3.2. General Procedure for the Ugi Reaction of 4-(Dimethylamino)-2-pyridinecarboxaldehyde (1)
To a suspension of L-valine (23.1 mg, 0.20 mmol) and aldehyde 1 (36.6 mg, 0.24 mmol) in dry methanol (0.4 mL) in a screw-cap test tube, tert-butyl isocyanide (17.2 mg, 0.21 mmol) was added and the reaction mixture was stirred for 15 h at room temperature. The solvent was evaporated in vacuo and the resulting residue was purified by silica gel column chromatography (EtOAc/Et3N = 97:3, v/v) to give (1R) N-(1-(N-tert-butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-2-yl)methyl)-L-valine methyl ester (2a) as a brown gummy oil (70.5 mg, 98% yield, d.r. 63:37). For mixture of two diastereomers: IR (neat) υ = 3327, 2964, 1738, 1681, 1603 cm–1; 1H-NMR (CDCl3, major diastereomer) δ 1.03 (d, J = 6.0 Hz, 6H), 1.32 (s, 9H), 2.03 (sext, J = 6.8 Hz, 1H), 2.03 (br, 1H), 2.97 (s, 6H), 3.02–3.07 (m, 1H), 3.60 (s, 3H), 3.90 (s, 1H), 6.39 (dd, J = 2.6, 6.0 Hz, 1H), 6.69 (d, J = 2.6 Hz, 1H), 7.60 (br, 1H), 8.14 (d, J = 6.0 Hz, 1H); 13C-NMR (CDCl3, major diastereomer) δ 18.4, 19.9, 28.6, 31.5, 39.1, 50.5, 51.5, 65.8, 66.8, 105.1, 105.8, 148.6, 154.6, 156.8, 171.0, 174.9; HRMS-FAB (m/z): [M+H]+ calcd. for C19H33N4O3 365.2553, found 365.2535.
(1SR) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-2-yl)methyl)-L-t-leucine methyl ester (2b): A pale yellow oil (53.6 mg, 70% yield, d.r. 62:38); For mixture of two diastereomers: IR (neat) υ = 3337, 2965, 1732, 1674, 1604 cm–1; 1H-NMR (CDCl3, major diastereomer) δ 1.04 (s, 9H), 1.32 (s, 9H), 2.57 (br, 1H), 2.95 (br, 1H), 2.97 (s, 6H), 3.58 (s, 3H), 3.81 (s, 1H), 6.38 (dd, J = 2.4, 6.0 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 7.57 (br, 1H), 8.15 (d, J = 6.0 Hz, 1H); 13C-NMR (CDCl3, major diastereomer) δ 26.9, 28.6, 34.2, 39.1, 50.5, 51.1, 67.4, 70.1, 105.1, 105.8, 148.6, 154.6, 156.7, 170.8, 174.5; HRMS-FAB (m/z): [M+H]+ calcd. for C20H35N4O3 379.2709, found 379.2739.
(1SR) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-2-yl)methyl)-L-isoleucine methyl ester (2c): A pale yellow oil (40.5 mg, 54% yield, d.r. 60:40); For mixture of two diastereomers: IR (neat) υ = 2967, 1733, 1673, 1604 cm–1; 1H-NMR (CDCl3, major diastereomer) δ 0.91 (t, J = 7.4 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 1.31 (s, 9H), 1.55–1.67 (m, 1H), 1.74–1.84 (m, 1H), 2.35 (br, 1H), 2.97 (s, 6H), 3.02–3.06 (m, 1H), 3.15 (d, J = 6.0 Hz, 1H), 3.59 (s, 3H), 3.90 (s, 1H), 6.38 (dd, J = 2.4, 6.0 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 7.60 (br, 1H), 8.14 (d, J = 6.0 Hz, 1H); 13C-NMR (CDCl3, major diastereomer) δ 11.4, 16.2, 25.2, 28.6, 38.2, 39.1, 50.5, 51.5, 65.5, 67.2, 105.1, 105.8, 148.5, 154.6, 156.8, 171.0, 174.8; HRMS-FAB (m/z): [M+H]+ calcd. for C20H35N4O3 379.2709, found 379.2703.
