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

More documents

Recommendations

Info

Chapter 4 – Synthesis of carbasugars that this strategy for hydrolysis could work. Whilst this was being pursued, another strategy was providing promising results. 4.5.2 Strategy II: Cyclohexene oxides The lactonisation strategy was appealing since hydrolysis of the resulting epoxide was expected to give good regioselectivity (Scheme 4.43). Whilst it would be possible to make this diastereomeric epoxide (vide supra) initial experiments would focus on opening epoxides already in hand. A similar strategy to the final altrose synthesis may be envisaged (Scheme 4.51). The main difference being that oxidation of the allylic alcohol is directed by hydrogen bonding, and that steric encumbrance at C1 is unimportant. Ox* Ox* HO D O 276 a OH 97% b, 78% O OH 216 OH H 2 O d (i) HO HO OH OH α-L-Mannose analogue 324 Ph Ph Ph Ph HO O N O N HO E OH 310 OH [O] c, 79% O OH 306 OH HO OH OH α-L-Idose analogue 322 d (ii, iii) 83% 3 steps HO HO F OH 312 OH [O] O OH 309 OH H 2 O a) i) NaBH 4 , MeOH, 0 °C, 6 hr, 98% ii) mCPBA, CH 2 Cl 2 , 0 °C, 6 hr, 99%; b) MeOTf, CH 2 Cl 2 , then NaBH 4 , 0 °C, MeOH/THF, 78%; c) i) (CO 2 H) 2 , THF/H 2 O, 50 °C, 24 hr, ii) NaBH 4 , MeOH, 79% (2 steps); d) 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). Scheme 4.51 – proposed synthesis of diastereomeric carbasugar 171
4.5 – Mannose synthesis One clear advantage of this synthetic plan is that much of the chemistry has already been completed; the only query that remains is at which stage the oxidation and hydrolysis will prove most selective. Hydrolysis of epoxyoxazolidine 306 is not included in this synthetic plan since oxazolidine hydrolysis has proven problematic and reactions would likely be very complicated. 4.5.2.a Epoxidations Epoxidation D has been shown to work very well (section 4.2.6), but requires an extra synthetic step than oxidations E and F. Furthermore, unlike the altrose synthesis, hindrance of one side of the olefin should not affect the facial selectivity, whilst having late stage intermediates in common would make the two syntheses less divergent and more amenable to future scale-up. The oxidant would again be mCPBA since it had performed excellently in the epoxidation of alkene 216. Oxidation E of oxazolidine 310 was conducted at low temperature since it was hoped that reduced temperature would favour stereoselective epoxidation whilst minimising oxidation of the tertiary amine, which often requires elevated temperatures. 171 However epoxidation was accompanied by oxidation of the amine and only N-oxide 332 (Scheme 4.52) was isolated. This is consistent with the observations of Ganem (Scheme 4.53). 207 Ph O OH N 310 Ph OH mCPBA (2 eq) CH 2 Cl 2 −40 °C O Ph O OH 332 Ph O N OH 53% (CO 2 H) 2 , rt THF/H 2 O, 5 d Scheme 4.52 – epoxidation (route E) no isolable products It was thought that oxazolidine N-oxides might hydrolyse more rapidly to the aldehyde than the parent oxazolidine. Initial results were promising since after two days of mild hydrolytic conditions, an aldehyde was observed in the 1 H NMR spectrum of the crude mixture in a 1:2 ratio with starting material 332. Unfortunately, upon consumption of the oxazolidine, no aldehyde was present in the final reaction mixture (Scheme 4.52), 172
Page 1 and 2:
Dearomatising Addition of Organolit
Page 3 and 4:
2.3 Synthetic Scope 64 2.3.1 Organo
Page 5 and 6:
Abstract Dearomatising Addition of
Page 7 and 8:
The Author The Author graduated fro
Page 9 and 10:
Abbreviations & Conventions Ac acet
Page 11 and 12:
RDS rate determining step R f RC rt
Page 14 and 15:
Chapter 1: Introduction Chapter 1 -
Page 16 and 17:
Chapter 1: Introduction controlled
Page 18 and 19:
Chapter 1: Introduction diastereome
Page 20 and 21:
Chapter 1: Introduction combine mor
Page 22 and 23:
Chapter 1: Introduction O Ar Cl TMP
Page 24 and 25:
Chapter 1: Introduction conditions,
Page 26 and 27:
Chapter 1: Introduction chiral oxaz
Page 28 and 29:
Chapter 1: Introduction Again a lar
Page 30 and 31:
Chapter 1: Introduction 34 Scheme 1
Page 32 and 33:
Chapter 1: Introduction The amino a
Page 34 and 35:
Chapter 1: Introduction It was envi
Page 36 and 37:
