Am. Chem. Soc.

THE SYNTHESIS AND FREE-RADICAL REACTIONS OF 2-CHLOROETHYL SILYL ENGL ETHERS;
A SYNTHESIS OF THE CARBON-9 TO CARBON-21 SUBUNIT OF THE
APLYSIATOXINS AND OSCILLATOXINS
ROBERT RONALD KANE, B.S
A DISSERTATION
CHEMISTRY
Submitted to the Graduate Faculty
of Texas Tech University in
Partial Fulfillment of
the Requirements for
the Degree of
DOCTOR OF PHILOSOPHY
Approved
Accepted
Dean/of the Graduate School
December, 1990

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© ROBERT RONALD KANE, 1990

ACKNOWLEDGEMENTS
This dissertation, the culmination of four years of research in the laboratory as well
as numerous years of education, would not have been possible without the encouragement
and assistance of numerous individuals.
Heartfelt appreciation goes out to Professors Harold Bier, Preston Reeves, and
David Wasmund of Texas Lutheran CoUege, who patiently provided a first rate
undergraduate education while nurturing the interest in chemistry of one of their least
ccx)perative students. The attainment of the undergraduate degree would not have been
possible without their assistance, as well as that of Dr. Charles Oestreich (president of
Texas Lutheran College).
The Graduate School of Texas Tech, as well as the Department of Chemistry, are
appreciated for the providing an opportunity for a postgraduate education to a questionably
motivated candidate. The Department of Chemistry has provided a faculty who have
proved to be excellent instructors, both inside and outside of the classroom. Especially
helpful have been the members of the advisory committee, Professors Henry Shine, Bruce
Whittlesey, John Marx, David Bimey, and Richard Bartsch, who have provided advice and
aid, scholarly and personal. Special thanks go to Professor David Bimey, who agreed to
serve as a member of the committee for the dissertation defense upon short notice.
This time at Texas Tech University has been made especially enjoyable by the
friendship of various coUeaeues in the department. Especially notable are the past and
present members of Professor Robert Walkup's research group, who have provided a
professional yet personable environment in which to work.
Professor Robert Walkup has been a patient and insightful research advisor as well
as a personal and professional inspiration. He consistently demonstrates that it is possible
to balance a great dedication to ones work with devotion to ones family.
None of this would have been possible without the patient support of a wonderful
family. The encouragement provided by my parents and sisters has been a motivation
when things seemed the most difficult. My wife Dawn and son Joey have filled the past
four years with love and joy, and to them I dedicate this dissertation.
Financial support, without which this work would not have been possible, was
provided by the Robert A. Welch Foundation, the Petroleum Research Fund, and the
Graduate School of Texas Tech University, as well as by David Close, M.D., Benny
Philips, M.D., and Ali A. ElDomeiri, M.D., and is gratefully adknowledged.
iu

ACKNOWLEDGEMENTS iu
FIGURES X
ABBREVL\TIONS xi
CHAPTER 1 INTRODUCTION 1
PARTI
THE SYNTHESIS AND FREE-RADICAL REACTIONS
OF 2-CHIJOROETHYL SILYL ENOL ETHERS
CHAPTER 2 BACKGROUND 3
OrganosiUcon Chemistry 3
Historical Background 3
Properties of OrganosiUcon Compounds 4
The 'P-Effect' in OrganosiUcon Compounds 6
Uses of OrganosUicon Compounds 7
OrganosiUcon Compounds as 'Ferrymen' 8
The Synthesis of Silyl Enol Ethers 9
Reactions of SUyl Enol Ethers 11
'Silicon Functionalized' Silyl Enol Ethers 13
Conclusions 14
Radical Transformations in Synthetic Organic Chemistry 14
General 14
Radical Cyclizations 16
The Effect of Silicon Substitution 17
Cyclization of p-Silyl Radicals 21
Conclusions 21
Rationale for this Research 21
CHAPTERS RESULTS AND DISCUSSION 23
General Considerations 23
iv

Initial Studies 25
The Synthesis and Attempted Radical Cyclization
of a Chloromethyl SUyl Enol Ether 25
The Synthesis and Radical Cyclization of a
2-Chloroethyl Silyl Enol Ether 27
Optimizing the Recipe for the Radical Cyclization 31
Oxidative Removal of the Silicon Atom 33
The Synthesis and Free-Radical CycUzations of
2-ChloroethyldimethylsUyl Enol Ethers 34
A Stereoselective Tandem CycUzation 39
Unsymmetrical Dialkyl Silyl Enol Ethers 40
Conclusions 41
CHAPTER 4 EXPERIMENTAL DETAILS 42
General Methods 42
(3,3-Dimethylbutenyl-2-oxy)ethoxymethyl(chloromethyl)silane (80) 43
(3,3-Dimethylbutene-2-oxy)ethoxy-2-chloroethyl-methylsUane (86) 44
3-(tert-Butyl)-l-ethoxy-1-methyl-l-sila-2-oxacyclohexane (90) 45
5,5-Dimethyl-l,4-hexanediol(92) 46
Chloro(2-chloroethyl)dimethylsilane (93) 47
Diethoxydimethylsilane (95) 48
(3,3-Dimethylbutene-2-oxy)(2-chloroethyl)dimethylsilane (99) 48
(1 -Cyclohexylethenyloxy)(2-chloroethyl)dimethy 1 silane (100) 49
(2-Chloroethyl)(l-cyclohexenyloxy)dimethylsUane (101) 50
(l-Phenylethenyloxy)(2-chloroethyl)dimethylsilane (102) 51
(2-Chloroethyl)(l-heptenyl-2-oxy)dimethylsilane (103) 52
(3'S,6'R)-(2-Chloroethyl)(3'-(l"-methylethyl)-5'-methyl-l'cyclohexenyl-2'-oxy)dimetiiylsilane
(104) : 53
l-Cyclopropylethenyloxy(2-chloroethyl)dimethylsilane (105) 54
V

2,2-Dimetiiyl-6-trimethylsilyl-3-hexanol(107) 54
l-Cyclohexyl-4-trimethylsilyl- 1-butanol (108) 55
l-TrimethylsUyl-4-nonanol (109) 56
2-(2'-Trimethylsnylethyl)cyclohexanol (110) 57
(2-Chloroethyl)(l,6-heptadien-2-yloxy)dimethylsilane (115) 58
2-Methyl-l-(3-trimethylsilylpropyl)cyclopentanol (118) 59
Bis-(3,3-dimethylbutene-2-oxy)(2-chloroethyl)methylsUane (119) 60
Bis-(cyclohexen-l-yloxy)(2-chloroethyl)methylsUane (120) 61
Chloro(2-chloroethyl)ethyhnethylsilane(121) 62
Chloro(2-chloroethyl)methyl(l-methylpropyl)silane (122) 63
Ethyl(2-chloroethyl)(l-cyclohexylethenyloxy)methylsUane (123) 63
(3,3-Dimethylbutenyl-2-oxy)ethyl(2-chloroethyl)-methylsUane (124) 64
t-Butyl(2-chloroethyl)methyl(l-phenylethenyloxy)silane (125) 65
t-Butyl(2-chloroethyl)(l-heptenyl-2-oxy)methylsUane (126) 66
REFERENCES 67
PARTE
A SYNTHESIS OF THE CARBON-9 TO CARBON-21
SUBUNIT OF THE APLYSLVTOXESfS AND
OSCILLATOXINS
CHAPTERS BACKGROUND 72
Discovery of the Aplysiatoxins and Oscillatoxins 72
Structure Determination 73
Biological Activity of the Aplysiatoxins and Oscillatoxins 76
Progress Toward the Total Synthesis of Oscillatoxin D 76
Other Synthetic Studies on the Aplysiatoxins 79
vi

Conclusions 81
CHAPTER 6 RESULTS AND DISCUSSION 82
Retrosynthetic Analysis of Target Aldehyde (36) 82
Studies on the Stereoselective Synthesis of a C14-C15 Epoxide 83
Model Studies on the AUcylation of a C14 Anion 86
Stereoselective Aldol Route to the C9-C13 Segment of the
OscUlatoxins and Aplysiatoxins 88
Elaboration of tiie Aldol Product (88) to a C9-C13 Iodide (90) 92
Coupling of C9-C13 Iodide (90) and C14-C21 Imine (69) 97
Asymmetric Reduction of C15 Ketone (101) 98
Elaboration of Alcohol (110) to Aldehyde (112) 102
Recent Progress - Synthesis of a C3-C21 Subunit
of the Aplysiatoxins and Oscillatoxins 103
Conclusions 105
CHAPTER7 EXPERIMENTAL DETAILS 106
General Methods 106
(R)-2'-Hydroxy-2'-(3"-benzyloxy)phenylethyl
4-(methyl)benzenesulfonate (61) 107
(R)-1 -(3'-[Benzyloxy]phenyl)etiiane-1,2-epoxide (62) 107
(R)-l"-(2'"-Napthol)-2"-napthyl 2-(3'-methoxy)-phenylethanoate (63) 108
3-(2'-Trimethylsilylethoxy)methoxyacetophenone (65) 109
(S)-l-(t-Butyldimethyl)silyloxy-2-methylpropyl methanesulfonate (67) 110
(S)-l-Iodo-2-methyl-3-t-butyldimethylsUyloxypentane (68) 111
N-l-(3'-[(2"-Trimethylsilylethoxy)methoxy]phenyl)
ethylidinecyclohexylamine (69) 112
(R)-1 -(3'-[(2"-Trimethy lsilylethoxy)methoxy]pheny l)-
4-metiiyl-5-(t-butyldimethyl)silyloxy- 1-pentanone (71) 113
(S)-3-(4'-Methoxyphenyl)methoxy-2-methylpropanal (82) 114
vu

(S)-Methyl 3-(4'-methoxyphenyl)methoxy-2-methylpropionate (84) 115
(2'R,3'S,4'S,4R,5S)-3-(3'-Hydroxy-5'-[4"-methoxy-phenyl]methoxy-
2',4'-dimethylpentanoyl)-5-phenyl-4-methyl-2-oxazoUdinone (88) 116
(l"S,2'R,3"S,4'R,5S,6"S)-3-(2'-[6"-Methyl-2",4"-dioxa-3"-
(4"methoxyphenyl)cyclohex-1 "-yl]-propanoyl)-5-phenyl-
4-methyl-2-oxazolidinone (89) 117
(2S,3S,4S)-l-Iodo-5-(4'-methoxyphenyl)methoxy-2,4dimetiiyl-3-t-butyldimethylsUoxypentane
(90) 118
(2'R,3'S,4'S,4R,5S)-3-(5'-[4"-Methoxy-phenyl]-methoxy-2',4'dimethyl-3'-t-butyldimethyl-sUyloxy-pentanoyl)-5-phenyl-4methyl-2-oxazolidinone
(91) 119
(2S,3R,4S)-3-t-ButyldimethylsUyloxy-5-(4'-methoxyphenyl)methoxy-2,4-dimethyl-l-pentanol(92)
120
(lR,2R,2'S,3'S,4'S)-N-(l'-Hydroxy-l'-phenylpropan-2'-yl)-5-(4'methoxyphenyl)methoxy-3-t-butyldimethyl-silyloxy-2,4-dimethy
1-1 -
pentylamine (93) 121
(2S,3R,4S)-5-(4'-Methoxyphenyl)methoxy-2,4dimethyl-l,3-pentanediol(94)
122
(2R,3S,4R)-Methyl3-hydroxy-5-(4'-methoxyphenyl)methoxy-2,4-dimethylpentanoate
(95) 123
(2S,3R,4S)-Methyl3-(t-butyldimethyl)sUyloxy-5-(4'methoxyphenyl)methoxy-2,4-dimethylpentanoate
(96) 124
(2S,3R,4S)-3-(t-Butyldimethyl)silyloxy-5-(4'-methoxyphenyl)methoxy-2,4-dimethylpent-1
-yl methanesulfonate (97) 125
(3S,5S)-3,5-Dimethyl-4-t-butyldimethylsUyloxytetrahydropyran (98) 126
(2S,3R,4S)-3-Hydroxy-5-(4'-methoxyphenyl)methoxy-2,4dimethylpent-1-yl
methanesulfonate (99) 127
(2S,3R,4S)-l-Iodo-5-(4'-methoxyphenyl)methoxy-2,4dimethyl-3-pentanol
(100) 128
(4S,5R,6S)-7-(4'-Methoxyphenylmethoxy)-4,6-dimethyl-5-
(t-butyldimethyl)silyloxy-l-(3"-(2'"-trimethylsilylethoxy)methoxy)phenyl-l-heptanone
(101) 129
(lS,4S,5R,6R)-7-(4'-Methoxyphenyl)methoxy-4,6-dimethyll-(3"-[2"'-trimethylsilylethoxy]methoxy)phenyl-5r-butyldimethylsiloxy-1-heptanol
(109) 130
viu

(lS,4S,5R,6S)-7-(4'-Methoxyphenyl)methoxy-l-methoxy-4,6-dimethyl-l-
(3"-(trimethylethoxymethoxy)phenyl)-5-(t-butyldimethyl)silyloxyheptane
(102) 132
(2S,3R,4S,7S)-7-Methoxy-2,4-dimethyl-7-(3'-trimethylsUylethoxymethoxy)phenyl-3-(t-butyldimethyl)sUyloxyl-heptanol(lll)
133
(2R,3R,4S)-7-Methoxy-2,4-dimethyl-7-(3'trimethylsUylethoxymethoxy)phenyl-2-
(t-butyldimethyl)sUyloxyheptanal (112) 134
(2S,8S,9R,10R)-7-Hydroxy-13-methoxy-l-(4'-methoxyphenyl)methoxy-2,4,4,8,10-pentamethyl-13-(3"-(trimethylsilylethoxymethoxy)phenyl-9-(t-butyldimethyl)silyloxy-5-tridecanone
(113) 135
(2S,8S,9R,10R)-13-Methoxy-l-(4'-methoxyphenyl)-methoxy-
2,4,4,8,10-pentamethyl-l 3-(3"-(trimethylsilylethoxymethoxy)phenyl-9-(r-butyldimethyl)-silyloxy-5,7-tridecanedione
(115) 136
REFERENCES 138
IX

FIGURES
Figure 2.1 Hyperconjugative StabUization of a-SUyl Anions 5
Figure 2.2 Orbital Interraction Responsible for the 'p-Effect' 6
Fi gure 2.3 Trajectory for Radical Addition 17
Figure 2.4 Polar Contributions in 5-exo CycUzation of a-SUyl Radical 18
Figure 2.5 Polar Contributions in Reduction of a-Silyl Radical 19

AEBN 2,2'-Azobisisobutyronitrile
BOM Benzyloxymethyl
CD Circular Dichroism
ABBREVL^TIONS
CI-MS Chemical lonization-Mass Spectrometry
d. e. Diastereomeric excess
DDQ 2,3-Dichloro-5,6-dicyanobenzoquinone
DMSO Dimetiiylsulfoxide
e. e. Enantiomeric excess
ether Diethyl ether
GC Gas Chromatography
HMPA Hexamethylphosphorictriamide
HRMS High resolution Mass Spec
Hz Hertz
Ipc2BCl Diisocampheylchloroborane
IR Infra red
LAH Lithium aluminum hydride
IDA Lithium dusopropylamide
MCPBA mera-Chloroperbenzoic acid
MPM Methoxyphenylmethyl
NBS N-Bromosuccinnimide
NMR Nuclear magnetic resonance
NOE Nuclear Overhauser Effect
ppm Parts per mUUon
SEM TrimethylsUylethoxymethyl
TBDMS rerr-ButyldimethylsUyl
TBTH Tri-rt-butyltin hydride
THF Tetrahydrofuran
TIPS TriisopropylsUyl
TLC Thin layer chromatography
TMS Trimethylsilyl
TMSE Trimetiiylsilylethyl
UV Ultra violet
XI

CHAPTER 1
INTRODUCTION
An enormous number of transformations of organic compounds are known. Still,
much of the research in organic chemistry is focused upon tiie study and/or development of
new transformations. This research is often based upon a search for practical synthetic
transformations, or new 'synthetic methodology.' The quest for higher yields, greater
chemoselectivity or stereoselectivity, simpler reaction conditions, more practical reagents,
or truly novel transformations are a few of the motivations for the development of new
'synthetic methodologies.'
Part I of this dissertation describes an attempt to develop a novel synthetic method
for the formation of carbon-carbon bonds based on the free radical cyclization of silyl enol
ethers. A new transformation of this type would be attractive for a number of reasons.
Simple silyl enol ethers are well known, and are often easily derived from ketone enolates.
Thus, a new reaction of silyl enol etiiers could potentially apply to an enormous number of
ketone containing substrates. Also, free radical reactions often occur under mild conditions
withstocxi by many sensitive functional groups. FinaUy, free radical cyclizations are often
efficient and selective, a result of the intramolecular nature of this type reaction.
Synthetic methodologies, tiien, are 'tools' which are utUized by organic chemists in
the construction of complex organic compounds. One class of complex organic molecules
that consistently attracts a large amount of attention is 'natural products,' organic
compounds that are isolated from biological sources. These compounds often have
interesting biological activities, and as such are of great interest. Often, the only feasible
method of obtaining the quantities of these compounds required for thorough study of their
biological behavior is through total synthesis. The study of synthetic analogues of natural
products is also extremely useful in determining and/or modifying thebiological activities of
these compounds.
Part II of this dissertation describes work toward the total synthesis of oscillatoxin
D. This compound, which has been isolated from several bluegreen algae, has been shown
to have interesting biological activity. However, this compound has not been isolated in
sufficient quantities to allow thorough biological testing. Thus die total syntiiesis of this
structurally complex compound is a worthwhile goal.
This dissertation, then, reports the results of two extremely different projects,
unified in that each is concerned with an important facet of synthetic organic chemistry.

PARTI
THE SYNTHESIS AND FREE-RADICAL REACTIONS
OF 2-CHIJOROETHYL SILYL ENOL ETHERS

Historical Background
CHAPTER 2
BACKGROUND
OrganosiUcon Chemistry
Silicon, the second most abundant element in the Earth's crust, exists in nature in
combination with oxygen as silica or the metal silicates. No naturally occurring
compounds which possess carbon-sUicon bonds, organosilanes, are known. The study of
OrganosiUcon chemistry began in 1863 with Friedel and Crafts, who prepared the first
organosilane, tetraethylsUane 1 (organosUicon compounds are named by Usting the
Ugands, excluding hydrogen, on sUicon, followed by the word 'silane'). This synthesis
CH3CH2^^ ^CH2CH3
CH3CH2 CH2CH3
was accomplished by reacting diethylzinc with tetrachlorosilane, which was
first prepared by BerzeUus in 1823. However, further progress in the field was slow, and
by 1937 F. S. Kipping, early-on a major investigator of the chemistry of organosUicon
compounds, had concluded that there was Uttle hope that the chemistry of organosUicon
compounds would become useful.^ Modem chemists have come to the glad realization that
Kipping was mistaken, and over the last twenty five years the study and utiUzation of
OrganosiUcon compounds has enjoyed explosive growth.
This boom actually began with the development in 1945 of the 'direct synthesis' of
chloromethylsilanes^ and was given an additional boost in 1957 with the discovery of the
transition-metal catalyzed 'hydrosilylation' of alkenes.^ These two techniques made
available thousands of new organosUanes, and the birth and phenomenal growth of the
silicone industry led to renewed interest in the chemistry of silicon-containing compounds
and insured the availability of a variety of low cost silicon monomers. Armed with these
more accessible starting materials, chemists painstakingly developed organosUicon
chemistry, once a very esoteric field, into a very useful and weU understood one. This has
resulted in organosUicon compounds becoming commonplace in the organic chemistry
laboratory, and in fact many uses of these compounds have become routine. To
understand why these compounds have become so pervasive in modem chemistry, one
3

should first consider the unique physical and chemical properties of organosUicon
compounds.
Properties of OrganosiUcon Compounds
Several characteristics of silicon affect its uniqueness and its utiUty in organic
chemistry. Silicon, with the electron configuration (Ne)3s23p23dO, is often compared to
carbon (electron configuration (He)2s22p2), which sits directly above siUcon in the periodic
table. Both elements are commonly tetravalent, although sUicon, by virtue of its empty 3d
orbitals, can expand its octet. Silicon is larger and more electropositive than carbon, and
carbon-silicon bonds are longer (1.9 A vs. I.SA) and weaker (318 kJ mopi vs. 334 kJ
mopi) than the corresponding carbon-carbon bonds. On the other hand, sUicon-oxygen
and silicon-fluorine bonds are stronger than the corresponding carbon-oxygen and carbon-
fluorine bonds. Although siUcon is formaUy considered a metal (or metalloid), it forms
strong, highly covalent bonds with carbon, hydrogen, and oxygen (among others). As
such, organosUicon compounds can often be handled without the need to resort to
techniques more elaborate than commonly used in modem synthetic organic chemistry.
This property alone has most likely been a significant factor in the widespread acceptance
of the use of organosUicon compounds in synthetic organic chemistry.
The ability of siUcon to expand its (Xtet has been used to explain sUicon's high
reactivity under SN2 conditions, as well as the propensity for certain SN2 reactions at
sUicon to proceed with retention of configuration. A number of hypervalent sUicon
compounds, caUed sUicates, have been weU characterized. Recent examples are the
octahedral hexafluorosUicate ion, SiF^^- and the pentacoordinate siUcates 2."^ Very recently
M=Li, (CH3)4N
R=CH3, CgHs
computer modeling studies of pentacoordinated siUcates SiFs" and SiHs" have
been published.^ These compounds, as well as silicates 2, can be considered as models
for pentacoordinated sUicon intermediates or activated states in SN2 type reactions.

An example of the useful selectivity that is a consequence of the high reactivity of
the chlorosilanes is the synthesis of chloromethylethylmethylpropylsilane 4 by reaction of
trichlorochloromethylsilane 3 with the appropriate Grignard reagents (Scheme 2.1).^ As
one can imagine, the possibility of replacing the chlorines of tetrachlorosilane sequentially
^'\c,i-C' p, 1)CH,MqBr CH3CH2^ CH3
Cl^ ' ^ ^ 2)EtMgBr CH3CH2CH2/^'--"
3 3)n-PrMgBr ^ 2 2 ^
Scheme 2.1
with four different nucleophiles has allowed the syntheses of countless organosilanes of
varied functionality. Thus, the vast availabiUty of chlorosilanes, coupled with these
compounds' high reactivity under SN2 conditions, is another significant factor in the
widespread utiUty of organosUicon compounds in synthetic organic chemistry.
The involvement of the silicon 3d orbitals in other types of reactivity characteristic
of organosUicon compounds has been debated, with the consensus being that the 3d
orbitals have little influence. The widening of the bond angle about the oxygen of silyl
ethers, as opposed to alkyl ethers (dimethyl ether, C-O-C = 112°; methoxy silane, Si-O-C =
121°; disiloxane, Si-O-Si = 144°), as weU as the reduced basicity of the silyl ethers, has in
the past been attributed to the mixing of oxygen lone pair and silicon 3d orbitals.
However, a recent inquiry into this problem using crystallographic and ab initio modeling
techniques suggests that this trend is caused by orbital interactions exclusive of the silicon
3d orbitals.^ The stabilization of organosUyl a-anions (or a-metalloids) can be explained
by a combination of molecular polarization and nc-a*si-c overlap (Figure 2.1), without
0*^
71
Figure 2.1
Hyperconjugative Stabilization
of a-Silyl Anions
resorting to (p-d)^ bonding. These findings are analogous to those for the corresponding
organosulfur a-anion species.^ The relative ease for the formation of a-silyl radicals
5

(relative to aUcyl radicals) has been attributed to a polar transition state having substantial
anionic character a to siUcon.^
The 'B-Effect' in OrganosiUcon Compounds
The propensity for sUicon to stabilize an electron deficient center one atom removed
is commonly called the 'p-effect'. As the 'p-effect' is central to the work we are reporting,
a more thorough description of the explanation for this phenomenon will be provided.
The exceptional reactivity of p-chloroaUcylsilanes (general structure 5) was noted in
1937, and by 1946 it had been shown that these compounds were more reactive than the
respective a- or y- substituted compounds towards heat or aluminum chloride^o, as well as
nucleophilic reagents,ii including Grignard reagents.^^ The general reaction in each case
was die elimination of a sUyl chloride 6 and the formation of an olefin (Scheme 2.2). A
heat,AlC^or ^ ^^.^ -^etiiylene
nucleophUe ^ ^ci
Scheme 2.2
review of the literature concerning the p-effect was pubUshed in 1970.^3 Much
work is still being done in order to understand better the anomalous properties of p-
functional organosilanes, including studies of p-silyl cations^"^, ESR^^ and kinetic^^
studies of P-silyl radicals, an electrochemical and theoretical study of P-silyl cation
radicals^^, and a study of the influence of the other Ugands on silicon upon the 'p-effect'.^^
The 'p-effect' has recently been utiUzed to direct a photolytic radical decarbonylation.^9
The accepted explanation for the stabiUzation of electron deficient atoms p to silicon
is a hyperconjugative interaction between the bonding Oc-Si orbital and the electron
deficient p orbital on the atom p to sUicon (Figure 2.2). This overlap is accentuated by the
Figure 2.2
Orbital Interaction Responsible for
the 'p-Effect'
6

high coefficient on the a-carbon, which is a consequence of the polar silicon-carbon bond.
As expected, electron withdrawing Ugands on silicon were found to enhance the 'p-
effect'i8, as they would increase the electrophilicity of the siUcon atom and thus the polarity
of the carbon-silicon bond and the coefficient on the a-carbon. It has been found that the
p-effect is greatest when the silicon-carbon bond and the electron deficient p orbital can
achieve coplanarity, as would be expected. This hyperconjugation has also been invoked
to explain the weakening of the bonds to the p-carbons in organosUicon compounds.^o
Empirical evidence for this hyperconjugative interaction has been provided in the
electrochemical oxidation of compounds such as T.i^ The relative ease of the electro­
chemical oxidation of these compounds was ascribed to an increase in die HOMO energy,
relative to the all-carbon systems, caused by CJsi-c-Po overlap. That homoconjugative
(p-d)7t interactions also play a part in the StabUization of p-silyl radicals was shown by the
ESR studyi^, in which the authors calculated approximately 10% electron density in the 3d
orbitals from the observed hyperfine splitting. One could imagine that this 'back-bonding'
could result in an unusually electrophiUc radical.
Uses of OrganosUicon Compounds
CH3^ ^CH3
SiC ^0CH3
CH3'^ "^ ^
1
A large number of organosUicon compounds are known, and many have unique
properties that make them extremely useful. For example, the ubiquitous organosUicon
compound tetramethylsUane is employed in the majority of ^H NMR experiments as an
intemal chemical shift standard. Its ^H NMR signal, which is found slightly upfield of the
normal range for organic compounds, as well as its inertness, make it an almost perfect
standard. Silicon containing crown ethers have been found to have interesting and unique
properties.^^ The interesting silatranes 8, which have aroused theoretical interest because
7

of the possibiUty of nitrogen-sUicon bond formation, have been found to be extremely toxic
to warm-blooded animals when the substituent 'R' is an aryl group. In fact, the para-
chlorobenzene substituted analogue (8, R =p-Cl-C6H4) has been marketed in the USA as a
rodenticide since 1971. The rapid detoxification of this compound in the bodies of
poisoned rodents has made it especially attractive.22 SiUcon-substituted drugs have been
investigated and in some instances have been found to have useful differences in activities
from the analogous carbon containing drugs. For example, sUa-difenidol (9, E=Si) has
been found to be ten times more potent than difenidol (9, E=C) in its antimuscarinic
activity.23
OrganosUicon Compounds as 'Ferrymen'
Despite these and many other uses of organosUicon compounds as final products
(with the siUcone industry as a notable example), sUicon owes much of its utiUty in the
modem organic chemistry laboratory to its role as a 'ferryman,' a term introduced by
Colvin.2^ This word aptiy describes silicon's role in a large part of practical organosUicon
chemistry—its presence selectively directs the course of a reaction or transformation, yet
sUicon is ultimately absent from the final product. One example of OrganosiUcon
compounds functioning as 'ferrymen' is the drastic change in the product distribution of the
thermal rearrangement of silyl ether 10 as compared to hydroxydiene 11 (Scheme 2.3) In
this case, the trimethylsilyl group has facilitated the formation of a product different than
that found for the unprotected diene.^^ Another common example of the ferryman role for
organosUicon compounds is the use of sUyl ethers as protecting groups. Routinely,
chemists will 'mask' a hydroxyl group, perform upon this protected compound various
reactions not compatible with the free hydroxyl group but compatible with the silyl ether,
and finaUy remove the silyl protecting group to 'unmask' the alcohol.
8

\ = /
10 R=SiMe3
11 R=H
heat
Major path for
diene 10 *"
Major path for
diene 11 *"
Scheme 2.3
Another class of OrganosiUcon compounds is the silyl enol ethers,
OSiMe^
whose appUcations in organic synthesis are vast and varied. These relatively stable
compounds undergo a large number of useful transformations, and the products most often
no longer incorporate silicon. Therefore, these compounds can serve as another example
of organosUicon compounds as 'ferrymen.' As the research we are reporting herein
involves a transformation of silyl enol ethers, the synthesis and reactions of this class of
compounds will be discussed more thoroughly.
The Synthesis of Silyl Enol Ethers
SUyl enol ethers, of general structure 14, have been known for some time, and
have come to be of considerable utiUty. The most frequently used method
14
of their formation is the trapping of enolate anions, which can be generated under either
kinetic or thermodynamic control (Scheme 2.4).26 Other regioselective methods for the
13

OSiMe. OSiMe.
+
15 16 17
Scheme 2.4
Conditions
Thermodynamic-
Me3SiCl,DMF,
Et3N, heat
Kinetic-LDA,
Me3SiCl, DME
formation of silyl enol ethers are via the rhodium catalyzed hydrosilylation of cx,p
10
16:17
22:78
unsaturated ketones, via silylation of the enolates formed by various conjugate additions to
cyclic a,p-unsaturated ketones, and via the dehydrogenative sUyation of ketones by silyl
hydrides in the presence of a cobalt catalyst (Scheme 2.5).^^
22
O
R^SiH,
Rhodium catalyst
a) Li, NH3, BUHDH^
• ^
b) Me3SiCl '
Me3SiO
a) Me2CuLi
b) Me^SiCl (R=Me) ^
-or-
Et3Al, Me3SiCN
(R=CN)
R3SiH. pvridine ^
C02(CO)8
19
24 25
Scheme 2.5
\ OSiR.
99:1

Reactions of Silvl Enol Ethers
The body of literature concerning the reactions of silyl enol ethers is prodigious,
and has been extensively reviewed.^8 It has been found that suitably substituted silyl enol
ethers can be hydrolytically stable, and many have been purified by distillation. An
important feauire of these compounds is their high electron density relative to simple
aUcenes, a characteristic that often allows chemodifferentiation in multifunctional
compounds. At this point some of the most common reactions wUl be noted, as they serve
to give a sense of the reactivity of these compounds.
An extremely common fate of a silyl enol ether is the cleavage of the siUcon-oxygen
bond via attack on sUicon by a nucleophUe. Nucleophiles commonly used for this purpose
include methyUithium and fluoride ion (from various sources). Subsequently, the free
enolate anion is avaUable to react with an electrophUe to give a product Thus,
regioselective silyl enol ether formation and purification, foUowed by enolate regeneration,
allows for the production of regiodefined enolates, which often react with excellent
selectivity. As an example, regioselectively produced silyl enol ether 26 reacts cleanly with
benzaldehyde, in the presence of a catalytic amount of tetrabutylammonium fluoride, to
give ketone 27 (Scheme 2.6).^^ Reaction of the enolate anion with other types of
electrophUes (alkyl haUdes, for example) is also common.
0SiMe3
26
PHCHO, THF,
5-10% rt-Bu4N'' F"
Scheme 2.6
Me3SiO O
Another common reaction of silyl enol ethers is condensation with Lewis acid
activated electrophUes, the most common Lewis acid used being titanium tetrachloride. For
example, the silyl enol ether 26 was alkylated cleanly with tert-buty\ chloride, a reaction
that would be difficult under other conditions (Scheme 2.7).^^
27
11

0SiMe3
(CH3)3CC1,
TiCL
26 28
Scheme 2.7
Many other reactions of silyl enol ethers are known, although they are used less
commonly. Some examples include hydroboration, oxidation by various oxidants
including mem-chloroperbenzoic acid (MCPBA), ozone, lead(IV) carboxylates, and singlet
oxygen, and cycloaddition reactions including cyclopropanations, [2-F2] reactions with
electron deficient alkenes, and the Diels-Alder reaction of a,p-unsaturated silyl enol ethers.
'Danishefsky's Diene' 29 is an example of a silyl enol ether commonly used in the Diels-
OMe
J
MeoSiO in^V
29
Alder reaction. A recent paper reports several reactions of silyl enol ethers
that involve the addition of an electrophUe, without the loss of the silyl enol ether
functionaUty.31 For example, the triisopropylsilyl (TIPS) enol ether 30 reacts with N-
bromosuccinnimide (NBS) to afford the brominated silyl enol ether 31 in 90% yield
(Scheme 2.8). Although the product in many of these reactions still includes sUicon, this
group is usually removed at a later point, and as such the silicon is usually still acting as a
'ferryman.'
0Si(/-Pr)3
NBS
(90%)
0Si(/-Pr)3
»»»'
Y
30 31
Scheme 2.8
Br
LJ
12

