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

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Chapter 4 – Synthesis of carbasugars O Ox* OH 216 OH Conditions X HO HO Ox* OH 333 OH Entry Conditions Result a KOH (1M, aq) THF, Δ 22 hr nr b KOH (3M, aq) THF, Δ 36 hr nr c KOH (3M, aq) dioxane, Δ 36 hr nr d KOH, d 6 -DMSO, rt, 2 hr nr e KOH, d 6 -DMSO, 50 °C, 1 hr no isolable product f KOH, d 6 -DMSO, 18-crown-6, rt, 2 hr no isolable product g HCl (3M) THF, Δ 24 hr polymerised h HCl (1M) THF, rt, 1 hr nr i HCl (1M) THF, rt, 18 hr polymerised j H 2 SO 4 (1M), THF, rt, 5 hr nr k H 2 SO 4 (1M), THF, rt, 28 hr polymerised m HClO 4 (1M), dioxane, rt, 28 hr 20% ester * * rest SM, see section 3.2.4 Table 4.8 – attempted epoxide hydrolysis (route D) Initial work attempted to repeat the above hydrolysis using the original and more forcing conditions (entries a-c). The nucleophilicity of potassium hydroxide is enhanced by the use of DMSO 208 which solvates potassium 185 making the counter ion more reactive. At ambient temperature (entries d-f), no reaction was observed when followed by 1 H NMR, however raising the temperature caused rapid decomposition of the oxazoline ring. Similar degradation occurred when 18-crown-6 was added to the reaction at ambient temperature. Upon treatment with acid, the epoxyoxazoline rapidly turned to baseline salts (c. 10 min), and reverted back to starting material upon workup. This is most likely due to protonation of the oxazoline which has previously been shown to be susceptible to acid 175
4.5 – Mannose synthesis hydrolysis (section 3.2.4). Extended reaction with aqueous sulfuric and hydrochloric acids led to polymerisation, with greater than ten times the mass of the reaction being isolated as a globular oil. Treatment with perchloric acid (entry m) caused incomplete hydrolysis to the ester, which could not be further hydrolysed. Despite the initially promising result, the reactivity of the oxazoline was dominating the reaction of 216. In light of this, the hydrolysis of the free epoxide 309 was attempted (Table 4.9). HO HO HO O OH 309 OH Conditions HO HO OH 324 OH + HO HO OH 322 OH Entry Conditions Result a KOH (1M, aq) THF, Δ 16 hr no isolable product b KOH, d 6 -DMSO, 50 °C, 1 hr elimination c TFA:H 2 O 1:3, rt, 16 hr nr d H 2 SO 4 (3M), THF, rt, 5 hr polymerised e HClO 4 (3M), dioxane, rt, 1 hr polymerised f HCl (3M) THF, rt, 3 hr 50% 5:1 (324:322) g HCl (3M) THF, 0 °C to rt, 8 hr 81% (324) * * no crude NMR ratio obtainable Table 4.9 – epoxide hydrolysis (route F) Hydroxide opening of the epoxide was again unsuccessful (entries a-b). The KOH- DMSO system again gave mixed oxirane products which were inseparable by chromatography and only identified by similar chemical shift and couplings in the crude 1 H NMR. Further analysis of the crude mixture indicates the product of elimination at C3-C4. A range of acid conditions were also employed (entries c-g); the epoxide was unreactive under TFA-H 2 O conditions despite good precedent. 201 It is likely this is due to the poor solubility of the epoxide in water. Treatment with perchloric acid and sulfuric acid returned crude reaction mixtures with UV active products, and significant mass increase; this is again attributed to polymerisation. 176
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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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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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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
Page 145 and 146: 4.2 - Carbasugar synthesis Ox* Ox*
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Page 157 and 158: 4.4 - Revised altrose synthesis 4.4
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Page 163 and 164: 4.5 - Mannose synthesis 4.5 Synthes
Page 165 and 166: 4.5 - Mannose synthesis It is clear
Page 167 and 168: 4.5 - Mannose synthesis considering
Page 169 and 170: 4.5 - Mannose synthesis which would
Page 171 and 172: 4.5 - Mannose synthesis One clear a
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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
Page 197 and 198: Experimental for chapter 2 Synthesi
Page 199 and 200: Experimental for chapter 2 (CDCl 3
Page 201 and 202: Experimental for chapter 2 3H, OMe
Page 203 and 204: Experimental for chapter 2 Ph), 139
Page 205 and 206: Experimental for chapter 2 H4), 5.2
Page 207 and 208: Experimental for chapter 2 108 R f
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Page 213 and 214: Experimental for chapter 3.1 Na 2 S
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Page 221 and 222: Experimental for chapter 3.1 Microw
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Experimental for chapter 3.1 Synthe
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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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