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

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CHD), 3.7 1-3.67 (m, lH, B-CHH), 2.60 (br s, IH, OH), 0.8 1 (S. 3H, OB0 ester CC&); 13c NMR (-13, 62.9 MHz) 6 156.3 GONH), 136.4 (Ar=-), 128.4, 128.0, 127.9 ( , 108.0 (OB0 ester O ), 72.7 (OB0 ester ÇHzO), 66.9 (-H20), 6 1.9 (8- - CH2), 55.3 (a-CH), 30.5 (OB0 ester CCH3), 14.2 (OB0 ester CCH3); IR (cast from CH2Cl2) 3407,3063,3033,2948,2883,1716,1607, 1586,1527,1399,1352, 1237, 1048, 1010 cm-'; HRMS (FAB) caiculated for (M + H?) C16HuN06: 324.1447. Found: 324.1435; bai. Calcd for C16H21N06: C, 59.43; H, 6.55; N, 4.33. Found: C, 59.43; H, 6.64; N, 4.34. 3.43 l-[N-(Benzy10xy~ny~)-(lS)Il-aminol21o~oetbyl]4-methyl-2,6,7-tri0~8- bicyclo[2.2.2]0ctane, Cbz-L-Ser(dd)lOBO ester, 337. Cbz-Ser OB0 ester 3.41 (9.04 g, 27.86 mol) was dissolved in freshly distilled CH2CI2 (80 mL) under Ar and cooled to -7g0C in flask 1. Oxaiyl chloride (3.89 mL, 44.58 mrnol, 1.60 equiv) was added to CHzCb (120 mL) in a separate round bottom flask (flask 2) under Ar, and cooled to -7g°C. Dry DMSO (7.03 mL, 91.94 mrnol, 3.30 equiv) was added quickly (to prevent freezing in the syringe) to the oxalyl chloride solution (flask 2 - taking care to release the evolved gas) and the mixture was stirred at -7g0C for 15 minutes. The alcohol solution was transferred slowly by cannula to flask 2 over a period of 30 minutes and then rinsed with CH2C12 (50 mL). The resulting cloudy, white mixture was stirred for 1.5 hours at -7S°C. DPEA (24.27 mL, 0.14 mol) was added and the solution stirred for 30 minutes at -78OC and 10 minutes at 0°C. Ice-cold CHXl2 (250 rnL) was added and the solution was washed with ice-cold 3% NaCl (3 x 250 d), brine (250 mL) and dried over MgS04 before being evaporated to dryness. The reaction
yielded a slightiy yellowish solid in 96% (8.68 g) yield. Recrystallization was possible from EtOAdhexane but the aldehyde was generally used without further purification. mp 139.5- 141.5 OC; [alZ0~ = -99.3 (c = 1-03, EtOAc); TU3 (3: 1 EtOAc:Hex), Rr = 0.60; 'H NMR (CDCI392SO MHz) 6 9-69 (s, 1 HT CHO), 7.38-7.30 (III, SH, AM), 5.34 (d, IH, J = 9.2Hz, NH), 5.15-5.10 (m, 2H, ArCH20), 4.61 (d, lHT J= 8.9Hz, a-CH), 3.94 (s, 6H, OB0 ester CH@), 0.83 (S. 3H, OB0 ester CCH3); 13c NMR (CDCls, 63 MHz); 6 195.6, 156.1 (CONH), 136.1 (A-=), 128.4, 128.1, 127.9 (m, 107.1 (OB0 ester - O), 72.8 (OB0 ater a20), 67.1 (Ch-m), 63.2 (aCH), 30.8 (OB0 ester CCH3), 14.2 (OB0 ester Cm3); IR (cast fiom Cl&C12) 3353, 3063, 3033, 2947, 2884, 1723, 1599, 1521, 1355, 1234, 1192, 1071, 1046 cm-'; HRMS (FAB) calculated for (M + H+) C1t&N06: 322.12906; observed : 322.12854. And. Calcd for C1&flo6: C, 59.8 1 ; H, 5.96; N, 4.36. Found: C, 59.72; H, 6.12; N, 4.33. 3*4*4 Takai olefination of Cbz-LSer(dd)-080 ester 3.37: 1-[N-(Benyl- oxy~8rbnyl)-(lS)-l-amui012-propeoe]4-~ Cbz-L-Giy(-CH=CH2)-OB0 ester, 338. Cnide Cbz-Ser(a1d)-OB0 ester 3.37 (0.50 g, 1.56 mm01 assuming 100% yield of the aldehyde from the oxidation) was dissolved in dry THF (10 rnL) then added via cannula to a stimng mixture of purified zinc dusr" (0.918 g, 14.04 mrnol), freshly distilled
