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

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Chapter 1: Introduction Chapter 1 – Dearomatising Additions in Organic Synthesis 1.1 Introduction Aromaticity and aromatic compounds have enjoyed a central role in chemistry throughout its history. Since Kekule’s first visions, the cyclic delocalised systems have captured the imagination of chemists of all flavours, and their predictable behaviour means that no undergraduate course goes without early examples of the manipulation of aromatic compounds. Much work in organic synthesis has involved the functionalisation of the aromatic nucleus, and it is fundamental to the repertoire of any synthetic chemist. Arenes are widely available, highly stable and affordable starting materials, and this pool of available building blocks may extended by technologies such as cross-coupling, ortho-lithiation, and electrophilic or nucleophilic substitution. This thesis concerns the development of a dearomatising functionalisation of a benzenoid system, and a brief survey of existing methods follows. A recent review by Ortiz et al. 1 covers a range of methods for dearomatising anthracenes, naphthalenes and benzene systems. The following survey will study reductive intermolecular methods for the nucleophilic dearomatisation of the benzene system, although some exceptions have been made where they are of particular relevance or interest. 1.2 Dearomatisation with Electrophilic Functionalisation 1.2.1 Von Auwers-Woodward When subjecting ortho- and para- alkylated phenols to Reimer-Tiemann conditions, 2 Von Auwers isolated significant amounts of cyclohexadienone 2, as well as the expected phenolic aldehyde 1 (Scheme 1.1). 3 First reported in 1902, this appears to be the first dearomatisation of a benzene nucleus. Like phenol 1, dienone 2 is the product of addition of dichlorocarbene to p-cresol, but unlike its regioisomer the product of para-addition is unable to undergo rearomatisation, but must abstract a proton from elsewhere to become dienone 2. 15
1.2 – Electrophilic dearomatisation HO NaOH, CHCl 3 OHC HO 1 + O 2 CHCl 2 NaOH, CHCl 3 CHCl 2 HO O 3 80% Scheme 1.1 – the first dearomatising addition by Von Auwers 3 Other than providing mechanistic evidence for the Reimer-Tiemann reaction, this dearomatisation remained unexplored until Woodward proposed its use to introduce the angular methyl group in the synthesis of sterols. Tetralin 4 was subjected to the conditions, giving both the aldehyde and the desired dienone 5 (Scheme 1.2a). 4 Upon gentle hydrogenation alcohol 6 was obtained, whilst stronger conditions led to dehalogenation. This observation led Woodward to postulate the possible biosynthesis of the male hormone oesterone from androstone (Scheme 1.2b). a) H 2 CHCl 2 HO 4 NaOH, CHCl 3 O OHC CHCl 2 15% 5 + HO 6 b) Me O HO 50% Me O proposed biosynthesis Me HO HO oestrone androstone Scheme 1.2 – a) introduction of the angular methyl group b) proposed biosynthesis 4 1.2.2 The Birch reduction The most widely used dearomatising reaction is the dissolving metal reduction discovered by Birch. 5 The reduction yields the product of the 1,4-addition of hydrogen across the arene system, giving the non-conjugated diene 8 (Scheme 1.3). The formation of the thermodynamically unfavoured 1,4-diene is due to the kinetically- 16
Page 1 and 2: Dearomatising Addition of Organolit
Page 3 and 4: 2.3 Synthetic Scope 64 2.3.1 Organo
Page 5 and 6: Abstract Dearomatising Addition of
Page 7 and 8: The Author The Author graduated fro
Page 9 and 10: Abbreviations & Conventions Ac acet
Page 11 and 12: RDS rate determining step R f RC rt
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Page 18 and 19: Chapter 1: Introduction diastereome
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Page 32 and 33: Chapter 1: Introduction The amino a
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Page 36 and 37: Chapter 1: Introduction COR' i) ATP
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Page 44 and 45: Chapter 1: Introduction Diene (-)-8
Page 46 and 47: Chapter 1: Introduction A scheme su
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Chapter 2 - Dearomatising additions
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3.1 - Oxazoline synthesis 3.1.1.a H
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3.1 - Oxazoline synthesis O Ar OH i
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3.1 - Oxazoline synthesis 3.1.2 Gen
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3.1 - Oxazoline synthesis mCPBA O N
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3.1 - Oxazoline synthesis 3.1.4.b M
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3.1 - Oxazoline synthesis Ph Ph Ph
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3.2 - Oxazoline removal O N O OH 3N
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3.2 - Oxazoline removal O Me O N OM
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3.2 - Oxazoline removal However, th
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3.2 - Oxazoline removal 3.2.3 Reduc
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3.2 - Oxazoline removal Ph O N Ph P
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3.2 - Oxazoline removal 3.2.3.c Ami
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3.2 - Oxazoline removal Ph Ph Ph Ph
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3.2 - Oxazoline removal 3.2.5.b N-A
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3.2 - Oxazoline removal Ph Ph O N H
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3.2 - Oxazoline removal Ph Me Ph Me
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3.2 - Oxazoline removal 3.2.6 Deter
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Better, however, would be a method
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4.1 - Introduction HO OH OH HO OH O
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4.1 - Introduction (-)-Shikimic aci
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4.1 - Introduction followed by Flem
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4.2 - Carbasugar synthesis 4.2 Synt
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4.2 - Carbasugar synthesis stereoce
