The Journal of Organic Chemistry
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1206, 1111, 1087, 1029, 836, 776, 775; 1H NMR (400 MHz, CDCl3, δ
ppm) 7.39−7.23 (m, 5H), 4.68 (d, J = 11.7 Hz, 1H), 4.45 (d, J = 11.7
Hz, 1H), 3.64−3.52 (m, 1H), 3.01 (dd, J = 11.7, 4.3 Hz, 1H), 2.84−
2.7 (m, 1H), 2.53−2.28 (m, 2H), 2.14−1.83 (m, 4H), 1.76−1.46 (m,
2H), 1.38−1.07 (m, 3H), 1.05 (d, J = 6.6 Hz, 3H), 1.03 (s, 3H), 1.01
(s, 3H), 0.94 (s, 3H), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR (100 MHz,
CDCl3, δ ppm) 198.9, 162.6, 139.0, 135.4, 128.2, 127.4, 127.3, 85.2,
71.5, 68.1, 48.3, 41.1, 39.2, 38.5, 35.4, 35.0, 33.5, 31.6, 29.1, 27.5, 25.8,
22.8, 22.6, 21.5, 18.2, 16.7, 16.0, 14.1, −4.6, −4.7; HRMS (ESI) m/z
[M + H]+ calcd for C31H49O3Si 497.3445, found 497.3442.
(2S,4aS,6R,8S,10aR)-6-((tert-Butyldimethylsilyl)oxy)-2-hy-
droxy-1,1,4a,8-tetramethyl-2,3,4,4a,5,6,7,8,10,10a-decahydro-
phenanthren-9(1H)-one (57). To 56 (1.0 g, 2.01 mmol) dissolved
in reagent-grade EtOAc (10 mL) in a pressure vessel was added 10%
Pd/C (100 mg, 10 wt % of the substrate). The pressure vessel was
evacuated three times with argon and two times with H2 and then
filled with hydrogen (15 psi), and the reaction mixture was stirred for
24 h at room temperature. After completion of the reaction, the
mixture was diluted with chloroform (10 mL), filtered using a Celite-
sintered funnel, and washed with chloroform. The solvent was
evaporated under reduced pressure, and the crude product was
purified by silica gel column chromatography (30% EtOAc/hexanes)
to furnish the title compound 57 (736 mg, 90% yield). TLC (20%
EtOAc/hexanes) Rf = 0.25, visualized with CAM; [α]2D0 +84.0 (c 0.5,
CHCl3); IR (neat/NaCl) ν (cm−1) 3444, 2952, 2932, 2857, 1661,
1605, 1471, 1462, 1378, 1256, 1189, 1110, 1087, 1058, 854; 1H NMR
(400 MHz, CDCl3, δ ppm) 3.61−3.5 (m, 1H), 3.28 (dd, J = 11.7, 4.3
Hz, 1H), 2.8−2.68 (m, 1H), 2.49−2.26 (m, 2H), 2.12−1.93 (m, 2H),
1.9−1.57 (m, 4H), 1.41−1.09 (m, 3H), 1.02 (d, J = 6.6 Hz, 3H), 0.98
(s, 3H), 0.97 (s, 3H), 0.86 (s, 9H), 0.83 (s, 3H), 0.03 (s, 6H); 13C
NMR (100 MHz, CDCl3, δ ppm) 198.9, 162.6, 135.3, 77.8, 68.1, 47.8,
41.0, 39.2, 38.4, 35.4, 35.0, 33.6, 29.1, 27.3, 27.1, 25.8, 21.4, 18.1, 16.7,
15.1, −4.6, −4.7; HRMS (ESI) m/z [M + H]+ calcd for C24H43O3Si
407.2976, found 407.2990.
yield). TLC (30% EtOAc/hexanes) Rf = 0.75, visualized with CAM;
[α]2D0 +21.8 (c 0.5, CHCl3); IR (neat/NaCl) ν (cm−1) 3444, 2951,
2928, 2855, 1703, 1462, 1389, 1362, 1147, 1105, 1050, 917, 880, 835,
774; 1H NMR (400 MHz, CDCl3, δ ppm) 4.77 (d, J = 7 Hz, 1H), 4.62
(d, J = 7 Hz, 1H), 4.12−4.08 (m, 1H), 3.39 (s, 3H), 3.17 (dd, J = 11.7,
3.9 Hz, 1H), 2.57−2.48 (m, 1H), 2.4 (dd, J = 16.7, 3.9 Hz, 1H), 2.31−
2.21 (m, 1H), 1.98 (dd, J = 12.5, 3.9 Hz, 1H), 1.87−1.46 (m, 8H),
1.37−1.16 (m, 2H), 1.05 (d, J = 7 Hz, 3H), 0.96 (s, 6H), 0.88 (s, 9H),
0.86 (s, 3H), 0.02 (s, 6H); 13C NMR (100 MHz, CDCl3, δ ppm)
211.6, 95.9, 84.4, 67.6, 55.6, 53.1, 51.1, 41.4, 39.1, 38.6, 38.5, 36.6,
35.1, 34.7, 27.5, 27.4, 25.8, 23.9, 17.9, 16.7, 15.7, 13.4, −4.9, −5.0;
HRMS (ESI) m/z [M + H]+ calcd for C26H49O4Si 453.3395, found
453.3381.
