Design of Nonpeptidic HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 7 1159
5a (0.97 g, 2.1 mmoL), 10% Pd/C (0.24 g), and 100 mL of
methanol were shaken under 48 psi of H2 for 18 h. The
reaction mixture was then filtered, washed with EtOAc, and
concentrated in vacuo to give 0.652 g of crude material. This
was dissolved in 5 mL of CH2Cl2, filtered through Celite, and
concentrated in vacuo to give 0.56 g (82%) of 6a as a white
solid: 1H NMR (CDCl3) δ 7.26 (s, 1H), 7.17 (t, J ) 7.5 Hz,
1H), 6.97 (d, J ) 7.8 Hz, 1H), 6.79 (s, 1H), 6.62-6.60 (m, 1H),
4.20 (br s, 1H), 3.85 (d, J ) 9 Hz, 1H), 2.71-2.67 (m, 2H),
2.45-2.41 (m, 2H), 1.77-1.50 (m, 7H), 1.35-1.26 (m, 1H),
0.72-0.56 (m, 3H), 0.27-0.23 (m, 1H) ppm; MS (EI) m/ z 325
(M+); HRMS (EI) calcd for C28H29NO5 325.1678, found 325.1675.
Rep r esen ta tive P r oced u r e for th e Syn th esis of 42a -
d . 3-[1-(3-Am in op h en yl)bu tyl]-5,6,7,8,9,10-h exa h yd r o-4-
h yd r oxy-2H-cycloocta [b]p yr a n -2-on e (42a ). A mixture of
41a (0.75 g, 1.58 mmol) and 10% Pd/C (0.40 g) in cyclohexene
(12 mL) and absolute ethanol (12 mL) was warmed to reflux
for 1.5 h. The mixture was then filtered through Celite
(rinsing with EtOH) and concentrated in vacuo to give 0.51 g
(95%) of 42a as a beige solid. An analytical sample was
J ) 8.8 Hz, 1H), 2.97 (s, 3H), 2.62-2.58 (m, 2H), 2.51-2.47
(m, 2H), 1.73-1.40 (m, 9H), 0.74-0.72 (m, 1H), 0.61-0.57 (m,
1H), 0.48-0.43 (m, 1H), 0.27-0.23 (m, 1H) ppm; MS (EI) m/ z
417 (M+); HRMS (EI) calcd for C22H27NO5S 417.1610, found
417.1619.
N-[3-[Cyclop r op yl(5,6,7,8,9,10-h exa h yd r o-4-h yd r oxy-2-
oxo-2H -cyclooct a [b]p yr a n -3-yl)m et h yl]p h en yl]b en zen -
1
em eth a n esu lfon a m id e (32a ): white foam (49%); H NMR
(CDCl3) δ 7.34-7.24 (m, 8H), 7.11-7.08 (m, 1H), 6.46 (br s,
1H), 4.30 (s, 2H), 3.87 (d, J ) 8.7 Hz, 1H), 2.64-2.60 (m, 2H),
2.50-2.46 (m, 2H), 1.75 (m, 2H), 1.59-1.42 (m, 8H), 0.75-
0.71 (m, 1H), 0.62-0.56 (m, 1H), 0.54-0.49 (m, 1H), 0.31-
0.28 (m, 1H) ppm; MS (EI) m/ z 493 (M+). Anal. (C28H31NO5S)
C, H, N.
N-[3-[Cyclop r op yl(5,6,7,8,9,10-h exa h yd r o-4-h yd r oxy-2-
oxo-2H -cyclooct a [b]p yr a n -3-yl)m et h yl]p h en yl]-2-m et h -
1
ylben zen esu lfon a m id e (33a ): white foam (76%); H NMR
(CDCl3 and CD3OD) δ 7.90 (d, J ) 7.8 Hz, 1H), 7.62 (d, J )
8.1 Hz, 1H), 7.42-7.38 (m, 1H), 7.26-7.08 (m, 5H), 6.87 (m,
1H), 3.43-3.55 (m, 2H), 2.63-2.59 (m, 5H), 2.55-2.51 (m, 2H),
1.74-1.26 (m, 9H), 0.62-0.58 (m, 1H), 0.47-0.42 (m, 1H),
0.23-0.18 (m, 1H), 0.13-0.08 (m, 1H) ppm; MS (EI) m/ z 493
(M+). Anal. (C28H31NO5S) C, H, N, S.
