ࡱ> PRO}9 Nbjbj .+-lpppp,,,@ \ T@h| ( gggCEEEEEE$f !vi,gcgggiSpp "SSSgp , CSgCSS6, p @XcT@ g@480h!!S@@ppppSUPPORTING INFORMATION Asymmetric Synthesis of b-Substituted a-Methyl-b-amino Esters by Mannich Reaction of (S,S)-(+)-Pseudoephedrine Acetamide Derived Enolate with Imines Jose L. Vicario, Dolores Bada,* and Luisa Carrillo 1.- Full characterization data for b-aminoamides 2a-e and b-aminoesters 4a-e. [2R,3S,1 S,2 S]-(+)-3-(4-methoxyphenylamino)-N,2-dimethyl-3-phenyl-N-(2 -phenyl-2 -hydroxy-1 -methylethyl)propanamide (2a). Yield: 86%. Mp. : 112-115C (Et2O). [a]D20 : +66.8 (c=0.1, CH2Cl2). 1H-NMR (d, ppm) (2:1; rotamer ratio *indicates minor rotamer resonances): 0.69 (d, 3H, J=6.8 Hz); 0.90* (d, 3H, J=6.6 Hz); 0.97* (d, 3H, J=6.8 Hz); 1.27 (d, 3H, J=6.6 Hz); 2.35 (s, 3H); 2.81* (s, 3H); 3.19 (m, 1H); 3.22* (m, 1H); 3.59* (s, 3H); 3.62 (s, 3H); 3.97* (m, 1H); 4.13 (m, 1H); 4.32 (m, 1H); 4.56 (m, 1H); 6.41-6.69 (m, 4H); 7.16-7.44 (m, 5H). 13C-NMR (d, ppm) (2:1; rotamer ratio *indicates minor rotamer resonances): 13.8; 15.5*; 16.4; 16.5*; 27.0; 30.8*; 41.8*; 42.1; 55.5; 58.2; 61.4; 62.3*; 74.9*; 75.8; 113.8*, 114.4, 114.5, 114.8*, 126.2*, 126.3, 126.4, 126.8*, 127.0, 127.3*, 127.3*, 127.6, 128.2, 128.3*, 128.5*, 128.6; 141.3*, 141.5, 141.6, 141.7*, 142.5*, 142.6; 151.0*, 151.2; 175.8*, 176.3. IR (KBr): 3354 (OH+NH); 1615 (C=O). MS (EI) m/z (Rel. Int.): 432 (M+, 1), 211 (87), 196 (100), Anal. Calcdo for C27H32N2O3: C, 74.97; H, 7.46; N, 6.48. Found: C, 75.06; H, 7.39; N, 6.40. [2R,3S,1S,2S]-(+)-3-(3,4-dimethoxyphenyl)-3-(4-methoxyphenylamino)-N,2-dimethyl-N-(2-phenyl-2-hydroxy-1-methylethyl)propanamide (2b) Yield: 77%. Mp. : 112-115C (Et2O). [a]D20 : +77.6 (c=0.1, CH2Cl2). 1H-NMR (d, ppm) (2:1 rotamer ratio; *indicates minor rotamer resonances): 0.71 (d, 3H, J=6.8 Hz); 0.88* (d, 3H, J=6.6 Hz); 1.02* (d, 3H, J=6.8 Hz); 1.26 (d, 3H, J=6.6 Hz); 2.33 (s, 3H); 2.77* (s, 3H); 3.21 (m, 1H); 3.29* (m, 1H); 3.58* (s, 3H); 3.61 (s, 3H); 3.83* (s, 6H); 3.91 (s, 6H); 4.02* (m, 1H); 4.16 (m, 1H); 4.29 (m, 1H); 4.49 (m, 1H); 6.46-6.77 (m, 7H); 7.15-7.42 (m, 5H). 13C-NMR (d, ppm) (2:1 rotamer ratio; *indicates minor rotamer resonances): 13.7; 15.6*; 16.3; 16.7*; 26.9; 30.6*; 41.5*; 42.3; 55.5; 55.7; 58.8; 61.3; 62.4*; 80.1*; 75.6; 110.4, 111.0*, 111.5*, 111.9, 113.8*, 114.4, 114.7, 114.8*, 120.2, 120.6*, 126.2*, 126.3, 127.0, 127.3*, 128.2, 128.3*; 135.3, 135.8*, 141.2*, 141.6, 141.8*, 142.2; 147.9, 148.8*, 151.0*, 151.2, 154.2*, 154.4; 175.8*, 176.2. IR (KBr): 3350 (OH+NH); 1612 (C=O). MS (EI) m/z (Rel. Int.): 492 (M+, 1), 178 (100). Anal: Calcd for C29H36N2O5: C, 70.71; H, 7.37; N, 5.69. Found: C, 70.76; H, 7.35; N, 5.65. [2R,3S,1S,2S]-(+)-3-(2-furyl)-3-(4-methoxyphenylamino)-N,2-dimethyl-N-(2 -phenyl-2 -hydroxy-1 -methylethyl)propanamide (2c). Yield: 80%. Mp. : 80-82C (Et2O). [a]D20 : +74.6 (c=0.1, CH2Cl2). 