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

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List <strong>of</strong> Abbreviations H-NMR 13c-hJAd~ AB0 Ac ACC AD AE Aib . Ala AMPA A% Asn A~P 9-BBN BEMP BINAP BMI Bn Boc BSA Bu CAD Calcd Cbz COD CNS CSA proton nuclear magnetic resonance carbon nuclear magnetic resonance 2.7,s-trioxabicyclo[3.2. Iloctane acetyl 1 -Arninocyclopropane- 1 -carboxylate synthase asymrnetric dihydroxylation asymmetric epoxidation a-arninoisobuytric acid alanine 2-amino-3-(3- h ydrox y -5-methylisoxazol4yl)propanoic acid arginine as paragi ni ne aspartic acid 9-borabicyclo[3.3. Ilnonane 2-?en-butylamino-2-diethylamino- 1,3-dimethylperhydro- 1 -3.2- diazaphosphorine binapthol bis-N-methyl imidazolidine benzyl tert-buty loxycarbon y 1 N, O-bis(trimethysi1 y1)acetamide buty 1 carbarnoylphosphate dihdroorotase complex calculated benz ylox ycarbon y1 I,5cyclooctadiene central nervous system camphor sulfonic acid synthetase II, aspartate transcarbamoylase, xvi
CYS d DAST DBAD DBU DCC de DEAD dec DIB AL-H DIPAMP DIPEA DMAP DMDO DMF DMSO DTBAD EAA ee eq ESI-MS Et EtOAc EtOH FAB Fmoc FT GC GDH GIa Gln cysteine doublet diethylaminosulfur trifiuoride di-tert-bu ty 1 azodicarboxy late 1,8-diazabicyclo[S .4.0]undec-7-ene NJ-dic yclohex ylcarbodiimide diastereomeric excess diethyl azodicarboxylate decomposed diisobutyialurninium hydride ((R,R)- 1,2-ethanediylbis[(o-methoxyphenyl)phenylphosphine 1) diisopropylethylamine 4-dimethy laminopyridine dimethyldioxirane dimethylfonnamide dimeth ylsulfoxide di-tert-bu tylazodicarboxylate excitatory amino acid enantiomeric excess equivalence eiectrospray ionization mass spectrometry ethyl ethyl acetate ethanol fast atom bombardment 9-fluoren ylmethox ycarbon y l fourier transfonn gas chromatography glutamate dehydrogenase y-carboxyglutamic acid glutamine xvii
Page 1 and 2: Solution and Solid Phase Synthesis
Page 3 and 4: The University of Waterloo requires
Page 5 and 6: Many people have made the experienc
Page 7 and 8: Table of Contents Abstract ........
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: Figure 4.1 O Figure 5.1 Figure 5.2
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
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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.
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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
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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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Solution and Solid Phase Synthesis of Unusual a-Amino Acids From

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