1
purified by column chromatography: mp 86-91 °C; H NMR
(CDCl3) δ 7.17 (t, J ) 7.8 Hz, 1H), 6.83 (d, J ) 7.5 Hz, 1H),
6.71 (s, 1H), 6.59 (br d, J ) 7.8 Hz, 1H), 6.15 (br s, 1H), 4.37
(t, J ) 7.7 Hz, 1H), 3.73 (br s, 2H), 2.64-2.56 (m, 2H), 2.45-
2.33 (m, 2H), 2.10-1.97 (m, 1H), 1.96-1.83 (m, 1H), 1.82-
1.70 (m, 2H), 1.60-1.33 (m, 8H), 0.97 (t, J ) 7.3 Hz, 3H) ppm;
MS (EI) m/ z 341 (M+). Anal. (C21H27NO3) C, H, N.
N-[3-[Cyclop r op yl(5,6,7,8,9,10-h exa h yd r o-4-h yd r oxy-2-
oxo-2H -cyclooct a [b]p yr a n -3-yl)m et h yl]p h en yl]-3-m et h -
1
ylben zen esu lfon a m id e (34a ): white foam (79%); H NMR
(CDCl3) δ 7.58-7.53 (m, 2H), 7.30-7.13 (m, 6H), 6.98-6.96
(m, 1H), 3.80 (d, J ) 8.7 Hz, 1H), 2.61-2.57 (m, 2H), 2.47-
2.43 (m, 2H), 2.32 (s, 3H), 1.57-1.25 (m, 9H), 0.90-0.85 (m,
1H), 0.65-0.52 (m, 2H), 0.44-0.40 (m, 1H), 0.14-0.09 (m, 1H)
ppm; MS (EI) m/ z 493 (M+); HRMS (EI) calcd for C28H31NO5S
493.1923, found 493.1931.
5-Th ia zolesu lfon yl Ch lor id e. A mixture of 5-thiazole-
sulfonic acid,32 PCl5, and POCl3 was warmed to reflux for 5 h.
The reaction mixture was concentrated in vacuo, and the
residue was partitioned between CH2Cl2 and saturated
NaHCO3(aq). The organic layer was separated, washed twice
with aqueous NaHCO3, dried over Na2SO4, and concentrated
in vacuo to give the title compound as a colorless oil which
was used without further purification.
N-[3-[Cyclop r op yl(5,6,7,8,9,10-h exa h yd r o-4-h yd r oxy-2-
oxo-2H -cyclooct a [b]p yr a n -3-yl)m et h yl]p h en yl]-4-m et h -
1
ylben zen esu lfon a m id e (35a ): white foam (45%); H NMR
2-P yr id in esu lfon yl Ch lor id e. Chlorine gas was bubbled
into a mixture of 2-mercaptopyridine (5.0 g, 45 mmol) and
concentrated HCl (40 mL) at 0 °C for 1.5 h. The reaction
mixture was then poured into ice water (100 mL), and a low-
melting solid formed. The solid was dissolved in CH2Cl2,
washed with water, dried over Na2SO4, filtered, and concen-
trated in vacuo to give 6.1 g (76%) of 2-pyridinesulfonyl
chloride as a colorless oil which was used without further
purification. 4-Cyano-2-pyridinesulfonyl chloride, 2-pyrim-
idinesulfonyl chloride, and 2-pyrazinesulfonyl chloride were
prepared in an analogous fashion.
