Total Synthesis of Desogestrel
J. Am. Chem. Soc., Vol. 121, No. 4, 1999 713
43.5, 40.8, 32.0, 31.6, 30.9, 25.9, 25.0, 18.1, 17.2, 10.4, -4.5, -4.8;
HRMS (EI, M+) calculated for [C19H34O4Si]+ 354.2226, found 354.2225.
(+)-(1S,3aS,4S,7aS)-hexahydro-1-(tert-butyldimethylsiloxy)-4-car-
bomethoxy-7a-ethyl-5-indanone (0.41 g, 8%) was also isolated: mp
98.6-99.2 °C; [R]D25 +8.7 (c 2.49, benzene); Rf 0.12 (10% EtOAc in
Most of the DMF was removed by evaporating the mixture at 0.3 Torr
and 50 °C. The residue was treated with 10 mL of water. Extractive
workup with ethyl acetate afforded a residue which was purified by
silica gel chromatography (5% EtOAc in hexanes) to give 482 mg of
pure 10 (73% for four steps) as a colorless oil which solidified upon
25
hexanes); FTIR (neat) υ 2956, 2933, 2874, 1749, 1712, 1252 cm-1
;
cooling: mp 93-94 °C; [R]D +201.1 (c 0.945, benzene); Rf 0.46
1H NMR (CDCl3, 500 MHz) δ 3.75 (t, J ) 8.4 Hz, 1H), 3.70 (s, 3H),
2.40 (d, J ) 13.6 Hz, 1H), 2.41-2.26 (m, 3H), 2.10 (dt, J ) 13.0, 7.2
Hz, 1H), 2.02 (m, 1H), 1.68 (m, 2H), 1.55 (m, 1H), 1.49-1.28 (m,
3H), 1.08 (t, J ) 7.5 Hz, 3H), 0.85 (s, 9H), 0.00 (s, 6H); 13C
NMR (CDCl3, 101 MHz) δ 205.9, 169.9, 82.1, 58.6, 52.0, 47.8, 43.7,
37.6, 31.7, 31.2, 25.9, 23.6, 18.1, 17.8, 9.8, -4.6, -5.9; HRMS (CI,
M + NH4+) calculated for [C19H34O4Si + NH4]+ 372.2570, found
372.2557.
(20% EtOAc in hexanes); FTIR (neat) υ 2946, 2860, 1710, 1608, 1499,
1463, 1253 cm-1; 1H NMR (CDCl3, 500 MHz) δ 7.05 (d, J ) 8.5 Hz,
1H), 6.61 (d, J ) 8.5 Hz, 1H), 6.60 (s, 1H), 3.77 (t, J ) 8.3 Hz, 1H),
3.76 (s, 3H), 3.61 (s, 3H), 3.00 (d, J ) 18.1 Hz, 1H), 2.95-2.80 (m,
2H), 2.13 (m, 2H), 1.98 (m, 1H), 1.87 (dd, J ) 17.5, 2.7 Hz, 1H), 1.77
(m, 1H), 1.63 (m, 1H), 1.56-1.42 (m, 2H), 1.39 (dq, J ) 12.0, 5.6
Hz, 1H), 1.33 (m, 1H), 1.22 (m, 1H), 1.01 (t, J ) 7.5 Hz, 3H), 0.88 (s,
9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3, 101 MHz) δ 173.7,
159.4, 142.1, 138.7, 129.3, 127.6, 123.4, 113.1, 111.6, 83.6, 55.2, 51.7,
48.4, 43.2, 39.8, 38.4, 31.5, 29.0, 25.9, 25.9, 23.9, 18.2, 18.1 10.4,
-4.5, -4.7; HRMS (CI, M + H+) calculated for [C28H42O4Si + H]+
471.2931, found 471.2925.
