Journal of Medicinal Chemistry
ARTICLE
(8.53 min), 8c (8.28 min), 8d (8.06), 8e (7.46 min), 8f (7.45 min), 8g
(9.10 min), 8h (8.67 min), 8i (7.75 min), 8j (9.01 min), 8k (8.75 min).
(20R)-21-Benzyloxy-6β-methoxy-20-methyl-3R,5R-cyclopregnane-
16β,17R-diol (3). To a solution of (20R)-6β-methoxy-20-methyl-
3R,5R-cyclopregnane-16β,17R,21-triol (triol 2, 0.5 g, 1.3 mmol) in
dry THF (15 mL), NaH (1.5 equiv, 0.048 g) was added at 0 °C. The
reaction mixture was stirred for 15 min at 0 °C. Then a solution of benzyl
bromide (1.1 equiv, 0.17 mL) in THF (2 mL) was added dropwise. The
reaction mixture was stirred for 1 h under reflux. The reaction was
carefully quenched with water, and products were extracted with ether.
The extract was dried over MgSO4, and solvent was evaporated in vacuo.
The crude product was purified by silica gel column chromatography
with hexaneꢁethyl acetate (8:2 v/v). Yield: 70% (0.43 g). 1H NMR (400
MHz, CDCl3, δ): 7.34 (m, 5H), 4.54 (s, 2H), 3.92 (bs, 1H), 3.90 (m,
1H), 3.70 (t, J = 9.0 Hz, 1H), 3.43 (dd, J1 = 3.2 Hz, J2 = 9.2 Hz, 1H), 3.33
(s, 3H), 2.78 (m, 1H), 1.04 (s, 3H), 1.01 (s, 3H), 0.95 (d, J = 7.1 Hz,
3H), 0.66 (m, 1H), 0.44 (dd, J1 = 5.1 Hz, J2 = 8.0 Hz, 1H).
(CH3), 12.9 (CH3). ESI-MS m/z 917.4 (MNaþ). HRMS-ESI (m/z):
[M þ Na]þ calcd for C49H66O15Na, 917.4299; found, 917.4312.
(20R)-6β-Methoxy-20-methyl-3R,5R-cyclopregnane-16β,17R,21-triol
16-O-{2-O-(4-Methoxybenzoyl)-3,4-di-O-triethylsilyl-β-D-xylopyranosyl-
(1f3)-20-O-acetyl-40-O-triethylsilyl-R-L-arabinopyranoside} (6). To a
stirred solution of glycoside 4 (0.5 g, 0.4 mmol) in ethyl acetate and
anhydrous ethanol (1:1 v/v, 20 mL), 10% Pd/C (0.53 g) and triethy-
lamine (0.18 mL) were added. The reaction was carried out under
hydrogen atmosphere (5 MPa) at 50 °C for 20 h. Then the catalyst was
filtered off and the solvent was evaporated in vacuo. The desired alcohol
was purified by silica gel column chromatography with hexaneꢁethyl
1
acetate (8:2 v/v) elution. Yield: 82% (0.38 g). H NMR (400 MHz,
CDCl3, δ): 7.99 (d, J = 9.0 Hz, 2H), 6.91 (d, J = 9.0Hz, 2H), 4.96 (dd, J1 =
4.9 Hz, J2 = 7.1Hz, 1H), 4.91 (dd, J1 = 5.5Hz, J2 = 6.9Hz, 1H), 4.39 (d, J =
5.3 Hz, 1H), 4.36 (d, J = 4.9 Hz, 1H), 4.14 (m, 1H), 4.01 (m, 1H), 3.87
(s, 3H), 3.68ꢁ3.78 (m, 6H), 3.54 (dd, J1 = 3.1 Hz, J2 = 11.0 Hz, 1H),
3.36 (m, 1H), 3.32 (s, 3H), 3.24 (dd, J1 = 7.7 Hz, J2 = 11.4 Hz, 1H), 2.76
(m, 1H), 1.90 (s, 3H), 0.86ꢁ1.07 (m, 34H), 0.53ꢁ0.66 (m, 19H), 0.42
(dd, J1 = 5.1 Hz, J2 = 7.9 Hz, 1H).
General Procedure for Synthesis of Compounds 7aꢁk. A solution of
compound 6 (1 equiv), carboxylic acid (1.2 equiv), DCC (1.2 equiv),
and DMAP (0.1 equiv) in dichloromethane was stirred for 16 h at room
temperature. Then N,N-dicyclohexylurea was filtered off, and the filtrate
was washed with 5% acetic acid, water and dried over MgSO4. The
solvent was evaporated. Silica gel column chromatography (elution with
hexaneꢁethyl acetate) afforded the ester 7, which was subsequently
subjected to deprotection of functional groups.
