5320 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22
SauVaˆıtre et al.
by column chromatography on alumina with dichloromethane-
methanol (98:2) as eluent followed by trituration in acetone to afford
a colorless powder of 4 (105 mg, 42%), whose spectroscopic
characteristics are identical to those described.30 Second procedure
in the oven: Compound 2 (100 mg, 0.20 mmol, 1 equiv) was heated
at 240 °C under 0.05 mmHg in a rotating distillation oven with
four bulbs. A product sublimated in 3 h. The sublimate was
composed of a mixture of the expected product 4 (18%) and
dihydrooxazine 1 (82%). The sublimate was purified by column
chromatography on alumina with dichloromethane-methanol (98:
2) as eluent followed by trituration in acetone to afford a colorless
powder of 4 (91 mg, 91%), whose spectroscopic characteristics were
(CH3, C-21), 11.4 (CH3, C-30), 17.9 (CH3, C-18), 18.4 (CH2, C-6),
20.9 (CH3, C-28), 24.4 (CH2, C-7), 27.7 (CH2, C-1), 27.7 (CH2,
C-2), 30.6 (CH2, C-19), 34.5 (C, C-9), 37.8 (C, C-10), 41.3 (CH,
C-5), 41.4 (CH, C-8), 42.8 (CH2, C-15), 44.5 (C, C-4), 44.9 (C,
C-13), 47.2 (C, C-14), 51.5 (CH, C-3), 51.7 (CH2, C-12), 55.8 (CH,
C-17), 62.1 (CH, C-20), 64.3 (CH2, C-29), 78.3 (CH, C-16), 127.0,
128.8 (CH, C-Ar ) 3′,4′,6′,7′), 131.9 (C, C-5′), 133.9 (C, C-2′),
168.8 (C, C-1′), 211.6 (C, C-11); ES-MS m/z 537.4 [M + H]+
(100), 538.4 (15); HRES-MS m/z calcd for C33H49N2O4, 537.3692;
found, 537.3679. Anal. (C33H48N2O4‚0.5H2O) C, H, N, O.
N-[(2R,3S,3aR,5aR,9S,10S,10aR,12aR,12bS)-3-[(1S)-1-(Di-
methylamino)ethyl]-1,2,3,3a,4,5,5a,6,8,9,10,10a,11,12,12a,12b-
hexadecahydro-2-hydroxy-10-(hydroxymethyl)-3a,10,12b-tri-
methyl-5-oxobenzo[4,5]cyclohept[1,2-e]inden-9-yl]acetamide (8a).
Compound 7a (221 mg, 0.46 mmol, 1 equiv) was heated at 240 °C
under 0.03 mmHg in a rotating distillation oven with four bulbs.
A product sublimated in 3 h. The sublimate was composed of a
mixture of the expected product 8a (98%) and dihydrooxazine 9a
(2%). The sublimate was purified by column chromatography on
alumina with dichloromethane-methanol (99.7:0.3) as eluent
followed by trituration in acetone to afford a colorless powder of
8a (79.4 mg, 88%). Mp 253 °C; IR (CHCl3) υmax (cm-1) 3435,
