2820
A. Iuliano et al. / Tetrahedron: Asymmetry 12 (2001) 2811–2825
aromatics); 8.30 (d, 1H, amide NH); 12.00 (br s, 1H,
COOH). 13C NMR (50 MHz, DMSO-d6, l): 13.6, 17.1,
23.1, 23.5, 25.7, 26.5, 27.0, 27.2, 30.1, 30.6, 30.8, 33.7,
33.9, 34.2, 34.3, 35.0, 36.1, 44.3, 48.0, 48.1, 53.2 (C12),
70.0 (C3), 125.1, 130.3, 134.2, 137.9 (aromatics), 162.3
(amide CꢀO), 174.9 (24 CꢀO). IR (KBr, cm−1): 3448,
3358, 3078, 2948, 2868, 2661, 1741, 1705, 1634, 1567,
1516, 1448, 1364, 1262, 1202, 1167, 1099, 1046, 1031,
937, 909, 862, 807, 759, 710, 663, 620.
4.11.1.
N-Allyl-N%-methyl-3a-3,5-dimethylbenzoyl)-
amino-12a-hydroxy-5b-cholan-24-amide 8a. Yield 1.89 g,
82% after flash chromatography (SiO2, CH2Cl2: acetone
1
88:12). Mp 96–98°C. [h]2D5 +53.8 (c=0.92, CH2Cl2). H
NMR (200 MHz, CDCl3, l): 0.70 (s, 3H, CH3); 0.95 (s,
3H, CH3); 1.00 (d, 3H, 21-CH3); 1.00–2.00 (m, 25H,
steroidal CH and CH2, 12-OH); 2.15–2.50 (m, 2H); 2.40
(s, 6H, benzylic CH3); 2.90 and 2.92 (s, 3H, CONCH3);
3.95 (m, 4H, CH2
2H, CH2ꢀCH); 5.70 (m, 1H, CH
6
CHꢀCH2, 3-CH and 12-CH); 5.20 (m,
6
6
ꢀCH2); 6.00 (d, 1H,
4.10.3. 3a-Hydroxy-12a-N-(3,5-dimethylbenzoyl)amino-
5b-cholan-24-oic acid 15a. Yield 740 mg, 97%. Mp
173–175°C. [h]2D4 +70.5 (c=1.00, acetone). 1H NMR
(200 MHz, DMSO-d6, l): 0.75 (d, 3H, 21-CH3); 0.80 (s,
3H, CH3); 0.85 (s, 3H, CH3); 0.80–2.10 (m, 24H,
steroidal CH and CH2); 2.10–2.6 (m, 2H); 2.30 (s, 6H,
benzylic CH3); 3.40 (m, 1H, 3-CH); 4.25 (dt, 1H, 12-
CH); 4.50 (br s, 1H, 3-OH); 7.30 (s, 1H, Ha); 7.60 (s,
2H, Hb); 7.95 (d, 1H, amide NH); 12.00 (br s, 1H,
COOH). 13C NMR (50 MHz, DMSO-d6, l): 13.5, 17.0,
20.9 (benzylic CH3), 23.0, 23.5, 25.6, 26.5, 27.0, 27.2,
30.0, 30.4, 30.6, 33.6, 33.8, 34.4, 35.6, 36.0, 41.7, 41.2,
47.7, 48.0, 49.7, 52.4 (C12), 70.9 (C12), 125.1, 130.3,
134.2, 137.9 (aromatics), 162.3 (amide CꢀO), 174.9 (24
CꢀO). IR (KBr, cm−1): 3330, 2934, 2869, 1706, 1640,
1602, 1533, 1449, 1384, 1307, 1252, 1207, 1168, 1094,
1015, 939, 908, 855, 801, 680.
amide NH); 7.10 (s, 1H, Ha); 7.35 (s, 2H, Hb). 13C
NMR (50 MHz, CDCl3, l): 12.8, 17.7, 21.1 (benzylic
CH3), 23.2, 23.6, 26.1, 26.9, 27.4, 27.9, 28.6, 29.8 and
30.4 (NCH3), 31.1, 31.4, 33.7, 33.8, 34.1, 35.2, 35.8,
36.0, 42.4, 46.6, 47.6, 48.5, 49.6 (C3), 50.0 and 52.2
(NCH2), 73.3 (C12), 116.6 and 117.0 (CH2ꢀ), 124.6,
132.7 (aromatics), 132.8 and 133.3 (CHꢀ), 135.1, 138.0
(aromatics), 167.0 (CONH), 173.8 and 173.3 (24 CꢀO).
IR (KBr, cm−1): 3407, 3342, 3082, 2945, 2869, 1630,
1541, 1461, 1448, 1400, 1378, 1334, 1301, 1287, 1276,
1261, 1239, 1196, 1162, 1099, 1089, 1064, 1052, 988,
970, 945, 931, 865, 803, 762, 686, 641, 624.
4.11.2.