(+)-(1S,3aS,4S,7aS)-3a,4,7,7a-Tetrahydro-1-(tert-butyldimethyl-
siloxy)-6-carbomethoxy-7a-ethyl-5-hydroxy-4-(2-(3-methoxyphenyl)-
ethyl)indane (8). To a stirred suspension of 87 mg of NaH (60%
suspension in mineral oil, 2.2 mmol) in 3.0 mL of THF was added
dropwise a solution of 6 (500 mg, 1.4 mmol) in 2.0 mL of THF. The
resulting mixture was heated to 45 °C for 30 min and then cooled to
-78 °C. A 1.6 M solution of n-BuLi in hexanes (1.19 mL, 1.90 mmol)
was added dropwise. The mixture was warmed slowly to 0 °C over a
1-h period and maintained at that temperature for 30 min. To the
resulting orange solution was added 714 (388 mg, 1.48 mmol) via
syringe at -78 °C. The resulting mixture was stirred at -45 °C for 12
h and slowly warmed to 0 °C over a 4-h period. The reaction mixture
was treated with 0.30 mL of acetic acid, 15 mL of hexanes, and 2 g of
Celite, and the whole was passed through a short silica gel column,
which was further eluted with 4:1 hexanes-ethyl acetate. The eluent
was evaporated in vacuo to give crude 8 as an oil, which was used
without further purification in the subsequent reaction. A pure sample
was obtained by preparative TLC: [R]D25 +2.10 (c 2.42, benzene); Rf
0.24 (10% EtOAc in hexanes); FTIR (neat) υ 2943, 2872, 1728, 1612,
17â-(tert-Butyldimethylsiloxy)-13-ethyl-11-(hydroxymethyl)-3-
methoxygona-1,3,5(10),9(11)-tetraene (11). To a solution of 10 (650
mg, 1.38 mmol) in 7.0 mL of THF at 0 °C was slowly added 79 mg
(2.07 mmol) of lithium aluminum hydride powder. The mixture was
warmed to 23 °C and stirred for 2 h. After dilution with 30 mL of
Et2O, the reaction mixture was cooled to 0 °C, and 0.80 g of finely
ground Na2SO4‚10H2O powder was added slowly, followed by 1 g of
Celite. The resulting mixture was stirred at 23 °C for 16 h, and the
whole was passed through a short column of silica which had been
washed with 5% Et3N in Et2O. The column was further eluted with 50
mL of 5% Et3N in Et2O. The combined eluent was concentrated in
vacuo to give 580 mg (95%) of 11 as a white foam, which was pure
and used in the next step without further purification: mp 127-128
°C; [R]D25 +198.4 (c 2.91, benzene); Rf 0.34 (20% EtOAc in hexanes);
1
FTIR (neat) υ 3419, 2940, 2868, 1601, 1473, 1376, 1252 cm-1; H
1
1460, 1360, 1252 cm-1; H NMR (CDCl3, 400 MHz) δ 9.37 (s, 1H),
NMR (C6D6, 500 MHz) δ 7.56 (d, J ) 8.5 Hz, 1H), 6.73 (dd, J ) 8.5,
2.7 Hz, 1H), 6.70 (s, 1H), 4.34 (d, J ) 10.9 Hz, 1H), 3.97 (d J ) 10.9
Hz, 1H), 3.74 (t, J ) 8.5 Hz, 1H), 3.37 (s, 3H), 2.96 (d, J ) 17.2 Hz,
1H), 2.79-2.62 (m, 2H), 2.07 (m, 1H), 1.89 (m, 2H), 1.79 (dd, J )
17.2, 2.6 Hz, 1H), 1.62-1.50 (m, 3H), 1.37 (m, 2H), 1.23 (t, J ) 7.5
Hz, 3H), 1.19 (m, 1H), 1.33 (m, 1H), 1.03 (s, 9H), 0.14 (s, 3H), 0.11
(s, 3H); 13C NMR (C6D6, 101 MHz) δ 159.4, 139.2, 136.3, 130.9, 129.3,
129.1, 113.7, 111.3, 84.3, 64.4, 54.7, 49.0, 43.8, 39.9, 38.9, 31.8, 29.8,
29.3, 26.2, 24.3, 18.4, 18.3, 10.9, -4.4, -4.6.
7.17 (t, J ) 7.8 Hz, 1H), 6.78 (d, J ) 7.6 Hz, 1H), 6.74-6.70 (m,
2H), 3.80 (t, J ) 8.5 Hz, 1H), 3.78 (s, 6H), 2.76 (d, J ) 15.5 Hz, 1H),
2.68-2.45 (m, 2H), 2.41 (m, 1H), 2.10 (m, 1H), 1.99 (m, 1H), 1.85-
1.53 (m, 5H), 1.50-1.28 (m, 2H), 1.18 (m, 1H), 0.92 (t, J ) 7.3 Hz,
3H), 0.91 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (CDCl3, 101
MHz) δ 174.9, 173.7, 159.7, 144.4, 129.2, 120.9, 114.2, 111.1, 97.3,
83.2, 55.1, 51.6, 44.9, 43.4, 41.4, 32.2, 31.5, 31.2, 30.9, 25.9, 24.1,
18.1, 17.9, 10.5, -4.6, -5.8; HRMS (EI, M+) calculated for [C28H44O5-
Si]+ 488.2958, found 488.2948.
17â-(tert-Butyldimethylsiloxy)-13-ethyl-11-methylene-3-methoxy-
gona-1,3,5(10)-triene (12). To a solution of 534 mg (2.07 mmol) of
PPh3 in 5 mL of THF at -15 °C was added 326 µL of diethyl
azodicarboxylate (361 mg, 2.07 mmol) dropwise. The resulting yellow
solution was stirred at -15 °C for 15 min and cooled to -40 °C. A
solution of 11 prepared above in 3 mL of THF was added via cannula,
followed by a solution of o-nitrobenzenesulfonylhydrazide (420 mg,
1.93 mmol) in 5 mL of THF 5 min later. The resulting solution was
warmed to -15 °C over a period of 1 h, stirred at -15 °C for 1 h, and
finally warmed to 23 °C and stirred for 12 h. The mixture was
evaporated in vacuo to give an orange residue, which was dissolved in
minimal amount of CH2Cl2 and passed through a silica gel column.