(2S,4aR,4bS,6R,8S,8aS,9S,10aR)-6-((tert-Butyldimethylsilyl)-
oxy)-2-(methoxymethoxy)-1,1,4a,8-tetramethyltetradecahy-
drophenanthren-9-ol (60). Compound 59 (500 mg, 1.10 mmol)
was dissolved in methanol, and NaBH4 (83.6 mg, 2.20 mmol) was
added to the solution at 0 °C. The solution was stirred for 1 h at 0 °C
under an argon atmosphere. After complete conversion as monitored
by TLC, saturated aqueous sodium chloride solution was added,
followed by EtOAc (50 mL). The mixture was extracted with ethyl
acetate (2 × 50 mL), dried over anhydrous MgSO4, and filtered, and
the solvent was removed under reduced pressure. The crude product
was purified by silica gel column chromatography (16% EtOAc/
hexanes) to afford the title compound 60 (452 mg, 90% yield). TLC
(30% EtOAc/hexanes) Rf = 0.6, visualized with CAM; [α]2D0 +28.54 (c
1
0.55, CHCl3); H NMR (400 MHz, CDCl3, δ ppm) 4.76 (d, J = 6.6
Hz, 1H), 4.62 (d, J = 6.6 Hz, 1H), 4.1−4.05 (m, 1H), 3.59−3.48 (m,
1H), 3.39 (s, 3H), 3.12 (dd, J = 11.7, 4.3 Hz, 1H), 2.27−2.16 (m, 1H),
1.91−1.83 (m, 1H), 1.8−1.22 (m, 12H), 1.08 (d, J = 7.4 Hz, 3H), 0.99
(s, 3H), 0.87 (s, 9H), 0.85 (s, 6H), 0.01 (s, 3H), 0.005 (s, 3H); 13C
NMR (100 MHz, CDCl3, δ ppm) 95.9, 84.9, 72.3, 67.8, 55.5, 51.4,
46.2, 40.0, 39.2, 38.5, 37.1, 35.9, 33.3, 30.7, 28.3, 27.1, 24.1, 25.8, 17.9,
16.7, 16.5, 14.4, −4.9, −5.0; HRMS (ESI) m/z [M + Na]+ calcd for
C26H50NaO4Si 477.3371, found 477.3355.
(2S,4aS,6R,8S,10aR)-6-((tert-Butyldimethylsilyl)oxy)-2-(me-
thoxymethoxy)-1,1,4a,8-tetramethyl-2,3,4,4a,5,6,7,8,10,10a-
decahydrophenanthren-9(1H)-one (61). Compound 57 (300 mg,
0.73 mmol) was dissolved in anhydrous dichloromethane (8 mL), and
the solution was cooled to 0 °C. Chloromethyl methyl ether (1.68 mL,
22.1 mmol) and diisopropylethylamine (0.385 mL, 2.21 mmol) were
added to the above solution at 0 °C under an argon atmosphere, and
the mixture was allowed to warm to room temperature. The mixture
was stirred for 48 h at room temperature and then quenched with
aqueous NH4Cl solution. The mixture was extracted with CH2Cl2 (3 ×
10 mL), and the combined organic phases were washed with brine,
dried with MgSO4, filtered, and evaporated. Silica gel column
chromatography of the residue (20% EtOAc/Hex) afforded the title
compound 61 (272 mg, 82% yield). TLC (30% EtOAc/hexanes) Rf =
0.72, visualized with CAM; IR (neat/NaCl) ν (cm−1) 2951, 2930,
2856, 1665, 1608, 1256, 1204, 1148, 1110, 1087, 1047, 854, 836, 775;
1H NMR (400 MHz, CDCl3, δ ppm) 4.73 (d, J = 6.6 Hz, 1H), 4.59 (d,
J = 6.6 Hz, 1H), 3.62−3.51 (m, 1H), 3.36 (s, 3H), 3.15 (dd, J = 11.7,
4.3 Hz, 1H), 2.81−2.69 (m, 1H), 2.5−2.26 (m, 3H), 2.11−1.92 (m,
2H), 1.91−1.78 (m, 2H), 1.64 (dd, J = 13.2, 4.3 Hz, 1H), 1.38−1.1
(m, 3H), 1.03 (d, J = 6.6 Hz, 3H), 1.0 (s, 3H), 0.96 (s, 3H), 0.88 (s,
3H), 0.87 (s, 9H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3, δ ppm)
198.8, 162.5, 135.4, 95.9, 83.9, 68.1, 55.5, 48.2, 41.0, 39.1, 38.2, 35.4,
35.0, 33.5, 29.1, 27.3, 25.8, 24.0, 21.5, 18.1, 16.7, 15.8, −4.6, −4.7;
HRMS (ESI) m/z [M + H]+ calcd for C26H47O4Si 451.3238; found
451.3242.