N-Allyl-N%-methyl-3a-(3,5-dichlorobenzoyl)-
amino-12a-hydroxy-5b-cholan-24-amide 8b. Yield 1.23 g,
50% after flash chromatography (SiO2, CH2Cl2:acetone
1
90:10). Mp 90–93°C. [h]2D4 +58.2 (c=1.00, CH2Cl2). H
NMR (200 MHz, CDCl3, l): 0.70 (s, 3H, CH3); 0.90 (s,
3H, CH3); 1.00 (d, 3H, 21-CH3); 1.00–2.00 (m, 25H,
steroidal CH and CH2, 12-OH); 2.15–2.50 (m, 2H); 2.90
4.10.4. 3a-Hydroxy-12a-N-(3,5-dichlorobenzoyl)amino-
5b-cholan-24-oic acid 15b. Yield 770 mg, 94%. Mp
1
163–166°C. [h]2D7 +96.2 (c=1.01, EtOH). H NMR (200
and 2.92 (s, 3H, CONCH3); 3.95 (m, 4H, CH2
3-CH and 12-CH); 5.20 (m, 2H, CH2ꢀCH); 5.75 (m,
1H, CHꢀCH2); 6.20 (d, 1H, CONH); 7.4 (t, 1H, Ha);
6 CHꢀCH2,
MHz, DMSO-d6, l): o.70 (d, 3H, 21-CH3); 0.80 (s, 3H,
CH3); 0.90 (s, 3H, CH3); 1.00–2.00 (m, 24H, steroidal
CH and CH2); 2.10 (m, 2H); 3.40 (m, 1H, 3-CH); 4.25
(dt, 1H, 12-CH); 4.50 (br s, 1H, 3-OH); 7.80 (m, 3H, H
aromatics); 8.30 (d, 1H, amide NH); 12.00 (br s, 1H,
COOH). 13C NMR (200 MHz, DMSO-d6, l): 13.6,
17.1, 23.1, 23.5, 25.7, 26.5, 27.0, 27.2, 30.1, 30.6, 30.8,
33.7, 33.9, 34.2, 34.3, 35.0, 36.1, 44.3, 48.0, 48.1, 53.2
(C12), 70.0 (C3), 125.1, 130.3, 134.), 137.9 (aromatics),
162.3 (amide CꢀO), 174.9 (24 CꢀO). IR (KBr, cm−1):
3448, 3358, 3078, 2948, 2868, 2661, 1741, 1705, 1634,
1567, 1516, 1448, 1364, 1262, 1202, 1167, 1099, 1046,
1031, 937, 909, 862, 807, 759, 710, 663, 620.
6
6
7.60 (d, 2H, Hb). 13C NMR (50 MHz, CDCl3, l): 12.8,
17.7, 23.2, 23.6, 26.1, 26.7, 27.5, 27.8, 28.5, 29.7 and
30.5 (NCH3), 31.1, 31.4, 33.4, 33.7, 35.3, 35.7, 36.0,
42.3, 46.6, 47.6, 48.5, 50.0 (C3), 50.1 and 52.2 (NCH2),
73.2 (C12), 116.6 and 117.0 (ꢀCH2), 125.6, 131.04 (aro-
matics), 132.7 and 133.2 (CHꢀ), 135.4, 138.0 (aromat-
ics, 164.0 (CONH), 173.8 and 173.3 (24 CꢀO). IR (KBr,
cm−1): 3448, 3328, 3078, 2935, 2863, 1654, 1646, 1636,
1628, 1566, 1542, 1466, 1458, 1448, 1414, 1405, 1399,
1377, 1325, 1289, 1242, 1098, 1049, 920, 866, 802, 760,
732, 670.
4.11. N-Allyl-N%-methyl-5b-cholan-24-amides: general
procedure
4.11.3.
N-Allyl-N%-methyl-3a-hydroxy-12a-(3,5-di-
methylbenzoyl)amino-5b-cholan-24-amide 16a. Yield 1.5
g 65% after flash chromatography (SiO2, CH2Cl2:
acetone 85:15). Mp 88–90°C. [h]2D5 +69.4 (c=1.00,
Dry tri-n-butyl amine (0.96 mL, 4.02 mmol) was added
to a solution of cholan-24-oic acid (4.02 mmol) in dry
dioxane (60 mL) and the mixture was cooled to 10°C.
Ethyl chloroformate (0.39 mL, 4.02 mmol) in dry diox-
ane (6 mL) was added and, after 10 min, N-methyl
allylamine (0.96 mL, 10.05 mmol) were added dropwise
at the same temperature under stirring. The mixture
was stirred at the same temperature for 30 min, then at
room temperature for 2.5 h. The reaction mixture was
poured into water (150 mL) then extracted with ethyl
acetate (4×50 mL). The collected organic extracts were
washed with 10% HCl (1×20 mL), 10% NaHCO3 (2×20
mL) and water (2×20 mL), then dried (Na2SO4). The
solvent was evaporated at reduced pressure and the
crude product purified by flash chromatography.
1
CH2Cl2). H NMR (200 MHz, CDCl3, l): 0.88 (s, 3H,
CH3); 0.90 (d, 3H, 21-CH3); 0.92 (s, 3H, CH3); 1.00–
2.10 (m, 25H, steroidal CH and CH2, 3-OH); 2.10–2.40
(m, 2H); 2.40 (s, 6H, benzylic CH3); 2.80 and 2.83 (s,
3H, NCH3); 3.60 (m, 1H, 3-CH); 3.90 (dd, 2H,
CH2
2H, CH2
6 CHꢀCH2); 4.50 (dt, J=7 Hz, 1H, CH12); 5.10 (m,
6
ꢀCH); 5.70 (m, 1H, CH6 ꢀCH2); 6.30 (d, J=7
Hz, 1H, CONH); 7.10 (s, 1H, Ha); 7.30 (s, 2H, Hb); 13C
NMR (50 MHz, CDCl3, l): 13.9, 17.5, 21.3 (benzylic
CH3), 23.3, 23.7, 26.1, 26.6, 27.0, 27.4, 29.7, 30.5, 30.9
and 31.2 (NCH3), 34.2, 35.1, 35.2, 36.0, 36.2, 41.9, 44.6,
49.4, 49.9, 51.3 and 52.2 (CH2
71.6 (C3), 116.5 and 117.0 (CH2
6
CHꢀCH2), 52.4 (C12),
6
ꢀCH), 124.5, 133.0,