Cycloamide-Derived HIV-1 Protease Inhibitors
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10 3583
cm-1. 1H NMR (500 MHz, CDCl3): δ 7.73 (m, 3 H), 7.48 (dd, 1
H, J ) 2.3, 7.3 Hz), 7.10 (m, 2 H), 6.98 (dd, 1 H, J ) 2.9, 11.9
Hz), 6.97 (dd, 1 H, J ) 2.0, 6.9 Hz), 5.96 (tdd, 1 H, J ) 6.9,
10.2, 17.2 Hz), 5.83 (s, 1 H) 5.77 (tdd, 1 H, J ) 6.7, 10.3, 17.1,
Hz), 5.33 (m, 1 H), 5.29 (d, 1 H, J ) 10.2 Hz), 4.97 (ddd, 1 H,
J ) 1.7, 3.5, 17.0 Hz), 4.91 (m, 1 H), 4.09 (m, 2 H), 3.95 (m, 2
H), 3.87 (s, 3 H), 3.80 (d, 1 H, J ) 3.2, Hz), 3.21 (dd, 1 H, J )
9.1, 15.1 Hz), 3.01 (m, 1 H), 2.98 (dd, 1 H, J ) 2.9, 5.6 Hz),
2.83 (dd, 1 H, J ) 6.6, 13.3 Hz), 2.57 (m 2 H), 2.04 (m, 2 H),
1.86 (m, 1 H), 1.60 (m, 2 H), 1.45 (m, 2 H), 1.38 (m, 2 H), 0.91
(d, 3 H, J ) 6.6 Hz), 0.86 (d, 3 H, J ) 6.6 Hz). 13C NMR (125
MHz, CDCl3): δ 165.9, 163.5, 149.6, 144.3, 139.1, 134.6, 130.3,
129.9, 127.3, 125.8, 122.6, 119.7, 119.5, 115.0, 114.8, 74.8, 73.5,
59.1, 56.0, 54.1, 53.2, 34.6, 34.0, 30.1, 29.3, 27.6, 26.1, 20.5,
20.3. MS-ESI (m/z): 589.2 (M + H)+. HRMS-ESI (m/z) [M +
Na]+ calcd for C31H44N2O7NaS, 611.2769; found, 611.2767.
of major isomer (500 MHz, CDCl3): δ 7.69 (d, 2 H, J ) 8.9
Hz), 7.51 (m, 2 H), 7.10 (m, 2 H), 6.94 (d, 2 H, J ) 8.9 Hz),
5.78 (ddd, 1 H, J ) 5.5, 10.9, 14.9 Hz), 5.50 (m, 1 H), 5.47 (s,
1 H), 4.16 (d, 1 H, J ) 4.7 Hz), 3.99 (m, 2 H), 3.86 (s, 3 H),
3.81 (m, 1 H), 3.18 (dd, 1 H, J ) 2.8, 15.1 Hz), 3.07 (dd, 1 H,
J ) 8.4, 15.1 Hz), 2.91 (d, 2 H, J ) 7.6 Hz), 2.59 (m, 1 H), 2.44
(m, 1 H), 2.19 (m, 2 H), 1.85 (m, 1 H), 1.74 (m, 1 H), 1.65-
1.42 (m, 5 H), 1.36 (m, 1 H), 0.86 (d, 3 H, J ) 6.6 Hz), 0.84 (d,
3 H, J ) 6.7 Hz). 13C NMR (125 MHz, CDCl3): δ 166.8, 163.3,
149.4, 144.8, 133.2, 130.8, 129.8, 128.5, 127.2, 125.6, 123.3,
120.0, 114.7, 75.9, 74.4, 58.4, 56.0, 55.1, 53.4, 34.2, 29.5, 27.3,
26.8, 25.3, 22.7, 20.5, 20.4.
