S. C. Annedi et al. / Bioorg. Med. Chem. 14 (2006) 214–236
231
A solution of BocHN-L-Ala-OH (0.05 g, 0.26 mmol) in
anhydrous CH2Cl2 (5 mL) was treated with HOBt
(0.035 g, 0.26 mmol) and EDAC (0.06 g, 0.31 mmol) at
0 ꢁC. After stirring for 30 min, Et3N (0.036 mL,
0.26 mmol) and the above amine (0.17 g, 0.26 mmol)
were added to the reaction mixture at the same temper-
ature, and a protocol similar to that for compound 21
was used to obtain compound 35i (0.1 g, 13% from
34c, inseparable mixture of diastereomers) as a syrup.
1H NMR (CDCl3) d 0.77 (t, 3H, J = 7.5 Hz), 0.96–1.12
(m, 10H), 1.19–1.44 (m, 13H), 1.80–1.94 (m, 2H),
2.22–2.34 (m, 2H), 3.05 (dd, 1H, J = 5.4, 14.7 Hz),
3.25 (dd, 1H, J = 6.0, 14.7 Hz), 3.41–3.72 (m, 2H),
4.04 (t, 1H, J = 6.9 Hz), 4.36–4.41 (m, 3H), 5.04 (d,
1H, J = 5.4 Hz), 6.84 (s, 1H), 7.17–7.41 (m, 13H),
7.60–7.85 (m, 5H), 8.57 (s, 1H); 13C NMR (CDCl3) d
14.23, 16.72, 18.45, 19.24, 26.62, 26.74, 27.03, 28.45,
31.89, 36.86, 37.73, 43.64, 50.86, 54.63, 60.75, 63.30,
70.71, 77.43, 80.22, 116.15, 127.08, 127.71, 127.88,
128.49, 129.54, 129.87, 133.53, 134.98, 135.64, 135.70,
138.92, 152.54, 153.27, 155.72, 169.77, 173.00, 173.45.
128.63, 129.79, 129.83, 133.58, 133.81, 135.57, 135.62,
136.25, 138.89, 156.12, 169.94, 170.88, 172.35, 173.07;
MS (ESI) m/z (%) 872 (M+Na, 28), 851 (MH+, 59), 850
(M+, 100), 687 (37), 594 (30).
5.1.35. [(1S)-1-((1S)-1-{1-Benzylcarbamoyl-1-(2-tert-bu-
tyl diphenyl silyloxy-ethyl)-3-methyl-butyl carbamoyl}-2-
dimentylcarbamoyl-ethyl carbamoyl)-2-methyl-propyl]-
carbamic acid benzyl ester (35k). Isolated as an insepara-
ble mixture of diastereomers (84:16 ratio); yield 89%,
foam; 1H NMR (CDCl3) d 0.78 (d, 3H, J = 6.3 Hz),
0.83 (d, 3H, J = 6.3 Hz), 0.90–1.04 (m, 18H), 1.50–1.59
(m, 1H), 1.87–2.01 (m, 2H), 2.26–2.53 (m, 3H), 2.57 (s,
3H), 2.70 (s, 3H), 2.88 (br d, 1H, J = 16.2 Hz), 3.64–
3.73 (m, 2H), 3.90 (d, 1H, J = 7.8 Hz), 4.33 (d, 2H,
J = 5.1 Hz), 4.60–4.70 (m, 1H), 5.07 (s, 2H), 5.61 (d,
1H, J = 7.8 Hz), 7.16–7.38 (m, 18H), 7.62 (d, 4H,
J = 7.2 Hz); 13C NMR (CDCl3) d 19.07, 23.58, 23.73,
24.43, 26.57, 26.84, 34.30, 34.89, 35.10, 36.84, 38.36,
42.29, 43.38, 50.36, 60.16, 62.36, 63.20, 66.93, 126.79,
127.42, 127.66, 127.94, 128.08, 128.18, 128.45, 129.65,
133.40, 133.61, 135.44, 136.18, 138.71, 156.38, 169.74,
170.35, 170.47, 172.66.