(20R)-21-O-[(E)-But-2-enoyl]-6β-methoxy-20-methyl-3R,5R-cyclo-
pregnane-16β,17R,21-triol 16-O-{2-O-(4-Methoxybenzoyl)-3,4-di-O-
triethylsilyl-β-D-xylopyranosyl-(1f3)-20-O-acetyl-40-O-triethylsilyl-R-
L-arabinopyranoside} (7g). Silica gel column chromatography (elution
with hexaneꢁethyl acetate, 82:18 v/v) afforded the desired ester 7g in
95% yield. 1H NMR (400 MHz, CDCl3, δ): 7.98 (d, J = 8.7 Hz, 2H),
7.08 (dd J1 = 6.9 Hz, J2 = 15.5 Hz, 1H), 6.90 (d, J = 8.7 Hz, 2H), 5.77 (dq,
J1 = 1.7 Hz, J2 = 15.5 Hz, 1H), 5.03 (m, 1H), 4.94 (m, 1H), 4.77 (m, 1H),
4.31 (m, 1H), 4.00ꢁ4.18 (m, 4H), 3.87 (s, 3H), 3.63ꢁ3.74 (m, 4H),
3.36 (m, 2H), 3.31 (s, 3H), 3.24 (m, 1H), 2.75 (m, 1H), 1.89 (s, 3H),
1.84 (d, J = 1.7 Hz, 3H), 0.87ꢁ1.02 (m, 34H), 0.52ꢁ0.66 (m, 19H), 0.42
(m, 1H).
(20R)-21-O-(Undec-10-enoyl)-20-methyl-6β-methoxy-3R,5R-cyclo-
pregnan-16β,17R,21-triol 16-O-{2-O-(4-Methoxybenzoyl)-3,4-di-O-
triethylsilyl-β-D-xylopyranosyl-(1f3)-20-O-acetyl-40-O-triethylsilyl-R-
L-arabinopyranoside} (7i). Silica gel column chromatography (elution
with hexaneꢁethyl acetate, 7:1 v/v) afforded the desired ester 7i in 63%
yield. 1H NMR (400 MHz, CDCl3, δ) 7.99 (d, J = 8.7Hz, 2H), 6.90 (d, J =
8.7 Hz, 2H), 5.82 (m, 1H), 4.93ꢁ5.02 (m, 4H), 4.75 (m, 1H), 4.31 (m,
1H), 4.12 (m, 2H), 4.01 (m, 2H), 3.87 (s, 3H), 3.62ꢁ3.87 (m, 4H), 3.36
(m, 2H), 3.31 (s, 3H), 3.25 (m, 1H), 2,.5 (m, 1H), 2.23 (m, 2H), 1.91
(s, 3H), 0.89ꢁ1.02 (m, 40H), 0.56ꢁ0.64 (m, 19H), 0.42 (m, 1H).
(20R)-21-O-(4-Methoxybenzoyl)-6β-methoxy-20-methyl-3R,5R-
cyclopregnane-16β,17R,21-triol 16-O-{2-O-(4-Methoxybenzoyl)-3,4-
di-O-triethylsilyl-β-D-xylopyranosyl-(1f3)-20-O-acetyl-40-O-triethylsi-
lyl-R-L-arabinopyranoside} (7k). Silica gel column (hexaneꢁethyl
acetate, 84:16 v/v) afforded the desired ester 7k in 65% yield. 1H
NMR (400 MHz, CDCl3, δ): 8.07 (d, J = 8.8 Hz, 2H), 7.95 (d, J = 8.8
Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.06 (m, 1H),
4.95(t, J = 6.1 Hz, 1H), 4.74 (m, 1H), 4.36 (m, 2H), 4.25 (dd, J1 = 3.4 Hz,
J2 = 11.1 Hz, 1H), 4.12 (m, 1H), 4.01 (m, 1H), 3.89 (s, 3H), 3.85
(s, 4H), 3.60ꢁ3.75 (m, 4H), 3.37 (m, 1H), 3.31 (s, 3H), 3.24 (m, 1H),
2.75 (m, 1H), 1.85 (s, 3H), 0.86ꢁ1.27 (m, 34H), 0.53ꢁ0.66 (m, 19H),
0.42 (m, 1H).
(20R)-21-Benzyloxy-6β-methoxy-20-methyl-3R,5R-cyclopregnane-
16β17R-diol 16-O-{2-O-(4-Methoxybenzoyl)-3,4-di-O-triethylsilyl-β-D-
xylopyranosyl-(1f3)-20-O-acetyl-40-O-triethylsilyl-R-L-arabinopyranoside}
(4). A solution of compound 3 (0.19 g, 0.41 mmol) and 2-O-(4-
methoxybenzoyl)-3,4-di-O-triethylsilyl-β-D-xylopyranosyl-(1f3)-20-O-
acetyl-40-O-triethylosilyl-R-L-arabinopyranosyl trichloroacetimidate
(1.2 equiv, 0.46 g) in dry dichloromethane (10 mL) was stirred with 4 Å
molecular sieves (MS, 1.28 g) for 15 min at room temperature. Then the
reaction mixture was cooled to ꢁ68 °C (dry iceꢁethanol bath) and a
0.14 M solution of TMSOTf in dry dichloromethane (1.1 mL) was
slowly added. The reaction mixture was stirred for an additional 30 min
at ꢁ40 °C (dry iceꢁacetonitrile bath), and the reaction was quenched
with triethylamine (0.5 mL). Then molecular sieves were filtered off and
the solvent was evaporated in vacuo. The crude product was purified by
silica gel column chromatography with hexaneꢁethyl acetate (95:5 v/v).