(2′′R,15S)-N-[2′′-Hydroxy-2′′-(4-hydroxy-17-oxo-6,7,8,-
11,12,13,14,15,16,17-decahydro-5-oxa-16-aza-benzocyclo-
pentadecen-15-yl)ethyl]isobutyl-4-methoxy-benzene-
sulfonamide (24). Acyclic diene 21 was subjected to the
conditions of olefin metathesis as described for 20 resulting
in 24 (29 mg, 89%) as a white solid (2:1 mixture). IR (neat):
(1′′S,1′′′R)-3-Hydroxy-N-(1′′-{1′′′-hydroxy-2′′′-[isobutyl-
(4-methoxy-benzenesulfonyl)amino]ethyl}hept-6′′-enyl)-
2-pent-4′′′′-enyloxy-benzamide (21). Acid 11 was coupled
with amine 18 according to the general procedure for 20 to
1
3338, 1640, 1596, 1530 cm-1. H NMR of major isomer (400
MHz, CDCl3): δ 7.71 (d, 2 H, J ) 8.9 Hz), 7.37 (m, 1 H), 7.06
(m, 2 H), 6.95 (d, 2 H J ) 8.8 Hz), 5.78 (s, 1 H), 5.42 (m, 1 H),
5.25 (m, 1 H), 4.11 (m, 1H), 4.04 (m, 1 H), 3.86 (m, 4 H), 2.9
(d, 1 H, J ) 2.9 Hz), 3.2 (dd, 1 H, J ) 9.0, 15.2 Hz), 2.97 (m,
2 H), 2.81 (dd, 1 H, J ) 6.8, 15.0 Hz), 2.30-2.00 (m, 3 H),
2.00-1.80 (m, 3 H), 1.70 (m, 1 H), 1.57 (m, 4 H), 1.4 (m, 2 H),
1.3 (m, 2 H), 0.91 (d, 3 H, J ) 6.7 Hz), 0.85 (d, 3 H, J ) 6.7
Hz). 13C NMR (100 MHz, CDCl3): δ 165.6, 163.0, 149.1, 144.4,
131.6, 130.5, 129.5, 126.6, 124.8, 121.8, 118.5, 114.4, 75.4, 74.4,
73.2, 58.7, 55.6, 53.9, 52.7, 30.9, 29.0, 27.6, 27.5, 27.2, 26.7,
24.0, 20.1, 19.9.
23
give 21 (39 mg, 76%) as an oil: [R]D -15.3 (c 0.15, CHCl3).
1
IR (neat): 3347, 1638, 1577, 1535, 1335 cm-1. H NMR (500
MHz, CDCl3): δ 7.77 (d, 1 H, J ) 8.6 Hz), 7.73 (dd, 1 H, J )
2.9, 11.9 Hz), 7.71 (dd, 1 H, J ) 2.0, 6.9 Hz), 7.51 (dd, 1 H, J
) 2.9, 6.7 Hz), 7.10 (m, 2 H), 6.98 (dd, 1 H, J ) 2.9, 11.8 Hz),
6.97 (dd, 1 H, J ) 2.0, 6.9 Hz), 5.89 (tdd, 1 H, J ) 6.7, 10.2,
17.1 Hz), 5.77 (tdd, 1 H, J ) 6.7, 10.3, 17.0 Hz), 5.71 (s, 1 H),
5.15 (ddd, 1 H, J ) 1.6, 3.2, 17.2 Hz), 5.08 (dd, 1 H, J ) 1.5,
10.1 Hz), 4.98 (ddd, 1 H, J ) 1.6, 3.4, 17.1 Hz), 4.92 (m, 1 H),
4.09 (m, 1 H), 4.01 (m, 1 H), 3.93 (m, 2 H), 3.87 (s, 3 H), 3.78
(d, 1 H, J ) 3.2 Hz), 3.21 (dd, 1 H, J ) 9.1, 15.1 Hz), 3.01 (d,
1 H, J ) 1.9 Hz), 2.98 (m, 1 H), 2.83 (dd, 1 H, J ) 6.6, 13.2
Hz), 2.29 (q, 2 H, J ) 7.0 Hz), 2.03 (m, 2 H), 1.98 (quint., 2 H,
J ) 7.0 Hz), 1.85 (m, 1 H), 1.63 (m, 2 H), 1.45 (m, 2 H), 1.38
(m, 2 H), 0.91 (d, 3 H, J ) 6.6 Hz), 0.86 (d, 3 H, J ) 6.6 Hz).
13C NMR (125 MHz, CDCl3): δ 165.8, 163.4, 149.6, 144.4,
139.1, 138.3, 130.3, 129.9, 127.1, 125.7, 122.9, 119.6, 116.3,
115.0, 114.8, 75.5, 73.5, 59.0, 56.0, 54.1, 53.2, 34.0, 30.7, 30.1,
29.4, 29.3, 27.6, 26.1, 20.5, 20.3. HRMS-ESI (m/z): (M + Na)+
calcd for C32H46N2O7NaS, 625.2934; found, 625.2923.