(CDCl3) δ 7.65-7.62 (m, 2H), 7.26-7.12 (m, 6H), 6.98-6.94
(m, 1H), 3.80 (d, J ) 8.7 Hz, 1H), 2.61-2.57 (m, 2H), 2.48-
2.44 (m, 2H), 2.35 (s, 3H), 1.73-1.33 (m, 9H), 0.65-0.52 (m,
2H), 0.44-0.40 (m, 1H), 0.15-0.10 (m, 1H) ppm; MS (EI) m/ z
493 (M+). Anal. (C28H31NO5S) C, H, N, S.
N-[3-[Cyclop r op yl(5,6,7,8,9,10-h exa h yd r o-4-h yd r oxy-2-
oxo-2H -cyclooct a [b]p yr a n -3-yl)m et h yl]p h en yl]-4-flu o-
r oben zen esu lfon a m id e (35f): white solid (32%); mp 227-
1
228 °C; H NMR (CDCl3) δ 7.69-7.65 (m, 2H), 7.29-7.00 (m,
6H), 6.55 (s, 1H), 6.25 (s, 1H), 3.35 (d, J ) 10 Hz, 1H), 2.55
(m, 2H), 2.44 (m, 2H), 1.80-1.25 (m, 9H), 0.68-0.75 (m, 1H),
0.70-0.60 (m, 1H), 0.60-0.50 (m, 1H), 0.22-0.12 (m, 1H) ppm;
MS (EI) m/ z 497 (M+). Anal. (C27H28FNO5S) C, H, N, F.
Syn th esis of m -Su lfon a m id e-Su bstitu ted Cycloa lk yl-
p yr a n on es: Rep r esen ta tive P r oced u r e for th e Syn th esis
of 7, 8, 32-37, a n d 43-48. N-[3-[Cyclop r op yl(5,6,7,8,9,
10-h exa h yd r o-4-h yd r oxy-2-oxo-2H-cycloocta [b]p yr a n -3-
yl)m eth yl]p h en yl]ben zen esu lfon a m id e (8h ). A solution
of 6b (0.100 g, 0.29 mmol), benzenesulfonyl chloride (0.053 g,
0.3 mmol), pyridine (0.05 mL), and 5 mL of CH2Cl2 was stirred
at room temperature for 18 h. Column chromatography of the
reaction mixture (elution with 50% EtOAc/hexane) gave 0.127
g (90%) of 8h as a white foam: 1H NMR (CDCl3) δ 7.76-7.35
(m, 2H), 7.52-7.41 (m, 3H), 7.26-7.17 (m, 4H), 7.04-6.98 (m,
1H), 3.81 (d, J ) 8.4 Hz, 1H), 2.61 (m, 2H), 2.46 (m, 2H), 1.71-
1.42 (m, 10H), 0.72-0.52 (m, 2H), 0.52-0.40 (m, 1H), 0.20-
0.08 (m, 1H) ppm; 13C NMR (CD3OD) δ 169.8, 168.6, 165.2,
147.8, 143.2, 140.7, 136.6, 132.9, 132.7, 130.9, 128.4, 124.8,
123.4, 114.8, 110.1, 48.6, 34.8, 33.0, 32.8, 30.1, 29.6, 26.1, 16.3,
9.6, 7.9 ppm; IR (mineral oil) 3211, 1665, 1652, 1609, 1593,
4-Cya n o-N-[3-[cyclop r op yl(5,6,7,8,9,10-h exa h yd r o-4-
h ydr oxy-2-oxo-2H-cycloocta[b]pyr an -3-yl)m eth yl]ph en yl]-
ben zen esu lfon a m id e (35k ): white solid (51%); mp 183-
183.5 °C; 1H NMR (DMSO-d6) δ 10.39 (s, 1H), 8.01 (d, J ) 8.5
Hz, 2H), 7.85-7.82 (m, 2H), 7.85 (d, J ) 8.5 Hz, 2H), 7.13-
7.04 (m, 3H), 6.84 (d, J ) 7.9 Hz, 1H), 3.30 (d, J ) 10.7 Hz,
1H), 1.75-1.38 (m, 9H), 0.62-0.59 (m, 1H), 0.38-0.34 (m, 1H),
0.11-0.01 (m, 2H) ppm; 13C NMR (CDCl3) δ 169.7, 168.6,
165.3, 148.4, 147.7, 140.0, 136.6, 132.9, 131.7, 129.0, 125.2,
123.6, 114.7, 110.2, 48.7, 34.8, 33.0, 32.8, 30.1, 29.6, 26.2, 16.2,
9.7, 7.9 ppm; IR (mineral oil) 3234, 2234, 1666, 1652, 1608,
1587, 1550, 1497, 1441, 1414, 1349, 1248, 1168, 1157 cm-1
;
MS (EI) m/ z 504 (M+). Anal. (C28H28N2O5S) C, H, N, S.
