Solution and Solid Phase Synthesis of Unusual a-Amino Acids From

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To Julian. It is not because things are dtflcult thut we dare not venture. If is because we dare not venture that they are dtpcult. Seneca Writing a book is an adventure. To begin with it is a toy and an amusement, and then it becomes a mistress. and then it becomes a master. and then it becomes a orant, and the las? phase is that just as you are about to be reconciled to your servitude you kill the munster. Nobel Laureate, Sir Winston Churchill after writing his monumental six volume history of World War II
Table of Contents Abstract .............................................................................................................................. iv Acknowledgements ............................................................................................................. v Dedication .......................................................................................................................... vi . * Table of Contents .............................. .... ............................................................................ vii ... List of Tables .................................................................................................................. xiri List of Figures .................................................................................................................. xiv List of Abbreviations and Acronyms ........................................................................... xvi Chapter One Introduction: The Synthesis of a-Amino Acids 1.1 General Introduction .............................................................................................. 1 1.2 Chernical Synthesis of Racemic a-Amino Acids ............................................... 3 1.2. 1 Addition of the Amino or Carboq Function to the Side Chain ........................... 3 1.2.2 A l@latiott of Glycine Derivatives ................................................................... 4 1.2.3 Other Synthetic Routes to Racemic a-Amino Acids ............................................. 5 1.3 Synthesis of Optidy Active a-Ami00 Acids .......................................................... 5 1.3.1 Enantioselective htruduction of the Mydrogen ............................................. 6 1.3.1.1 Asylluttettic Hydrogenation of &Didehydro Amino Acids ...................... 6 1.3.1.2 Reductive Amination of a-Ketoacids .......................................................... 8 1.3.1.3 Asymmetric Protonation of Enolates ........................................................... 9 1.3.2 Enantiose lective htroduction of the a-Amino Function .................................. 9 1.3.2.1 Nucleophilic Amination ............................................................................. 10 1.3.2.2 Electrophilic Amination of Enolutes ...................................................... 1 2 1.3.3 Stereoselective Introduction of the Side Chain ................................................. 1 3 1.3.3.1 Glycine a-Asion Equivulents .................................................................... 1 3 1.3.3.2 Glycine a-Cation Equivalents ................................................................... 1 8 1.3.4 Synthesis fiom a-Arnim Acids ........................................................................... 1 9 vii
Page 1 and 2: Solution and Solid Phase Synthesis
Page 3 and 4: The University of Waterloo requires
Page 5: Many people have made the experienc
Page 9 and 10: 23 Summary ........................
Page 11 and 12: 5.1.4.1 Enzymatic Methods .........
Page 13 and 14: List of Tables Table 2.1 Table 2.2
Page 15 and 16: Figure 4.1 O Figure 5.1 Figure 5.2
Page 17 and 18: CYS d DAST DBAD DBU DCC de DEAD dec
Page 19 and 20: NMP Nu OB0 ester PEG Ph Phe PhFl Ph
Page 21 and 22: 1.1 General Introduction Chapter On
Page 23 and 24: acids will be presented including a
Page 25 and 26: .J generation of the enolate and ad
Page 27 and 28: classical techniques (Scheme 1.7) a
Page 29 and 30: s~ccess.~ The same principle has be
Page 31 and 32: O Scheme 1.11 O R1,qH2 m OH RI= H,
Page 33 and 34: stereosele~tivities.~ Numerous exam
Page 35 and 36: Williams and coworlcers have examin
Page 37 and 38: template, reaction with alkyl halid
Page 39 and 40: The 3-bromo analog of Williams and
Page 41 and 42: formation of serine aldehydes; dire
Page 43 and 44: Scheme 1.24 R dimethoxy- R ProPane
Page 45 and 46: of thiol trityl led to racemic cyst
Page 47 and 48: nucleophiles such as acetate and im
Page 49 and 50: may be employed, while the oxidatio
Page 51 and 52: Several methods for the removal of
Page 53 and 54: 1.5 References Barrett, G.C. Chemis
Page 55 and 56: (a) Schmidt, U.; Meyer, R.; Leitenb
Page 57 and 58:
R.M. Tetrahedron Le#. 2001,42, 769.
Page 59 and 60:
(a) Lubell, W.D.; Rapport, H. J. Am
Page 61 and 62:
Nakajima, K.; Takai, F.; Tanaka, T.
