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

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4.2.5 Protecting group strategy 147 4.2.6 Oxidation of the allylic alcohol 148 4.2.7 Synthesis of an altrose analogue 153 4.2.8 Synthesis of an epoxycarbasugar 155 4.2.9 1,4 transannular relationship for oxazolidine hydrolysis 157 4.3 Revised Synthetic Strategy 157 4.4 The Protecting Group-Free Synthesis of an Altrose Analogue 158 4.4.1 Route A 159 4.4.2 Route B or C: a model dihydroxylation 159 4.4.3 Route B 160 4.4.4 Route C 163 4.5 Synthesis of a Mannose Analogue 164 4.5.1 Strategy I: Lactonisation 166 4.5.2 Strategy II: Cyclohexene oxides 171 4.6 Summary & Future Work 180 References for Chapters 1-4 185 Chapter 5 – Experimental Section . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 5.1 General 193 5.2 Experimental Procedures for Chapter 2 197 5.3 Experimental Procedures for Chapter 3.1 211 5.4 Experimental Procedures for Chapter 3.2 235 5.5 Experimental Procedures for Chapter 4.1 247 5.6 Experimental Procedures for Chapter 4.2 263 5.7 References for Experimental Section 274 Appendix A Selected NMR spectra 275 Appendix B Crystallographic Information Files 285 Word count: 58,000 5
Abstract Dearomatising Addition of Organolithiums to 2-Aryloxazolines: A Route to Carbasugar Analogues A submission for the degree of Doctor of Philosophy at The University of Manchester, Sean Parris April 2008 Nucleophilic addition to functionalised benzenoid nuclei with concomitant dearomatisation is a powerful method for the construction of highly substituted synthetic building blocks. This thesis presents a highly stereoselective dearomatising addition of organolithium nucleophiles to 2-aryloxazolines A as the key step in the synthesis of carbasugar analogues. Ph O Ph N R A i) NuLi, DMPU ii) MeI Nu: i-Pr, s-Bu Ph O Ph N Nu R B i) H + ii) MeOTf, then NaBH 4 iii) H 3 O + iv) NaBH 4 Nu = i-Pr R = 4-OMe HO OH >99:1 er This methodology is analogous to that of Meyers with 2-naphthyloxazolines, but requires less rigorous conditions than existing dearomatising additions to sixmembered carbocycles which often use heavy metals (chapter 1). A range of oxazolines and reaction conditions have been studied and the diphenyl oxazoline A found to be optimal, with DMPU being crucial for the reaction (section 2.1). Reactivity of the nucleophile follows 2° > 3° >> 1° alkyllithiums, hinting at a single electron transfer process, which has been studied by preliminary EPR studies and cyclisable probes (section 2.4). Oxazolines A may be synthesised in high enantiomeric purity from trans-stilbene, whilst a number of methods have been studied for the cleavage of oxazolines to synthetically useful functional groups (chapter 3). The dearomatising functionalisation has been used as the key step in the protecting groupfree synthesis of carbasugar analogues C and D, in fewer steps and better yields than most chiral pool syntheses, whilst permitting far greater flexibility (chapter 4). HO HO HO HO HO H O B Nu = i-Pr R = 4-OMe Ox* O OH OH OH HO O OH OH HO OH C HO HO HO OH D OH 33%, 6 steps from A OH 43%, 8 steps from A HO OH OH α-L-Altrose HO H HO O HO OH OH α-L-Mannose 6
Page 1 and 2: Dearomatising Addition of Organolit
Page 3: 2.3 Synthetic Scope 64 2.3.1 Organo
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
Page 14 and 15: Chapter 1: Introduction Chapter 1 -
Page 16 and 17: Chapter 1: Introduction controlled
Page 18 and 19: Chapter 1: Introduction diastereome
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Page 22 and 23: Chapter 1: Introduction O Ar Cl TMP
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Page 30 and 31: Chapter 1: Introduction 34 Scheme 1
Page 32 and 33: Chapter 1: Introduction The amino a
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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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