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4.2 - Carbasugar synthesis of the o
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4.2 - Carbasugar synthesis support
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4.2 - Carbasugar synthesis Ox* Ox*
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4.2 - Carbasugar synthesis OsO 4 (c
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4.2 - Carbasugar synthesis taken on
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4.2 - Carbasugar synthesis As well
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4.4 - Revised altrose synthesis 4.4
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4.4 - Revised altrose synthesis suf
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4.4 - Revised altrose synthesis ind
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4.5 - Mannose synthesis 4.5 Synthes
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4.5 - Mannose synthesis It is clear
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4.5 - Mannose synthesis considering
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4.5 - Mannose synthesis which would
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4.5 - Mannose synthesis One clear a
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4.5 - Mannose synthesis 4.5.2.b Epo
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4.5 - Mannose synthesis hydrolysis
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4.5 - Mannose synthesis The second
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4.6 - Summary 4.6 Summary & Future
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4.6 - Summary OH CDI, NH 2 OH.HCl,
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184
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References (37) Rawson, D. J.; Meye
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References (105) Gajewski, J. J.; B
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References (169) McCormick, J. P.;
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References 192
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Experimental section 254nm, dodecam
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Experimental section General Proced
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Experimental for chapter 2 Synthesi
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Experimental for chapter 2 (CDCl 3
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Experimental for chapter 2 3H, OMe
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Experimental for chapter 2 Ph), 139
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Experimental for chapter 2 H4), 5.2
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Experimental for chapter 2 108 R f
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Experimental for chapter 2 Synthesi
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Experimental for chapter 3.1 satura
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Experimental for chapter 3.1 Na 2 S
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Experimental for chapter 3.1 Synthe
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Experimental for chapter 3.1 128.9,
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Experimental for chapter 3.1 Microw
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Experimental for chapter 3.1 R f :
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Experimental for chapter 4.1 281 R
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Experimental for chapter 4.1 combin
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Experimental for chapter 4.1 3H, OB
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Experimental for chapter 4.2 (1S*,2
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Experimental for chapter 4.2 10.0,
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Experimental for chapter 4.2 cm 3 )
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Experimental for chapter 4.2 5.7 Re
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Absolute structure parameter 1.3(11
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_diffrn_standards_interval_time ? _
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H13 H 0.8405 0.7136 -0.0889 0.026 U
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C4 C5 1.454(2) . ? C5 C6 1.324(2) .
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C24 C23 C22 120.0(2) . . ? C24 C23
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. Compound 102c Ph O N Ph Me 102c O
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_diffrn_standards_interval_time ? _
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H11 H 0.8924 0.9592 0.6829 0.022 Ui
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C2 H2 1.0000 . ? C3 C21 1.506(2) .
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C26 C21 C3 121.41(15) . . ? C23 C22
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c. Compound 213 Ph O N Ph Me OH 213
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_cell_volume 1080.9(4) _cell_formul
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_refine_ls_number_reflns 4736 _refi
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H25 H 0.7979 0.2335 0.3365 0.028 Ui
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C4 0.025(4) 0.019(4) 0.018(4) 0.001
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loop_ _geom_bond_atom_site_label_1
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C9 C4 C1 107.1(5) . . ? C10 C4 C1 1
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C36 C38 H38A 109.5 . . ? C36 C38 H3
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C29 C30 C36 C37 -90.4(7) . . . . ?
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The structure was solved by the dir
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_reflns_number_total 2447 _reflns_n
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C7 C 1.1671(4) 0.7629(7) 1.2254(4)
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C3 0.015(3) 0.016(3) 0.021(3) -0.00
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C21 H21A 0.9800 . ? C21 H21B 0.9800
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H21A C21 H21C 109.5 . . ? H21B C21
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