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

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Chapter 4 – Synthesis of carbasugars plane of the olefin and the allylic C–O bond. Hydrogen-bonding reagents generally proceed through a transition state with α ~120° whilst metal-alcoholate reagents prefer α ~ 40°. Adam applied this analysis to cyclohexenols, concluding that since α for equatorial cyclohexenols is approximately 140°, hydrogen bonding reagents are more suited to their epoxidation. This is somewhat borne out when such reagents are considered in a rigid system such as allylic alcohols 290 (Table 4.4). t-Bu 290a pseudoaxial OH OH H α t-Bu H α OH α = +110° α = +140° 290b pseudoequatorial OH Me R Ox* 213 OH OH α = +134° syn : anti ratio Entry oxidant solvent axial 290a equatorial 290b a 168 mCPBA CH 2 Cl 2 90:10 98:2 b 189 CF 3 CO 3 H CH 2 Cl 2 99:1 99:1 c 168 DMDO CCl 4 58:42 82:18 d 168 DMDO acetone 30:70 60:40 Table 4.4 – epoxidation of allylic alcohols 290 by different reagents However it should be noted that epoxidation of cyclohexen-3-ol (α = 110° or 140°) with VO(acac) 2 proceeds with 98:2 syn-selectivity 190 despite the apparent unoptimal α- values. This casts some doubt upon the validity of Adam’s argument, but with many examples demonstrating their use, peracids are clearly the reagents of choice since they are cheap, readily available and easily handled. The crystal structure of 213 shows the allylic C6–C5=C4–O torsional angle to be 134°; well-suited to the conditions suggested by Adam. To direct the mCPBA to the synface the free alcohol 213 would be used for the epoxidation. The slightly more polar epoxide is not expected to present any isolation problems since it has the same number of hydrogen bonding sites as the diol which showed no hydrophilicity. 149
4.2 – Carbasugar synthesis Ox* Ox* mCPBA, CH 2 Cl 2 O OH 0 °C OH OH 213 216 OH quant. Scheme 4.20 – epoxidation of allylic alcohol Pleasingly, complete facial selectivity was observed without the need for optimisation; the epoxide is isolated cleanly from the reductive workup without the need for further purification. In keeping with the protecting group strategy, epoxide 216 was benzylated. Ox* Ox* Ox* O OH 216 OH NaH (2.4 eq), BnBr Bu 4 NI (cat), DMF O OBn 291 O OH OBn 68% OBn 10% 292 NaH, BnBr, Bu 4 NI DMF 35% (55% conv) Scheme 4.21 – benzylation When using a slight excess of sodium hydride, monobenzyl ether 291 – identified by 1 H- 1 H correlation spectroscopy – was isolated with moderate selectivity. With no clear use for this alcohol it was re-subjected to the reaction conditions, returning mainly the desired dibenzyl ether 292, with some mono-benzylated starting material recovered. 4.2.6.b Dihydroxylation of the allylic alcohol The anti-selectivity in the osmylation of cyclic and acyclic allylic alcohols was discovered in the laboratories of Kishi 191 and has been borne out by the research of a number of other groups. 192 The Kishi model to rationalise the stereochemical outcome assumes a transition state resembling the ground state of the alkene which is governed by allylic (1,3) strain. 150
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Dearomatising Addition of Organolit
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2.3 Synthetic Scope 64 2.3.1 Organo
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Abstract Dearomatising Addition of
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The Author The Author graduated fro
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Abbreviations & Conventions Ac acet
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RDS rate determining step R f RC rt
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Chapter 1: Introduction Chapter 1 -
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Chapter 1: Introduction controlled
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Chapter 1: Introduction diastereome
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Chapter 1: Introduction combine mor
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Chapter 1: Introduction O Ar Cl TMP
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Chapter 1: Introduction conditions,
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Chapter 1: Introduction chiral oxaz
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Chapter 1: Introduction Again a lar
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Chapter 1: Introduction 34 Scheme 1
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Chapter 1: Introduction The amino a
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Chapter 1: Introduction It was envi
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Chapter 1: Introduction COR' i) ATP
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Chapter 1: Introduction O i) ATPH,
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Chapter 1: Introduction 1.4 Nucleop
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Chapter 1: Introduction Unlike the
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Chapter 1: Introduction Diene (-)-8
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Chapter 1: Introduction A scheme su
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Chapter 1: Introduction Cl R + 93 S
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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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Page 105 and 106: 3.1 - Oxazoline synthesis Ph Ph Ph
Page 107 and 108: 3.2 - Oxazoline removal O N O OH 3N
Page 109 and 110: 3.2 - Oxazoline removal O Me O N OM
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Page 125 and 126: 3.2 - Oxazoline removal Ph Me Ph Me
Page 127 and 128: 3.2 - Oxazoline removal 3.2.6 Deter
Page 129 and 130: Better, however, would be a method
Page 131 and 132: 4.1 - Introduction HO OH OH HO OH O
Page 133 and 134: 4.1 - Introduction (-)-Shikimic aci
Page 135 and 136: 4.1 - Introduction followed by Flem
Page 137 and 138: 4.2 - Carbasugar synthesis 4.2 Synt
Page 139 and 140: 4.2 - Carbasugar synthesis stereoce
Page 141 and 142: 4.2 - Carbasugar synthesis of the o
Page 143 and 144: 4.2 - Carbasugar synthesis support
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Page 177 and 178: 4.5 - Mannose synthesis The second
Page 179 and 180: 4.6 - Summary 4.6 Summary & Future
Page 181 and 182: 4.6 - Summary OH CDI, NH 2 OH.HCl,
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Page 185 and 186: References (37) Rawson, D. J.; Meye
Page 187 and 188: References (105) Gajewski, J. J.; B
Page 189 and 190: References (169) McCormick, J. P.;
Page 191 and 192: References 192
Page 193 and 194: Experimental section 254nm, dodecam
Page 195 and 196: Experimental section General Proced
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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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