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

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127, 298. (h) Nicolaou, ILC.; Theodoraiis, E.A.; Rutjes, F.P.J.T.; Sato, M.; Tiebes, J.; Xiao, X.-Y.; Hwang, C.-K.; Duggan, M.E.; Yang, Z.; Couladouros, E.A.; Sato, F.; Shin, J.; He, H.-M.; Bleckman, T. J. Am. Chem. Soc. 1995, 117, 10239. Krüger, J.; Hoffman, R.W. J. Am. Chem. Soc. 1997,119,7499. (a) Wipf, P.; Xu, W.; Kim, H.; Takahashi, H. Tetrahedron, 199'7.53, 16575. (b) Wipf, P.; Aslan, D.C. J. Org. Chem. 2001,66,337. Corey, E.I.; Raju, N. Tetrahedron Len. 1983,24, 5571. Saitoh, Y.; Moriyama, Y.; Takahashi, T. Tetrahedron Le#. 1980,21,75. Bannai, K.; Tanaka, T.; Okamura, N.; Hazato, A.; Sugiura, S.; Manabe, K.; Tornimori, K.; Kurozumi, S. Tetrahedron Lett. 1986,27,6353. Bergmann, M.; Zervas, L. Ber. 1932,65, 1 192. Carpino, L. A. Acc. Chem. Res. 1973,6, 1 9 1. Bodanszky , M. Principles of Peptide Chemistry, Springer-Verlag: New York, 1984, pp 99- 135.
2.1 Introduction Chapter Two Synthesis of Boc Protected &Hydroxy-a-Amino Acids p-Hydroxy-a-amino acids are of immense interest due to either their direct biological action or as structural components of compounds with biological activities (Figure 2.1).'.' For example, D-do-threonine is found in antibiotics such as the katanosins 2.1,3 while &hydroxyleucine is found in the leucinostatins 2.2 and the katanosins 2.1. B-Hydroxytyrosine is present in antibiotics such as vancomycin 2.3' (widely used to treat deep seated Gram negative bacterial infections), the orienticins 2A6 and chloroorienticins 2.5,' risocetins 2.@ and chloramphenicol2.~ and a number of other cyclic peptides (avoparcin, teicoplanin, actapanin, parvocidin, actinodin, and chloropolysp~rin).~ The catecholamine class of neurotransrnitters (adrenaline 2.8 and norepinephrine 2.9) incorporate a ~hydroxytyrosine moiety whereas epinephrine 2.10 contains P-hydroxyphenylalanine. p-Hydroxyproline and fbhydroxyaspartic acid have been isolated from empedopeptin1° and p-hydroxyaspartic acid is also believed to play a role in hemeostasis proteins." 8-Hydroxyglutamine has been identified in antibiotics such as neopep tin.12 (4R)-4-(E)-2-Butenyl-4J-dimethyl-L-threonine 2.1 1, probabl y the most well known f3-hydroxy-a-amino acid, is a crucial constituent of cyclosporin A, a potent irnmunosuppressive drug." b-Hydroxy-a-arnino acids are also important intermediates in the synthesis of other compounds, for exarnple, many p-Iactams (with antimicrobial activity) have been synthesized via B-hydroxy-a-arnino acids.I4
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Solution and Solid Phase Synthesis
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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 ........................
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: Nakajima, K.; Takai, F.; Tanaka, T.
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
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esin column (Bio-Rad AGa 10x4 10-20
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Jung, M.E.; Jung, Y.H. Tetruhedron
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(a) Adams, Z.M.; Jackson, R.F.W.; P
Page 121 and 122:
(a) Roemmele, R.C.; Rapport, H. J.
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- - 68. Gawley, R.E.; Aubé, J. Pri
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pyridoxal phosphate dependent enzym
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Vinylglycines are also useful as sy
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In 1984, a modified Strecker synthe
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The main byproduct of elimination w
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, HO- OH Scheme 3.14 , 1) pb(OAc),
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L-vinylglycine has also been synthe
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Ser(a1d)-OB0 gave the desired olefi
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A tram relationship for H2IH3 in th
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33 Summary The Cbz OB0 ester protec
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67.1 (Ar_cH20), 63.2 @--a), 56.3 (a
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yielded a slightiy yellowish solid
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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
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(a) Tashiro, T.; Fushiya, S.; Nome,
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Sawada, S.; Nakayama, T.; Esaki, N.
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of Rheum rhaponticum over forty yea
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Glutamic acid derivatives are aiso
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syntheses exist for the functionaii
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4.1.4 Synthesis of Optically Active
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4.1.4.3 Catalytic HydrogeMrion The
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Scheme 4.10 C02Et CO*Et R=Me, Et, P
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stereochemicaî induction at the re
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protected glutamate did not adopt a
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Scheme 4.16 The first synthesis of
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stereoselectivi ty during electroph
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kt, when we repeated the synthesis
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CbzH Scheme 4.2û OH pTsW CbzH Figu
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5.21 5.00 16.63 Figure 4.5: GCMS of
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Glu(y-Me)(OMe)OBO ester 4.73. Howev
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OB0 ester. Moreover, the stereochem
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Table 4.1: Optimilgtion of Methyiat
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Scheme 4.22 M'2aL O 2) 1) LiHMDS, P
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Table 4.2: Optimization of Hydroxyi
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Cb2H 1 OsO,. NMO acetone:H& OH m 2)
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The direct electrophilic azidizatio
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to the mesylate Alûû in 80% yield
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which were not isolated. ESI-MS and
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concentrateci reaction mixhue of 4.
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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
Page 217 and 218:
4m4.11 5-Methyl-(~,~-2-[(betl~gIo~)
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= 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
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1 H. J = 10.3Hz (detennined by deco
Page 229 and 230:
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 .
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(3:2 Et0Ac:hexanes) to give 4.99 (1
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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
Page 251 and 252:
(Cbz=@), 128.5, 128.2, 128.1 (a-=),
Page 253 and 254:
TU3 ( 1 : 1, EtOAc:Hex), Rf = 0.17;
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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
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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
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amount of unreacted starting materi
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provided crystals of sufficient qua
Page 287 and 288:
5.2.2 Addition of Other AIkylation
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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
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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
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- - 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
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Dehydroamino acids have also been u
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Pyroglutarnate was reduced into the
Page 331 and 332:
. - 6.2.1 Synthesis of Resin-Bod BH
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" 6.29 NMM, CH& Scheme 6.11 The arn
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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
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(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
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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
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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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