232 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Leftheris et al.
(S)-N-[(N-L-Cystein yl-L-va lyl)-1,2,3,4-tetr a h yd r o-3-iso-
qu in olin yl]-L-m eth ion in e Tr iflu or oa ceta te (32): mp 129-
(m, 15H); 13C-NMR (CD3OD) δ 19.1, 19.6, 28.8, 30.7, 32.6, 36.0,
51.6, 51.9, 52.3, 53.0, 67.6, 68.5, 80.1, 127.8, 128.9, 130.8, 146.2,
130 °C; [R]25 ) +110 ° (c 0.1, CH3OH); MS (M + H)+ 495;
157.7, 169.0, 169.9, 171.2, 176.7, 202.9. Anal. (C33H42-
N2O4S‚0.17H2O) C, H, N.
D
1H-NMR (CD3OD, 400 MHz) δ 7.74 (1H, m), 7.66 (1H, m), 7.44
(1H, m), 7.33 (1H, m), 5.01 (1H, m), 4.68 (1H, m), 4.28 (2H,
m), 4.14 (1H, m), 3.99 (1H, m), 3.73 (1H, m), 3.45 (1H, m),
2.94 (1H, m), 2.81 (1H, m), 2.54 (2H, m), 2.00 (3H, s), 2.02
(1H, m), 1.91 (2H, m), 0.94 (6H, m); 13C-NMR (CD3OD, 100
MHz) δ 174.1, 172.7, 160.84, 160.43, 160.03, 159.6, 116.50,
113.6, 61.03, 53.50, 47.4, 44.4, 41.5, 39.7, 33.4, 29.2, 26.1, 24.3,
23.0, 21.2; IR 3434, 2928, 2556, 1680, 1576, 1429, 1204, 1138,
837, 801, 723 cm-1. Anal. (C22H32N4O5S2‚2.03CHF3O2‚1.8H2O)
C, H, N.
(R*)-N-[[2-[[(1,1-Dim et h ylet h oxy)ca r b on yl]a m in o]-3-
[(tr ip h en ylm eth yl)th io]p r op yl]ca r bon yl]-N-(ben zyloxy-
ca r bon yl)-L-va lin e Meth yl Ester (27). Benzyl chlorofor-
mate (90%, 10% BzCl, 3.2 mL, 20 mmol) was added to a
solution of 26 (3.8 g, 6.8 mmol) and DIEA (3.8 mL, 22 mmol)
in CH2Cl2 (20 mL) at 0 °C. The mixture was warmed to room
temperature and stirred for 16 h. The reaction mixture was
diluted with CH2Cl2 (100 mL) and washed sequentially with
1 N HCl (2 × 100 mL) and 10% NaHCO3 (2 × 100 mL). The
organic layer was dried, filtered, and concentrated under
vacuum. The residue was purified by flash chromatography
(eluting with 8:1 hexane:acetone) to afford 27 (4.3 g, 92%) as
a white solid: mp 48-52 °C; MS (M - H)- 695; 1H-NMR (CD3-
OD, 270 MHz) δ 0.73 (d, 3H, J ) 6.45 Hz), 0.93 (d, 3H, J )
6.45 Hz), 1.42 (s, 9H), 2.27 (m, 3H), 3.14 (m, 6H), 4.97-5.10
(m, 3H), 7.14-7.36 (m, 20H); 13C-NMR (CD3OD) δ 19.6, 20.8,
28.8, 29.5, 29.9, 36.2, 50.6, 51.0, 51.8, 52.7, 65.2, 67.5, 68.8,
80.3, 127.8, 128.0, 128.2, 128.9, 129.2, 129.5, 130.7, 137.5,
146.1, 157.4, 158.1, 172.9; IR (KBr) 1709 cm-1; [R]D ) -9.7° (c
1.5, CH3OH). Anal. (C40H46N2O6S) C, H, N, S.