consistent and identical to those described.30 Mp 242 °C; [R]25
)
D
-46 (c 1.0, CHCl3); IR (CHCl3) υmax (cm-1) 3433, 1693, 1652,
1513, 1462, 1380, 1097, 1043, 1015; 1H NMR (300 MHz, CDCl3)
δ 0.47 (3H, s, H-30), 0.69 (3H, s, H-18), 0.87 (3H, d, J ) 6.2 Hz,
H-21), 1.19 (6H, 2d, J ) 7.0 Hz, H-3′, H-4′), 1.27 (3H, s, H-28),
1.29 (1H, m, H-6â), 1.50 (1H, dd, J ) 2.3, 13.8 Hz, H-15R), 1.58
(1H, bd, J ) 11.7 Hz, H-7R), 1.64 (1H, m, H-8â), 1.83 (1H, m,
H-6R), 1.88 (1H, m, H-7â), 1.92 (1H, m, H-2â), 1.99 (1H, m,
H-15â), 2.02 (1H, dd, J ) 7.0, 11.0, H-17R), 2.03 (1H, m, H-9R),
2.08 (1H, m, H-19â), 2.24 (6H, bs, NB-CH3), 2.28 (1H, m, H-2R),
2.34 (1H, d, J ) 16.0 Hz, H-12â), 2.42 (1H, m, J ) 7.0 Hz, H-2′),
2.44 (1H, m, H-19â), 2.58 (1H, bd, J ) 16.0 Hz, H-12R), 2.59
(1H, m, H-20), 2.60 (1H, m, H-5R), 3.10 (1H, dd, J ) 4.3, 11.0
Hz, H-29a), 3.35 (1H, d, J ) 13.9 Hz, H-19R), 3.38 (1H, m, H-29b),
4.08 (1H, m, H-3R), 4.09 (1H, m, J ) 6.6 Hz, H-16â), 4.57 (1H,
dd, J ) 4.3, 10.6 Hz, OH), 5.32 (1H, d, J ) 8.9 Hz, NAH), 5.48
(1H, m, H-1); 13C NMR (75.5 MHz, CDCl3) δ 9.9 (CH3, C-21),
10.0 (CH3, C-30), 17.8 (CH3, C-18), 19.0, 19.5 (CH3, C-3′, C-4′),
20.1 (CH3, C-28), 25.0 (CH2, C-6), 30.0 (CH2, C-2), 33.5 (CH2,
C-7), 35.9 (CH, C-2′), 37.6 (CH2, C-19), 42.1 (C, C-4), 42.4 (CH2,
C-15), 43.4 (CH, C-5), 46.2 (C, C-14), 47.1 (C, C-13), 47.7 (CH,
C-3), 49.9 (CH, C-8), 50.0 (CH2, C-12), 50.1 (CH, C-9), 55.3 (CH,
C-17), 62.0 (CH, C-20), 63.8 (CH2, C-29), 78.4 (CH, C-16), 117.9
(CH, C-1), 140.0 (C, C-10), 178.9 (C, C-1′), 212.1 (C, C-11); ES-
MS m/z 503.3 [M + H]+ (100), 504.3 (90); HRES-MS m/z calcd
for C30H51N2O4, 503.3849; found, 503.3852. Anal. (C30H50N2O4‚
0.5H2O) C, H, N.
1
2928, 1694, 1654, 1516, 1462, 1375, 1095, 1043; H NMR (300
MHz, CDCl3) δ 0.46 (3H, s, H-30), 0.67 (3H, s, H-18), 0.85 (3H,
d, J ) 6.2 Hz, H-21), 1.27 (3H, s, H-28), 1.28 (1H, m, H-6â), 1.43
(1H, dd, J ) 2.3, 13.9 Hz, H-15R), 1.58 (1H, bd, J ) 11.9 Hz,
H-7R), 1.57 (1H, m, H-8â), 1.76 (1H, m, H-6R), 1.81 (1H, m,
H-7â), 1.88 (1H, m, H-2â), 1.89 (1H, m, H-15â), 1.92 (1H, m,
H-9R), 2.02 (1H, m, H-17R), 2.04 (1H, s, H-2′), 2.11 (1H, m,
H-19â), 2.22 (6H, bs, NB-CH3), 2.28 (1H, m, H-2R), 2.32 (1H, d,
J ) 15.8 Hz, H-12â), 2.56 (1H, bd, J ) 15.8 Hz, H-12R), 2.58
(1H, m, H-5R), 2.59 (1H, m, H-20), 3.17 (1H, dd, J ) 4.5, 12.7