(1SR) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-2-yl)methyl)-L-phenylalanine methylester (2d): A pale yellow oil (45.6 mg, 57% yield, d.r. 55:45); For mixture of two diastereomers: IR (neat) υ = 2964, 1739, 1676, 1604 cm–1; 1H-NMR (CDCl3, major diastereomer) δ 1.09 (s, 9H), 2.81–2.92 (m, 1H), 2.96 (s, 6H), 3.01–3.08 (m, 2H), 3.48–3.54 (m, 1H), 3.57 (s, 3H), 3.95 (s, 1H), 6.38 (dd, J = 2.4, 5.6 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 7.12 (br, 1H), 7.14–7.31 (m, 5H), 8.14 (d, J = 5.6 Hz, 1H); 13C-NMR (CDCl3, major diastereomer) δ 28.3, 39.1, 39.8, 50.2, 51.7, 62.6, 66.5, 105.0, 105.7, 126.6, 128.5, 129.3, 137.9, 148.5, 154.6, 156.7, 170.6, 174.5; HRMS-FAB (m/z): [M+H]+ calcd. for C23H33N4O3 413.2553, found 413.2551.
(1SR) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-2-yl)methyl)-L-phenylglycine methyl ester (2e): A pale yellow oil (47.6 mg, 59% yield, d.r. 55:45); For mixture of two diastereomers: IR (neat) υ = 2916, 1739, 1673, 1604 cm–1; 1H-NMR (CDCl3, major diastereomer) δ 1.22 (s, 9H), 2.04 (s, 1H), 3.02 (s, 6H), 3.65 (s, 3H), 4.10 (br, 1H), 4.36 (s, 1H), 6.42 (dd, J = 2.8, 6.0 Hz, 1H), 6.74 (d, J = 2.8 Hz, 1H), 7.25–7.38 (m, 5H), 7.46 (br, 1H), 8.15 (d, J = 6.0 Hz, 1H); 13C-NMR (CDCl3, major diastereomer) δ 28.5, 39.2, 50.7, 52.3, 64.3, 65.5, 105.1, 105.7, 127.8, 128.2, 128.8, 129.8, 137.9, 155.1, 157.0, 170.0, 172.8; HRMS-FAB (m/z): [M+H]+ calcd. for C22H31N4O3 399.2396, found 399.2409.
(1SR) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-2-yl)methyl)-L-threonine methyl ester (2f): A pale yellow oil (61.7 mg, 77% yield, d.r. 50:50); For mixture of two diastereomers: IR (neat) υ = 3329, 2972, 1737, 1673, 1604 cm–1; 1H-NMR (CDCl3, major diastereomer) δ 1.17 (d, J = 6.4 Hz, 3H), 1.30 (s, 9H), 1.98 (br, 1H), 3.01 (s, 6H), 3.14 (d, J = 6.4 Hz, 1H), 3.65 (s, 3H), 3.95 (quin, J = 6.4 Hz, 1H), 4.19 (s, 1H), 4.54 (br, 1H), 6.41 (dd, J = 2.4, 6.0 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 7.48 (br, 1H), 8.14 (d, J = 6.0 Hz, 1H); 13C-NMR (CDCl3, major diastereomer) δ 19.7, 22.7, 28.5, 39.2, 50.9, 52.0, 66.3, 68.0, 105.1, 105.8, 147.3, 155.2, 156.2, 169.8, 173.5; HRMS-FAB (m/z): [M+H]+ calcd. for C18H31N4O4 367.2345, found 367.2319.
