . ?
O9 C16 C17 111.4(4) . . ?
C15 C16 C17 109.8(4) . . ?
O9 C16 H16 107.5 . . ?
C15 C16 H16 107.5 . . ?
C17 C16 H16 107.5 . . ?
O10 C17 C16 108.3(3) . . ?
O10 C17 C12 109.2(4) . . ?
C16 C17 C12 114.5(4) . . ?
O10 C17 H17 108.2 . . ?
C16 C17 H17 108.2 . . ?
C12 C17 H17 108.2 . . ?
O6 C18 C12 116.7(4) . . ?
O6 C18 H18A 108.1 . . ?
C12 C18 H18A 108.1 . . ?
O6 C18 H18B 108.1 . . ?
C12 C18 H18B 108.1 . . ?
H18A C18 H18B 107.3 . . ?
C12 C19 H19A 109.5 . . ?
C12 C19 H19B 109.5 . . ?
H19A C19 H19B 109.5 . . ?
C12 C19 H19C 109.5 . . ?
H19A C19 H19C 109.5 . . ?
H19B C19 H19C 109.5 . . ?
C21 C20 C22 110.1(4) . . ?
C21 C20 C13 114.4(4) . . ?
C22 C20 C13 110.6(4) . . ?
C21 C20 H20 107.1 . . ?
C22 C20 H20 107.1 . . ?
C13 C20 H20 107.1 . . ?
C20 C21 H21A 109.5 . . ?
C20 C21 H21B 109.5 . . ?
H21A C21 H21B 109.5 . . ?
C20 C21 H21C 109.5 . . ?
333

H21A C21 H21C 109.5 . . ?
H21B C21 H21C 109.5 . . ?
C20 C22 H22A 109.5 . . ?
C20 C22 H22B 109.5 . . ?
H22A C22 H22B 109.5 . . ?
C20 C22 H22C 109.5 . . ?
H22A C22 H22C 109.5 . . ?
H22B C22 H22C 109.5 . . ?
H1S O1S H2S 105(5) . . ?
H3S O2S H4S 101(5) . . ?
loop_
_geom_torsion_atom_site_label_1
_geom_torsion_atom_site_label_2
_geom_torsion_atom_site_label_3
_geom_torsion_atom_site_label_4
_geom_torsion
_geom_torsion_site_symmetry_1
_geom_torsion_site_symmetry_2
_geom_torsion_site_symmetry_3
_geom_torsion_site_symmetry_4
_geom_torsion_publ_flag
C8 C1 C2 C3 167.5(4) . . . . ?
C6 C1 C2 C3 47.9(5) . . . . ?
C7 C1 C2 C3 -72.1(5) . . . . ?
C8 C1 C2 C9 -60.7(5) . . . . ?
C6 C1 C2 C9 179.6(4) . . . . ?
C7 C1 C2 C9 59.6(5) . . . . ?
C9 C2 C3 O2 57.9(5) . . . . ?
C1 C2 C3 O2 -170.5(4) . . . . ?
C9 C2 C3 C4 178.0(4) . . . . ?
C1 C2 C3 C4 -50.4(5) . . . . ?
O2 C3 C4 O3 -62.8(5) . . . . ?
C2 C3 C4 O3 176.8(3) . . . . ?
O2 C3 C4 C5 175.5(4) . . . . ?
C2 C3 C4 C5 55.1(5) . . . . ?
O3 C4 C5 O4 61.1(5) . . . . ?
C3 C4 C5 O4 -176.3(4) . . . . ?
O3 C4 C5 C6 -179.9(4) . . . . ?
C3 C4 C5 C6 -57.3(5) . . . . ?
O4 C5 C6 O5 57.1(5) . . . . ?
C4 C5 C6 O5 -65.2(5) . . . . ?
O4 C5 C6 C1 177.1(4) . . . . ?
C4 C5 C6 C1 54.8(5) . . . . ?
C8 C1 C6 O5 -51.1(5) . . . . ?
C7 C1 C6 O5 -168.9(4) . . . . ?
C2 C1 C6 O5 70.3(5) . . . . ?
C8 C1 C6 C5 -171.5(4) . . . . ?
C7 C1 C6 C5 70.7(5) . . . . ?
C2 C1 C6 C5 -50.1(5) . . . . ?
C8 C1 C7 O1 -66.9(5) . . . . ?
C6 C1 C7 O1 50.0(5) . . . . ?
