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

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The synthetic strategy described provides a route to various Boc protected threo- P-dialkyl- and p-alkyl-$-hydroxy-a-arnino acids from the Boc-Ser(a1d)-OB0 ester 2.46 and Boc-Thr(ket)-OB0 ester 2.47 synthons. Overall yieids ranged from 1640% and al1 products had >96% ee. Diastereomeric purities ranged from 70:30 to 99: 1 threo:erythro; with ratios generally increasing with steric bulk and reduced reaction ternperatures. The overall yields and diastereoselectivity of Grignard additions to Boc- Ser(a1d)OBO ester 2.46 and Boc-Thr(ket)OBO ester 2.47 generaily correspond to those achieved for the analogous Fmoc and Cbz protected derivatives. In most cases, the diastereoselectivities are comparable to previously published methods (Section 2.1.3) but the method does not require harsh oxidation or deprotection steps. A variety of sidechains have been readily introduced and deprotection to the free amino acid is easily achieved.
2.4.1 General Methods. Most reagents were purchased fiom the Aldrich Chemicai Company. Boc-Ser and Boc-Thr were purchased fiom Advanced ChemTech. CH2Clz was distilled from Ca&; toluene, THF and Et20 frorn Nalbenzophenone. Reâctions were carried out under Nz or A. in glassware dried ovemight at l2O0C or fiame dried before use. NMR spectra were recorded in CDCll (referenced to TMS at 0.00 ppm for 'H. to CDCI, at 77.00 ppm for I3c) or D20 (referenced to 2,2,3,3-dr3-(trimethy1silyl)propionic acid, sodium sait at 0.00 ppm for both 'H and 13c) on a Baker AC-200, AM-250. AM- 300, Avance 300 or Avance 500 spectrometer. CDClp used for NMR sarnples containing an ortho ester was prefiltered through basic alumina to remove traces of acid. IR spectra were recorded on a Bomem MB-100 FT-IR spectrophotometer. Optical rotations were measured on a Perkin-Elmer 241 digital polarimeter. Melting points were determined on a Mel-Temp apparatus in an open capillary tube and are uncorrected. Low resolution mass spectral analysis were performed on a VG Quattro II triple quadrupole mass spectrometer (Micromass, UK) equipped with an electrospray source interfaced with an Hewlett-Packard HPLC running 5050 H20MeCN (0.1 % formic acid) at a flow rate of 30 @min at the University of Waterloo. Elernental analyses were performed by MHW Laboratones, Pheonix, Arizona TLC was canied out on Merck aluminurn backed silica gel 60 Fm with visualization by W, ninhydrin solution (2% in EtOH), or 12. HPLC analyses were performed using a Waters 600E System Controller with Waters 600 Multisolvent Delivery System, Mode1 481 or 486 Variable Wavelength UVNis Detector, and Waters 745 Data Module.
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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 ........................
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5.1.4.1 Enzymatic Methods .........
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List of Tables Table 2.1 Table 2.2
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Figure 4.1 O Figure 5.1 Figure 5.2
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CYS d DAST DBAD DBU DCC de DEAD dec
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NMP Nu OB0 ester PEG Ph Phe PhFl Ph
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1.1 General Introduction Chapter On
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acids will be presented including a
Page 25 and 26:
.J generation of the enolate and ad
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classical techniques (Scheme 1.7) a
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s~ccess.~ The same principle has be
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O Scheme 1.11 O R1,qH2 m OH RI= H,
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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
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: minof si face aîîack mior re face
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
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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-
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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
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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~)
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= l2JHz, CbzCHHO), 3.87-3.78 (s + r
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1016; HRMS (FAB) calcd for (M + H+)
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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==).
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min. The solvent was removed under
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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),
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3.7, 10.7, 14.5Hz. BCHH), 0.76 (S.
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TLC (1:1, EtOAc:Hex), Rc = 0.35; 'H
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1515, 1227, 1048, 1016,909; ESI-MS
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(Cbz=@), 128.5, 128.2, 128.1 (a-=),
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TU3 ( 1 : 1, EtOAc:Hex), Rf = 0.17;
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4-4-46 (2S,4S)-2-My14aminopentanedi
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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
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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
Page 321 and 322:
- - Sardina, F.J.; Paz, MM.; Femihd
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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
Page 329 and 330:
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
Page 351 and 352:
6.4.16 (zs)-2-Pmmo-3-hydroruy-3-met
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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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