Page 63 and 64:
2.1 Introduction Chapter Two Synthe
Page 65 and 66:
2.1.1 Synthesis of SHydroxy-a-Amino
Page 67 and 68:
typically generated in both poor yi
Page 69 and 70:
2.1.3.3 Electrophilic%Nucfeophilic
Page 71 and 72:
Scheme 2.8 2-(Arylthi0)-2-nitrooxir
Page 73 and 74:
Scheme 2.10 Schollkopf et al. have
Page 75 and 76:
2.1.3.5 Synthesis fiom #-Amino Acid
Page 77 and 78:
HO Scheme 2.17 This laboratory prev
Page 79 and 80:
Scheme 2.19 NaBr, acetone The best
Page 81 and 82:
equires carefiil attention to preve
Page 83 and 84:
order to investigate this as a poss
Page 85 and 86:
etained its optical activity indica
Page 87 and 88:
2.2.3.2 Ortho Ester Cleavage Concom
Page 89 and 90:
2.2.4 Determination of Enantiomeric
Page 91 and 92:
minof si face aîîack mior re face
Page 93 and 94:
2.4.1 General Methods. Most reagent
Page 95 and 96:
The crude product was fiitered thro
Page 97 and 98:
250 MHz) 6 5.47 (br ci, lH, J = S.O
Page 99 and 100:
evaporated to dryness. The residue
Page 101 and 102:
minutes. The akohol solution was tr
Page 103 and 104:
302.1604, found 302.1593; Anai. cal
Page 105 and 106:
CCH3), 28.3 (a3)C), 20.1 (fLm3) 13.
Page 107 and 108:
TLC (4: 1, CH2C12:EtOAc) Rf = 0.44;
Page 109 and 110:
100-200 mesh, hydrogen form, 1x10 c
Page 111 and 112:
(br d. IH. J= 10.6Hz, CHH-CH), 4.63
Page 113 and 114:
mp 80-8 1 OC; [a~~*~a= -67.0 (0 1.5
Page 115 and 116:
esin column (Bio-Rad AGa 10x4 10-20
Page 117 and 118:
Jung, M.E.; Jung, Y.H. Tetruhedron
Page 119 and 120:
(a) Adams, Z.M.; Jackson, R.F.W.; P
Page 121 and 122:
(a) Roemmele, R.C.; Rapport, H. J.
Page 123 and 124:
- - 68. Gawley, R.E.; Aubé, J. Pri
Page 125 and 126:
pyridoxal phosphate dependent enzym
Page 127 and 128:
Vinylglycines are also useful as sy
Page 129 and 130:
In 1984, a modified Strecker synthe
Page 131 and 132:
The main byproduct of elimination w
Page 133 and 134:
, HO- OH Scheme 3.14 , 1) pb(OAc),
Page 135 and 136:
L-vinylglycine has also been synthe
Page 137 and 138:
Ser(a1d)-OB0 gave the desired olefi
Page 139 and 140:
A tram relationship for H2IH3 in th
Page 141 and 142:
33 Summary The Cbz OB0 ester protec
Page 143 and 144:
67.1 (Ar_cH20), 63.2 @--a), 56.3 (a
Page 145 and 146:
yielded a slightiy yellowish solid
Page 147 and 148:
JAS Grigiarà ddition of trimethyls
Page 149 and 150:
6 158.9 (CONH), 107.4 (OB0 ester C-
Page 151 and 152:
Rutjes, F.P.J.T.; Wolf, L.B.; Schoe
Page 153 and 154:
(a) Tashiro, T.; Fushiya, S.; Nome,
Page 155 and 156:
Sawada, S.; Nakayama, T.; Esaki, N.