(1SR) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-2-yl)methyl)-L-serine methyl ester (2g): A pale yellow oil (60.3 mg, 85% yield, d.r. 53:47); For mixture of two diastereomers: IR (neat) υ = 3329, 2969, 1739, 1671, 1604 cm–1; 1H-NMR (CDCl3, major diastereomer) δ 1.30 (s, 9H), 2.99 (s, 6H), 3.43 (br, 1H), 3.47–3.50 (m, 1H), 3.66 (s, 3H), 3.75–3.78 (m, 1H), 3.82 (d, J = 4.2 Hz, 1H), 4.21 (s, 1H), 4.38 (br, 1H), 6.39 (dd, J = 2.8, 6.0 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H), 7.52 (br, 1H), 8.10 (d, J = 6.0 Hz, 1H); 13C-NMR (CDCl3, major diastereomer) δ 28.4, 39.1, 50.8, 52.1, 61.8, 62.3, 65.1, 104.9, 105.6, 147.7, 155.2, 156.8, 170.3, 172.8; HRMS-FAB (m/z): [M+H]+ calcd. for C17H29N4O4 353.2189, found 353.2200.
Procedure for the Synthesis of 2h
To the mixture of L-proline (33.9 mg, 0.29 mmol) and aldehyde 1 (39.8 mg, 0.27 mmol) in dry methanol (0.4 mL) in a screw-cap test tube, tert-butyl isocyanide (30.4 μL, 0.27 mmol) was added and the reaction mixture was stirred for 24 h at room temperature. The solvent was evaporated in vacuo. To a solution of the crude product in MeOH (4 mL) was added NaBH4 (31.6 mg, 0.84 mmol) at 0 °C owing to reduction of unreacted aldehyde 1. The reaction mixture was stirred at the same temperature for one hour before being quenched with saturated aq. NH4Cl (4 mL). The resulting solution was warmed to room temperature and extracted with Et2O (3 × 4 mL). The combined organic phase was washed with brine (15 mL), dried over MgSO4, filtered, and concentrated in vacuo to give (1SR) N-(1-(N-tert-butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-2-yl)methyl)-L-proline methyl ester (2h) as a pale yellow oil (18.0 mg, 19% yield, d.r. 51:49). For mixture of two diastereomers: IR (neat) υ = 2967, 1737, 1671, 1603 cm–1; 1H-NMR (CDCl3) δ 1.31 (s, 9H), 1.37 (s, 9H), 1.78–1.89 (m, 6H), 2.07–2.17 (m, 2H), 2.68–2.81 (m, 2H), 2.98 (s, 6H), 2.99 (s, 6H), 3.09–3.15 (m, 2H), 3.57 (s, 3H), 3.63 (s, 3H), 3.65–3.69 (m, 2H), 4.22 (s, 2H), 6.38 (dd, J = 2.8, 6.0 Hz, 1H), 6.39 (dd, J = 2.8, 6.0 Hz, 1H), 6.51 (d, J = 2.8 Hz, 1H), 6.54 (d, J = 2.8 Hz, 1H), 7.38 (br, 1H), 7.93 (br, 1H), 8.15 (d, J = 6.0 Hz, 1H), 8.17 (d, J = 6.0 Hz, 1H); 13C-NMR (CDCl3) δ 23.6, 23.7, 28.5, 28.6, 29.9, 30.4, 39.1, 39.1, 50.6, 50.7, 50.9, 51.4, 51.5, 52.7, 61.6, 62.9, 74.2, 74.8, 105.6, 105.7, 106.6, 107.1, 149.0, 149.1, 154.7, 154.8, 156.5, 157.1, 170.0, 170.2, 175.4, 175.9; HRMS-FAB (m/z): [M+H]+ calcd. for C19H31N4O3 363.2396, found 363.2391.
