Novel stereoselective synthesis of 7β-methyl-substituted 5-androstene derivatives

Article abstract of DOI:10.1021/jo020290x

The 7β-methyl-5-androstene derivatives 11a-c were prepared in good yield with high stereoselectivities starting from 3β-acetoxyandrost-5-en-17-one 4. The addition of methylmagnesium iodide to the 7-carbonyl group of 7a-c gave, after hydrolysis, two isomers 9a-c and 10a-c, which were stereoselectively deoxygenated by means of an ionic hydrogenation to afford the compounds 11a-c.

Full text of DOI:10.1021/jo020290x

Novel Ster eoselective Syn th esis of
Ionic hydrogenation is an effective method to reduce
tertiary carbinols. Ionic hydrogenation with triethylsi-
lane has already been used in the stereoselective reduc-
7
7
â-Meth yl-Su bstitu ted 5-An d r osten e
Der iva tives
tion of hydroxylated and unsaturated estradiol deriva-
tives.8
-10
According to these previous findings, we hy-
Yunhong Zheng and Yuanchao Li*
pothesized that 7-hydroxy derivatives of steroids, which
possessed a tertiary allylic alcohol, would be readily
reduced with triethylsilane and boron trifluoride ether-
ate. With regard to the stereochemical result of the
Institute of Materia Medica, Shanghai Institute for
Biological Sciences, Chinese Academy of Sciences,
94 Taiyuan Road, Shanghai 200031, P.R. China
2
9
reduction, we referred to the literature and anticipated
ycli@mail.shcnc.ac.cn
Received April 24, 2002
that the approach of relatively bulky triethylsilane to the
7
-carbocation would occur from the slightly less hindered
R-side, resulting in a predominant product with the
methyl function having the desired 7â-configuration.
We report here a novel approach to stereoselective
introduction of â-methyl at the C-7 position of steroids
in high yield, using 3â-acetoxyandrost-5-en-17-one 4 as
starting material (Scheme 1). It involves oxidation at C-7,
addition of methyl Grignard to the resulting 7-carbonyl
group to give two isomers, and the stereoselective deoxy-
genation of the 7-hydroxy steroids by means of an ionic
hydrogenation. The alkylation/reduction protocol was
Abstr a ct: The 7â-methyl-5-androstene derivatives 11a -c
were prepared in good yield with high stereoselectivities
starting from 3â-acetoxyandrost-5-en-17-one 4. The addition
of methylmagnesium iodide to the 7-carbonyl group of 7a -c
gave, after hydrolysis, two isomers 9a -c and 10a -c, which
were stereoselectively deoxygenated by means of an ionic
hydrogenation to afford the compounds 11a -c.
9
previously reported by Tedesco et al. The overall yield
The introduction of methyl at C-7 in steroids has been
the subject of several investigations, especially regarding
is 37-62% via five-stage synthesis with 96-99% de.
Androst-5-en-17-one 4 was reduced with KBH and
4
hydrolyzed under basic conditions to give diol 5 in 95%
yield. To selectively oxidize the C-7 position, the two
hydroxyls of 5 were protected. The acetyl was first se-
lected as the protection group, and oxidation of 6a with
7
R-methyl derivatives. Such compounds have shown
significant biological activities, for example, tibolone 1
therapeutic against tumors, cardiovascular disorders,
(
1
and osteoporosis), 7R-methyltestosterone 2 (antifertil-
2
3
ity), and mibolerone 3 (estrus inhibition). However, the
synthesis of 7â-methyl derivatives of steroids and their
biological activities has not been extensively studied. To
explore the effect of such methylation on biological
activities, we set out to synthesize 7â-methyl-5-andros-
tene derivatives. Previous reports on the introduction of
a 7â-methyl mainly concerned the copper-mediated 1,6-
Na
2
Cr
2
O
7
‚2H
2
O gave 3â,17â-diacetoxy-5-androsten-7-one
7
a in 90% yield. The addition of methylmagnesium iodide
to 7a at -40 °C yielded a mixture of the 7R- and 7â-iso-
mers 9a and 10a , which could be isolated by column
chromatography to afford 23% and 33% of 9a and 10a ,
respectively. Under these conditions, the Grignard re-
agent also attacked the ester functions, together with
other side reactions, which resulted in the relatively low
yield. To improve the yield, we used the protecting groups
that will not react with the Grignard reagent. The
methyl- and TBDMS-protected 5-androstene-7-ones 7b
conjugate addition of organometallic reagents to various
steroidal 4,6-dien-3-ones.4,5 Because of the special position
of C-7, which features little proximal steric difference
between the R-side and â-side, both 7R-and 7â-methyl
isomers were obtained. Zeelen et al. reported that 7â-
methyl derivatives of steroids could be stereoselectively
synthesized using 19-hydroxyandrost-4-ene-3,17-dione
(1) (a) de Visser, J .; Coert, A.; Feenstra, H. and van der Vies, J .