The column further was eluted with 100 mL of CH2Cl2. The eluent
was concentrated, and the resulting residue was purified by silica gel
chromatography (1% EtOAc in hexanes) to give 478 mg (85%) of 12
11-Carbomethoxy-13-ethyl-3-methoxygona-1,3,5(10),9(11)-tetraen-
17â-ol (9). To a stirred solution of the alkylation product 8 obtained
as above in 15 mL of CH2Cl2 at 23 °C was added 1.5 mL of
trifluoroacetic acid (2.2 g, 19.5 mmol). The solution was protected from
light (aluminum foil) and stirred for 24 h. The resulting tan solution
was evaporated in vacuo to yield a brown residue containing 9 and
corresponding trifluoroacetate. Treatment of this mixture in methanol
(15 mL) with 585 mg of anhydrous K2CO3 at 23 °C for 1 h effected
cleavage of the trifluoroacetate. Evaporation in vacuo, addition of 6.5
mL of 1.0 M aqueous HCl, and extractive workup with ethyl acetate
gave crude 9, which was dried azeotropically with toluene and directly
used in the next step. A pure sample of 9 was obtained by preparative
TLC: mp 156-157 °C; [R]D25 +219.6 (c 1.45, benzene); Rf 0.34 (40%
EtOAc in hexanes); FTIR (neat) υ 3470, 2942, 2869, 1702, 1605, 1487,
1
1442 cm-1; H NMR (CDCl3, 400 MHz) δ 7.03 (d, J ) 8.3 Hz, 1H),
25
as a colorless oil which solidified upon cooling: mp 71-72 °C; [R]D
6.60 (d, J ) 8.3 Hz, 1H), 6.59 (s, 1H), 3.86 (t, J ) 8.8 Hz, 1H), 3.75
(s, 3H), 3.59 (s, 3H), 3.09 (d, J ) 17.5 Hz, 1H), 2.96-2.78 (m, 2H),
2.13 (m, 3H), 2.03 (br, 1H), 1.92 (dd, J ) 17.5, 2.6 Hz, 1H), 1.79 (m,
1H), 1.65 (m, 1H), 1.58-1.22 (m, 5H), 1.02 (t, J ) 7.5 Hz, 3H); 13C
NMR (CDCl3, 101 MHz) δ 173.4, 159.4, 142.7, 138.7, 129.3, 127.4,
122.9, 113.1, 111.6, 83.5, 55.2, 51.7, 48.8, 43.1, 39.8, 38.0, 30.8, 28.9,
28.9, 23.7, 17.8, 10.5; HRMS (CI, M + H+) calculated for [C22H28O4
+ H]+ 357.2066, found 357.2075.
17â-(tert-Butyldimethylsiloxy)-11-carbomethoxy-13-ethyl-3-meth-
oxygona-1,3,5(10),9(11)-tetraene (10). To a solution of the crude
product 9 obtained as above in 5 mL of anhydrous DMF were added
425 mg (2.8 mmol) of tert-butyldimethyl chloride and 240 mg of (3.53
mmol) imidazole. The resulting solution was stirred at 50 °C for 12 h.
+256.0 (c 2.65, benzene); Rf 0.42 (5% EtOAc in hexanes); FTIR (neat)
υ 3065, 2939, 2871, 1611, 1477, 1253 cm-1; H NMR (CDCl3, 500
1
MHz) δ 7.26 (d, J ) 8.7 Hz, 1H), 6.70 (dd, J ) 8.6, 2.7 Hz, 1H), 6.63
(d, J ) 2.6 Hz, 1H), 4.96 (s, 1H), 4.85 (s, 1H), 3.82 (t, J ) 9.0 Hz,
1H), 3.78 (s, 3H), 2.99 (d, J ) 10.5 Hz, 1H), 2.91 (d, J ) 12.1 Hz,
1H), 2.83 (dt, J ) 12.5 3.7 Hz, 1H), 2.71 (m, 1H), 2.00 (m, 1H), 1.79
(m, 1H), 1.72 (d J ) 12.1 Hz, 1H), 1.68-1.53 (m, 2H), 1.48-1.36
(m, 1H), 1.33 (m, 3H), 1.36-1.23 (m, 3H), 1.04 (t, J ) 7.4 Hz, 3H),
0.91 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (CDCl3, 126 MHz)
δ 157.3, 147.9, 139.3, 131.1, 128.0, 113.7, 111.4, 108.8, 83.3, 55.2,
51.8, 51.5, 47.2, 44.8, 41.7, 31.8, 31.0, 27.0, 26.0, 22.2, 19.2, 18.1
9.1-4.6, -4.7; HRMS (EI, M+) calculated for [C27H42O2Si]+ 426.2954,
found 426.2951.