3.3. General Procedure for the Ugi Reaction of 4-(Dimethylamino)-3-pyridinecarboxaldehyde (3)
To the suspension of aldehyde
3 (75.1 mg, 0.50 mmol) and L-valine (64.4 mg, 0.55 mmol) in dry methanol (1.0 mL) in a screw-cap test tube,
tert-butyl isocyanide (62.0 μL, 0.55 mmol) was added and the reaction mixture was stirred for 15 hours at 50 °C. The solvent was evaporated
in vacuo and the resulting residue was purified by silica gel column chromatography on SiO
2 (EtOAc/toluene = 4:1, v/v) to give (1
R)
N-(1-(
N-
tert-butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-3-yl)methyl)-L-valine methyl ester (
4a) as a colorless solid (99.7 mg, 55% yield, d.r. 92:8,
Table 5, entry 1). For the major diastereomer: m.p. 119 °C; IR (KBr) υ = 3200, 2963, 1737, 1673 cm
–1;
1H-NMR (CDCl
3) δ 0.85 (d,
J = 6.7 Hz, 3H), 0.90 (d,
J = 6.7 Hz, 3H), 1.34 (s, 9H), 1.92 (sext,
J = 6.7 Hz, 1H), 2.40 (br, 1H), 2.79 (br, 1H), 2.85 (s, 6H), 3.70 (s, 3H), 4.58 (s, 1H), 6.88 (d,
J = 5.6 Hz, 1H), 7.26 (br, 1H), 8.36 (d,
J = 5.6 Hz, 1H), 8.48 (s, 1H);
13C-NMR (CDCl
3) δ 18.4, 19.1, 28.6, 31.3, 44.3, 50.8, 51.5, 58.8, 64.8, 113.6, 127.9, 149.8, 150.3, 159.4, 170.9, 174.6; HRMS-FAB (
m/z): [M+H]
+ calcd. for C
19H
33N
4O
3 365.2553, found 365.2554; [α]
D25–137 (c 0.715, MeOH).
(1R) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-3-yl)methyl)-L-leucine methyl ester (4b): A colorless solid (118.6 mg, 63% yield, d.r. 86:14); For the major diastereomer: m.p. 139–141 °C; IR (KBr) υ = 3372, 3210, 2952, 1734, 1666 cm–1; 1H-NMR (CDCl3) δ 0.72 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H), 1.35 (s, 9H), 1.42–1.45 (m, 2H), 1.61 (sext, J = 6.6 Hz, 1H), 2.13 (br, 1H, 2.84 (s, 6H), 3.03–3.07 (m, 1H), 3.68 (s, 3H), 4.58 (s, 1H), 6.87 (d, J = 5.5 Hz, 1H), 7.37 (br, 1H), 8.35 (d, J = 5.5 Hz, 1H), 8.42 (s, 1H); 13C-NMR (CDCl3) δ 21.7, 22.9, 24.7, 28.6, 42.3, 44.3, 50.9, 51.8, 57.8, 59.0, 113.6, 128.3, 149.9, 150.1, 159.4, 171.0, 175.3; HRMS-FAB (m/z): [M+H]+ calcd. for C20H35N4O3 379.2709, found 379.2702; [α]D25 –148 (c 0.205, MeOH).
(1R) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-3-yl)methyl)-L-t-leucine methyl ester (4c): A colorless solid (39.6 mg, 52% yield, d.r. 89:11); For the major diastereomer: m.p. 165–166 °C; IR (KBr) υ = 3353, 3214, 2965, 1737, 1677 cm–1; 1H-NMR (CDCl3) δ 0.91 (s, 9H), 1.32 (s, 9H), 2.57–2.66 (m, 2H), 2.84 (s, 6H), 3.68 (s, 3H), 4.49 (s, 1H), 6.89 (d, J = 5.5 Hz, 1H), 7.07 (br, 1H), 8.37 (d, J = 5.5 Hz, 1H), 8.50 (s, 1H); 13C-NMR (CDCl3) δ 26.7, 28.7, 34.0, 44.3, 50.8, 51.2, 58.8, 67.7, 113.7, 127.5, 149.9, 150.5, 159.6, 170.8, 174.5; HRMS-FAB (m/z): [M+H]+ calcd. for C20H35N4O3 379.2709, found 379.2733; [α]D25 –146 (c 0.270, MeOH).