(R*)-N-[[2-[[[(1,1-Dim eth yleth oxy)ca r bon yl]a m in o]-3-
[(tr ip h en ylm eth yl)th io]p r op yl]ca r bon yl]-N-(ben zyloxy-
ca r bon yl)-L-va lin e (28). Lithium hydroxide (2 N, 1.5 mL,
3.0 mmol) was added dropwise to a solution of 27 (0.70 g, 1.0
mmol) in THF (5 mL) and methanol (3.5 mL). The homoge-
neous reaction mixture was warmed to room temperature and
stirred for 16 h. The mixture was concentrated under vacuum,
diluted with 1 N HCl (30 mL), and extracted with CH2Cl2 (3
× 50 mL). The combined organic extracts were dried, filtered,
and concentrated under vacuum to afford 28 (0.68 g, 100%):
mp 66-72 °C; TLC Rf 0.61 (9:1:0.05 chloroform:methanol:acetic
acid, visualization by UV); MS (M - H)- 681; [R]D ) -0.2° (c
0.83, CH3OH); 1H-NMR (CD3OD) δ 0.83 (m, 3H), 0.93 (m, 3H),
1.50 (m, 9H), 1.90-1.92 (m, 1H), 2.35-2.60 (m, 2H), 3.30-
3.55 (m, 2H), 3.77-4.20 (m, 2H), 4.95-5.22 (m, 2H), 7.24-
7.45 (m, 20H); 13C-NMR (CD3OD) δ 19.9, 21.1, 21.4, 28.8, 29.2,
29.5, 29.9, 36.2, 51.1, 51.6, 51.7, 52.0, 54.8, 61.8, 65.2, 67.7,
67.8, 68.7, 80.3, 127.7, 127.9, 128.2, 128.9, 129.1, 129.3, 129.5,
130.7, 137.4, 146.0, 157.4, 157.9, 158.4, 173.9, 178.2; IR (KBr)
1653, 1707 cm-1. Anal. (C40H46N2O6S) C, H, N, S.
(R*,R*)-N-[[2-[2-[(2-Am in o-3-th iop r op yl)a m in o]-3-m e-
th ylbu tyl]-1,2,3,4-tetr a h yd r o-3-isoqu in olin yl]ca r bon yl]-
L-m eth ion in e Tr iflu or oa ceta te (33): mp 72-73 °C; [R]25
D
) -30.0° (c 0.18, CH3OH); MS (M + H)+ 483; H-NMR (CD3-
1
OD, 270 MHz) δ 7.28 (4H, m), 4.68 (1H, m), 4.19 (1H, m), 3.66
(1H, m), 3.42 (2H, m), 3.24 (2H, m), 3.03 (2H, m), 2.94 (2H, d,
J ) 4.28 Hz), 2.60 (2H, m), 2.20 (2H, m), 2.10 (3H, s), 2.07
(3H, m), 1.01 (3H, d, J ) 7.03 Hz), 0.93 (3H, d, J ) 7.04 Hz).
Anal. (C22H32N4O5S2‚1.9CHF3O2‚1.5H2O) C, H, N, F.
(R)-N-[[3-[[N-(2-Am in o-3-m er ca p top r op yl)-L-va lyl]a m i-
n o]-2-n a p h th a len yl]ca r bon yl]-L-m eth ion in e Tr iflor oa ce-
ta te (36): mp 101-102 °C; [R]25 ) -28.7° (c 0.15, CH3OH);
D
MS (M + H)+ 507; 1H-NMR (CD3OD, 270 MHz) δ 8.80 (1H, s),
8.24 (1H, s), 7.80 (2H, m), 7.42 (2H, m), 4.74 (2H, m), 3.41
(1H, m), 3.05 (1H, m), 2.91 (1H, m), 2.81 (2H, m), 2.62 (2H,
m), 2.17 (3H, m), 2.05 (3H, s), 0.97 (6H, m). Anal. (C24H34
-
N4O5S2‚2.5‚CHF3O2‚1.9H2O) C, H, N, F.
