Journal of Medicinal Chemistry
Article
137.8, 130.8, 129.5, 129.2, 126.0, 124.6, 112.2, 61.5, 53.8, 53.6, 50.0,
49.4, 46.2, 42.9, 42.4, 41.6, 38.2, 38.1, 37.0, 35.0, 34.4, 33.1, 30.8,
30.0, 28.9, 27.8, 26.9, 25.9, 21.8, 21.6, 21.5, 20.5, 19.6, 17.1, 16.8,
14.9.
bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-((1S,4S)-5-(meth-
ylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)amino)-1-(prop-
1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octade-
cahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as a light-brown
solid (69 mg, 78% yield). LC/MS: m/e 746.8 (M + H)+, 246 min
(method 3). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.1 Hz, 2H),
7.15 (d, J = 8.1 Hz, 2H), 5.25 (d, J = 4.6 Hz, 1H), 4.71 (s, 1H), 4.57
(s, 1H), 4.26 (s, 1H), 3.86 (s, 3H), 3.69 (br s, 1H), 3.58 (d, J = 9.5
Hz, 1H), 3.19 (dd, J = 9.4, 1.8 Hz, 1H), 2.97 (dd, J = 9.8, 2.0 Hz,
1H), 2.85 (s, 3H), 2.80 (dd, J = 8.3, 4.2 Hz, 2H), 2.65 (d, J = 9.8 Hz,
1H), 2.61−2.44 (m, 2H), 2.07 (dd, J = 17.1, 6.4 Hz, 2H), 1.95−1.68
(m, 6H), 1.66 (s, 3H), 1.65−1.37 (m, 9H), 1.31−1.06 (m, 7H), 1.04
(s, 3H), 0.96 (s, 3H), 0.94 (s, 3H), 0.89 (s, 6H).
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11-
bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-((1S,4S)-5-(meth-
ylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)amino)-1-(prop-
1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octade-
cahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (65 mg, 0.09 mmol)
in THF (2 mL) and MeOH (1 mL) was added a solution of
LiOH.H2O(14.6 mg, 0.35 mmol). The reaction mixture was stirred at
75 °C for 1 h, concentrated, and the residue dissolved in a mixture of
THF (1.5 mL) and MeOH (0.5 mL) and the product purified by
preparative reversed phase HPLC (method 8) to give 46 (46.6 mg,
54.6% yield) as a white solid. LC/MS: m/e 732.7 (M + H)+, 2.22 min
(method 3). 1H NMR (400 MHz, 1:1 CDCl3:MeOH-d4) δ 7.90 (d, J
= 8.3 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 5.27 (d, J = 4.9 Hz, 1H), 4.82
(s, 1H), 4.71 (br s, 1H), 4.45 (br s, 1H), 4.14 (br s, 1H), 3.72 (d, J =
10.5 Hz, 1H), 3.56 (dt, J = 9.8, 6.5 Hz, 1H), 3.41 (d, J = 10.0 Hz,
3H), 3.29−3.09 (m, 3H), 2.97 (s, 3H), 2.85 (td, J = 11.0, 5.1 Hz,
1H), 2.22−1.96 (m, 7H), 1.93−1.75 (m, 3H), 1.72 (s, 3H), 1.68 (br
s, 1H), 1.66−1.47 (m, 8H), 1.47−1.32 (m, 4H), 1.26 (d, J = 10.5 Hz,
1H), 1.16 (s, 3H), 1.08 (s, 3H), 1.01 (s, 3H), 0.93 (br s, 3H), 0.92
(br s, 3H). 13C NMR (101 MHz, 1:1 CDCl3:MeOH-d4) δ 169.8,
149.4, 148.2, 147.2, 130.8, 129.5, 129.1, 124.6, 112.3, 78.7, 73.1, 64.9,
61.7 (br s, 1C), 60.1, 53.6, 50.1, 46.4, 42.9, 42.5, 41.6, 38.8, 38.2, 38.2,
37.0, 34.4, 33.1, 30.5, 30.0, 28.9, 27.9, 27.0, 25.9, 21.8, 21.6, 20.4,
19.4, 17.1, 16.7, 15.0.
