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Dynamic Kinetic Resolution of L-Threonine-derived α-Bromo Esters for Asymmetric Synthesis of α-Amino Esters

  • Received : 2013.08.30
  • Accepted : 2013.10.08
  • Published : 2014.01.20
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Abstract

Keywords

Experimental

General Procedure for the Asymmetric Nucleophilic Substitution via Dynamic Kinetic Resolution. To a solution of L-threonine-derived α-bromo ester (1-7) in CH2Cl2(ca. 0.1 M) at rt were added DIEA (1.0 equiv), TBAI (1.0 equiv) and an amine nucleophile (1.2 equiv). After the resulting reaction mixture was stirred at room temperature for 12-24 h, the solvent was evaporated and the crude material was purified by column chromatography to give a α-amino ester. The drs of 8a-u were determined by 1H NMR integration of hydrogens of two diastereomers and the ers of 9 and 10 were determined by CSP-HPLC.

N-Acetyl-O-(α-(p-methoxyanilino)phenylacetyl)-L-threonine Isopropyl Ester (8a). 63% yield; 1H NMR (CDCl3, 400 MHz, major epimer) δ 7.44-7.30 (m, 5H), 6.72 (d, J = 8.8 Hz, 2H), 6.54 (d, J = 8.8 Hz, 2H), 6.20 (d, J = 9.2 Hz, 1H), 5.40 (m, 1H), 4.98 (s, 1H), 4.94 (m, 1H), 4.77 (m, 1H), 3.69 (s, 3H), 2.01 (s, 1H), 1.22 (d, J = 6.0 Hz, 3H), 1.06 (m, 6H); 13C NMR (CDCl3, 100 MHz, major epimer) δ 170.9, 170.4, 169.2, 152.7, 140.2, 137.4, 128.9, 128.5, 127.3, 127.2, 114.8, 72.2, 70.0, 61.8, 55.7, 55.4, 23.1, 21.7, 21.5, 16.4.

N-Pivaloyl-O-(α-(p-methoxyanilino)phenylacetyl)-L-threonine Isopropyl Ester (8b). 64% yield; 1H NMR (CDCl3, 400 MHz, major epimer) δ 7.45-7.26 (m, 5H), 6.71 (d, J = 8.8 Hz, 2H), 6.54 (d, J = 8.8 Hz, 2H), 6.15 (d, J = 9.2 Hz, 1H), 5.41 (m, 1H), 4.99 (m, 1H), 4.94 (s, 1H), 4.72 (m, 1H), 3.69 (s, 3H), 1.25 (m, 3H), 1.19 (s, 9H), 1.12 (m, 3H), 1.02 (m, 3H); 13C NMR (CDCl3, 100 MHz, major epimer) δ 178.7, 170.8, 169.2, 152.7, 140.1, 137.6, 128.9, 128.4, 127.2, 121.9, 114.8, 72.7, 69.8, 61.8, 55.6, 55.2, 38.8, 27.4, 21.7, 21.5, 16.2.

N-Boc-O-(α-(p-methoxyanilino)phenylacetyl)-L-threonine Isopropyl Ester (8c). 58% yield; 1H NMR (CDCl3, 400 MHz, major epimer) δ 7.44-7.30 (m, 5H), 6.72 (d, J = 8.8 Hz, 2H), 6.52 (d, J = 8.8 Hz, 2H), 5.42 (m, 1H), 5.15 (d, J = 9.6 Hz, 1H), 4.93 (m, 2H), 4.50 (m, 1H), 4.38 (m, 1H), 3.69 (s, 3H), 1.50 (s, 9H), 1.24 (m, 3H), 1.08 (m, 6H); 13C NMR (CDCl3, 100 MHz, major epimer) δ 170.9, 169.3, 155.8, 152.6, 140.2, 137.3, 128.9, 128.4, 127.2, 114.8, 80.2, 72.5, 69.8, 61.7, 57.2, 55.7, 28.8, 21.7, 21.5, 16.3.

N-Benzoyl-O-(α-(p-methoxyanilino)phenylacetyl)-L-threonine Isopropyl Ester (8d). 62% yield; 1H NMR (CDCl3, 400 MHz, major epimer) δ 7.55-7.26 (m, 10H), 6.70 (d, J = 8.8 Hz, 2H), 6.53 (d, J = 8.8 Hz, 2H), 5.49 (m, 1H), 5.02-4.95 (m, 3H), 4.57 (m, 1H), 3.68 (s, 3H), 1.25 (d, J= 6.0 Hz, 3H), 1.15 (m, 6H); 13C NMR (CDCl3, 100 MHz, major epimer) δ 171.0, 169.1, 167.6, 152.7, 140.2, 137.6, 133.7, 132.0, 128.9, 128.7, 128.4, 127.3, 127.2, 114.9, 114.7, 72.7, 70.1, 61.9, 55.9, 55.7, 21.8, 21.6, 16.6.