Arzneim-Forshch./ Drug Res. 1984, 34, 1010-1017. (b) Gompel, A. et
al. Fertile Steril. 2002, 78 (2), 351-9. (c) Palomba S. et al. Fertil Steril.
2002, 78 (1), 63-8.
6
1
9-acetate as starting material, but the yield was very
low (6.0% overall yield in four steps).
(2) Kendle K. E. et al. J . Reprod. Fertil. 1978, 52, 373
(3) (a) Emmens, C. W.; Humphrey, K.; Martin, L.; Owen, W. H.
Steroids 1967, 9, 235. (b) J aglan, P. S. Adv. Exp. Med. Biol. 1986, 197,
19-24. (c) Martindale. The Extra Pharmacopoeia, 30th ed.; Pharma-
ceutical Press: London, 1993, 1188. (d) Perry, J . E. et al. Cancer Res.
996, 56, 1539.
4) Grunwell, J . F.; Benson, H. D.; O’Neal J ohnston, J .; Petrow, V.
Steroids 1976, 27, 759-771.
5) Ni, Y.; Hao, R. Y.; Zhou, W. S. Chin. Acta Pharm. Sinica 1987,
2 (7), 495-500.
6) van Vliet, N. P.; Broess, A. I. A.; Peters, J . A. M.; van den Broek,
A. J .; Leemhuis, J . A. J .; Zeelen, F. J . Recl. Trav. Chim. Pays-Bas 1986,
9
1
(
(
2
(
1
05, 111-115.
(
7) (a) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974,
6
2
33-651. (b) Adlington, M. G. et al. Tetrahedron Lett. 1976, 17, 2955-
958.
(
8) Peters, R. H.; Crowe, D. F.; Avery, M. A.; Chong, W. K. M.;
Tanabe, M. J . Med. Chem. 1989, 32, 2306-2310.
9) Tedesco, R.; Fiaschi, R.; Napolitano, E. J . Org. Chem. 1995, 60,
(
5
316-5318.
*
22.
To whom correspondence shoud be sent. Fax: (086) 021 64311833-
(10) Posner, G. H.; Switzer, C. J . Am. Chem. Soc. 1986, 108, 1239-
4
1
1244.
0.1021/jo020290x CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/21/2003
J . Org. Chem. 2003, 68, 1603-1606
1603

SCHEME 1a
a
Key: (a) KBH4, MeOH; (b) NaOH, MeOH; (c) Ac2O, Py for 6a or MeI, NaH for 6b; (d) Na2Cr2O7‚2H2O, NOS, acetone; (e) 10%NaOH,
MeOH; (f) imidazole, TBDMSCl, DMF; (g) CH3MgI, Et2O, THF; (h) triethylsilane, BF3‚Et2O.
4
and 7c were prepared in 67% yield from 5 and in 83%
yield from 7a , respectively. The addition of methylmag-
nesium iodide to 7b at -8 °C and 7c at 0 °C gave equal
amounts of the addition products 9b and 10b in 96%
overall yield and 9c and 10c in 91% overall yield,
respectively.
5-androstene derivative. In addition, single-crystal X-ray
diffraction analysis confirmed that 11c is the 7â-isomer
(Figure S1, Supporting Information).
In conclusion, we have developed a novel approach to
7â-methyl-substituted 5-androstene derivatives in 96-99%
de, starting with 3â-acetoxyandrost-5-en-17-one 4. This
method will make 7â-alkyl-substituted derivatives more
easily obtainable than before. The availability of 7â-
alkylated steroids will provide the opportunities to study
their structure-activity relationship and possibility to
develop potent new drugs for clinical use.
The structural assignments of the 7R- and 7â-isomers
were determined by 13C NMR. It has been reported that
the chemical shift of the carbinyl carbon depends on the
orientation of the hydroxyl group; i.e., that an axial
hydroxyl group shields the R-carbon atom more than does
the corresponding equatorial substituent.11 The equa-
Exp er im en ta l Section
torial 7â-hydroxy derivative 9a and the axial 7R-hydroxy
derivative 10a showed 13C NMR signals for C-7 at δ 72.8
3â,17â-Dih yr oxya n d r ost-5-en e (5). A stirring suspension
of 4 (10.05 g, 30.41 mmol) in methanol (300 mL) was heated to
6 °C. KBH (1.04 g, 19.29 mmol) was added in portion in 7 min,
4
and 69.5, respectively. Compounds 9b and 10b showed
3
1
3
C NMR signals for C-7 at δ 72.9 and 69.9, respectively.