'Silicon FunctionaUzed' Silvl Enol Ethers
AU of the silyl enol ethers discussed thus far have had simple alkyl or aryl groups
as the three non-enoxy Ugands on siUcon. For some time, however, workers in tiiis
laboratory have been interested in the chemistry of sUyl enol ethers with various
functionaUzed Ugands on sUicon, a class of compounds that we caU siUcon functionalized
silyl enol ethers. One would imagine that by placing one or more non-aUcyl Ugands on
sUicon, one could, via electronic or steric effects, modulate the reactivity of silyl enol
ethers, possibly in an extremely useful manner. A manuscript reporting the appUcation of
this concept to silyl ethers, rather than silyl enol ethers, appeared in 1988^2. This paper
reported the synthesis of a number of differentiy substituted aUcoxydialkylchlorosilanes 33,
which were then reacted with dodecanol to afford a variety of dialkoxydiaUcylsUane
protected ethers 34. It was reported that by varying the Ugands of the chlorosilanes 33,
the reactivity of sUyl ethers 34 towards the fluoride ion or towards acidic conditions could
be tailored, in some cases resulting in useful selectivities (Scheme 2.9).
RaSiCIa
32
R'OH,
EtsN,
CH2CI2
OR"
/
RgSi
\
01
CH3(CH2)iiOH,
EtsN, CH2CI2
33
Scheme 2.9
34
OCH2{CH2)ioCH3
Prior to work in this laboratory, few silicon functionaUzed silyl enol ethers had
been reported, and no systematic studies of the synthesis or reactions of these type
compounds had been pubUshed. Thus Walkup's report in 1987 of the synthesis of a
number of pinacolone derived siUcon functionaUzed silyl enol ethers 35 was the first study
of this interesting class of compounds.^^ A subsequent pubUcation from this laboratory
reported the successful synthesis of a number of silicon functionalized sUyl enol etiiers. A
focal point of this study was the resolution of diastereomeric silicon functionalized silyl
enol ethers (36) that were chkal at the siUcon atom. Disappointingly, it was found that the
O XR
XR = alkoxy, enoxy,
allyloxy, or amino
ligand
Xc = a chiral
alkoxy group
13

chirality about the siUcon atom did not result in a stereochemical bias in the MCPBA
oxidation34 or other various reactions^S of these silyl enol ethers. However, expertise
gained in these studies did encourage us to investigate other transformations of silicon
functionaUzed silyl enol ethers.
Conclusions
The field of OrganosiUcon chemistry is rich and varied. The unique properties of
OrganosiUcon compounds insure them an important niche in organic chemistry.
OrganosUicon compounds, although useful as final products, are most often used in
synthetic organic chemistry as 'ferrymen'-that is, they are temporarily utilized to direct
and/or alter the reactivity of an organic substrate, and are eventually removed to afford the
desired organic compound. Silyl enol ethers, a subclass of organosUicon compounds, can
be formed in a number of selective reactions, and have been found to undergo a variety of
interesting and useful transformations. Finally, siUcon functionalized sUyl enol ethers can
be expected to exhibit interesting, and perhaps novel, reactivities.
General
Radical Transformations in Synthetic Organic Chemistrv
Literature concerning the study of radical chemistry, a field that dates back to 1900,
documents the painstaking acquisition of a vast amount of insight into the formation,
structure, and reactions of radicals. Fortunately, the groundbreaking work has been
extensively reviewed and summarized.^^ A number of researchers recognized that the
unique properties of radicals could result in useful reactivities, and began to focus on
synthetically useful transformations of these interesting intermediates. The first burst of
activity (other than that concerned with polymer chemistry) began in the 1970's with
investigations of the radical substitution reactions of aromatic compounds. Recent work
has brought rapid development in the use of alkyl radicals in the formation of aliphatic
compounds, especially by the addition of the radicals to various unsaturated compounds.
The utility of radicals in the formation of carbon-carbon bonds has recently been the subject
of several review articles^'^ and a very useful book.^s Articles corroborating computer
models of radical reactions with experimental results have been published recently.39
In this account we will be concerned with the organic chemistry of carbon centered
radicals (henceforth simply called 'radicals'), and thus this introduction will be concerned
with these species, and will not discuss other aspects of radical chemistry. Radicals are
14

most often formed indirectly by the abstraction of some atom or group by another radical.
They are very seldom generated directly. Perhaps the most common metiiod used to
generate carbon centered radicals is the cascade outiined in Scheme 2.10.
Azobisisobutyronitrile (AIBN) undergoes homolytic decomposition readily, under thermal
or photolytic conditions. The resulting isobutyronitrile radical 37 abstracts a hydrogen
atom from tributylstannane (TBTH), a reaction tiiat is favored by the weak tin-hydrogen
bond as well as die polar character of the transition state. The tin radical 38 tiien abstracts
an atom (most often iodine or bromine) or a group 'X' from the functionaUzed organic
compound 40, finaUy forming the desired organic radical 42. A number of other indirect
methods for producing carbon centered radicals are known.^^
AIBN
NC—C- -h n-Bu3SnH
37
n-Bu3Sn- + RX
39 40
heat or light
Scheme 2.10
-^- NC-^C-
37
-f-N,
NC--C—H + n-Bu3Sn-
38 39
n-BugSnX
41
+ R
Radicals are energetic intermediates, with a propensity to combine with themselves
or other radicals, an incUnation not shared by cations or anions. Since radical combination
is usually diffusion controlled in the liquid phase (although the electronic or steric
characteristics of the radical can slow down this process), these combinations occur with
little selectivity. Therefore radical-radical combination reactions are relatively unimportant
as a synthetic method. The most useful reactions of radicals are the result of the
transformation of one radical into another. Reactions of this type include addition
reactions, abstraction reactions, elimination reactions, and rearrangement reactions. These
reactions are well suited for use as propagating steps in a chain reaction, allowing for the
maintenance of low free-radical concentrations and avoiding problems with radical
combination. Of these reactions, addition reactions have taken 'center stage' and found
great utility in preparative organic chemistry.
42
15

The most useful addition reaction of radicals is addition to alkenes or aUcynes.
These reactions result in the formation of a carbon-carbon o bond and the cleavage of a
carbon-carbon n bond, a highly exothermic exchange. Other reactions, such as the
abstraction of a hydroxyl hydrogen or addition to a carbonyl carbon, are endothermic (or,
at least, less exotiiermic), and tiierefore these radical addition reactions are often highly
chemoselective and are tolerant of a large variety of functional groups. Although radicals
are electroneutral (die radical center has no formal charge), substituted radicals are often
considered to be nucleophilic or electrophiUc. Thus radical 43, which is substituted with
electron releasing groups, is considered electron rich and tiierefore nucleophiUc, whereas
radical 44 is electron deficient and electrophiUc. These characteristics of radicals often
CH3^
H-C
CH3O
43
CH3O2C
H-O
CH3O2C
aUow radical additions to act as complements towards otiier types of reactions. For
example, while the cation 45 formed from the bromoglucose 46 will add to electron rich
aUcenes, the corresponding radical 47 will be nucleophUic and wiU tiierefore add efficientiy
to electron poor aUcenes (Scheme 2.11).^
AcO
AcO
CHoOAc
45
O
H
+
^C
AcO \ H
AcO
AcO
CH2OAC
AcO I
Br
46
Scheme 2.11
•H
44
AcO
AcO
CHoOAc
47
O
16
AcO \ H
Radical Cvclizations
Although intermolecular radical additions can be useful,^^ die intramolecularity of
radical cyclizations makes them particularly useful transformations.^^ Probably the most
studied radical cycUzation is tiiat of 5-hexen-l-yl radicals. The kinetics of tiiis cyclization
have been very tiioroughly studied, and it is often used as a 'radical clock' for the indirect
determination of the rates of other radical reactions tiirough competition experiments. In
fact. Wilt has called tiiis cycUzation tiie 'Greenwich Meridian Time' of radical chemistry'."^^

The unsubstituted 5-hexen-l-yl radical 48 cyclizes witii contrathermodynamic
regioselectivity ahnost exclusively to the cyclopentyhnethyl radical 49, with very little of
the more stable cyclohexyl radical 50 produced (Scheme 2.12). This behavior has
6
+
48 49 50
Scheme 2.12
been explained by a greater loss of entropy in the transition state for the 6-endo cycUzation
relative to the 5-exo cycUzation. An alternative explanation is that non-bonded repulsions
cause the transition state for the 6-endo cyclization to be disfavored. However, the most
reasonable explanation seems to be that the geometry necessary for the overlap of the
radical with the n* orbitals of the alkene is less strained in the 5-exo mode of cyclization
(Figure 2.3). Molecular modeling calculations based upon this stereoelectronic approach
have been of good, predictive value in more complex cycUzations, providing evidence for
the vaUdity of this approach.'*^
The Effect of SiUcon Substitution
—cvC*
Figure 2.3
Tra jectory for Radical Add ition
Since stereoelectronic effects are so important in these radical cycUzations, one
would expect that small changes in the geometry of the radical could effect significant
changes in the reaction patiiway. In fact. Wilt reported in 1985 that the replacement of a
C2, C3, or C4 methylene unit in the 5-hexen-l-yl radical with a dimethylsilyl group led to
dramatic changes in the product distribution from the cyclization."^2 These results were not
17

altogether unexpected, as the longer carbon-siUcon bonds, as well as the metiiyl groups
attached to silicon, would be expected to alter the transition state geometry.
In this 1985 publication. Wilt compared rate constants for the reactions indicated in
Scheme 2.13. The behavior of the a-silyl radical 51 as well as the y-silyl radical 52 could
be compared to that of the all-carbon system 53. Compound 54 was also considered, as it
appeared to be a better model for a-sUyl radical 51.
Radical
51
52
53
54
+nBu3Sn»
El
CH2
SiMe2
CH2
CH2
TBTH = «-Bu3SnH Scheme 2.13
E2
SiMe2
CH2
CH2
CMe2
k5(s-i)
6.6x10^
6.5x10"^
2.5x10^
4.7x10^
k6(s-')
1.4x10'
4.3x10^
3.5x10^
unknown
kH(M-^s-^)
1.9x10*^
2.1x10^
2.4x10^
3.6x10^
From the data, one can see that a-sUyl radical 51 cyclizes much more slowly in a
5-exo fashion than does the all carbon system 53. This attenuation in rates was explained
by invoking unfavorable polar contributions in the transition state (Figure 2.4) and strain
.6"
&
^—SiMe2_
Figure 2.4
Polar Contributions in 5-exo
CycUzation of a-SUyl Radical
caused by the long carbon-sUicon bonds. The sUghtly larger kH for tiie a-silyl radical, as
compared to the all-carbon systems 53 or 54 could be explained by invoking favorable
polar contributions to the transition state for this step (Figure 2.5). The slight reduction in
18

Figure 2.5
Polar Contributions in Reduction
of a-SUyl Radical
tiie rate of 5-exo cyclization of y-sUyl radical 52 was attributed to strain caused by the
longer carbon-silicon bonds. Unfortunately, Wilt was unable to dissect rate constants for
the cycUzation of compound 55 as the kH for P-sUyl radicals were not known. All of the

60
56
OtBu
Me, ,CI
^.*°e so^
,s^t^i
a) 5-exo cyclization pi
b) H-atom source
Scheme 2.14
'CH2Br
Et3N, CH2CI2
Scheme 2.15
R^^Y^,
OtBu
R3
O—SiMe.
O—SiMsc
57
OtBu
20

Cyclization of B-Silvl Radicals
The results Wilt obtained with the p-silyl radical 55 are particulary notable. These
radicals showed very Uttie propensity to cyclize, and virtually all cyclization occurred in the
6-endo fashion. These results were explained by invoking this type radical's known
preference to adopt a syn-periplanar conformation, a consequence of the 'P-effect' (see
Figure 2.2). Any cycUzation would require the radical center to twist out of the plane and
lose its homoconjugative stabiUzation. Wilt claimed that a combination of this and the
longer carbon-silicon bonds caused cycUzation, especially in the 5-exo mode, to be
extremely disfavored. A communication pubUshed in 1988 corroborated Wilt's work by
virtue of gas chromatographic (GC) product studies on radicals 55 and 64, without really
reporting anything new (Scheme 2.16)."^'^
r"
egSi—
55 (R=H)
64 (R=CH3)
Conclusions
TBTH ^-
MegSi '
65
(R=H or
CH3, 0%)
+
Scheme 2.16
MOsSi ^
66
(R=H, 7%;
R=CH3, 4%)
+ Me2Si-
H
67
(R=H, 83%;
R=CH3, 61%)
Radical transformations of organic molecules are relatively well understood and are
becoming useful tools for the synthetic organic chemist. Of all the radical reactions of
organic molecules,excluding polymerization, radical cyclizations are the most synthetically
useful. Radical cycUzations of molecules containing siUcon are possible, and these
compounds react differently than the aU carbon systems.
Rationale for this Research
In accord with our ongoing interest in the chemistry of silyl enol ethers, a study of
the free radical chemistry of silicon functionalized silyl enol ethers was enticing. Especially
attractive in this respect was the possibility of an intramolecular free radical reaction of
suitably substituted silyl enol ethers. Although die propensity for simple silicon substituted
5-hexenyl radicals to undergo cycUzation is attenuated relative to tiie all carbon systems, it
21

was not obvious what effects adding an oxygen, especially as part of a silyl enol ether,
would have upon the reactivity of these systems. The success reported for 5-exo
cycUzations of allyl sUyl ethers such as 61 was somewhat suprising given the lack of
cyclization for the simple silicon substituted 5-hexenyl radicals, and was therefore
encouraging. This project was embarked upon with three major goals. First, it was
necessary to discern whether or not a sUyl enol etiier could be suitably functionalized so as
to undergo a free radical cyclization. If this is possible, then a study of how the
incorporation of a functionalized sUyl enol ether affects the outcome of the cycUzation will
add to our knowledge about the properties of siUcon functionalized silyl enol ethers in a
general way. Finally, if such a cyclization is possible, the question can be asked: can it be
developed into a versatUe synthetic method for the use of synthetic organic chemists, who
are more concerned with tiie products of a transformation tiian with the route by which tiie
transformation is carried out.
22

CHAPTER 3
RESULTS AND DISCUSSION
General Considerations
In embarking upon this project the first consideration was the choice of the method
of radical formation. The thermally initiated tri-w-butyltin hydride (TBTH) / azobisiso­
butyronitrile (AIBN) method, outiined in Scheme 2.10, was chosen. This is the most
common metiiod of producing syntheticaUy useful carbon centered radicals, and it has been
utUized in previous studies involving the formation of siUcon substituted alkyl
radicals.'^2,45.47 xhe availabiUty of the requisite silicon substituted aUcyl chlorides"^^ causes
this route to be especiaUy appealing. Since die ultimate fate of tiie aUcyl radicals formed in
tills cascade is hydrogen atom abstraction from TBTH, which regenerates tiie tin radical
39, this reaction is a chain reaction. Therefore, only a catalytic amount of the initiator
(AEBN) is necessary.
Chlorosilanes have been demonstrated to be versatUe starting materials for the
synthesis of 'simple' silyl enol ethers,^ as well as 'silicon functionalized' silyl enol
ethers.^^'^'^'^^ Fortunately, chloroalkylsilanes with either 2 or 3 chlorine atoms on silicon
are readily available. As the synthesis of the simplest 'silicon functionalized' silyl enol
ethers requires the addition of two groups, an enol ether and an additional non-alkyl ligand
"L" to the silicon, the commerciaUy avaUable chloroalkyl methyldichlorosUanes 68 were
chosen as starting materials for the initial studies (Scheme 3.1). That only straight chain
chloroalkylsilanes are avaUable was accepted as an initial limitation upon this research.
Addition of an enolate anion and a functionaUzed group "L," although not necessarily in
that order, to the dichlorosilanes 68 would then afford the siUcon functionalized
chloroalkylsilyl enol ethers 69 (Scheme 3.1) desired for the study of their free radical
cyclizations.
Cl\ .^CH3 ^^^ O^ ^(CH2)n-CH2CI
C|/^'^(CH2)n-CH2CI
68
>
Scheme 3.1
23

Abstraction of the chlorine atom of 69 by tiie tin radical 39 (generated as shown in
Scheme 2.10) would afford sUyl enol etiier substituted aUcyl radicals of general structure
70 (Scheme 3.2). These radicals could cyclize in an endo fashion to afford radical 71, or
an exo fashion to afford radical 72. Radicals 71 or 72 would finally abstract a hydrogen
atom from TBTH, producing the cyclized products 74 and 75. Alternatively, the radical
70 could abstract a hydrogen atom from TBTH, forming the 'directiy reduced' silyl enol
ether 73. This was by far the predominant reaction of the previously studied 'simple' silyl
substituted 5-hexenyl radicals 55'^2 and 64.^7 Any of these hydrogen atom abstractions
would regenerate the tin radical 39, tiius propagating the chain reaction.
{CH2)n
e
ro
3
CQ n-BusSn*
39
{CH2)n
rt-BusSn- (39)
.SI.
O' •(CH2)n
R' R"
Scheme 3.2
L. .^CH3
R'
R'
^ ^ ^
L^^.^CH3
O-^ "^(CH2)n
/ \
.. H
R
75
O-^ ''^{CH2)n-CH3
24

Initial Studies
Much of the work done in this laboratory involving the study of the synthesis and
reactions of silicon functionalized sUyl enol ethers has utUized tiie 3,3-dimethylbuten-
2-yloxy enol etiier ligand. These silyl enol etiiers have been syntiiesized by reaction of the
enolate of pinacolone (3,3-dimethyl-2-butanone, r-butyl methyl ketone) witii various
chlorosilanes.33.34.35 These compounds have been found to be relatively stable to
hydrolysis, by virtue of the buU

Upon homolytic chlorine atom abstraction from 69 (n=0), tiie a-sUyl carbon centered
radical 70 (n=0) would be formed. What is of interest, then, is the fate of this radical.
Du-ect hydrogen atom atom abstraction by tiiis radical to afford 73 (n=0) would be
relatively uninteresting. Exo cycUzation of radical 69 (n=0), to afford 74 (n=0) (after
hydrogen atom abstraction), would require a 4-exo cyclization and would result in the
formation of a l-oxa-2-sUacyclobutane. Stereoelectronic effects would be expected to
disfavor greatly a 4-exo cyclization of this system. The alternative endo cyclization mode
would require the formation of a l-oxa-2-silacyclopentane via a 5-endo cycUzation.
Although 5-endo cycUzations are rare in free radical chemistry, an intramolecular metal
catalyzed hydrosilylation of silyl ether 78 did produce a product (79) from tiiis type
cyclization (Scheme 3.3).^^ However, the stereoelectronic requirement for the metal
mediated reaction is quite different from that of a radical cyclization.
MSv ^Me Me ^e
O H H2PtCl6 - 6H2O ^ o'^
\ ^^ isopropanol reflux \
78 79
Scheme 3.3
Chloromethyl silyl enol ether 80 was easily synthesized following the 'one pot'
procedure developed by Walkup (75% crude yield, 26% distilled. Scheme 3.4).33 This
compound could not be purified by either silica gel or alumina chromatography, as it was
found to undergo rapid decomposition under these conditions. However, purification by
distillation was successful.
EtO. ^Me
a) 1 eq.LDA, ether, Q CHgCI
-78°. 10 minutes ^
b) 1 eq. 77, -78°- 0°,
1 hour
c) 1 eq. EtsN, 1 eq EtOH,
0°- r.t., 12 hours
Scheme 3.4
Silyl enol ether 80 was submitted to typical free radical cyclization conditions
(Scheme 3.5).'*^ Upon examination of the ^H NMR spectrum of the crude reaction mixture
26

it was obvious that a reaction had occurred, as the signals for the chloromethyl ligand on
the starting material had disappeared. Also, in tiie ^H NMR spectrum, the signal for the
methyl ligand on siUcon, a clear singlet in the starting enol etiier, had disappeared and was
replaced by a number of peaks in the area 5 0.2-0.0 ppm of the spectrum. Unfortunately,
there was no sign in the proton NMR of the crude reaction mixture that the 5-endo
cycUzation had occurred. Analysis of the crude reaction was complicated by the fact tiiat
much of the upfield region (6 1.75-0.75 ppm) of the spectrum was obscured by the alkyl
signals of the tri-/i-butyltin byproducts. However, it was expected that the C5 methine
proton of 5-endo cyclized material 83 would appear as a doublet of doublets, or some
similar pattern, in the relatively clear downfield (~ 6 4.00) region of the ^H NMR
spectrum. Attempted purification of the crude reaction mixture was unsuccessful, with
decomposition of the mixture occurring rapidly. These discouraging results led to an
investigation of the next homologue of the series (69, n=l).
TBT'
80 z: >.
TBT-Cl
EtO. ^Me
O CHg-
Scheme 3.5
a) 4-exo cyclization^^
b)TBTH (-TBT- f
The Svnthesis and Radical CvcUzation of a
2-rhloroethvl Silvl Enol Ether
OEt
• -Me
The free radical chemistry of the next homologue of the chloroalkylsilyl enol ethers
69 (n=l) would involve the intermediacy of the p-silyl radical 70 (n=l). As was noted in
the introduction, p-silyl radicals behave unusually. The unusual behavior of these radicals
27

has been attributed to the homoconjugative stabiUzation that is responsible for the p-effect
(see Figure 2.2). It should be noted tiiat homoconjugation would result in a relatively
electrophiUc radical, which would be an especially good match for the electron rich silyl
enol ether alkene.
P-Silyl radicals 70 (n=l) could undergo a 6-endo cyclization to afford, after
hydrogen atom abstraction, a l-oxa-2-silacyclohexane 74 (n=l). The alternate 5-exo
cyclization would afford a l-oxa-2-sUacyclopentane 75 (n=l). Endo cyclization has been
demonstrated to be the major cyclization path for the simple siUcon substituted 5-hexenyl
radicals 51, 55, and 64. The radical cyclization of the steroidal silyl etiier 84 also
proceeded in a 6-endo fashion.^o This reaction models the radical reaction of 2-
chloroethylsUyl enol ethers more closely, as it includes a silicon-oxygen bond in the chain.
However, the stericaUy hindered environment of the disubstituted intemal end of the double
bond of 84, accentuated by the rigid steroid ring system, may have played a significant role
in directing the course of this cyclization. Recall that the similar sUyl ether 61 cyclized in a
5-exo fashion. This is as one would expect when simply considering the steric bulk
surrounding the double bond. Therefore, in order to study the free radical reactions of 2-
chloroethylsilyl enol ethers, an n=l analogue of 69 (86) was synthesized.
THPO
84
TBTH, AIBN,
benzene reflux
70%
Scheme 3.6
Dichloro(2-chloroetiiyl)metiiylsilane is commercially avaUable. The synthesis of
the 2-chloroethyl silyl enol ether 86, according to the proceedure developed by Walkup,
was uneventful (95% crude yield. Scheme 3.7). However, the purification of 86 was a
problem, and once again distUlation was the purification method of choice, although in
practice the crude reaction mixtures were often utiUzed.
28

a) 1 eq.LDA, ether,
-78°. 10 minutes
b) CI
CI
-78°- 0°,1 hour
c) 1 eq. EtsN, 1 eq EtOH,
0°- r.t., 12 hours
Scheme 3.7
EtO. ^Me
:Si
Silyl enol ether 86 was submitted to the free radical cyclization conditions (Scheme
3.8). Once again, it was clear that abstraction of the chlorine atom had occurred, as the
signals for the methylene group attached to the chlorine atom had completely disappeared.
However, the disappearance of these signals was accompanied by the appearance of four
doublets at -3.45 ppm. This is the pattern expected for the proton on the carbon a to the
r-butyl group of the 6-endo cyclized product 90. That is, the C6 proton of 90 would be a
doublet of doublets as a result of coupUng with the two nonequivalent hydrogens on the
neighboring carbon C5. As E and Z isomers are possible for the ring closed product 90, a
total of two doublets of doublets would be expected. Also noted was the disappearance of
the signals for the enol ether vinyl protons and the appearance of a singlet slightiy upfield
86
TBT-
1
TBT-Cl L.
EtO^ .Me
:Si.
CHo-
Scheme 3.8
a) 5-exo cyclization^
b) TBTH (TBT- f
EtO^ ^Me
O Et
29

from where the enol etiier signals had been. Unfortunately, once again the majority of die
upfield region was obscurred by tiie aUcyl signals of the tin byproducts. Finally, inspection
of tiie region about 0.0 ppm revealed tiiat the signal for tiie metiiyl groups on silicon in the
starting material had disappeared, and tiiree peaks, with approximately equal integrations,
had appeared.
Every attempt to purify this crude reaction mixture by chromatography resulted in
rapid decomposition. In Ught of tiie successes in the purification of the silyl enol etiiers by
distiUation, a large scale radical reaction was performed in order to afford sufficient product
to attempt purification by distiUation.
This distillation did, in fact, result in the isolation of a small amount of the 6-endo
cyclized product 90. The product resulting from hydrogen atom abstraction by the p-silyl
radical 87 prior to cyclization, 88, was also identified. It was found that the singlet that
had appeared slightly upfield from the signals for the vinyUc hydrogens of the starting enol
ether was the vinyl signal for this 'directiy reduced' product. Thus, two of the possible
products for this cyclization (88 and 90) were observed in the crude reaction mixture. No
evidence for product 89, resulting from the alternate mode of cyclization (5-exo), was
noted.
By considering relative ^H NMR integrations in the cmde reaction mixture, it was
calculated that the two diastereomers of the cycUzed material were produced in equal
amounts, and that the directly reduced product (88) and the cycUzed products (90, sum of
both isomers) were produced in approximately equal amounts. Two of the signals in the
region about 0.00 ppm correspond to the cyclized isomers, while the tiiird signal
corresponds to the directiy reduced material. Thus all of the signals in the 0.00 region were
accounted for. This would seem to suggest that the identified products were produced
more or less quantitatively, as any conceivable product would have a metiiyl on silicon that
would appear in this region of the ^H NMR spectrum. Unfortunately, the total isolated
yield of the three identified products was only 53%. This problem of mass balance has
been consistant throughout tiiis project, and has as yet to be explained. Possibly some
volatile and/or insolubile byproducts are formed under tiie reaction conditions.
One probable side reaction would be the loss of ethylene from the starting enol ether
86 to afford the silyl chloride 91 (Scheme 3.9). This kind of fragmentation is known (see
Scheme 2.2). Although this type transformation can be thermaUy initiated,^ a control
experiment in which tiie reaction conditions were duplicated in the absence of AIBN did not
result in the decomposition of 86. However, it should be noted that the radical reaction
(86 => 87) results in a build-up of tri-n-butyltin chloride. This tin chloride could promote
30

the formation of 91, eitiier by acting as a Lewis acid, or by serving as a source of chloride
ion (especially if water is present). Silyl chloride 91 could then catalyze its own formation
in the same manner. In any case, 91 most Ukely would not be easily isolable, because of
problems with volatUity and/or polymerization during workup.
EtO^^.^Me EtO^ ^Me
A, Lewis acid, O CI
or nucleophile •^ I + CHo=CHc
Scheme 3.9
Compounds 88 and 90 were found to decompose upon standing. This was not
suprising, considering that it is well known from previous studies that l-oxa-2-
silacyclohexanes are, as a class, very unstable, polymerizing spontaneously upon contact
with water.51 In any case, it was encouraging that 2-chloroethylsilyl enol ether 86 would
cyclize in an 6-endo fashion. Compound 90 is simply an intramolecularly protected y-silyl
alcohol, and as such this cyclization has resulted in the 'reductive a-alkylation' of the
starting ketone (pinacolone). A general transformation of this type would be a worthwhile
synthetic method, and as such this reaction was studied with this as the ultimate goal.
Optimizing the Recipe for the Radical Cyclization
As a competing direct reduction, at ~50% of the products, would prohibit the use of
this radical cycUzation reaction as a general synthetic method, various attempts to optimize
the ring forming reaction were made. Various reaction conditions were explored, and the
88/90 ratio determined by comparison of the ^H NMR peak areas in the crude reaction
mixtures.
In a preUminary experiment, the radical reaction was performed with
triphenylstannane as the hydrogen atom source. This reagent would not obscure the
upfield region of the ^H NMR spectra of the crude reaction mixtures, thus allowing for
easier analyses of the crude reaction mixtures. However, tiie use of this reagent resulted in
almost complete formation of the directiy reduced product 88.
Acting upon a suggestion that compound 88 could be produced by a competing
'ionic' hydride reduction of the starting p-silyl alkyl chloride, enol ether 86 was treated
with TBTH under the 'standard' free radical conditions, excepti that cyclohexane was used
31

as solvent instead of benzene. The nonpolar solvent would be expected to inhibit ionic
reactions relative to tiie 'polarizable' benzene solvent. However, inspection of tiie ^H
NMR spectrum of the crude mixture from tiiis reaction showed complete conversion of the
enol etiier 86 to the directly reduced material 88, witii no cyclized material evident. Using
THF as tiie solvent gave the same results. Toluene was found to behave similarily to
benzene.
One common method used to lessen competing direct reduction in slow radical
cycUzations is the maintenence of extremely low hydrogen atom donor concentrations. Up
to this point this had been accomplished in this research by adding the tin hydride slowly to
the reaction mixture. Another method is the use of a catalytic amount of the tin reagent,
with a hydride reducing agent utUized to reduce the tin chloride formed during the reaction,
and to therefore regenerate the tin hydride.
An early report of a reaction involving the use of catalytic amounts of the tin reagent
used sodium borohydride (NaBH4) as the reagent to re-reduce the tin chlorides formed
when the tin radicals abstracted chlorine to form the alkyl radicals. To make this reaction
homogeneous, r-butanol was used as solvent. Unfortunately, a model reaction of silyl enol
ether 86, performed in r-butanol under the standard stoichoimetric tin hydride conditions,
resulted in the formation of only 88.
An alternate catalytic recipe used sodium cyanoborohydride (NaCNBH3) as the
reducing agent (Scheme 3.10).^2 These reactions were performed in benzene solvent, with
15-crown-5 added to the reaction mixture in order to solubiUze the borohydride. In fact,
upon UtiUzation of this recipe the ratio of cycUzed:directiy reduced products was enhanced
substantially. The yield of the desired products was not significantly increased, however,
and various other products were formed as evidenced by a proliferation of peaks in the 0.0
ppm region of the ^H NMR spectrum. A control experiment established that this was not a
result of reduction of the alkeke moiety of the silyl enol ether 86 by the NaCNBH3.
However, compound 90 may be relatively sensitive to reducing agents. It is also possible
that the chloroborohydrides formed during the course of the reaction catalyze the
decomposition of the starting materials or products. Another problem was that this catalytic
recipe was found to be somewhat less than reliable; at times no reaction occurred under
these conditions. This may be a consequence of the increased number of reagents, each of
questionable purity, that are used in the catalytic recipe, as compared to the recipe involving
stoichiometric amounts of the tin hydride.
32

EtO. ^Me
,Si 0.10 eq. TBTH,
0.20 eq. AIBN,
1.0eq.NaCNBH3,
Ql O.lOeq. Benzo-15-crown-5,
benzene reflux, 12 hours
Scheme 3.10
EtO. ^Me
O^ ^Et
Oxidative Removal of the SiUcon Atom
+
EtO. ^Me
:Si
Although the formation of l-oxa-2-sUacyclohexane 90 had been demonstrated to be
reproducible, the difficulty of efficiently isolating it was discouraging. Therefore, it was
decided that various derivatization methods should be explored, with the hope of finding a
simple reaction of 90 that would afford easUy isolable products. Also, an efficient method
for forming derivatives was necessary for the development of this reaction as a new
synthetic method, so that sUicon could perform in its role as a 'ferryman.'
A well precedented reaction, the oxidation of substituted silyl ethers by hydrogen
peroxide in the presence of fluoride, was thereby attempted.^3 of the procedures described
in this paper, a 'neutral' recipe worked the best. This reaction resiUted in the production of
the diol 92, which could easily be separated from the nonpolar trialkyl tin byproducts (27%
overall from the silyl enol ether. Scheme 3.11). The isolation of diol 92 also confirms that
EtO. ^Me
.31.
10 eq. aqueous H2O2,
10 eq. KHF2,
DMF, 60°, 48 hours
Scheme 3.11
the l-oxa-2-silacyclohexane was indeed formed. This derivatization was reproducible,
altiiough low yields were always obtained.
In any case, these preliminary explorations have demonstrated that the 6-endo
radical cycUzation of 2-chloroetiiylsilyl enol ethers would proceed, and that the resulting 1
oxa-2-sUacyclohexanes could be derivatized in order to afford isolable materials. To
discern the scope of this reaction an attempt was made to synthesize analogues of 86,
differing only in the nature of the enol ether Ugands. However, this was found to be less
33

than trivial. Although this difficulty was eventually surmounted^^ by modifying a recipe
described by Corey and Gross,^^ it was decided to explore simpler systems during this
preliminary stage of this study.
The Svnthesis and Free-Radical Cvclizations of 2-
Chloroethvldimethvlsilvl Enol Etiiers
In order to simpUfy the synthesis and characterization of the 2-chloroethylsilyl enol
etiiers, we decided to study the dimethyl sUyl substituted analogues. The requisite
dimethylchlorosUane 93 was synthesized by the addition of methyUithium to dichloro(2-
chloroethyl)methylsilane(Scheme 3.12). This product could be distilled to high purity. It
was noted that if the distUlation temperature became elevated (-100° or higher), 93, whose
identity had been demonstrated by ^H analysis of the cmde reaction mixtiu'e, would
decompose to dichlorodimethylsilane 94. The identity of this product was discerned by ^H
NMR and verified by conversion to diethoxydimethylsilane 95. The facile decomposition
of 93, which may have been catalyzed by the presence of lithium chloride (a byproduct of
addition of the alkyllithium to the chlorosilane), accents the inherent high reactivity of the 2-
chloroethylsilanes. ^
M^^c-^" CHsLi ^"^si" A S^2_^ Me^ Me EtOH, Me^ Me
L 94 95
'CI 93 XI
Scheme 3.12
Chlorosilane 93 reacted with a variety of lithium ketone enolates to afford the sUyl
enol etiiers (Scheme 3.13, Table 3.1). This condensation was most efficient when HMPA
was UtUized as a cosolvent. These silyl enol ethers were found to be unstable to silica gel
chromatography. Therefore, the relatively clean 'crude' silyl enol ethers 96 were usually
used 'as is' in the radical reactions.
^^ R^>f"CH2R4
'2 p
Me^ ^Me ^
^Si ^^v. THF:HMPA(2:n.-7,g°
b) LDA,-78°-r.t.
O
Scheme 3.13
34