N-(p-Methoxybenzoyl)-O-(α-(p-methoxyanilino)phenyl acetyl)-L-threonine Isopropyl Ester (8e). 86% yield; 1H NMR (CDCl3, 400 MHz, major epimer) δ 7.69 (d, J = 8.8 Hz, 2H), 7.48-7.26 (m, 5H), 6.93 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 6.53 (d, J = 8.8 Hz, 2H), 5.47 (m, 1H), 5.02-4.94 (m, 3H), 4.59 (br, 1H), 3.85 (s, 3H), 3.68 (s, 3H), 1.25 (m, 3H), 1.15 (m, 6H); 13C NMR (CDCl3, 100 MHz, major epimer) δ 178.7, 170.8, 169.2, 152.7, 140.1, 137.6, 129.9, 128.9, 128.4, 127.8, 127.2, 121.9, 114.8, 114.7, 72.7, 69.8, 61.8, 55.6, 55.2, 21.7, 21.5, 16.2.

N-(2-pyridinylcarbonyl)-O-(α-(p-methoxyanilino)phenylacetyl)-L-threonine Isopropyl Ester (8f). 62% yield; 1H NMR (CDCl3, 400 MHz, major epimer) δ 8.67 (m, 2H), 8.18 (m, 1H), 7.86 (m, 1H), 7.50-7.26 (m, 5H), 6.70 (d, J = 8.8 Hz, 2H), 6.53 (d, J = 8.8 Hz, 2H), 5.54 (m, 1H), 5.05-4.92 (m, 3H), 4.57 (m, 1H), 3.69 (s, 3H), 1.24 (d, J = 6.0 Hz, 3H), 1.10 (m, 6H); 13C NMR (CDCl3, 100 MHz, major epimer) δ 170.9, 168.8, 164.7, 152.6, 148.4, 140.2, 140.0, 139.9, 137.4, 128.8, 128.3, 127.2, 126.6, 122.5, 116.4, 114.9, 72.3, 70.0, 61.8, 55.7, 55.6, 21.7, 21.5, 16.5.

N,N-Dibenzyl-O-(α-(p-methoxyanilino)phenylacetyl)-L-threonine Isopropyl Ester (8g). 66% yield; 1H NMR (CDCl3, 400 MHz, major epimer) δ 7.38-7.21 (m, 15H), 6.71 (d, J = 8.8 Hz, 2H), 6.50 (d, J = 8.8 Hz, 2H), 5.43 (m, 1H), 5.10 (m, 1H), 4.98 (d, J = 5.6 Hz, 1H), 4.70 (d, J = 6.0 Hz, 1H), 4.03 (d, J = 13.6 Hz, 2H), 3.69 (s, 3H), 3.59 (d, J = 13.6 Hz, 2H), 3.36 (d, J = 7.6 Hz, 1H), 1.31 (d, J = 6.0 Hz, 3H), 1.22 (d, J = 6.0 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz, major epimer) δ 171.1, 169.3, 152.5, 140.3, 139.3, 137.8, 129.0, 128.8, 128.4, 128.1, 127.2, 114.9, 114.7, 70.2, 68.5, 64.7, 61.9, 55.7, 55.4, 22.3, 22.0, 17.0.

N,N-Dibenzyl-O-(α-(o-methoxyanilino)phenylacetyl)-L-threonine Isopropyl Ester (8m). 67% yield; 1H NMR (CDCl3, 400 MHz, major epimer) 7.40-7.23 (m, 15H), 6.78- 6.32 (m, 4H), 5.55 (d, J = 5.2 Hz, 1H), 5.45 (m, 1H), 5.11 (m, 1H), 5.04 (d, J = 5.2 Hz, 1H), 4.03 (d, J = 13.6 Hz, 2H), 3.82 (s, 3H), 3.61 (d, J = 13.6 Hz, 2H), 3.36 (d, J = 7.2 Hz, 1H), 1.31 (d, J = 6.4 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H), 0.95 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz, major epimer) δ 170.9, 169.3, 147.1, 139.5, 139.3, 137.7, 136.1, 129.1, 128.9, 128.8, 128.7, 128.3, 128.1, 127.6, 127.2, 127.0, 121.0, 117.2, 110.7, 109.5, 70.3, 68.4, 64.7, 61.0, 55.4, 55.3, 22.3, 22.0, 17.0.