(1R) N-(1-(N-tert-butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-3-yl)methyl)-L-isoleucine methyl ester (4d): A colorless solid (104.3 mg, 55% yield, d.r. 93:7); For the major diastereomer: m.p. 97–100 °C; IR (KBr) υ = 3333, 3204, 2967, 1739, 1676 cm–1; 1H-NMR (CDCl3) δ 0.79 (d, J = 7.7 Hz, 3H), 0.80 (t, J = 7.7 Hz, 3H), 1.06–1.17 (m, 1H), 1.32 (s, 9H), 1.43–1.49 (m, 1H), 1.63–1.69 (m, 1H), 2.37 (br, 1H), 2.83 (s, 6H), 2.86 (d, J = 6.0 Hz, 1H), 3.68 (s, 3H), 4.55 (s, 1H), 6.87 (d, J = 5.6 Hz, 1H), 7.25 (br, 1H), 8.34 (d, J = 5.6 Hz, 1H), 8.45 (s, 1H); 13C-NMR (CDCl3) δ 11.2, 15.5, 25.2, 28.6, 37.9, 44.3, 50.8, 51.5, 58.9, 63.8, 113.7, 128.0, 149.8, 150.3, 159.4, 170.9, 174.6; HRMS-FAB (m/z): [M+H]+ calcd. for C20H35N4O3 379.2709, found 379.2713; [α]D25 –115 (c 0.325, MeOH).
(1SR) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-3-yl)methyl)-L-phenylalanine methyl ester (4e): A colorless solid (123.3 mg, 60% yield, d.r. 88:12); For mixture of two diastereomers: m.p. 128–129 °C; IR (KBr) υ = 3319, 3202, 2962, 1739, 1673 cm–1; 1H-NMR (CDCl3, major diastereomer) δ 1.31 (s, 9H), 2.27 (br, 1H), 2.74 (s, 6H), 2.83 (dd, J = 7.9, 13.7 Hz, 1H), 2.97 (dd, J = 5.9, 13.7 Hz, 1H), 3.32–3.36 (m, 1H), 3.64 (s, 3H), 4.58 (s, 1H), 6.81 (d, J = 5.6 Hz, 1H), 7.02–7.04 (m, 2H), 7.18–7.26 (m, 3H), 7.41 (br, 1H), 8.20 (s, 1H), 8.31 (d, J = 5.6 Hz, 1H); 13C-NMR (CDCl3, major diastereomer) δ 28.6, 38.9, 44.3, 50.7, 51.8, 58.8, 60.7, 113.6, 126.8, 127.9, 128.5, 128.9, 136.6, 149.8, 150.0, 159.2, 170.8, 173.9; HRMS-FAB (m/z): [M+H]+ calcd. for C23H33N4O3 413.2553, found 413.2532.
(1SR) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-3-yl)methyl)-L-phenylglycine methyl ester (4f): A colorless solid (90.0 mg, 45% yield, d.r. 59:41); For mixture of two diastereomers: m.p. 146–149 °C; IR (KBr) υ = 3195, 2995, 1738, 1666 cm–1; 1H-NMR (CDCl3, major diastereomer) δ 1.39 (s, 9H), 1.75 (br, 1H), 2.62 (s, 6H), 3.69 (s, 3H), 4.29 (br, 1H), 4.43 (s, 1H), 6.79 (d, J = 5.6 Hz, 1H), 7.30–7.40 (m, 5H), 7.43 (br, 1H), 8.31 (d, J = 5.6 Hz, 1H), 8.40 (s, 1H); 13C-NMR (CDCl3, major diastereomer) δ 28.7, 43.9, 51.0, 52.4, 57.9, 64.0, 113.6, 127.8, 128.5, 128.7, 128.9, 137.2, 149.7, 149.8, 158.9, 170.6, 172.4; HRMS-FAB (m/z): [M+H]+ calcd. for C22H31N4O3 399.2396, found 399.2382.