Table 3.1 tabulates data from the synthesis (% yield, ^H NMR data for hydrogens
on C*) and radical reaction (^H NMR data for C* of tiie directiy reduced compound 97 and
IH NMR data for HA of the cycUzed compound 98) of 2-chloroetiiyldimethylsUyl enol
ethers 99-105.
1.05 eq. TBTH,
0.2 eg. AIBN. ^
benzene reflux, R^
12 hours R,
R3
Scheme 3.14
Me^ ^Me
O^ Et
C*HR4
97
+
^ ^
That silyl enol ethers 99-105 reacted under the radical conditions was
Me. .Me
suggested by the disappearance of the proton NMR signals for the hydrogens on the carbon
originally bound directly to the chlorine atom. However, no products from these reactions
were isolable as pure materials by chromatography. Careful examination of the crude ^H
NMR spectra of the radical reaction mixtures of enol,ethers 99,100, 101, and 103
revealed signals that suggested that these sUyl enol ethers had undergone the previously
observed 6-endo cyclization, as well as direct reduction. These cycUc products would be
trialkyl silanes, which are known to be difficult to oxidize under the conditions developed
by Tamao^3 (and used previously to derivatize the dialkoxy-2-oxa-l-silacyclohexane 90).
Therefore, the crude reaction mixtures were derivatized by reaction with a large excess of
methyUithium in ether at room temperature. NucleophiUc displacement of the alkoxy ligand
opened the l-oxa-2-silacyclohexanes efficientiy, and the expected trimethylsilyl alcohols
were easily isolated by siUca gel chromatography. Thus pinacolone was transformed into
the substituted hexanone 107 in 15% overall yield for the tiiree steps (enol ether formation,
radical cyclization, and methyUithium treatment) without purification of any intermediate
(Scheme 3.15). No other identifiable compounds were isolated. This nucleophUic ring
opening of l-oxa-2-silacyclohexanes is known.55
Me^ ^Me
106
Scheme 3.15
107
R4
98
SIMe^
35

#
99
100
101
102
103
104
105
TABLE 3.1
Synthesis and ^H NMR Data for 2-Chloroetiiyldimetiiyl
SUyl Enol Ethers
ENOXY
LIGAND
^
o'''
a^
6
0'"^
1 °^'^
^ • . . . .
O'"^
YIFID
(%)
91
97
39
33
43
96
53
96^
6 4.10(d)
6 3.90(d)
5 4.03(d)
6 3.95(d)
6 4.85(br t)
6 4.93(d)
6 4.42(d)
6 4.06(d)
6 4.01(d)
6 4.67(br s)
6 4.16(d)
6 3.99(d)
iH NMR^
97c
5 4.08(s)
6 4.00(s)
6 3.96(s)
6 4.92(br t)
6 4.02(s)
6 4.67(br s)
NOTES: a) ^H NMR diagnostic peaks, blanks denote peak not present or not identified
b) hydrogcn(s) on C* c) hydrogen(s) on C* d)HA methine hydrogen
98^^
6 3.46(d of d)
6 3.38(dofd)
6 3.47(d of d)
6 3.42(d of d)
5 3.43(m)
6 3.75(m)
36

When the three step procedure was performed via tiie silyl enol ethers 100 and 103
(Table 3.1) without intermediate purification steps, alcohols 108 and 109 were isolated in
22% and 25% overall yields, respectively, from the ketones. Once again, no other
characterizable products were isolated.
SIMe. SIMer
108 109
SUyl enol ether 101 also underwent radical cyclization and subsequent
nucleophilic ring opening. In this case, however, cis and trans isomers are possible. In
fact, the cis alcohol 110-cis was found to be the predominant isomer of an 8:2 mixture
with trans alcohol 110-trans.^^ This selectivity is a consequence of the steric
environment of the cycUzed radical, as the hydrogen atom source can approach more easily
from opposite the newly formed carbon-carbon bond (Scheme 3.16). This type of
stereoselectivity has been reported for other free-radical cyclizations.^^
110-cis
Scheme 3.16
110-trans
SiMer
A careful examination of the ^H NMR spectrum of the cmde reaction mixture from
the radical reaction of silyl enol ether 104 suggested tiiat no cycUzed product was formed.
Signals were observed tiiat could belong to the directly reduced product. Furthermore, no
identifiable product was isolable after metiiyUitiiium derivatization of this crude reaction
mixture. This absence of cyclization is possibly a result of steric hindrance to die approach
of the alkene by the p-silyl radical. This result was disappointing as silyl enol ether 104, if
it did in fact cyclize, could be expected to show stereoselectivity in the radical addition. In
37

fact, considering die selectivity of tiie hydrogen atom abstraction demonstrated in die
selectivity for the formation of alcohol 110-cis, one would expect die selective formation
of l-oxa-2-silacyclohexane 111. The net result would have been the selective formation of
two new chiral centers.
Me>. ,Me
^81
111
Although the ^H NMR spectrum of the cmde reaction mixture from submission
of 102 to the radical cycUzation conditions showed a complete loss of the signals for the
enol ether protons and the protons on the CH2CI moiety, no signals characteristic of the
cycUzed product nor the directly reduced product were evident. Reaction of the cmde
radical reaction mixture with excess methyUitiiium produced no isolable products.
Apparently this enol ether decomposed under the radical cycUzation conditions. It had been
noted that enol ether 102 was more unstable than the other enol ethers used in this study.
The free radical reaction of silyl enol ether 105 gave similar results. No products,
or even characteristic ^H NMR peaks, were noted in either the cmde radical reaction
mixture or the mixture resulting from reaction of this mixture with methyUithium. This was
disappointing, as this reaction was to produce a novel product and serve as a mechanistic
probe. The free radical cyclization of this compound would produce the intermediate
radical 112, which would rapidly rearrange to a new silyl enol ether 113. Ketone 114,
then, was the product expected after treatment of the cmde radical reaction mixture with
methyUithium (Scheme 3.17).
105
- TBT-Cl
Scheme 3.17
MeLi
114
SiMe.
38

A Stereoselective Tandem CvcUzation
SUyl enol ether 115 was synthesized in order to provide evidence for the radical
nature of this cycUzation protocol. If this reaction does, in fact, proceed tiirough an
intermediate cyclized radical (in the case of 115, radical 116), then a rapid 5-exo
cyclization of 116 would be expected to afford the spirobicyclic compound 117. It was
not at all obvious upon inspection of the ^H NMR of the cmde radical reaction mixture that
117 had been formed. However, treatment of die cmde reaction mixture with
metiiyUithium followed by silica gel chromatography afforded the alcohols 118, in 30%
overaU yield from l-heptene-2-one. It was noted that these diastereomeric alcohols were
formed in a 6:1 ratio (discerned by ^H NMR and HPLC analysis of the crude reaction
mixtures). The major isomer was predicted to be the E isomer, by analogy with similar
selective cyclizations.^^ This assignment was supported by the fact that the isomer
assigned as Z was the major isomer produced upon addition of 3-
trimethylsilylpropylmagnesium bromide to 1-methylcyclopentanone. This exciting
stereoselective transformation, a 'tandem cyclization', enriches the possible synthetic utility
of this radical cyclization methodology.
115
118
TBT-
TBT-Cl
SiMe3 -*-
MeLi IP
Scheme 3.18
117
Dienol ethers 119 and 120 could possibly undergo 'tandem cyclization' similar to
tiiat shown above. Upon treatment of tiiese dienol ethers under the radical reaction
conditions the chlorines were efficientiy abstracted. Both crude reaction mixtures were
treated under the Tamao oxidation conditions (the two oxygen Ugands on the silicon allow
for the success of the oxidation procedure).^^ Diol 92 was isolated (14%) from the
39

mixture that originated with dienol ether 119. This is evidence that this silyl dienol ether
underwent only a single cyclization.
^ \
120
Unsvmmetrical Dialkyl Silvl Enol Ethers
In an attempt to synthesize 2-chloroethylsilyl enol ethers that might exhibit better
stability than the dimethylsUyl enol ethers 96, the unsymmetrical dialkyl-2-chloroethylsilyl
chlorides 121 and 122 were synthesized by adding the appropriate nucleophiles to
dichloro-2-chloroethyl-methylsilane. Unfortunately, the silyl enol ethers 123-126,
derived from these chlorosilanes (and r-butyl-(2-chloroethyl)methyl chlorosilane, which
was synthesized by another worker in this laboratory^^), did not exhibit extraordinary
stabilities nor cyclization propensities. Although it was obvious that the radical cyclization
was sensitive to the nature of the alkyl Ugands on sUicon, no real trend was clear. It was
therefore determined that these chlorosUanes demonstrated no advantage for the possible
development of this synthetic methodology.
Me^ ^CH2CH3
cr
121 C'
Me.. ^CH2CH3
O^
124
CI
Me.
O'
:si ^CH2CH3
123
126
CI
40

Conclusions
A number of differently substituted 2-chloroethylsilyl enol etiiers have been
synthesized. By utilizing the appropriate 2-chloroethylsilyl chloride starting materials,
diaUcyl, alkyl-aUcoxy, and dialkoxy 59 substituted 2-chloroethylsilyl enol ethers were
synthesized. Several of these compounds have been demonstrated to undergo free-radical
cyclizations in a 6-endo fashion, when submitted under 'standard' free radical conditions.
A competing reaction is the 'direct reduction' of die chloroetiiyl group. 6-endo radical
cyclizations are rare, and as such these cyclizations are noteworthy. Apparently, the
inclusion of sUicon in these molecules greatiy alters the stereoelectronic requirements for
cycUzation.
The unstable l-oxa-2-silacyclohexane compounds produced by these cyclizations
are derivatized by oxidation by peroxide or by reaction with methylUthium. These
transformations produce 1,4-diols or y-trimethylsilyl alcohols, respectively. The net
reaction, then, is a 'reductive a-alkylation' of the starting ketones. The overall yields for
the three step transformation - enol ether formation, radical cyclization, and derivatization,
were consistantiy low, limiting this route's usefulness as a general synthetic methodology.
However, the stereoselectivity found for the radical cyclization of the 2-chloroethylsUyl
enol ether of cyclohexanone demonstrates a possible advantage of this intramolecular
cyclization reaction. A tandem cyclization of a suitably substituted 2-chloroethylsilyl enol
ether also proceeded with good stereoselectivity. Finally, it was noted that the cycUzation
behavior of this system depends upon the substituents on silicon, although no trends were
discemed for the dialkyl substituted system. These results have been reported in two
preliminary communications.^^-^^ Improvements in the yields of these transformations
could result in this methodology's becoming tmly useful.
41

CHAPTER 4
EXPERIMENTAL DETAU^S
General Methods
Unless otherwise noted all commerciaUy avaUable starting materials were used as
received. Tetrahydrofuran (THF) and diethyl ether (ether) were distilled under nitrogen
from a dark blue solution containing the sodium ketyl of benzophenone immediately before
use. Dichloromethane and trietiiylamine were distiUed from calcium hydride immediately
before use. EtiiyldUsopropylamine (Hunig's base), dimethylsulfoxide (DMSO), and
hexamethylphosphorictriamide (HMPA) were distiUed over calcium hydride and stored
over oven dried 4A molecular sieves. Etiiyl acetate and hexanes were distiUed before use.
Benzene and toluene used for the free radical reactions were distilled under nitrogen from a
dark blue solution of the sodium ketyl of benzophenone, then deoxygenated either by three
freeze/vacuum purge/thaw cycles under a dry nitrogen atmosphere or by bubbling dry
nitrogen through the solvent for 30 minutes, immediately before use.
NMR spectra were obtained on either an IBM AF-200 (200 MHz for proton, 50
MHz for carbon) or an IBM AF-300 (300 MHz for proton, 75 MHz for carbon)
instmment. Unless otherwise noted, all spectra were obtained in deuterochloroform
(CDCI3) solvent, with either residual chloroform or tetramethylsUane (TMS) as an intemal
reference. Spectra are reported as follows: peak position (6) (multiplicity, coupling
constant[s], number of protons). The peak position (6) is in parts per mUlion (ppm). The
coupling constant (J) is in hertz (Hz).
Infrared (IR) spectra were measured on either a Perkin Ehner 1600 series FT-IR or
a Nicolet MX-S spectrometer. Samples were neat films or concentrated chloroform
solutions between NaCl plates.
High resolution mass spectral (HRMS) analyses were performed by the Midwest
Center for Mass Spectrometry, Lincoln, Nebraska.
Analytical thin layer chromatography (TLC) was performed using Merck silica gel
60 F254 aluminum backed plates. Flash chromatography was performed according to the
method reported by Still,^^ using 230-400 mesh silica gel.
42

(33-Dimetiivlbutenvl-2-oxv)ethoxvmetiivl('chlorometiivl)-
silane (80)
^OCH2CH3
.81.
CioH2iC102Si f.w. = 236.82
rt-Butyllithium (1.7 ml of a 2.4 M solution in hexane, 4.0 mmol) was added
dropwise over a 5 minute period to 0.57 ml (4.0 mmol) dUsopropylamine and 10 ml ether
stirring at -78° under nitrogen. After stirring for 10 minutes, 0.50 ml (4.0 mmol)
pinacolone was added, and the mixture was stirred at -78° for an additional 30 minutes.
Dichloro(chloromethyl)methylsUane 77 (0.51 ml, 4.0 mmol)was carefully added, and the
resulting mixture allowed to warm to -0° over one hour. Triethylamine (0.56ml, 4.0
mmol), then dry ethanol (0.23 ml, 4.0 mmol) were added, and the milky suspension
aUowed to warm to room temperature overnight The reaction mixture was added to a
seperatory funnel containing 25 ml ether and 50 ml saturated aqueous NaHCOs, the layers
seperated, and the aqueous layer extracted with three 25 ml portions of ether. The organic
extracts were then combined, washed with 25 ml brine, dried over MgS04, and
concentrated under vacuum to afford 0.75 g (79%) of a clear liquid. Although ^H and ^^c
NMR analysis suggested that the desired product was formed, attempts at purification by
flash column chromatography on silica gel or neutral alumina were unsuccessful.
Purification by distillation was successful, although only 0.25 g (26%) of the product was
isolated.
iR (200 MHZ) 6 4.17 (d, J=1.7, IH), 4.14 (d, J=1.7, IH), 3.86 (q, J=7.0, 2H),
2.86 (s, 2H), 1.26 (t, J=7.0, 3H), 1.07(s, 9H), 0.35 (s, 3H).
13C (50 MHZ) 6 166.05, 87.49, 59.20, 36.59, 27.99, 26.74, 18.16, -6.21.
BP 58° at 1.0 mm Hg.
43

(33-Dimethvlbutene-2-oxv)ethoxv-2-chloroethvl-
metiivlsilane (86^
O'
^OCH2CH3
Si.
CI
Ci iH23C102Si f.w. = 250.84
n-ButyUithium (1.7 ml of a 2.4 M solution in hexane, 4.0 mmol) was added
dropwise over a 5 minute period to 0.57 ml (4.0 mmol) dUsopropylamine and 10 ml ether
stirring at -78° under nitrogen. After stirring for 10 minutes, 0.50 ml (4.0 mmol)
pinacolone was added, and the mixture was stirred at -78° for an additional 30 minutes.
Dichloro(2-chloroethyl)methylsilane (0.71 ml, 4.0 mmol)was carefully added, and the
resulting mixture aUowed to warm to 0° over one hour (at —15° [bath temperature] a white
precipitate separated from the reaction mixture). Triethylamine (0.56ml, 4.0 mmol), then
dry ethanol (0.23 ml, 4.0 mmol) were added, and the milky suspension allowed to warm to
room temperature overnight. The reaction mixture was added to a separatory funnel
containing 25 ml ether and 50 ml saturated aqueous NaHCOs, the layers separated, and the
aqueous layer extracted with three 25 ml portions of ether. The organic extracts were then
combined, washed with 25 ml brine, dried over MgS04, and concentrated under vacuum to
afford 0.95 g (3.8 mmol, 95%) of a clear liquid. ^H and 13c NMR suggested tiiat the
desired product was formed cleanly. Although this product could not be purified by flash
column chromatography, distUlation under high vacuum was successful, allowing the
isolation of a good yield of pure product.
IH (300 MHZ) 6 4.20 (d, J=1.6, IH), 4.15 (d, J=1.6, IH), 3.86 (q, J=7.0, 2H),
3.77 (d of d , 1=9.7,7.8, 2H), 1.43 (d of d, 1=10.6,7.8, 2H), 1.27 (t, J=7.0, 3H),
1.04 (s, 9H), 0.22 (s, 3H).
13C (75 MHZ) 6 166.00, 87.06, 58.64, 41.75, 36.40, 27.97, 20.82, 18.18, -4.12.
IR 2980, 1680, 1660, 1560, 1520, 1385, 1322.
B P 66-69° at 0.5 mm Hg.
44

3-(tert-Butvl)-l-ethoxv-l-methvl-l-sila-2-oxacvclohexane
{901
EtO^ ^Me
CiiH2402Si f.w-= 216.40
A 500 ml three necked flask, fitted with a stopper, a water jacketed reflux condensor, and a
pressure equaUzing 100 ml addition funnel, was carefully flushed with nitrogen, then
charged with 2.5 g (10 mmol) freshly distiUed sUyl enol etiier 86 and 450 ml dry,
deoxygenated benzene. The addition funnel was charged with 2.7 ml (10 mmol) tributyltin
hydride, 0.025 g (0.15 mmol) AIBN, and 25 ml benzene. The flask was then immersed in
an oil bath and brought to reflux, then the contents of the addition funnel were added in
eight portions over a four hour period. The mixture was allowed to reflux for an additional
15 hours, then cooled and concentrated under vacuum to afford a clear oil, consisting of a
1:1 mixture of the 1:1 mixture of diastereomers 90 and the sUyl enol ether 88, as well as a
large amount of tin containing byproducts (^H NMR). Distillation under a nitrogen
atmosphere afforded 1.14 g (5.3 mmol, 53%) of various mixtures of 90 and 88 distilling
over the range 40-47°, with the lowest boding fraction almost pure 'directiy reduced
product' 88, and with the final fraction almost pure l-oxa-2-silacyclohexane 90. The final
fraction was separated by HPLC to afford the pure diastereomers of 90. This product
decomposed rapidly upon chromatography, and slowly (ti/2 =-7 days) upon storage.
Less polar diastereomer:
iR (200 MHZ, relative to CHCI3 at 6 7.24) 6 3.78 (q, J=7.0, 2H), 3.39 (d of d,
1=11.0,2.1, IH), 2.12-1.98 (m, IH), 1.69-1.60 (m, IH), 1.56-1.33 (m, IH),
1.24-1.11 (m, IH), 1.20 (t, J=7.0, 3H), 0.846 (s, 9H), 0.60-0.51 (m, 2H), 0.10
(s, 3H).
13C (75 MHZ) 6 83.68, 58.11, 29.33, 26.35, 25.71, 21.99, 18.48, 11.18, -4.19.
B P 47°.
MS (GC, retention time=283 seconds, m/e) 216 (M+), 201 (M+-CH3), 159 (M+-
C(CH3)3, base peak).
45

More polar diastereomer:
iR (300 MHZ, relative to CHCI3 at 6 7.24) 6 3.75 (q, J=7.0, 2H), 3.47 (d of d,
1=11.1,1.8, IH). 2.12-1.98 (m, IH), 1.69-1.60 (m, IH), 1.56-1.33 (m, IH),
1.24-1.11 (m, IH), 1.23 (t, J=7.0, 3H), 0.834 (s, 9H), 0.83-0.73 (m, IH), 0.55-
0.30 (m, IH), 0.08 (s, 3H).
13C (75 MHZ) 6 82.59, 57.82, 29.27, 26.35, 25.66, 21.92, 18.42, 11.48, -3.05.
B P 47°.
MS (GC, retention time=293 seconds, m/e) 216 (M+), 201 (M+-CH3), 159 (M+-
C(CH3)3, base peak).
Directly reduced silyl enol ether (88):
IR (300 MHZ, relative to CHCI3 at 6 7.24) 6 4.08 (d, J=1.3, 2H), 3.78 (q, 7.0, 2H),
B P 40°.
1.21 (t, J=7.0, 3H), 1.05 (s, 9H), 0.97 (t, 1=8.9, 3H), 0.70-0.55 (m, 2H), 0.15
(s, 3H).
MS (GC, retention time=238 seconds, m/e) 216 (M+), 201 (M+-CH3), 159 (M+-
C(CH3)3, base peak), 117 (M+-C6H11O).
5.5-Dimetiivl-1.4-hexanediol (92)
C8H18O2 f.w. = 146.23
Aqueous H2O2 (5.88 ml of a 30% solution, 58 mmol), then KHF2 (0.75 g, 9.6
mmol) were added to 0.13 g (0.60 mmol) of a 2:1 mixture of l-oxa-2-silacyclohexane 90
and silyl enol ether 88 stirring at room temperature in 10 ml DMF. The resulting mixture
was warmed to 60° (oil bath temperature) for 48 hours, then cooled and washed with 50 ml
distilled water. The aqueous layer was extracted with 3x25 ml ether, and the organic
extracts combined, washed with 25 ml brine, dried over MgS04, and concentrated under
vacuum. Flash column chromatography (20 g sigel, 8:2 hexanes:etiiyl acetate eluent)
aforded 0.024 g (0.16 mmol, 27%) of the desired product as a clear oU.
46

IR (300 MHZ, rel to CHCI3 at 6 7.26) 6 3.63 (m, 2H), 3.17 (d of d, 1=10.5,1.3,
IH), 2.53 (br s, 2H[variable, -OH]), 1.66 (m, 2H), 1.25 (m, 2H), 0.84 (s, 9H).
13C (75 MHZ) 6 80.17, 63.07, 34.98, 30.44, 28.43, 25.67.
IR 3331, 2955, 2868.
TLC Rf = 0.50 (1:1 hexanes:ediyl acetate eluent).
GC (GC, retention time = 5.04 min, m/e) 89 (M+ - C(CH3)3, base peak).
Chloro(2-chloroethvl)dimethvlsilane(93)
:8i
CK
^Cl
C4HioCl2Si f.w. = 157.12
MethyUithium (60 ml of a 1.4 M solution in hexanes, 84 mmol) was added to 15 ml
(84 mmol) dichloro(2-chloroethyl)methylsUane and 25 ml ether stirring in a 100 ml round
bottomed flask under a nitrogen atmosphere at -78°(bath temperature). After one hour, the
mixture was allowed to warm to room temperature, and the resulting milky suspension was
allowed to stir for an additional 12 hours. The suspension was then filtered through a 5 cm
pad of oven dried ceUte and concentrated under vacuum, taking care to minimize exposure
to the atmosphere. Distillation under aspirator vacuum (-35 mm Hg) afforded 6.8 g (43
mmol, 51%) of the pure product as the fraction distilling between 70-75°. The lower
boiUng fractions were mixtures of the desired product and dichlorodimethylsilane. NOTE:
care must be taken to avoid heating this material too >100°, as its decomposition with the
loss of ethene is facile.
iR (300 MHZ, relative to CHCI3 at 6 7.26) 6 3.76-3.71 (m, 2H), 1.53-1.48 (m, 2H),
0.48 (s, 6H).
13C (50 MHZ) 6 41.70, 24.39, 1.94.
IR 2960 cm-1.
B P 70-75° at 35 mm Hg.
Density (three measurements) 1.06 g/ml.
47

Diethoxvdimetiivlsilane (95)
CH3\ ^OCH2CH3
CH3^ '^OCH2CH3
C6Hi602Si f.w. = 148.28
Ethanol (0.64 ml, 11 mmol) was added to 1.5 ml (11 mmol) triethylamine, 10 ml
dichlorometiiane, and 0.64 g of a compound proposed to be dichlorodimetiiylsUane 94
(5.0 mmol if so), stirring in a 10 ml pear shaped flask under a nitrogen atmosphere at room
temperature. After one hour, die milky suspension was added to a separatory funnel
containing 15 ml distilled water, die layers separated, and die organic layer washed with 10
ml brine. The organic extract was dried over MgS04 and concentrated under vacuum to
afford 0.52 g (3.5 mmol, 70%) of the product 95, >90% pure by iR NMR. The crude ^H
NMR data was deemed sufficient to prove the nature of the starting material, and as such
this volatile product was not purified or characterized further.
IR (200 MHZ, relative to CHCI3 at 6 7.26) 6 3.76 (q, 1=6.3, 4H), 1.21 (t, J=6.3,
6H), 0.13 (s, 6H).
(3.3-Dimethylbutene-2-oxy)(2-chloroethyl)dimethylsUane
199)
CioH2iC10Si f.w. = 220.82
Lithium dusopropylamide (0.37 ml of a 1.5 M solution in hexane, 0.55 mmol) was
added dropwise to 0.063 ml (0.50 mmol) pinacolone, 0.5 ml HMPA, and 1 ml THF
stirring in a 5 ml pear shaped flask at -78° (bath temperature) under a nitrogen atmosphere.
This mixture was stirred for 10 minutes, and then 0.078 ml (1.1 mmol)
48

chloro(2-chloroetiiyl)dimetiiylsilane, 93, was added. The resulting solution was allowed
to warm to room temperature over two hours and stirred at room temperature for an
additional 10 hours, tiien quenched by addition to 15 ml distilled water and 10 ml ether in a
separatory funnel. The layers were separated, the aqueous phase extracted with 3x10 ml
ether, and die combined organic extracts washed with 10 ml brine. Removal of the
solvents under vacuum after drying over MgS04 afforded 0.10 g (0.46 mmol, 91% ) yield
of the desired product, contaminated with a small amount of a siUcon containing impurity
(according to ^H NMR).
iR (200 MHZ, relative to CHCI3 at 6 7.26) 6 4.10 (d, 1=1.7, IH), 3.90 (d, J=1.7,
IH), 3.78-3.70 (m, 2H), 1.44-1.35 (m, 2H), 1.04 (s, 9H), 0.26 (s, 6H).
13C (50 MHZ) 5 166.75, 86.05, 42.24, 36.39, 28.00, 23.15, -1.24.
IR 3122, 2962 cm-l.
(l-CVclohexvlethenvloxv)(2-chloroethvl)dimethvlsilane
£1001
Ci2H23C10Si f.w. = 246.89
Lithium diisopropylamide (0.37 ml of a 1.5 M solution in hexane, 0.55 mmol),
followed immediately by 0.5 ml HMPA, were added dropwise to 0.069 ml (0.50 mmol)
cyclohexyl methyl ketone, 0.082 ml (0.55 mmol) chloro(2-chloroethyl)dimethylsilane,
93,and 2 ml THF stirring in a 5 ml pear shaped flask at -78° (bath temperature) under a
nitrogen atmosphere. The resulting solution was allowed to warm to room temperature
over two hours, stirred at room temperature for an additional 2 hours, then quenched by
addition to 5 ml distiUed water and 5 ml ether in a separatory funnel. The layers were
separated, the aqueous phase extracted with 3x10 ml ether, and die combined organic
extracts washed with 10 ml brine. Removal of the solvents under vacuum after drying over
49

50
MgS04 afforded 0.12 g (0.49 mmol, 97%) of the desired product as a clear oil, >95% pure
(according to iR NMR).
iR (200 MHZ, relative to CHCI3 at 6 7.26) 6 4.03 (d, 1=1.1, IH), 3.95 (d, 1=1.1,
IH), 3.77-3.68 (m, 2H), 1.81-1.73 (m, 5H), 1.43-1.34 (m, 2H), 1.24-1.11 (m,
6H), 0.25 (s, 6H).
13C (50 MHZ) 6 163.71, 87.62, 44.24, 42.23, 30.81, 26.17, 24.80, 23.07, -1.16.
(2-Chloroethvl)( 1 -cvclohexenvloxv)dimethvlsilane (101)
CioHi9C10Si f.w. = 218.80
Lithium diisopropylamide (0.37 ml of a 1.5 M solution in hexane, 0.55 mmol),
followed immediately by 0.5 ml HMPA, were added dropwise to 0.052 ml (0.50 mmol)
cyclohexanol, 0.082 ml (0.55 mmol) chloro(2-chloroethyl)dimethylsilane, 93,and 2 ml
THF stirring in a 10 ml pear shaped flask at -78° (bath temperature) under a nitrogen
atmosphere. The resulting solution was allowed to warm to room temperature over two
hours, stirred at room temperature for an additional 2 hours, then quenched by addition to
15 ml distilled water and 10 ml ether in a separatory funnel. The layers were separated, the
aqueous phase extracted with 3x10 nd ether, and the combined organic extracts washed
with 10 ml brine. Removal of the solvents under vacuum after drying over MgS04
afforded 0.066 g (0.19 mmol, 39% adjusted for impurities) of the desired product and
silicon containing impurities as a -1:1 mixture (according to ^H NMR).
iR (200 MHZ, relative to CHCI3 at 6 7.26) 6 4.85 (br t, 1=3.8, IH), 3.76-3.62 (m,
2H), 2.00-1.98 (m, 4H), 1.69-1.63 (m, 2H), 1.56-1.48 (m, 2H), 1.36-1.27 (m,
2H), 0.22 (s, 6H).
13C (50 MHZ, partial) 6 104.55, 42.38, 29.78, 24.33, 23.74, 23.08, 22.22, -0.94.