(S*,R*)-N-[[2-[N-(2-Am in o-3-m er captopr opyl)-L-alan yl]-
1,2,3,4-t et r a h yd r o-3-isoq u in olin yl]ca r b on yl]-L-m et h io-
n in e Tr iflu or oa ceta te (37): mp 89-90 °C; [R]25 ) -32.1°
D
(c 1.0, CH3OH); MS (M + H)+ 469; 1H-NMR (CD3OD, 270 MHz)
δ 7.16 (4H, m), 4.71 (2H, m), 4.57 (2H, m), 4.43 (1H, m), 4.32
(1H, m), 3.98 (1H, m), 3.56 (1H, m), 3.33-3.02 (2H, m), 2.84
(2H, m), 2.37 (1H, m), 1.98 (2H, m), 1.89 (1H, m), 2.10-1.76
(3H, m), 1.57 (2H, m), 1.43 (1H, m). Anal. (C21H32N4O4S2‚
1.9CHF3O2‚3.17H2O) C, H, N, F.
[R*-[R*-(S*)]]-N-[[2-[2-[(2-Am in o-3-m er ca p t op r op yl)-
a m in o]-1-oxob u t yl]-1,2,3,4-t et r a h yd r o-3-isoq u in olin yl]-
ca r bon yl]-L-m eth ion in e Tr iflu or oa ceta te (38): mp 85-
95 °C; [R]D ) -31° (c 0.1, CH3CH2OH); IR (KBr) 3435, 2924,
1674, 1431 cm-1; MS (M + H)+ 483; 1H-NMR (CD3OD, 270
MHz) δ 7.25 (4H, m), 1.8-4.9 (20H, m), 1.97, 2.07 (3H, 2s,
rotamers), 1.1 (6H, m). Anal. (C22H34N4O4S2‚1.9CHF3O2‚
1.5H2O) C, H, N, S, F.
[R-(R*,S*)]-N-[[2-[N-(2-Am in o-3-m e r ca p t op r op yl)-3-
m eth yl-L-va lyl]-1,2,3,4-tetr a h yd r o-3-isoqu in olin yl]ca r bo-
n yl]-L-m eth ion in e Tr iflu or oa ceta te (49): mp 87-90 °C;
MS (M + H)+ 511; IR (KBr) 1676, 1204 cm-1; [R]D ) -27° (c
0.46, CH3OH); 1H-NMR (CD3OD, 400 MHz) δ 7.35-7.20 (4H,
m), 5.0-4.55 (5H, m), 3.45-3.1 (2H, m), 2.90-2.45 (5H, m),
2.07, 2.03 (3H, 2 s, rotameric), 2.2-1.95 (2H, m), 1.12, 1.06
(9H, 2s). Anal. (C24H38N4O4S2‚1.9CHF3O2‚1.5H2O) C, H, N,
S, F.
