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

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Chapter 4 – Synthesis of carbasugars Acidic conditions favour epoxide attack at the centre with nearby orbitals available to stabilise a developing positive charge. In these examples the only difference in available orbitals are the adjacent σ bonds which could in principle stabilise developing p-character at either C5 or C6 through hyperconjugation. However, for this to be responsible for the high selectivity, the two σ C1-C orbitals would have to be significantly more stabilising for C6 than the σ C4-H and σ C4-O are for C5. This is 211 unlikely since the pseudo-axial σ C4-H should equivalent to the pseudo-axial σ C6-C whilst the remaining two pseudo-equatorial orbitals would have little overlap with an empty p-orbital. In light of this, it seems that there is no reason for such a stark, and irreproducible, change in reactivity, other than to assume that the alkaline hydrolysis of the epoxyoxazoline was spurious. Subsequent studies by Karlubíková have shown that azide opening occurs at the neopentylic position, consistent with these latter results. 66 179
4.6 – Summary 4.6 Summary & Future Work The synthesis of two carbasugar analogues is summarised below. The overall yields compare extremely well to the literature syntheses summarised in section 4.1, of which only six of the 104 routes had overall yields – taken from advanced intermediates or chiral pool materials – above 40%. Using a similar measure, altrose analogue 278 has been synthesised in 45% overall yield and mannose analogue 324 in 60% yield. Ox* Ox* Ox* a b OH OMe OMe O 101b 102b 276 HO HO HO d HO HO H O OH HO OH HO OH c OH OH OH 312 278 α-L-Altrose 276 45.3%, 5 steps from 102b 32.7%, 6 steps from 101b e, f O Ox g, h HO HO HO HO H O OH OH HO OH OH HO OH OH 309 324 α-L-Mannose 60.6%, 7 steps from 102b 42.5%, 8 steps from 101b a) i-PrLi, THF, 20 min, –78 °C, then MeI, 70%; b) OsO 4 , NMO, t-BuOH then Na 2 S 2 O 5 , 93%; c) MeOTf, CH 2 Cl 2 , then NaBH 4 , 0 °C, MeOH/THF, 78%; ii) (CO 2 H) 2 , THF/H 2 O, 50 °C 24 hr, iii) NaBH 4 , MeOH, 79% (2 steps); d) OsO 4 , quinuclidine, MeSO 2 NH 2 , K 2 CO 3 , K 3 Fe(CN) 6 , t-BuOH/H 2 O, 3 d, 79%. e) NaBH 4 , MeOH, 0 °C, 6 hr, 98%; f) mCPBA, CH 2 Cl 2 , 0 °C, 6 hr, 99%; g) i) MeOTf, CH 2 Cl 2 , then NaBH 4 , 0 °C, MeOH/THF, ii) (CO 2 H) 2 , THF/H 2 O, 50 °C 17 hr, iii) NaBH 4 , MeOH, 83% (3 steps); h) THF, HCl (aq), 0 °C rt, 8 hr, 81%. Scheme 4.58 – divergent synthesis of α-L-mannose and α-L-altrose analogues 180
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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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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 and 172: 4.5 - Mannose synthesis One clear a
Page 173 and 174: 4.5 - Mannose synthesis 4.5.2.b Epo
Page 175 and 176: 4.5 - Mannose synthesis hydrolysis
Page 177: 4.5 - Mannose synthesis The second
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
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Page 213 and 214: Experimental for chapter 3.1 Na 2 S
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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 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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