Monopyrrolinone-Based HIV-1 Protease Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 1839
(+)-8 (135.3 mg, 0.280 mmol) in CHCl3 (5 mL), and the solvent
was removed in vacuo. The residue was redissolved in dry
toluene (3-5 mL) and subsequently concentrated in vacuo with
gentle warming for five cycles. The resulting imine was then
stored under vacuum for 16 h, dissolved in THF (3 mL), and
treated dropwise with KHMDS (0.5 M solution in toluene, 1.68
mL, 0.84 mmol) at room temperature. During the addition,
the color of the reaction mixture changed from pale yellow to
deep violet. After 10 min, the reaction mixture was quenched
with 10% NaHSO4 (10 mL) and the resulting mixture was
extracted with EtOAc (2 × 15 mL). The combined organic
phases were washed with brine (10 mL), dried (MgSO4),
filtered, and concentrated in vacuo. Flash chromatography (5-
15% EtOAc/hexanes gradient) afforded (+)-18 (123.5 mg, 61%
yield) as a pale yellow glass: [R]D + 9.3 (c 0.4 CHCl3). IR
(CHCl3): 3425 (m), 2960 (m), 2930 (s), 2860 (m), 1685 (s), 1660
(s), 1580 (s), 1390 (s), 1370 (s), 1250 (s), 1170 (s), 1160 (s), 1120
(s), 900 (s) cm-1. 1H NMR (500 MHz, CDCl3, 330 K): δ 7.49 (s,
1H), 7.30-7.04 (m, 14H), 6.79 (br d, J ) 7.3 Hz, 1H), 6.34 (br
s, 1H), 5.03 (br d, J ) 9.1 Hz, 1H), 4.24 (m, 1H), 4.06 (d, J )
4.6 Hz, 1H), 4.00 (br d, J ) 8.9 Hz, 1H), 3.65 (q, J ) 7.7 Hz,
1H), 3.13 (d, J ) 13.2 Hz, 1H), 3.03 (dd, J ) 16.3, 5.0 Hz, 1H),
2.95 (m, 2H), 2.84-2.80 (m, 2H), 2.01 (dd, J ) 14.2, 9.4 Hz,
1H), 1.90 (br d, J ) 12.6 Hz, 1H), 1.40 (s, 9H). 13C NMR (125
MHz, CDCl3, 330 K): δ 204.4, 164.4, 156.6, 142.6, 141.7, 138.5,
134.9, 130.2, 129.5, 128.6, 128.1, 127.3, 127.0, 126.5, 126.5,
125.0, 124.2, 110.4, 79.7, 74.3, 70.6, 68.2, 57.5, 45.5, 42.2, 40.5,
40.5, 38.9, 28.4. HRMS (FAB, m-nitrobenzyl alcohol): m/z
591.2848 [(M + Na)+; calcd for C35H40N2O5Na, 591.2835]. Anal.
calcd for C35H40N2O5: C, 73.91; H, 7.10; N, 4.93. Found: C,
73.59; H, 7.19; N, 4.70.
Tet r a h yd r ofu r a n ylca r ba m a t e-Mon op yr r olin on e (-)-
7. A solution of free amine (+)-19 (170 mg, 0.363 mmol) in
CH2Cl2 (10 mL) was treated with tetrahydrofuranylsuccidi-
midyl carbonate (+)-20 (104 mg, 0.453 mmol) and Et3N (110
mg, 1.09 mmol), and the solution was stirred at room temper-
ature for 6.5 h. The reaction was quenched with CH2Cl2 (30
mL) and 10% NaHSO4 (30 mL), and the resultant phases were
separated. The organic layer was washed again with 10%
NaHSO4 (30 mL). The combined aqueous phases were ex-
tracted with CH2Cl2 (2 × 30 mL), and the combined organic
phases were washed with saturated NaHCO3 (30 mL) and
brine (30 mL), dried (MgSO4), filtered, and concentrated in
vacuo. Flash chromatography (80-90% EtOAc/hexanes, gradi-
ent) furnished (-)-7 (183 mg, 87% yield) as a pale yellow
glass: [R]D -55 (c 0.18, CHCl3). IR (CHCl3): 3700 (m), 3440
1
(m), 1090 (s), 1060 (s) cm-1. H NMR (500 MHz, CDCl3, 330
K): δ 7.61 (br d, J ) 2.7 Hz, 1H), 7.30-7.09 (m, 14H), 6.95 (br
t, J ) 7.4 Hz, 1H), 6.72 (br d, J ) 7.5 Hz, 1H), 5.17 (br s, 1H),
4.63 (m, 1H), 4.30 (br d, J ) 5.1 Hz, 1H), 3.73 (td, J ) 1.3, 8.3
Hz, 1H), 3.56 (td, J ) 2.2, 6.6 Hz, 1H), 3.15 (dd, J ) 5.2, 15.9
Hz, 1H), 2.94 (dd, J ) 2.6, 15.9 Hz, 1H), 2.85-2.75 (m, 2H),
2.07 (app br d, J ) 12.6 Hz, 1H), 1.79 (dd, J ) 9.4, 14.5 Hz,
1H), 1.51 (s, 9H), 1.33 (s, 3H), 0.86 (s, 12H, overlapping
singlets), 0.08 (s, 3H), 0.01 (s, 3H). 13C NMR (125 MHz, CDCl3,
330 K): δ 203.2, 164.8, 152.1, 144.6, 141.2, 136.8, 136.6, 130.5,
128.4, 128.3, 126.8, 126.5, 126.5, 126.3, 124.5, 124.5, 112.3,
94.4, 80.0, 75.5, 74.0, 69.1, 63.6, 53.2, 44.7, 43.4, 42.1, 38.8,
28.6, 27.9, 26.0, 25.8, 18.2, -4.4, -4.8. HRMS (FAB, m-
nitrobenzyl alcohol): m/z 745.4044 [(M + Na)+; calcd for
(m), 3350 (br m), 3020 (m), 1715 (s), 1360 (m), 1210 (s) cm-1
.