(R*)-N-[N-[2-[[(1,1-Dim eth yleth oxy)ca r bon yl]a m in o]-
3-[(tr iph en ylm eth yl)th io]pr opyl]-N-(ben zyloxycar bon yl)-
L-va lyl]-1,2,3,4-tetr a h yd r oisoqu in olin e-2-ca r boxylic Acid
Meth yl Ester (29). N,N-Diisopropylethylamine (20 mL, 110
mmol) was added to a solution of 28 (24 g, 35 mmol), Tic-OMe‚
HCl (9.7 g, 43 mmol), and Bop-Cl (11 g, 43 mmol) in CH2Cl2
(200 mL). The mixture was stirred at 0 °C for 16 h. The
reaction was quenched with 1 N HCl (300 mL) and the mixture
extracted with CH2Cl2 (3 × 100 mL). The combined organic
extracts were washed with 10% NaHCO3 (100 mL), dried,
filtered, and concentrated under vacuum. The residue was
purified by flash chromatography (eluting with 4:1 hexane:
acetone) to afford 29 (22 g, 72%) as a white solid: mp 66-70
°C; TLC Rf 0.28 (4:1 hexane:acetone, visualization by UV); MS
N-[[2-[[(1,1-Dim et h ylet h oxy)ca r b on yl]a m in o]-3-[(t r i-
p h en ylm eth yl)th io]p r op yl]ca r bon yl]-L-va lin e Meth yl Es-
ter (26). Acetic acid (2.6 mL, 45 mmol) was added to a solution
of 22 (20 g, 45 mmol) and L-valine methyl ester hydrochloride
(9.0 g, 54 mmol) in methanol (50 mL). The mixture was stirred
at room temperature for 30 min. NaBH3CN (2.8 g, 45 mmol)
in THF (50 mL) was added dropwise, and the mixture was
stirred at room temperature for 2 h. The reaction was
quenched with NaHCO3 (3.8 g, 45 mmol) in water (20 mL) and
the mixture concentrated under vacuum. The residue was
dissolved in 10% NaHCO3 (10 mL) and extracted with CH2Cl2
(3 × 100 mL). The combined organic extracts were dried,
filtered, and concentrated under vacuum. The residue was
purified by flash chromatography (eluting with 9:1 hexane:
acetone) to afford 26 (18 g, 70%) as a viscous oil: TLC Rf 0.25
(8:1 hexane:acetone, visualization by UV); MS (M + H)+ 563;
1
(M + H)+ 856; [R]D ) +21.0° (c 1.0, CH3OH); H-NMR (CD3-
OD, 400 MHz) δ 0.76-0.98 (m, 6H), 1.14-1.31 (m, 9H), 2.16-
2.40 (m, 3H), 2.96-3.59 (m, 8H), 3.93 (m, 1H), 4.50-5.30 (m,
5H), 7.12-7.42 (m, 24H); 13C-NMR (CD3OD) δ 14.4, 18.7, 18.8,
19.6, 23.7, 28.4, 28.7, 29.5, 31.7, 32.2, 32.7, 36.4, 36.7, 36.9,
41.4, 45.0, 46.2, 46.5, 47.0, 47.4, 47.6, 50.2, 50.8, 52.7, 55.0,
62.2, 62.4, 65.2, 67.7, 69.2, 72.9, 80.4, 93.1, 127.3, 127.5, 127.8,
128.0, 128.1, 128.3, 128.9, 129.1, 129.2, 129.3, 129.6, 129.9,
130.3, 130.7, 133.9, 134.4, 137.4, 146.0, 157.3, 158.6, 172.8,
173.2, 219.3; IR (KBr) 1638, 1711 cm-1. Anal. (C51H75N3O7S)
C, H, N.
(R*)-N-[N-[2-[[(1,1-Dim eth yleth oxy)ca r bon yl]a m in o]-
3-[(tr iph en ylm eth yl)th io]pr opyl]-N-(ben zyloxycar bon yl)-
L-va lyl]-1,2,3,4-tetr a h yd r oisoqu in olin e-2-ca r boxylic Acid
(30). Lithium hydroxide (1 N, 54 mL, 54 mmol) was added
dropwise to a solution of 29 (13 g, 15 mmol) in THF (100 mL)
and MeOH (50 mL). The homogeneous reaction mixture was
warmed to room temperature and stirred for 16 h. The
IR (CH2Cl2 film) 1491, 1715 cm-1; [R]D ) -3.8° (c 1.3, CH -
3
OH); 1H-NMR (CD3OD) δ 0.86, 0.87 (d, 6H, J ) 7.04, 6.45Hz),
1.43 (s, 9H), 1.80-1.82 (m, 1H), 2.29-2.31 (m, 2H), 2.53-2.70
(m, 2H), 2.89 (m, 1H), 3.60 (m, 1H), 3.66 (s, 3H), 7.16-7.40