Yield: 66% (0.34 g). 1H NMR (400 MHz, CDCl3, δ): 7.98 (d, J = 9.0 Hz,
2H), 7.32 (m, 5H), 6.91 (d, J = 9.0 Hz, 2H), 4.90 (m, 2H), 4.72 (d, J = 5.3
Hz, 1H), 4.57 (d, J = 12.0 Hz, 1H), 4.37 (d, J = 12.0 Hz, 1H), 4.18 (s,
1H), 4.15 (m, 1H), 3.99 (m, 1H), 3.87 (s, 3H), 3.87ꢁ3.59 (m, 6H), 3.47
(dd, J1 = 4.0 Hz, J2 = 7.8 Hz, 1H), 3.32ꢁ3.25 (m, 3H), 3.30 (s, 3H), 2.74
(m, 1H), 1.85 (s, 3H), 1.10 (d, J = 7.2 Hz, 3H), 1.01ꢁ0.87 (m, 34H),
0.67ꢁ0.54 (m, 19H), 0.40 (dd, J1 = 5.1 Hz, J2 = 8.0 Hz, 1H).
(20R)-21-Benzyloxy-20-methylpregn-5-ene-3β,16β,17R-triol 16-O-{2-
O-(4-Methoxybenzoyl)-β-D-xylopyranosyl-(1f3)-20-O-acetyl-R-L-arabi-
nopyranoside} (5). To a solution of the glycoside 4 (0.018 g, 0.014
mmol) in dioxaneꢁwater (7:1 v/v, 3.2 mL) was added p-TsOH H2O
3
(0.002 g). The reaction mixture was stirred for 1.5 h at 75 °C. Then the
reaction mixture was poured into the water and product was extracted
with ethyl acetate. The extract was dried over MgSO4, and the solvent
was evaporated in vacuo. The saponin 5 was purified by silica gel column
chromatography (elution with dichloromethaneꢁmethanol, 97:3 v/v).
Yield: 93% (0.015 g). 1H NMR (400 MHz, CDCl3, δ): 8.02 (d, J = 8.7
Hz, 2H), 7.28 (m, 5H), 6.96 (d, J = 8.7 Hz, 2H), 5.31 (bs, 1H) 4.90 (dd,
J1 = 4.9 Hz, J2 = 6.7 Hz, 1H), 4.84 (dd, J1 = 6.8 Hz, J2 = 7.3 Hz, 1H), 4.70
(d, J = 6.5 Hz, 1H), 4.51 (d, J = 12.0 Hz, 1H), 4.19 (d, J = 12.0 Hz, 1H),
4.16 (dd, J1 = 4.5 Hz, J2 = 11.6 Hz, 1H), 4.02 (s, 1H), 3.94 (m, 1H), 3.88
(s, 3H), 3.87 (m, 3H), 3.72 (m, 2H), 3.52 (m, 4H), 3.45ꢁ3.38 (m, 4H),
2.85 (m, 1H), 1.81 (s, 3H), 1.01 (s, 3H), 0.99 (d, J = 9.0 Hz, 3H), 0.77
(s, 3H). 13C NMR (100 MHz, CDCl3, δ): 169.3 (C), 166.3 (C), 164.1
(C), 140.6 (C), 137.6 (CH), 132.2 (2CH), 128.4 (2CH), 128.2 (2CH),
127.9 (CH), 121.6 (CH), 121.3 (C), 113.9 (2CH), 101.9 (CH), 101.8 (CH),
90.5 (CH), 87.2 (C), 80.4 (CH), 75.4 (CH2), 74.5 (CH), 74.0 (CH2),
73.6 (CH), 71.8 (CH), 70.7 (CH), 69.7 (CH), 66.4 (CH), 64.6 (CH2),
63.3 (CH2), 55.5 (CH3), 49.7 (CH), 48.3 (CH), 46.2 (C), 42.3 (CH2,
C), 37.2 (CH2), 36.4 (C), 35.1 (CH2), 33.8 (CH), 32.4 (CH2), 31.9
(CH), 31.6 (CH2), 29.7 (CH2), 20.6 (CH2, CH3), 19.4 (CH3), 13.7
Compounds 7aꢁf, 7h, and 7j were also prepared by this general
method, details of which are provided in Supporting Information.
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dx.doi.org/10.1021/jm101648h |J. Med. Chem. 2011, 54, 3298–3305