Journal of Medicinal Chemistry
Article
7.5), 1.39−1.50 (2H, m), 1.58 (2H, br s), 1.82−1.92 (2H, m), 2.06
(1H, t, J = 13.9), 2.18−2.30 (1H, m), 2.35 (1H, d, J = 12.8), 2.84−2.92
(3H, m), 3.21 (1H, J = 12.8), 6.50−6.57 (2H, m), 6.81 (1H, d, J =
8.3), 7.24−7.36 (5H, m). LC-MS: m/z 319.4 [M + 1 − H2O]+, 381.4
[M − 1 + H2CO2]−. Anal. Calcd for C22H24O3: C, 78.54; H, 7.16.
Found: C, 78.50; H 7.46. The more polar fractions were evaporated to
give 0.7 g (11%) of title diketone 12 as a white solid. 1H NMR
(CDCl3): δ 0.73 (3H, t, J = 7.3), 1.39−1.50 (1H, m), 1.46−1.82 (3H,
overlapping m and br s), 2.17 (1H, t, J = 13.5), 2.46 (1H, d, J = 12.8),
2.69−2.83 (3H, m), 2.89 (1H, d, J = 13.3), 3.28 (1H, d, J = 12.9),
6.93−7.02 (2H, m), 7.21−7.40 (5H, m), 7.49 (1H, d, J = 2.5). LC-MS:
m/z 349.3 [M − 1]−, 395.4 [M − H + H2CO2]−.
m/z 351.4 [M − H]−, 381.4 [M − OH + H2CO2]−. The analytical
sample was prepared from a previous sample by crystallization from
ethyl ether/hexanes, mp 197−199 °C. Anal. Calcd for C23H28O3: C,
78.38; H, 8.01. Found: C, 78.03; H, 7.91. The structure was confirmed
by single-crystal X-ray analysis of a sample that had been crystallized
first from chloroform and then recrystallized from ethyl ether/hexanes.
Evaporation of the more polar fractions gave title compound 14 as a
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white solid, 0.90 g (12%). H NMR (DMSO-d6): δ 0.65 (3H, t, J =
7.6), 1.10−1.22 (2H, m), 1.22 (3H, s), 1.28−1.35 (1H, m), 1.55−1.72
(3H, m), 1.78−1.91 (3H, m), 2.52−2.69 (2H, m), 4.12 (1H, s), 4.73
(1H, s), 6.31 (1H, d, J = 2.5), 6.42 (1H, dd, J = 2.5 and 8.7), 6.82 (1H,
d, J = 8.3), 7.05 (1H, t, J = 7.3), 7.14 (2H, t, J = 7.4), 7.68 (2H, d, J =
7.5), 8.89 (1H, s). LC-MS: m/z 351.4 [M − H]−, 397.4 [M − H +
H2CO2]−. The analytical sample was prepared from a previous sample
by recrystallization from ethyl ether/hexanes, mp 228−229 °C. Anal.
Calcd for C23H28O3: C, 78.38; H, 8.01. Found: C, 78.17; H, 8.29. The
structure was confirmed by single-crystal X-ray analysis.
(2R,3S,4aR,10aR)-4a-Ethyl-2-phenyl-1,2,3,4,4a,9,10,10a-oc-
tahydrophenanthrene-2,3,7-triol (4).
(2R,3R,4aR,10aR)-3,4a-Diethyl-2-phenyl-1,2,3,4,4a,9,10,10a-
octahydrophenanthrene-2,3,7-triol (15) and (2R,3R,4aR,10aR)-
4a-Ethyl-2-phenyl-1,2,3,4,4a,9,10,10a-octahydrophenan-
threne-2,3,7-triol (16).
A 30 mL round-bottom flask was charged with ketone 11 (75 mg, 0.22
mmol), THF (5 mL), and ethanol (10 mL). Solid NaBH4 (17 mg,
0.50 mmol) was added, and the mixture was stirred for 2 h. Additional
NaBH4 (15 mg, 0.40 mmol) was added, and stirring was continued for
2 h. A solution of 1 N hydrochloric acid (10 mL) and water (40 mL)
were added, and the mixture was extracted with ethyl acetate (3 × 60
mL). The combined organic layers were washed with brine, dried
(MgSO4), and concentrated to afford a white solid (78 mg, 100%).
The 1H NMR (CDCl3) spectrum showed two isomers (95:5) with the
major isomer corresponding to title compound 4. The minor isomer
corresponded to compound 16 (vide infra). The structure of 4 was
confirmed by single-crystal X-ray analysis of another sample which had
been purified by chromatography and crystallized out of CDCl3 as star
A dry 20 mL round-bottom flask was charged with ketone 11 (100 mg,
0.30 mmol), lithium chloride (94 mg, 2.2 mmol), and toluene (5 mL).
A solution of 1 M ethylmagnesium bromide in THF (2.2 mL, 2.2
mmol) was added, and the mixture was stirred overnight at room
temperature. The suspension was treated with 10% aqueous acetic acid
and then combined with additional material from a previous reaction
run identically (0.45 mmol of 11). Water (30 mL) was added, and the
mixture was extracted with ethyl acetate (3 × 30 mL). The combined
organic layers were washed with saturated sodium bicarbonate and
brine, dried (MgSO4), and concentrated to give an oil (0.29 g).
Purification was performed by flash chromatography (40 g silica gel)
eluting with ethyl acetate/hexanes (10, 25, and 35%, 400 mL each).