1H NMR (500 MHz, CDCl3, 330 K): δ 7.54 (s, 1H), 7.32-7.17
(m, 10H), 7.13 (t, J ) 7.3 Hz, 1H), 7.08 (t, J ) 7.3 Hz, 1H),
7.03 (d, J ) 6.6 Hz, 2H), 6.77 (d, J ) 7.4 Hz, 1H), 6.29 (br s,
1H), 5.17-5.12 (m, 2H), 4.31 (m, 1H), 4.07-4.03 (m, 2H), 3.90-
3.76 (m, 4H), 3.7 (m, 2H), 3.14 (d, J ) 13.4 Hz, 1H), 3.05 (dd,
J ) 5.2, 16.3 Hz, 1H), 2.98 (dd, J ) 7.8, 13.6 Hz, 1H), 2.93-
2.80 (m, 3H), 2.10 (app br s, 1H), 2.03-1.89 (m, 3H). 13C NMR
(125 MHz, CDCl3, 330 K): δ 204.7, 164.3, 156.5, 142.5, 141.6,
138.3, 134.8, 130.1, 129.5, 128.6, 128.2, 127.4, 127.0, 126.6,
126.6, 125.1, 124.2, 110.8, 75.5, 74.3, 73.3, 70.6, 67.9, 67.0, 57.9,
45.5, 42.3, 40.5, 40.4, 38.9, 32.8. HRMS (CI, NH3): m/z
583.2802 [(M + H)+; calcd for C35H39N2O6, 583.2808; σ ) 1
ppm].
C
44H58N2O5SiNa, 745.4013].
Mon op yr r olin on e (+)-19. Monopyrrolinone (+)-18 (161
mg, 0.223 mmol) was dissolved in 1 N anhydrous methanolic
HCl (22 mL), and the resulting solution was stirred at room
temperature for 4.5 h. Solid NaHCO3 was then added portion-
wise until the evolution of gas ceased. Most of the methanol
was then removed in vacuo, and the residue was dissolved in
a mixture of EtOAc (30 mL) and saturated NaHCO3 (30 mL).
The phases were separated, and the aqueous phase was
extracted with EtOAc (2 × 30 mL). The combined organic
phases were then washed with brine (30 mL), dried (MgSO4),
filtered, and concentrated in vacuo. Flash chromatography (6%
MeOH-saturated with NH3/CH2Cl2) furnished (+)-19 (95 mg,
91% yield) as a white solid: mp 74 °C (dec); [R]D + 3.8 (c 0.99,
CHCl3). IR (CHCl3): 3570 (m), 3450 (m), 3400 (br m), 3300
(br m), 2920 (m), 1650 (s), 1570 (s), 1460 (m), 1170 (m), 900
In d a n ol (+)-21. To a solution of pyrrolinone (+)-18 (83 mg,
0.115 mmol) in THF (1 mL) at room temperature was added
TBAF (0.23 mL, 0.23 mmol, 1.0 M solution in THF). After it
was stirred for 24 h, saturated NH4Cl (1 mL) was added and
the reaction mixture was poured into EtOAc (2 mL). The
aqueous phase was then extracted with EtOAc (2 × 3 mL),
the combined organic extracts were dried (MgSO4), filtered,
and concentrated in vacuo. Flash chromatography (50% EtOAc:
hexanes) afforded (+)-21 (53 mg, 76%) as a white amorphous
solid: [R]D + 14.7 (c 1.00, CHCl3). IR (CHCl3): 3560 (w), 3420
(w), 3002 (w), 2980 (s), 2920 (m), 1680 (s), 1665 (s), 1575 (s),
1395 (s), 1380 (s), 1370 (s), 1200 (m), 1170 (m), 1120 (m), 1080
(m), 1040 (w), 700 (s) cm-1. 1H NMR (500 MHz, CDCl3): δ 7.38
(d, J ) 3.6 Hz, 1H), 7.30-7.10 (m, 14H), 7.00 (t, J ) 7.1 Hz,
1H), 6.58 (d, J ) 7.2 Hz, 1H), 5.40 (apparent bs, 1H), 4.15 (m,