(l-Phenvlethenvloxv)(2-chloroetiivl)dimethvlsUane(102)
x^
CnHnClOSi f.w. = 240.83
Lithium diisopropylamide (0.73 ml of a 1.5 M solution in hexane, 1.1 mmol) was
added dropwise to 0.12 ml ( 1.0 mmol) acetophenone, 1 ml HMPA, and 2 ml THF stirring
in a 10 ml pear shaped flask at -78° (bath temperattire) under a nitrogen atmosphere. This
mixture was stirred for 10 minutes,and then 0.24 g (1.5 mmol) chloro(2-chloroethyl)-
dimethylsilane, 93, was added. The resulting solution was aUowed to warm to room
temperature over two hours and stirred at room temperature for an additional 5 hours, then
quenched by addition to 15 ml distiUed water and 10 ml ether in a separatory funnel. The
layers were separated, the aqueous phase extracted with 3x10 ml ether, and the combined
organic extracts washed with 10 ml brine. Removal of the solvents under vacuum after
drying over MgS04 left a 4:1 mixture of the desired product and unwanted sUicon
containing byproducts (according to ^H NMR). Flash column chromatography (20 g silica
gel, hexanes eluent) afforded 0.12 g of a 1:1 mixture of the desired product and the siUcon
byproducts, corresponding to -0.33 mmol (33%) of the product, corrected for its purity.
^n(desired product) (200 MHZ, relative to CHCI3 at 6 7.26) 6 7.59-7.54 (m,
2H), 7.37-7.31 (m, 3H), 4.93 (d, 1=1.9, IH), 4.42 (d, 1=1.9, IH), 3.70-3.62
(m, 2H), 1.28-1.20 (m, 2H), 0.32 (s, 6H).
^H(impurity) (200 MHZ, relative to CHCI3 at 6 7.26) 6 3.79-3.70 (m, 2H),
1.50-1.42 (m, 2H), 0.13 (s, 6H).
51

(2-Chloroethvl)(l-heptenvl-2-oxv)dimethvlsUane(103)
CiiH230ClSi f.w. = 234.84
Lithium dusopropylamide (0.73 ml of a 1.5 M solution in hexane, 1.1 mmol) was
added dropwise to 0.14 ml ( 1.0 mmol) 2-heptanone, 1 ml HMPA, and 2 ml THF stirring
in a 10 ml pear shaped flask at -78° (bath temperature) under a nitrogen atmosphere. This
mbcture was stirred for 10 minutes,and then 0.24 g (1.5 mmol) chloro(2-chloroethyl)-
dimethylsilane, 93, was added. The resulting solution was aUowed to warm to room
temperature over two hours and stirred at room temperature for an additional 5 hours, then
quenched by addition to 15 ml distiUed water and 10 ml ether in a separatory funnel. The
layers were separated, the aqueous phase extracted with 3x10 ml ether, and the combined
organic extracts washed with 10 ml brine. Removal of the solvents under vacuum after
drying over MgS04, foUowed by flash column chromatography (20 g siUca gel, hexanes
eluent) afforded 0.10 g (0.43 mmol, 43%) of the desired product, contaminated with

(3'S.6'R)-(2-Chloroethvl)(3'-(l"-methvlethvl)-5'-methvl-
r-cvclohexenvl-2'-oxv)dimethvlsilane(104)
Ci4H27C10Si f.w. = 274.95
Lithium diisopropylamide (0.68 ml of a 1.5 M solution in hexane, 1.1 mmol),
followed immediately by 1 ml HMPA, were added dropwise to 0.17 ml (1.0 mmol)
menthone, 0.15 g (1.0 mmol) chloro(2-chloroethyl)dimethylsilane, 93, and 4 ml THF
stirring in a 10 ml pear shaped flask at -78° (bath temperature) under a nitrogen atmosphere.
The resulting solution was allowed to warm to room temperature over two hours and
stirred at room temperature for an additional 3 hours, then quenched by addition to 15 ml
distUled water and 10 ml hexanes in a separatory funnel. The layers were seperated and the
aqueous layer wasextracted with 3x10 ml hexanes. The combined organic extracts were
dried over MgS04 and filtered through a 2 cm pad of ceUte. Removal of the solvents under
vacuum afforded 0.26 g (0.96 mmol, 96% yield) of the desu-ed product in -90% purity
(according to^H NMR).
1R (200 MHZ, relative to CHCI3 at 6 7.26) 6 4.67 (br s, IH), 3.77-3.68 (m, 2H),
2.25-1.97 (m, 2H), 1.41-1.32 (m, 2H), 1.31-1.20 (m, 5H), 0.94-0.83 (m, 6H),
0.74 (d, 1=6.7, 3H), 0.23 (s, 6H).
53

l-Cvclopropvlethenvloxv(2-chloroethvl)dimethvlsilane
005)
CgHnClOSi f.w. = 204.77
Lithium diisopropylamide (0.67 ml of a 1.5 M solution in hexane, 1.0 mmol),
followed immediately by 1 ml HMPA, were added dropwise to 0.099 ml (1.0 mmol)
cyclopropyl metiiyUcetone, 0.15 g (1.0 mmol) chloro(2-chloroethyl)dimethylsilane, 93,
and 4 ml THF stirring in a 10 ml pear shaped flask at -78° (badi temperature) under a
nitrogen atmosphere. The resulting solution was allowed to warm to room temperature
over two hours and stirred at room temperature for an additional three hours, then
quenched by addition to 15 ml distilled water and 10 ml hexanes in a separatory funnel.
The layers were seperated and the aqueous layer was extracted with 3x10 ml hexanes. The
combined organic extracts were dried over MgS04 and filtered through a 2 cm pad of
celite. Removal of the solvents under vacuum afforded 0.11 g (0.53 mmol, 53% yield) of
the desired product of -90% purity (according to ^H NMR).
1R (200 MHZ, relative to CHCI3 at 6 7.26) 6 4.16 (d, 1=1.3, IH), 3.99 (d, 1=1.3,
IH), 3.74-3.66 (m, 2H), 1.41-1.33 (m, 2H), 0.59-0.55 (m, 4H), 0.88 (br t,
1=0.9, IH), 0.25 (s, 6H).
2.2-Dimethvl-6-trimethylsilyl-3-hexanol(107)
SIMe.
CiiH260Si f.w. = 202.41
MethyUithium (2.0 ml of a 1.4 M solution in hexanes, 1.8 mmol) was slowly added
to 5 ml ether and die cmde reaction mixture (a -1; 1 mixture of tiie cycUzed [106] and
54

directiy reduced products by iR NMR) from free radical reaction of 0.225 mmol silyl enol
ether 99, stirring in a 10 ml round bottomed flask under a nitrogen atmosphere at room
temperature. After two hours, the mbcture was quenched by careful addition to a
separatory funnel containing 10 ml etiier and 10 ml saturated aqueous ammonium chloride,
die layers separated, and die aqueous layer extracted witii 3x5 ml etiier. The combined
organic extracts were then washed with brine, dried over MgS04, and concentrated under
vacuum to afford the desired product as a minor component of a yellow gum. Flash
column chromatography (10 g siUca gel, 8:2 hexanes:ethyl acetate eluent) afforded 0.0069
g (0.034 mmol, 15% from sUyl enol ether, 30% for tiiis reaction if the purity of the starting
material is taken into account) of the desired product as fine white crystals.
IR (300 MHZ, relative to CHCI3 at 6 7.26) 5 3.19 (br s, IH), 1.56 (br s, lH[OH,
variable]), 1.60-1.20 (m, 4H), 0.89 (s, 9H), 0.50 (d of t, 1=11.2,4.8, 2H), -0.02
(s, 9H).
13C (50 MHZ) 6 79.73, 35.46, 34.86, 25.69, 21.42, 16.77, -1.64.
1 -Cvclohexvl-4-trimethylsilyl-1 -butanol (108)
8i(CH3).
Ci3H280Si f.w. = 228.50
MethyUithium (1.5 ml of a 1.4 M solution in hexanes, 2.0 mmol) was slowly added
to 5 ml ether and the cmde reaction mixture (a 1:1:1 mixture of starting material, the
cycUzed material, and the directiy reduced material) from free radical reaction, using
stoichiometric tin hydride, of 0.50 mmol silyl enol ether 100, stirring in a 10 ml round
bottomed flask under a nitrogen atmosphere at room temperature. After two hours, the
mixture was quenched by careful addition to a separatory funnel containing 10 ml etiier and
10 ml saturated aqueous ammonium chloride, the layers separated, and the aqueous layer
extracted with 3x5 ml ether. The combined organic extracts were then washed widi brine,
dried over MgS04, and concentrated under vacuum to afford die desired product as a minor
component of a yellow oil (^H NMR). Flash column chromatography (10 g sUica gel, 8:2
55

56
hexanes:etiiyl acetate eluent) afforded 0.025 g (0.034 mmol, 22% from cyclohexyl methyl
ketone) of the desked product as a clear oil.
IR (300 MHZ, relative to CHCI3 at 6 7.26) 6 3.25-3.21 (m, IH), 1.72 (br s, lH[OH,
variable], 1.56-1.44 (m, 13H), 1.24-1.18 (m, 2H), 0.96-0.72 (m, 2H), -0.02 (s,
9H).
13C (50 MHZ) 6 75.99, 43.65, 38.05, 29.19, 27.72, 26.54, 20.39, 16.75, -1.66.
MS (high resolution, m/e) 137.1331 (M+-H2O, Si(CH3)3, 0.6 ppm deviation).
l-TrimethvlsUvl-4-nonanol (109)
.8iMe3
Ci2H280Si f.w. =216.49
MethyUithium (1.5 ml of a 1.4 M solution in hexanes, 2.0 mmol) was slowly added
to 5 ml ether and the cmde reaction mixture (an -1:1 mixture of starting material, the
cycUzed material, and the directiy reduced material) from free radical reaction, using
stoichiometric tin hydride, of 0.50 mmol silyl enol ether 103, stirring in a 10 ml round
bottomed flask under a nitrogen atmosphere at room temperature. After two hours, the
mixture was quenched by careful addition to a separatory funnel containing 10 ml ether and
10 ml saturated aqueous ammonium chloride, the layers separated, and the aqueous layer
extracted with 3x5 ml ether. The combined organic extracts were then washed with brine,
dried over MgS04, and concentrated under vacuum to afford the desired product as a minor
component of a yellow oU (^H NMR). Flash column chromatography (10 g sUica gel, 8:2
hexanes:ethyl acetate eluent) afforded 0.028 g (0.13 mmol, 25% from cyclohexyl metiiyl
ketone) of the desired product as a clear oil.
iR (300 MHZ, relative to CHCI3 at 6 7.26) 6 3.66-3.52 (m, IH), 1.49-1.13 (m,
lOH), 0.91-0.85 (m, 6H), 0.54-0.44 (m, 2H), -0.02 (s, 9H).
13C (50 MHZ) 6 71.79, 41.48, 37.51, 31.91, 25.34, 22.66, 20.06, 16.75, 14.06,
-1.66.
MS (high resolution, m/e) 129.0735 (M+-C5Hii,CH3, 0.6 ppm deviation).

2-(2'-TrimethylsUvlethvl)cvclohexanol (110)
8i(CH3),
CiiH240Si f.w. = 200.44
MethyUitiiium (1.5 ml of a 1.4 M solution in hexanes, 2.0 mmol) was slowly added
to 5 ml ether and the cmde reaction mixttire (an -1:1 mixture of cyclized and directiy
reduced products) from free radical reaction, using stoichiometric tin hydride, of 0.50
mmol silyl enol ether 101, stirring in a 10 ml round bottomed flask under a nitrogen
atmosphere at room temperature. After two hours, the mixture was quenched by careful
addition to a separatory funnel containing 10 ml ether and 10 ml saturated aqueous
ammonium chloride, the layers separated, and the aqueous layer extracted with 3x5 ml
ether. The combined organic extracts were then washed with brine, dried over MgS04,
and concentrated under vacuum to afford the desired product as a component of a yellow
oU. HPLC analysis of this mixture suggests a 4:1 mixture of diastereomers. Flash column
chromatography (10 g sUica gel, 8:2 hexanes:ethyl acetate eluent) afforded 0.019 g (0.097
mmol, 19% from cyclohexanone) of the desired product as a clear oil. The diastereomers
were well separated by careful flash chromatography of this oil (10 g sUica gel, hexanes -
8:2 hexanes:ethyl acetate eluent gradient).
Major Diastereomer (110-cis, as shown):
IR (300 MHZ, relative to CHCI3 at 5 7.26) 6 3.29-3.17 (br s, IH,), 1.96-1.62 (m,
4H), 1.43 (br s, lH[OH, variable]), 1.29-1.02 (m, 6H), 0.88 (m, IH), 0.60 (d of
t, 1=14.5,4.2, IH), 0.32 (d of t, 1=4.2,14.5, IH), -0.02 (s, 9H).
13C (50 MHZ) 6 74.43, 47.65, 35.73, 29.39, 25.84, 25.57, 24.95, 12.68, -1.77.
MS (high resolution, mixture of diastereomers, m/e) 200.1595 (M+, 0.5 ppm
deviation), 185.1354 (M+-CH3, 4.1 ppm deviation), 170.1129 (M+-C2H6, 1.2
ppm deviation), 167.1257 (M+-CH3,H20, 0.6 ppm deviation).
RPLC tR=870 seconds, 9:1 hexanes:ethyl acetate eluent at 1.0 ml/min on a 25 cm
(4.6 mm ID) Dupont Zorbax siUca gel column.
57

Minor Diastereomer (110-trans, not shown):
IR (300 MHZ, relative to CHCI3 at 6 7.26) 6 3.94 (br s, IH), 1.82-1.16 (m, 12H),
0.47 (m, 2H), -0.01 (s, 9H).
RPLC tR=678 seconds, 9:1 hexanes:ethyl acetate eluent at 1.0 ml/min on a 25 cm
(4.6 mm ID) Zorbax silica gel column.
(2-Chloroethvl)ri -6-heptadien-2-vloxv)dimethvlsUane (115)
CiiH2iC10Si f.w. = 232.83
Lithium dusopropylamide (0.68 ml of a 1.5 M solution in hexane, 1.1 mmol),
followed immediately by 1 ml HMPA, were added dropwise to 0.13 g (1.1 mmol) 1-
heptene-6-one,62 0.15 g (1.0 mmol) chloro(2-chloroethyl)dimethylsUane, 93, and 4 ml
THF stirring in a 10 ml pear shaped flask at -78° (bath temperature) under a nitrogen
atmosphere. The resulting solution was allowed to warm to room temperattu-e over two
hours and stirred at room temperature for an additional 3 hours, then quenched by addition
to 15 ml distilled water and 10 ml ether in a separatory funnel. The phases were separated
and the organic layer was dried over MgS04 and filtered tiirough a 2 cm pad of celite.
Removal of the solvents under vacuum afforded 0.28 g (1.2 mmol, >100% yield) of the
desired product, contaminated with a silicon containing impurity (^H NMR). Flash column
chromatography (20 g silica gel, hexanes eluent) afforded 0.16 g (0.68 mmol, 68%) of the
desired product
iR (300 MHZ, relative to CHCI3 at 5 7.26) 6 5.87-5.74 (m, IH), 5.01 (d, J=19.2,
IH), 4.97 (d, 1=7.9, IH), 4.07 (d, J=l.l, IH), 4.03 (d, J=l.l, IH), 3.75-3.69
(m, 2H), 2.10-1.99 (m, 4H), 1.59-1.49 (m, 2H), 1.35-1.28 (m, 2H), 0.25 (s,
6H).
13C (75 MHZ) 5 158.84, 138.48, 114.73, 90.32, 42.13, 35.71, 30.03, 25.98, 22.94,
-1.19.
58

2-Methyl-l-(3-trimethvkilylDropvl)cvcloDentanol (118)
8i(CH3)3
Ci2H260Si f.w. = 214.43
MethyUithium (1.5 ml of a 1.4 M solution in hexanes, 2.0 mmol) was slowly added
to 5 ml ether and the cmde reaction mixture from free radical reaction, using stoichiometric
tin hydride, of 0.50 mmol silyl enol ether 115, stirring in a 10 ml round bottomed flask
under a nitrogen atmosphere at room temperature. After two hours, the mixture was
quenched by careful addition to a separatory funnel containing 10 ml ether and 10 ml
saturated aqueous ammonium chloride, the layers separated, and the aqueous layer
extracted with 3x5 ml ether. The combined organic extracts were then washed with brine,
dried over MgS04, and concentrated under vacuum to afford the desired product as a
component of a yellow oU. HPLC analysis of this mixture suggests a 6:1 E:Z ratio. Flash
column chromatography (10 g siUca gel, 8:2 hexanes:ethyl acetate eluent) afforded 0.032 g
(0.015 mmol, 30% from 6-heptene-2-one) of the desired product as a clear oil. The
diastereomers were separated by careful flash chromatography of this oil (10 g silica gel,
hexanes - 8:2 hexanes:ethyl acetate eluent gradient).
Major Isomer (E, as shown):
iR (300 MHZ, relative to CHCI3 at 67.26) 62.05 (m, IH), 1.85 (m, IH), 1.73-1.12
(m, 9H), 1.13 (s, lH[OH, variable]), 0.84 (d, J=7.1, 3H), 0.50 (m, 2H), -0.06
(s, 9H).
13C (75 MHZ) 684.05, 44.36, 40.42, 36.85, 31.77, 20.64, 18.27, 17.53, 16.63,
-1.60.
IR 3383, 2953, 1248, 862, 837 cm-L
RPLC tR=582 seconds, 9:1 hexanes:ethyl acetate eluent at 1.0 ml/min on a 25 cm
(4.6 mm ID) Zorbax silica gel column.
MS (mixture of diastereomers, high resolution, m/e) 214.1759 (M+, 1.0 ppm
deviation), 199.1516 (M+-CH3, 1.0 ppm deviation), 196.1651 (M+-H2O, 2.1
ppm deviation, 181.1414 (M+-CH3,H20, 0.8 ppm deviation).
59

Minor Isomer (Z, not shown):
IR (300 MHZ, relative to CHCI3 at 6 7.26) 6 1.83-1.25 (m, 1 IH), 0.97 (s, lH[OH,
variable]), 0.92 (d, 1=6.7, 3H), 0.49 (t, 1=8.3, 2H), -0.02 (s, 9H).
13C (75 MHZ) 6 82.17, 43.72, 42.90, 38.14, 31.93, 20.92, 18.99, 17.50, 12.50,
-1.60.
IR 3481, 2953, 2930, 2870, 1248, 862, 837 cm-l.
RPLC tR=426 seconds, 9:1 hexanes:ethyl acetate eluent at 1.0 ml/min on a 25 cm
(4.6 mm ID) Zorbax silica gel column.
Bis-(33-dimethvlbutene-2-oxy)(2-chloroethyl)methvlsilane
am
Ci5H29C102Si f.w. = 304.94
n-ButyUithium (1.8 ml of a 2.2 M solution in hexane, 4.0 mmol) was added
dropwise over a 5 minute period to 0.57 ml (4.0 mmol) dUsopropylamine and 10 ml ether
stirring at -78° under nitrogen. After stirring for 10 minutes, 0.50 ml (4.0 mmol)
pinacolone was added, and the mixture was stirred at -78° for an additional 30 minutes.
Dichlorochloroethyl-methylsUane (0.28 ml, 2.0 mmol) was carefully added, and die
resulting mbcture allowed to warm to room temperature. After stirring at rcx)m temperature
overnight (-18 hours) the reaction mixture was added to a seperatory funnel containing 25
ml ether and 50 ml saturated aqueous NaHC03, the layers seperated, and die aqueous layer
extracted witii tiiree 25 ml portions of etiier. The organic extracts were tiien combined,
washed witii 25 ml brine, dried over MgS04, and concentrated under vacuum to afford
0.74 g (>100%) of a yellow liquid. Flash column chromatography (20g Sigel, hexanes
eluent) afforded 0.33 g (54%) of relatively pure product. Attempted free-radical cyclization
60

61
of the crude product resulted in the formation of a number of products (TLC and ^H NMR)
with no evidence of products resulting from cyclization (iR NMR).
IR (200 MHZ, rel to CHCI3 at 6 7.24) 6 4.15 (d, 1=1.6, 2H), 4.12 (d, 1=1.6, 2H),
3.74 (d of d, 1=8.6,8.6, 2H), 1.45 (d of d, 1=8.6,8.6, 2H), 1.05 (s, 18H), 0.29
(s, 3H).
IR 2955, 1910, 1868, 1631, 1472, 1293, 1171, 1036, 1015 cm-l.
Rf 0.65 (hexanes).
Bis-(cvclohexen-l-vloxv)(2-chloroethvl)methvlsilane(12Q)
Ci5H25C102Si f.w. = 300.90
In an attempt to synthesize (cyclohexen-l-yloxy)ethoxy(2-chloroethyl)methylsilane,
n-butyUithium (1.7 ml of a 2.4 M solution in hexane, 4.0 mmol) was added dropwise over
a 5 minute period to 0.57 ml (4.0 mmol) dUsopropylamine and 10 ml ether stirring at -78°
under nitrogen. After stirring for 10 minutes, 0.42 ml (4.0 mmol) cyclohexanone was
added, and the mixture was stirred at -78° for an additional 30 minutes. Dichloro-(2-
chloroethyl)methylsilane (0.56 ml, 4.0 mmol)was carefully added, and the resulting
mixture allowed to warm to -0° over one hour. Triethylamine (0.56ml, 4.0 mmol), then
dry ethanol (0.23 ml, 4.0 mmol) were added, and die miUcy suspension allowed to warm to
room temperature overnight. The reaction mixture was added to a seperatory funnel
containing 25 ml etiier and 50 ml saturated aqueous NaHC03, the layers seperated, and the
aqueous layer extracted with three 25 ml portions of ether. The organic extracts were then
combined, washed witii 25 ml brine, dried over MgS04, and concentrated under vacuum to
afford 1.1 g (4.4 mmol, >100% if mono-enol ether; 3.7 mmol, 91% if bis-enol ether) of a

clear Uquid. Altiiough iR and 13c NMR analysis suggested that die desUed product was
formed (albeit in low yield) flash column chromatography (20 g sigel, 9:1 hexanes;etiiyl
acetate eluent) successfuUy purified only the bis-enol etiier (0.128 g, 0.43 mmol, 11 %).
IR (200 MHZ, rel to CHCI3 at 6 7.24) 5 4.98 (br s, 2H), 3.74-3.65 (m, 2H), 2.03-
1.96 (m, 8H), 1.68-1.62 (m, 4R), 1.54-1.43 (m, 4H), 11.38-1.33 (m, 2H), 0.25
(s, 3H).
13C (50 MHZ) 6 149.26, 105.25, 41.62, 29.43, 23.68, 22.98, 22.11, 20.94,
-3.32.
Chloro(2-chloroetiivl)ethvlmethvlsilane(121)
cr ^
XI
C5Hi2Cl2Si f.w. = 171.16
Ethylmagnesium chloride (19 ml of a 2.0 M solution in THF, 38 mmol) was added
dropwise over a 10 minute period to 5 ml (36 mmol) dichloro(2-chloroethyl)methylsUane
and 20 ml ether stirring in a 100 ml round bottomed flask under a nitrogen atmosphere at
-78°(bath temperature). After one hour, the mixture was aUowed to warm to room
temperature, and the resulting milky suspension was allowed to stir for an additional 12
hours. The suspension was then filtered through a 5 cm pad of oven dried celite and
concentrated under vacuum, taking care to minimize exposure to the atmosphere.
DistiUation under high vacuum (-1 mm Hg) afforded 2.4 g (14 mmol, 39%) of the pure
product.
iR (300 MHZ,, relative to CHCI3 at 6 7.26) 6 3.75 (d of d of d, 1=7.5,3.2,0.9, IH),
3.72 (d of d of d, 1=7.5,3.0,0.8, IH), 1.51 (d of d, 1=7.5,3.2, IH), 1.49 (d of d,
1=7.5,3.0, IH), 1.04 (t oft, 1=8.2,1.4, 3H), 0.91-0.81 (m, 2H), 0.42 (s, 3H).
13C (75 MHZ) 6 41.28, 22.82, 9.75, 6.38, -0.31.
Density (three measurements) 1.04 g/ml.
62

Chloro(2-chloroetiivDmethvl( 1 -metiivlpropvl) silane (122)
CI' Si
CI
CvHieChSi f.w. = 199.20
5-ButyUithium (62 ml of a 1.3 M solution in hexanes, 80 mmol) was added to 11
ml (80 mmol) dichloro(2-chloroethyl)methylsilane and 25 ml ether stirring in a 100 ml
round bottomed flask under a nitrogen atmosphere at -78°(bath temperature). After one
hour, the mixture was allowed to warm to room temperature, and die resulting milky
suspension was allowed to stir for an additional 2 hours. The siispension was then filtered
through a 5 cm pad of oven dried ceUte and concentrated under vacuum, taking care to
minimize exposure to the atmosphere. High vacuum distiUation (1 mm Hg) afforded 3.0 g
(15 mmol, 19%) of die pure product as the fraction distUUng between 73-77°. The product
appears to be a 5:4 mixture of d,l and meso products.
iR (300 MHZ, relative to CHCI3 at 6 7.26) 6 3.77-3.69 (m, 2H), 1.55-1.40 (m, 2H),
1.29-1.18 (m, 2H), 1.05 (d, 1=2.8, 1.3H), 1.02 (d, J=2.8, 1.7H), 0.98 (t, 1=7.3,
3H), 0.93-0.83 (m, IH), 0.415 (s, 1.7H), 0.411 (s, 1.3H).
13C (75 MHZ) 6 41.49, 23.60, 23.12, 21.89, 13.07, 12.62, -1.46.
B P 73-77° at 1 mm Hg.
Ethvl(2-chloroethvl)( 1 -cvclohexvletiienyloxv)methylsilane
11231
\ ^CH2CH3
Ci3H25C10Si f.w. = 260.92
63

Lithium diisopropylamide (0.67 ml of a 1.5 M solution in hexane, 1.0 mmol),
followed immediately by 0.75 ml HMPA, were added dropwise to 0.14 ml (1.0 mmol)
cyclohexyl methyUcetone, 0.17 ml (1.0 mmol) chloro-(2-chloroediyl)-etiiylmethylsilane,
and 2 ml THF stirring in a 5 ml pear shaped flask at -78° (badi temperature) under a
nitrogen atmosphere. The resulting solution was allowed to warm to room temperature
over two hours, stirred at room temperature for an additional 2 hours, tiien quenched by
addition to 5 ml distUled water and 5 ml hexanes in a separatory funnel. The layers were
separated, die aqueous phase extracted with 3x5 ml hexanes, and die combined organic
extracts washed with 5 ml brine. Drying over MgS04 and filtration tiirough a 2 cm pad of
celite, followed by removal of solvents afforded 0.24 g (0.92 mmol, 92%) of the desired
product in -90% purity ( according to iR NMR).
1R (200 MHZ, relative to CHCI3 at 6 7.26) 6 4.02 (d, 1=0.9, IH), 3.94 (d, 1=0.9,
IH), 3.75 (d, 1=9.9, IH), 3.71 (d, 1=10.1, IH), 1.92-1.59 (m, 8H), 1.40 (t,
1=8.0, IH), 1.38 (t, 1=9.5, IH), 1.30-1.18 (m, 3H), 0.99 (t, 1=7.5, 3H), 0.73 (t,
1=7.5, 2H), 0.22 (s, 3H).
(33-Dimethvlbutenvl-2-oxv)ethvl(2-chloroethvl)-
methvlsUane (124)
>^ ^CHoCHo
O^ ^
CI
CiiH23C10Si f.w. = 234.88
Lithium diisopropylamide (0.67 ml of a 1.5 M solution in hexane, 1.0 mmol),
followed immediately by 0.75 ml HMPA, were added dropwise to 0.13 ml (1.0 mmol)
pinacolone, 0.17 ml (1.0 mmol) chloro-(2-chloroethyl)-ethylmethylsilane, and 2 ml THF
stirring in a 5 ml pear shaped flask at -78° (bath temperature) under a nitrogen atmosphere.
The resulting solution was allowed to warm to room temperature over two hours, stirred at
room temperature for an additional 2 hours, then quenched by addition to 5 ml distilled
water and 5 ml hexanes in a separatory funnel. The layers were separated, the aqueous
64

phase extracted witii 3x5 ml hexanes, and the combined organic extracts washed witii 5 ml
brine. Drying over MgS04 and filtration through a 2 cm pad of ceUte, foUowed by removal
of solvents under vacuum afforded 0.16 g (0.66 mmol, 66%) of die desired product in
-90% purity (according to iR NMR).
iR (200 MHZ, relative to CHCI3 at 6 7.26) 6 4.09 (d, 1=1.7, IH), 3.89 (d, 1=1.7,
IH), 3.76 (d, 1=9.9, IH), 3.72 (d, 1=10.0, IH), 1.40 (t, 1=8.0, IH), 1.37 (t,
1=9.6, IH), 1.05 (s, 9H), 1.04-0.96 (m, 2H), 0.78-0.67 (m, 3H), 0.23 (s, 3H).
r-Butvl(2-chloroethvl)methvl( 1 -phen vlethenvloxv)silane
(125)
Ci5H23C10Si f.w. = 282.89
Lithium dusopropylamide (0.73 ml of a 1.5 M solution in hexane, 1.1 mmol) was
added dropwise to 0.12 ml (1.0 mmol) acetophenone, 1 ml HMPA, and 2 ml THF stirring
in a 10 ml pear shaped flask at -78° (bath temperature) under a nitrogen atmosphere. This
mixture was stirred for 10 minutes,and then 0.22 g (1.1 mmol) r-butylchloro(2-
chloroethyl)methylsilane,3^ was added. The resulting solution was allowed to warm to
room temperature over two hours and stirred at room temperature for an additional 10
hours, then quenched by addition to 15 ml distilled water and 10 ml ether in a separatory
funnel. The layers were separated, the aqueous phase extracted with 3x10 ml ether, and
the combined organic extracts washed widi 10 ml brine. Removal of the solvents under
vacuum after drying over MgS04, followed by flash column chromatography (20 g sigel,
hexanes eluent) afforded 0.27 g (0.88 mmol, 88%) of the desired product.
IR (200 MHZ, relative to CRCI3 at 6 7.26) 6 7.61-7.56 (m, 2R), 7.37-7.27 (m, 3H),
65

4.91 (d, 1=1.9. IH), 4.43 (d, 1=1.9, IH), 3.75 (d of d, 1=6.7,1.7, IH), 3.69 (d
of d, 1=6.7,1.4, IR), 1.56-1.40 (m, 2H), 1.01 (s, 9H), 0.27 (s, 3H).
13C (50 MHZ) 6 128.42, 128.18, 126.23, 125.15, 167.51, 194.37, 91.43, 42.59,
25.80, 18.78, -5.68.
r-Butvl(2-chloroethvl)(l -heptenvl-2-oxv)methvlsilane (126)
Ci4H29C10Si f.w. = 276.93
Lithium dusopropylamide (0.73 ml of a 1.5 M solution in hexane, 1.1 mmol) was
added dropwise to 0.14 ml (1.0 mmol) 2-heptanone, 1 ml HMPA, and 2 ml THF stirring
in a 10 ml pear shaped flask at -78° (bath temperature) under a nitrogen atmosphere. This
mixture was stirred for 10 minutes, and then 0.22 g (1.1 mmol) tert-butylchloro(2-
chloroethyl)-methylsilane,^^ was added. The resulting solution was aUowed to warm to
room temperature over two hours and stirred at room temperature for an additional 10
hours, then quenched by addition to 15 ml distilled water and 10 ml ether in a separatory
funnel. The layers were separated, the aqueous phase extracted with 3x10 ml ether, and
the combined organic extracts washed with 10 ml brine. Removal of the solvents under
vacuum after drying over MgS04, foUowed by flash column chromatography (20 g silica
gel, 9:1 hexanes:ethyl acetate eluent) afforded 0.23 g (0.83 mmol, 83%) of the desired
product, contaminated with

REFERENCES
1. Colvin, E. Silicon in Organic Synthesis; Butterworths: London, 1981; p 1.
2. Rochow, E.G. /. Am. Chem. Soc. 1945, 67(6), 963-965.
3. Speier, I.E.; Webster, I.A.; Barnes, G.H. /. Am. Chem. Soc. 1957, 79(4), 974-
979.
4. Perozzi, E.F. and Martin, LC. /. Am. Chem. Soc. 1979,101(6), 1591-1593.
5. Gordon, M.S.; Windus, T.L.; Burggraf, L.W.; Davis, L.P. /. Am. Chem. Soc.
1990,112(20), 7167-7171. Deiters, LA. and Holmes, R.R. /. Am. Chem. Soc.
1990, 112(20), 7197-7202.
6. Whitmore, F.C.; Sommer, L.H.; Gold, 1. /. Am. Chem. Soc. 1947, 69(8),
1976-1977.
7. Shambayati, S.; Blake, J.F.; Wierschke, S.G.; Jorgenson, W.L.; Schreiber, S.L.
/. Am. Chem. Soc. 1990, /72(2j, 697-703.
8. Epiotis, N.D.; Yates, R.L.; Bernardi, F.; Wolfe, S. J. Am. Chem. Soc. 1976,
98(18), 5435-5439. Lehn, J.-M. and Wipff, G. /. Am. Chem. Soc. 1976,
98(24), 7498-7505.
9. lackson, R.A.; Ingold, K.U.; Griller, D.; Nazran, A.S. J. Am. Chem. Soc.
1985,107(1), 208-211.
10. Sommer, L.H.; Bailey, D.L.; Whitmore, F.C. /. Am. Chem. Soc. 1948, 70(9),
2869-2872.
11. Sommer, L.H.; Dorfman, E.; Goldberg, G.M.; Whitmore, F.C. /. Am. Chem.
Soc. 1946, 68(3), 488-489.
12. Sommer, L.H.; Goldberg, G.M.; Dorfman, E.; Whitmore, F.C. /. Am. Chem.
Soc. 1946,68(6), 1083-1085.
13. larvie, A.W.P. Organometal. Chem. Rev. A 1970, 6, 153-207.
14. Lambert, J.B; Finzel, R.B. J. Am. Chem. Soc. 1982, 104(7), 2020-2022.
15. Kawamura, T.; Kochi, J.K. J. Am. Chem. Soc. 1972, 94(2), 648-650.
16. Wilt, J.W.; Belmonte, F.G.; Zieske, P.A. /. Am. Chem. Soc. 1983, 105(17),
5665-5675. WUt, J.W.; Lusztyk, J.; Peeran, M.; Ingold, K.U. J. Am. Chem.
Soc. 1988,110(1), 281-287.
17. Yoshida, 1-i.; Maekawa, T.; Murata, T.; Matsunaga, S-i.; Isoe, S. /. Am. Chem.
Soc. 1990,112(5), 61962-1970.
67

18. Brook, M.A.; Neuy, A. /. Org. Chem. 1990,55(11), 3609-3616.
19. Hwu, I.R.; Furth, P.S. /. Am. Chem. Soc. 1989, 111(24), 8834-8841.
20. lackson, R.A.; Ingold, K.U.; Griller, D.; Nazran, A.S. /. Am. Chem. Soc.
19S5,107(1), 208-211.
21. Arkles, B.; Peterson, W.R. Ir.; King, K. Silacrowns, a New Class of
ImmobUizable Phase Transfer Catalysts. In Chemically Modified Surfaces in
Catalysis and Electrocatalysis; No. 192 of the ACS Symposium Series; Miller,
I.S., Ed.; American Chemical Society: Washington, D.C., 1982; pp 281-292.
22. Tacke, R. and Wannagat, U. Syntheses and Properties of Bioactive Organo-
SiUcon Compounds. In Bioactive Organo-Silicon Compounds, No. 84 of Topics
in Current Chemistry, Boschke, F.L., Ed.; Springer-Verlag: BerUn, 1979; pp 16-
18.
23. Tacke, R. and Zilch, H. Drug-design by SUa-substitution and Microbial
Transformations of OrganosUicon Compounds: Some Recent Results. In Silicon
Compounds Register and Review, the Petrarch Systems Silanes and Silicones
Catalogue, Anderson, R.; Arkles, B.; Larson, G.L., Eds.; Petrarch Systems:
Bristol, PA, 1987; p 47.
24. Colvin, E.W. Silicon Reagents in Organic Synthesis; Academic Press: London,
1988; p ix.
25. Thies, R.W.; MiUs, M.T.; Chin, A.W.; Schick, L.E.; Walton, E.S. J. Am. Chem.
Soc. 1973, 95(16), 5281-5285. Thies, R.W.; Bolesta, R.E. /. Org. Chem.
1916,41(7), 1233-1236.
26. reference 23, p 99.
27. reference l,p 199-200.
28. Rasmussen, l.K. Synthesis 1911,9\. Fleming, L Chimia 19m, 34,265.
Brownbridge, P. Synthesis 1983, 1; 85. Taylor, R.LK. Synthesis 1985, 364.
Also see reference 23, pp 99-117.
29. reference 1, p 219.
30. reference 1, p 221.
31. Magnus, P. and Mugrage, B. /. Am. Chem. Soc. 1990,112(1), 462-464.
32. GiUard, I.W.; Fortin, R.; Morton, H.E.; Yoakim, C; Quesnelle, C.A.; Daignault,
S.; Guindon, Y. /. Org. Chem. 19SS, 53(11), 2602-2608.
33. Walkup, R.D. Tetrahedron Lett. 1987, 28(5), 511-514.
34. Walkup, R.D. and Obeyesekere, N.U. J. Org. Chem. 1988,53(4), 920-923.
68