(2S,4aR,4bS,6R,8S,8aS,9S,10aR)-6-((tert-Butyldimethylsilyl)-
oxy)-2-(methoxymethoxy)-1,1,4a,8-tetramethyltetradecahy-
drophenanthren-9-ol (60). Lithium pieces (53.3 mg, 8.88 mmol)
were washed with hexanes and placed in a flask topped with a dry ice
condenser, and the entire system was flushed with argon. The flask was
cooled to −78 °C, and then ammonia was condensed until no further
lithium was seen. The cooling bath was removed, and the system was
allowed to equilibrate to the refluxing temperature (−33 °C).
Anhydrous THF (6 mL) was added to the reaction mixture, followed
(2S,4aR,4bS,6R,8S,8aS,10aR)-6-((tert-Butyldimethylsilyl)oxy)-
2-hydroxy-1,1,4a,8-tetramethyldodecahydrophenanthren-
9(1H)-one (58). To compound 57 (600 mg, 1.47 mmol) dissolved in
anhydrous EtOAc (5 mL) in a pressure vessel was added 10% Pd/C
(60 mg, 10 wt % of the substrate). The pressure vessel was evacuated
three times with argon and two times with H2 and then filled with
hydrogen (20 psi). The reaction mixture was stirred at room
temperature for 48 h and then diluted with CHCl3 (10 mL) and
filtered using a Celite-sintered funnel. The filtrate was concentrated
under reduced pressure. Purification of the crude product by silica gel
column chromatography (30% EtOAc/hexanes) afforded the title
compound 58 (572 mg, 95% yield). TLC (20% EtOAc/hexanes) Rf =
0.3, visualized with CAM; mp 148−149 °C; IR (neat/NaCl) ν (cm−1)
3453, 2952, 2855, 2708, 1694, 1462, 1426, 1371, 1343, 1307, 1252,
1
1144, 976, 880, 773, 737, 666; H NMR (400 MHz, CDCl3, δ ppm)
4.14−4.07 (m, 1H), 3.30 (dd, J = 11.3, 3.5 Hz, 1H), 2.57−2.47 (m,
1H), 2.4 (dd, J = 16.4, 3.5 Hz, 1H), 2.26 (t, J = 16.4 Hz, 1H), 1.97 (dd,
J = 12.5, 3.5 Hz, 1H), 1.88−1.45 (m, 7H), 1.36−1.07 (m, 3H), 1.04
(d, J = 7.4 Hz, 3H), 0.96 (s, 3H), 0.94 (s, 3H), 0.86 (s, 9H), 0.83 (s,
3H), 0.01 (s, 6H); 13C NMR (100 MHz, CDCl3, δ ppm) 211.5, 78.5,
67.6, 53.0, 50.8, 41.4, 39.0, 38.8, 38.5, 36.6, 35.3, 34.7, 27.5, 27.4, 27.1,
25.8, 17.9, 16.7, 14.9, 13.4, −4.9, −5.2; HRMS (ESI) m/z [M + Na]+
calcd for C24H44NaO3Si 431.2952, found 431.2946.
(2S,4aR,4bS,6R,8S,8aS,10aR)-6-((tert-Butyldimethylsilyl)oxy)-
2-(methoxymethoxy)-1,1,4a,8-tetramethyldodecahydrophe-
nanthren-9(1H)-one (59). Compound 58 (750 mg, 1.83 mmol) was
dissolved in anhydrous dichloromethane (10 mL), and the solution
was cooled to 0 °C. To this solution were added chloromethyl methyl
ether (4.18 mL, 55.14 mmol) and diisopropylethylamine (0.958 mL,
5.51 mmol) under an argon atmosphere. The resulting mixture was
stirred for 48 h at rt and then quenched with aqueous NH4Cl solution.
The mixture was extracted with CH2Cl2 (3 × 10 mL), and the
combined organic phases were washed with brine, dried with
anhydrous MgSO4, filtered, and evaporated under reduced pressure.
Purification of the residue (16% EtOAc/hexanes) by silica gel column
chromatography furnished the title compound 59 (706 mg, 85%
Q
dx.doi.org/10.1021/jo501122k | J. Org. Chem. XXXX, XXX, XXX−XXX