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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
Page 93 and 94: 2.4.1 General Methods. Most reagent
Page 95 and 96: The crude product was fiitered thro
Page 97 and 98: 250 MHz) 6 5.47 (br ci, lH, J = S.O
Page 99 and 100: evaporated to dryness. The residue
Page 101 and 102: minutes. The akohol solution was tr
Page 103 and 104: 302.1604, found 302.1593; Anai. cal
Page 105 and 106: CCH3), 28.3 (a3)C), 20.1 (fLm3) 13.
Page 107 and 108: TLC (4: 1, CH2C12:EtOAc) Rf = 0.44;
Page 109 and 110: 100-200 mesh, hydrogen form, 1x10 c
Page 111 and 112: (br d. IH. J= 10.6Hz, CHH-CH), 4.63
Page 113 and 114: mp 80-8 1 OC; [a~~*~a= -67.0 (0 1.5
Page 115 and 116: esin column (Bio-Rad AGa 10x4 10-20
Page 117 and 118: Jung, M.E.; Jung, Y.H. Tetruhedron
Page 119 and 120: (a) Adams, Z.M.; Jackson, R.F.W.; P
Page 121 and 122: (a) Roemmele, R.C.; Rapport, H. J.
Page 123 and 124: - - 68. Gawley, R.E.; Aubé, J. Pri
Page 125 and 126: pyridoxal phosphate dependent enzym
Page 127 and 128: Vinylglycines are also useful as sy
Page 129 and 130: In 1984, a modified Strecker synthe
Page 131 and 132: The main byproduct of elimination w
Page 133 and 134: , HO- OH Scheme 3.14 , 1) pb(OAc),
Page 135 and 136: L-vinylglycine has also been synthe
Page 137 and 138: Ser(a1d)-OB0 gave the desired olefi
Page 139 and 140: A tram relationship for H2IH3 in th
Page 141 and 142: 33 Summary The Cbz OB0 ester protec
Page 143: 67.1 (Ar_cH20), 63.2 @--a), 56.3 (a
Page 147 and 148: JAS Grigiarà ddition of trimethyls
Page 149 and 150: 6 158.9 (CONH), 107.4 (OB0 ester C-
Page 151 and 152: Rutjes, F.P.J.T.; Wolf, L.B.; Schoe
Page 153 and 154: (a) Tashiro, T.; Fushiya, S.; Nome,
Page 155 and 156: Sawada, S.; Nakayama, T.; Esaki, N.
Page 157 and 158: of Rheum rhaponticum over forty yea
Page 159 and 160: Glutamic acid derivatives are aiso
Page 161 and 162: syntheses exist for the functionaii
Page 163 and 164: 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
Page 171 and 172: protected glutamate did not adopt a
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)
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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
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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;
Page 317 and 318:
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,
Page 345 and 346:
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
Page 363 and 364:
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
Page 371 and 372:
Calculation of Free Energy Dinerenc
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Table 1. Crymtal data and mtructure
Page 375 and 376:
. 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
Page 384 and 385:
Calcdation to Determine Resin Loadi
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