1H-NMR (d, ppm) (3:1 rotamer ratio; *indicates minor rotamer resonances): 0.78* (d, 3H, J=6.8 Hz,); 0.85 (d, 3H, J=6.6 Hz); 1.05 (d, 3H, J=6.8 Hz); 1.24* (d, 3H, J=6.6 Hz); 2.92 (s, 3H); 2.94* (s, 3H); 3.11 (m, 1H); 3.19* (m, 1H); 3.71* (s, 3H); 3.76 (s, 3H); 3.84* (m, 1H); 4.21 (m, 1H); 4.56 (m, 1H); 4.65 (m, 1H); 6.44-7.01 (m, 5H); 7.15-7.46 (m, 5H). 13C-NMR (d, ppm) (3:1 rotamer ratio; *indicates minor rotamer resonances): 10.2; 13.2*; 14.6; 15.4*; 26.5; 30.1*; 42.3*; 42.9; 55.5; 57.0*; 58.9; 73.2*; 74.6; 81.4; 82.3*; 111.6*, 111.9, 114.5, 114.9*, 115.0*, 116.6 , 123.2, 124.6*, 126.6, 126.8*, 127.3, 128.0*, 128.5*, 129.0; 141.3*, 141.9, 143.5*, 143.9; 145.6*, 148.0; 152.3*, 153.1; 157.3*, 157.8; 178.4*, 179.0. IR (KBr): 3348 (OH+NH); 1619 (C=O). MS (EI) m/z (Rel. Int.): 422 (M+, 1), 242 (100), Anal: Calcd for C25H30N2O4: C, 71.07; H, 7.16; N, 6.63. Found C, 71.00; H, 7.10; N, 6.69. [2R,3S,1S,2S]-(+)-3-(4-methoxyphenylamino)-N,2-dimethyl-N-(2-phenyl-2-hydroxy-1-methylethyl)-3-(2-thienyl)propanamide (2d). Yield: 83%. Mp. : 98-100C (Et2O). [a]D20 := +73.2 (c=0.2, CH2Cl2). 1H-NMR (d, ppm) (3:1 rotamer ratio; *indicates minor rotamer resonances): 0.87* (d, 3H, J=6.8 Hz); 0.89 (d, 3H, J=6.6 Hz); 1.07 (d, 3H, J=6.8 Hz); 1.26* (d, 3H, J=6.6 Hz); 2.94 (s, 3H); 2.96* (s, 3H); 3.21 (m, 1H); 3.26* (m, 1H); 3.69* (s, 3H); 3.73 (s, 3H); 3.87* (m, 1H); 4.03 (m, 1H); 4.54 (m, 1H); 4.68 (m, 1H); 6.58-7.05 (m, 5H); 7.18-7.43 (m, 5H). 13C-NMR (d, ppm) (3:1 rotamer ratio; *indicates minor rotamer resonances): 10.1; 12.9*; 14.2; 15.5*; 26.7; 29.6*; 41.9*; 43.0; 55.6; 57.1*; 58.2; 74.9*; 75.8; 81.5; 82.2*; 114.6, 114.8*, 115.0, 116.3*, 123.0, 123.4*, 123.7*, 124.0, 126.2, 126.5*, 127.8, 128.0*, 128.4*, 128.7, 131.0*, 131.8; 141.2*, 141.8; 144.7*, 145.0, 145.3*, 146.1; 152.2*, 153.3; 178.2*, 178.7. IR (KBr): 3350 (OH+NH); 1621 (C=O). MS (EI) m/z (Rel. Int.): 438 (M+, 1), 258 (100). Anal: Calcd for C25H30N2O3S: C, 68.46; H, 6.89; N, 6.39. Found: C, 68.52; H, 6.85; N, 6.43. [2R,3S,1S,2S]-(+)-3-(4-methoxyphenylamino)-N,2,4,4-tetramethyl-N-(2-phenyl-2-hydroxy-1-methylethyl)pentanamide (2e). Yield: 69%. Mp. : 112-114C (Et2O). [a]D20 : +89.4 (c=0.2, CH2Cl2). 1H-NMR (d, ppm) (4:1 rotamer ratio; *indicates minor rotamer resonances): 0.58* (s, 9H); 0.76 (s, 9H); 0.93-1.24 (m, 6H); 2.58 (m, 1H); 2.94* (s, 3H); 3.06 (s, 3H); 3.22 (m, 1H); 3.32* (m, 1H); 3.71* (s, 3H); 3.75 (s, 3H); 3.84 (m, 1H); 4.36 (m, 1H); 6.73 (d, 2H, J=5.3 Hz); 7.06 (d, 2H, J=9.1 Hz); 7.16-7.34 (m, 5H). 