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

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Chapter 4 – Synthesis of carbasugars Pleasingly, the epoxide reacted with hydrochloric acid at ambient temperature (Table 4.9, entry f) in a clean and rapid reaction with 5:1 regioselectivity favouring the product of neopentylic, trans-diaxial opening. The relative stereochemistries of the products were assigned by vicinal couplings, but their identities were initially uncertain since their polarities were similar to that of the starting material. - Furthermore, EI mass spectroscopy showed a C 11 H 22 ClO 5 ion which was taken to indicate the oxirane had undergone chloride opening to give carbocycle 335. HO HO HO O OH 309 OH HCl (aq), THF 0 °C - rt 8 hr HO HO OH 324 OH 81% Cl HO OH OH 335 C 11 H 21 ClO 4 13C δ/ppm CH: 75.5, 73.7 70.8, 69.1 CH 2 : 67.1 Scheme 4.56 – final hydrolysis of epoxide δ C 51.0 Cl OH Repetition of the reaction at low temperature (entry g) gave enough product for 13 C NMR showing four methine carbons above 69 ppm, significantly downfield of that expected for chloride 335 (51 ppm for 2-chloro-1-propanol 209 ). The EI+ mass spectrum confirmed that chloride had been the ionising species, and revealed that a tightly bound molecule of water might be responsible for the unexpected hydrophobicity. Unfortunately, the crystals grown from methanol-water were not of high enough quality for x-ray diffraction. 4.5.2.c Discussion of epoxide hydrolysis The outcome of this final hydrolysis was surprising for three reasons. Firstly the reaction proceeded rapidly at ambient temperature, which whilst common for epoxides that develop no torsional strain, is surprising in light of the encumbrance present (vide supra). 177
4.5 – Mannose synthesis The second interesting feature is the high regioselectivity of the reaction. Whilst a diastereomeric ratio was not obtained for the final conditions, it should be greater than 5:1, as none of the diastereomer was isolated. This is much more selective than the similar example from Gonzalez presented earlier (Scheme 4.42) which showed approximately 3:2 preference for a similar hydrolysis. It is possible that some of this reduced selectivity reflects the elevated temperature of the Gonzalez reaction, skewing the Bolzmann distribution. A literature survey of the hydrolysis of epoxides with adjacent quaternary centres shows that in contrast to the results above, the vast majority favour opening at the distal centre. 210 The third surprise was that the regioselectivity apparently switched when changing from alkali to acid conditions (Scheme 4.57). Whilst it is often possible to change the regioselectivity of epoxide hydrolysis by changing the pH of the reaction, this requires an adjacent system to stabilise a developing positive charge. No such system exists in these two instances, yet basic hydrolysis of epoxyoxazoline 216 occurred at the distal centre (albeit as an isolated case), whilst acid hydrolysis of epoxide 309 took place at the proximal one. In principle, the primary alcohol of 309 might participate in the oxirane opening, but this would require a 6,5 trans-fused intermediate and result in retention of stereochemistry at C5. Since the epoxides are very similar and are expected to have similar stereoelectronic characteristics – corroborated by 13 C NMR data – the only significant change in the reaction seem to be the conditions of hydrolysis. δ C6 61.0 δ C5 56.0 O Ox* OH 216 OH THF, KOH (1M, aq), Δ 22 hr HO HO Ox* OH 333 OH dr: high irreproducible δ C6 61.9 δ c5 58.8 HO O OH 309 OH HCl (aq), THF 0 °C - rt 8 hr HO HO HO OH 324 OH dr >5:1 Scheme 4.57– chemical shift and reactivity of the two epoxides 178
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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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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
Page 143 and 144: 4.2 - Carbasugar synthesis support
Page 145 and 146: 4.2 - Carbasugar synthesis Ox* Ox*
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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
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Page 173 and 174: 4.5 - Mannose synthesis 4.5.2.b Epo
Page 175: 4.5 - Mannose synthesis hydrolysis
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
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Page 203 and 204: Experimental for chapter 2 Ph), 139
Page 205 and 206: Experimental for chapter 2 H4), 5.2
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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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