2H), 3.80 (dd, J ) 7.1, 6.7 Hz, 1H), 3.75 (bm, 1H), 3.38 (bm,
1H), 3.05 (m, 2H), 2.90 (m, 1H), 2.84 (s, 1H), 2.80 (d, J ) 4.7
Hz, 1H), 2.38-2.12 (br m, 1H), 2.20 (dd, J ) 8.4, 14.6 Hz, 1H),
1.58 (s, 12H), 1.12-0.88 (br m, 3H). 13C NMR (125 MHz,
CDCl3): δ 202.8, 164.6, 142.4, 141.9, 136.7, 135.0, 130.1, 128.4,
127.8, 127.2, 126.8, 126.3, 124.9, 124.2, 111.2, 80.2, 73.5, 70.2,
63.2, 45.4, 43.3, 40.2, 28.5, 25.7. HRMS (Cl, NH3): m/z
609.3316 [(M + H)+; calcd for C38H45N2O5, 609.3328; σ ) 2
ppm].
(br s), 730 (br s) cm-1 1H NMR (500 MHz, CDCl3): 7.56 (s,
.
1H), 7.31 (t, J ) 7.6 Hz, 2H), 7.28-7.18 (m, 9H), 7.14 (t, J )
7.4 Hz, 1H), 7.09 (t, J ) 7.3 Hz, 1H), 6.99 (br s, 1H), 6.77 (d,
J ) 7.4 Hz, 1H), 4.24 (td, J ) 4.9, 1.3 Hz, 1H), 4.07 (d, J ) 4.6
Hz, 1H), 3.57-3.54 (m, 1H), 3.16 (d, J ) 13.1 Hz, 1H), 3.04
(dd, J ) 5.1, 16.3 Hz, 1H), 2.98 (d, J ) 13.2 Hz, 1H), 3.00-
2.96 (m, overlapping with another signal, 1H), 2.90 (m, 1H),
2.86 (d, J ) 16.3 Hz, 1H), 2.55 (dd, J ) 9.1, 13.5 Hz, 1H), 2.24
(dd, J ) 2.5, 14.4 Hz, 1H), 2.19 (very br s, ∼4H), 2.02 (dd, J )
9.0, 14.4 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 203.8, 165.0,
142.6, 141.6, 138.5, 135.1, 130.1, 129.2, 128.6 127.8, 127.1,
126.7, 126.5, 126.4, 124.9, 124.1, 109.8, 74.2, 70.6, 69.8, 57.0,
45.7, 43.6, 40.9, 40.5, 40.4. HRMS (CI, NH3): m/z 469.2489
[(M + H)+; calcd for C30H33N2O3, 469.2490; σ ) 1 ppm].
Boc-Mon op yr r olin on e In h ibitor (-)-6. A solution of free
amine (+)-19 (13.0 mg, 0.0277 mmol) in CH2Cl2 (1 mL) was
treated with (Boc)2O (7.2 mg, 0.033 mmol) and Et3N (0.0097
mL, 0.069 mmol), and the resultant solution was stirred at
room temperature for 2.5 h. The reaction was then quenched
with 10% NaHSO4 (5 mL), and the mixture was extracted with
EtOAc (2 × 8 mL). The combined organic phases were then
washed with 10% NaHSO4 (5 mL), saturated NaHCO3 (5 mL),
and brine (5 mL), dried (MgSO4), filtered, and concentrated
in vacuo. Flash chromatography (45-65% EtOAc/hexanes,
gradient) afforded (-)-6 (13.5 mg, 86% yield) as a white solid:
mp 212-213 °C; [R]D -26 (c 1.0, CHCl3). IR (CHCl3): 3560
(m), 3440 (m), 3280 (br m), 3000 (m), 1680 (s), 1490 (s), 1160
Tr ich lor oa cetyl Ca r ba m a te (+)-22. To a solution of
indanol (+)-18 (67 mg, 0.110 mmol) in CH2Cl2 (1 mL) at room
temperature was added trichloroacetylisocyanate (0.013 mL,
0.110 mmol), and after 1 h, the solvent was removed in vacuo.
Flash chromatography (5-25% EtOAc:hexanes, gradient)
furnished (+)-22 (67 mg, 76%) as a colorless oil; [R]D + 7.0 (c
1.00, CHCl3). IR (CHCl3): 3680 (w), 3540 (w), 3450 (m), 3010