4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-
Pentamethyl-3a-((2-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo-
[2.2.1]heptan-2-yl)ethyl)amino)-1-(prop-1-en-2-yl)-
2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahy-
dro-1H-cyclopenta[a]chrysen-9-yl)benzoic Acid (46). To a vial
containing 22 (82 mg, 0.14 mmol) and (1S,4S)-tert-butyl 2,5-
diazabicyclo[2.2.1]heptane-2-carboxylate (86 mg, 0.43 mmol) was
added THF (1 mL), followed by DIPEA (0.18 mL, 1.0 mmol). The
mixture was heated at 100 °C for 14 h, cooled to rt, and the product
purified by preparative reversed phase HPLC (method 7) to give
(1S,4S)-tert-butyl 5-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11-
bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pen-
tamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11-
b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)-
amino)ethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (52 mg,
36.2% yield) as a white solid. LC/MS: m/e 768.7 (M + H)+, 2.43
min (method 3). 1H NMR (400 MHz, CDCl3) δ 8.14 (br s, 2H), 7.93
(d, J = 8.1 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 5.29 (d, J = 4.6 Hz, 1H),
4.78 (s, 1H), 4.70 (s, 1H), 4.65−4.49 (m, 1H), 4.28 (br s, 1H), 3.91
(s, 3H), 3.70 (d, J = 11.7 Hz, 3H), 3.55−3.35 (m, 4H), 2.78−2.62
(m, 1H), 2.23−1.97 (m, 6H), 1.94 (d, J = 12.0 Hz, 1H), 1.86 (t, J =
12.0 Hz, 1H), 1.80−1.71 (m, 2H), 1.69 (s, 3H), 1.67−1.61 (m, 2H),
1.54 (dd, J = 15.5, 3.5 Hz, 5H), 1.46 (s, 9H), 1.43−1.28 (m, 4H),
1.27−1.17 (m, 1H), 1.10 (s, 3H), 1.04 (s, 3H), 0.99 (s, 3H), 0.93 (br
s, 3H), 0.93 (br s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.3, 148.6,
146.6, 146.3, 130.0, 128.5, 127.9, 123.8, 117.2, 114.3, 112.1, 81.5,
77.2, 73.5, 52.8, 52.0, 49.3, 48.9, 45.4, 42.0, 41.7, 40.7, 38.6, 37.5,
37.4, 36.2, 33.4, 32.4, 29.4, 28.2, 28.0, 27.5, 26.3, 25.0, 21.0, 20.8,
19.6, 18.8, 16.4, 15.4, 14.5.
To a solution of (1S,4S)-tert-butyl 5-(2-(((1R,3aS,5aR,5bR,7aR,11-
aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-
pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11-
b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)-
amino)ethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (419 mg,
0.55 mmol) in CH2Cl2 (10 mL) was added CF3CO2H (2 mL, 26.0
mmol), and the mixture was stirred at rt for 3 h. The reaction mixture
was concentrated and the product purified by preparative reversed
phase HPLC (method 8) to give methyl 4-((1R,3aS,5aR,5bR,7aR,11-
aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-
2-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-
2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-
cyclopenta[a]chrysen-9-yl)benzoate (75.2 mg, 12% yield) as a light-
brown solid. LC/MS: m/e 668.7 (M + H)+, 2.36 min (method 3). 1H
NMR (400 MHz, CDCl3) δ 9.77 (br s, 1H), 9.49 (br s, 1H), 7.92 (d,
J = 8.1 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 5.28 (d, J = 4.4 Hz, 1H),
4.76 (br s, 1H), 4.69 (br s, 1H), 4.31 (br s, 1H), 3.96 (br s, 1H), 3.90
(s, 3H), 3.66 (br s, 1H), 3.40−3.10 (m, 5H), 3.09−2.89 (m, 2H),
2.81 (br s, 1H), 2.23−2.06 (m, 4H), 2.05−1.91 (m, 3H), 1.85 (br s,
1H), 1.78−1.73 (m, 1H), 1.69 (br s, 3H), 1.65 (br s, 1H), 1.62−1.30
(m, 11H), 1.26−1.17 (m, 2H), 1.11 (br s, 3H), 1.05 (br s, 3H), 0.99
(br s, 3H), 0.93 (br s, 6H). 13C NMR (101 MHz, CDCl3) δ 167.2,
148.5, 147.1, 146.2, 130.0, 128.5, 127.9, 123.8, 114.8, 111.6, 77.24−
77.18, 71.3, 65.8, 60.9, 57.7, 54.4, 52.7, 52.0, 49.2, 48.7, 48.62−48.49,
46.3, 45.0, 42.0, 41.6, 40.6, 37.4, 37.0, 36.2, 33.6, 32.5, 29.4, 28.0,
27.3, 25.8, 25.0, 20.9, 20.8, 19.5, 19.1, 16.3, 15.9, 15.2, 14.4.
