3910 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 13
Ghosh et al.
quenched with 2 drops of benzylamine and concentrated under
reduced pressure. Flash chromatography purification (4% MeOH
in CHCl3 as the eluent) provided the Cbz-protected inhibitor (26.1
mg, 82%) as a white solid. Rf ) 0.49 (10% MeOH in CHCl3).
To a solution of the above protected inhibitor (17 mg, 0.02
mmol), in EtOAc (5 mL) under argon, was added Pd/C (3 mg).
The mixture was stirred at 23 °C under a H2 filled balloon for 5 h,
then filtered over Celite, and the filter cake was washed with EtOAc
and MeOH. Removal of solvent under reduced pressure, followed
by flash chromatography purification (5% MeOH in CHCl3 as the
eluent) provided inhibitor 18b (14 mg, 75%) as a white solid. Rf )
0.27 (10% MeOH in CHCl3); 1H NMR (500 MHz, CDCl3) δ
1.41-1.45 (m, 1H), 1.56-1.67 (m, 3H), 1.85 (d, 1H, J ) 13.4
Hz), 1.96-2.04 (m, 3H), 2.14-2.21 (m, 1H), 2.31-2.42 (m, 2H),
2.61 (brs, 1H), 2.74-2.85 (m, 3H), 3.09 (dd, 1H, J ) 4.4, 14.4
Hz), 3.15-3.20 (m, 1H), 3.25 (d,1H, J ) 14.3 Hz), 3.66-3.70 (q,
1H, J ) 7.1, 7.4 Hz), 3.83-3.88 (m, 2H), 3.91-3.96 (m, 1H),
3.96-4.25 (m, 1H), 4.40 (t, 1H, J ) 5.9 Hz), 4.87 (brs, 1H), 4.93
(d, 1H, J ) 8.9 Hz), 6.69 (d, 2H), 7.18-7.22 (m, 3H), 7.28-7.30
(m, 2H), 7.55 (d, 2H, J ) 8.4 Hz), 7.63 (s, 1H); 13C NMR (125
MHz, CDCl3) δ 24.3, 30.1, 34.1, 36.7, 38.7, 39.8, 41.9, 53.5, 54.3,
55.3, 56.8, 68.0, 72.8, 84.1, 114.6, 125.3, 126.8, 128.8, 129.9, 130.1,
138.1, 151.4, 156.6, 178.9. LRMS-ESI (m/z) [M + H]+ 586.9;
HRMS-ESI (m/z) [M + H]+ calcd for C29H39N4O7S 587.2539, found
587.2539.
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-(2S,3R)-3-hy-
droxy-4-(4-methoxy-N-(((R)-5-oxopyrrolidin-2-yl)methyl)phe-
nylsulfonamido)-1-phenylbutan-2ylcarbamate 19a. A solution of
compound 11 (20 mg, 0.03 mmol) in 30% trifluoroacetic acid (in
CH2Cl2, 3 mL) was stirred 23 °C for 40 min, then concentrated
under reduced pressure. The residue was redissolved in CH2Cl2 (3
mL), treated with Et3N (51 µL, 0.36 mmol), followed by carbonate
15 (11 mg, 0.04 mmol), and stirred at 23 °C for 12 h. The reaction
mixture was then concentrated under reduced pressure and the
residue was purified by flash chromatography (2% MeOH in CHCl3
as the eluent) to give inhibitor 19a (21 mg, 92%) as a white solid.
Rf ) 0.41 (10% MeOH in CHCl3); 1H NMR (500 MHz, CDCl3) δ
1.44 (dd, 1H, J ) 5.6, 13.2 Hz), 1.57-1.67 (m, 2H), 1.81-1.91
(m, 1H), 2.19-2.27 (m, 1H), 2.33-2.41 (m, 2H), 2.73 (dd, 1H J
) 10.35, 13.9 Hz), 2.83-2.91 (m, 2H), 2.95 (dd, 1H, J ) 8.9,
14.9 Hz), 3.11 (dd, 1H, J ) 4.2, 14.0 Hz), 3.26-3.30 (ddd, 2H, J
) 2.6, 7.0, 14.3 Hz), 3.64-3.70 (m, 1H), 3.74 (dd, 1H, J ) 5.5,
9.8 Hz), 3.76-3.81 (dt, 1H, J ) 1.62, 8.0 Hz), 3.87 (s, 3H),
3.89-3.93 (q, 1H, J ) 4.0, 5.6 Hz), 4.03-4.06 (m, 2H), 4.98-5.02
(q, 1H, J ) 5.65, 7.9 Hz), 5.62 (d, 1H, J ) 5.4 Hz), 6.98 (d, 2H,
J ) 8.9 Hz), 7.17-7.27 (m, 5H), 7.70 (d, 2H, J ) 8.8 Hz), 7.89 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 24.2, 25.7, 29.8, 35.4, 45.4,
55.0, 55.3, 55.5, 55.7, 58.1, 69.5, 71.0, 73.3, 74.0, 109.2, 114.4,
126.3, 128.3, 128.8, 129.2, 129.4, 137.8, 155.5, 163.2, 178.5.
