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

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Chapter 4 – Synthesis of carbasugars during the course of the reactions black deposits were observed at the neck of the reaction vessel. This is presumed to be osmium dioxide, indicating a lack of available re-oxidant, even though two equivalents of NMO were used, and the oxidant is stable under the conditions. Benzylation of the resulting diol gave a mixture of mono- and dibenzylation products. Tribenzyl ether 301 was isolated as a single compound and characterised by COSY NMR, implying that benzylation first occurs at the more encumbered neopentylic alcohol. This alcohol was re-subjected to the reaction conditions to give perbenzyl ether 302 in good yield, ready for onward reaction. Ox* Ox* Ox* HO BnO NaH (2.4 eq), BnBr BnO HO OBn 300 OBn Bu 4 NI (cat), DMF HO OBn BnO OBn OBn 54 % OBn 33% 301 302 NaH, BnBr, Bu 4 NI DMF 70% Scheme 4.27 – benzylation of diol 4.2.7 Synthesis of an altrose analogue Oxazoline 302 has all the stereocentres of α-L-altrose (Scheme 4.11). Employing the alkylation-reduction-hydrolysis-reduction procedure (section 3.2), would reveal the primary alcohol, and debenzylation would yield the desired carbasugar analogue. 302 MeOTf then NaBH 4 BnO BnO Ph O Ph NMe i) (CO 2 H) 2 , THF/water 7 d, 60 °C ii) NaBH 4 , MeOH OBn OBn 70% 225 Scheme 4.28 – removal of oxazoline auxiliary The alkylation-reduction step proceeded well; however as previously discussed the hydrolysis was much slower than for other related oxazolidines, which had typically BnO BnO OH OBn 304 OBn 85% 153
4.2 – Carbasugar synthesis taken one to three days at ambient temperature. In the next section, this is shown to be due to neighbouring group participation of a cis hydroxyl group at the 4 position. OH OH OH BnO Pd(OH) 2 HO HO H O BnO OBn 304 OBn 85% H 2 , 20 bar HO OH 278 OH quant. HO OH OH α-L-Altrose Scheme 4.29 – final step in synthesis of α-L-altrose analogue Pleasingly, hydrogenolysis using Pearlman’s catalyst 197 proceeded cleanly without the need for purification, and the relative stereochemistry was confirmed by crystal structure. water molecule Scheme 4.30 – crystal structure confirming relative stereochemistry of 278 Somewhat surprisingly, pentaol 278 was apolar enough to be purified on normal phase silica, eluting with just ethyl acetate (R f ~0.1). This was unexpected and led to the review of the protecting group strategy (vide infra). 154
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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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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 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: 4.2 - Carbasugar synthesis OsO 4 (c
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 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
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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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