13C-NMR (d, ppm) (4:1 rotamer ratio; *indicates minor rotamer resonances): 10.4*; 12.8; 15.4*; 16.3; 26.5*; 27.0; 29.0; 31.4*; 35.3*; 36.6; 55.0; 56.0*; 57.2*; 58.9; 74.5; 75.5*; 114.4*, 115.2, 116.1, 116.4*, 125.8*, 126.6, 126.9, 127.0*, 127.8, 128.4*; 141.4, 142.0*; 144.7*, 145.6; 156.2*, 156.6; 180.0*, 182.3. IR (KBr): 3340 (NH); 1614 (C=O). MS (EI) m/z (Rel. Int.): 412 (M+, 1), 176 (100). Anal: Calcd for C25H36N2O3: C, 72.78; H, 8.80; N, 6.79. Found: C, 72.83; H, 8.81; N, 6.85. [2R,3S]-(-)-methyl 3-(4-methoxyphenylamino)-2-methyl-3-phenylpropanoate (4a). Yield: 83%. [a]D20 : -51.2 (c=0.2, CH2Cl2). 1H-NMR (d, ppm): 1.13 (d, 3H, J=7.0 Hz); 2.85 (m, 1H); 3.65 (s, 3H, OCH3); 3.67 (s, 3H); 4.43 (d, 1H, J=7.8 Hz); 6.49 (dd, 2H, J=1.9, 8.0Hz); 6.68 (dd, 2H, J=1.9, 8.0 Hz); 7.18-7.31 (m, 5H). 13C-NMR (d, ppm): 15.2; 46.8; 51.8; 55.6; 61.6; 114.6, 114.8, 126.8, 127.4, 128.5; 127.4, 128.5; 152.0; 175.5. IR (CHCl3): 3377 (NH); 1731 (C=O). MS (EI) m/z (Rel. Int.): 299 (M+, 16), 212 (100). Anal: Calcd for C18H21NO3: C, 72.22; H, 7.07; N, 4.68. Found: C, 72.19; H, 7.11; N, 4.65. [2R,3S]-(-)-methyl 3-(3,4-dimethoxyphenyl)-3-(4-methoxyphenylamino)-2-methyl-propanoate (4b). Yield: 78%. Mp. : 120-122C (Et2O). [a]D20 : -54.6 (c=0.1, CH2Cl2). 1H-NMR (d, ppm): 1.15 (d, 3H, J=7.0 Hz); 2.83 (m, 1H); 3.61 (s, 3H); 3.68 (s, 3H); 3.72 (s, 6H); 4.39 (d, 1H, J=7.7 Hz); 6.52 (dd, 2H, J=1.9, 8.0 Hz); 6.77-7.27 (m, 5H). 13C-NMR (d, ppm): 15.4; 46.5; 51.7; 55.5; 55.7; 61.3; 111.2, 112.6, 114.6, 115.2, 121.3; 127.2, 128.7; 149.9, 151.8; 175.4. IR (KBr): 3372 (NH); 1728 (C=O). MS (EI) m/z (Rel. Int.): 359 (M+, 10), 212 (100). Anal: Calcd for C20H25NO5: C, 66.83; H, 7.01; N, 3.90. Found: C, 66.85; H, 7.06; N, 3.86. [2R,3S]-(-)-methyl 3-(2-furyl)-3-(4-methoxyphenylamino)-2-methylpropanoate (4c). Yield: 68%. [a]D20 : -48.3 (c=0.1, CH2Cl2). 1H-NMR (d, ppm): 1.18 (d, 3H, J=7.3 Hz); 2.87 (m, 1H); 3.59 (s, 3H); 3.64 (s, 3H); 4.58 (d, 1H, J=7.5 Hz); 6.49 (d, 2H, J=1.2 Hz); 6.83 (m, 1H); 6.81 (dd, 2H, J=1.7, 7.1 Hz); 7.26 (dd, 2H, J=1.7, 7.1 Hz); 7.39 (d, 1H, J=1.5 Hz). 13C-NMR (d, ppm): 15.3; 46.4; 51.6; 55.5; 61.0; 111.1, 114.4, 115.9, 121.8; 136.2; 144.2; 146.1; 156.6; 176.1. IR (CHCl3): 3365 (NH); 1732 (C=O). MS (EI) m/z (Rel. Int.): 289 (M+, 10), 151 (100). Anal: Calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84. Found: C, 66.49; H, 6.58; N, 4.90. [2R,3S]-(-)-methyl 3-(4-methoxyphenylamino)-2-methyl-3-(2-thienyl)propanoate (4d). Yield: 72%. [a]D20 : -45.5 (c=0.1, CH2Cl2). 1H-NMR (d, ppm): 1.15 (d, 3H, J=7.1 Hz); 2.85 (m, 1H); 3.51 (s, 3H); 3.65 (s, 3H); 4.49 (d, 1H, J=7.6 Hz); 6.88 (dd, 2H, J=1.8, 7.0Hz); 7.02 (dd, 1H, J=1.2, 4.8 Hz); 7.25 (dd, 2H, J=1.8, 7.0Hz); 7.49 (m, 2H). 13C-NMR (d, ppm): 15.5; 46.2; 51.5; 55.8; 61.3; 113.9, 121.9, 126.8, 129.3, 130.0; 141.8, 144.6; 157.5; 176.8. IR (CHCl3): 3363 (NH); 1740 (C=O). MS (EI) m/z (Rel. Int.): 305 (M+, 10), 151 (100). Anal: Calcd for C16H19NO3S: C, 62.93; H, 6.27; N, 4.59. Found: C, 63.02; H, 6.25; N, 4.63. [2R,3S]-(-)-methyl 3-(4-methoxyphenylamino)-2,3,3-trimethylpentanoate (4e). Yield: 86%. [a]D20 : -39.3 (c=0.1, CH2Cl2). 