(1′S,1′′R)-2,3-Dihydroxy-N-(1′-{1′′-hydroxy-2′′-[isobutyl-
(4-methoxy-benzenesulfonyl)amino]ethyl}octyl)-
benzamide (25). To a stirred solution of 22 (20.4 mg, 0.03
mmol), 2.8 mg of 10% Pd-C in 6 mL of MeOH was added,
and the resulting suspension was stirred at 23 °C under H2
balloon for 3 h. The mixture was filtered through Celite and
concentrated. Flash silica gel chromatography (35% EtOAc/
hexanes) provided 25 (12.9 mg, 63%); mp 44-46 °C; [R]D23 +3.6
(c 0.30, CHCl3). IR (neat): 3381, 2926, 1640, 1595, 1540, 1459,
1331, 1264, 1150, 1091, 1025, 806, 760 cm-1 1H NMR (500
.
(2′′R,13S)-N-[2′′Hydroxy-2′′-(4-hydroxy-15-oxo-6,9,10,-
11,12,13,14,15-octahydro-5-oxa-14-aza-benzocyclotri-
decen-13-yl)ethyl]-N-isobutyl-4-methoxy-benzenesulfon-
amide (22). To a stirred solution of 19 (29.3 mg, 0.05 mmol)
in 20 mL of CH2Cl2 was added 4.2 mg (0.0051 mmol) of Grubbs’
catalyst. The solution was allowed to stir for 45 min under Ar
and then concentrated. Flash silica gel chromatography (40
to 45% EtOAc/ hexanes) resulted in 22 (26.8 mg, 96%) as a
pale yellow foam as a mixture (5.5:1). IR (neat): 3341, 2953,
1635, 1575, 1538, 1463, 1333, 1260, 1152, 1091, 756 cm-1. 1H
NMR of trans diastereomer (400 MHz, CDCl3): δ 8.13 (d, 1
H, J ) 9.2 Hz), 7.66 (m, 2 H), 7.09 (d, 2 H, J ) 4.8 Hz), 6.90
(d, 2 H, J ) 8.8 Hz), 5.75 (m, 2 H), 5.35 (s, 1 H), 4.99 (dd, 1 H,
J ) 6.4, 11.2 Hz), 4.27 (dd, 1 H, J ) 7.2, 11.2 Hz), 4.00 (m, 1
H), 3.84 (s, 3 H), 3.81 (m, 1 H), 3.61 (d, 1 H, J ) 3.1 Hz), 3.11
(dd, 1 H, J ) 8.7, 15.2 Hz), 3.00 (m, 1 H), 2.89 (dd, 1 H, J )
8.2, 13.4 Hz), 2.80 (dd, 1 H, J ) 6.9, 13.4 Hz), 2.25 (m, 1 H),
2.15 (m, 1 H), 1.79 (m, 1 H), 1.57-1.7 (m, 2 H), 1.56 (m, 3 H),
1.42 (m, 2 H), 0.87 (d, 3 H, J ) 6.6 Hz), 0.81 (d, 3 H, J ) 6.7
Hz). 13C NMR (100 MHz, CDCl3): δ 165.4, 162.9,148.8, 145.3,
137.7, 129.7, 129.5, 126.3, 125.7, 124.6, 123.2, 120.0, 114.3,
73.4, 58.6, 55.6, 53.9, 52.9, 30.5, 27.1, 26.9, 24.0, 22.3, 20.0,
19.9. MS-ESI (m/z): 547.2 (M + H)+. HRMS-ESI (m/z) [M +
Na]+ calcd for C28H38N2O7NaS, 569.2299; found, 569.2297.