and the mixture was stirred at 36 °C for 40 min. After the
addition of glacial acetic acid (4.0 mL), most of the methanol
was evaporated, and the crude mixture of 3â-acetoxy-17â-
hydroxyandrost-5-ene and 5 was precipitated by the addition of
water (400 mL). The residue was collected by filtration. The
residue was dissolved in methanol (250 mL), and then 20%
NaOH (15 mL) was added. After the mixture was stirred at room
temperature for 1 h, glacial acetic acid (5.0 mL) was added to
the mixture. The mixture was poured into water (800 mL). The
solid was collected by filtration and dried to give 8.40 g (95%
yield) of 5. A sample was recrystallized from ethyl acetate: mp
1
3
Compounds 9c and 10c showed C NMR signals for C-7
at δ 74.0 and 70.0, respectively. In addition, cross-peaks
in the NOESY spectrum between H of 7-methyl and H-14
and H-17 in 9a , 9b, and 9c indicated their R-orientation
of 7-methyl groups.
The 7-hydroxy-5-androstene derivatives 9a -c and
1
0a -c were cleanly reduced by treatment with trieth-
ylsilane and boron trifluoride etherate, giving the desired
7
â-methyl-5-androstene derivatives 11a -c in high yields
1
81 °C (lit.12 mp 180.5 °C).
â,17â-Dia cetoxya n d r ost-5-en e (6a ). A mixture of 5 (8.00
g, 27.54 mmol), p-toluenesulfonic acid monohydrate (0.15 g, 0.78
with 99%, 96%, and 98% de, respectively, which were
determined by integration of the H NMR of the crude
3
1
reaction products. The silyl ether groups at C-3 and C-17
mmol), Ac O (5.5 mL, 59.21 mmol), and Py (7.5 mL) was stirred
2
of 9c and 10c were easily removed under deoxygenation
conditions. The H NMR chemical shifts of the 7â-methyl
at room temperature for 1 h and then heated to 95 °C for 3.5 h.
After the mixture was cooled to room temperature, 400 mL of
water was added. The solid was collected by filtration and dried
to give 10.00 g (97% yield) of 6a . Recrystallization from ethyl
1
group of 11a -c appeared at δ 0.94 (d, J ) 6.95 Hz, 3H),
δ 0.91 (d, J ) 6.97 Hz, 3H), and δ 0.95 (d, J ) 6.59 Hz,
13
acetate afforded white crystals: mp 158-160 °C (lit. mp 153-
3
H), respectively, which are similar to that [δ0.98 (d, J
1
55 °C).
)
7 Hz, 3H)] of the 7â-methyl group of a related
(
12) Dannenberg, H.; Neumann, H. G. Chem. Ber. 1961, 94, 3094-
3
0109.
(
11) Eggert, H.; VanAntwerp, C. L.; Bhacca, N. S.; Djerassi, C.J .
(13) Kagan, F.; Martin, D. G. U.S. Patent 3,297,728, 1967; Chem.
Abstr. 1967, 66, 117101q.
Org. Chem. 1976, 41, 71-78.
1
604 J . Org. Chem., Vol. 68, No. 4, 2003

3
â,17â-Dim et h oxya n d r ost -5-en e (6b). To a solution of 5
0.83 g, 2.86 mmol) in dry THF (20 mL) was added NaH (0.44 g,
0.90 mmol). The mixture was stirred for 30 min, and then MeI
1.2 mL, 19.30 mmol) was added. After continued stirring for
.5 h, 0.6 mL of glacial acetic acid and 10 mL of water were
3â,17â-Dia cetoxy-7r-m eth yla n d r ost-5-en -7â-ol (9a ) a n d
3â,17â-Dia cetoxy-7â-m eth yla n d r ost-5-en -7r-ol (10a ). A so-
lution of methylmagnesium iodide prepared from magnesium
(0.46 g, 0.019 mol), methyl iodide (1.2 mL, 0.019 mol), and
anhydrous ether (20 mL) was cooled to -40 °C, and at this
temperature, a solution of 7a (0.50 g, 1.29 mmol) in dry THF
(25 mL) was added dropwise over 15 min. Stirring was continued
at -40 °C for 1 h. The reaction was quenched with saturated
ammonium chloride (15 mL) and the mixture partitioned
between water and ether. The aqueous layer was extracted with
ethyl acetate (6 mL × 3). The combined extracts were washed
(
1
(
1
added to the mixture. The aqueous layer was extracted with 10
mL of ethyl acetate three times. The combined extracts were
washed with brine, dried over anhydrous Na SO , and concen-
2 4
trated in vacuo to give the yellow solid. Recrystallization from
acetone afforded white crystals of 6b (0.88 g, 97%yield): mp
2
0
1
1
3
6
2
5
2
37-139 °C; [R]
664, 1452 cm ; H NMR (CDCl
D
1
-69.0 (c 0.92, CHCl
3
); IR vmax (KBr) 2941,
) δ 0.76 (s, 3H), 0.99 (s, 3H),
-
1
3
2 4
with brine, dried over anhydrous Na SO , and concentrated in
.05 (m, 1H), 3.22 (t, J ) 8.43 Hz, 1H), 3.34 (d, J ) 1.29 Hz,
vacuo. The crude mixture was chromatographed with cyclohex-
ane/ethyl acetate 8/1 to give 9a (0.12 g, 23% yield), which was
recrystallized from diisopropyl ether to give an analytical sample
H), 5.34 (d, J ) 5.13 Hz, 1H); 13C NMR (CDCl
) δ 11.4, 19.4,
3
0.7, 23.3, 27.6, 27.9, 31.5, 31.6, 36.9, 37.1, 37.8, 38.6, 42.6, 50.2,
+
20
1.5, 55.6, 57.8, 80.2, 90.7, 120.2, 140.9; MS (m/z) 318 [M] (67),
86 [M - CH
H, 10.76. Found: C, 79.37; H, 10.74.
