Journal of Medicinal Chemistry
Article
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(R)-4-((3R,5R,7S,8R,9S,10S,13R,14S,17R)-7-Hydroxy-3-methoxy-
10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-
yl)pentanoic Acid (5b) and (R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-
3,7-Dimethoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]-
phenanthren-17-yl)pentanoic Acid (6b). To a solution of 2b (0.660
g, 1.62 mmol) in THF (8.1 mL) was added NaH (60% dispersion in
mineral oil, 0.143 g, 3.57 mmol) and the reaction stirred at room
temperature for 15 min. MeI (0.213 mL, 3.41 mmol) was added
dropwise, and the mixture stirred for 3 h. The reaction was quenched
by the addition of saturated aqueous NH4Cl (5 mL), and the aqueous
layer was extracted with EtOAc (3 × 10 mL). The combined organic
layers were washed with water (10 mL), dried over MgSO4, filtered,
and concentrated. The crude material was purified by flash column
chromatography on silica gel (25−67% EtOAc in hexanes) to obtain
6b (0.018 g, 3% yield), followed by the elution of 5b (0.224 g, 34%
yield). Data for 6b: 1H NMR (400 MHz, CDCl3) δ 3.35 (s, 3H), 3.23
(s, 3H), 3.13 (qd, J = 10.2, 9.5, 4.1 Hz, 1H), 2.99 (dq, J = 9.0, 5.0 Hz,
1H), 2.39 (ddd, J = 15.3, 10.2, 4.9 Hz, 1H), 2.24 (ddd, J = 15.5, 9.5,
6.3 Hz, 1H), 1.96 (dt, J = 12.7, 3.3 Hz, 1H), 1.89−0.95 (m, 22H), 0.93
(s, 3H), 0.92 (d, J = 5.7 Hz, 3H), 0.84 (ddd, J = 13.1, 9.5, 7.1 Hz, 1H),
0.65 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 179.7, 80.6, 80.3, 56.3,
55.8, 55.6, 55.4, 43.8, 42.4, 41.7, 40.4, 39.5, 35.5, 35.1, 34.6, 33.9, 32.3,
31.2, 31.1, 28.8, 26.8, 26.6, 23.6, 21.5, 18.6, 12.4. HRMS (ESI): m/z
calcd C26H44NaO4 (M + Na+) 443.3137, found 443.3111. Data for 5b:
1H NMR (400 MHz, CDCl3) δ 3.60 (ddd, J = 11.5, 8.6, 5.1 Hz, 1H),
3.35 (s, 3H), 3.13 (tt, J = 10.4, 4.8 Hz, 1H), 2.40 (ddd, J = 15.3, 10.1,
5.0 Hz, 1H), 2.25 (ddd, J = 15.8, 9.5, 6.5 Hz, 1H), 2.05−1.03 (m,
23H), 1.00 (dd, J = 14.5, 3.0 Hz, 1H), 0.95 (s, 3H), 0.93 (d, J = 7.12
Hz, 3H), 0.68 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 179.4, 80.2,
71.5, 55.8, 55.7, 55.1, 43.9, 43.9, 42.5, 40.3, 39.2, 37.0, 35.4, 35.0, 34.5,
33.8, 31.1, 31.0, 28.8, 27.0, 26.7, 23.6, 21.3, 18.5, 12.3. HRMS (ESI):
m/z calcd C25H42NO4Na (M + Na+) 429.2981, found 429.2960.
Compound 6a was obtained in trace amounts and was not evaluated in
the spore germination assays. Compound 5a was prepared in the same
manner as 5b. Data for (R)-4-((3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-
hydroxy-3-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]-
phenanthren-17-yl)pentanoic acid (5a): 1H NMR (400 MHz, CDCl3)
δ 3.84 (d, J = 3.2 Hz, 1H), 3.34 (s, 3H), 3.02 (td, J = 10.9, 5.4 Hz,
1H), 2.40 (ddd, J = 15.5, 10.2, 5.1 Hz, 1H), 2.25 (ddd, J = 15.8, 9.7,
6.4 Hz, 1H), 2.18−1.02 (m, 23H), 0.99 (d, J = 3.3 Hz, 1H), 0.94 (d, J
= 6.4 Hz, 3H), 0.90 (s, 3H), 0.66 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 178.5, 80.8, 68.7, 56.0, 55.7, 50.6, 42.9, 41.6, 39.9, 39.7, 36.0,
35.6, 35.6, 35.5, 34.9, 33.0, 31.0, 30.9, 28.4, 27.2, 23.9, 23.1, 20.8, 18.5,
12.0. HRMS (ESI): m/z calcd C25H42NO4Na (M + Na+) 429.2981,
found 429.2998.