(1SR) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-3-yl)methyl)-L-serine methyl ester (4g): A yellowish solid (76.2 mg, 43% yield, d.r. 77:23); For mixture of two diastereomers: m.p. 121 °C; IR (KBr) υ = 3451, 3202, 2959, 1722, 1666 cm–1; 1H-NMR (CDCl3, major diastereomer) δ 1.35 (s, 9H), 2.86 (br, 1H), 2.86 (s, 6H), 3.29 (dd, J = 4.4, 5.3 Hz, 1H), 3.70–3.72 (m, 1H), 3.74 (s, 3H), 3.79–3.85 (m, 1H), 4.71 (s, 1H), 6.92 (d, J = 5.6 Hz, 1H), 7.28 (br, 1H), 8.36 (d, J = 5.6 Hz, 1H), 8.43 (s, 1H); 13C-NMR (CDCl3, major diastereomer) δ 28.6, 44.5, 51.1, 52.2, 58.5, 61.0, 62.5, 114.0, 128.5, 149.7, 149.8, 159.3, 170.7, 172.7; HRMS-FAB (m/z): [M+H]+ calcd. for C17H29N4O4 353.2189, found 353.2175.
(1R) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-3-yl)methyl)-L-methionine methyl ester (4h): A colorless solid (115.0 mg, 58% yield, d.r. 83:17). For the major diastereomer: m.p. 98–100 °C; IR (KBr) υ = 3203, 2971, 1735, 1671 cm–1; 1H-NMR (CDCl3) δ 1.26 (s, 9H), 1.70–1.79 (m, 1H), 1.83–1.91 (m, 1H), 1.95 (s, 3H), 2.34–2.49 (m, 2H), 2.35 (br, 1H), 2.77 (s, 6H), 3.14 (br, 1H), 3.63 (s, 3H), 4.57 (s, 1H), 6.82 (d, J = 5.5 Hz, 1H), 7.18 (br, 1H), 8.28 (d, J = 5.5 Hz, 1H), 8.39 (s, 1H); 13C-NMR (CDCl3) δ 15.2, 28.5, 30.3, 32.2, 44.2, 50.7, 51.8, 58.0, 58.4, 113.6, 128.0, 149.8, 150.0, 159.1, 170.6, 174.2; HRMS-FAB (m/z): [M+H]+ calcd. for C19H33N4O3S 397.2273, found 397.2245; [α]D25 −156 (c 0.420, MeOH).
(1SR) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-3-yl)methyl) O-t-butyl L-threonine methyl ester (4i): A colorless solid (132.6 mg, 63% yield, d.r. 82:18); For mixture of two diastereomers: m.p. 136 °C; IR (KBr) υ = 3387, 3249, 2977, 1732, 1675 cm–1; 1H-NMR (CDCl3, major diastereomer) δ 1.05 (s, 9H), 1.08 (d, J = 6.2 Hz, 3H), 1.35 (s, 9H), 2.20 (br, 1H), 2.54 (br, 1H), 2.84 (s, 6H), 3.68 (s, 3H), 3.86 (td, J = 6.2, 10.7 Hz, 1H), 4.65 (s, 1H), 6.84 (d, J = 5.6 Hz, 1H), 7.55 (br, 1H), 8.31 (d, J = 5.6 Hz, 1H), 8.40 (s, 1H); 13C-NMR (CDCl3, major diastereomer) δ 20.5, 28.3, 28.6, 44.4, 50.8, 51.7, 59.1, 65.5, 68.2, 74.0, 113.5, 128.2, 149.7, 149.9, 159.5, 171.3, 173.5; HRMS-FAB (m/z): [M+H]+ calcd. for C22H39N4O4 423.2971, found 423.2973.