(2′′R,14S)-N-[2′′-Hydroxy-2′′-(4-hydroxy-16-oxo-7,10,11,-
12,13,14,15,16-octahydro-6H-5-oxa-15-aza-benzocyclotet-
radecen-14-yl)ethyl]-N-isobutyl-4-methoxy-benzene-
sulfonamide (23). To a stirring solution of 29 mg (0.046
mmol) of 20 in 25 mL of CH2Cl2 at 23 °C was added 3.6 mg
(0.0044 mmol) of Grubbs’ catalyst. The solution was stirred
at 23 °C for 13.5 h and then concentrated. Purification by flash
silica gel chromatography (35-40% EtOAc/hexanes) resulted
in 23 (25 mg) as a white solid (89%) as a mixture of isomers
(10:1). IR (neat): 3340, 1634, 1577, 1530, 1332 cm-1. 1H NMR
MHz, CDCl3): δ 7.70 (dd, 1 H, J ) 3.0, 11.9 Hz), 7.69 (dd, 1
H, J ) 2.0, 6.9 Hz), 7.07 (d, 1 H, J ) 7.2 Hz), 7.02 (dd, 1 H, J
) 1.1, 8.2 Hz), 6.96 (dd, 1 H, J ) 1.6, 5.6 Hz), 6.95 (dd, 1 H, J
) 2.3, 11.8 Hz), 6.80 (m, 2 H), 5.80 (s, 1 H), 4.14 (qd, 1 H, J )
4.3, 13.7 Hz), 3.94 (td, 1 H, J ) 4.1, 11.6 Hz), 3.86 (s, 3 H),
3.54 (d, 1 H, J ) 3.7 Hz), 3.09 (m, 2 H), 2.92 (dd, 1 H, J ) 7.8,
13.4 Hz), 2.87 (dd, 1 H, J ) 7.3, 13.4 Hz), 1.86 (septet, 1 H, J
) 6.8 Hz), 1.69 (m, 2 H), 1.25-1.30 (m, 9 H), 0.90 (d, 3 H, J )
6.3 Hz), 0.89 (d, 3 H, J ) 6.3 Hz), 0.86 (t, 3 H, J ) 6.9 Hz). 13
C
NMR (125 MHz, CDCl3): δ 170.6, 163.5, 149.6, 146.3, 130.0,
129.9, 119.2, 118.7, 116.6, 114.8, 114.1, 73.5, 59.3, 56.0, 53.9,
53.3, 32.2, 29.8, 29.7, 29.6, 27.7, 26.6, 23.0, 20.5, 20.4, 14.5.
MS-ESI (m/z): 573.3 (M + Na)+. HRMS-ESI (m/z) [M + Na]+
calcd for C28H42N2O7NaS, 573.2613; found, 573.2610.
(2′′R,14S)-N-[2′′-Hydroxy-2′′-(4-hydroxy-16-oxo-7,8,9,-
10,11,12,13,14,15,16-decahydro-6H-5-oxa-15-aza-benzocy-
clotetradecen-14-yl)ethyl]-N-isobutyl-4-methoxy-ben-
zenesulfonamide (26). A mixture of 23 (21 mg, 0.037 mmol)
and 2.7 mg of 10% Pd-C in 10 mL of MeOH was stirred at 23
°C under H2 balloon for 4 h. The mixture was then filtered
through Celite and concentrated. Purification by flash silica
gel chromatography (40% EtOAc/hexanes) provided 26 (14 mg,
23
69%) as a white solid; mp 63-65 °C. [R]D +12.9 (c 0.35,
CHCl3). IR (neat): 3350, 1637, 1596, 1531, 1331 cm-1. 1H NMR
(500 MHz, CDCl3): δ 7.69 (dd, 1 H, J ) 2.9, 11.7 Hz), 7.68
(dd, 1 H, J ) 1.8, 7.0 Hz), 7.38 (dd, 1 H, J ) 3.6, 5.9 Hz), 7.28
(d, 1 H, J ) 7.3 Hz), 7.09 (m, 2 H), 6.94 (dd, 2 H, J ) 2.9, 11.7
Hz), 5.79 (m, 1 H), 4.16-4.10 (m, 2 H), 3.86 (m, 4 H), 3.72 (d,
1 H, J ) 3.2 Hz), 3.14 (dd, 1 H, J ) 8.7, 15.2 Hz), 3.04 (dd, 1
H, J ) 3.0, 15.2 Hz), 2.91 (dd, 1 H, J ) 8.1, 13.4 Hz), 2.83 (dd,
1 H, J ) 7.0, 13.4 Hz), 1.92 (m, 2 H), 1.82 (septet, 1 H, J ) 6.9
Hz), 1.68 (m, 2 H), 1.57-1.37 (m, 9 H), 1.25 (m, 2 H), 0.87 (d,
3 H, J ) 7.1 Hz), 0.83 (d, 3 H, J ) 6.6 Hz). 13C NMR (125
MHz, CDCl3): δ 166.7, 163.4, 149.6, 144.5, 130.3, 129.9, 128.1,