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

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2-4-11 MeMgBr addition to 2.46: l-[N~ert-Butoxgcarbonyl-(1S~)-l-smin0-2- h ydroxypropy~]-4-methy 1-2,6,7-trioxabicycio[2.2.2 ]octane, Boc-L-Ser(Me)OBO ester, 2.49. Cnide Boc-L-Ser(a1d) OB0 ester 2-46 (0.478 g, 1.66 mrnol) was dissolved in dry EtzO (5 mL) and CH2C12 (5 mi,) under N2. A solution of MeMgBr in Et20 (1.66 d, 4.98 mmol) was added quickly by syringe at -78°C and the mixture stirred vigorously. Mer 2 h the reaction was quenched by pouring into 25 mL of 3% =Cl. CH2C12 (80mL) was added and the organic Iayer was separated, washed with 3% m l (1 x 50 rnL) and bnne (1 x 50 rnL), dried (MgSO& and evaporated to dryness. The product was punfied by flash chromatography (4:1, CH2C12:EtOAc) to give 0.307 g of a light oil (6196). A diastereornetric ratio of 85: 15 threo:erythro was determined using 'H NMR integration of the threo P-CH3 at 6 1.12- 1 .O7 ppm and the erythro B-C& at 6 1.2 1 - 1.14 ppm in the crude product. The two diastereomers were separable by flash chromatography, the threo diastereomer with a RI of 0.39 and eryrhro diastereomer a Rf of 0.34. [a120578= - 15.4 (C = 1.01, CH2CIZ); TU3 (4: 1, CH2C12:EtOA~) Rf = 0.39: 'H NMR (CDCl3, 250 MHz, rhreo isomer) 6 5.06 (br d, 1 H, J = 1 O.4EIz, NH), 4.3 1 (br q, 1 H, I = 6.4Hz7 P-CH), 3.89 (s, 6H, OB0 ester CH20), 3.63 (br d, 1H, J = 10.4Hz, a-CH), 2.88, (br s, 1 H, OH), 1.42 (s, 9H, (CH3)3C), 1 .O6, (d, 3H, J = 6.4H2, B-CH3), 0.77 (s, 3H, OB0 ester CCH3); 13c NMR (CDCk, 63 Mm) 6 155.8 (CONH), 108.4 (OB0 ester -O), 79.1 ((CH3)3Q, 72.5 (OB0 ester w20), 65.6 (p-CH), 59.0 (a-CH), 30.9 (OB0 ester 84
CCH3), 28.3 (a3)C), 20.1 (fLm3) 13.9 (OB0 ester IR (cast from CH2CL2) I - 3386, 2975, 1694, 1515, 1367, 1164, 1055; HRMS (FAB) cdculated for (M + ! C 14H&06 304.176 1, found 304.1769; Anal. cdcd for Cifi25N06: C, 53.78; H, 8.33; N, l 4.83. Found: C, 54.08; H, 8.66; N, 5.16. 2.4.12 EtMgBr addition to 2.46: l-~~ert-Butoxy~~~bonyl-(1S~)-1-amin0-2- hydroxybutyl]-4-methyl-2,6,7-trio~8bicyc10 [2.2.2]octane, Boc-L-Ser(Et)OBO ester, 2.50. Cnide Boc-L-Ser(a1d) OB0 ester 2.46 (0.101 g, 0.35 mmol) was dissolved in dry Et20:CH2C12 (5 mt. L : 1) under N2. A solution of EtMgBr in Et20 (0.35 mL, 1 .O5 mmol) was added quickly by syringe at -78°C and the mixture stimd vigorously. After 2 h the reaction was quenched by pouring into 5 rnL of 3% -1. CH2C12 (40 mL) was added and the organic layer separated, washed with 3% WC1 (1 x 10 mL) and brine (1 x 10 mL), dned (MgS04) then evaporated to dryness. The product was purified by flash chromatography (4:1, CH2C12:EtOAc) to give 0.072 g of a light oil (65%) with a diastereometric ratio of 84: 16 threo:erythro. [alto~8= -26.3 (c = 0.96, CHzC12); TU3 (4:1, CH2C12:EtOAc) Rf = 0.45; 'H NMR (CDC13, 250 MHz) major isomer = threo (84%), rninor = erythro (168) 6 5.30 (br d, 0.84H, J= 10.4Hz, threoNH), 5.13 (brd,O.ldH, J = 10.4Hz, erythroNH),4.21 (brt, lH, J = 6.4H.2, P-CH), 3.87 (S. 6H, OB0 ester C m), 3.69 (br d, lH, J = 10.4Hz, a-CH), 85
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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
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.
Page 63 and 64: 2.1 Introduction Chapter Two Synthe
Page 65 and 66: 2.1.1 Synthesis of SHydroxy-a-Amino
Page 67 and 68: typically generated in both poor yi
Page 69 and 70: 2.1.3.3 Electrophilic%Nucfeophilic
Page 71 and 72: Scheme 2.8 2-(Arylthi0)-2-nitrooxir
Page 73 and 74: Scheme 2.10 Schollkopf et al. have
Page 75 and 76: 2.1.3.5 Synthesis fiom #-Amino Acid
Page 77 and 78: HO Scheme 2.17 This laboratory prev
Page 79 and 80: Scheme 2.19 NaBr, acetone The best
Page 81 and 82: equires carefiil attention to preve
Page 83 and 84: order to investigate this as a poss
Page 85 and 86: etained its optical activity indica
Page 87 and 88: 2.2.3.2 Ortho Ester Cleavage Concom
Page 89 and 90: 2.2.4 Determination of Enantiomeric
Page 91 and 92: 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: 302.1604, found 302.1593; Anai. cal
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 and 144: 67.1 (Ar_cH20), 63.2 @--a), 56.3 (a
Page 145 and 146: yielded a slightiy yellowish solid
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,
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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
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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,
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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
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
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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
Page 373 and 374:
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
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Calcdation to Determine Resin Loadi
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