35. Obeyesekere, N.O. PhD. Dissertation, Texas Tech University, 1988.
36. Waters, W.A. The Chemistry of Free Radicals; Clarendon Press: Oxford, 1946.
Walhng, C. Free Radicals in Solution; Wiley: New York, 1957. Kochi, J.K. (ed.)
Free Radicals; Wiley: New York, 1973.
37. Curran,D.P. Synthesis 198H,4\1-439, 4S9-5\3. Ramaiah, M. Tetrahedron
1987,43, 3541-3676.
3 8. Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds;
Pergammon Press: Oxford, 1986.
39. Laird, E.R. and Jorgenson, W.L. /. Org. Chem. 1990,55(1), 9-27. Shaik, S.S.
and CanadeU, E. /. Am. Chem. Soc. 1990,112(4), 1446-1452.
40. Giese, B.; Gonzales-Gomes, J.A.; Witzel, T. Angew.Chem. Int. Ed. Engl. 1984,
23(1), 69-70.
41. For example, see Stork, G. Radical Mediated Cyclization Processes. In Selectivity
- a Goal for Synthetic Efficiency, Bartmann, W. and Trost, B.M., Ed.; Verlag
Chemie: Basel, 1984; pp 281-298. Choi, L-K.; Ha, D.-C; Hart, D.J.; Lee, C.-S.;
Ramesh, S.; Wu, S. /. Org. Chem. 1989,54(2), 279-290.
42. WUt, J.W. Tetrahedron 1985, 41(19), 3979-4000.
43. Beckwith, A.L.J, and Schiesser, C.H. Tetrahedron 1985, 41(19), 3925-3941.
44. Nishiyama, H.; Kitajima, T.; Matsumoto, M.; Itoh, K. /. Org. Chem. 1984,
49(12), 2298-2300.
45. Stork, G. and Kahn, M. /. Am. Chem. Soc. 1985,107, 500-501. Stork, G. and
Sofia, M.J. /. Am. Chem. Soc. 1986,108(21), 6826-6828.
46. Tamao, K.; Ishida, N.; Kumada, M. /. Org. Chem. 1983,48, 2120.
47. Saigo, K.; Tateishi, K.; Adachi, H.; Saotome, Y. J. Org. Chem. 1988,53(7),
1572-1574.
48. Petrarch Systems, Bristol PA has the largest selection of commerciaUy available
OrganosiUcon compounds
49. Mironov, V.F.; KozlUcov, V.L.; Fedotov, N.S. Zh. Obshch. Khim. 1969, 39,
966-970.
50. Koreeda, M. and George, LA. /. Am. Chem. Soc. 1986,108, 8098-8100.
51. Smith, C.L. and Gooden, R. J. Organomett. Chem. 1974, 81, 33-40. Corriu,
R.J.P. and Moreau, J.IE. /. Organomet. Chem. 1976, 114, 135-144. Barton,
T.L and Revis, A. /. Am. Chem. Soc. 1984,106, 3802-3805.
69

52. Stork, G. and Sher, P.M. /. Am. Chem. Soc. 1986,108, 303.
53. Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics 1983, 2(11),
1694-1696. Tamao, K.; Kumada, M.; Maeda, K. Tetrahedron Lett. 1984, 25(8),
321-324.
54. Corey, E.l. and Gross, A.W. Tetrahedron Lett. 1984, 25, 495. This proceedure
was modified by the adcUtion of HMPA to tiie reaction mixture.
55. Boroni, P.I.; Corriu, R.J.P.; Guerin, C. /. Organomet. Chem. 1976,104, C17-
C19.
56. This stereochemistry was assigned in analogy with 2-ethylcyclohexanol. lones,
J.B. and Takemura, T. Can. J. Chem. 1982, 60, 2950-2956.
57. Giese, B.; Gonzalez-Gomez, J.A.; Lachhein, S.; Metzger, J.O. Angew. Chem.
Int. Ed. Engl. 1987, 26, 479-480.
58. Curran, D.P.; Kim, D.; Liu, H.T.; Shen, W. /. Am. Chem. Soc. 1988,110,
5900.
59. WaUcup, R.D.; Obeyesekere, N.U.; Kane, R.R. Chemistry Lett. 1990, 31(7),
1055-1058.
60. Walkup, R.D.; Kane, R.R.; Obeyesekere, N.U. Tetrahedron Lett. 1990, 31(11),
1531-1534.
61. StiU, W.C; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2933.
62. House, H.O. and Lee, L.F. J. Org. Chem. 1976,41(5), 863-866.
70

PARTE
A SYNTHESIS OF THE CARBON-9 TO CARBON-21
SUBUNIT OF THE APLYSL\TOXINS AND
OSCILLATOXINS

CHAPTER 5
BACKGROUND
Discovery of the Aplysiatoxins and OsciUatoxins
The aplysiatoxins and oscillatoxins are natural products isolated from marine
sources. The first toxins isolated, aplysiatoxin (1) and debromoaplysiatoxin (2), were
found in the digestive gland of the moUusk Stylocheilus longicauda which were coUected
off the coast of Hawaii. ^ Later, Moore reported the isolation of these compounds from the
bluegreen alga Lyngbya majuscula.'^ Outbreaks of severe contact dermatitus affecting
swimmers off the coast of Hawau have been attributed to these toxins.^ It has been shown
that the toxins found in the moUusks were a result of these animals feecUng upon toxin
producing algae. Several other algal sotu^ces of these classes of toxins have been
identified. Debromoaplysiatoxin (2) and 19-bromoaplysiatoxin (3), as well as the 31-nor
compounds oscillatoxin A (4), 17-bromoosciUatoxin (5), and 17,19-dibromooscillatoxin A
(6), were isolated from a mixture of the bluegreen algae Schizothrix calcicola and
Oscillatoria nigroviridis?-
1: Aplysiatoxin -
R=CH3, Xi=Br, X2=H
2: Debromoaplysiatoxin -
R=CH3, Xi=X2=H
3: 19-Bromoaplysiatoxin -
R=CH3, Xi=X2=Br
4: Oscillatoxin A -
R=H, Xi=X2=H
5: 17-Bromooscillatoxin A -
R=H, Xi=Br, X2=H
6: 17,19-DibromooscUlatoxin A
R=H,Xi=Br, X2=Br
CH3O Xi CH3O Xi
72
7: Anhydrodebromoaplysiatoxin -
R=CH3, Xi=X2=H
8: Anhydro-19-bromoaplysiatoxin
R=CH3, Xi=X2=Br
9: Anhydrooscillatoxin A -
R=H, Xi=X2=H
10: Anhydro-17-bromooscillatoxin A -
R=H, Xi=Br, X2=H
11: Anhydro-19-dibromooscillatoxin A
R=H, Xi=Br, X2=Br

The anhydrotoxins 7-11 were also isolated, and it was claimed that these
compounds always accompany the otiier toxins and are not artifacts of the isolation
conditions.4 Finally, the toxins 12-16 were also isolated from this mixture of algae. The
oscillatoxins 12, 13, and 16 have also been isolated, along with 2 and 7, from an
OscUlatoriaceae alga collected near the MarshaU Islands.^
I
OH OH
12: OsciUatoxin B1 -
Ri=CH3, R2=CH3, R3=OH
13: Oscillatoxin B2-
Ri=CH3, R2=OR, R3=CH3
14: 31-NorosciUatoxin B -
Ri=CH3, R2,R3=CH3,OH
(mixture of epimers)
Stmcture Determination
15: OsciUatoxin D
R=H
16: 30-MethyloscUlatoxin D
R=CH3
Using information gleaned from chemical ionization mass spectroscopy (CI-MS),
ultraviolet spectroscopy (UV), infrared spectroscopy (IR), and proton nuclear magnetic
resonance spectroscopy (^H NMR) on the natural compounds and on various degradation
products, Kato and Scheuer were able to discern the gross stmctures of aplysiatoxins 1 and
2.1 Careful consideration of ^H NMR data and of the chemical behavior of these
molecules (as well as the anhydro compound 7) under certain reaction conditions allowed
these researchers to propose relative stereochemistry for the stereo-centers from C4 to
Cii.^ Subsequent ^H NMR studies by Moore et al. supported these assignments."^
Difference Nuclear Overhauser Effect (NOE) experiments allowed Moore's group to extend
the assignment of relative stereochemistries to include C12 and C29. The absolute
stereochemistry at C15 was determined by comparing the circular dichroism (CD) spectra of
compounds 2 and 4 with those of compounds 17-22. The authors proposed that the a-
band (the band arising from a 7r-7t* transition in an aromatic chromophore situated in a
chiral environment) in these compounds' CD spectra should be comparable, as they are all
73

substituted benzyl alcohols. In fact, the CD spectra of compounds 2, 4, and 17-22 are
remarkably similar, with each exhibiting positive Cotton effects at -280 nm. Therefore
Moore assigned to the natural product die corresponding stereochemistry (15S). However,
Johnson has questioned the appUcability of these comparisons.'^ Since CD spectra result
OH
17
OH
20
OH
'V^
OH
18
OCH.
^ ^
OCH.
OCH.
from the net chiral environment surrounding the chromophore, significant
21
changes in the conformation of the model compounds and the natural products could cause
a perturbation of the spectra. EspeciaUy worrisome is the possibiUty of through-space
effects upon the chromophore by the large chiral ring system of the natural product.
Johnson also noted that the achh-al substitution pattern on tiie aromatic ring can greatly
affect the magnitude and even the sign of CD spectra of similar compounds, an important
point that suggests that comparisons of die CD spectra of the aplysiatoxins with those of
the model compounds 17,18, and 20-22 are especially risky. Although Johnson claims
to have addressed this last point by making CD comparisons of 2 with compound 23
(synthesized as part of his Ph.D. research), it appears that this comparison attracts his very
own criticisms. In any case, his results supported Moore's assignment of the absolute
configuration of C\s in compounds 1-11 as S.
H3C,
OCH3
23
OCH.
OH
74

Moore was able to complete the assignment of the absolute stereochemistry of
compounds 1-6 (and thus 7-11 by analogy) and 12-16 by utilizing various other CD and
molecular rotation comparisons,^ and even though several of die analogies that he drew
seem to be questionable,'^ a total synthesis of 2 has demonstrated that these assignments are
correct.^
At this point the relationship between oscUlatoxin D (15) and oscillatoxin A (4),
and analogously that between 30-metiiylosciUatoxin D (16) and debromoaplysiatoxin (2),
should be noted (Scheme 5.1). One could imagine that compound 24, the triketo tautomer
^^T]) ?^
0=
HO>
^^-^^^^^^4^0
OCH,
Scheme 5.1
-H2O
H2O ^ 15
of OsciUatoxin A (4), could undergo an intramolecular aldol condensation with concomitant
loss of water to afford cyclohexenone 25. The combination of a Michael addition of the
hydroxyl group to the doubly activated alkene and a dehydrative translactonization would
then complete the transformation to 15.
75

Bioloeical Activity of the Aplvsiatoxins and Oscillatoxins
As was previously noted, aplysiatoxin (1) and debromoaplysiatoxin (2) can cause
severe contact dermatitus. The aplysiatoxins have been demonstrated to be potent
cocarcinogens. Cocarcinogens are compounds tiiat enhance tumor development in tissues
diat have been exposed to a carcinogen, but tiiat wiU not act as a carcinogen in then- own
right. Much of the interest that these compounds have garnered is a result of this activity.^
As dieir names suggest, the aplysiatoxins (1-3) and A osciUatoxins (4-6) are highly toxic,
although the corresponding anhydrotoxins (7-11) and die B and D oscillatoxins (12-16)
do not appear to have significant toxicity. Debromoaplysiatoxin (2) and oscillatoxin A (4)
have demonstrated interesting antileukemic activity against the P-388 ceU line.
Unfortunately the optimum antUeidcemic activity occurred at toxic levels. Interestingly,
Professor R.E. Moore observed that the D oscUlatoxins are active against the L1210
leukemia cell line, but that insufficient material was avaUable to thoroughly analyze this
activity.^o Since these " toxins" have been shown to be relatively non-toxic, this
antileukemic activity should be further explored. Also, as it has been shown that bromine
substitution of the aromatic ring of the aplysiatoxins significantiy enhances their biological
activity, it seems possible that the hitiiero unisolated brominated D oscillatoxins could also
have enhanced biological activities.
Progress Toward the Total Svnthesis of
OsciUatoxin D
The total synthesis of oscillatoxin D (15) is an ongoing project in our laboratories.
The aforementioned biological activity of this compound is a major reason for our interest
in pursuing this project. A total synthesis could allow sufficient quantities of 15 (as well
as various analogues including bromine containing analogues) to be produced to allow a
diorough evaluation of their biological activities. The inherent chaUenge in synthesizing
such a complex molecule is also a factor in our interest. This spirobicyclic allyl ether is a
foreboding challenge, especially considering die requisite stereochemistry.
76

Model stucUes performed in our laboratory have recentiy culminated with the ring
closure of 26 to form spirobicycle 27 (Scheme 5.2).ii Although this compound was
formed unexpectedly and has undesired functionaUty at C9, its formation has provided us
with confidence that the proposed route to the desired model 30 (as indicated in Scheme
5.2), and eventually to the natural product, will be successful. Especially encouraging was
R3SiO
28
26
0
(TBDMS = tBuMe2Si,
Tf=CF3S02,
TMSE = Me3SiCH2CH2)
• ^ TM8E0
iPrNEt2,
TBDMSOTf.
CH2CI2
29
Scheme 5.2
TBDM80
27
(major diastereomer
of a 12:2:2:1 mixture,
72% combined yield)
30
77

78
the high degree of stereoselectivity found for die formation of the spirobicyclic ring of 27
from 26.
A route to compound 26 is outUned in Scheme 5.3. Aldol condensation between
thepara-methoxyphenylmethyl (MPM)-protected 6-hydroxy ketone 31 and the aldehyde
32, foUowed by oxidation to the P-diketone and removal of the 11-hydroxyl protecting
group affords alcohol 33 in good yield. 12 Acid catalyzed ketalization of 33 with
concomitant dehydration, followed by removal of the MPM protecting group and oxidation
produces aldehyde 34, which is then condensed widi trimetiiylsilylethyl (TMSE) acetate
enolate 35 followed by oxidation to afford p-ketoester 26. It can be easily recognized that
if one utilizes aldehyde 36 instead of aldehyde 32, then an analogue of 26 containing all of
the functionality required to complete the total synthesis of Oscillatoxin D (15) will be
produced. Therefore, as part of a convergent total synthesis of 15, an efficient means of
producing the C9-C21 aldehyde 36 was necessary, and such was the goal of the project
described herein.
26
TMSEO
35
Scheme 5.3
O OR OCH.
36
-^ MPMO' O
O
OR'
.y^^^L
34
33
11
{/

Other Synthetic Studies on the Aplysiatoxins
The synthesis of a suitably protected C9-C21 aldehyde 36 is especially attractive, as
this compound is a potential precursor for the total synthesis of all of the compounds 1-14.
Several research groups have focused tiieir attention upon the total synthesis of aplysiatoxin
1 and debromoaplysiatoxin 2, because of the interesting stmctures and biological activities
of these compounds. Kishi's group at Harvard University has reported the only total
synthesis of any of these compounds to date.^ They synthesized compound 37, a C8-C21
synthon simUar to our proposed C9-C21 aldehyde intermediate 36, en route to the total
synthesis of 2. An outUne of their synthesis of this fragment is given in Scheme 5.4.
(Bn = C6H5CH2)
BnO
OH
A
S02Ph
3 steps,
54%
+
OBOM
13 steps,
31% A
11
OBn
/ A \ 8 steps,
68%
(-)-diethyl D-tartrate Scheme 5.4
OBOM
3 steps,
43%
79

Kishi obtained the correct stereochemistry at C9-C12 by a performing series of
stereoselective reactions upon the protected triol 39, which was synthesized according to
Uterature precedent in eight steps of 68% overaU yield. Thirteen steps, in 31 % overall
yield, transformed 39 into sulfone 38, which is a precursor of the anionic nucleophile that
Kishi required. The stereochemistry at C15 was obtained by Kishi by stcu-ting with tiie
enantiomerically pure amidoalcohol 41, which was converted to the benzyloxymethyl
(BOM) protected epoxide 40 in three steps and 43% overall yield. Coupling of 38 and
40, followed by reductive desulfurization and ether formation, afforded 37 in three steps
and 54% yield. Therefore, the longest linear series of reactions involved twentyfour
transformations and was performed in 11% overaU yield.
A 1988 pubUcation by Ireland et al^^ reported an aborted attempt at the total
synthesis of aplysiatoxin. Although they did not synthesize a subunit comparable to ours,
the method that they used to establish the absolute stereochemistry at C15 should be noted.
Thus, ketone 42 was stereoselectively reduced using the Uthium aluminum hydride (LAH)
/ (S)-2,2'-binapthol complex developed by Noyori (Scheme 5.5).^^ This reaction yielded
71% of the alcohol 43 of greater than 95% ee on a large scale (>3 grams 43 isolated).
OCH.
(S)-2,2'-binapthol,
EtOH. LAH. THF^
-100°for4hrs
-78°forl6hrs
Scheme 5.5
OH
OCH.
The total synthesis of the unnatural aplysiatoxin, 3-deoxydebromoaplysiatoxin 44,
was the subject of two recent papers by .^^ Compound 44 has been shown to have
biological activity comparable to diat of debromoaplysiatoxin (2). The removal of die labile
hemUcetal functionality should increase the stabiUty of compound 44 relative to the natural
products, and as such this compound deserves attention. (This is a good example of a
totally synthetic analogue that may have characteristics superior to the natural product.)
This synthesis of 44 utilized the protected C8-C21 tetraol 46 (TBDMS = tert-
butyldimethyl-silyl), which is comparable to Kishi's intermediate 37 and to our proposed
aldehyde 36. Ketone 45 was synthesized in 13 steps and 19% overall yield from
diacetone glucose. This ketone was then stereoselectively reduced by Brown's
dUsocampheylchloroborane (Ipc2BCl) reagent,^^ i^ 74% yield and -100% ee, and finally
80

methylated to afford the ether 46 (Schema '^ A^ TU AH , • , •
iiici HO (,5cneme 5.6). Thus 46 was obtamed in 15 steps and
14% overall yield from commercially available material.
44 R=H
2 R=OH
OBn
1) IPC2BCI,
THF, -25°
2)NaH, THF,
Mel
Scheme 5.6 OBn
Conclusions
The aplysiatoxins and osciUatoxins are interesting new marine natural products.
Oscillatoxin D is a minor constituent of several algae, and although it is of interest because
of reported antileukemic activity, thorough biological testing has not been done as
insufficient quantities of it have been isolated. Model studies performed by another student
in this laboratory have demonstrated a possible synthetic route to the spirocyclic ring
system, therefore a C9-C21 aldehyde 36 is necessary to complete the actual synthesis of the
natural product. Synthetic work on the aplysatoxins has resulted in the development of
several lengthy pathways to compounds similar to aldehyde 36, a compound which could
be used in the synthesis of all of the aplysiatoxins.
81

CHAPTER 6
RESULTS AND DISCUSSION
Retrosynthetic Analysis of Target Aldehyde (36)
In approaching the synthesis of aldehyde 36, it was recognized that it would be
advantageous to introduce the aldehyde functionaUty at the very end of the synthesis. This
would reduce problems stemming from the high reactivity of this functional group. An
aldehyde functionaUty would also facilitate epimerization of the Cio chiral center.
Therefore compound 47, in which an MPM (para-metiioxyphenyhnethyl) protected C9
hydroxy group serves as a 'masked' aldehyde, was chosen as a penultimate target (Scheme
6.1).
OCH.
V
MPMO OR OCH3
MPM = ^ara-methoxyphenylmethyl OR'
MPMO OR X
V OCH.
+
Scheme 6.1
82
OR'

The MPM group was chosen because it could be removed under mild oxidizing
conditions (2,3-dichloro-5,6-dicyanobenzoquinone, DDQ) that most other hydroxyl
protecting groups wiU widistand.17 Selective removal of the MPM protecting group,
foUowed by oxidation, would afford aldehyde 36.
To simplify matters further a convergent route, where some fragment containing
C9-C13 would be somehow joined with a fragment containing C15-C21, was considered.
In fact, the previous syntheses of C8-C21 containing intermediates 37 and 46 have utilized
this approach.8.15 Consequentiy, compounds 48 and 49, in which X and Y are functional
groups that will aUow coupling, were chosen as targets. The coupUng combinations that
were considered were a C13 nucleophile displacing a C14 leaving group, and a C14
nucleophile displacing a C13 leaving group. Kishi's synthesis of debromoaplysiatoxin 2
used the former combination to form the C13-C14 bond (Scheme 5.4),8 while Yamamura's
synthesis of deoxydebromoaplysiatoxin 44 relied upon a Wittig coupling, followed by
hydrogenation of the resulting C13-C14 double bond.^^
Studies on the Stereoselective Synthesis of a
Ci4zCi5.Epo2cide
The oxirane functional group is very useful in synthetic organic chemistry.^^ One
common transformation of this functional group is attack by a nucleophile at the least
substituted carbon. In this manner oxiranes function as 'masked' a-hydroxy electrophUes.
Since this is exactly what was desired for the C14-C21 synthon, the fu-st goal of this project
was an efficient stereoselective synthesis of a C14-C15 epoxide. Kishi utilized this strategy
in his total synthesis of debromoaplysiatoxin 2, where he opened a C14-C15 epoxide with
an a-sulfonyl carbanion.8 It was perceived that Kishi's route to the epoxide could possibly
be improved, and that a C13 nucleophile (probably an a-sulfonyl carbanion similar to
Kishi's but one relevant to die synthesis of oscUlatoxin D) could be fashioned and would
open the epoxide in an analogous fashion. Also noted was that it would be desirable to
protect the phenolic hydroxy group with a hardy protecting group, as this hydroxy group
should remain protected until the last stages of the total synthesis. Therefore efforts to
synthesize epoxide 50, where R is an appropriate protecting group, were begun.
83

The first attempt at synthesizing the chiral epoxide 50 reUed upon an asymmetric
reduction of a-ketoester 51 to the a-hydroxy ester 52 by an actively fermenting culture of
bakers yeast (Scheme 6.2). Compound 51 was synthesized from meta-hydoxy-
acetophenone by protection as a benzyl etiier, permanganate oxidation to the a-keto acid,
and esterification. Yeast cultures have been demonstrated to reduce simUar aromatic a-
ketoesters (lacking, however, tiie meta substituents) in high yield and witii exceUent
stereoselectivity. 19 Although the desired a-hydroxy ester 52 was produced,20 the low
overaU yield (-30%) and especially the disappointing 80% enantiomeric excess (e.e.) of the
product necessitated a search for a more efficacious route.
l)BnBr
2) KMn04
3) MeOH, H^
(Bn^CgHsCHz)
^-
MeOoC
21
51 BnO
Scheme 6.2
actively fermenting
bakers yeast
MeOsC
OH
21
52 BnO
One of the most powerful methods for producing chiral alcohols is the Sharpless
epoxidation.2i This reaction relies upon the directing affect of an allyUc alcohol, coupled
with a chiral titanium - tartrate complex, to achieve phenomenal sucess in an
enantioselective epoxidation by r-butylhydroperoxide. The mechanism has been studied
and a complex mechanistic picture proposed,22 although Corey has recently proposed a
simpler mechanistic explanation for the selectivity of this reaction.23 This reaction can also
be used to resolve a racemic mixture of aUyUc alcohols (Scheme 6.3).24 For example,
when a racemic mixture of allylic alcohol 53 was treated with -0.6 molar equivalents of
rerr-butyl hydroperoxide under Sharpless' epoxidation conditions, one enantiomer of the
alcohol (S) was rapidly epoxidized, while the other enantiomer reacted very slowly (for this
allylic alcohol kfast/ksiow=83). Separation of the epoxide 55 from the unreacted 'resolved'
alcohol 54 afforded products with high e.e.'s.
84

OH
53
(racemic
mixture)
CH2{CH2)4CH3
1.0 eq. Ti(0-i-Pr)4
1.2 eq. (+)-diisopropyl
, tartrate
0.6 eq. t-BuOOH
CH2Cl2,-20°C,12days
Scheme 6.3
OH
54
96% e.e.
OH
55
92% e.e.
CH2{CH2)4CH3
CH2(CH2)4CH3
To investigate this appUcation of Sharpless' resolution procedure to our problem,
aUyUc alcohol 57, synthesized by addition of vinylmagnesium bromide to meta-
benzyloxybenzaldehyde 56, was submitted to the kinetic resolution conditions (Scheme
6.4). The resolution and subsequent separation of the enantiomer 59 of this alcohol posed
TsO,
56
NaH,
THF
0„
BnO
OH
a)CH2CHMgBr
b)H20
BnO
61
L>-v^-^
62 BnO
57
BnO
TsCl, EtsN
-^-
(Ts=paratoluenesulfonyl)
1.0eq.Ti(O-i-gr)4
1.2 eq. (+)-diisopropyl
tartrate
0.6 eq. t-BuOOH
CH2CI2. -20°C
OH
Scheme 6.4
OH
59
BnO
85

no special problems, altiiough it should be noted tiiat as this is a resolution the maximum
yield is 50%. The subsequent reductive ozonolysis of die resolved allylic alcohol 59 was
especially troublesome, and low yields (-40%) of 60 were isolated.20 Jt was demonstrated
that tills diol could be converted to its monotosylate 61 (33%), and finally to the desired
epoxide 62 (61%)(Scheme 6.4).
Faced with the low yields and lengthy procedure of the route outlined in Scheme
6.4, another route to a chiral epoxide 49 was explored. It has been demonstrated that
enolates derived from chUal binapthol monoesters of phenylacetic acids undergo alkylation
stereoselectively.25 It was envisioned that the oxidation of an enolate 64 could proceed
witii some similar directing effect by the molecular chiraUty of the binapthol system. A
compound that has been demonstrated to oxidize ester enolates efficiently to a-hydroxy
esters is the MoOPH26 reagent (MoOspyridineHMPA [hexamethylphosphorictriamide])
developed by Vedejs.2'7 Although the synthesis of the binapthol monoester 63 was
relatively straightforward, attempts at using the MoOPH reagent to oxidize the enolate 64
to an a-hydroxy ester were unsuccessful (Scheme 6.5). At this point, the lack of success
in synthesizing a chiral C14-C21 epoxide in high yield and with high stereoselectivity made
the alternate 48 + 49 coupUng route attractive.
63
MeO
2.2 eq.LDA
(Lithium
diisopropylamide)
Scheme 6.5
iy4.^H^l c^fndies on thp. Alkvlation of a Cu Anion
(M0O5: (PA =
pyridine: hexamethyl-
HMPA) Phosphorict
triamide)
N.R.
The lack of success in developing an improved route to a C14-C15 epoxide led to
the exploration of the reaction of a C14 carbanionic nucleophile with a C9-C13 synthon
fitted with a leaving group on C13. Since it had been established for similar systems that a
86

Ct5 ketone can be stereoselectively reduced to give the desired 15S configuration n.is it
was proposed that the simplest Ct4 nucleophile would be the enolate (66) of a
trimetiiylsilylethoxymethyl (SEM) protected m.r.-hydroxy acetophenone 65 (Scheme 6 6)
This protecting group,28 which was fitted to m-hydroxyacetophenone in 80% yield, was
chosen because this phenolic hydroxyl group required a robust protecting group so as to
survive until the very end of the total synthesis. Model studies were performed in an
attempt to react enolate 66 with a model mesylate (67) or iodide (68). However, very little
alkylation of enolate 66 was observed under various conditions, including an attempt to
increase the reactivity of the enolate by the addition of HMPA to the reaction mixture.
^
HO
O
SEMC^
R3N
CH2CI2
(SEM = trimethylsilylethoxymethyl
TBDMS = tert-buiyldimethylsilyl)
Scheme 6.6
67 or
67, HMPA ^^
68 or ^^^^^^^"
68, HMPA''
TBDMSO OSOoMe TBDMSO
In an attempt to find a 'ketone enolate equivalent' that would
67 68
undergo the desired alkylation, it was noted that imine anions are known to undergo
efficient alkylation.29 The synthesis of the imine derivative (69) of the ketone 65 was
straightforward (Scheme 6.7), and involved simply refluxing the ketone and
cyclohexylamine in benzene with powdered 4A molecular sieves (cmde yield = 91%).
Imine 69 was readily distilled to high purity, and it was found to be suprisingly stable
towards hydrolysis.
Gratifyingly, it was found that reaction of the imine anion 70 with model iodide 68
was efficient, and that pH 4 buffer rapidly hydrolyzed the imine to the desired alkylated
ketone 71 in 72% overall yield (Scheme 6.8). This alkylation was deemed sufficiently
effective that the model study was halted and the synthesis of a C9-C13 synthon 47, where
'X' is iodine, was explored.
87

LDA
69 ^
8EM0
65
N-LI-
15
^
8EM0
70
o NH,
powdered 4 A *^^
molecular selves
benzene reflux SEMO
Scheme 6.7
a) 68
b) pH 4 buffer
Scheme 6.8
69
TBDMSO
Stereoselective Aldol Route to the CQ-CI^ Segment of the
OsciUatoxins and Aplvsiatoxins
The aldol condensation is a transformation which has long been a powerful tool for
the construction of carbon-carbon bonds. 18 Thus, the recent development of chiral
enolates which participate in the aldol condensation with a high degree of stereocontrol has
provided the organic chemist witii a powerful new tool for the stereocontrolled synthesis of
multifunctional acyclic compounds. Especially useful are the boron enolates of chiral
oxazolidinones (for example 72 [Scheme 6.9]) reported by Evans, who has found that
these enolates undergo aldol condensations witii a high degree of stereoselectivity.^o The
relative stereochemistry of the aldol product is always syn, while the absolute
stereochemistry is determined by the configuration of the ring substituents of the chiral
auxiUary. Removal of the chiral auxiliaries under reducing, transesterifying, or
saponifying conditions allows the isolation of p-hydroxy acids (74), p-hydroxy esters
88

89
75 , or M.01S 76) as well as the recovery of the oxazolidinone chiral auxtliaty (Scheme
6.9). Compour,ds 74-76 are typically isolated in high yields (70-90%), and in >90%
dtastereomeric purity . The utUity of these reactions is enhanced by Evans' observation that
die enolate chiraUty strongly overrides die resident chirality of die aldehyde. For example,
the aldol condensation of chiral aldehyde 77 with the dibutylboron enolate 72 gave 78
(86% yield, >96% diastereomeric excess [d.e.J, Scheme 6.10), while reaction of the same
aldehyde with the enolate 79 gave 80 (>99% d.e.).3i
Given the obvious similarity between 78 and target compound 48, die possible
utiUty of this asymmetric aldol reaction for the stereoselective synthesis of a C9-C13 iodide
81, where R is an appropriate protecting group, is appealing (Scheme 6.11). The syn
relationship and absolute configuration of chiral centers Cn and C12 suggest that the C12-
Ci3 portion of 81 could be derived from the boron enolate 72. The C9-C11 portion would
then have its start as the aldehyde 82, with the absolute configuration of Cio already fixed.
An enantiomerically pure MPM protected p-hydroxy aldehyde 82 was required to
utUize Evans' aldol methodology in the synthesis of 81. Fortunately, an eariy worker in
this laboratory, during the course of studies aimed at the total syntiiesis of oscillatoxin A
(4), had synthesized this very compound.32 This was accomplished in three steps and in
55% overall yield from the commercially available (S)-methyl 3-hydroxy-2-
methylpropionate (83). Recent improvements of tiiis synthesis have resulted in the

n-Bu^BO O a)
A
H
N "O
Ph ^) ^2^2
72
(Ph = C6H5)
n-BupBO O
79
a)
O
YY^"
(77)
b) H2O2
Scheme 6.10
MPMO MPMO
CHO
11 + 72
Scheme 6.11
— ^
>
x'
HO O O
production of 82 in two steps (Scheme 6.12). Thus, p-hydroxy ester 83 was protected as
its MPM ether (67%) by reaction with para-methoxyphenylmethyl trichloroacetimidate (85)
under acid catalysis, as per Yonemitsu.l^ Direct reduction of the protected hydroxy ester
84 to the aldehyde 82 was accomplished efficientiy (-100%) using a modification of
Corey's procedure.^^ This protocol allowed the production of multigram quantities of
aldehyde 82 in good overall yield (67-73%).
N-Propionyl oxazolidinone 87 was prepared by reaction of propionyl chloride
with the Uthium amide of oxazolidinone 86 (80%, Scheme 6.13).30 \i j^g Q^^^^ of this
project the commercially available 86 was used. However, it was found that its synthesis
90

MeO"^-^ 85
CO2CH3 85
NH
A
ecu
20 % PPTS
(pyridinium paratoluenesulphonate)
Scheme 6.12
CO2CH3 l.Oeq.DIBAL-H
eg- ^
(diisobutyl
aluminum hydride)
CH2CI2, -78°
is simple and economical.^^ Using the procedure developed in Evans' laboratories at
Harvard University,3^ enolization of oxazolidinone 87 by treatment with ethyldUsopropyl
amine and di-n-butylboron triflate, foUowed by condensation with aldehyde 82, produced
the desired aldol product 88 as a crystalline mass. Upon recrystalUzation from
ethenhexanes, pure 88 was obtained in moderate yields (43-57%) (Scheme 6.13). A smaU
O
1
O o
HN' . ^O P aU,05ea:J^Mli_J^^"^^^'l ? a) 1.1 eq n-Bu^BOTf 72
\ / b) L1 eq. CH3CH2COCI \ / b) EtN(i-Pr)2
86
n-Bu2B0 O
^ Ph
72
1)82
2) H2O2 -^"
Scheme 6.13
(Tf=CF3S02)
88 ' Ph
43-57% recrystalUzed
amount «10%) of another isomer of the product was evident from the 'H NMR spectrum
of the crude product. The stereochemistry of this byproduct was not ascertained.
Subsequently, it was noted that the yields from this type condensation were irreproducible
over time when commercially available solutions of di-«-butyIboron triflate were used, and
that the use of freshly prepared diethylboron triflate alleviated this problem." Therefore,
an aldol condensation between 82 and the diethylboron enolate of 87 (prepared follown,g
82
91