Hz, H-29a), 3.33 (1H, d, J ) 14.5 Hz, H-19R), 3.40 (1H, m, H-29b),
4.04 (1H, m, H-3R), 4.07 (1H, m, H-16â), 4.53 (1H, dd, J ) 4.5,
11.0 Hz, OH), 5.46 (1H, bs, H-1), 5.50 (1H, d, J ) 8.9 Hz, NAH);
13C NMR (75.5 MHz, CDCl3) δ 9.9 (CH3, C-21), 10.0 (CH3, C-30),
17.8 (CH3, C-18), 18.9 (CH3, C-28), 23.3 (CH, C-2′), 24.9 (CH2,
C-6), 29.9 (CH, C-2), 33.5 (CH2, C-7), 37.5 (CH2, C-19), 42.0 (C,
C-4), 42.4 (CH2, C-15), 43.4 (CH, C-5), 46.2 (C, C-14), 47.0 (C,
C-13), 48.4 (CH, C-3), 49.9 (CH, C-8), 50.0 (CH2, C-12), 50.1
(CH, C-9), 55.3 (CH, C-17), 62.0 (CH, C-20), 63.8 (CH2, C-29),
78.4 (CH, C-16), 117.9 (CH, C-1), 140.0 (C, C-10), 172.0 (C, C-1′),
212.1 (C, C-11); ES-MS m/z 475.3 [M+H]+ (100), 476.3 (60);
HRES-MS m/z calcd for C28H47N2O4, 475.3536; found, 475.3548.
(4aS,7aR,9aR,10S,11R,12aS,12bR,14bS)-10-[1-(Dimethylami-
no)ethyl]-11-hydroxy-3,9a,12a,14b-tetramethyl-1,4a,5,7,7a,9,
9a,10,11,12,12a,12b,13,14,14a,14b-hexadecahydro-8H-indeno-
[5′¢,4′¢:4′,5′]cyclohepta[1′,2′:3,4]benzo[1,2-d][1,3]oxazin-8-one
(9a). To a solution of compound 7a (171 mg, 0.36 mmol, 1 equiv)
in 2 mL of dichloromethane was added 25% tetraethylammonium
hydroxide (1059 mg, 1.8 mmol, 5 equiv) solution in methanol. The
solvent was evaporated under reduced pressure. The dark red residue
was heated at 240 °C under 0.03 mmHg in a rotating distillation
oven with four bulbs. A product sublimated in 3 h. This crude
product was crystallized in acetone to afford a pale yellow powder
of 9a (125 mg, 76%): mp 284 °C; [R]23D ) +123 (c 0.25, CHCl3);
IR (CHCl3) υmax (cm-1) 3331, 2971, 1694, 1672, 1462, 1383, 1039;
1H NMR (300 MHz, CDCl3) δ 0.70 (3H, s, H-18), 0.79 (3H, s,
H-30), 0.87 (3H, d, J ) 6.6 Hz, H-21), 1.24 (3H, s, H-28), 1.29
(1H, m, H-6â), 1.33 (1H, m, H-7R), 1.50 (1H, dd, J ) 2.3, 13.7
Hz, H-15R), 1.63 (1H, m, H-6R), 1.66 (1H, m, H-8â), 1.74 (1H,
m, H-2â), 1.83 (1H, m, H-5R), 1.89 (1H, m, H-7â), 1.92 (3H, s,
H-2′), 1.96 (1H, m, H-9R), 2.02 (1H, m, H-15â), 2.03 (1H, m,
H-17R), 2.09 (1H, m, H-19â), 2.24 (6H, bs, NB-CH3), 2.34 (1H,
d, J ) 16.0 Hz, H-12â), 2.30 (1H, m, H-2R), 2.56 (1H, bd, J )
16.0 Hz, H-12R), 2.60 (1H, dd, J ) 6.6, 11.0 Hz, H-20), 3.25 (1H,
dd, J ) 6.0, 12.0 Hz, H-3R), 3.34 (1H, d, J ) 15.4 Hz, H-19R),
