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

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(57% yield) of the âesired produa which was recrystallized h m Et0Ac:hexanes to give 0.20 g (44% yield) of small dense white crystals. mp. 121-122.S°C; [ U]~D = -38.3 (c = 1 .O7, CH2Cu; TU3 (2: 1, Et0Ac:Hex). Rf = 0.2 1 ; 1 H NMR (Acetone-&, 300 MHz) 6 7.40-7.26 (m, 5H, A&), 6.09 (d, 1 Hl J = 9.6Hz. NH), 5.06 (S. 2H, CbzCH20), 4.47 (m, 1 H, WH), 4.20 (m, 1 H, PCH), 4.12 (dd, 1 H, J = 7 -3, 10.3Hz, a-CH) 3.97-3.93 (s + m, 7H. OB0 ester CHD, $-OH), 3.86 (d, lH, J = 7.9Hz. y- ON), 3.70 (s, 3H, C&CH3), 0.84 (S. 3H, OB0 ester CCH3); I3c NMR (Acetone-&. 75 MHz) 6 173.3 C C), 156.3 (CONH), 137.5 (Cbz
Cbz-L-Glu(Z-B,y-dehydro)(OMe)OBO 499 (0.150 g, 0.40 rnmol) and N-methylrnorph- oline (0.049 g, 0.42 rnmol) were combined and dissolved in acetone:water (4: 1,s mL) to which Os04 (1 grain) was added. After the mixture had stined for 48 hours at room temperature the solvent was reduced in vacuo, dissolved in methanol (20 mL), reduced again then dissolved in a minimum of methanol to which an equal amount of Et0Ac:Hex (2: 1) was added and then flash chromatographed to give 0.074 g (45% yield) of 4.101 as a light coloured oïl. [al2'o = +4.4 (c = 0.9, CH5Cl2); TLC (2: 1, EtOAc:Hex), Rr = 0.21; 'H NMR (Acetone-Q, 300 MHz) 6 7.40-7.26 (m, 5H, ArH), 6.09 (d, IH, J = 10.3Hz. NH), 5.07 (s, 2H, CbzCH20), 4.66 (br d, lH, J = 7.3Hz, yrCH), 4.16 (dd, IH, J = 9.8, 10.3Hz, a-CH), 3.91 (s, 6H, OB0 ester CHB), 3.83 (dd, lH, J = 7.3, 9.8Hz, p-CH) 3.66 (s, 3H, C02CH3), 0.80 (s, 3H, OB0 ester CC&); I3c NMR (Acetone-4, 75 MHz) 6 172.8 C=O), 156.7 (CONH), 137.4 (Cbz*), 128.4, 127.8, 127.8 (Cbz=CJI=), 108.6 (OB0 ester -O), 72.4 (OB0 ester cH20), 71.5 (PSH), 70.8 (y=, 66.1 (CbzÇ&O), 53.8 (a-CH), 50.9 (COS&), 30.4 (OB0 ester CCH3), 13.2 (OB0 ester CcH3); IR (cast from CHzClz) 3447,2953,2883, 1734, 1717, 1521, 1228, 1048; ESI-MS (M + 412.15; Anal. cdcd for ClgHsNQ: C, 55.47; H, 6.12; N, 3.04. Found: C, 55.69; H, 6.24; N, 3.06.
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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 .........
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
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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
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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
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
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: (3:2 Et0Ac:hexanes) to give 4.99 (1
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.
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
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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
Page 380 and 381:
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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