N,N-Dibenzyl-O-(α-(diphenylmethylamino)phenyl acetyl)-L-threonine isopropyl ester (8n). 67% yield; 1H NMR (CDCl3, 400 MHz, major epimer) 7.49-7.17 (m, 25H), 5.60 (s, 1H), 5.45 (m, 1H), 5.11 (m, 1H), 4.81 (s, 1H), 3.95 (d, J = 13.6 Hz, 2H), 3.51 (d, J = 13.6 Hz, 2H), 3.26 (d, J = 6.4 Hz, 1H), 1.33 (d, J = 6.4 Hz, 3H), 1.24 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz, major epimer) δ 172.4, 169.3, 143.3, 139.3, 129.2, 128.8, 128.7, 128.6, 128.3, 127.8, 127.7, 127.6, 127.5, 127.2, 69.4, 68.4, 64.8, 64.2, 63.0, 55.4, 22.4, 22.1, 17.1.

N,N-Dibenzyl-O-(α-((R)-phenethylamino)phenyl acetyl)-L-threonine Isopropyl Ester (8o). 54% yield; 1H NMR (CDCl3, 400 MHz, major epimer) 7.31-7.15 (m, 20H), 5.38 (m, 1H), 5.08 (m, 1H), 4.19 (s, 1H), 3.93 (d, J = 13.6 Hz, 2H), 3.57 (m, 1H), 3.49 (d, J = 13.6 Hz, 2H), 3.22 (d, J = 8.0 Hz, 1H), 1.36 (d, J = 6.4 Hz, 3H), 1.30 (d, J = 6.4 Hz, 3H), 1.21 (d, J = 6.4 Hz, 3H), 0.90 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz, major epimer) δ 171.9, 169.2, 139.3, 129.0, 128.7, 128.5, 128.2, 127.9, 127.7, 127.2, 127.0, 126.8, 69.1, 68.2, 64.7, 62.6, 55.2, 54.3, 24.7, 22.2, 22.0, 17.0.

N,N-Dibenzyl-O-(α-(benzylamino)phenylacetyl)-L-threonine Isopropyl Ester (8p). 71% yield; 1H NMR (CDCl3, 400 MHz, major epimer) 7.24-7.14 (m, 20H), 5.36 (m, 1H), 5.01 (m, 1H), 4.28 (s, 1H), 3.92 (d, J = 13.6 Hz, 2H), 3.69 (m, 2H), 3.48 (d, J = 13.6 Hz, 2H), 3.22 (d, J = 7.2 Hz, 1H), 2.32 (br, 1H), 1.30 (d, J = 6.4 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz, major epimer) 172.2, 169.4, 139.7, 139.4, 138.1, 129.1, 128.7, 128.6, 128.3, 128.0, 127.6, 127.2, 127.1, 69.7, 68.4, 64.7, 64.6, 55.5, 51.3, 22.3, 22.1, 17.2.

N,N-Dibenzyl-O-(α-(3,4-dihydro-2(1H)-isoquinolinyl)phenylacetyl)-L-threonine Isopropyl Ester (8q). 66% yield; 1H NMR (CDCl3, 400 MHz, major epimer) 7.28-6.88 (m, 19H), 5.44 (m, 1H), 5.06 (m, 1H), 4.14 (s, 1H), 4.08 (d, J= 13.6 Hz, 2H), 3.75-3.62 (m, 4H), 3.34 (d, J = 6.8 Hz, 1H), 2.84-2.79 (m, 4H), 1.32 (d, J = 6.4 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H), 0.98 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz, major epimer) 170.7, 169.5, 139.4, 136.0, 134.4, 134.3, 129.0, 128.8, 128.7, 128.6, 128.3, 128.2, 127.1, 126.7, 126.2, 125.6, 73.8, 69.9, 68.3, 64.6, 55.5, 53.4, 48.5, 28.9, 22.2, 22.0, 17.0.

N,N-Dibenzyl-O-(α-(dibenzylamino)phenylacetyl)-L-threonine Isopropyl Ester (8r). 73% yield; 1H NMR (CDCl3, 400 MHz, major epimer) δ 7.28-7.16 (m, 25H), 5.58 (m, 1H), 5.11 (m, 1H), 4.59 (s, 1H), 3.95 (d, J = 13.6 Hz, 2H), 3.88 (d, J = 13.6 Hz, 2H), 3.66 (d, J = 13.6 Hz, 2H), 3.58 (d, J = 13.6 Hz, 2H), 3.30 (d, J = 6.4 Hz, 1H), 1.32 (d, J = 6.4 Hz, 3H), 1.24 (d, J = 6.4 Hz, 3H), 1.14 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz, major epimer) δ 171.5, 169.6, 139.6, 139.4, 139.3, 136.2, 129.1, 128.9, 128.3, 128.2, 127.0, 69.8, 68.3, 66.1, 64.5, 55.7, 54.0, 22.3, 22.0, 17.5.