92
Oppoltzer's protocol for the in situ formation of diethylboron triflate), was performed.36
Altiiough the cmde product from this procedure appeared to be much cleaner, the
recrystalUzed yield from tiiis reaction was stUl low (53%).
The stereochemistry of the aldol product was assumed to be as desired by analogy
witii previous work, and was further verified by iH NMR experiments. A decoupling
experiment in which the methyl group attached to C12 of compound 88 was irradiated
revealed a 3.4 hertz (Hz) coupling between the hydrogens attached to Cn and C12. This is
in the range expected for a syn aldol product,^^ suggesting tiiat the relative stereochemistry
at Cu and C12 is syn as shown in 88. DDQ oxidation of 88 produced the acetal 89 in
60% yield (Scheme 6.14). This compound was found to have an 11 Hz coupUng between
HA and HB, which is consistent with the trans-diaxial disposition expected for these
hydrogens. Therefore the stereochemistry of compound 88, both relative and absolute, is
as shown. With the C9-C13 carbon skeleton in place with the desired stereochemistry,
protection of the Ci 1 hydroxyl and manipulation of the C13 amide to a primary iodide will
afford the C9-C13 electrophiUc synthon 81. Therefore these functional group
manipulations were the next goal of this project.
88 CH2CI2/PH 7
buffer (5:1)
p-MeOC6H4
Scheme 6.14
F1nhor;irion of the, Aldol Product (88) to a
C9iCi3jQdide_(901
It was expected that aldol product 88 could be transformed into a suitably protected
iodide 81 in a straightforward fashion using common reactions. It was detemiined that the
Cn hydroxyl group would be protected as a rm-butyldimetiiylsilyl (TBDMS) etiier. This
protecting group is stable to a large number of syntiietic transfomiations.3S Especially
important, the TBDMS ether is stable to the conditions used to remove the MPM protecting
group. Indeed, this protecting group was used in eariy model studies concerning the

93
fomiation of the spirobicycle 27.n Iodide 90, then, was the actual C-C,3 intermediate
desired.
MPMO OTBDMS
Besides choosing a protecting group for the Cn hydroxyl group, it was also
necessary to consider by what means die oxazolidinone chiral auxiliary would be removed
and Ci3 converted into a primary iodide group. It was noted that the reductive removal of
the chiral auxiliary (c./. 73-76, Scheme 6.9) results in tiie conversion of Cn to a primary
alcohol, a functionality that can be readily converted to a primary iodide. Therefore a
reductive removal of the chiral auxiliary was considered especiaUy attractive, and was the
first route to 90 that was pursued.
Although lithium borohydride has been shown to reduce efficiently aldol products
such as 88 to diols,^! it was deemed desirable to avoid problems in the differentiation the
two hydroxyl groups. Protection of the Cn hydroxyl group of 88 as its TBDMS etiier
was straightforward (Scheme 6.15), and the silyl ether 91 was isolated in good yield
(82%). It was expected that this compound would be reduced by Uthium borohydride to
the Ci3 alcohol 92. In practice, however, amino alcohol 93 was the major product
88
MPMO
L25 eg .TBDMSOTf,
1.5 eq. 2,6-lutidine
CH2CI2
OTBDMS
MPMO
H OH
TBDMSO
Scheme 6.15
MPMO OTBDMS

94
isolated upon reduction of 91 under a variety of conditions (in 40-60% purified yields).
Apparentiy either the free Cn hydroxyl is necessary to direct the reducing agent to die Cn
carbonyl, or the buUcy TBDMS etiier in 91 is blocking tiie approach of the reducing agents
to the Ci3 carbonyl. In any case, this route to 92 was abandoned, and a less direct
approach to 90 was explored.
Since the Uthium borohydride reduction of aldol products such as 88 to diols such
as 93 was so well precedented, this strategy was the next one pursued (Scheme 6.16).
This route had earUer been shunned so as to avoid problems with the differentiation of the
primary and secondary hydroxyl groups of the diol. However, it was assumed that the
hydroxyl groups could most lUcely be easily differentiated by reaction of 94 with one
equivalent of methanesulfonyl chloride in the presence of an amine base. A similar reaction
was found to be useful in the synthesis of epoxide 62 from diol 60 via the monotosylate
61 (Scheme 6.4). The reduction of 88 to diol 94 and the chiral auxiliary oxazolidinone
86 proceeded cleanly. However, the chromatographic separation of these two products
was difficult. This problematic separation, which would be exacerbated by the large scale
(multigrams) desirable in the early stages of the lengthy total synthesis, led to the
exploration of another route to transfom 88 into the Cg-Cn iodide 90.
88 J^^—•
MPMO
Scheme 6.16
+
O
A,
HN' ^O
94 86
It was envisioned that esterification of the aldol product 88 to the methyl ester 95
would be a simple method to remove the chiral auxiUary 86. The esterification of the
products from aldol reactions using the oxazolidinone chiral auxiliary is well established.^o
It was hoped that the ester 95 would behave more predictably than the carbamate 88, and
as such would finally allow the synthesis of 90. Therefore, reaction of the aldol product
88 with a slight excess of sodium methylate afforded ester 95 and the oxazolidinone 86.
These compounds were easily separated, with 95 isolated in excellent yield (77-83%,
Scheme 6.17). Direct reduction of p-hydroxy ester 95 witii DIBAL-H was uneventful,
with tiie crystaUine diol 94 isolated in 75-89% yield (72% after rectystallization). In order
to avoid the intennediacy of diol 94 and the aforementioned differentiation problems, ester
Ph

95 was protected as its Cn TBDMS ether Qfi (Q9io/ \ o«^ o u
95
^ ^ ^ ^ ^^"^^ ^" ^^^^o) and subsequentiy reduced to afford
the alcohol 92 in 71% yield.
J.J. LI eg.MeO Na""^
MeOH, CH2CI2
0'', 15 min
OTBDMS
COoMe 2.5 eg. DffiAL-H,
CH2CI2, 0°
Scheme 6.17
OMe
4 eq. DIBAL-H
CH2Cl2,0° r.t.
MPMO OTBDMS
An attempt to convert alcohol 92 to iodide 90 via the intermediate mesylate was
made next. Thus, upon reaction with excess methanesulfonyl chloride in the presence of
trietiiylamine, compound 92 was cleanly converted to the mesylate 97 (92%
chromatographed yield. Scheme 6.18). However, attempted displacement of the mesylate
by iodide resulted in the quantitative (according to ^H NMR) formation of the pyran 98
plus MPM-iodide! At first this was thought to be a result of an acid catalyzed loss of the
o- 1.25 eq. MeS02Cl
L5 eq. EtsN, *"
CH2CI2, 0°
MPMO OTBDMS
97
OSOoMe
Scheme 6.18
Nal (sat'd soln),
acetone retlux, ^
6 hrs
92
0
•9 13
94
11 ^^ "', V
OTBDMS
MPM protecting group, followed by an intramolecular displacement of a leaving group (X
= MeS03 or I), as indicated in Scheme 6.19. However, a recipe for die desired
displacement which had been shown to be useful for acid sensitive substrates, the addition
of 1% EtN(i-Pr)2 to the acetone solvent as an acid scavenger,39 had no affect upon the
results of this reaction. As a final attempt, a recipe that involves the in situ formation and
displacement of a triflate by iodide was followed.^o This reaction occurs rapidly at
98

moderate temperatures, and it was hoped that side reactions would be minimized.
Unfortunately, pyran 98 was the major product under these conditions, also.
97
r
p-CH30C6H4^''^ 4:0
a) 2 eq. n-Bu4N'' I",
2.2 eq. pyridine,
CH9CI9, -78°
b) 2 eq. (CF3S02)0,
-78° to 0°, 1 hour.
• ^ -
Scheme 6.19
O
9 13
11 ^'''/i V
OTBDMS
Acting on the assumption that the bulky silyl protecting group was somehow
causing this unexpected side reaction, we synthesized the unprotected hydroxy mesylate 99
by careful monomesylation of the diol 94, a reaction which proceeded in approximately
quantitative yield (Scheme 6.20). Displacement of the mesylate under the conditions used
for acid sensitive substrates followed by column chromatography afforded 60% of the
desired iodide 100, which could then be silylated under standard conditions in high yield
94 1 eq. MeS02Cl
L2eq. EtsN, *"
CH2CI2, 0°
MPMO
OSOoMe
Scheme 6.20
98
5eqNaI,
refluxing acetone,
1% EtN(i-Pr)2
100
96

97
(99%) to afford the C9-C13 iodide 90. Thus the intermediate 90 was synthesized in eight
steps and 17% overall yield from die commercially avaUable p-hydroxy ester 83.
Altiiough tiie yields for the aldol reaction and the iodide displacement could
possibly be optimized to higher levels, this route to the C9-C13 fragment 90 allowed the
production of significant quantities of tiiis iodide, and it was decided at this point to test die
viabiUty of die remainder of the proposed synthesis of the entire C9-C21 fragment,
beginning with the coupUng of the C14-C21 imine (69) and the C9-C13 iodide (90).
CoupUng of CQ-CI^ Iodide (90^ and C^A-Co^ Imine (69)
Witii concise routes to both the iodide 90 and the imine 69 available, the next step
was die coupling of these two fragments. This coupling to form the ketone 101 would put
in place the entire C9-C21 backbone of oscillatoxin D (15), and of the rest of the
oscUlatoxins and aplysiatoxins as well. Since the stereochemistry of the iodide 90 had
been estabUshed, the C10-C12 stereochemistry of tiiis coupled C9-C21 backbone would be
in place in 101.
MPMO OTBDMS
Model studies had demonstrated that the lithium anion of the imine
69 would react with a primary iodide (68) having branching at the a-position and a
101
SEMO
TBDMS ether at the P-position. Although this model iodide closely resembles iodide 90,
compound 90 is more hindered as it has additional branching at the P-position. In any
case, it was found that deprotonation of 1.5 equivalents of the imine 69 with lithium
dusopropylamide (LDA), followed by die addition of tiie iodide 90, resulted in alkylation
of the imine anion. An excess of the imine anion was used, as the imine was the less
'precious' reagent, and it was desirable to consume all of the hard-won iodide. Subsequent
hydrolysis of the alkylated imine afforded the desired ketone 101 (Scheme 6.21).

69
SEMO
a) 1 eq. LDA, THF, 0°, 30 min
b) 0.67 eq. 90,0°-r.t.. 12 hrs
c) pH 4 buffer, 1 hr
57%
a) 1 eq. LDA, LO eq. HMPA
THF, 0°, 30 min
b) 1.07 eq. 90, 0°- r.t. 10 hrs
c) pH 4 buffer, 1 hr
78%
Scheme 6.21
Unfortunately, the yield for tiiis coupling, with 90 as the limiting reagent, was
lower than that obtained with die model system (57% vs. 72% for the model alkylation). A
further shortcoming of tiiis condensation was that the separation of tiie aUcylated ketone
101 from the excess of starting ketone 65 (generated upon hydrolysis of the leftover imine
starting material 69) was difficult.
Because of die problems associated with die previous aUcylation protocol (low
yield, difficult separation), when it became necessary to repeat this coupling a recipe for
imine aUcylation that included HMPA (to increase die nucleophiUcity of tiie imine anion)
was foUowed.'^i The iodide 90 was used in 7% excess, which was expected to be
advantageous for the purification of the product (as it had been noted that die separation of
the iodide 90 from the alkylated ketone 101 was easier than the separation of the starting
ketone 65 from 101). In fact, this procedure was a substantial improvement over the one
used previously, and a simple purification afforded a 78% purified yield (from the imine
69) of the ketone 101 (Scheme 6.21). •
Asymmetric Reduction of Ci^ Ketone (101)
With ketone 101 in hand, an asymmetric reduction and a subsequent methylation of
the Ci5 carbonyl would afford the 'masked' aldehyde 102 (36, where R=TBDMS and
R'=SEM). Therefore the next step examined was the asymmetric reduction of the Cn
carbonyl of the ketone 101.
Ireland, in die course of an attempted syntiiesis of aplysiatoxin,i3 found good
success in the reduction of the Cn ketone 42 using Noyori's binapthol modified LiAUl4
reagent (Scheme 5.5). 13 The active reducing agent is a trialkoxy Utiiium aluminum hydride
103. The (S)-reagent, which is prepared from (S)-2,2'-binapthol and which reduces
101
98

MPMO OTBDMS OCH.
102
OSEM
prochiral aryl ketones to the (S)-alcohols, is shown (103). (R)-2,2'-Binapthol is used to
make the (R)-reducing reagent, which reduces prochiral aryl ketones to die (R)-alcohols.
The reducing agent is prepared by the addition of ethanol, followed by 2,2'-binapthol, to a
solution of LiAlH4 in THF. This preparation requires extreme care with the stoichiometry
of die reagents. An excess of either ethanol or binaptiiol results in the formation of a
nonreducing tetraalkoxy aluminate. On the other hand, an excess of the LiAlH4 results in
the existence of various hydride species with less than three alkoxy Ugands. These species
would reduce ketones with little or no stereoselectivity, and at higher rates than 103.
Although good control of the stoichiometry is easy to obtain on a large scale (Ireland's
reduction was a 65 mmol scale, with -19 g binapthol used), the small amounts of material
avaUable for preUminary explorations precluded such large scale reactions. It was not
suprising, then, that an attempt to reduce ketone 101 on a 1 mmol scale failed (the ketone
was recovered). At this point it was decided to try another method for tiiis reduction, one
which seemed simpler to perform.
103
An alternative to Noyori's binapthol/LAH reagent 103 was suggested by
Yamamura's utilization of Brown's diisocampheylchloroborane (Ipc2BCl) reagent (104)^6
as an important step in the total synthesis of 3-deoxydebromoaplysiatoxin 44 (Scheme
5.6).i5 Yamamura reported good success at stereoselectively reducing the Cn ketone 45
with this reagent. Although the synthesis of this reagent is reported to be straightforward
OEt
Li"
99

100
(Scheme 6.22), in this laboratory efforts to produce 104 failed. Although this problem
could surely be sumiounted, work with this compound was stopped when the advantages
of a new chiral catalyst developed by Corey became evident.
(+)-a-pinene
92% e.e
BH3-SMe2,
THF,0'
99% e.e.
Scheme 6.22
.o^V2 )2BH
HCl(anhv), ^
Et20, -78°- 0°
104
99% e.e.
In 1987 Corey and coworkers reported the development of a catalytic
enantioselective method for the reduction of prochiral ketones to chiral secondary
,»»vV2 )2BC1
alcohols.'^^ The catalyst for this reaction was oxaboroUdine 105, which is prepared by the
reaction of the chiral amino alcohol 106 with borane (Scheme 6.23). As both enantiomers
of the amino alcohol are available, either isomer of the catalyst 105 is readily synthesized.
o-^
Ph
Ph
\ /
V NH MW OH
106
BH3 - SMe2
THF, A
Scheme 6.23
MeB(0H)2, ^^
4A mol sieves,
benzene reflux
Ph
^—N. .0 ^ 05
^B^
I
H
^ ipitiiiiiir^
Compound 105 efficiently catalyzed the enantioselective reduction of a variety of ketones
I
CH,
via the borane complex 107. This complex has several qualities which cause it to be a
useful chiral catalyst. Complexation of BH3 with the tertiary amine activates it for hydnde
donation, which causes the reduction in the presence of 105 to be much faster than in the
absence of 105. The boron bound between the oxygen and the quaternary (cation.c)
nitrogen is especially Lewis acidic, and as such will coordinate strongly to carbonyl groups
and thereby activate them. In practice, catalyst 105 is quite effective. For example.
Ph

a
^Ph
H,B-
I
R
Ph
iHiiniK^
107 R=H
109 R=CHc
benzophenone was reduced to (S)-phenylethanol in quantitative yield and in 97% e.e. by
BH3 in the presence of 10 mol % of 105.^2
Although catalyst 105 was quite useful, its air and water sensitivity caused it to be
difficult to work with. This led to the development of the catalyst 108,^^3 which is
synthesized by reaction of amino alcohol 106 with methylboronic acid."^ Compound 108
reacts with borane to form complex 109, which reduces ketones as rapidly and as
stereoselectively as 107. As oxazaborolidine 108 is much less air and water sensitive than
105, it is more easUy handled and thus is more practical than the reactive borane 105. As
such, 108 is the reagent of choice in this procedure for asymmetric reductions.
Oxazaborolidine 108, prepared according to the Uterature and used as a cmde
reaction mixture, catalyzed the reduction of ketone 101 by BH3 - THF (Scheme 6.24).
The product, alcohol 110, was isolated in 74% yield. Comparison of the 300 MHz ^^c
NMR spectrum of this product with the spectmm of a 1:1 mixture of diastereomers
epimeric at Cn (produced by a NaBH4 reduction of 101) suggested that the ratio of
diastereomers produced in this reaction was >12:1. The assignment of the absolute
stereochemistry at this newly formed chu-al center was made by analogy with examples of
this reduction in the Uterature. Support for this assignment was provided by the CD
spectrum of 111 (Scheme 6.26, below) which demonstrated positive Cotton effects at 268
and 271 nm, simUar to those observed for debromoaplysiatoxin 2 and various analogues
(17-22). Thus die carbon backbone and absolute stereochemistry of the C9-C21 fragment
110 of the aplysiatoxins and oscUlatoxins have been established.
MPMO OTBDMS MPMO OTBDMS OH
101
L0eq.BH3,
0.20 eq. lof
^ THF,0°.
SEMO 110 SEMO
Scheme 6.24
101

Elaboration of Alcohol (110) tn Aldehyde (119)
With the C9-C21 backbone and absolute stereochemistry in place, metiiylation of the
alcohol 110 using Ireland's recipe proceeded in high yield (75%, Scheme 6.25).
Interestingly, tiie minor Cn epimer of the ether 102 was not evident in the purified
product, as determined by a comparison of the i^c NMR specn-um of this product with that
of a 1:1 mixture of diastereomers epimeric at Cn- Possibly there was a kinetic resolution
in the methylation. That is, it is possible that the 'natural' Cn(S) diastereomer was
methylated more rapidly than the 'unnatural' Cn(R) epimer, and as such the 'unnatural'
isomer was left unreacted and upon chromatography separated from the 'natural' metiiyl
ether. Another explanation is that upon chromatography the isomers were separated, and
that this went unnoticed. In any case, the 'masked aldehyde' 102 was synthesized in
eleven steps and in 7.4% overall yield from the commercially available p-hydroxyester 83.
110
a) 2.5 eq. KH,
THF. 0°- r.t. 1 hr.^
b) 2.5 eq. Mel,
0°, 2 hrs.
MPMO OTBDMS OMe
Scheme 6.25
102
SEMO
Removal of the MPM protecting group from the 9-hydroxyl oxygen was
straightforward. Treatment of the methyl ether 102 with an excess of DDQ in a
CH2CI2/PH 7 buffer solvent mixture produced the alcohol Ul which was isolated in 86%
yield (Scheme 6.26). The mixture of epimers at Cn behaved simUarily. The CD spectmm
of compound 111 had a positive Cotton curve with peaks at 268 and 271 nm, supporting
102
1.3 eq. DDQ. r.t,
CH2Cl2:pH 7 buffer (5:1),
30 min 86%
Scheme 6.26
OTBDMS OMe
111
SEMO
102

103
the stere«:hemical assignt^ent a. €.. TT,e CD spectrum was obtained on this compound
tnstead of an earher tntermediate because of possible interference by the absorption of the
MPM chromophore.
Further progress on this synthesis was perfomied on the mixture of epimers at Cn
so as to preserve the precious diastereomerically pure material. Alcohol lll,asa 1 I
mixture of Cn epimers, was cleanly oxidized to the aldehyde 112 by the conditions
developed by Swern (Scheme 6.27).45 The crude material, which was >95% pure by ^H
NMR, was obtained in quantitative yield. Thus, this aldehyde was syntiiesized in 13 steps
and 8.4% overall yield from 83. This compares weU with Kishi's synthesis of the C8-C21
intertnediate 37 (24 steps from (-)-diethyl D-tartrate, 12% overall yield), and Yamamura's
synthesis of the C8-C21 intermediate 45 (15 steps, 14% overall yield. It is assumed that
the diastereomerically pure alcohol 111 will undergo oxidation in the same manner as the
mixture of epimers to yield the target aldehyde.
111
a) DMSO, (C0C1)2,
CH2CI2, -78°, 20 min
-^~
b) EtsN, -78° - r.t.,
quantitative
Scheme 6.27
O OTBDMS OMe
111
Recent Progress - Synthesis of a C^-C9i Subunit of the
Aplysiatoxins and Oscillatoxins
SEMO
With the aldehyde 112 as a 1:1 mixture of Cn epimers in hand, the C8-C9 bond
forming aldol reaction was attempted. The lithium enolate of ketone 31, kindly provided
by Doug Boatman of our laboratory, was found to undergo an efficient aldol reaction with
112, resulting in the formation of alcohols 113 (Scheme 6.28). The analysis of the ^^C
NMR data for this product is complicated by the fact that the starting aldehyde is a mixture
of diastereomers. However, the ^H NMR spectrum is relatively uncomplicated, suggesting

MPMO o^*\
31
MPMO
a) 1 eq. LDA, THF,
-78°
b) 0.67 eq. 112 '^
Scheme 6.28
113
SEMO
that die aldol reaction may have possibly proceeded with some amount of stereochemical
control. In the investigation of a model system, odier workers in this laboratory have
observed the formation of a 4:1 mixture of diastereomers in die aldol reaction between the
enolate of 31 and aldehyde 32 (R=TBDMS or Bn, Scheme 6.29).ll'l2 This stereocontrol
has been attributed to a chelation-controUed addition of tiie enolate to the protected p-
hydroxy aldehyde 32. If this is the case, tiien the aldol product would favor a 9S
configuration. This is an important point, as the natural products 1-14 require this very
stereochemistry at C9. Further work needs to be done to elucidate die actual C9
stereochemistry of the aldol product 113.
31
a) LDA
32
Scheme 6.29
•'t
3
^ /
MPMO 0^
114
7
HO*^
9 i
OR
1 ^
1
Finally, the p-hydroxy ketone 113 was oxidized, once again utilizing the Swern
protocol, to the P-diketone 115 in moderate yield (53% after purification, Scheme 6.30).
This compound, a protected version of the model compound 33, is the most advanced
intermediate of oscillatoxin D (15) yet synthesized in this laboratory. Because results from
the model study tiiat resulted in the fortiiation of the spirocyclic ether 27 appear to suggest
that sUght modifications in the syntiietic plan may be advantageous (for example, a different
Cn hydroxyl protecting group may be desirable), further work on the total synthesis of
oscUlatoxin D (15) awaits die completion of those model studies.
104

4 eq. DMSO,
2 eq. (C0C1)2,
CH2CI2. -78°
MPMO
a) 113, -78°
b) EtsN, -78°-r.t.
Scheme 6.30
0

CHAPTER 7
EXPERIMENTAL DETAILS
General Method

(R)-2'-Hvdroxy-2'-(T'-hPn.yi^vy>)phenvlPthylA-
(methvnhenyenesulfonntp (^1)
TsO
9H
BnO
C22H22O5S f.w. = 380.48
To 0.024g (0.10 mmol) of (R)-l-(3'-benzyloxy)phenyl-l,2-ethanediol,48 9.7 [Jd
pyridine, and 0.5 ml CH2CI2 stirring at room temperature in a 5 ml round bottomed flask
was added 0.019 g (0.12 mmol) 4-methylbenzenesulfonyl chloride. This mixuire was
allowed to stir for 12 hours, then added to a separatory funnel containing 10 ml ether and
10 ml water. The phases were separated and the aqueous layer was washed with 3x5 ml
ether. The organic layers were combined, washed with 10 ml brine, and dried over
MgS04. Concentration under vacuum followed by flash column chromatography (10 g
silica gel, 1:1 hexanes:ethyl acetate) afforded 0.011 g (0.033 mmol, 33%) of the epoxide.
iH (200 MHz, relative to CHCI3 at 7.26 ppm) 8 7.79-7.73 (m, 2H), 7.45-7.18 (m,
8H), 6.95-6.85 (m, 3H), 5.03 (s, 2H), 5.00-4.91 (m, IH), 4.18-3.97 (m, 2H),
2.68-2.50 (m, 1H[-0H, variable]), 2.44 (s, 3H).
13C (50 MHz) 5 159.02, 145.07, 139.83, 136.67, 132.55, 129.92, 129.74, 128.58,
128.00, 127.94, 127.49, 118.66, 114.83, 112.62, 74.29, 71.80, 69.97, 21.64.
(RV1-(3'-rBenzyloxv1phenyl)ethane-1.2-epoxide(62)
BnO
CnHi402 f-w. = 226.29
107

To 0.0077 g (0.020 mmol) tosylate 61 and 4 ml THF stirring under a nitrogen
atmosphere at room temperature in a 10 ml round bottomed flask was added 0.0023 g NaH
(-0.056 mmol, 60% suspension in mineral oil). After 1.5 hours the reaction mixture was
diluted witii 10 ml hexanes and filtered tiirough a medium fritted funnel. Concentration
under vacuum afforded the desired product and mineral oil (^H NMR). Flash column
chromatography (10 g sUica gel, solvent gradient form 98:2 to 8:2 hexanes:etiiyl acetate)
afforded 0.0028 g (0.012 mmol, 61%) of the desired product as a clear oU, which was
only characterized by ^H-NMR spectrometry.
IH (200 MHz, relative to CHCI3 at 7.26 ppm) 5 7.45-7.22 (m, 6H), 6.93-6.89 (m,
3H), 5.06 (s, 2H), 3.84 (d of d, 1=4.2,2.5, IH), 3.13 (d of d, 1=5.6,4.2, IH),
2.76 (d of d, 1=5.6,2.5, IH).
(RVl"-(2"'-NaDthon-2"-napthyl 2-(3'-methoxv)phenvlethanoate
(63)
MeO
C29H22O4 f.w. =434.51
To 1 66 g (10 mmol) 2-(3'-metiioxy)phenylethanoic acid and 15 ml
CH2Cl2,stirring in a 25 ml round bottomed flask at room temperature under a nitrogen
with a reflux condenser and brought to reflux for 16 hours. The tlasK
a distillation apparatus and the solvent and residual thionyl chloride - - ~ ^ ;^
distiUation under a nitrogen atmosphere. The distillation apparatus -^ *-;> ^^
high vacuum (0.4 mm Hg) and the residue distilled to afford 0.77 g (42%) of 2-(3
niethoxy)phenylethanoic acid chloride.
108

109
IH (200 MHz, relative to CHCI3 at 7.26 ppm) 5 7.29 (t, J=7.8, IH), 6.91-6.79 (m,
3H), 4.11 (s, 2H), 3.81 (s, 3H).
BP 97° at 0.4 mm Hg.
To 0.063 g(0.2 mmol) (R)-2,2'-binaptiiol and 3 ml ether stirring at 0° (ice bath)
under a nitrogen atmosphere in a 5 ml round bottomed flask was added 0.096 ml n-BuLi
(2.3 M solution in hexanes, 0.22 mmol), followed by 0.037 g (0.2 mmol) of the
aforementioned acid chloride in 1 ml ether. The resulting suspension was allowed to warm
to room temperature over 1 hour, and then was stirred at room temperature for an additional
3 hours. The milky suspension was then dissolved in 25 ml CH2CI2, filtered through a
fritted glass funnel (medium frit), and concentrated under vacuum to afford 0.84 g (97%)
of a white solid that is >95% pure (according to ^H NMR). This product was characterized
only by ^H NMR spectrometry.
IH (300 MHz, relative to TMS at 0.00) d 7.99-7.88 (m, 4H), 7.44-7.33 (m, 6H),
7.15 (t, 1=6.0, 2H), 6.98 (t, 1=7.9, IH), 6.69 (m, IH), 6.49 (d, 1.7, IH), 6.42
(d, J=7.5, IH), 3.68 (s, 3H), 3.36 (s, 2H).
:^-(2'-TrimetiiylsUvlethoxy)methoxvacetophenone(65)
'SiMeg
Ci4H2203Si f-w. = 266.45
To a 25 mL round bottomed flask containing 0.641 g (4.71 mmol) of 3-hydroxy-
acetophenone, 1.22 mL (7.00 mmol) ethyldUsopropylamine, and 10 mL dichloromethane
stimng at 0° under nitrogen was added 1.00 mL (5.65 mmol) 2-trimetiiylsilylethoxymethyl
chloride dropwise over die course of 5 minutes. The reaction mixture was then dUuted
widi 25 mL ether and washed successiyely witii 25 mL water, 25 mL saturated NaHC03,
and 25 mL brine, then dried over MgS04 and concentrated under vacuum. Flash

110
chromatography (20 g siUca gel, 9:1 hexanes:etiiyl acetate) afforded 0.985 g (3 70 mmol
78.6%) of the desired compound as a clear liquid.
'" ?'? ^^' -lative to CHC13 at 7.26 ppm) 6 7.59 (m, 2H), 7.38 (t, 1=7.8, IH),
7.24 (m, IH), 5.26 (s, 2H), 3.76 (d of d, 1=8.3,8.3, 2H), 2.59 (s, 3H), 0 96
(d of d, 1=8.3,8.3, 2H), -0.01 (s, 9H).
13C (50 MHz) 5 197.76, 157.57, 138.48, 129.56, 121.72, 121.02, 115 64 92 84
66.39, 26.70, 17.98, -1.46. ' " '
IR 3072, 2954, 2898, 1686, 1584, 1485 cm-l.
TLC Rf = 0.53 (8:2 hexanes:ethyl acetate).
ANALYSIS Calcd: C, 63.12; H, 8.33
Found: C, 63.09; H, 8.43.
(S)-l-(r-Butyldimedivnsilyloxv-2-methvlpropyl
methanesulfonate. (67)
TBDMSO OSOoMe
CiiH2604SSi f.w. = 282.52
To 0.82 g (4 mmol) (R)-3-(r-butyldimethyl)silyloxy-2-methylpropanol,48 0.78 ml
(0.56 mmol) triethylamine and 20 ml CH2CI2 stirring at 0° (ice/water bath) under nitrogen
in a 50 ml round bottomed flask was added 0.37 ml (4.8 mmol) methanesulfonyl chloride.
After 1 hour the reaction mixture was diluted with 50 ml ether and washed with 25 ml
water, 25 ml saturated aqueous NaHC03, and 25 ml brine. The mixture was then dried
over MgS04 and concentrated under vacuum to afford 1.09 g (96%) of the desired product
as a yellow oil.
*H (300 MHz, relative to CHCI3 at 7.26 ppm) 5 4.23 (d of d, 1=9.5,5.9, IH), 4.15 (d
of d, 1=9.5,5.7, IH), 3.61 (d of d, 1=10.1,4.8, IH), 3.49 (d of d, 1=10.1,6.5,
IH), 3.00 (s, 3H), 2.06 (m, IH), 0.98 (d, 1=6.9, 3H), 0.89 (s, 9H), 0.05 (s,
6H).
*^C (50 MHz) 5 71.69, 63.62, 36.98 35.69, 25.85, 18.24, 13.20, -5.51.

IR 2955, 1472, 1356 cm-i.
TLC RpO.33 (9:1 hexanes:etiiyl acetate).
(S)-l-Iodo-2-metiiyl-^-?-hutyldimp.fhy1silvloxvpentnne (f^R)
TBDMSO
C10H23IO f.w. = 286.23
To a solution of the crude mesylate 67 (1.09 g, 3.9 mmol) and 20 ml acetone in a
50 ml round bottomed flask was added Nal until tiie solution was saturated. The flask was
then fitted with a water cooled condenser and heated to reflux for 4 hours. The reaction
mixture was cooled, diluted witii 100 ml ether, and washed with 4x50 ml water and 50 ml
brine. The ether solution was then dried over MgS04 and concentrated under vacuum to
afford an orange oil. Flash column chromatography (20 g sUica gel, hexanes eluent)
afforded 0.98 g (3.4 mmol, 86% overall for two steps) of die desired product as a clear oil.
IH (200 MHz, relative to TMS at 0.00 ppm) 5 3.53 (d of d, 1=9.9,5.0, IH), 3.39 (d
of d, 1=9.9,6.8, IH), 3.28 (m, 2H), 1.63 (m, IH), 0.95 (d, 1=6.7, 3H), 0.90
(s,9H), 0.06 (s, 6H).
13C (50 MHz) 5 66.64, 37.32, 25.88, 18.23, 17.22, 13.80, -5.38.
TLC Rf=0.51 (hexanes).
Ill

N-l-(3'-[(2"-Trimethylsilylethoxy)mPfbr.vy]ph.n:'n
etiivlidinecyrlohexvlaminp (^Q)
C20H33NO2Si
SiMe.
f.w. = 347.63
A 25 mL round bottomed flask fitted with a magnetic stir bar, a Dean-Stark trap
(filled with benzene), and a condenser under nitrogen was charged witii 2.00 g (7.51
mmol) of m-(2-trimetiiylsilylethoxy)methoxyacetophenone, 3.43 mL (30.0 mmol)
cyclohexylamine (distilled from CaH2 and stored under nitrogen until use), 5 g activated
4A molecular sieves, and 15 mL benzene. The mixture was then brought to reflux (bath
temperature 95°) for 12 hours, filtered, and the molecidar sieves washed with 10 mL
benzene. Concentration of the organic extracts afforded 2.36 g (6.79 mmol, 90.5% cmde)
of a sUghtiy yeUow oU that is >95% pure by ^H NMR. In practice this imine was used as
the cmde material. It could, however, be distUled to high purity witii minimal loss of
material.
*H (300 MHz, relative to CHCI3 at 7.26 ppm) 5 7.41 (m, IH), 7.37 (d of d of d,
1=7.7,1.6,1.1, IH), 7.26 (d of d, 1=7.7,8.1, IH), 7.04 (d of d of d,
1=8.1,2.5,1.1, IH), 5.24 (s, 2H), 3.76 (d of d, 1=9.6,7.1, 2H), 3.47 (m, IH),
2.22 (s, 3H), 1.83 (m, 2H), 1.70 (m, 3H), 1.60 (m, 2H), 1.36 (m, 3H), 0.96 (d
of d, 1=9.6,7.1, 2H), 0.00 (s, 9H).
13C (50 MHz) 5 162.10, 157.33, 143.50, 129.09, 120.14, 116.71, 114.77, 92.90,
66.15, 59.85, 33.51, 25.78, 24.85, 18.01, 15.36, -1.42.
BP 185° at 2 mm Hg.
IR 2928, 2854, 1634, 1580, 1249, 1088, 1015, 859, 836, 692 cm"!.
TLC Rf = 0.42 (8:2 hexanes:ethyl acetate).
112

ANALYSIS Calcd: C, 69.11; H, 9.57
Found: C, 69.48; H, 9.66.
(R)-l-(3'-[(2"-Trimethylsilylethoxv^methoxy1php.ny1)-4methyl-5-(f-butvldimp.thynsUvloxV-1
-pentanone (11)
TBDMSO
SEMO
C24H4404Si2 f.w.= 452.86
To 0.092 g (0.26 mmol) of die imine 69 and 1 ml THF stming at 0° under a
nitrogen atmosphere in a 5 ml pear shaped flask was added 0.26 ml (0.29 mmol) LDA
dropwise. The resulting bright yellow solution was aUowed to stir for 30 minutes, then
0.089 g (0.40 mmol) of iodide 68 in 1 ml THF was added dropwise. The solution was
aUowed to warm to room temperature over 1 hour, then stirred at room temperature for an
additional 12 hours. The mixtiu-e was then added to a 50 ml round bottomed flask
containing 20 ml THF and 20 ml pH 4 buffer, and this mixmre was allowed to stir at room
temperamre for 4 hours. The layers were tiien separated, the aqueous layer extracted widi
3x10 ml ether, and die organic layers combined and washed witii 25 ml brine. The organic
solution was dried over MgS04 and concentrated under vacuum to afford a yellow oil.
Hash column chromatography (20 g silica gel, 9:1 hexanes:ethyl acetate) afforded 0.085 g
(0.19 mmol, 72%) of the desired ketone as a clear oil.
*H (200 MHz, relative to CHCI3 at 5 7.26 ppm) d 7.63-7.58 (m, 2H), 7.39 (t, J=7.7,
IH), 7.28-7.23 (m, IH), 5.28 (s, 2H), 3.78 (d of d, 1=2.9,2.9, 2H), 3.49 (d of d,
1=4.8,1.0, 2H), 3.00 (t, 1=8.2, 2H), 1.95-1.50 (m, 6H), 1.02-0.89 (m, 5H),
0.91 (s, 9H), 0.06 (s, 6H), 0.02 (s, 6H).
IR 2928, 2856, 1689, 1631, 1581 cm-i.
TLC Rf = 0.68 (8:2 hexanes:ethyl acetate).

