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

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(AG:) 17.3 kcal- mol", calculami From the coalescence temperature using the graphical method of Shanan-Atidi and Bar-Eli (Appendix B)." Conformational isomers have been reporteci for amidesn and carbamatesn as the C-N bond adopts a less stable syn conformation (Figure 4.7a) and have ken observed in aspartic acid ~ierivatives.'~ Typical values for rotation about the C-N bond are 22 kcal mol-' in the case of amides (N~-dirnethylfor~namide)~~ and 16 kcal mol-' for carbarnates (Na-dimeth ylbenz ylcarbamate). Figure 4.6: Variable-Temperature 5(10 M& 'B-NMR studies ia toukne-4 of Cbz- L-Glu(pMe)(OMe)OBO ester 4.73. This conformational isomerism is observed in the methyl ester 4.73, the t-butyl ester 4.76 and benzyl ester 4.77 derivatives and also in 2S,4S-Boc-Glu(y-Me)(OMe)-
OB0 ester. Moreover, the stereochemistry at the parbon appears to induce this effect since the minor rotamer seems to be absent in the 2S,4R-Cbz-Glu(y-Me)(OMe)OBO ester 4.74 isomer (Figure 4.4 bottom) regardless of solvent. Since anti carbarnate rotamers are more stable than syn rotamers, presumably the anti rotamer corresponds to the major doublet at 6 1.26 ppm and the syn rotamer the minor doublet at 6 1.08 ppm. Some intrinsic property present in ~S,~S-C~~-G~U('~LM~XOM~)(OM~)OBO ester 4.73 is therefore responsible for the observed rotamer. Intramolecular hydrogen bonding may stabilize the conformation depicted in Figure 4.7b in which both the OB0 and methyl groups are equatorial in the syn-2S,4S conformer whereas the syn02S,4R conformer has the methyl group axial, perhaps sufficiently disfavoured to explain the absence of the syn-2S,4R isomer in the 2S,4R-Cbz-Glu(y-Me)(OMe)OBO ester 4.14 'H-NMR spectrurn. Similar seven-membered hydrogen bond interactions have ken shown to be responsible for the configurational stability in sugar thioureas," N-(a-hydr~peroxyalkyl)arnides,~ and macrocyclic polypeptides." Corey and Lee also recently discussed the importance of hydrogen-bonding as an organizing element in the restriction of rotation leading to enantioselectivity in many rea~tions.'~ Polar pro tic solvents should disrupt the propensity of the 2S,4S-methyl denvative to intramolecular hydrogen bond which would be detected in the 'H-NMR specûum, however, the rotamer doublet is observed with solvents such as methanold. If this phenornenon is indeed due to intramolecular hydrogen bonding, the seven-member hydrogen bond must be sufficiently strong to overcome the disniptive nature of methanol-c4.
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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
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 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: Glu(y-Me)(OMe)OBO ester 4.73. Howev
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
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
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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
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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
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
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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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