The less polar fractions were pooled and concentrated to afford 51 mg
1
needles, mp 191−192 °C. H NMR (DMSO-d6): δ 0.68 (3H, t, J =
7.3), 1.09−1.12 (1H, m), 1.25−1.49 (2H, m), 1.56−1.70 (1H, m),
1.72−1.80 (2H, m), 1.96 (1H, dd, J = 2.9 and 13.7), 2.39 (1H, dd, J =
3.7 and 13.3), 2.54−2.74 (2H, m), 3.83−3.89 (1H, m), 4.82 (1H, s),
4.86 (1H, d, J = 3.3), 4.91 (1H, s), 6.36 (1H, d, J = 2.5), 6.42 (1H, dd,
J = 2.7 and 8.4), 6.84 (1H, d, J = 8.3), 7.08−7.12 (1H, m), 7.15−7.21
(2H, m), 7.70 (2H, d, J = 7.5), 8.95 (1H, s). LC-MS: m/z 321.3 [M +
H − H2O]+.
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(19%) of title analogue 15 as a foam. H NMR (DMSO-d6): δ 0.67
(2R, 3R, 4aR, 10aR)-4a-Ethyl-3-methyl-2-phenyl-
1,2,3,4,4a,9,10,10a-octahydrophenanthrene-2,3,7-triol (13)
and (2R,3S,4aR,10aR)-4a-Ethyl-3-methyl-2-phenyl-
1,2,3,4,4a,9,10,10a-octahydrophenanthrene-2,3,7-triol (14).
(3H, t, J = 7.1), 0.79 (3H, t, J = 7.6), 1.09−1.36 (5H, m), 1.49 (1H, d,
J = 15.0), 1.62−1.77 (2H, m), 2.10−2.23 (2H, m), 2.58−2.74 (3H,
m), 3.67 (1H, s), 5.22 (1H, s), 6.36 (1H, d, J = 2.5), 6.45 (1H, dd, J =
2.5 and 8.3), 6.91 (1H, d, J = 8.7), 7.09 (1H, t, J = 7.3), 7.18 (2H, t, J =
7.5), 7.49 (2H, d, J = 7.5), 8.93 (1H, s). LC-MS: m/z 365.4 [M − H]−,
411.4 [M − H + H2CO2]−. The more polar fractions were pooled and
concentrated to afford 45 mg (18%) of title alcohol 16 as a foam,
which was crystallized from ethyl ether/hexanes, mp 207−209 °C. 1H
NMR (CDCl3 + drop of CD3OD): δ 0.83 (3H, t, J = 7.3), 1.19−1.23
(3H, m), 1.22−1.30 (1H,m), 1.42 (1H, d, J = 13.5), 1.61−1.72 (2H,
m), 1.88−2.00 (1H, m), 2.07 (1H, d, J = 13.5), 2.20−2.33 (2H, m),
2.75−2.88 (3H, m), 4.56 (1H, br s), 6.50−6.54 (2H, m), 6.94 (1H, d, J
= 8.3), 7.25−7.35 (3H, m), 7.52 (2H, d, J = 7.3). LC-MS: m/z 321.4
[M + H − H2O]+, 383.4 [M − 1 + H2CO2]−. The structure of 16 was
confirmed by single-crystal X-ray analysis.
A 1- L round-bottom flask was charged with ketone 11 (6.95 g, 20.7
mmol) and THF (700 mL). The solution was cooled to 0 °C, and a
solution of 1 M methyllithium−lithium iodide complex in diethyl ether
(100 mL, 100 mmol) was added dropwise. The mixture was allowed to
warm to room temperature and then stirred overnight. To the
resulting light green mixture was added a solution of 10% aqueous
acetic acid (100 mL) followed by water (200 mL). The organic layer
was separated and the aqueous layer extracted with ethyl acetate (2 ×
300 mL). The combined organic layers were washed with saturated
sodium bicarbonate solution and brine, dried (MgSO4), and
concentrated. The oily residue (8.2 g) was purified by flash
chromatography (dry loaded onto 400 g of silica gel) eluting with
ethyl ether/hexanes (30−100% gradient in 10% increments).
Evaporation of the less polar fractions afforded 5.2 g (72%) title
compound 13 as a white solid. 1H NMR (CD3OD): δ 0.78 (3H, t, J =
7.1,7.5), 1.12 (3H, s), 1.15−1.31 (1H, m), 1.33−1.40 (1H, m), 1.42
(1H, d, J = 12.8), 1.75−1.92 (3H, m), 2.23−2.37 (2H, m), 2.68−2.80
(3H, m), 6.50 (1H, s), 6.53 (1H, d, J = 8.7), 6.99 (1H, d, J = 8.3),
7.12−7.18 (1H, m), 7.19−7.24 (2H, m), 7.59 (2H, d, J = 7.9). LC-MS:
( 2 R , 3 S , 4 a R , 1 0 a R ) - 4 a - E t h y l - 2 - p h e n y l - 3 - v i n y l -
1,2,3,4,4a,9,10,10a-octahydrophenanthrene-2,3,7-triol (17).
To a stirred solution of 1 M vinyl bromide in THF (9 mL, 9 mmol) at
−78 °C was added a solution of 1.7 M tert-butyllithium in hexane (10
mL, 17 mmol). After stirring for 1 h, the mixture was warmed to 0 °C,
and a solution of ketone 11 (0.30 g, 0.89 mmol) in THF (10 mL) was
added. The mixture was allowed to warm to room temperature and
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J. Med. Chem. 2015, 58, 2658−2677