(S)-3-(4'-MethoxvphenYl)mPthoxv-2-methylprnp.n.l(QO)
C12H16O3 f.w. = 208.28
Dnsobutylaluminum hydride (10.49 ml of a 1.5 M solution in toluene, 15.73
mmol) was added over the course of two hours to a 250 ml round bottomed flask
containing 3.00 g (12.58 mmol) of the ester and 125 ml CH2CI2 stirring under nitrogen at
-78°. After stirring one additional hour at -78°, tiiis mixture was quenched by the dropwise
addition of 3 ml anhydrous methanol. This solution was warmed to room temperature and
dUuted with 100 ml ether, then 2 ml water were carefuUy added, and the mixture was
aUowed to stir for 15 minutes. The milky suspension was then filtered through a 3 cm pad
of ceUte, and the filtrate concentrated under vacuum to afford 2.69 g (102.7%) of a clear
liquid. Proton NMR indicated that the aldehyde was ~95% pure, with a small amount of
the alcohol (resulting from over reduction) as the other major product. No attempt was
made to obtain an elemental analysis of this compound.
IR (200 MHz, relative to TMS at 0.00 ppm) 5 9.71 (d, J=1.5, IH), 7.24 (d, J=8.6,
2H), 6.88 (d, 1=8.6, 2H), 4.45 (s, 2H), 3.80 (s, 3H), 3.63 (m, 2H), 2.65 (m,
IH), 1.08 (d, 1=6.1, 3H).
13c (50 MHz) 5 204.0, 159.2, 130.0, 129.2, 113.8, 73.0, 69.7, 55.2, 46.8, 10.7.
IR 2962, 2935, 2858, 1723, 1612, 1513, 1458, 1302, 1248, 1034, 819cm-l.
TLC Rf = 0.49 (7:3 hexanes:ethyl acetate).
OPTICAL ROTATION [a]D= +29.42° (c=0.0906 g/ml, CH2CI2).

(S)-Methyl3-(4'-mp,rhnvyphqnvnmethnyY-9methvlpropionate
(84)
MPMO
XOaCHg
C13H18O4 f.w. = 238.31
To a 250 ml round bottomed flask containing 17.03 g (123.29 mmol) p-methoxy-
benzyl alcohol and 150 ml etiier stming under nitrogen was added 0.46 g sodium hydride
(60% mineral oil dispersion, 11.63 mmol), and the resulting suspension allowed to stir
untU the solid had dissolved and gas evolution ceased (one hour). The mixture was then
cooled to 0° and 12.36 ml (123.30 mmol) of trichloroacetonitrile was added over 14
minutes. After stirring for an additional five minutes at 0° the mixture was warmed to room
temperature, stured for an additional 20 minutes, then washed with 50 ml saturated
aqueous NaHCOs foUowed by 50 ml brine, dried over MgS04 and concentrated under
vacuum. The resulting yellow oU was dissolved in 150 ml CH2CI2 and 9.07 ml (82.20
mmol) of (S)-methyl 3-hydroxy-2-methylpropionate, foUowed by 0.90 g (3.59 mmol) of
pyridinium p-toluenesulfonate, were added, and the mixture allowed to stk at room
temperature for 22 hours (a white crystalUne precipitate fornis). The reaction mixture was
then washed with 75 ml saturated NaHCOs foUowed by 75 ml brine, dried over MgS04,
and concentrated under vacuum. The trichloroacetamide was precipitated by the addition of
a 1:1 mixture of hexanes:CH2Cl2, the solid filtered off, the liquid phase concentrated under
vacuum, and the remaining dissolved trichloroacetamide removed by a bulb to bulb
distillation at 0.07 mm Hg. The residue was distilled through a 10 cm vigreux column,
collecting the distiUate over die range 98° - 110° (0.07 mm Hg), for a yield of 13.10 g
(54.97 mmol, 66.9%)) of die desUed product.
iH (200 MHz, relative to TMS at 0.00 ppm) 5 7.24 (d, J=8.7, 2H), 6.87 (d, 1=8.7,
2H), 4.45 (s, 2H), 3.80 (s, 3H), 3.69 (s, 3H), 3.63 (d of d, J=9.2, 7.4, IH),
3.45 (d of d, 1=9.2, 5.9, IH), 2.77 (m, IH), 1.17 (d, J=7.1, 3H).
13C (50 MHz) 6 159.2, 129.4, 129.2, 113.8, 72.8, 71.7, 71.5, 55.3, 51.7, 40.2,
14.0.
IR 2951, 2861, 1739, 1612, 1513, 1248, 820cm-l.

BP 98-110° at 0.07 mm Hg. ^16
TLC Rf = 0.51 (7:3 hexanes:ethyl acetate)
OPTICAL ROTATION [a]o= +9.67° (c=0.0838 g/ml CHCh)
ANALYSIS Calcd: C, 65.52; H, 7.61 '
Found: C, 65.34; H, 7.45.
phenyl]methoxy-r,4^dim^h^^^^i^^^
Phenvl-4-mPfhy1-9-oxa7.nliHmnn.(g^)
MPMO
C25H31NO6 f.w. =441.57
To a 100 mL round bottomed flask containing 13.72 ml (1.0 M in hexanes, 13.72
mmol) triethylborane stining at 0° under nitrogen was added dropwise 1.11 ml (12.58
mmol) of triflic acid. The flask was tiien immersed in a 40° oU batii and allowed to stir for
30 minutes (gas evolution ceased at that time), tiien cooled in an ice/water bath and 2.69 g
(11.44 mmol) of the N-propionyloxazoUdinone^o in 56 ml CH2CI2 was added, followed
by 2.19 ml (12.58 mmol) of ethyl dUsopropylamine. After 30 minutes, the reaction
mixture was cooled to -78° and 2.62 g (12.58 mmol) of the freshly prepared aldehyde was
slowly added. The reaction was maintained at -78° for one hour, then warmed to room
temperature. Four hours later the reaction was quenched by the addition of 20 ml pH 7
buffer, the layers separated, and the buffer was back extracted with 2x25 ml CH2CI2. The
combined organic extracts were concentrated, and the resulting yellow oil was dissolved in
35 ml methanol, cooled in an ice/water bath, and 12 ml 30% aqueous H2O2 were added.
The solution was warmed to room temperature over the course of one hour, then water (60
ml) was added, the methanol was removed under vacuum, and the aqueous suspension
was extracted with 3x75 ml CH2CI2. The combined organic extracts were then washed
with 100 ml brine, dried over MgS04, and concentrated to afford a yellow oil which
slowly crystaUized. The product was recrystalUzed from ether/hexanes (two crops; 2.46 g,
5.57 mmol, 48.7% combined) and die mother liquor chromatographed (60 g flash silica

gel, 8:2 hexanesxthyl acetate), then recrystallized (0.24g, 0.54 mmol, 4.8%) to afford a^ '^
total of 2.70 g (6.11 mmol, 53.1%) of the diastereomerieaUy pure aldol product as white
needles.
iH (300 MHz, relative to TMS at 0.00 ppm) 5 7.40 (m, 5H), 7.28 (d, 1=8 7 2H)
6.87 (d, 1=8.7, 2H), 5.62 (d, 1=7.1, IH), 4.74 (p, 1=6.7, IH), 4.45 (s, 2H), '
3.90 (m, 2H), 3.80 (s, lH[OH, variable]), 3.79 (s, 3H), 3.57 (m, 2H), 1.97 (m,
IH), 1.22 (d, 1=6.8, 3H), 0.96 (d, J=7.0, 3H), 0.90 (d, 1=6.6, 3H). '
13C (50 MHz) 6 175.93, 159.27, 152.82, 133.24, 129.82, 129.40, 128.71(two
carbons), 125.62, 113.81, 78.95, 75.58, 74.75, 73.19, 55.26, 55.21, 40.85,
35.90, 14.31, 13.55, 9.51.
IR 3478, 3056, 2966, 2935, 1770, 1698, 1613, 1586, 1514, 1455 cm-l.
MP 113-115°
TLC Rf = 0.55 (1:1 hexanes:ethyl acetate).
OPTICAL ROTATION [a]D= +23.74° (c=0.1100 g/ml, CH2CI2).
ANALYSIS Calcd: C, 68.00; H, 7.08
Found: C, 69.13; H, 7.20.
(l"S.2'R.3"S.4'R.5S.6"S)-3-(2'-r6"-Methvl-2".4"-dioxa-
3"-(4"methoxyphenyl)cyclohex-l"-yl1-propanoyl)-5-phenyl-
4-methyl-2-oxazolidinone (89)
p-MeOC6H4
C25H29NO6 f.w. = 439.55
To 0.042 g (0.1 mmol) of the aldol (88), 4 ml CH2CI2, and 1 ml pH 7 buffer
stining at room temperature in a 10 ml round bottomed flask was added 0.030 g (0.13
mmol) 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). The solution immediately turned
brownish green. After 30 minutes the mixture was added to 50 ml hexanes, and this
mixture was extracted witii 10x25 ml samrated aqueous NaHC03. The ether layer was

118
then dried over MgS04 and concentrated under vacuum. Hash column chromatography
(10 g silica gel, 8:2 hexanes:etiiyl acetate) afforded 0.027 g (0.06 mmol) of die acetal as a
colorless oU. This compound was only characterized by iH NMR spectrometry.
iH (300 MHz, relative to TMS at 0.00 ppm) 5 7.45-7.28 (m, 7H), 6.88-6 92 (m
2H), 5.65 (d, 1=7.1, IH), 5.49 (s, IH), 4.72 (p, 1=6.7, IH), 4.17-4.09 (m 2H) 4 01-
3.38 (m, 2H), 3.80 (s, 3H), 3.58 (d of d, 1=11.0,11.0, IH), 2.11-2.01 (m, lH),'l.68-
1.55 (m, 2H), 1.48-1.15 (m, 6H), 1.22 (d, J=6.8, 3H), 0.97 (d, J=7.0, 3H), 0.88 (d
J=6.6, 3H).
(2S,3S,4S)-l-Iodo-5-(4'-methoxvphenvnmethoxv-2.4dimethyl-3-r-hutvldimetiiylsiloxvpentane(Qn)
MPMO OTBDMS
C2iH3703SiI f.w. = 492.57
To the iodo alcohol (0.50 g, 1.33 mmol), 2,6-lutidine (0.23 ml, 2.00 mmol) and 2
ml CH2CI2 stirring in a 10 ml pear shaped flask under nitrogen was added 0.37 ml (1.60
mmol) of tert-butyldimetiiylsUyl trifluoromethanesulfonate (TBDMSOTf) dropwise. After
30 minutes the starting material had been consumed (TLC) so die reaction was poured onto
25 ml saturated NaHC03 solution, which was then extracted with 3x25 ml ether. The
organic extracts were washed with brine, dried over MgS04, and concenmated under
vacuum to afford a clear oil (0.84 g, >100%). Flash column chromatography (9:1
hexanes:ethyl acetate, 20 g sUica gel) gave 0.65 g (99.4%) of die desired product as a clear
oil. This corresponds to a 43% yield over the five steps from the aldol product 88. No
attempt was made to obtain an elemental analysis of this compound.
^H (200 MHz, relative to TMS at 0.00 ppm) 5 7.25 (d, J=8.8, 2H), 6.88 (d J=8.8,
2H), 4.45 (d, 1=10.1, IH), 4.38 (d, 1=10.1, IH), 3.81 (s, 3H), 3.67 (d of d,
1=6.1,.3.0, IH), 3.50 (d of d, 1=9.0,4.9, IH), 3.24 (d of d, 1=11.4, 7.0, IH),
3.21 (d of d, 1=9.5,4.2, IH), 3.11 (d of d, 1=9.5,7.1, IH), 1.93 (m, 2H), 0.99
(d, 1=6.8, 3H), 0.94 (d, 1=7.0, 3H), 0.88 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H).

13C (75MHz) 5 159.09,130.03,129.15,113.74,76.37,72.72,72 29 55 27
39.61, 38.09, 26.09, 18.40, 15.28, 14.90, 14.55, -3.70, -4.12.
IR 2955, 2930, 2856, 1612, 1513, 1463, 1249, 1038, 835, 774cm-l.
TLC Rf = 0.40 (95:5 hexanes:ethyl acetate).
OPTICAL ROTATION [a]D=+7.84° (c=0.0430 g/ml, CH2CI2).
(2'R,3'S,4'S,4R,5S)-3-(5'-r4"-MPthoxv-phenv11-n.Pth^vy.
2'.4'-dimethyl-3'-r-hntyldimethy1-sUvloxv-pp.ntannyl)-Sphenyl-4-methvl-2-oxazolidinonp
(Ql)
MPMO^
TBDMSO
C3iH45N06Si f.w. = 551 86
To 0.068 g (0.16 mmol) of the aldol 88, 0.047 ml (0.40 mmol) 2,6-lutidine, and
0.5 ml CH2CI2 stirring under a nitrogen atmosphere in a 5 ml pear shaped flask was added
0.055 ml (0.24 mmol) of TBDMSOTf. After 2 minutes the reaction mixmre was quenched
by addition to a separatory funnel containing 10 ml ether and 10 ml water. The layers were
separated and the aqueous layer extracted witii 3x5 ml ether. The organic phases were
combined and extracted with 10 ml brine, and tiien dried over MgS04. Concentration
under vacuum, followed by flash column chromatography (10 g silica gel, 8:2
hexanes:etiiyl acetate) afforded 0.070 g (0.13 mmol, 82%) of die desked product as a
colorless oil.
1H (300 MHz, relative to TMS at 0.00 ppm) 5 7.42-7.26 (m, 7H), 6.89-6.81 (m,
2H), 5.04 (d, 1=7.1, IH), 4.53 (p, 1=6.7, IH), 4.41 (d, J=14.0, IH), 4.40 (d,
J=14.0, IH), 4.04-3.96 (m, 2H), 3.67 (s, 3H), 3.59 (d of d, 1=9.2,5.8, IH),
3.19 (d of d, 1=9.2,5.6, IH), 2.02-1.92 (m, IH), 1.21 (d, J=7.1, 3H), 1.03 (d,
J=7.1, 3H), 0.90 (s, 9H), 0.82 (d, 1=6.6, 3H), 0.070 (s, 3H), 0.068 (s, 3H) .
13c (50 MHz) 5 175.87, 158.99, 152.37, 133.31, 130.68, 129.12, 128.53 [two
carbons], 112.54, 113.63, 78.42, 75.47, 72.59, 71.69, 55.04, 54.89, 41.65,
38.80, 26.05, 18.30, 15.15, 14.81, 14.10, -3.85, -3.90.
119

IR 3065, 3034, 2932, 2856, 1783, 1698, 1613, 1513 cm-l.
TLC Rf = 0.60 (8:2 hexanes:ethyl acetate).
(2S,3R,4S)-3-f-Butvldimethvlsilvlnxy-5-(4'-mpthnYyphenvDmethoxv-7.,4-dimethvl-1
-pentanol (92^
MPMO OTBDMS
C2iH3804Si f.w. = 382.68
To 0.36 g (0.87 mmol) of the p-silyloxy ester 96 and 5 ml THF stming at 0°
(ice/water bath) under a nitrogen atmosphere in a 25 ml pear shaped flask was added 2.2 ml
DIBAL-H (2.2 mmol, 1.0 M solution in toluene) dropwise. After 30 minutes, the reaction
mixture was quenched by the careful addition of 2 ml methanol, followed by 5 ml water.
The resulting grey gel was filtered tiirough a one inch pad of celite, foUowed by 4x25 ml
ether washes. The filtrate was washed witii 25 ml brine, dried over MgS04, and
concentrated under vacumm to afford 0.32 g (0.83 mmol, 96%) of the desired product as a
clear oil, >90% pure by ^H NMR. Flash column chromatography (20 g silica gel, 8:2
hexanes;ethyl acetate) afforded 0.30 g (0.78 mmol, 90%) of the pure alcohol.
IH (300 MHz, relative to TMS at 0.00 ppm) 5 7.25 (d, J=8.7, 2H), 6.87 (d, J=8.7,
2H), 4.44 (d, 1=13.4, IH), 4.27 (d, 1=13.4, IH), 3.80 (s, 3H), 3.74 (d of d,
1=5.7,2.9, IH), 3.51 (m. 3H), 3.27 (d of d, 1=9.1,7.1, IH), 2.03 (m, 2H), 1.87
(m, IH), 0.96 (d, 1=7.0, 3H), 0.88 (s, 9H), 0.86 (d, 1=7.0, 3H), 0.06 (s, 3H),
0.04 (s, 3H).
13C (50 MHz) 5 159.07, 130.54, 129.19, 113.70, 74.72, 72.66, 72.61, 65.98, 55.21,
38.86, 37.53, 25.99, 18.26, 15.04, 11.89, -4.25.
IR 3428, 2961, 2926, 2849, 1613, 1514, 1249 cm-i.
OPTICAL ROTATION [a]D= -5.29° (c=0.2180 g/ml, CH2CI2).
TLC Rf=0.25 (hexanes).
120

(lR,2R,2'S,3'S.4'SVN-(r-HYH..vy,r_^henv1prnp.n-0'.
yl)-5-(4'-methoxyphpnynmethoyy-^-r-butvldimpthYlsUyloxv-2,4-HimPthyl-1-pp.nty1aminp(0^)
OTBDMS
MPMO' ^Y^^'^Nr^'^H OH
C3oH48N04Si f.w = 515.89
To 0.070 g (0.13 mmol) of die silylated aldol product 91 and 2 ml ether stirring in
a 5 ml pear shaped flask at -78° under a nitrogen atmosphere was added 0.0038 g (0.1
mmol) LiAlH4. After warming to room temperamre (2 hours) the reaction was quenched
by the addition of 3 drops water, followed by 3 drops IN NaOH and 6 more drops water.
MgS04 was added and the solution filtered through a medium fritted funnel, with a 10 ml
ether wash. Concentration under vacuum foUowed by flash column chromatography (10 g
siUcal gel, 8:2 hexanes:ethyl acetate) afforded 0.04 g (0.078 mmol, 60%) of the amino
alcohol.
iH (300 MHz, relative to CHCI3 at 7.26 ppm) 5 7.49-7.46 (m, 2H), 7.32-7.23 (m,
5H), 6.90-6.87 (m, 2H), 5.95 (d of d, 1=10.5,4.0, IH), 4.92 (d of d, 1=12.7,4.3,
IH), 4.86 (s, IH), 4.72 (br q, 1=6.9, IH), 4.66 (s, IH), 4.47 (d of d,
1=12.8,11.6, 2H), 4.43-4.34 (M, IH), 4.99 (d, J=9.6, IH), 3.81 (s, 3H), 3.75 (d
of d, 1=9.8,9.8, IH), 3.43 (d of q, 1=9.6,6.9, IH), 1.85-1.80 (m, IH), 1.15 (d,
J=6.9, 3H), 0.97 (d, 1=7.2, 3H), 0.94 (s, 9H), 0.88 (d, J=7.2, 3H), 0.15 (s,
3H), 0.10 (s, 3H).
i^C (50 MHz) 5 177.05, 159.59, 141.56, 130.06, 127.95, 126.81, 125.82, 113.94,
78.75, 74.32, 73.44, 71.75, 70.84, 56.25, 55.24, 42.04, 37.14, 26.28, 18.53,
17.38, 16.96, 9.43, -3.25, -3.52.
IR 3386, 2956, 2931, 2856, 1614, 1514, 1250, 1046 cm-i.
TLC Rf=0.24 (8:2 hexanes:ethyl acetate).
121

(2S,3R,4S)-5-(4'-MpthnvYDhenvnmprhoxv-2.4-HimPfhYi-
13-Dentanpdir>1 (Q^i)
MPMO
C15H24O4 f.w. = 268.39
DUsobutylaluminum hydride (13.4 ml of a 1.5 M solution in toluene, 20.1 mmol)
was added dropwise over a 15 minute period to 1.5 g (5.0 mmol) of the p-hydroxy ester
and 10 ml CH2CI2 stming at 0° under nitrogen. The reaction mixture was warmed to room
temperature, and aUowed to stir for an additional 30 minutes. The reaction was carefully
quenched by the slow addition of 3.5 ml anhydrous methanol, and then 20 ml of ether,
followed by 1.6 ml water, were added. After stirring for an additional 15 minutes the
milky suspension was filtered through a 3 cm pad of ceUte and concentrated under vacuum
to afford 1.2 g (89%) of a viscous clear oil which solidified upon standing. This solid was
then chromatographed (20 g sUica gel, 6:4 hexanes:ethyl acetate) to afford 1.1 g (82%) of a
white soUd. This soUd could be further purified by crystaUization from edier:pentane to
give fluffy white needles (0.97 g, 72%).
1H (200 MHz, relative to TMS at 0.00 ppm) 5 7.24 (d, J=8.6, 2H), 6.89 (d, J=8.6,
2H), 4.46 (s, 2H), 4.16 (s, 1H[0H, variable]), 3.81 (s, 3H), 3.78-3.66 (m, 3H),
3.60 (d of d, 1=9.1, 4.1, IH), 3.45 (t, 1=9.1, IH), 2.76(br. s, 1H[0H, variable]),
1.98 (m, IH), 1.72 (m, IH), 0.98 (d, J=7.0, 3H), 0.77(d, J=6.9, 3H).
13c (50 MHz) 5 159.23, 129.29, 113.77, 78.90, 76.17, 73.09, 67.37, 67.30, 55.14,
36.25, 35.75, 13.03, 8.63.
IR 3422, 2967, 1645, 1514, 1248 cm'l.
MP 53-56°
TLC Rf = 0.17 (1:1 hexanes:ethyl acetate).
OPTICAL ROTATION [a]D=+37.9° (c=0.0391 g/ml, CH2CI2).
ANALYSIS Calcd: C, 67.12; H, 9.02
Found: C, 67.01; H, 9.19.
122

(2R,3S,4R)-Methyl3-hvdrnvY-5-(4'-mpthnvYp>^^nYl)
methoxy-2.4-dimetiiylppntanoate(Q5)
MPMO
'OMe
C16H24O5 f.w. = 296.40
To a 25 mL round bottomed flask containing 1.08 g (2.40 mmol) of the
recrystalUzed aldol product, 5 ml CH2CI2, and 6 ml metiianol stirring at 0° under nitrogen
was added dropwise a freshly prepared solution of sodium medioxide (prepared by the
addition of 0.06 g{2.64 mmol} of clean sodium to 6 ml metiianol), and die mixture was
allowed to stir for 10 minutes. The reaction mixmre was tiien added to 25 ml of 10%
aqueous NaHC03 and 15 ml ether, the layers separated, and the aqueous phase extracted
with 25 ml CH2CI2. The combined organic extracts were tiien washed witii 10 ml brine,
dried over MgS04, and concentrated under vacuum. Rash column chromatography (60 g
silica gel, 8:2 hexanes:etiiyl acetate) afforded 0.58 g (2.0 mmol, 81.5%) of die p-hydroxy
ester plus 0.44 g (-100%) of the recovered crystallme chiral auxiUary (oxazolidinone ) 86.
iH (200 MHz, relative to TMS at 0.00 ppm) 5 7.24 (d, J=8.8, 2H), 6.87 (d, J=8.8,
2H), 4.44 (s, 2H), 3.89 (d of d of d, 1=8.2, 4.3, 3.9, IH), 3.80 (s, 3H), 3.70 (s,
3H), 3.63 (d of d, 1=9.2, 4.3, IH), 3.62 (d, J=4.3, 1H[0H, variable]), 3.51 (d of
d, 1=9.2, 6.7, IH), 2.61 (d of q, J=7.0, 3.9, IH), 1.88 (m, IH), 1.19 (d, J=7.0,
3H), 0.90 (d, 1=7.0, 3H).
13C (50 MHz) 5175.86, 159.13, 129.68, 129.15, 113.66, 75.86, 74.26, 72.99,
55.07, 51.59, 42.34, 35.62, 13.78, 9.64.
IR 3483, 2952, 1734, 1613, 1514 cm"!.
TLC Rf = 0.58 (1:1 hexanes:ethyl acetate).
OPTICAL ROTATION [a]D= +6.72° (c=0.2233 g/ml, CH2CI2).
ANALYSIS Calcd: C, 64.83; H, 8.17
Found: C, 64.00; 8.33.
123

(2S,3R,4S)-Methvl3-(r-hntyldimethy1)dlvloxv-5-(4'metiioxyphenvDmethoxY-9,4-dimethylppnft^n^^t-
("6)
MPMO OTBDMS
-COgMe
C22H3805Si f.w. = 410.69
To 0.46 g (1.6 mmol) of the p-hydroxy ester 95, 0.37 ml 2,6-lutidine, and 2 ml
CH2CI2 stirring under a nitrogen atmosphere in a 5 ml round bottomed flask at room
temperaturewas added 0.55 ml (2.4 mmol) of r-butyldimethylsilyltrifluoromethanesulfonate
dropwise. This mixture was stirred for 30 minutes, then added to a separatory funnel
containing 10 ml ether and 10 ml saturated aqueous NaHCOs. The phases were separated,
the aqueous layer back extracted with 3x10 ml ether, and the organic layers combined and
washed with 10 ml brine. The organic solution was then dried over MgS04 and
concentrated under vacuum. The cmde material was subjected to flash chromatography (20
g siUca gel, 95:5 hexanes;ethyl acetate) to afford 0.63 g (1.5 mmol, 98%) of the desired
product as a clear oil.
IH (200 MHz, relative to TMS at 0.00 ppm) 5 7.26 (d, J=8.7, 2H), 6.87 (d, J=8.7,
2H), 4.44 (d, 1=12.0, IH), 4.36 (d, 1=12.0, IH), 4.05 (d of d, 1=6.0,4.5, IH),
3.81 (s, 3H), 3.64 (s, 3H), 3.50 (d of d, 1=9.1,4.8, IH), 3.24 (d of d, 1=9.1,7.3,
IH), 2.65 (d of q, 1=7.0,4.5, IH), 1.91 (m, IH), 1.13 (d, J=7.0, 3H), 0.97 (d,
J=6.9, 3H), 0.86 (s, 9H), 0.03 (s, 3H), -0.03 (s, 3H).
13C (50 MHz) 5 175.76, 159.02, 130.73, 129.05, 113.66, 74.51, 72.60, 71.97,
55.20, 51.49, 42.76, 38.78, 25.96, 18.26, 14.42, 11.44, -4.33, -4.39.
IR 2954, 2856, 1736, 1612, 1513, 1460, 1249 cm-i.
OPTICAL ROTATION [a]D = -11-28° (c=0.2753 g/ml, CH2CI2).
TLC Rf=0.59 (8:2 hexanes;ethyl acetate).
124

(2S,3RAS)-3-(r-ButvlHimpthynsUvloYY-^-(^'methoxvphpnYl)mPthr^vY-2.4-d^mp.fhY1p^nt-1_y]
methanesulfonate (Q7)
MPMO OTBDMS
^OSOgMe
C22H4o06SSi f.w. = 460.77
To 0.43 g (1.1 mmol) of the alcohol 92, 0.23 ml (1.7 mmol), and 2.5 ml CH2CI2
stirring in a 10 ml pear shaped flask under a nitrogen atmosphere at 0° (ice/water bath) was
added 0.11 ml (1.4 mmol) metiianesulfonyl chloride. After stirring for 45 minutes at 0° die
reaction mixture was added to a separatory funnel containing 10 ml ether and 10 ml
saturated aqueous NaHC03 solution. The layers were separated and die aqueous layer
washed with 3x10 ml ether. The organic phases were combined and washed with 15 ml
brine, and then dried over MgS04 and concentrated under vacuum to afford 0.51 g (1.1
mmol, 98%) of the desfred product in >90% purity (^H NMR). Flash column
chromatography afforded 0.47 g (92%) of the mesylate as a clear oil.
iR (200 MHz, relative to TMS at 0.00 ppm) 5 7.25 (d, J=8.6, 2H), 6.87 (d, 1=8.6,
2H), 4.43 (d, 1=15.6, IH), 4.36 (d, 1=15.6, IH), 4.11-4.04 (m, 2H), 3.80 (s,
3H), 3.73 (d of d, 1=6.2,2.6, IH), 3.46 (d of d, 1=9.1,5.4, IH), 3.27 (d of d,
1=9.1,6.5, IH), 2.94 (s, 3H), 2.10 (d of q, 1=6.9,2.6, IH), 2.00-1.94 (m, IH),
0.95 (d, J=7.0, 3H), 0.94 (d, J=6,8, 3H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s,
3H).
13C (50 MHz) 5 159.05, 130.54, 129.12, 113.67, 72.75, 72.66, 72.57, 72.13, 55.18,
38.15, 37.19, 36.18, 25.96, 18.29, 14.43, 10.95, -4.19, -4.26.
IR 2954, 2934, 2856, 1613, 1514, 1359, 1249, 1177 cm-^.
OPTICAL ROTATION [a]D = +0.40° (c=0.2391 g/ml, CH2CI2).
TLC Rf=0.29 (8:2 hexanes;ethyl acetate).
125

(3S,5S)-3,5-DimethYl-4-f-butvldimpthvlsUvlnyYtetrahvdropvran
(QR)
^
'%
OTBDMS
Ci3H2802Si f.w = 244.50
To 0.20 g (0.45 mmol) of the mesylate 97 and 5 ml acetone in a 50 ml round
bottomed flask was added sodium iodide untU the solution was samrated. The flask was
fitted witii a water cooled condensor and immersed in a 65° oU badi. The mixture was
allowed to reflux for 6 hours, then cooled and dissolved in 100 ml ether. This orange
solution was washed with 50 ml saturated aqueous NaHC03, and this aqueous layer was
extracted with 3x15 ml ether. The combined organic layers were then washed with 50 ml
brine and dried over MgS04, and then concentrated under vacuum to afford 0.44 g of a
mixture of die pyran and MPM-I (87 % of a 1:1 mixture) as die only organic products
(accordmg to ^H NMR). Altiiough column chromatography partially purified this product,
the MPM-I streaked badly on siUca gel, and thereby contaminated die pyran. This pyran
was found to be extremely volatile, and losses occurred upon high vacuum treatment.
IH (200 MHz, relative to CHCI3 at 7.26 ppm) 5 3.80 (d of d, 1=8.2,4.1, IH), 3.58 (d
of d, 1=6.9,3.9, IH), 3.49-3.38 (m, 2H), 3.12 (d of d, 1=6.7,4.3, IH), 1.94-
1.80 (m, IH), 1.79-1.68 (m, IH), 0.91 (d, J=6.9, 3H), 0.90 (d, 1=6.7, 3H), 0.90
(s, 9H), 0.04 (s, 6H).
13C (50 MHz) 5 75.15, 70.83, 70.59, 35.00, 34.06, 25.82, 18.09, 14.52, 11.96, -
4.54, -4.75.
IR 2963, 2758, 1610, 1513, 1464, 1382, 1360, 1251 cm-i.
1 'y/i