N-[3-[Cyclop r op yl(5,6,7,8,9,10-h exa h yd r o-4-h yd r oxy-2-
oxo-2H -cyclooct a [b]p yr a n -3-yl)m et h yl]p h en yl]-2,6-d i-
1555, 1533, 1438, 1420, 1345, 1252, 1199, 1168, 1156 cm-1
;
1
MS (EI) m/ z 479 (M+). Anal. (C27H29NO5S) C, H, N.
m eth ylben zen esu lfon a m id e (36a ): white foam (69%); H
NMR (CDCl3 and CD3OD) δ 7.75 (s, 1H), 7.72-7.19 (m, 2H),
7.14-7.07 (m, 3H), 6.89-6.86 (m, 1H), 3.40-3.27 (m, 2H),
2.62-2.55 (m, 7H), 2.31 (s, 3H), 1.74-1.26 (m, 9H), 0.62-0.56
(m, 1H), 0.47-0.41 (m, 1H), 0.23-0.18 (m, 1H), 0.13-0.09 (m,
N-[3-[Cyclop r op yl(2,5,6,7,8,9-h exa h yd r o-4-h yd r oxy-2-
oxocycloh ep t a [b]p yr a n -3-yl)m et h yl]p h en yl]m et h a n e-
su lfon a m id e (7a ): prepared from 6a ; white foam (15%); H
1
NMR (CDCl3) δ 7.31-7.15 (m, 5H), 3.85 (d, J ) 9 Hz, 1H),
3.01 (s, 3H), 2.73-2.68 (m, 2H), 2.53-2.48 (m, 2H), 1.80-1.25
(m, 7H), 0.92-0.86 (m, 1H), 0.82-0.45 (m, 3H), 0.35-0.25 (m,
1H) ppm; MS (EI) m/ z 507 (M+); HRMS (EI) calcd for C29H33
-
NO5S 507.2079, found 507.2082.
1H) ppm; MS (EI) m/ z 403 (M+); HRMS (EI) calcd for C21H25
-
N-[3-[Cyclop r op yl(5,6,7,8,9,10-h exa h yd r o-4-h yd r oxy-2-
oxo-2H-cycloocta [b]p yr a n -3-yl)m eth yl]p h en yl]-1-m eth yl-
NO5S 403.1453, found 403.1463.
1
N-[3-[Cyclop r op yl(5,6,7,8,9,10-h exa h yd r o-4-h yd r oxy-2-
oxo-2H-cycloocta [b]p yr a n -3-yl)m eth yl]p h en yl]m eth a n e-
su lfon a m id e (8a ): white foam (59%); 1H NMR (CDCl3) δ
7.31-7.24 (m, 4H), 7.16-7.13 (m, 1H), 7.06 (br s, 1H), 3.81 (d,
1H-im id a zole-4-su lfon a m id e (37a ): white foam (72%); H
NMR (DMF-d7) δ 10.50 (s, 1H), 9.90 (s, 1H), 7.70 (s, 2H), 7.57
(s, 1H), 6.90 (s, 3H), 3.58 (s, 3H), 3.38 (br s, 1H), 3.25 (d, J )
11.3 Hz, 1H), 2.73-2.42 (m, 4H), 1.80-1.70 (m, 1H), 1.60-