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

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Marcotte, P.; Walsh, C. J. BioL Chem. 19R. 252, 1571. (d) Chang, M.N.T.; Walsh, C. J. Am. Chem. Soc. 1980, 102, 7368. (e) Johnston, M.; Raines, R.; Chang, M.; Esaki, N.; Soda, K.; Walsh, C. J. Biol. Chem. 1981, 20, 4325. (f) Chang, M.N.T.; Walsh, C. J. Am. Chem. Soc. 1981,103,4921. Angst, C. Pure & AppL Chem. 1987,59,373. Castelhano, A.L.; Pliura, D.H.; Taylor, G.J.; Hsieh, K.C.; Krantz, A. J. Am. Chem. Soc. 1984,106,2734. Zabriske, T.M.; Cheng, H.; Vederas, J-C. J. Am. Chem. Suc. 1)92,114,2270. Flavin, M.; Slaughter, C. J. Biol. Chem. 1960,235, 1 1 12. Feng, L.; Geck, M.K.; Eliot, A.C.; Kirsch, J.F. Biochemistry, 2000,39, 15242. Zheng, L.; White, R.H.; Cash, V.L.; Dean, D.R. Biuchemistry, 1994,33,47 14. (a) Hagedorn, A.A.; Miller, B.J.; Nagy, J.O. Tetrahedron Len. 198û. 21, 229. (b) Baldwin, LE.; Hoskins, C.; Kxuse, L. J. Chem. Soc.. Chem. Comm. 1976,795. (c) Wade, P.A.; Pillay, M.K.; Singh, S.M. Tetrahedron Lm. 1982, 23, 4563. (d) Vyas, D.M.; Chiang, Y.; Doyle, T.W. Tetrahedron Le#. 1984, 25, 487. (e) Mzengeza, S.; Whitney, R.A. J. Chem. Soc.. Chem. Comm. 1984,606. (0 Wade, P.A.; Singh, S.M.; Pilay, M.K. Tetrahedron, 1984,40,60 1. (g) Wityak, J.; Gould, S.J.; Hein, S.J.; Heszler, D.A. J. Org. Chem. 1987, 52, 2 179. (h) Mzengeza, S.; Yang, C.M.; Whitney, R.A. J. Am Chenr Soc. 1987,109,276. Shaw, K.J.; Luly, J.R.; Rapoport, H. J. Org. Chem. 1985,50,45 15. Rajendra, G.; Miller, M.J. J. Org. Chem. 1987,52,447 1.
(a) Tashiro, T.; Fushiya, S.; Nome, S. Chem. Pham Bull. 1988, 36, 893. (b) Meffre, P.; Vo-Quang, L.; Vo-Quang, Y.; Le G<strong>of</strong>ic, F. Tetrahedron Le#. 1990, 31, 229 1. (c) Krol, W.I.; Mao, S.; Steele, DL; Townsend, C.A. J. Org. Chem. 1991,56,728. Yanagida, M.; Hashimoto, K.; Ishida, M.; Shinozaki, H.; Shiraharna, H. Tetrahedron Leît. 1989,30,3799. Sakai, N.; Ohfune, Y. Tewahedron Lett. 1990,3 1,4 15 1. (a) Shimamoto, K.; Ohfune, Y. Tetrahedron Le#. 1990.3 1,4049. (b) deFrutos, P.; Ferniindez, D.; FemAndez-Alvarez, E.; Bernabé, M. Tetrahedron Lett. 1991, 32, 541. (c) deFrutos, P.; Femhdez, D.; Fernhdez-Alvarez, E.; Bemabé, M. Tetrahedron, 1992,48, 1 123. Shimamoto, K.; Ishida, M.; Shinozaki, H.; Ohîùne, Y. I. Org. Chem. 1991, 56, 4167. Koskinen, A.M.P.; Chen, J. Tetrahedron Lm. 1991,32,6977. Jako, 1.; Uiber, P.; Mann, A.; Wermuth, C.-G.; Boulanger, T.; Norberg, B.; Evrard, G.; Durant, F. Org. Chem. 1991,56,5729. Fris, P.; Helboe, P.; ben, P.O. Acta. Chern. Sc<strong>and</strong>. B, 1974,28,317. Baldwin, LE.; Haber, S.B.; Hoskins, C.; Knise, L.I. J. Org. Chem. 1977, 42, 1239. Hurdlik, P.; Kulkami, A.K. J. Am. Chem. Soc. 1981,103,625 1. Greenlee, W.J. J. Org. Chem. 1984,49,2632. Vyas, D.M.; Chiang, Y.; Doyle, T.W. J. Org. Chem. 1984,49,2037.
Page 1 and 2:
Solution and Solid Phase Synthesis
Page 3 and 4:
The University of Waterloo requires
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Many people have made the experienc
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Table of Contents Abstract ........
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23 Summary ........................
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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
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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
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Williams and coworlcers have examin
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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
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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
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typically generated in both poor yi
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2.1.3.3 Electrophilic%Nucfeophilic
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Scheme 2.8 2-(Arylthi0)-2-nitrooxir
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Scheme 2.10 Schollkopf et al. have
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2.1.3.5 Synthesis fiom #-Amino Acid
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HO Scheme 2.17 This laboratory prev
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Scheme 2.19 NaBr, acetone The best
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equires carefiil attention to preve
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order to investigate this as a poss
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etained its optical activity indica
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2.2.3.2 Ortho Ester Cleavage Concom
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2.2.4 Determination of Enantiomeric
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minof si face aîîack mior re face
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2.4.1 General Methods. Most reagent
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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: Rutjes, F.P.J.T.; Wolf, L.B.; Schoe
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
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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,
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ester -0). 72.4 (OB0 ester w20), 65
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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
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hotu before benzyl brornide (0.21 m
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1 H. J = 10.3Hz (detennined by deco
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378.22; Anal. cdcd for CI9Ha07: C,
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(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
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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
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(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
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(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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