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

More documents

Recommendations

Info

$uWaterloo LaTeX Thesis Template - UWSpace - University of Waterloo$

CH), 3.85 (s, 6H, OB0 ester CH20), 3.68 (ddâ, lH, J= 2.9, 10.4, 12.2Hz, a-CH), 3.57 (s, 3H, C02CH3), 2.86 (br s, 2H, y-NH2), 2.24 (ddd, IH, J = 2.4, 10.7, 1 3.7H2, p-CHH), 1.88 (ddd, lH, J = 3.4, 12.2, 13.7Hz, p-CHH), 0.76 (S. 3H, OB0 ester CCH3); I3c NMR (Acetone-4, 75 MHz) 6 172.0 156.1 (ÇONH), 137.7 (a-=), 128.4, 127.7, 127.7 (Cbz===), 108.5 (OB0 ester C-O), 72.3 (OB0 ester CJ120), 65.6 (CbzW20), 59.5 (y-cm, 5 1.8 (a-CH), 5 1.1 (COD3), 33.0 (OB0 ester ÇCH3), 30.3 (B-w2), 1 3.4 (OB0 ester CQi3); IR (cast fkom CHC13) 3374, 2949, 2880, 1730, 15 16, 1224, 1046, 101 1; ESI-MS (M + H+) 394.90. Anal. caicd for Ci9Hz&J2@: C, 57.86; H, 6.64; N, 7.10. Found: C, 58.08; H, 6.75; N, 7.12. 4-4-38 Metbyl-(2S,4S)-2-[(be11zyloxy)carbnyl ]am wthyI-2,6,7-trioxabicyc10[2~2.2~0~t-l-y~ Cbz-L-Glu(~OMs)(OMe)OBO ester, 4.108. Cbz-L-Glu(y-OH)(OMe)OBO ester 4.% was dissolved in dry CHzC12 (5 mL) then cooled to 0°C. Et3N (57 pL, 0.42 rnmol) was then added followed by mesyl chloride (16 pL, 0.21 rnmol). The mixture was allow to stir for 12 h before the solvent was removed in vacuo der which the desired product could be purifieci by flash chromatography to give 4.108 in 80% yield (76 mg). However, the mesylate was generally displaced by azide without isolation.
TLC (1:1, EtOAc:Hex), Rc = 0.35; 'H NMR (Acetone*, 300 MHz) 6 7.38-7.24 (m, SH, ArH), 6.22 (d, lH, J = 10.3Hz, NH), 5.10 (d, lH, J = 12.7Hz, CbzCHHO), 5.03 (d, 1H, J = 12.7Hz, CbzCHHO), 4.83 (dd, lH, J = 2.9, 11.7Hz, yCH), 3.96 (ddd, IH, J = 2.4, 10.3, 11.7Hz, a-CH), 3.88 (s, 6H, OB0 ester O-), 3.71 (s, 3H, C02CH3), 2.19 (ddd, 1H. J = 2.9. 11.7, lS.lH., BCHH), 1.89 (ddd, lH, J = 2.4, 11.7, lS.lHi, B-CHH), 0.76 (s, 3H, OB0 ester CCH3); I3c NMR (CDC13, 75 MHz) 6 170.0 (T=O), 157.1 (CONH), 137.7 (Cbz
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 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: 3.7, 10.7, 14.5Hz. BCHH), 0.76 (S.
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
show all

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

Create successful ePaper yourself

Delete template?

Save as template?