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

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Inverse addition was used to generate the dianion (based on results described in chapter 5) and addition of electrophile were both carried out at -78'C to prevent decomposition of the enolate and erosion of diastereoselectivity which occurred upon warming to -30°C. Methyl iodide was chosen as the alkylating agent since an easily identifiable doublet would be formed which could be integrated by NMR methods to determine diastereoselectivity . At first, &ter generation of the enolate and addition of methyl iodide. the y- methylglutamate 4.73 denvative was seemingly generated in approximately 10: 1 ratio based upon 'H-NMR intcgration of the new methyl group at 61.15 ppm (Figure 4.2) although no other signals comsponding to the other diastenomer were observed. High field NMR analysis (2 300 MHz) was essential since examination of the methyl doublets on lower field instruments failed to distinguish between diastereomers (vide infra). In
kt, when we repeated the synthesis of 2S,4S-Cbz-Glu(yMe)(OMe)OMe 4.46 e-Cbz, R'=R2=E=~e) reprted by Hanessian and MargariaM we observed (500 MHz 'H-NMR) diastereomecïc contamination of the crude product as a 6:1 mixture of the 2S94R2S,4R diastereomers. However, the 2S,4R isomer was not observed when using conditions identical to those by Hanessian and Margarita to analyze their product (200 MHz 'H- Figure 4.2: 3ûû MBz 'H-NMR of Cbz-L-GJu(pMe)(OMe)OBO ester 4.73. Numerous attempts at optirnization failed to alter the 10:l ratio. suggesting the 1 existence of some other phenomena H-NMR studies in CDC13, CD&&, acetone-&, methanol-ci4, m-&, DMF-d7 and DMSQ& al1 showed the same ratio of methyl
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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
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: stereoselectivi ty during electroph
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
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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,
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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
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
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X-Ray Crystallographic Data for Com
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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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