C2 C1 C7 O1 171.7(4) . . . . ?
C3 C2 C9 C11 -90.4(5) . . . . ?
C1 C2 C9 C11 138.4(4) . . . . ?
C3 C2 C9 C10 34.8(6) . . . . ?
C1 C2 C9 C10 -96.5(5) . . . . ?
C19 C12 C13 C14 167.2(4) . . . . ?
C18 C12 C13 C14 -75.4(5) . . . . ?
C17 C12 C13 C14 48.5(5) . . . . ?
C19 C12 C13 C20 -63.3(5) . . . . ?
C18 C12 C13 C20 54.0(5) . . . . ?
C17 C12 C13 C20 177.9(4) . . . . ?
C20 C13 C14 O7 50.0(5) . . . . ?
C12 C13 C14 O7 179.3(4) . . . . ?
C20 C13 C14 C15 173.1(4) . . . . ?
C12 C13 C14 C15 -57.7(5) . . . . ?
O7 C14 C15 O8 -51.9(5) . . . . ?
C13 C14 C15 O8 -176.5(4) . . . . ?
O7 C14 C15 C16 -170.7(4) . . . . ?
C13 C14 C15 C16 64.7(5) . . . . ?
O8 C15 C16 O9 52.4(5) . . . . ?
C14 C15 C16 O9 172.8(4) . . . . ?
O8 C15 C16 C17 177.4(3) . . . . ?
C14 C15 C16 C17 -62.2(5) . . . . ?
O9 C16 C17 O10 58.0(5) . . . . ?
C15 C16 C17 O10 -67.9(4) . . . . ?
334

O9 C16 C17 C12 -179.9(4) . . . . ?
C15 C16 C17 C12 54.2(5) . . . . ?
C19 C12 C17 O10 -45.1(5) . . . . ?
C18 C12 C17 O10 -158.6(4) . . . . ?
C13 C12 C17 O10 74.7(4) . . . . ?
C19 C12 C17 C16 -166.8(4) . . . . ?
C18 C12 C17 C16 79.8(5) . . . . ?
C13 C12 C17 C16 -46.9(5) . . . . ?
C19 C12 C18 O6 -175.9(4) . . . . ?
C17 C12 C18 O6 -60.4(5) . . . . ?
C13 C12 C18 O6 64.0(5) . . . . ?
C14 C13 C20 C21 34.1(6) . . . . ?
C12 C13 C20 C21 -94.5(5) . . . . ?
C14 C13 C20 C22 -90.9(5) . . . . ?
C12 C13 C20 C22 140.5(4) . . . . ?
loop_
_geom_hbond_atom_site_label_D
_geom_hbond_atom_site_label_H
_geom_hbond_atom_site_label_A
_geom_hbond_distance_DH
_geom_hbond_distance_HA
_geom_hbond_distance_DA
_geom_hbond_angle_DHA
_geom_hbond_site_symmetry_A
O2S H4S O2 0.93(7) 1.84(8) 2.760(5) 171(7)
2_647
O2S H3S O8 0.93(6) 1.91(6) 2.770(4) 153(5)
2_647
O1S H2S O1 0.91(5) 1.81(5) 2.705(5) 167(5)
2_747
O1S H1S O3 0.78(6) 1.99(6) 2.748(5) 163(6) .
O10 H10 O5 0.84 1.89 2.727(4) 171.3 2_647
O9 H9A O1S 0.84 1.83 2.644(5) 162.6 2_657
O8 H8 O9 0.84 1.83 2.628(4) 156.8 2_657
O7 H7 O2S 0.84 2.04 2.867(5) 166.6 1_565
O6 H6A O2S 0.84 1.92 2.756(5) 178.3 .
O5 H5 O1S 0.84 2.09 2.854(5) 151.0 1_565
O4 H4 O3 0.84 2.44 2.849(5) 110.7 .
O3 H3 O8 0.84 1.90 2.705(4) 159.5 .
O2 H2 O10 0.84 1.98 2.808(5) 170.5 2_647
O1 H1 O6 0.84 1.97 2.709(5) 146.8 2_757
_diffrn_measured_fraction_theta_max 0.998
_diffrn_reflns_theta_full 25.02
_diffrn_measured_fraction_theta_full 0.998
_refine_diff_density_max 0.250
_refine_diff_density_min -0.203
_refine_diff_density_rms 0.
335