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

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Chapter 3 – Oxazoline synthesis & removal Ph Ph BnO O N (CO 2 H) 2 , THF/water 4:1 BnO H O BnO T / Days of rxn °C (total) OBn OBn 226 Remaining 226 * /% 40 7 (7) 82 50 10 (17) 39 60 4.5 (21) 10 60 7 (28.5) 0 * ratio SM:aldehyde in 1 H NMR T °C 100 80 60 40 20 0 % BnO OBn OBn 40 °C 50 °C 60 °C 0 5 10 15 20 25 Total days of reaction Table 3.13 – effect of temperature on hydrolysis of oxazolidine Two significant discrepancies have arisen; firstly, that oxazolidine 222 hydrolysed significantly faster (3 d) than oxazolidines 224 and 226 (>10 d), and secondly that all three hydrolyse considerably slower than the reports of either Meyers (c. 20 hr) or Bundgaard (c. 12 hr 146 ). The solution to the first quandary was found during the synthesis of carbasugars (section 4.2.9). Neighbouring group participation by the cishydroxyl group catalyses the reaction through intramolecular attack of Schiff base 228 147 to form cyclic ether 229, which quickly hydrolyses to diol 225. Ph Ph Ph HO OH HO O N Ph N Ph Ph N i-Pr O OH 222 pK a ≈ 6.0 144 OH 228 229 OH 225 Scheme 3.36 – neighbouring group participation in the hydrolysis of oxazolidines The second situation is not as clear. Bundgaard studied both the role of the carbonyl 144 (Scheme 3.37) and amino alcohol 145 portion of the oxazolidine and identified some clear trends in the rate of hydrolysis. 125
3.2 – Oxazoline removal Ph Me Ph Me Ph Me O N O N O N 230 t ½ (pH 7.4) 0.08 0.3 30 min t ½ (pH 1.0) 96 70 - min 144 Scheme 3.37 – half-lives of some oxazolidines at 37 °C This work clearly shows that a β-quaternary centre on the aldehyde clearly retards hydrolysis, but the half lives reported are still shorter than those observed for alcohol 222 let alone benzyl ether 226. When looking at the role of amino alcohol substitution, Bundgaard also found that substitution α to nitrogen led to significant retardation, with geminal methyl groups causing a 50 times increase in half life than a simple methylene. However, whilst they did not compare a phenyl group with a methyl group, it is unlikely to be responsible for such a difference. In addition, recent calculations by Walker based upon this research shows that cis substituted oxazolidines hydrolyse more rapidly than their trans epimer, but do not quantify this. 148 Whilst these combined effects might explain why the diphenyl oxazolidine with an adjacent quaternary centre hydrolyses much more slowly than many apparently similar oxazolidines, it does not explain the difference with the similarly substituted Meyers oxazolidine. Furthermore, the reaction does not seem to share the same pH dependence as Bungaard reported, meaning that it is possible that a change in mechanism has occurred. Two pathways for hydrolysis are considered (Scheme 3.38). 126
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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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Page 95 and 96: 3.1 - Oxazoline synthesis 3.1.1.a H
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Page 103 and 104: 3.1 - Oxazoline synthesis 3.1.4.b M
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 119 and 120: 3.2 - Oxazoline removal Ph Ph Ph Ph
Page 121 and 122: 3.2 - Oxazoline removal 3.2.5.b N-A
Page 123: 3.2 - Oxazoline removal Ph Ph O N H
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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
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Page 145 and 146: 4.2 - Carbasugar synthesis Ox* Ox*
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Page 153 and 154: 4.2 - Carbasugar synthesis taken on
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Page 157 and 158: 4.4 - Revised altrose synthesis 4.4
Page 159 and 160: 4.4 - Revised altrose synthesis suf
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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
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Page 171 and 172: 4.5 - Mannose synthesis One clear a
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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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