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

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Chapter 4 – Synthesis of carbasugars 4.4.1 Route A Route A is the same as the first synthesis but excludes the two protecting groups steps. Intermediate 213 had been previously synthesised in 64% in three steps from the anisole derivative. Entry Conditions Ox* OH 213 OH OsO 4 , conditions no reaction a CH 2 Cl 2, NMO.H 2 O nr b t-BuOH/H 2 O, NMO nr c quinuclidine, K 3 Fe(CN) 6 , K 2 CO 3 nr Table 4.5 – dihydroxylation of allylic alcohol (route A) Surprisingly, no reaction was seen for this dihydroxylation under a range of conditions. No reaction had occurred after 4 weeks under the Poli conditions (entry a, Table 4.5), whilst standard Upjohn conditions failed, as did the modified AD conditions of Warren, 176 the racemic dihydroxylation, RD (entry c). In light of the close precedent in the previous synthesis this is especially disappointing, however the remaining routes are both one step shorter than route A. 4.4.2 Route B or C: a model dihydroxylation Routes B and C involve the same number of synthetic steps, but differ in the execution of the key dihydroxylation step. In the previous synthesis it was assumed that the matched “Kishi” stereoelectronics and the encumbrance afforded by the axial oxazoline were responsible for the high diastereoselectivity. However this was not tested, and is only now important since two different routes are being considered. Whilst it may seem clear that route B would afford greater stereoselectivity, it is also possible that the internal amine will complex osmium, shutting down the catalytic cycle; dihydroxylation in route C would not face this problem. In a model study, the dihydroxylation of allylic alcohol 225 was undertaken, also serving to assign the relative stereochemistry of C4 (Scheme 4.37). As expected, the anti-diol was favoured by Kishi selectivity (vide supra), however the selectivity was significantly worse than in the previous synthesis, when it was matched by the encumbrance of the oxazoline. In light of this, it seemed likely that route C would 159
4.4 – Revised altrose synthesis suffer from poor facial selectivity and route B was favoured. Debenzylation of the resulting diol gave tetraol 315, which was apolar enough to elute on silica gel. HO BnO BnO BnBr, NaH OsO 4 , NMO HO 6 Bu 4 NI, DMF CH 2 Cl 2 HO OH OBn 93% OBn 225 313 314 3 60% (80% conv.) 5:1 dr BnO HO HO OBn 314 Pd/C, H 2 10 bar, MeOH HO HO HO OH 315 quant. 3 J H2-H3ax = 13.5 3 J H3ax-H4 = 11.0 3 J H3eq-H4 = 5.0 3 J H4-H5 = 11.0 3 J H5-H6 = 3.0 Scheme 4.37 – model dihydroxylation and assignment of relative stereochemistry 4.4.3 Route B This route would be four steps shorter than the previous altrose synthesis; three protecting group manipulations, and the simultaneous reduction of the enone and oxazoline. Furthermore, since there is no available hydroxyl group during the alkylation step, lactonisation is not possible. Ph Ph Ph Ph Ox* O NMe O NMe MeOTf, 7 hr O 276 OH then NaBH 4 0 °C OH 310 OH OH 78% OH 1% 316 Scheme 4.38 – synthesis of the allylic alcohol (Route B) The alkylation-reduction sequence proceeded in good yield and with excellent diastereoselectivity, consistent with the previous enone reduction with sodium borohydride (Table 4.3). The resulting oxazolidine was treated under a range of dihydroxylation conditions. 160
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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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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 and 152: 4.2 - Carbasugar synthesis OsO 4 (c
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Page 155 and 156: 4.2 - Carbasugar synthesis As well
Page 157: 4.4 - Revised altrose synthesis 4.4
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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
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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Page 205 and 206: Experimental for chapter 2 H4), 5.2
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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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