(1SR) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-3-yl)methyl) L-glutamic acid dimethyl ester (4j): A colorless solid (94.9 mg, 47% yield, d.r. 83:17); For the major diastereomer: m.p. 89–90 °C; IR (KBr) υ = 3202, 2970, 1740, 1672 cm–1; 1H-NMR (CDCl3) δ 1.34 (s, 9H), 1.82–2.02 (m, 2H), 2.30 (br, 1H), 2.35 (t, J = 7.6 Hz, 2H), 2.84 (s, 6H), 3.04 (dd, J = 5.8, 7.6 Hz, 1H), 3.63 (s, 3H), 3.70 (s, 3H), 4.64 (s, 1H), 6.88 (d, J = 5.6 Hz, 1H), 7.11 (br, 1H), 8.36 (d, J = 5.6 Hz, 1H), 8.43 (s, 1H); 13C-NMR (CDCl3) δ 27.9, 28.7, 30.2, 44.4, 51.0, 51.7, 52.0, 58.2, 58.3, 113.7, 127.9, 149.9, 150.0, 159.5, 170.7, 173.2, 174.2; HRMS-FAB (m/z): [M+H]+ calcd. for C20H33N4O5 409.2451, found 409.2426; [α]D25 −156 (c 0.120, MeOH).
(1SR) -Benzyl N-(1-(N-tert-butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-3-yl)methyl)-L-aspartic acid methyl ester (4k): A colorless solid (122.5 mg, 52% yield, d.r. 79:21); For mixture of two diastereomers: m.p. 105 °C; IR (KBr) υ = 3334, 3202, 2971, 1739, 1668 cm–1; 1H-NMR (CDCl3, major diastereomer) δ 1.34 (s, 9H), 1.98 (br, 1H), 2.75 (dd, J = 3.0, 6.1 Hz, 2H), 2.81 (s, 6H), 3.52 (br, 1H), 3.66 (s, 3H), 4.67 (s, 1H), 5.06 (dd, J =12.2, 18.4 Hz, 2H), 6.87 (d, J = 5.5 Hz, 1H), 7.27–7.36 (m, 5H), 7.40 (br, 1H), 8.36 (d, J = 5.5 Hz, 1H), 8.41 (s, 1H); 13C-NMR (CDCl3, major diastereomer) δ 28.6, 36.9, 44.4, 50.9, 52.2, 56.0, 58.4, 66.6, 113.9, 128.3, 128.3, 128.4, 128.5, 135.4, 150.0, 150.0, 159.2, 170.4, 170.7, 172.8; HRMS-FAB (m/z): [M+H]+ calcd. for C25H35N4O5 471.2607, found 471.2593.
(1SR) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-3-yl)methyl) O-benzyl L-serine methyl ester (4l): A colorless solid (120.2 mg, 54% yield, d.r. 75:25); For mixture of two diastereomers: m.p. 145 °C; IR (KBr) υ = 3203, 2969, 1743, 1667 cm–1; 1H-NMR (CDCl3, major diastereomer) δ 1.36 (s, 9H), 1.74 (br, 1H), 2.80 (s, 6H), 3.33 (br, 1H), 3.52–3.65 (m, 2H), 3.71 (s, 3H), 4.41 (dd, J = 12.2, 14.3 Hz, 2H), 4.69 (s, 1H), 6.86 (d, J = 5.6 Hz, 1H), 7.17–7.19 (m, 2H), 7.24–7.37 (m, 3H), 7.57 (br, 1H), 8.35 (d, J = 5.6 Hz, 1H), 8.41 (s, 1H); 13C-NMR (CDCl3, major diastereomer) δ 28.7, 44.4, 50.9, 52.1, 59.0, 59.6, 70.1, 73.1, 113.8, 127.6, 127.8, 128.4, 128.5, 137.5, 149.8, 150.0, 159.4, 171.0, 172.4; HRMS-FAB (m/z): [M+H]+ calcd. for C24H35N4O4 443.2658, found 443.2681.
