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

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Chapter 4 – Synthesis of carbasugars TBSO HO HO OH OH OH TFA/H 2 O HO HO O 80 °C, 11 hr OH HO OH HO OH OH OH OH 42% 58% 325 326 Scheme 4.42 – hydrolysis of an epoxycyclohexane similar to 309 201 Assuming that the ground state conformation of epoxide 325 is the same as that of 309, the same choice of transition states exists; clearly these were very close in energy, with a 3:2 preference for neopentylic, trans-diaxial opening (326). The elevated temperature and prolonged time of the reaction may be indicative of the strain that had to be overcome in both transition states. This conflict of high torsional strain in the regioisomeric transition states may be overcome if we consider the opening of the diastereomeric epoxide 327 (Scheme 4.43). trans-Diaxial hydrolysis of this epoxide would instead proceed by attack at the distal centre; presenting a strong preference for the isomer with the stereocentres of α- L-mannose. O HO OH 327 OH H 2 O H 2 O R = i-Pr Me HO Me HO R R O trans-diaxial OH 2 OH 2 O OH Twist boat & neopentyllic OH OH OH HO HO OH OH α-L-Mannose analogue 324 HO HO HO FAVOURED HO OH α-L-Idose analogue 322 OH DISFAVOURED Scheme 4.43 – possible hydrolysis of a diastereomer of epoxide 309 165
4.5 – Mannose synthesis It is clear that if such an epoxide could be synthesised, selective hydrolysis would be expected to yield an analogue of mannose with good regioselectivity. The next section will discuss the synthesis of the diastereomeric epoxide by employing the lactonisation previously discovered (section 4.2.8). This approach was chosen since it explores a new method of oxazoline removal, and would complement the previous synthesis. It should be noted that it would also possible to favour anti epoxidation by making the silyl ether, 189 or by employing the Sharpless-Katsuki asymmetric epoxidation. 188 4.5.1 Strategy I: Lactonisation It was recognised that lactonisation of diol 213 would leave only one hydrogen bond donor to direct epoxidation in the newly formed bicycle 328 (Scheme 4.44). Simple MM2 modelling indicates that whilst there is little to encumber the approach of the oxidant to either face of the alkene, the pseudo-equatorial alcohol is well placed to direct a hydrogen bonding reagent. Ox* MeOTf O [O] O O OH O O OH OH 213 328 329 OH Scheme 4.44 – proposed lactonisation-epoxidation & molecular model (MM2) If successful, the resulting epoxide 329 should undergo diaxial hydrolysis to give an analogue of mannose (Scheme 4.45). Whilst it might be possible to hydrolyse both the epoxide and lactone in a single reaction, the resulting carboxylic acid would be extremely polar and hard to isolate, instead a reduction-hydrolysis strategy is preferred. 166
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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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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
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
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Page 161 and 162: 4.4 - Revised altrose synthesis ind
Page 163: 4.5 - Mannose synthesis 4.5 Synthes
Page 167 and 168: 4.5 - Mannose synthesis considering
Page 169 and 170: 4.5 - Mannose synthesis which would
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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
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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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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