(2S,3R,4S)-3-Hydroxy-5-(4'-mpthr)YYphenvnmp.thr>YY-9^/idimethvloent-l-vl
methanesulfonate (QQ)
MPMO OH OSOoMe
C16H26O6S f.w. = 346.48
Methanesulfonyl chloride (0.11 ml, 1.4 mmol) was added dropwise to a solution of
the diol (0.38 g, 1.4 mmol), triethylamine (0.24 ml, 1.7 mmol) and CH2CI2 (3 ml) stirring
in a 10 ml pear shaped flask at 0° under nitrogen. After 30 minutes the reaction was poured
onto 10 ml of saturated NaHC03, the layers separated, and the aqueous layer back
extracted with 3x10 ml ether. The organic phases were combined, dried over MgS04, and
concentrated under vacuum to afford 0.49 g (>100%) of the desUed product as a faintly
yeUow gum, contaminated with less than 10% of other products (bis-mesylate, diol). In
practice this cmde product was used directiy m the next step. It could, however, be
purified by flash chromatography (6:4 hexanes:ethyl acetate). No attempt was made to
obtain an elemental analysis of this compound.
IH (300 MHz, relative to TMS at 0.00 ppm) 5 7.24 (d, J=8.7, 2H), 6.88 (d, J=8.7,
2H), 4.46 (s, 2H), 4.28 (d of d, 1=9.5,8.4, IH), 4.10 (d of d, 1=9.5,6.4, IH),
3.92 (t, 1=1.5, IH [OH, variable]), 3.81 (s, 3H), 3.63 (d of d, 1=9.2,2.3, IH),
3.60 (d of d, 1=9.1,3.8, IH), 3.45 (t, 1=9.2, IH), 3.01 (s, 3H), 2.09 (m, IH),
1.96 (m, IH), 0.92 (d, J=6.9, 3H), 0.77 (d, 1=6.9, 3H).
13C (50 MHz) 6 159.30, 129.32 (two carbons), 113.80, 76.23, 74.85, 73.12, 72.68,
55.16, 36.80, 35.24, 34.54, 12.79, 8.42.
IR 3456, 2970, 1613, 1514, 1353, 1248, 1175cm-l.
TLC Rf = 0.27 (1:1 hexanes:ethyl acetate).
OPTICAL ROTATION [a]D=+21.2° (c=0.0327 g/ml, CH2CI2).
127

(2S,3R,4S)-l-Iodo-5-(4'-methoxyphpnYl)m.th^.Y o ^
dimetiivl-3-ppntanr.] (100^
MPMO
C15H22O3I f.w. = 378.28
A 25 ml round bottomed flask fitted with a water cooled condensor was charged
with die cmde mesylate 99 (0.78 g, 2.24 mmol), 10 ml acetone (freshly distiUed from
activated 4A molecular sieves), 1.68 g (11.2 mmol) sodium iodide (dried at 100° under
vacuum [~1 mm Hg] for 3 hours), and 0.1 ml ethyl dUsopropylamine. The flask was
placed in an oil batii and heated to reflux for ~ 2 hrs, with careful monitoring by TLC.
After die starting material was consumed the mixture was cooled to room temperature and
added to 50 ml 5% Na2S203. The mixmre was extracted with 3x50 ml ethyl acetate, and
die combined organic extracts washed with brine, dried over MgS04, and concentrated
under vacuum to afford a yellow oil. Flash chromatography (8:2 hexanes:ethyl acetate, 20
g sUica gel) afforded 0.50 g (1.33 mmol, 59.5%) of the desired product as a clear oil. No
attempt was made to obtain an elemental analysis of this compound.
iR (300 MHz, relative to TMS at 0.00 ppm) 5 7.24 (d, J=8.6, 2H), 6.88 (d, J=8.6,
2H), 4.49 (d, 1=11.4, IH), 4.42 (d, 1=11.4, IH), 3.80 (s, 3H), 3.63 (d of d,
1=8.8,2.6, IH), 3.58 (d of d, 1=9.1,3.9, IH), 3.46 (t, 1=8.9, IH), 3.36 (d of d,
1=9.5,7.5, IH), 3.18 (d of d, 1=9.5,6.6, IH), 1.88 (m, 2H), 1.00(d, 1=6.8, 3H),
0.78 (d, 1=7.0, 3H).
13C (75 MHz) 6 159.30, 129.44, 129.34, 113.84, 77.88, 76.03, 73.16, 55.21,
38.66, 35.98, 13.29, 13.11, 12.84.
IR 3481, 2962, 2932, 2860, 1612, 1513, 1459, 1248, 1085, 1035, 820 cm-l.
TLC Rf = 0.41 (8:2 hexanes:ethyl acetate).
OPTICAL ROTATION [a]D=+46.4 (c=0.0221 g/ml, CH2CI2).
128

(4S,5R,6S)-7-(4'-MethnvYp>^.nvimethnvY)-d/;-H^TTif-thvl5
(r-butyldimethvl).ilYlr.vY-1 (3"-(2'"-fnmPthYic^V~
ethoxy)methoxy)php.nvl-1 -hppt«nr^n^ (i n^ ^
MPMO OTBDMS
SEMO
C35H5806Si2 f.w. = 631.11
To a 10 ml pear shaped flask containmg 1.07 ml (1.12 M solution in hexane, 1.20
mmol) lithium diisopropylamide and 0.21 ml (1.20 mmol) hexamethylphosphoric triamide
stirring at 0° under a nitrogen atmosphere was added 0.42 g (1.20 mmol) of the imine as a
solution in 0.6 ml THF, followed by a 0.6 ml THF wash. This bright yellow solution was
stirred at 0° for 10 minutes, then cooled to "78° and stirred for an additional 30 minutes.
The neat iodide was then added dropwise, followed by 3x0.5 ml THF washes. The
mixture was allowed to warm to room temperature over the course of three hoiu^s, and
maintained at room temperature for an additional seven hours. The reaction was quenched
by die addition of 10 ml pH 4 buffer and the layers separated. The aqueous layer was
extracted with ether (3x20 ml) and the organic extracts combined, tiien washed with 20 ml
brine, dried over MgS04, and concentrated under vacuum to afford a yellow oil. This
cmde imine was dissolved in 10 ml ether, and 10 ml pH 4 buffer were added. After
stirring die biphasic mixture vigorously for four hours at room temperature die hydrolysis
was complete so the phases were separated and the aqueous layer extracted with 3x20 ml
ether. The combined organic extracts were washed widi brine, dried over MgS04, and
concentrated under vacuum to afford an orange oil. Flash chromatography (20 g silica gel,
98:2 hexanes:ethyl acetate) afforded 0.592 g (78.2%) of the ketone as a slightiy yellow oil.
Repeating tiie chromatography could purify tiiis material further, to a clear oil.
IH (300 MHz, relative to CHCI3 at 7.26 ppm) 5 7.59 (t, 1=1.9, IH), 7.56 (d of t,
1=7.8,1.2, IH), 7.35 (t, 1=7.8, IH), 7.24 (d, 1=8.8, 2H), 6.85 (d, 1=8.8, 2H),
5.25 (s, 2H), 4.41 (d, 1=6.3, IH), 4.38 (d, 1=6.3, IH), 3.79 (s, 3H), 3.76 (d of
d, 1=9.5,7.1, 2H), 3.53 (m, 2H), 3.25 (d of d, 1=9.1, 7.5, IH), 2.98 - 2.88 (m.
129

130
2H), 1.96-(m. IH), 1.82 (m,4H), 1.68 -1.57 (m,-3H), 0.98 - 0.89 (m 8H) 0 88
(s, 9H), 0.04 (s, 3H), 0.03 (s, 3H), 0.00 (s, 9H).
13C (75 MHz) 5 200.05, 159.01, 157.63, 138.48, 130.88, 129.55, 129.12, 121.42,
120.75, 115.50, 113.68, 92.89, 77.35, 72.76, 72.61, 66.40, 55.23, 38.04,
37.04, 35.98, 29.31, 26.13, 18.41, 18.02, 15.06, 14.25, -1.43, -3.71, -4.06.
IR 2955, 2856, 1685, 1583, 1509, 1248, 1091, 1039, 836, 771, 689, 669'cm-l.
TLC Rf = 0.18 (95:5 hexanes:ethyl acetate).
ANALYSIS Calcd: C, 6.62; H, 9.26
Found: C, 66.57; H, 9.15.
(1S .4S .5R.6R)-7-(4'-Methoxvphenynmethoxv-4.6-
dimethyl-1 -(3"-r2"'-trimethylsilvlethoxv1 methoxy)
phenyl-5-r-butyldimethvlsiloxV-1 -heptanol (109)
MPMO OTBDMS
SEMO
C35H6o06Si2 f.w. = 633.13
To a 5 ml pear shaped flask contaming 0.5 ml THF, 0.05 ml (0.05 mmol of a 1.0
M solution in THF) BH3 solution, and 0.006 g (0.023 mmol) of Corey's (R)-
oxaboroUdine (prepared from (R)-(+)-2-(Diphenylhydroxymethyl)pyrtolidine42 stining at
0° under a nitrogen atmosphere was added 0.057 g (0.09 mmol) of the ketone dropwise as
a solution in 0.3 ml THF, followed by 2x0.3 ml THF washes. The mixture was
maintained at 0° for one hour, at which time TLC analysis indicated that die reaction was
still incomplete. Another 0.05 ml BH3 solution (1.0 M in THF, 0.05 mmol) was added,
and the reaction aUowed to stir at 0° for an additional 30 minutes. The completed reacnon
was dien quenched by die addition of 1 ml methanol, followed by 5 ml saturated aqueous
NaHC03 solution. The phases were separated, the aqueous phase back extracted with
3x10 ml ether, the combined organic extracts washed widi brine, dried over MgS04, and
concentrated under vacuum. Flash column chromatography (20 g silica gel, 9 .^ - •

hexanesiethyl acetate gradient) to afford 0.0423 g (74.2%) of the desi.^ alcohol as
approximately a 12:1 mixture of epimers (75 MHz I3c integrations).
Spectra for separate diastereomers were discemed by comparing the spectra of the
product from this reaction with the spectra of a 1:1 mixture of diastereomers obtained from
reduction of the ketone with sodium borohydride.
IH Major isomer: (300 MHz, relative to CHCI3 at 7.26 ppm) 6 7.21 (m, 3H), 6.98
(t, 1=1.8, IH), 6.92 (d of d, 1=7.9,2.0, 2H), 6.83 (d of t, 1=8.6,2.0, 2H),'5.21
(s, 2H), 4.58 (t, 1=5.8, IH), 4.41 (d, 1=11.7, IH), 4.36 (d, 1=11.7, 1H),'3.79
(s, 3H), 3.76 (d of d, 1=8.4,8.3, 2H), 3.50 (d of d, 1=9.0,4.7, IH), 3.43 (d of d,
1=6.1,3.1, IH), 3.20 (d of d, 1=8.9,7.5, IH), 2.01 (br s, 1H[0H, variable]),
1.95-1.88 (m, IH), 1.83-1.71 (m, IH), 1.68-1.52 (m. 2H), 1.36-1.25 (m, 2H),
0.96 (d of d, 1=8.4,8.3, 2H), 0.90 (d, 1=6.7, 3H), 0.844 (s, 9H), 0.82 (d, 1=6.4,
3H), 0.00 (s, 9H), -0.01 (s, 3H), -0.04 (s, 3H).
Minor isomer: (300 MHz, relative to CHCI3 at 7.26 ppm) 5 7.21 (m, 3H), 6.96
(t, 1=1.8, IH), 6.95 (d of d, 1=7.9,2.0, 2H), 6.87 (d of t, 1=8.6,2.0, 2H), 5.21
(s, 2H), 4.58 (t, 1=5.8, IH), 4.41 (d, 1=11.7, IH), 4.36 (d, 1=11.7, IH), 3.80
(s, 3H), 3.76 (d of d, 1=8.4,8.3, 2H), 3.42-3.52 (m, 2H), 3.21 (d of d,
1=8.9,7.5, IH), 2.01 (br s, 1H[0H, variable]), 1.95-1.88 (m, IH), 1.83-1.71 (m,
IH), 1.68-1.52 (m. 2H), 1.36-1.25 (m, 2H), 0.96 (d of d, 1=8.4,8.3, 2H), 0.90
(d, 1=6.7, 3H), 0.836 (s, 9H), 0.82 (d, 1=6.4, 3H), 0.00 (s, 9H), -0.02 (s, 3H), -
0.05 (s, 3H).
13C Major isomer: (75 MHz) 5 159.003, 157.626, 146.684, 130.820, 129.413,
129.128, 119.102, 115.020, 113.724, 113.671, 92.85, 77.383, 74.505, 72.708,
72.577, 66.166, 55.202, 37.811, 37.341, 36.192, 30.639, 26.111, 18.389,
18.010, 15.274, 14.395, -1.43, -3.773, -4.055.
Minor isomer: (75 MHz) 6 159.003, 157.648, 146.505, 130.880, 129.413,
129.102, 119.128, 115.117, 113.819, 113.671, 92.876, 77.383, 74.884, 72.776,
72.577, 66.166, 55.202, 37.516, 37.241, 36.277, 30.879, 26.111, 18.389,
18.010, 15.150, 14.072, -1.43, -3.773, -4.055.
IR 3447, 2954, 2929, 2956, 1611, 1513, 1248, 1089, 1036, 859, 836, 773 cm'l.
TLC Rf = 0.26 (8:2 hexanes:ethyl acetate).
ANALYSIS Calcd: C, 66.41; H, 9.56
Found: C, 66.73; H, 9.45.
131

(lS,4S,5R,6S)-7-(4'-MethoxyDhenvnmptbnvv-i,me.,hnvy-
4,6-dimethyl-l-(3"-(trimethylethoxvmpthnvv-)Dhenv1)-S-(rbutvldimethynsUvlnxYhpptane
(109)
MPMO OTBDMS OMe
SEMO
C3oH6206Si2 f.w. = 647.16
To a suspension of potassium hydride (0.13 g, 1.13 mmol) and 1.5 ml THF
stining in a 5 ml pear shaped flask at 0° (ice/water bath) under a nitrogen atmosphere was
added 0.28 g (0.45 mmol) of the alcohol 110 as a solution in 1 ml THF. This suspension
was allowed to warm to room temperature over 1 hour, then re-cooled to 0°. Methyl iodide
(0.07 ml, 1.13 mmol) was added, and the reaction was maintained at 0° for 2 hours, after
which die reaction was quenched by die careful addition of 1 ml methanol. The mixture
was then added to a separatory funnel containing 10 ml etiier and 10 ml water and the
layers were separated. The aqueous phase was washed with 3x10 ml ether, and then the
organic layers were combined and washed witii 10 ml brine. The ether solution was then
dried over MgS04 and concentrated under vacuum to afford a mixture of the product and
mineral oU. Rash column chromatography (20 g siUca gel, 9:1 hexanes:ethyl acetate)
afforded 0.22 g (0.34 mmol, 75%) of the methyl etiier as a colorless oU.
IH (300 MHz, relative to CHCI3 at 5 7.26 ppm) 5 7.26-7.22 (m, 3H), 6.96-6.83 (m,
5H), 5.22 (s, 2H), 4.38 (s, 2H), 4.00 (d of d, 1=7.2,5.7, IH), 3.80 (s, 3H), 3.77
(d of d, 1=9.1,7.6, 2H), 3.51-3.45 (m, IH), 3.41 (d of d, 1=6.4,2.8, IH), 3.23-
3.17 (m, IH), 3.20 (s, 3H), 1.92-1.75 (m, 2H), 1.58-1.49 (m, 2H), 1.32-1.23
(m, 2H), 0.96 (d of d, 1=9.1,9.1, 2H), 0.91 (d 1=6.9, 3H), 0.84 (s, 9H), 0.83 (d,
1=8.1, 3H), 0.00 (s, 9H), -0.03 (s, 3H), -0.06 (s, 3H).
^3C (75 MHz) 5 159.01, 157.66, 144.29, 130.93, 129.34, 129.12, 119.98 115^0U
114.48, 113.68, 92.96, 84.22, 77.31, 72.86, 72.60, 66.21, 56-71, 5 -26^ 7.91,
36.56, 36.30, 30.84, 26.14, 18.41, 18.03, 15.23, 14.17, -1.41, -3.77, -4.07.
ANALYSIS Calcd: C, 66.83; H, 9.67
Found: C, 66.57; H, 9.76.
132

(2S,3R,4S,7S)-7-MethnYY-2.4-dimp.thYl-7-(3'-triniPthYisilylethoxymethnxY)phPnyl-3-(NhnfYlHim.thY])
silyloxv-l-hp.ptanni(in)
OTBDMS
SEMO
C28H5405Si2 f.w. = 527.00
To the 0.14 g (0.21 mmol) of the ether 102, 2 ml CH2CI2, and 0.4 ml pH 4 buffer
stirring in a 10 ml pear shaped flask at room temperature was added 0.60 g (0.26 mmol)
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). The solution immediately turned dark
green. After 30 minutes the reaction mixmre was added to a separatory funnel containing
20 ml ether and 20 ml saturated aqueous NaHC03 solution. The layers were separated and
the aqueous layer was extracted with 3x10 ml ether. The organic layers were combined
and washed witii 3x25 ml of the bicarbonate solution, doUowed by 25 ml brine. The
organic phase was then dried over MgS04 and concentrated under vacuum. Flash column
chromatography afforded 0.96 g (0.18 mmol, 86%) of the alcohol 111 as a white wax.
Spectra for separate diastereomers were discemed by comparing die spectra of die
product from this reaction with tiie spectra of a 1:1 mixture of diastereomers
iR (200 MHz, relative to CHC13 at 5 7.26 ppm, 'natural* 7S isomer) 5 7.29-7.20 (m,
IH), 6.96-6.88 (m, 3H), 5.21 (s, 2H), 4.01 ( d of d, 1=5.6, 4.3, IH), 3.76 (d of
d, 1=8.2,7.5, 2H), 3.56 (d, 1=5.2, 2H), 3.45 (d of d, 1=5.2,4.3, IH), 3.20 (s,
3H), 2.53 (br s, lH[-OH, variable]), 1.90-1.28 (m, H), 0.99-0.82 (m, 8H), 0.86
(s, 9H), 0.07 (s, 3H), 0.01 (s, 3H), -0.01 (s, 9H).
iH (200 MHz, relative to CHC13 at 5 7.26 ppm, 'unnatural' 7R isomer) 5 7.29-7.20
(m, IH), 6.96-6.88 (m, 3H), 5.21 (s, 2H), 4.01 ( d of d, 1=5.6, 4.3, IH), 3.76 (d
of d, 1=8.2,7.5, 2H), 3.56 (d, 1=5.2, 2H), 3.45 (d of d, 1=5.2,4.3, IH), 3.19 (s
3H), 2.53 (br s, lH[-OH, variable]), 1.90-1.28 (m, H), 0.99-0.82 (m, 8H), 0.87
(s, 9H), 0.06 (s, 3H), 0.00 (s, 3H), -0.01 (s, 9H).
133

13C
13C
CD
(50 MHz, 'natural' 7S isomer) 6 157.64, 144 12 129 .. ion
114.49, 92.91, 84.21, 80.74 66 17 56 65 VR '^' ^^^1^'
26.04, 18.26, 17.99, 16.08, 14.95,-145 '3 99'Vof''^^^^^
(50 MHz, 'unnatural' 7R isomer) 8 157.6^, 143 95 no ..no
114.39, 92.91, 84.11, 80.63, 66.03, 56.65 37^3 ^3^^^ '''''^
26.04, 18.26, 17.99, 15.95, 14.59, -1.45, -3 99 4 14 ' ^'''^ ^'''^^
(ethanol) Positive cotton effects at 268 and 271 nm
C28H5203Si2 f.w. = 524.98
OTBDMS
SEMO
C28H5203Si2 f.w. = 524.98
To a solution of DMSO (0.052 ml, 0.72 mmol) and 2 ml CH2CI2 stimng in a 5 ml
round bottomed flask at -78° under a nitrogen atmosphere was added the oxalyl chloride
(0,032 ml, 0,32 rmnol) dropwise. After this mixture was stin-ed for 10 minutes 0.096 g
(0.181 mmol) of the alcohol 111 was added dropwise as a solution in 0.5 ml CH2CI2,
with 2x0.3 ml CH2CI2 washes. This solution was maintained at -78° for 20 minutes, and
t en 0.25 ml (1.81 mmol) triethylamine was added dropwise. The resulting suspension
was stirred at -78° for 15 minutes and tiien it was warmed to room temperature over 10
minutes and stirred at room temperamre for 10 more minutes. The reaction mixture was
t en added to a separatory funnel containing 20 ml ether, 10 ml water, and 10 ml saturated
ous NaHC03. The layers were separated and the aqueous phase was extracted with
nil ether. The organic phases were combined and washed with 25 ml brine, and then
^ed over MgS04 and concentrated under vacuum to afford 0.095 g (0.18 mmol, 100%)
of the aldehyde as a clear oil, >95% pure by ^H NMR.
134

IH (300 MHz, relative to CHCI3 at 7.26 ppm, 1:1 mixture of C7 epimers) 5 9.72 (d of
d, 1=1.7,1.1, IH), 7.24 (t, 1=7.6, IH), 6.97-6.88 (m, 3H), 5.22 (s, 2H), 4.00 (t,
1=6.9, IH), 3.76 (d of d, 1=7.8,7.4, 2H), 3.72-3.68 (m, IH), 3.20 (s, 1.5H),
3.19 (s, 1.5H), 2.54-2.46 (m, IH), 1.90-1.82 (m, IH), 1.70 (q, 1=7.9, IH),
1.67-1.52 (m, 2H), 1.38-1.12 (m, IH), 1.03 (d, 1=7.1, 1.5H), 1.02 (d, 1=7.1,
1.5H), 0.96 (d of d, 1=7.8, 7.4, 2H), 0.90-0.82 (m, 3H), 0.84 (s, 4.5H), 0.83 (s,
4.5H), 0.04 (s, 3H), -0.01 (s, 9H), -0.02 (s, 1.5H), -0.03 (s, 1.5H).
(2S.8S.9R.10R)-7-Hvdroxv-13-methoxv-l-(4'methoxyphenyl)methoxy-2,4.4,8.10-pentamethyl-13-(3"-(trimethylsilylethoxvmethoxy)phenyl-9-(rbutyldimethyl)silyloxy-5-tridecanone
(113)
MPMO OTBDMS OMe
C45H7808Si2 f.w. = 803.41
SEMO
To a solution of ketone 31 (0.075 g, 0.27 mmol) and 1 ml THF stirting in a 5 ml
round bottomed flask at -78° under a nitrogen atmosphere was added 0.24 ml (0.27 mmol)
LDA. This solution was maintained at -78° for 15 minutes, dien the aldehyde 112 (0.095
g, 0.18 mmol) was added dropwise as a solution in 0.5 ml THF, followed by 3x0.3 ml
THF washes. After 10 minutes at -78° the reaction mixture was added to a separatory
funnel containing 20 ml ether, 10 ml water, and 10 ml samrated aqueous NaHCOs- The
layers were separated and the aqueous phase was extracted widi 3x25 ml etiier. 1 e
organic phases were combined and washed with 25 ml brine, and dien dned over MgSU
and concentrated under vacuum. Flash column chromatography (20 g silica gel so v
gradient hexanes to 9:1 hexanes:ethyl acetate) afforded 0.122 g (0.15 mmol, 85%)
aldol product 113 as a clear oil.
135

IH (300 MHz, relative to CHCI3 at 7.26 ppm, 1:1 mixture of C13 epimers,
indeterminate mixture of C7 epimers) 5 7.26-7.22 (m, 3H), 6.95-6.85 (m 5H)
5.22 (s, 2H), 4.39 (s, 3H), 4.02 (t, 1=6.8, IH), 3.80 (s, 3H), 3.77 (d of d,
1=8.4,7-4, 2H), 3.59-3.55 (m, IH), 3.57 (d, 1=2.9, IH), 3.20 (s, 1.5H), 3.20 (s,
1.5H), 3.16 (d of d, 1=6.1,2.4, 2H), 2.66 (d of d, 1=17.7,8.7, IH), 2.48'(d of t,'
1=17.7,3.7, IH), 0.96 (d of d, 1=8.4,7.4, 2H), 0.87-0.79 (m, 15H), 0.85 (s,
4.5H), 0.84 (s, 4.5H), 0.10 (s, 1.5H), 0.09 (s, 1.5H), 0.01 (s, 1.5H), 0.00 (s,
9H), -0.01 (s, 1.5H).
(2S.8S.9R.10R)-13-Methoxy-l-(4'-methoxvphenvlV
methoxy-2,4,4,8,10-pentamethyl-13-(3"-(trimethylsilylethoxymethoxy)phenyl-9-(f-butyldimethyl)sUyloxy-5,7-tridecanedione
(115)
MPMO
C45H7608Si2 f.w. = 801.39
SEMO
136
To a solution of DMSO (0.043 g, 0.61 mmol) and CH2CI2 d ml) in a 10 ml round
bottomed flask under a nitrogen atmosphere at -78° was added oxalyl chloride (0.027 ml,
0.31 mmol) dropwise. This reaction mixture was maintained at -78° for 10 minutes, and
then the P-hydroxy ketone 113, in 0.5 ml CH2CI2, followed by 2x0.3 ml CH2CI2 washes
were added dropwise. This mixture was stirred at -78° for 20 minutes, then 0.21 ml (1.5
mmol) trietiiylamine was added. The reaction mixmre was stirred at -78° for an additional
10 minutes, then it was wanned to room temperature oyer 10 minutes and allowed to sur at
room temperamre for 10 minutes. The reaction mixture was dien added to a separatory
funnel containing 20 ml ether and 20 ml saturated aqueous NaHC03 and the layers
u A ifh ^^O'^ ml ether and dien the organic layers
separated. The aqueous layer was washed with 3x25 ml etner, diiu
were combined and washed witii 25 ml brine. The organic solution was dned over

137
MgS04, concentrated under vacuum, and submitted to flash chromatography (20 g silica
gel, 93:7 hexanes:ediyl acetate) to afford 0.064 g (0.079 mmol, 53%) of the desired
compound as a clear oU. iR NMR analysis suggests that this is a 1:2 mixture of die p
diketone and its various enol forms.
iR (300 MHz, relative to CHCI3 at 7.26 ppm, 1:1 mixture of C13 epimers, mixture of
keto/enol tautomers, diagnostic peaks only) 5 5.22 (s, 2H), 3.80 (s, 3H), 3.21 (s,
1.5H), 3.20 (s, 1.5H), 1.13 (s, 1.5H), 1.13 (s, 1.5H), 0.80 (s, 4.5H), 0.78 (s,
4.5H), 0.00 (s, 9H).

REFERENCES
1. Kato, Y. and Scheuer, P.l. /. Am. Chem. Soc. 1974, 96(7), 2245-2246
^' ^38l40.'' ^•^•' ^''''''' ^•^•' ^^^^^^^§i' M-' Norton, TR. 5de«c. 1977,196,
3. Serdula, M.; Bartolini, G.; Moore, R.E.; Gooch 1 • Wieben^a N w..,..- ;.^ w
y. 1982, 47(7j, 200-201. ' ^'^^^"g^' N- //flwan Merf.
4. Moore, R.E^Blackm^, A.l, Cheuk C.E.; Mynderse, I.S.; Matsumoto, G.K •
Cl^dy, 1.; Woodard, R.W.; Craig, l.C. /. Org. Chem. 1984,49(13), 2484
5,
7.
Entzeroth, M.; Blackman, A.l.; Mynderse, I.S.; Moore, R.E. / Org Chem
1985,50(8), 1255-1259. ^'
6. Kato, Y. and Scheuer, P.l. Pure Appl. Chem. 1976,48, 29-33.
lohnson, B.F. P;z.D. Dissertation (Harvard University) - 'Structural and Synthetic
Studies on the Aplysiatoxins;' University Microfilms International: Ann Arbor
1985; pp 16-19.
8. Park, P.; Broka, C.A.; lohnson, B.F.; Kishi, Y. /. Am. Chem. Soc. 1987,
109(20), 6205-6207.
9. Fujiki, H.; Ikegami, K.; HakU, H.; Suganuma, M.; Yamaizumi, Z.; Yamazato, K.;
Moore, R.M.; Sugimura, T. Jpn. J. Cancer Res. (Gann) 1985, 76(4), 257-259.
10. Personal communication from Professor R.E. Moore to Professor R.D. Walkup.
11. Boatman, P.D., Ir., Ph.D. dissertation, Texas Tech University, 1990.
12. This work was initiated in tiiis laboratory by Dr. Ray Cunningham, who developed
mediodology culminating in the aldol product from condensation of 31 and 32.
Cunningham, R.T., Ph.D. dissertation, Texas Tech University, 1988. Doug
Boatman improved the synthesis to this point, and further elaborated die aldol
product to enol ether 27 (reference 11).
13. Ireland, R.E.; Thiasrivongs, S.; Dussault, P.H. /. Am. Chem. Soc. 1988,
110(17), 5768-5779.
14. Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem. Soc. 1984,
106(22), 6709-6716.
15. Toshima, H.; Yoshida, S-i.; Suzuki, T.; Nishiyama, S.; Yamamura, S.
Tetrahedron Lett. 1989, 30(48), 6721-6724. Toshirna, ^;^.^^f%\-..,^
Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1989, 30(48), b/l>ou^.
138

'^' mtlf^^^^^^ Ramachandran, P.V.; Brown, HC. /. Org. Chem. 1985,
17. Nakajima, N.; Horita, H.; Abe, R.; YonemUsu, O. Tetrahedron Lett 1Q88
29(33), 4139-4142. anearon Lett. 1988,
18. Fuhrhop, 1. and Penzlin, G. Organic Synthesis, Veriag Chemie: Weinheim 1984pp
52-58.
19. Deol, B.S.; Ridley, D.D.; Simpson, G.W. Aus. J. Chem 1976 29 2459-
2467. ' '
20. Unpublished results, R.D. Walkup.
21. Katsuki, T. and Sharpless, K.B. /. Am. Chem. Soc. 1980,102(18), 5974-5976.
22. Sharpless, K.B.; Woodard, S.S.; Finn, M.G. Pure Appl. Chem. 1983,55(77),
1823-1836.
23. Corey, E.l. /. Org. Chem. 1990, 55(6), 1693-1694.
24. Martin, V.S.; Woodard, S.S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless,
K.B. J. Am. Chem. Soc. 1981, 103(20), 6237-6240.
25. Fugi, K.; Node, M.; Tanaka, F.; Hosoi, S. Tetrahedron Lett. 1989,30(21),
2825-2828.
26. To properly pronounce tiiis abbreviation one should note that tiiere are five O's
(oxygens) in MoOPH.
27. Vedejs, E. /. Am. Chem. Soc. 1974, 96(18), 5944-5946. Vedejs, E.; Engler,
D.A.; Telschow, I.E. /. Org. Chem. 1918,43(2), 188-195.
28. Lipshutz, B.H. and Pegram, ^i.Z. Tetrahedron Lett. 1980,27, 3343-3346.
29. WhiteseU, l.K. and WhiteseU, M.A. Synthesis 1983, 517-536.
30. Evans, D.A.; BartroU, 1.; Shih, T.L. /. Am. Chem. Soc. 1981,103(8), 2127-
2129. Other reactions of enolates derived from these oxazolidinoiies proceed with
excellent diastereoselectivity. Alkylations: Evans, DA.; Enms, M.D.; Mathre
D.I. /. Am. Chem. Soc. 1982,104(6), 1737-1739. Azidation and brom^^ation .
Evans, D.A.; Britton, T.C.; EUman, I.A.; Dorow, R.L. /. Am. Chem. Soc.
1990,112(10), 4011-4030.
31. Evans, D.A. Aldrichimica Acta 1982,15(2), 23-32^ f^^^^^^^
Polniaszek, R.P. Tetrahedron Lett. 1986, 27(47), 5683-5686.
32. Cunningham, R.T., Ph. D. dissertation, Texas Tech University, 1988.
139

33. Corey, E.l.; Nicolaou, K.C.; Torn, T. ./. Am. Chem. Soc. 1975, 97(8), 2287-
34. Newman, M.S.; Kutner, A. J. Am. Chem. Soc. 1951, 73(9), 4199-4204
^^* 4675-4676'^'' ^^'"''''' ^*' ^'*'"''""' ^'^' ^- ^^- ^h^^- ^oc. 1986, lOS,
36. 55'27i''2767'-^7^^^^ ^'' Rodriguez. I.; Walther, E. 7. Am. C/^m. Soc. 1990,
37. Evans, D.A.; Nelson, J.V.; Taber, T.R. Topics in Stereochem. 1982, 75, 1-115.
38. Greene, T.W. Protective Groups in Organic Synthesis; lohn Wiley and Sons- New
York, 1981; pp 44-47.
39. Aristoff, P.A.; lohnson, P.D.; Harrison, A.W. J. Am. Chem Soc 1985
107(26), 1961-1914.
40. Binkely, R.W.; Ambrose, M.G.; Hehemann, D.G. ./. Org. Chem 1980 4S(2^)
4387-4391.
41. Kieczykowski, G.R.; Kowski, G.R.; Schlessinger, R.H.; Suisky, R.B.
Tetrahedron Lett. 1976, (8), 597-600.
42. Corey, E.l.; Bakshi, R.K.; Shibata, S. J. Am. Chem. Soc. 1987, 709, 5551-
5553.
43. Corey, E.l.; Bakshi, R.K.; Shibata, S.; Chen, C.-P.; Singh, V.P. J. Am. Chem.
Soc. 1987, 709(25;, 7925-7926.
44. Brown, H.C. and Cole, T.E. Organometal. 1985,4(5), 816-821.
45. Swern, D. and Mancuso, A. Synthesis 1981, 165.
46. Walkup, R.D.; Kane, R.R.; Boatman, P.D., Jr.; Cunningham, R.T. Tetrahedron
Lett., in press.
47. StiU, W.C; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2933.
48. Prepared by Professor R.D. Walkup in these laboratories.
49. Davis, D.R.; Hermanson, R.C.; Pistel, W.R.; Spaude, E.A. J. Med. Chem.
1985,28(8), 1106-1109.
mm^m::^i
140