Page 157 and 158:
of Rheum rhaponticum over forty yea
Page 159 and 160:
Glutamic acid derivatives are aiso
Page 161 and 162:
syntheses exist for the functionaii
Page 163 and 164:
4.1.4 Synthesis of Optically Active
Page 165 and 166:
4.1.4.3 Catalytic HydrogeMrion The
Page 167 and 168:
Scheme 4.10 C02Et CO*Et R=Me, Et, P
Page 169 and 170:
stereochemicaî induction at the re
Page 171 and 172:
protected glutamate did not adopt a
Page 173 and 174:
Scheme 4.16 The first synthesis of
Page 175 and 176:
stereoselectivi ty during electroph
Page 177 and 178:
kt, when we repeated the synthesis
Page 179 and 180:
CbzH Scheme 4.2û OH pTsW CbzH Figu
Page 181 and 182:
5.21 5.00 16.63 Figure 4.5: GCMS of
Page 183 and 184:
Glu(y-Me)(OMe)OBO ester 4.73. Howev
Page 185 and 186:
OB0 ester. Moreover, the stereochem
Page 187 and 188:
Table 4.1: Optimilgtion of Methyiat
Page 189 and 190:
Scheme 4.22 M'2aL O 2) 1) LiHMDS, P
Page 191 and 192:
Table 4.2: Optimization of Hydroxyi
Page 193 and 194:
Cb2H 1 OsO,. NMO acetone:H& OH m 2)
Page 195 and 196:
The direct electrophilic azidizatio
Page 197 and 198:
to the mesylate Alûû in 80% yield
Page 199 and 200:
which were not isolated. ESI-MS and
Page 201 and 202:
concentrateci reaction mixhue of 4.
Page 203 and 204:
and during acid hydrolysis. HPLC an
Page 205 and 206:
A general method for the synthesis
Page 207 and 208:
Generai Procedure for Removd of Rot
Page 209 and 210:
Same procedure as in 4.4.1. TU3 (1:
Page 211 and 212:
Same procedure as in 4.4.3. [al% =
Page 213 and 214:
ffom CH2Cl2) 3338,2962,2875, 1732,
Page 215 and 216:
ester -0). 72.4 (OB0 ester w20), 65
Page 217 and 218:
4m4.11 5-Methyl-(~,~-2-[(betl~gIo~)
Page 219 and 220:
= l2JHz, CbzCHHO), 3.87-3.78 (s + r
Page 221 and 222:
1016; HRMS (FAB) calcd for (M + H+)
Page 223 and 224:
7.3&, CHZCH~), 0.78 (s, 3H, OB0 est
Page 225 and 226:
hotu before benzyl brornide (0.21 m
Page 227 and 228:
1 H. J = 10.3Hz (detennined by deco
Page 229 and 230:
378.22; Anal. cdcd for CI9Ha07: C,
Page 231 and 232:
(ça), 164.0 EONH), 143.3 (Cbz==).
Page 233 and 234:
min. The solvent was removed under
Page 235 and 236:
173.8 c=O), 156.3 CONH), 137.6 ( Cb
Page 237 and 238:
mp. 1 16- 1 165°C; [al2'D = -2 1 .
Page 239 and 240:
(3:2 Et0Ac:hexanes) to give 4.99 (1
Page 241 and 242:
Cbz-L-Glu(Z-B,y-dehydro)(OMe)OBO 49
Page 243 and 244:
(CbzQI20), 57.4 (am, 39.8 (yCJS2),
Page 245 and 246:
3.7, 10.7, 14.5Hz. BCHH), 0.76 (S.
Page 247 and 248:
TLC (1:1, EtOAc:Hex), Rc = 0.35; 'H
Page 249 and 250:
1515, 1227, 1048, 1016,909; ESI-MS
Page 251 and 252:
(Cbz=@), 128.5, 128.2, 128.1 (a-=),
Page 253 and 254:
TU3 ( 1 : 1, EtOAc:Hex), Rf = 0.17;
Page 255 and 256:
4-4-46 (2S,4S)-2-My14aminopentanedi
Page 257 and 258:
give 0.020 g (54%) of the monoamrno
Page 259 and 260:
1. (a) Virtanen, A.I.; Berg, A.M. A
Page 261 and 262:
Bory, S.; Dubois, J.; Gaudry, M.; M
Page 263 and 264:
(a) Ezquerra, J.; Pedregal, C.; Ymr
Page 265 and 266:
(a) Blaskovich, M.A.; Lajoie. G.A.
