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

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amino acids- The extent of racemization caused by oxidation of Boc-Ser-OB0 ester 2.44 to the aldehyde 2.46 was detennined by comparing deprotected reduced aldehyde to a sample of deprotected Boc-Ser-OB0 ester starting material. Enantiomeric purities of >97% ee were routinely assessed for the reduced deprotected aldehyde. HPLC analysis conditions were generally established independently for each amino acid. in general, the threo and erythro diastereomers were well resolved but the L- and D-enan tiomers presented more of a challenge. Racemic D,L-N-i-Buc ys teine w as used to establish conditions for the separation of the amino acid D,L enantiomers. 2.2.5 Stereoselectivity of Carbonyl Additions to Boc-Ser(a1d)OBO ester 2.46 and Boc- Thr(ket)OBO ester 2.47. The nucleophilic carbonyl addition reactions described (vide supra) show surprising diastereoselectivity for an acyclic system. Diastereoselectivity ranged from 79:21 to 99: 1 (threo:erythro) for the addition of various Grignard reagents to both Boc- Ser(ald)OBO ester 2.46 and Boc-ThrO
minof si face aîîack mior re face attack Figure 2.2: Felkin-Anh Mode1 Predicting n Face Attack on the Side Chain Carbonyl of 2.46 and 2.47 A) Chelation, B) Non-Chelation models. The diastereoselectivities observed for the addition of Grignard reagents to Boc protected OB0 denvatives are in most cases comparable to those achieved upon nucleophilic addition to Fmoc and Cbz protected OB0 de ri vat ive^?^.^' However, the addition of MeMgBr to Boc-Ser(a1d)OBO ester 2.46 gave an 85: 15 threo:erythro ratio whereas addition to the Fmoc and Cbz equivalent~~~ resulted in 96:4 and 97:3 ratios respectively. This might be attributed to the stenc attributes of the Fmoc and Cbz groups compared to Boc, an observation alluded to by the apparently more accessible carbarnate in the case of 2-47 due to the absence of formation of side-products 2-61 in the Fmoc and Cbz derivatives.
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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
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.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: 2.2.4 Determination of Enantiomeric
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
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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
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Same procedure as in 4.4.1. TU3 (1:
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Same procedure as in 4.4.3. [al% =
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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
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1. (a) Virtanen, A.I.; Berg, A.M. A
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Bory, S.; Dubois, J.; Gaudry, M.; M
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(a) Ezquerra, J.; Pedregal, C.; Ymr
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(a) Blaskovich, M.A.; Lajoie. G.A.
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Rathke, M-W.; Sullivan, D.F. J. Am,
Page 269 and 270:
Chapter Five Stereoselective Synthe
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of p-methylaspartate 5.1 to glutama
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OAc Ac kfN&O@ 5.8 C02Et AC lU&02Et
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of 2:7 respectively, both of which
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MH). Changing the reaction conditio
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Garner's aldehyde 1.53 was also use
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Rotected ~-aminoaspartate Sm6 was s
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amount of unreacted starting materi
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provided crystals of sufficient qua
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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
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face) to give rise to the B,3S ster
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The synthesis of threo-L-b-substitu
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TU3 (1: 1, CHC13:EtOAc, 1 % AcOH) R
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156.0 (ÇONH), 1 36.2 (Cbz*), 128.5
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ester COI3), 30.6 (p-cH2), 14.1 (OB
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extracted with EtzO (3 x 25 d), the
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TU3 (1: 1, EtOAc:Hex), Rr = 0.48; '
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63 MHz) 6 175.9 cd), 156.0 EONH), 1
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175.1 CC-O), 155.8 (CONH), 136.1 (C
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'H-NMR @20, 300 MHz) 6 7.26-7.03 (m
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12.7Hz, CbzCHHO), 5.02 (ci, lH, J =
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TU3 ( 1 : 1, EtOAc:Hex), Rr = 0.40;
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1. 2. 3. 4. 5. 6. 7. 8. 9. IO. 11.
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Eager, R.G. Jr.; Baltimore, B.G.; H
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- - Sardina, F.J.; Paz, MM.; Femihd
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Chapter Si Solid Phase Synthesis of
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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
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. - 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
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Figure 6.4: MAS 13c-N..~ (500 MHz)
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Table 6.1: Addition of R'M~B~ to 6.
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63 Summ Attachrnent of Ser-OB0 este
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(S. 2H, CbzCHzO), 4.57-4.40 (m, 7H,
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I C-O), 7 1.9 (OB0 ester GHzO), 61.
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insed, altemating with dry DMF (5 x
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- MAS 'H NMR (Spin-Echd ms): 8 3.87
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6.4.16 (zs)-2-Pmmo-3-hydroruy-3-met
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O.; Gilliarn, CL.; Boisclair, M.D.;
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38. Rakita, P.E.; Silverman, G.S. W
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of these important derivatives due
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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
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Tabla 3. Bond langths [Al and amglr
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- - - . - Table 5. Eyârogen coordi
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Calculation of Free Energy Dinerenc
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Table 1. Crymtal data and mtructure
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. Tabla 3. Bond lenpths [il and rng
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X-Ray Crystallographic Data for Com
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4 Tabla 2. Atomic coordinates 1 x 1
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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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