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

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Chapter 4 – Synthesis of carbasugars nor was any the desired triol 309 isolated upon reduction of this mixture with sodium borohydride. OH OH BnO NBn mCPBA (3.5 eq) CH 2 Cl 2 BnO O NBn BnO OBn 0 °C to rt BnO OBn O 207 Scheme 4.53 – N-oxidation of tertiary amines at ambient temperature Oxidation F of allylic alcohol 312, the final intermediate in the final altrose synthesis, was problematic due to its low solubility. The triol was only sparingly soluble in most non-alcoholic solvents, and although small amounts of alcohol made the triol completely soluble it was believed it would saturate the peracid with hydrogen bond donors and prevent facial discrimination. Under high dilution conditions at ambient temperature, the allylic alcohol was sparingly soluble in chloroform, but under these conditions oxidation gave no discernable products by TLC or upon workup. It was later found that whilst alcoholic solvents do destroy selectivity for the majority of hydrogen bond oxidants, they have little effect on mCPBA. 168 HO HO OH OH mCPBA CHCl 3 rt, 8 hr no isolable products O OH 312 312 OH Scheme 4.54 – epoxidation (route F) Although only single reactions had been performed, there were clear problems in both instances; oxidation E would suffer with competing oxidation of the amine, and oxidation F presented a significant practical challenge to which no solution was immediately clear. Before returning to these problems, it seemed prudent to attempt the hydrolysis of the respective epoxides which could be synthesised from epoxyoxazoline 216. 173
4.5 – Mannose synthesis 4.5.2.b Epoxide hydrolysis Following conditions employed in similar carbasugar syntheses, 165 epoxyoxazoline 216 was heated under alkaline conditions. Whilst the reaction did not go to completion, the crude mixture showed hydrolysis was occurring to give a 2:1 mixture of acylated starting material to oxazoline 333-Ac with the all trans stereochemistry of the unnatural sugar idose. O Ox* OH 216 OH i) THF, KOH (1M), Δ 22 hr ii) Ac 2 O, pyr., DMAP AcO AcO Ox* OAc 333-Ac OAc 30% conversion by 1 H NMR HO H HO O HO OH OH α-L-Idose 3 J H3-H4 = 9.0 3 J H4-H5 = 10.0 3 J H5-H6 = 9.5 Scheme 4.55 – base catalysed epoxide hydrolysis (route D) Such high regioselectivity was unexpected, especially since it requires a strained twistboat transition state. The regioselectivity suggests severe congestion around C6, and that forcing conditions will continue to be needed to promote reaction. Unfortunately the mixed acetates could not be separated, and 333-Ac was not fully characterised. Furthermore, this reaction could not be reproduced under the same or different conditions (Table 4.8). 174
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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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Page 123 and 124: 3.2 - Oxazoline removal Ph Ph O N H
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*
Page 151 and 152: 4.2 - Carbasugar synthesis OsO 4 (c
Page 153 and 154: 4.2 - Carbasugar synthesis taken on
Page 155 and 156: 4.2 - Carbasugar synthesis As well
Page 157 and 158: 4.4 - Revised altrose synthesis 4.4
Page 159 and 160: 4.4 - Revised altrose synthesis suf
Page 161 and 162: 4.4 - Revised altrose synthesis ind
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: 4.5 - Mannose synthesis One clear a
Page 175 and 176: 4.5 - Mannose synthesis hydrolysis
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
Page 209 and 210: Experimental for chapter 2 Synthesi
Page 211 and 212: Experimental for chapter 3.1 satura
Page 213 and 214: Experimental for chapter 3.1 Na 2 S
Page 215 and 216: Experimental for chapter 3.1 Synthe
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Page 219 and 220: Experimental for chapter 3.1 128.9,
Page 221 and 222: Experimental for chapter 3.1 Microw
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Experimental for chapter 3.1 R f :
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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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