(1SR) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-3-yl)methyl)-L-histidine methyl ester (4m): A colorless solid (88.1 mg, 44% yield, d.r. 77:23); For mixture of two diastereomers: m.p. 110–113 °C; IR (KBr) υ = 3320, 3206, 2960, 1741, 1676 cm–1; 1H-NMR (CDCl3, major diastereomer) δ 1.33 (s, 9H), 2.55 (br, 1H), 2.81 (s, 6H), 2.86–3.06 (m, 2H), 3.42 (dd, J = 5.1, 7.6 Hz, 1H), 3.70 (s, 3H), 4.65 (s, 1H), 6.67 (s, 1H), 6.86 (d, J = 5.6 Hz, 1H), 7.44 (s, 1H), 7.46 (br, 1H), 8.23 (s, 1H), 8.29 (d, J = 5.6 Hz, 1H); 13C-NMR (CDCl3, major diastereomer) δ 28.6, 28.6 30.1, 44.3, 44.4, 50.9, 52.1, 58.7, 59.7, 113.7, 128.5, 135.1, 149.5, 149.6, 159.4, 171.0, 174.0; HRMS-FAB (m/z): [M+H]+ calcd. for C20H31N6O3 403.2458, found 403.2460.
(1SR) N-Benzyl-(1-(N-tert-butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-3-yl)methyl)-L-valine methyl ester (4n): A colorless syrup (15.9 mg, 18% yield, d.r. 92:8); For mixture of two diastereomers: IR (KBr) υ = 3362, 2966, 1732, 1673 cm–1; 1H-NMR (CDCl3, major diastereomer) δ 0.65 (d, J = 6.6 Hz, 3H), 0.75 (d, J = 6.6 Hz, 3H), 1.37 (s, 9H), 1.89–2.05 (m, J = 6.6 Hz, 1H), 2.74 (s, 6H), 2.84 (s, 1H), 3.70 (d, J = 14.4 Hz, 1H), 3.79 (s, 3H), 4.30 (d, J = 14.4 Hz, 1H), 5.18 (s, 1H), 6.85 (d, J = 5.6 Hz, 1H), 6.90 (br, 1H), 7.19–7.28 (m, 5H), 8.28 (d, J = 5.6 Hz, 1H), 8.47 (s, 1H); 13C-NMR (CDCl3, major diastereomer) δ 19.7, 20.4, 28.7, 44.2, 51.1, 51.3, 53.4, 60.8, 68.7, 113.3, 127.1, 128.2, 128.6, 139.4, 149.1, 149.8, 150.3, 152.1, 159.4, 170.3, 174.8; HRMS-FAB (m/z): [M+H]+ calcd. for C26H39N4O3 455.3022, found 455.3043.
(1SR) N-(1-(N-tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-3-yl)methyl)-L-proline methyl ester (4o): A yellowish solid (93.5 mg, 51% yield, d.r. 74:26); For mixture of two diastereomers: m.p. 105–109 °C; IR (KBr) υ = 3276, 2967, 1734, 1663 cm–1; 1H-NMR (CDCl3, major diastereomer) δ 1.38 (s, 9H), 1.69–1.87 (m, 3H), 1.99–2.09 (m, 1H), 2.27–2.33 (m, 1H), 2.76–2.81 (m, 1H), 2.87 (s, 6H), 3.46 (dd, J = 3.6, 9.5 Hz, 1H), 3.69 (s, 3H), 4.89 (s, 1H), 6.86 (d, J = 5.6 Hz, 1H), 7.50 (br, 1H), 8.32 (d, J = 5.6 Hz, 1H), 8.41 (s,1H); 13C-NMR (CDCl3, major diastereomer) δ 23.7, 28.7, 29.6, 44.6, 50.0, 50.9, 51.7, 63.1, 63.9, 113.6, 125.4, 149.4, 151.3, 160.4, 170.7, 175.1; HRMS-FAB (m/z): [M+H]+ calcd. for C19H31N4O3 363.2396, found 363.2399.