1H-NMR (d, ppm): 0.91 (s, 9H); 1.11 (d, 3H, J=7.1 Hz); 2.83 (m, 1H); 3.64 (s, 3H); 3.68 (s, 3H); 4.35 (d, 1H, J=7.5 Hz); 6.52 (dd, 2H, J=1.8, 7.9 Hz); 6.65 (dd, 2H, J=1.8, 7.9 Hz). 13C-NMR (d, ppm): 15.6; 25.9; 34.8; 46.5; 51.5; 55.5; 61.3; 114.4, 119; 141.1; 156.8; 174.3. IR (CHCl3): 3375 (NH); 1728 (C=O). MS (EI) m/z (Rel. Int.): 279 (M+, 16), 264 (100). Anal: Calcd for C16H25NO3: C, 68.79; H, 9.02; N, 5.01. Found: C, 68.82; H, 8.98; N, 5.11. Synthesis of all four isomers of b-aminoamides 2a-e. Amide 1 (1mmol) was slowly added to a suspension of LDA (2mmol) and LiCl (5mmol) in THF at 78C. After stirring for 1h at this temperature the mixture was allowed to reach to room temperature and stirred for another 15min. Then, a solution of the corresponding imine (4mmol) was slowly added at room temperature. The mixture was stirred until TLC analysis of aliquots indicated full conversion (typically 2h) and it was quenched with water, extracted with CH2Cl2 and the combined organic fractions were collected, dried over Na2SO4, filtered and the solvent removed in vacuo affording a mixture of anti/syn amides 2 in different ratios. Both diastereoisomers were separated by flash column chromatography purification (hexanes:AcOEt 2:8).  EMBED ChemDraw.Document.4.5  (i) 1. LDA, LiCl, THF, -78C. 2. RCH=NPMP, THF, rt. Once both diastereoisomers were separated we proceeded to epimerize the a-carbon to the amido group with both diastereoisomers by an enolization/water quenching procedure. The racemization procedure was performed as follows. A solution of the starting amide (2 or syn-2, 1.00mmol) was added over a cooled (-78C) solution of LDA (3.50mmol). The mixture was allowed to reach rt, stirred at this temperature for 1h and refluxed for additional 30min. After this, the reaction was quenched with a 4M HCl solution, extracted with CH2Cl2 and the combined organic fractions were collected, dried over Na2SO4, filtered and the solvent was removed in vacuo, affording a mixture of 2/syn-3 (from 2) or syn-2/3 (from syn-2) amides in 1:1 ratio. Both diastereoisomers were separated by flash column chromatography purification (hexanes:AcOEt 2:8).  EMBED ChemDraw.Document.4.5  (i) LDA, THF, -78 C(reflux. A 1:1:1:1 sample of all diastereoisomers was analyzed by chiral HPLC in order to find the conditions for the separation of all these products. Table 1: Retention times observed for all isomers of b-aminoamides 2a-e. R.tR (syn-2) (min)tR (syn-3) (min)tR (2) (min)tR (3) (min)Ph7.99.011.212.53,4-(MeO)2C6H38.19.811.213.32-furyl6.08.210.112.62-thienyl8.210.112.313.7t-Bu8.310.112.214.2(Chiralcel OD column, UV detector, n-Hexane/iso-propanol 70:30, 1.00mL/min). Synthesis of racemic b-aminoesters (()-4a-e. 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