LRMS-ESI (m/z) [M + Na]+ 626.3; HRMS-ESI (m/z) [M + Na]+
calcd for C29H37N3 Na O9S 626.2148, found 626.2156.
22.5, 30.0, 31.4, 33.9, 35.8, 38.2, 39.5, 41.7, 54.6, 54.9, 55.5, 56.0,
57.7, 67.7, 74.0, 83.9, 114.4, 126.2, 128.2, 128.9, 129.3, 129.4,
137.9, 156.1, 163.1, 178.5. LRMS-ESI (m/z) [M + H]+ 601.7;
HRMS-ESI (m/z) [M + H]+ calcd for C30H40N3O8S 602.2536, found
602.2536.
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-(2S,3R)-4-(4-
amino-N-(((R)-5-oxopyrrolidin-2-yl)methyl)phenylsulfonamido)-
3-hydroxy-1-phenylbutan-2-ylcarbamate 20a. A solution of the
(R)-aniline 12 (15 mg, 0.03 mmol) in 30% trifluoroacetic acid (in
CH2Cl2, 3 mL) was stirred at 23 °C for 40 min, then concentrated
under reduced pressure. The residue was redissolved in CH2Cl2 (3
mL), treated with Et3N (40 µL, 0.28 mmol), followed by carbonate
15 (9.2 mg, 0.03 mmol), and stirred at 23 °C for 6 h. The reaction
mixture was then concentrated under reduced pressure and the
residue was purified by flash chromatography (4% MeOH in CHCl3
as the eluent) to give inhibitor 20a (12.5 mg, 75%) as a white solid.
Rf ) 0.26 (10% MeOH in CHCl3); 1H NMR (500 MHz, CDCl3) δ
1.35 (dd, 1H, J ) 5.7 Hz), 1.50-1.63 (m, 2H), 2.15-2.23 (m,
1H), 2.27-2.31 (m, 2H), 2.56-2.72 (m, 3H), 2.82-2.87 (m, 2H),
3.07 (dd, 1H, J ) 4.0, 14.0 Hz), 3.36 (q, 1H, J ) 1.4, 3.5 Hz),
3.36 (q, 1H, J ) 2.0, 3.4 Hz), 3.60-3.65 (m, 1H), 3.70 (dd, 1H, J
) 5.4, 9.8 Hz), 3.75-3.79 (dt, 1H, J ) 1.96, 8.3 Hz), 3.80-3.86
(m, 1H), 3.88 (dd, 1H, J ) 5.9, 9.8 Hz), 3.90-3.94 (m, 1H),
3.99-4.02 (m, 1H), 4.92-4.97 (q, 1H, J ) 5.7, 8.1 Hz), 5.58 (d,
1H, J ) 5.8 Hz), 5.92 (d, 1H, J ) 9.5 Hz), 6.63 (d, 2H, J ) 8.7
Hz), 7.13-7.22 (m, 5H), 7.46 (d, 2H, J ) 8.7 Hz); 13C NMR (125
MHz, CDCl3) δ 24.1, 25.7, 29.7, 35.3, 45.4, 55.0, 55.5, 55.6, 58.1,
69.5, 71.0, 73.1, 73.9, 109.2, 113.8, 124.2, 126.2, 128.2, 129.1,
129.3, 137.8, 151.4, 155.6, 178.6. LRMS-ESI (m/z) [M + Na]+
611.4; HRMS-ESI (m/z) [M + Na]+ calcd for C28H36N4NaO8S
611.2152, found 611.2149.
(3aS,5R,6aR)-Hexahydro-2H-cyclopenta[b]furan-5-yl-(2S,3R)-
4-(4-amino-N-(((R)-5-oxopyrrolidin-2-yl)methyl)phenylsulfona-
mido)-3-hydroxy-1-phenylbutan-2-ylcarbamate 20b. The Cbz-
amine 12 (40 mg, 0.06 mmol) was treated with 30% trifluoroacetic
acid (in CH2Cl2, 6 mL) and stirred at 23 °C for 40 min, then
concentrated under reduced pressure. This residue was redissolved
in CH2Cl2 (6 mL), charged with Et3N (42 µL, 0.3 mmol), followed
by carbonate 16 (19 mg, 0.07 mmol), and stirred at 23 °C for 12 h.
Reaction was quenched with 3 drops of benzylamine and concen-
trated under reduced pressure. Flash chromatography purification
(5% MeOH in CHCl3 as the eluent) provided the Cbz-protected
inhibitor (32.1 mg, 75%) as a white solid. Rf ) 0.41 (10% MeOH
in CHCl3).
