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

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R Scheme 6.13 1) 1 :1 TFA:CH2CI2 2) Cs2C03, MeOH 3) cation exchange - H2 R1koH C02H Overall yields of the B-hydroxy-a-amino acids after purification ranged from 19- 418 on Wang or TentaGe1 PHBa resin. Derivatization and HPLC analysis (as described in section 2.4.15a) indicated a slight reduction in the diastereoselectivity of addition when compared to Grignard addition in the solution phase to Boc, Cbz and Fmoc protected Ser(aid)-OB0 ester 2.46, 3.42 and 2.37 respective1 y (Table 6.1 ).6 The optimized solvent conditions for the addition of Grignard reagents described in chapter two is a 1 : 1 mixture of Et20:CH2CI2. However. as previously described, the swelling problems associated with the use of Et20 meant it was oniy added to the reaction mixture during addition of the Grignard reagent. Of note. is the observation in chapter two that the use CH2C12 as the reaction solvent results in an erosion of diastereoselectivity. HPLC analysis also indicated a significant amount of racemization (15- 188) was occumng. Two likely sources are during Swern oxidation or after addition of the Grignard reagent. Racemization has been show to occur during the Swem oxidation,"
Table 6.1: Addition of R'M~B~ to 6.34 iad 6.35. Entry Resin R R ' Product (%)' threo:erythro (mb Me 6.46 30 80:20 18 I3c~3 Et Ph Bn vin yl Me 13cc3 Et Ph Me Et Ph Bn vin yl Me " After purification by cation exchange chromatography. Determined by derivatization and HPLC analysis. ' Not isolated. Et Ph but is typically dependent on individual systems and cannot be predicted. The prolonged exposure to base under conditions required to drive the oxidation to completion might be responsible for causing racemization. On the other hand, enolization is frequently encountered during Grignard reactions" and would cause racemization if occumng with 6.34 and 6.35. Aithough the Grignard reaction time on the solid phase is longer than in
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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
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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:
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Same procedure as in 4.4.3. [al% =
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ffom CH2Cl2) 3338,2962,2875, 1732,
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ester -0). 72.4 (OB0 ester w20), 65
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4m4.11 5-Methyl-(~,~-2-[(betl~gIo~)
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= l2JHz, CbzCHHO), 3.87-3.78 (s + r
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1016; HRMS (FAB) calcd for (M + H+)
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7.3&, CHZCH~), 0.78 (s, 3H, OB0 est
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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
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;
Page 317 and 318: 1. 2. 3. 4. 5. 6. 7. 8. 9. IO. 11.
Page 319 and 320: Eager, R.G. Jr.; Baltimore, B.G.; H
Page 321 and 322: - - Sardina, F.J.; Paz, MM.; Femihd
Page 323 and 324: Chapter Si Solid Phase Synthesis of
Page 325 and 326: eactions such as the Ugi condensati
Page 327 and 328: Dehydroamino acids have also been u
Page 329 and 330: Pyroglutarnate was reduced into the
Page 331 and 332: . - 6.2.1 Synthesis of Resin-Bod BH
Page 333 and 334: " 6.29 NMM, CH& Scheme 6.11 The arn
Page 335 and 336: esin placed hem Figure 6.3: Experim
Page 337: Figure 6.4: MAS 13c-N..~ (500 MHz)
Page 341 and 342: 63 Summ Attachrnent of Ser-OB0 este
Page 343 and 344: (S. 2H, CbzCHzO), 4.57-4.40 (m, 7H,
Page 345 and 346: I C-O), 7 1.9 (OB0 ester GHzO), 61.
Page 347 and 348: insed, altemating with dry DMF (5 x
Page 349 and 350: - MAS 'H NMR (Spin-Echd ms): 8 3.87
Page 351 and 352: 6.4.16 (zs)-2-Pmmo-3-hydroruy-3-met
Page 353 and 354: O.; Gilliarn, CL.; Boisclair, M.D.;
Page 355 and 356: 38. Rakita, P.E.; Silverman, G.S. W
Page 357 and 358: of these important derivatives due
Page 359 and 360: the glutamate dimer. It may also be
Page 361 and 362: Rose, N.G.W.; Blaskovich, M.A.; Won
Page 363 and 364: Appendices
Page 365 and 366: 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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Solution and Solid Phase Synthesis of Unusual a-Amino Acids From

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