Page 267 and 268:
Rathke, M-W.; Sullivan, D.F. J. Am,
Page 269 and 270:
Chapter Five Stereoselective Synthe
Page 271 and 272:
of p-methylaspartate 5.1 to glutama
Page 273 and 274:
OAc Ac kfN&O@ 5.8 C02Et AC lU&02Et
Page 275 and 276:
of 2:7 respectively, both of which
Page 277 and 278:
MH). Changing the reaction conditio
Page 279 and 280:
Garner's aldehyde 1.53 was also use
Page 281 and 282:
Rotected ~-aminoaspartate Sm6 was s
Page 283 and 284:
amount of unreacted starting materi
Page 285 and 286:
provided crystals of sufficient qua
Page 287 and 288:
5.2.2 Addition of Other AIkylation
Page 289 and 290:
Scheme 5-18 We also investigated az
Page 291 and 292:
5.2.5 Discussion of the Stereochist
Page 293 and 294:
face) to give rise to the B,3S ster
Page 295 and 296:
The synthesis of threo-L-b-substitu
Page 297 and 298:
TU3 (1: 1, CHC13:EtOAc, 1 % AcOH) R
Page 299 and 300:
156.0 (ÇONH), 1 36.2 (Cbz*), 128.5
Page 301 and 302:
ester COI3), 30.6 (p-cH2), 14.1 (OB
Page 303 and 304:
extracted with EtzO (3 x 25 d), the
Page 305 and 306:
TU3 (1: 1, EtOAc:Hex), Rr = 0.48; '
Page 307 and 308:
63 MHz) 6 175.9 cd), 156.0 EONH), 1
Page 309 and 310:
175.1 CC-O), 155.8 (CONH), 136.1 (C
Page 311 and 312:
'H-NMR @20, 300 MHz) 6 7.26-7.03 (m
Page 313 and 314:
12.7Hz, CbzCHHO), 5.02 (ci, lH, J =
Page 315 and 316:
TU3 ( 1 : 1, EtOAc:Hex), Rr = 0.40;
Page 317 and 318:
1. 2. 3. 4. 5. 6. 7. 8. 9. IO. 11.
Page 319 and 320:
Eager, R.G. Jr.; Baltimore, B.G.; H
Page 321 and 322:
- - Sardina, F.J.; Paz, MM.; Femihd
Page 323 and 324:
Chapter Si Solid Phase Synthesis of
Page 325 and 326:
eactions such as the Ugi condensati
Page 327 and 328:
Dehydroamino acids have also been u
Page 329 and 330:
Pyroglutarnate was reduced into the
Page 331 and 332:
. - 6.2.1 Synthesis of Resin-Bod BH
Page 333 and 334:
" 6.29 NMM, CH& Scheme 6.11 The arn
Page 335 and 336:
esin placed hem Figure 6.3: Experim
Page 337 and 338:
Figure 6.4: MAS 13c-N..~ (500 MHz)
Page 339 and 340:
Table 6.1: Addition of R'M~B~ to 6.
Page 341 and 342:
63 Summ Attachrnent of Ser-OB0 este
Page 343 and 344:
(S. 2H, CbzCHzO), 4.57-4.40 (m, 7H,
Page 345 and 346:
I C-O), 7 1.9 (OB0 ester GHzO), 61.
Page 347 and 348:
insed, altemating with dry DMF (5 x
Page 349 and 350:
- MAS 'H NMR (Spin-Echd ms): 8 3.87
Page 351 and 352:
6.4.16 (zs)-2-Pmmo-3-hydroruy-3-met
Page 353 and 354:
O.; Gilliarn, CL.; Boisclair, M.D.;
Page 355 and 356:
38. Rakita, P.E.; Silverman, G.S. W
Page 357 and 358:
of these important derivatives due
Page 359 and 360:
the glutamate dimer. It may also be
Page 361 and 362:
Rose, N.G.W.; Blaskovich, M.A.; Won
Page 363 and 364:
Appendices
Page 365 and 366:
Table 1, Cryatrl data and .tructuse
Page 367 and 368:
Tabla 3. Bond langths [Al and amglr
Page 369 and 370:
- - - . - Table 5. Eyârogen coordi
Page 371 and 372:
Calculation of Free Energy Dinerenc
Page 373 and 374:
Table 1. Crymtal data and mtructure
Page 375 and 376:
. Tabla 3. Bond lenpths [il and rng
Page 378 and 379:
X-Ray Crystallographic Data for Com
Page 380 and 381:
4 Tabla 2. Atomic coordinates 1 x 1
Page 382 and 383:
2 3 ? able 4. Aniiotsopic dfmplacea
Page 384 and 385:
Calcdation to Determine Resin Loadi
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