5.1.34. [(1S)-1-((1S)-1-{1-Benzylcarbamoyl-1-(2-tert-bu-
tyl diphenyl silyloxy-ethyl)-3-methyl-butyl carbamoyl}-2-
dimentylcarbamoyl-ethylcarbamoyl)-ethyl]-carbamic acid
benzyl ester (35j). A solution of compound 34d (0.08 g,
0.10 mmol) in anhydrous MeOH (3 mL) was treated with
Pd–C (0.05 g) and a procedure similar to that for com-
pound 33a was followed to obtain the amine derivative
(0.048 g, 73%) as an inseparable mixture of diastereomers
5.1.36. (3S)-N-[(1S)-1-{1-Benzylcarbamoyl-1-(2-tert-bu-
tyl diphenyl silyloxy-ethyl)-3-methyl butyl carbamoyl}-2-
dimethylcarbamoyl-ethyl carbamoyl]-3-benzyloxycarbon-
yl amino succinamic acid benzyl ester (35l). Isolated as an
inseparable mixture of diastereomers (84:16 ratio); yield
86%, foam, 1H NMR (CDCl3) d 0.78–0.90 (m, 6H),
0.98–1.05 (m, 9H), 1.48–1.59 (m, 1H), 1.91–2.15 (m,
2H), 2.30–2.60 (m, 7H), 2.72 (s, 3H), 2.76–2.90 (m,
2H), 3.01–3.20 (m, 1H), 3.64–3.78 (m, 2H), 4.15–4.26
(m, 1H), 4.38–4.51 (m, 2H), 4.65–4.73 (m, 1H), 5.00–
5.12 (m, 3H), 5.80–5.84 (m, 1H), 7.13–7.39 (m, 21H),
7.58–7.63 (m, 4H); 13C NMR (CDCl3) d 19.11, 19.17,
23.38, 2.47, 23.72, 23.78, 24.75, 24.88, 26.92, 34.74,
34.86, 36.12, 36.88, 38.77, 38.89, 40.71, 43.20, 43.31,
49.77, 50.08, 51.63, 60.07, 60.17, 61.92, 62.20, 66.96,
67.10, 67.24, 67.48, 126.60, 126.73, 127.21, 127.33,
127.70, 127.72, 128.08, 128.17, 128.19, 128.26, 128.34,
128.41, 128.50, 128.55, 128.59, 128.63, 129.61, 129.66,
133.57, 133.71, 134.99, 135.17, 135.50, 135.52, 135.81,
136.00, 139.01, 139.17, 155.94, 169.88, 170.14, 170.18,
170.64, 170.84, 171.26, 171.77, 172.91, 172.95.
1
(84:16 ratio); foam, H NMR (CDCl3) d 0.72–0.90 (m,
6H), 0.95–1.03 (m, 9H), 1.25 (br s, 2H), 1.43–1.51 (m,
1H), 1.84 (dd, 1H, J = 6.0, 14.5 Hz), 1.99 (dd, 1H,
J = 5.7, 15.6 Hz), 2.13–2.20 (m, 1H), 2.27–2.34 (m, 1H),
2.63, 2.65, 2.72, 2.73 (4s, 6H), 2.87 (dd, 1H, J = 5.4,
17.2 Hz), 3.09 (d, 1H, J = 4.5, 17.2 Hz), 3.54–3.68 (m,
2H), 4.24 (dd, 1H, J = 5.1, 14.5 Hz), 4.35–4.42 (m, 2H),
7.13–7.43 (m, 11H), 7.57–7.61 (m, 4H), 8.27 (s, 1H); 13C
NMR (CDCl3) d 14.30, 19.31, 23.96, 24.07, 24.54, 27.08,
29.87, 34.06, 35.62, 37.26, 38.43, 41.69, 43.81, 50.95,
60.26, 63.00, 127.19, 127.94, 127.98, 128.10, 128.58,
129.95, 133.45, 133.68, 135.69, 138.94, 167.20, 169.41,
172.71.