Chapter 1: Introduction COR' i) ATP
Page 38 and 39:
Chapter 1: Introduction O i) ATPH,
Page 40 and 41:
Chapter 1: Introduction 1.4 Nucleop
Page 42 and 43:
Chapter 1: Introduction Unlike the
Page 44 and 45:
Chapter 1: Introduction Diene (-)-8
Page 46 and 47:
Chapter 1: Introduction A scheme su
Page 48 and 49:
Chapter 1: Introduction Cl R + 93 S
Page 50 and 51:
Chapter 2 - Dearomatising additions
Page 52 and 53:
Page 54 and 55:
Page 56 and 57:
Page 58 and 59:
Page 60 and 61:
Page 62 and 63:
Page 64 and 65:
Page 66 and 67:
Page 68 and 69:
Page 70 and 71:
Page 72 and 73:
Page 74 and 75:
Page 76 and 77:
Page 78 and 79:
Page 80 and 81:
Page 82 and 83:
Page 84 and 85:
Page 86 and 87:
Page 88 and 89:
Page 90 and 91:
Page 92:
Page 95 and 96:
3.1 - Oxazoline synthesis 3.1.1.a H
Page 97 and 98:
3.1 - Oxazoline synthesis O Ar OH i
Page 99 and 100:
3.1 - Oxazoline synthesis 3.1.2 Gen
Page 101 and 102:
3.1 - Oxazoline synthesis mCPBA O N
Page 103 and 104:
3.1 - Oxazoline synthesis 3.1.4.b M
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
Page 111 and 112:
3.2 - Oxazoline removal However, th
Page 113 and 114:
3.2 - Oxazoline removal 3.2.3 Reduc
Page 115 and 116:
3.2 - Oxazoline removal Ph O N Ph P
Page 117 and 118:
3.2 - Oxazoline removal 3.2.3.c Ami
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
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: 4.5 - Mannose synthesis which would
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,
Page 183 and 184: 184
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
Page 211 and 212: Experimental for chapter 3.1 satura
Page 213 and 214: Experimental for chapter 3.1 Na 2 S
Page 215 and 216: Experimental for chapter 3.1 Synthe
Page 217 and 218: Experimental for chapter 3.1 Synthe
Page 219 and 220: Experimental for chapter 3.1 128.9,
Page 221 and 222:
Experimental for chapter 3.1 Microw
Page 223 and 224:
Experimental for chapter 3.1 R f :
Page 225 and 226:
Experimental for chapter 3.1 Synthe
Page 227 and 228:
Page 229 and 230:
Page 231 and 232:
Page 233 and 234:
Page 235 and 236:
Page 237 and 238:
Page 239 and 240:
Page 241 and 242:
Page 243 and 244:
Page 245 and 246:
Page 247 and 248:
Experimental for chapter 4.1 281 R
Page 249 and 250:
Experimental for chapter 4.1 combin
Page 251 and 252:
Page 253 and 254:
Page 255 and 256:
Page 257 and 258:
Experimental for chapter 4.1 3H, OB
Page 259 and 260:
Page 261 and 262:
Page 263 and 264:
Experimental for chapter 4.2 (1S*,2
Page 265 and 266:
Page 267 and 268:
Experimental for chapter 4.2 10.0,
Page 269 and 270:
Experimental for chapter 4.2 cm 3 )
Page 271 and 272:
Page 273 and 274:
Experimental for chapter 4.2 5.7 Re
Page 275 and 276:
276
Page 277 and 278:
278
Page 279 and 280:
280
Page 281 and 282:
282
Page 283 and 284:
284
Page 285 and 286:
Absolute structure parameter 1.3(11
Page 287 and 288:
_diffrn_standards_interval_time ? _
Page 289 and 290:
H13 H 0.8405 0.7136 -0.0889 0.026 U
Page 291 and 292:
C4 C5 1.454(2) . ? C5 C6 1.324(2) .
Page 293 and 294:
C24 C23 C22 120.0(2) . . ? C24 C23
Page 295 and 296:
. Compound 102c Ph O N Ph Me 102c O
Page 297 and 298:
_diffrn_standards_interval_time ? _
Page 299 and 300:
H11 H 0.8924 0.9592 0.6829 0.022 Ui
Page 301 and 302:
C2 H2 1.0000 . ? C3 C21 1.506(2) .
Page 303 and 304:
C26 C21 C3 121.41(15) . . ? C23 C22
Page 305 and 306:
c. Compound 213 Ph O N Ph Me OH 213
Page 307 and 308:
_cell_volume 1080.9(4) _cell_formul
Page 309 and 310:
_refine_ls_number_reflns 4736 _refi
Page 311 and 312:
H25 H 0.7979 0.2335 0.3365 0.028 Ui
Page 313 and 314:
C4 0.025(4) 0.019(4) 0.018(4) 0.001
Page 315 and 316:
loop_ _geom_bond_atom_site_label_1
Page 317 and 318:
C9 C4 C1 107.1(5) . . ? C10 C4 C1 1
Page 319 and 320:
C36 C38 H38A 109.5 . . ? C36 C38 H3
Page 321 and 322:
C29 C30 C36 C37 -90.4(7) . . . . ?
Page 323 and 324:
The structure was solved by the dir
Page 325 and 326:
_reflns_number_total 2447 _reflns_n
Page 327 and 328:
C7 C 1.1671(4) 0.7629(7) 1.2254(4)
Page 329 and 330:
C3 0.015(3) 0.016(3) 0.021(3) -0.00
Page 331 and 332:
C21 H21A 0.9800 . ? C21 H21B 0.9800
Page 333 and 334:
H21A C21 H21C 109.5 . . ? H21B C21
show all

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

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?