+ Na+) 457.3294, found 457.3278. Data for 8b: H NMR (400 MHz,
CDCl3) δ 3.66 (s, 3H), 3.58 (s, 1H), 3.34 (s, 3H), 3.11 (tt, J = 10.6,
4.5 Hz, 1H), 2.36 (ddd, J = 15.3, 10.2, 5.0 Hz, 1H), 2.22 (ddd, J =
15.6, 9.5, 6.5 Hz, 1H), 2.02−0.96 (m, 24H), 0.94 (s, 3H), 0.92 (d, J =
6.4 Hz, 3H), 0.67 (s, 3H). 1H NMR (400 MHz, DMSO-d6) δ 3.87 (d,
J = 6.9 Hz, 1H), 3.57 (s, 3H), 3.31−3.22 (m, 1H), 3.20 (s, 3H), 3.05
(tt, J = 9.7, 5.3 Hz, 1H), 2.32 (ddd, J = 15.2, 9.7, 5.2 Hz, 1H), 2.20
(ddd, J = 15.7, 9.3, 6.8 Hz, 1H), 1.91 (dd, J = 11.4, 3.6 Hz, 1H), 1.88−
1.79 (m, 1H), 1.78−1.59 (m, 6H), 1.47−1.28 (m, 7H), 1.27−1.09 (m,
6H), 1.06−0.88 (m, 3H), 0.88 (s, 3H), 0.86 (d, J = 6.8 Hz, 3H), 0.61
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 174.9, 80.2, 71.6, 55.9, 55.8,
55.1, 51.7, 44.0, 44.0, 42.6, 40.3, 39.3, 37.2, 35.5, 35.1, 34.6, 33.9, 31.3,
31.2, 28.8, 27.1, 26.9, 23.6, 21.4, 18.6, 12.3. HRMS (ESI): m/z calcd
C26H44NO4Na (M + Na+) 443.3137, found 443.3146. Compounds 7a
and 8a were prepared by the same method. Data for methyl (R)-4-
((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dimethoxy-10,13-dimethyl-
hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate (7a):
1H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 3.33 (s, 3H), 3.23 (s,
3H), 3.17 (q, J = 2.9 Hz, 1H), 3.01 (tt, J = 11.2, 4.3 Hz, 1H), 2.35
(ddd, J = 15.2, 10.2, 5.0 Hz, 1H), 2.29−2.08 (m, 2H), 1.97−1.66 (m,
8H), 1.62 (ddd, J = 15.0, 5.4, 3.2 Hz, 1H), 1.57−1.39 (m, 5H), 1.37−
1.10 (m, 8H), 1.08−0.99 (m, 1H), 0.92 (d, J = 6.4 Hz, 3H), 0.90 (s,
3H), 0.63 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 175.0, 80.8, 80.8,
68.7, 55.9, 55.7, 51.7, 50.6, 42.9, 41.6, 39.8, 39.7, 36.1, 35.6, 35.6, 35.5,
34.9, 33.0, 31.2, 31.2, 28.4, 27.2, 23.9, 23.1, 20.8, 18.5, 12.0. HRMS
(ESI): m/z calcd C27H46NaO4 (M + Na+) 457.3294, found 457.3290.
Data for methyl (R)-4-((3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-
3-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]-
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phenanthren-17-yl)pentanoate (8a): H NMR (400 MHz, CDCl3) δ
3.84 (q, J = 3.0 Hz, 1H), 3.67 (s, 3H), 3.35 (s, 3H), 3.02 (tt, J = 11.1,
4.3 Hz, 1H), 2.36 (ddd, J = 15.3, 10.1, 5.2 Hz, 1H), 2.23 (ddd, J =
15.6, 9.6, 6.6 Hz, 1H), 2.12 (td, J = 13.2, 11.2 Hz, 1H), 2.05−1.70 (m,
8H), 1.64 (dddd, J = 12.5, 9.9, 7.1, 2.9 Hz, 1H), 1.53−1.05 (m, 13H),
0.97 (dd, J = 15.2, 4.3 Hz, 1H), 0.93 (d, J = 6.5 Hz, 3H), 0.91 (s, 3H),
1
0.66 (s, 3H). H NMR (400 MHz, DMSO-d6) δ 4.10 (d, J = 3.4 Hz,
1H), 3.62 (q, J = 3.1 Hz, 1H), 3.57 (s, 3H), 3.20 (s, 3H), 2.92 (tt, J =
11.1, 4.3 Hz, 1H), 2.32 (ddd, J = 15.2, 9.6, 5.3 Hz, 1H), 2.26−2.09 (m,
2H), 1.94−1.86 (m, 1H), 1.86−1.57 (m, 9H), 1.46−1.31 (m, 5H),
1.29−1.15 (m, 4H), 1.15−1.03 (m, 3H), 0.99 (dq, J = 11.8, 5.7 Hz,
1H), 0.88 (d, J = 6.4 Hz, 3H), 0.85 (s, 3H), 0.60 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 175.0, 80.8, 68.7, 55.9, 55.7, 51.7, 50.6, 42.9,
41.6, 39.8, 39.7, 36.1, 35.6, 35.6, 35.5, 34.9, 33.0, 31.2, 31.2, 28.4, 27.2,
23.9, 23.1, 20.8, 18.5, 12.0. HRMS (ESI): m/z calcd C26H44NO4Na
(M + Na+) 443.3137, found 443.3121.