3.79 (1H, d, J ) 10.2 Hz, H-29R), 4.06 (1H, d, J ) 10.2 Hz,
H-29â), 4.09 (1H, m, H-16â), 5.60 (1H, m, H-1); 13C NMR (75.5
MHz, CDCl3) δ 9.9 (CH3, C-30), 10.0 (CH3, C-21), 17.8 (CH3,
C-18), 18.8 (CH3, C-28), 21.0 (CH3, C-2′), 24.6 (CH2, C-6), 30.6
N-3-Benzoylcycloxobuxidine-F (3) or N-[(3â,4R,5R,9â,16R,
20S)-20-(Dimethylamino)-16-hydroxy-4-(hydroxymethyl)-4,14-
dimethyl-11-oxo-9,19-cyclopregnan-3-yl]benzamide (7g). To a
solution of cycloxobuxidine-F 5 (166 mg, 0.38 mmol, 1 equiv) in
10 mL of methanol was added benzoic anhydride (95 mg, 0.46
mmol, 1.1 equiv). After stirring for 4 h at room temperature, the
mixture was neutralized with a few drops of a 10% sodium
bicarbonate solution (pH ) 8), then made basic with 50 mL of a
10% ammonia solution (pH ) 10), and extracted with dichloro-
methane (3 × 40 mL). The organic layer was washed with brine
(30 mL), dried over Na2SO4, and filtered, and the solvent was
evaporated. The crude product was purified by column chroma-
tography on alumina with dichloromethane-methanol (98:2) as
eluent followed by trituration in acetone to afford a colorless powder
of 7g (156 mg, 76%), whose spectroscopic characteristics are
identical to those described.30 Mp 277 °C; [R]25 ) +52 (c 1.00,
D
CHCl3); IR (CHCl3) υmax (cm-1) 3438, 1645, 1628, 1518, 1487,
1
1384, 1040; H NMR (300 MHz, CDCl3) δ 0.65 (3H, s, H-30),
0.85 (3H, s, H-18), 0.88 (3H, d, J ) 6.6 Hz, H-21), 0.92 (1H, m,
H-6â), 1.03 (1H, d, J ) 3.8 Hz, H-19R), 1.24 (3H, s, H-28), 1.34
(1H, m, H-1R), 1.42 (1H, m, H-7R), 1.52 (1H, dd, J ) 2.6, 14.1
Hz, H-15R), 1.55 (1H, m, H-7â), 1.60 (1H, d, J ) 3.8 Hz, H-19â),
1.70 (1H, m, H-2â), 1.75 (2H, m, H-6R, H-2R), 1.99 (1H, m,
H-17R), 2.03 (1H, m, H-15â), 2.07 (1H, m, H-8â), 2.14 (1H, dd,
J ) 3.3, 12.1 Hz, H-5R), 2.26 (6H, bs, NB-CH3), 2.32 (1H, d, J )
17.2 Hz, H-12â), 2.47 (1H, ddd, J ) 3.0, 3.3, 13.6 Hz, H-1â),
2.54 (1H, d, J ) 17.2 Hz, H-12R), 2.63 (1H, dq, J ) 6.6, 10.8 Hz,
H-20), 3.12 (1H, dd, J ) 3.4, 12.7 Hz, H-29a), 3.40 (1H, dd, J )
10.4, 12.7 Hz, H-29b), 4.12 (1H, ddd, J ) 3.0, 7.3, 10.0 Hz, H-16â),
4.24 (1H, ddd, J ) 4.3, 8.9, 12.5 Hz, H-3R), 4.44 (1H, dd, J )
3.4, 10.4 Hz, OH), 6.05 (1H, d, J ) 8.9 Hz, NAH), 7.48, 7.76
(5H, m, HAr ) 3′,4′,5′,6′,7′); 13C NMR (75.5 MHz, CDCl3) δ 10.0