N,N-Dibenzyl-O-(α-(benzylmethylamino)phenylacetyl)-L-threonine Isopropyl Ester (8s). 67% yield; 1H NMR (CDCl3, 400 MHz, major epimer) δ 7.42-7.20 (m, 20H), 5.45 (m, 1H), 4.98 (m, 1H), 4.23 (s, 1H), 4.10 (d, J = 13.6 Hz, 2H), 3.67 (d, J = 13.6 Hz, 2H), 3.60 (d, J = 13.6 Hz, 1H), 3.51 (d, J = 13.6 Hz, 1H), 3.34 (d, J = 6.4 Hz, 1H), 2.20 (s, 3H), 1.28 (d, J = 6.0 Hz, 3H), 1.13 (d, J = 6.4 Hz, 3H), 1.06 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz, major epimer) 171.0, 169.5, 139.5, 139.0, 136.5, 129.0, 128.9, 128.8, 128.5, 128.3, 128.1, 127.1, 127.0, 73.1, 70.1, 68.2, 64.5, 58.7, 55.5, 39.4, 22.2, 21.9, 17.1.

N,N-Dibenzyl-O-(α-(dibutylamino)phenylacetyl)-L-threonine Isopropyl Ester (8t). 64% yield; 1H NMR (CDCl3, 400 MHz, major epimer) 7.34-7.18 (m, 15H), 5.49 (m, 1H), 5.04 (m, 1H), 4.52 (s, 1H), 4.07 (d, J = 13.6 Hz, 2H), 3.68 (d, J = 13.6 Hz, 2H), 3.35 (d, J = 6.4 Hz, 1H), 2.25 (m, 4H), 1.40- 1.10 (m, 17H), 0.80 (m, 6H); 13C NMR (CDCl3, 100 MHz, major epimer) δ 171.7, 169.6, 139.5, 137.4, 129.0, 128.3, 128.2, 127.7, 127.1, 70.0, 69.5, 68.2, 64.6, 55.6, 50.5, 29.8, 22.2, 22.0, 20.4, 17.3, 14.1.

N,N-Dibenzyl-O-(α-(o-aminoanilino)phenylacetyl)-L-threonine Isopropyl Ester (8u). 93% yield; 1H NMR (CDCl3, 400 MHz, major epimer) 7.34-7.21 (m, 15H), 6.71-6.44 (m, 4H), 5.44 (m, 1H), 5.09 (m, 1H), 5.02 (d, J = 13.6 Hz, 1H), 4.63 (br, 1H), 4.03 (d, J = 13.6 Hz, 2H), 3.61 (d, J = 13.6 Hz, 2H), 3.40 (br, 2H), 3.36 (d, J = 6.8 Hz, 1H), 1.32 (d, J = 6.4 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 0.95 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz, major epimer) δ 171.2, 169.3, 139.3, 129.2, 129.0, 128.7, 128.6, 128.3, 127.2, 127.1, 120.5, 119.6, 116.9, 113.5, 70.4, 68.4, 64.6, 61.5, 55.4, 22.2, 22.0, 17.0.

N-(p-Methoxphenyl)phenylglycine Methyl Ester (9). 71% yield from 8d; 1H NMR (CDCl3, 400 MHz) δ 7.48-7.25 (m, 5H), 6.69 (d, J = 8.9 Hz, 2H), 6.52 (d, J = 8.9 Hz, 2H), 5.00 (s, 1H), 4.67 (br, 1H), 3.72 (s, 3H), 3.67 (s, 3H).1c Chiral HPLC: 87:13 er, tR (S)-major enantiomer, 76.2 min; tR (R)-minor enantiomer, 66.3 min (Chiralcel OJ-H column; 20% 2-propanol in hexane; 0.5 mL/min).

3-Phenyl-3,4-dihydro-1,4-quinoxalin-2-one (10). 83% yield; 1H NMR (CDCl3, 400 MHz) δ 7.95 (br, 1H), 7.43- 6.70 (m, 9H), 5.08 (s, 1H), 4.28 (br, 1H).1e Chiral HPLC: 92:8 er, tR (S)-major enantiomer, 45.0 min; tR (R)-minor enantiomer, 40.1 min (Chiralcel OJ-H column; 20% 2-propanol in hexane; 0.5 mL/min).

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