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

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Hogan, J.C. Nature Biotech. 1997,15,328. Molecdar Diversity and Combinatorial Chemishy, Chaiken, LM.; Janda, K.D. Eds. American Chernical Society, Washington, 1996, Chps. 22,23. Cornbinatorial Chemistry, Wilson, S.R.; Czarnik, A.W., Eds. John Wiley and Sons, Inc. Toronto, 1997. Dolle, R.E. J. Comb. Chem. 2000,2,383. Baldino, C.M. J. Comb. Chem. 2000,2,89. (a) Blaskovich, M.A.; Lajoie, G.A. J. Am. Chem. Soc. 1993, 115, 502 1. (b) Blaskovich, M.A.; Evindar, G.; Rose, N.G.W.; Luo, Y.; Lajoie, G.A. J. Org. Chem. 1998,63,4560. (c) Chapter two in this thesis. Memfield, R.B.J. J. Am. Chem-Soc. 1%3,85,2149. Barrett, G.C. Chemistry and Biochemistry of the Amino Acids, Chapman and Hall, New York, 1985, pp. 55-138. Poupart, M.-A.; Cameron, D.R.; Chabot, C.; Ghiro, E.; Goudreau, N.; Goulet, S.; Poirier, M.; Tsantrizos, Y.S. J. Org. Chem. 2001,66,4743. (a) Boldi, A.M.; Dener, J.M.; Hopkins, T.P. J. Comb. Chem. 2001, 3, 367. (b) Beebe, X.; Wodka, D.; Sowin, T.J. J. Cornb. Chem. 2001,3,360. Ugi, L; Goebel, M.; Gruber, B.; Heilingbrunner, M.; Heib, C.; Horl, W.; Kern, O.; Starnecker, M.; Domling, A. Res. Chem. Intemed. 19%, 22, 625. (b) Mjalli, A.M.M.; Sarshar, S.; Baiga, T.J. Tetrahedron Let?. 19%, 37, 2943. (c) Bergens,
O.; Gilliarn, CL.; Boisclair, M.D.; Blanchard, J.L.; Blake, K.V.; Epstein, D.M.; Pal, K. Bioorg. Med. Chem. Leîî. 1999,9,2849. Yamada, M.; Miyajima, T.; Horikawa, H. Tetrahedron Len. 1998,39,289. O'Donnell, M.J.; Zhou, C.; Scott, W.L. J. Am. Chem. Soc. 1996,118,6070. O'Donell, M. J.; Delgado, F.; Pottorf, R.S. Tetrahedron, 1999,55,6347. Sauvagnat, B.; Kulig, K.; Larnaty, F.; Lazaro, R.; Martinez, J. J. Comb. Chem. 2000,2, 134. O'Donnell, M.J.; Delgado, F.; Drew, M.D.; Pottorf, R.S.; Zhou, C.; Scott, W.L. Tetrahedron Leît. 1999,40,583 1. Scott, W.L.; Zhou, C.; Fang, 2.; O'DOM~~I, M.J. Tetrahehn Lez?- 1997, 38, 3698. Miyabe, H.; Fujishima, Y.; Naito, T. J. Org. Chem. 1999,64, 2174. Dominguez, E.; O'Donnell, M.J.; Scott, W.L. Tetrahedron Lea. 1998,39,2167. O'Donnell, M.J.; Delgado, F.; Dominguez, E.; de Blas, J.; Scott, W.L. Tetrahehn: Asymmeîry, 2001,12,82 1. See chapter 3 and references therein. (a) Burkett, B.A.; Chai, C.L.L. Tetrahedron Let?. 2000, 41, 6661. (b) Burkett, B.A.; Chai, C.L.L. Tetruhedron Le#. 1999,40,7035. (a) Yim, A.-M.; Vidal, Y.; Viallefont, P.; Martinez, J. Tetrahedron Le#. 1999,40, 4635. (b) Barbaste, M.; Rolland-Fulcrand, V.; Roumestant, M.-L.; Viallefont, P.; Martinez, J. Tetrahedron Le#. 1998,39,6287.
Page 1 and 2:
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 .........
Page 13 and 14:
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
Page 21 and 22:
1.1 General Introduction Chapter On
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acids will be presented including a
Page 25 and 26:
.J generation of the enolate and ad
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classical techniques (Scheme 1.7) a
Page 29 and 30:
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
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
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Several methods for the removal of
Page 53 and 54:
1.5 References Barrett, G.C. Chemis
Page 55 and 56:
(a) Schmidt, U.; Meyer, R.; Leitenb
Page 57 and 58:
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
Page 93 and 94:
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
Page 121 and 122:
(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% =
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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==).
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
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
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 and 338: Figure 6.4: MAS 13c-N..~ (500 MHz)
Page 339 and 340: Table 6.1: Addition of R'M~B~ to 6.
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: 6.4.16 (zs)-2-Pmmo-3-hydroruy-3-met
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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