(R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3-Hydroxy-7-methoxy-
10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-
yl)pentanoic Acid (10b). To a solution of 9b (0.300 g, 0.483 mmol)
and 2,6-di-tert-butylpyridine (0.22 mL, 0.97 mmol) in DCM (5 mL)
was methyl triflate (0.06 mL, 0.5 mmol). The reaction stirred at room
temperature for 24 h and was quenched by the addition of 1 M
aqueous HCl (5 mL). The aqueous layer was extracted with DCM (3
× 10 mL), and the combined organic layers were washed with
saturated aqueous NaHCO3 (2 × 10 mL), dried over MgSO4, filtered,
and concentrated. The crude material was purified by flash column
chromatography on silica gel (0−50% EtOAc in DCM) to obtain tert-
butyldimethylsilyl (R)-4-((3R,5R,7S,8R,9S,10S,13R,14S,17R)-3-((tert-
butyldimethylsilyl)oxy)-7-methoxy-10,13-dimethylhexadecahydro-1H-
cyclopenta[a]phenanthren-17-yl)pentanoate (0.207 g, 68% yield) as a
Methyl (R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-Dimethoxy-
10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-
y l ) p e n t a n o a t e ( 7 b ) a n d M e t h y l ( R ) - 4 -
((3R,5R,7S,8R,9S,10S,13R,14S,17R)-7-Hydroxy-3-methoxy-10,13-di-
methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-
pentanoate (8b). To a solution of 2b (0.260 g, 0.639 mmol) and 2,6-
di-tert-butylpyridine (0.29 mL, 1.3 mmol) in DCM (6.4 mL) was
added methyl triflate (approximately 0.1 mL). The reaction stirred at
room temperature for 24 h and was quenched by the addition of 1 M
aqueous HCl (5 mL). The aqueous layer was extracted with DCM (3
× 10 mL), and the combined organic layers were washed with
saturated aqueous NaHCO3 (2 × 10 mL), dried over MgSO4, filtered,
and concentrated. The crude material was purified by flash column
chromatography on silica gel (0−50% EtOAc in DCM) to obtain 7b
(0.147 g, 53% yield) as a clear colorless oil, followed by the elution of
8b (0.054 g, 21% yield) as clear, colorless oil that solidified over time
to a white amorphous solid. Data for 7b: 1H NMR (400 MHz, CDCl3)
δ 3.67 (s, 3H), 3.36 (s, 3H), 3.24 (s, 3H), 3.13 (tt, J = 10.2, 4.4 Hz,
1H), 2.99 (ddd, J = 11.3, 8.8, 5.0 Hz, 1H), 2.36 (ddd, J = 15.2, 10.2,
4.9 Hz, 1H), 2.22 (ddd, J = 15.6, 9.6, 6.4 Hz, 1H), 1.98 (dt, J = 12.8,
3.3 Hz, 1H), 1.90−1.71 (m, 6H), 1.71−1.61 (m, 2H), 1.53−1.37 (m,
7H), 1.37−1.30 (m, 1H), 1.30−1.09 (m, 5H), 1.09−0.97 (m, 2H),
0.94 (s, 3H), 0.92 (d, J = 6.4 Hz, 3H), 0.66 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 175.0, 80.6, 80.2, 56.4, 55.8, 55.7, 55.4, 51.7, 43.8,
42.4, 41.7, 40.5, 39.5, 35.6, 35.1, 34.6, 34.0, 32.3, 31.3, 31.3, 28.8, 26.9,
26.6, 23.6, 21.5, 18.6, 12.4. HRMS (ESI): m/z calcd C27H46NaO4 (M
1
white amorphous solid. H NMR (400 MHz, CDCl3) δ 3.54 (tt, J =
10.2, 4.7 Hz, 1H), 3.24 (s, 3H), 3.01 (ddd, J = 11.0, 9.1, 5.0 Hz, 1H),
2.36 (ddd, J = 15.2, 9.9, 5.1 Hz, 1H), 2.22 (ddd, J = 15.6, 9.4, 6.6 Hz,
1H), 1.97 (dt, J = 12.5, 3.1 Hz, 1H), 1.90−0.97 (m, 23H), 0.94 (s,
9H), 0.93 (d, J = 6.4 Hz, 3H), 0.92 (s, 3H), 0.90 (s, 9H), 0.66 (s, 3H),
0.27 (s, 3H), 0.27 (s, 3H), 0.07 (s, 3H), 0.07 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 174.9, 80.5, 77.4, 72.6, 56.2, 55.6, 55.4, 43.8, 42.5,
41.7, 40.4, 39.4, 38.0, 35.4, 35.3, 34.2, 33.3, 32.3, 31.4, 31.0, 28.7, 26.5,
26.1, 26.1, 25.7, 25.7, 23.5, 21.5, 18.6, 18.5, 17.8, 12.3, −4.4, −4.5,
− 4 . 6 , − 4 . 6 . T o t e r t - b u t y l d i m e t h y l s i l y l ( R ) - 4 -
((3R,5R,7S,8R,9S,10S,13R,14S,17R)-3-((tert-butyldimethylsilyl)oxy)-
7-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]-
M
J. Med. Chem. XXXX, XXX, XXX−XXX