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

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Koskinen, A.M.P.; Rapoporî, H. I. Org. Chem. 1989.54. 1859. Westwood, N.J.; Claridge, T.D.W.; Edwards, PN.; Schofield, C.J. Biorg. Med. Chem. Lett. 1997,23,2973. Hanessian, S.; Vanasse, B. Can. J. Chem. 1993, 71, 1401. Mulzer. J.; Schroder, F.; Lobbia, A.; Buschmann, J.; Luger, P. Angew. Chem. Int. Ed. Engl. 1994,33, 1737. (a) Johnstone, A.N.C.; Lopatriello, S.; North, M. Tetrahedron Len. 1994, 35, 6335. (b) Del Bosco, M.; Johnstone, A.N.C. Bazza, G.; Lopatriello, S.; North, M. Tetrahedron, 1995,51,8545. Gu, 2. -Q.; Hesson, D.P. Tetrahedron: Asymmetry, 1995,6,2 10 1. Mahalanabis, K.K.; Mumtaz, M.; Snieckus, V. Tetrahedron Lett. 1982,23,397 1. Gu, 2.-Q.; Lin, X.-F.; Hesson, D.P. Bioorg. Med. Chenz. Lcn. 1995,5, 1973. Hanessian, S.; Margarita, R. Tetrahedron Lett. 1998,39,5887. Tanaka, L I; Sawanishi, H. Tetrahedron: Asynmetry, 1998,9,7 1. Geffault, T. ; Bauer, U. ; AiroIa, K.; Koskinen, A.M.P. Tetrahedron: Asymmetry , 1996,7,3099. Dauban, P.; de Saint-Fuscien, C.; Dodd, R.H. Tetrahedron, 1999,55,7589. Dauban, P.; de Saint-Fuscien, C.; Acher, F.; Prézeau, L.; Brabet, L; Pin, J.-P.; Dodd, R.H. Biorg. Med. Chem. Let?. 2000,10, 129. Langlois, N. Tetrahedron Lett. 1999,40,8801. Belshaw, P.J.; Mzengeza, S .; Lajoie, G.A. Synth. Comm. 1990.20.3 157.
(a) Blaskovich, M.A.; Lajoie. G.A. J. Am Chem Soc. 1993, 115, 5021. (b) Blaskovich, M.A.; Evindar. G.; Rose, N.G.W.; Luo, Y.; Lajoie, G.A. J. Org. Chem. 1998,63,4560. (a) Vedejs, E.; Kruger, A.W. J. Org. Chem. 1999, 64, 4790. (b) Matsuo, J.4; Kobayashi, S.; Koga, K. Terrahedron kt?. 1998, 39, 9723. (c) Barlett, P.A.; Myerson, J. J. Org. Chem. 1979,44, 1625. Bailey, P.D.; Bryans, J.S. Tetrahedron Lett. 1988,29,223 1 . Kawabata, N,; Weisberg, M.; Goodman, M. J. Org. Ch. 1999,62,4362 Shanan-Etdi, H.; Bar-Eli, K.H. J. Phys. Chem. 1970, 74,961. (a) Dumy, P.; Keller, M.; Ryan, D.E.; Rohwedder, B.; Wohr, T.; Mutter, M. J. Am. C h . Soc. 1997,119,918. (b) Chen, J.K.; Schreiber. S.L. Angew. Chem. Int. Ed Engl. 1995,34,953. (c) Avent. A.G.; Bowler, A.N.; Doyle, P.M.; Marchand, C.M.; Young, D.W. Tetrahedmn Le#. 1992,33, 1509. (a) Moraczewski, AL.; Banaszynski, L.A.; From, A.M.; White, C.E.; Smith, B.D. J. Org. Chem. 1998, 63,7258. (b) Marcovici-Mizrahi, D.; Gottiieb, H.E.; Marks, V.; Nudelman, A. J. Org. Chem. 1996,61,8402. Seebach, D.; Wasmuth, D. Angew. Chem Int. Ed. EEngl. 1981,20,971. Lambert, J.B.; Shurvell, H.F.; Verbit, L.; Cooks, R.G. Stout, G.H. In Organic Structural Analysis. MacMillan Publishing Co. Inc., New Yrok, 1W6, Chapter 6. Mellet, C.O.; Man'n, A.M.; Blanco, J.L.J.; Fernhdez, J.M.G.; Fuentes, J. Tetrarhedron: Asymmetry, 1994.5.2325. Sagar, B.F. J. Chem. Soc. 0,1967,428.
Page 1 and 2:
Solution and Solid Phase Synthesis
Page 3 and 4:
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 .........
Page 13 and 14:
List of Tables Table 2.1 Table 2.2
Page 15 and 16:
Figure 4.1 O Figure 5.1 Figure 5.2
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CYS d DAST DBAD DBU DCC de DEAD dec
Page 19 and 20:
NMP Nu OB0 ester PEG Ph Phe PhFl Ph
Page 21 and 22:
1.1 General Introduction Chapter On
Page 23 and 24:
acids will be presented including a
Page 25 and 26:
.J generation of the enolate and ad
Page 27 and 28:
classical techniques (Scheme 1.7) a
Page 29 and 30:
s~ccess.~ The same principle has be
Page 31 and 32:
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
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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
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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
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(a) Schmidt, U.; Meyer, R.; Leitenb
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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.
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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
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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:
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
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: (a) Ezquerra, J.; Pedregal, C.; Ymr
Page 267 and 268: Rathke, M-W.; Sullivan, D.F. J. Am,
Page 269 and 270: Chapter Five Stereoselective Synthe
Page 271 and 272: of p-methylaspartate 5.1 to glutama
Page 273 and 274: OAc Ac kfN&O@ 5.8 C02Et AC lU&02Et
Page 275 and 276: of 2:7 respectively, both of which
Page 277 and 278: MH). Changing the reaction conditio
Page 279 and 280: Garner's aldehyde 1.53 was also use
Page 281 and 282: Rotected ~-aminoaspartate Sm6 was s
Page 283 and 284: amount of unreacted starting materi
Page 285 and 286: provided crystals of sufficient qua
Page 287 and 288: 5.2.2 Addition of Other AIkylation
Page 289 and 290: Scheme 5-18 We also investigated az
Page 291 and 292: 5.2.5 Discussion of the Stereochist
Page 293 and 294: face) to give rise to the B,3S ster
Page 295 and 296: The synthesis of threo-L-b-substitu
Page 297 and 298: TU3 (1: 1, CHC13:EtOAc, 1 % AcOH) R
Page 299 and 300: 156.0 (ÇONH), 1 36.2 (Cbz*), 128.5
Page 301 and 302: ester COI3), 30.6 (p-cH2), 14.1 (OB
Page 303 and 304: extracted with EtzO (3 x 25 d), the
Page 305 and 306: TU3 (1: 1, EtOAc:Hex), Rr = 0.48; '
Page 307 and 308: 63 MHz) 6 175.9 cd), 156.0 EONH), 1
Page 309 and 310: 175.1 CC-O), 155.8 (CONH), 136.1 (C
Page 311 and 312: 'H-NMR @20, 300 MHz) 6 7.26-7.03 (m
Page 313 and 314: 12.7Hz, CbzCHHO), 5.02 (ci, lH, J =
Page 315 and 316:
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
Page 331 and 332:
. - 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
Page 378 and 379:
X-Ray Crystallographic Data for Com
Page 380 and 381:
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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