4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1-Imino-
1-oxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-
1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11-
b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-
benzoic Acid (47). The title compound was prepared following the
representative procedure for the alkylation of C-17 amines and
hydrolysis of the benzoate ester described above using N-(4-(2-
chloroethyl)-1-oxidothiomorpholin-1-ylidene)-4-methylbenzenesulfo-
namide, HCl as the alkylating agent to give 16. 16 was purified by
flash chromatography using a 10−55% EtOAc in hexanes gradient
with 0.1% TEA added to the mobile phase. Instead of using the
standard hydrolysis procedure, the compound was treated with
Na2HPO4, (4 equiv) and Na(Hg) (10% sodium) (15 equiv). The
mixture was diluted with MeOH to 0.7 M and heated at reflux for
4.25 h, cooled to rt, and concentrated under reduced pressure. The
residue was diluted with MeOH and CH2Cl2 and filtered through a
plug of Celite to remove the metal formed in the reaction, and the
filtrate was concentrated under reduced pressure. The residue was
diluted with MeOH, and H2O was added dropwise until the mixture
was cloudy. The mixture was set aside until solids formed which were
collected by filtration and washed with H2O. A second crop of solids
formed in the mother liquor upon standing and were collected. The
solids were purified by preparative HPLC (method 9) to give 47 (410
mg, 92% HPLC purity, 0.59 mmol, 43% yield over 2 steps) as a white
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11-
bR,13aR,13bR)-3a-((2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-
ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-
2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-
cyclopenta[a]chrysen-9-yl)benzoate (75.2 mg, 0.11 mmol) and Et3N
(0.08 mL, 0.56 mmol) in CH2Cl2 (3 mL) was added CH3SO2Cl (10
μL, 0.14 mmol). The reaction mixture was stirred at rt for 1.5 h,
diluted with CH2Cl2 (25 mL), and washed with H2O (2 mL). The
aqueous layer was extracted with CH2Cl2 (15 mL), and the combined
organic layer was washed with brine, dried over MgSO4, filtered, and
concentrated to give methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11-
1
solid. LCMS: m/e 690.6 (M + H)+, 1.60 min (method 6). H NMR
(400 MHz, AcOH-d4) δ = 7.99 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 8.0
Hz, 2H), 5.34 (d, J = 5.0 Hz, 1H), 4.81 (s, 1H), 4.70 (s, 1H), 3.64−
3.04 (m, 12H), 2.93 (d, J = 4.3 Hz, 1H), 1.73 (s, 3H), 1.25 (s, 3H),
1.11 (s, 3H), 1.08 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H), 2.32−0.85 (m,
22H).
N-(4-(2-Chloroethyl)-1-oxidothiomorpholin-1-ylidene)-4-methyl-
benzenesulfonamide, HCl. To a suspension of PhI = NTs (9.8 g,
26.3 mmol) in toluene (100 mL) was added vinyl sulfoxide (2.0 mL,
U
J. Med. Chem. XXXX, XXX, XXX−XXX