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

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Figure 4.8: X-Ray Crystal stnict~re of Cbz-L-Glu(~Oa)(OMe)OBO ester 4.96. Dihydroxylation to give Cbz-Glu(~,')"dihydroxy)(OMe)OBO esters was accomplished by the osmylation of both the E 4.97 and Z 4.99 isomers of Cbz-Glu(p,y- dehydro)(OMe)OBO ester. E-Cbz-Glu(f3,y-dehydro)(OMe)OBO ester 4.97 was s ynthesized from Cbz-Ser(a1d)OBO es ter 3.42 and methyl(Enphenylphosphor~ylidene) in good yield (78%) and with 98:2 EZ ratio (Scheme 4.25). Cbz-Ser(a1d)OBO ester 3.42 was reacted with Ando's reagent" 4.98 to give zCbz-~lu(~,y-dehydro)(OMe)OBO ester 4.99 as a 10:l Z:E ratio. The E-isomer could be separateci by flash chromatopphy to give 4.99 in 6 196 yield.
Cb2H 1 OsO,. NMO acetone:H& OH m 2) ion exctrange 4.1OQ (from 4.1 00) 4.1- (frorn 4.101) I 0~04. NMO acetone:H20 Initially, dihydroxylation of 4.97 and 4.99 with stoichiometric amounts of Os04 in pyridine and reduction with refluxing methanolic sodium sulfite or sodium bisulfite gave a complex mixture of decomposed materials that were not is~lated.~ However, N- methylmorpholine N-oxide catalyzed osmylationgg gave the cis-diols 4.100 and 4.101 in 54% and 48% yield respectively. Detennining the stereochemistry of dihydroxylation proved to be problematic since attempts at crystallizing 4.102, its N-trityl derivative and bis-3,s-dinitrobenzoyl ester derivative failed to give crystals capable of X-ray analysis. With optical rotations reported for only two of the eight possible isomers of dihydroxyglutamic a~id,6~." deprotection of 4.102 and 4.103 and cornparison of opticai rotations held little promise for identiving the stereuchemistry of addition, especially due to the small amount of materiai available. Efforts are continuing in an attempt to grow cry stals for identification of stereochemistry b y X-ray anal y sis. Deprotection of the Cbz
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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
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The 3-bromo analog of Williams and
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formation of serine aldehydes; dire
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Scheme 1.24 R dimethoxy- R ProPane
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of thiol trityl led to racemic cyst
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nucleophiles such as acetate and im
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may be employed, while the oxidatio
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Several methods for the removal of
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1.5 References Barrett, G.C. Chemis
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(a) Schmidt, U.; Meyer, R.; Leitenb
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R.M. Tetrahedron Le#. 2001,42, 769.
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(a) Lubell, W.D.; Rapport, H. J. Am
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Nakajima, K.; Takai, F.; Tanaka, T.
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2.1 Introduction Chapter Two Synthe
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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
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250 MHz) 6 5.47 (br ci, lH, J = S.O
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evaporated to dryness. The residue
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minutes. The akohol solution was tr
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302.1604, found 302.1593; Anai. cal
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CCH3), 28.3 (a3)C), 20.1 (fLm3) 13.
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TLC (4: 1, CH2C12:EtOAc) Rf = 0.44;
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100-200 mesh, hydrogen form, 1x10 c
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(br d. IH. J= 10.6Hz, CHH-CH), 4.63
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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
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(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
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: Table 4.2: Optimization of Hydroxyi
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
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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,
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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
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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
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Rose, N.G.W.; Blaskovich, M.A.; Won
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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
Page 371 and 372:
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
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Calcdation to Determine Resin Loadi
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Solution and Solid Phase Synthesis of Unusual a-Amino Acids From

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