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

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1013; HRMS (FAB) calcd for (M + HÇ) C22H32N& 422.21786, found 422.2163 1. Anal. caicd for C22H31N4: C, 62.69; H, 7.41; N, 3.32. Found: C, 62.50; H, 7.28; N, 3.23. 4.4.10 S-Beazyl-(~-2-[(be~1oxy}carbonyi Jarnino-1-(4-me thyl-2,6,7-trioxabicycI0- [2.2.2]oct-l-yI)pentaao8~ Cbz-L-Glu(0Bn)-OB0 ester, 4.72. Same procedure as in 4.4.7. [al2OD = -27.2 (c = 1.6, EtOAc); TLC (1 : 1, EtOAc:Hex), Rf = 0.55; 'H NMR (Acetone-d6, 300 MHz) 6 7.39-7.24 (m, 10H, ArH), 5.73 (d, lH, J = 10.1 Hz, NH), 5.10-4.97 (m, 4H, CbzCH20, PhCH20), 3.87 (S. 6H, OB0 ester CH20), 3.80 (dt, IH, J = 3.9, 10.1Hz, a-CH), 2.42-2.34 (m. ZH, y-CHz), 2.11-2.00 (m, lH, B- CHH), 1.74-1 -62 (m. 1 H, B-CHH), 0.78 (s, 3H, OBO ester CCH3); "C NMR (Acetone-4, 75 MHz) 6 172.6 @O), 156.4 (CONH), 137.6 (Cbz
4m4.11 5-Methyl-(~,~-2-[(betl~gIo~)carbonyl]~&~~yl-l-(4~thyl-2,6,7- hiox~bicycio[2~2~]0~t-l-yl)pentan~te, Cbz-L-Giu(yMe)(OMe)-OB0 ester, 4.73. Cbz-L-Glu(0Me)-OB0 ester 4.69 (0.M g, 1.12 rnmol) was dissoived in dry THF (40 mL) then cwled to -78OC whilst stimng under Ar. In a second flask, LiHMDS (3.48 mL, 3.48 mrnol, 1.OM in THF) was added to dry THF (10 mL) then cooled to -78OC whilst stirring under Ar. The Cbz-L-Glu(0Me)-OB0 ester 4.69 was then transferred dropwise to the second flask via cannula The mixture was allowed to stir at -78°C for 1 hour before methyl iodide (0.28 mL, 5.60 mmol) was added by syringe. The mixture was allowed to stir for 4 hours at -78°C before king poured into 3% N&Cl (20 mL) and extracted with Et20 (10 mL). The organic layer was then extracted with 3% WC1 (20 rd), saturated NaHCO3 (20 mL), bnne (20 mL) and dned over MgSO*. The solvent was removed in vacuo to reveal a yellow oil which was fùrthcr purified by flash chromatography (1:l EtOAc:Hex, 0.5% Et3N) to give a clear oil in 82% yield (0.358 g). The product was crystailized h m Et0Ac:Hexanes to give 0.3 16 g of white needles (72% yield after crystallization). mp 75-76OC, [UJ*~II = -25.6 (c = 1.02, CHzCl*); TLC ( 1 : 1, EtOAcHex), Rf = 0.60; 'H NMR (Acetone-&, 300 MHz) 6 7.43-7.26 (m. SH, AH), 5.71 (d 1H, J = 10.2H., NH), 5.15-5.05 (m, 2H, CbzCH20), 3.9 1-3.85 (s + rn, 7H, OB0 ester CH20, a-CH), 3.58 (s, 3H, C02CH3). 2.50-2.38 (m. lH, yCH), 1.84 (ddd, lH, J = 5.1, 11.3, 14.OHz, P - 0 , 197
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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
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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
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
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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 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: ester -0). 72.4 (OB0 ester w20), 65
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
Page 243 and 244: (CbzQI20), 57.4 (am, 39.8 (yCJS2),
Page 245 and 246: 3.7, 10.7, 14.5Hz. BCHH), 0.76 (S.
Page 247 and 248: TLC (1:1, EtOAc:Hex), Rc = 0.35; 'H
Page 249 and 250: 1515, 1227, 1048, 1016,909; ESI-MS
Page 251 and 252: (Cbz=@), 128.5, 128.2, 128.1 (a-=),
Page 253 and 254: TU3 ( 1 : 1, EtOAc:Hex), Rf = 0.17;
Page 255 and 256: 4-4-46 (2S,4S)-2-My14aminopentanedi
Page 257 and 258: 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.
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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
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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
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Calcdation to Determine Resin Loadi
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