To the above Cbz-protected inhibitor (25.8 mg, 0.03 mmol), in
EtOAc (5 mL) under argon, was added Pd/C (5 mg). The mixture
was stirred at 23 °C under a hydrogen filled balloon for 3 h, then
filtered over Celite, and the filter cake was washed with EtOAc
and MeOH. Removal of solvent under reduced pressure followed
by flash chromatography purification (7.5% MeOH in CHCl3 as
the eluent) provided the title inhibitor 20b (16.2 mg, 77%) as a
white solid. Rf ) 0.51 (15% MeOH in CHCl3); 1H NMR (500 MHz,
CDCl3) δ 1.46 (m, 1H), 1.58-1.64 (m, 1H), 1.77-1.84 (m, 1H),
1.86-2.04 (m, 5H), 2.15-2.23 (m, 1H), 2.32-2.36 (m, 2H),
2.59-2.65 (m, 1H), 2.68 (dd, 1H, J ) 9.2, 14.0 Hz), 2.95-3.04
(m, 2H), 3.11 (d, 2H, J ) 13.7 Hz), 3.18 (d, 1H, J ) 14.9 Hz),
3.57-3.62 (q, 1H, J ) 6.9, 7.7 Hz), 3.82-3.87 (q, 2H, J ) 6.5,
7.9 Hz), 3.92-3.97 (m, 1H), 4.30 (s, 2H), 4.37 (t, 1H, J ) 5.7
Hz), 4.75 (s, 1H), 4.89 (s, 1H), 5.40 (d, 1H, J ) 8.4 Hz), 6.66 (d,
2H, J ) 8.6 Hz), 7.16-7.22 (m, 3H), 7.24-7.27 (m, 2H), 7.40 (s,
1H), 7.51 (d, 2H, J ) 8.6 Hz); 13C NMR (125 MHz, CDCl3) δ
23.7, 30.0, 33.9, 35.9, 38.1, 39.5, 41.7, 54.6, 54.8, 55.9, 57.6, 67.7,
74.0, 76.6, 84.0, 114.1, 124.9, 126.2, 128.2, 129.3, 129.4, 137.9,
151.0, 156.2, 178.4. LRMS-ESI (m/z) [M + Na]+ 609.0; HRMS-
ESI (m/z) [M + Na]+ calcd for C29H38N4NaO7S 609.2359, found
609.2362.
(3aS,5R,6aR)-Hexahydro-2H-cyclopenta[b]furan-5-yl-(2S,3R)-
3-hydroxy-4-(4-methoxy-N-(((R)-5-oxopyrrolidin-2-yl)methyl)phe-
nylsulfonamido)-1-phenylbutan-2-ylcarbamate 19b. A solution
of compound 11 (21 mg, 0.04 mmol) in 30% trifluoroacetic acid
(in CH2Cl2, 3 mL) was stirred at 23 °C for 40 min, then concentrated
under reduced pressure. The residue was redissolved in CH2Cl2 (3
mL), treated with Et3N (27 µL, 0.19 mmol), followed by carbonate
16 (12 mg, 0.04 mmol), and stirred at 23 °C for 12 h. The reaction
mixture was then concentrated under reduced pressure and the
residue was purified by flash chromatography (1% MeOH in CHCl3
as the eluent) to give inhibitor 19b (21 mg, 93%) as a white solid.
1
Rf ) 0.31 (5% MeOH in CHCl3); H NMR (500 MHz, CDCl3) δ
1.48 (d, 1H, J ) 14.1 Hz), 1.58-1.62 (m, 1H), 1.83-2.04 (m,
5H), 2.19-2.25 (m, 1H), 2.31-2.41 (m, 2H), 2.59-2.67 (m, 1H),
2.73 (dd, 1H, J ) 9.0, 13.9 Hz), 3.03 (dd, 1H, J ) 7.0, 15.0 Hz),
3.08-3.16 (m, 2H), 3.19 (d, 1H, J ) 14.9 Hz), 3.57-3.63 (m,
1H), 3.83-3.86 (m, 3H), 3.86 (s, 3H), 3.94-3.99 (m, 1H), 4.78
(d, 1H, J ) 13.7 Hz), 4.90 (s, 1H), 5.36 (d, 1H, J ) 8.1 Hz), 6.97
(d, 2H, J ) 8.6 Hz), 7.18-7.28 (m, 5H), 7.46 (d, 1H, J ) 18.4
Hz), 7.70 (d, 2H, J ) 8.8 Hz); 13C NMR (125 MHz, CDCl3) δ
(R)-tert-Butyl-4-(((2R,3S)-3-(tert-butoxycarbonylamino)-2-hy-
droxy-4-phenylbutylamino)methyl)-2,2-dimethyloxazolidine-3-
carboxylate 22. To a solution of the (R)-tert-butyl 4-(azidomethyl)-
2,2-dimethyloxazolidine-3-carboxylate 21 (411 mg, 1.60 mmol) in
MeOH (10 mL) was added Pd/C (40 mg). This mixture was stirred