A
solution of CBzHN-L-Ala-OH (0.1 g,
0.44 mmol) in anhydrous CH2Cl2 (5 mL) was treated with
HOBt (0.06 g, 0.44 mmol) and EDAC (0.1 g, 0.53 mmol)
at 0 ꢁC. After stirring for 30 min, Et3N (0.06 mL,
0.44 mmol) and the above amine (0.28 g, 0.44 mmol) were
added to the reaction mixture at the same temperature
and a procedure similar to that for compound 21 was used
to obtain compound 35j (0.37 g, 70% from 34d) as an
inseparable mixture of diastereomers (84:16 ratio);
foam, 1H NMR (CDCl3) d 0.76–0.88 (m, 6H), 1.00–1.05
(m, 9H), 1.26–1.41 (m, 3H), 1.51–1.60 (m, 1H), 1.90–
2.10 (m, 2H), 2.24–2.34 (m, 2H), 2.42 (dd, 1H, J = 5.1,
16.5 Hz), 2.57, 2.59 (2s, 3H), 2.79 (s, 3H), 3.08 (d, 1H,
J = 15.6 Hz), 3.65–3.78 (m, 2H), 3.96–4.06 (m, 1H), 4.24
(dd, 1H, J = 5.4, 15.3 Hz), 4.41 (d, 1H, J = 6.3,
15.3 Hz), 4.64–4.72 (m, 1H), 5.03–5.12 (m, 2H), 5.42 (d,
1H, J = 6.0 Hz), 7.10 (t, 1H, J = 5.1 Hz), 7.16–7.44 (m,
16H), 7.59–7.65 (m, 4H); 13C NMR (CDCl3) d 18.63,
19.28, 23.55, 23.89, 24.71, 27.02, 34.65, 35.01, 37.09,
38.75, 41.68, 43.56, 50.10, 51.20, 60.34, 62.29, 67.14,
126.97, 127.56, 127.82, 127.84, 128.16, 128.27, 128.37,
5.1.37.
(4S)-N-[(1S)-1-{1-Benzylcarbamoyl-1-(2-tert-
butyldiphenylsilyloxy-ethyl)-3-methyl butylcarbamoyl}-2-
(N,N-dimethylcarbamoyl)-ethylcarbamoyl]-4-benzyloxy-
carbonylamino-butyric acid benzyl ester (35m). Isolated
as an inseparable mixture of diastereomers (84:16 ratio);
yield 86%, foam, 1H NMR (CDCl3) d 0.79–0.90 (m, 6H),
0.97–1.05 (m, 9H), 1.52–1.64 (m, 2H), 1.85–2.11(m, 4H),
2.24–2.61 (m, 7H), 2.74, 2.80 (2s, 3H), 2.96–3.10 (m,
1H), 3.64–3.79 (m, 2H), 3.98–4.08 (m, 1H), 4.22 (dd,
1H, J = 5.1, 15.3 Hz), 4.36–4.46 (m, 1H), 4.60–4.72 (m,
1H), 5.00–5.13 (m, 4H), 5.87 (d, 1H, J = 5.4 Hz), 7.14–
7.39 (m, 22H), 7.49 (d, 1H, J = 8.4 Hz), 7.60–7.67 (m,
4H); 13C NMR (CDCl3) d 19.18, 23.47, 23.57, 23.76,
24.05, 24.71, 24.92, 26.92, 27.08, 30.32, 34.71, 34.88,
36.80, 36.91, 38.67, 41.16, 43.38, 50.10, 55.01, 60.27,
62.32, 62.95, 66.64, 67.09, 126.65, 126.76, 127.39,
127.43, 127.74, 128.04, 128.17, 128.21, 128.32, 128.52,