[mp 125-126 °C; [R]
D
-58.8 (c 0.79, CHCl
3
); IR vmax (KBr)
) δ 0.80 (s, 3H), 1.05 (s,
3H), 1.12 (s, 3H), 2.02 (s, 3H), 2.03 (s, 3H), 4.59 (m, 2H), 5.19 (s,
1H); 13C NMR (CDCl
+
-1 1
3
OH] (100). Anal. Calcd for C21
H
34
O
2
: C, 79.19;
3496, 2971, 1733 cm ; H NMR (CDCl
3
3
â,17â-Dia cetoxy-5-a n d r osten -7-on e (7a ). To a solution of
(23.23 g, 0.062 mol) in acetone (200 mL) were added
3
) δ 11.7, 19.0, 20.4, 21.1, 21.3, 23.6, 26.3,
27.6, 36.2, 36.9, 37.2, 37.4, 42.6, 43.0, 44.6, 46.5, 72.8, 73.3, 82.4,
132.0, 139.1, 170.5, 171.2; MS (m/z) 404 [M] (<1), 344 (41), 329
36 5
(92), 149 (100). Anal. Calcd for C24H O : C, 71.26; H, 8.97.
6
a
+
N-hydroxysuccinimide (28.23 g, 0.24 mol) and Na
21.24 g, 0.071 mol). The mixture was heated to 40 °C and stirred
for 48 h. The reaction was quenched with saturated sodium
sulfite (100 mL), and the mixture was poured into water (2500
mL). The solid was collected by filtration, washed thoroughly
with water, and dried. Crystallization from methanol gave 7a
2
Cr
2
O
7
‚2H
2
O
(
Found: C, 71.24; H, 9.19] and 10a (0.17 g, 33% yield), which
was recrystallized from diisopropyl ether to give an analytical
2
0
sample: mp 151-152 °C; [R]
D
3
-84.2 (c 0.80, CHCl ); IR vmax
-
1
1
(KBr) 3510, 2944, 1733 cm ; H NMR (CDCl
0.95 (s, 3H), 1.21 (s, 3H), 2.01 (s, 3H), 2.02 (s, 3H), 4.59 (m, 2H),
5.23 (s, 1H); 13C NMR (CDCl
) δ 12.1, 17.9, 20.6, 21.1, 21.3, 27.1,
3
3
) δ 0.80 (s, 3H),
1
4
(
21.68 g, 90% yield), mp 224-225 °C (lit. mp 225 °C).
â,17â-Dim eth oxy-5-a n d r osten -7-on e (7b). To a suspen-
sion of 6b (8.62 g, 0.027 mol) in acetone (250 mL) were added
N-hydroxysuccinimide (10.62 g, 0.092 mol) and Na Cr ‚2H
10.03 g, 0.034 mol). The mixture was heated to 50 °C and stirred
3
27.5, 27.6, 30.3, 36.4, 36.6, 36.8, 37.5, 42.1, 42.9, 44.8, 45.9, 69.5,
+
O
7
2
O
73.1, 82.5, 131.5, 141.4, 170.4, 171.2; MS (m/z) 404 [M] (<1),
344 (71), 329 (100), 149 (30). Anal. Calcd for C24
H, 8.97. Found: C, 71.43; H, 8.88.
2
2
(
36 5
H O : C, 71.26;
for 36 h. The reaction was quenched with saturated sodium
sulfite (50 mL), and the mixture was poured into water (2000
mL). The precipitate was filtered off, washed thoroughly with
water, and dried. Chromatography with cyclohexane/ethyl ace-
tate 10/1, followed by crystallization from diethyl ether, gave
3â,17â-Dim eth oxy-7r-m eth yla n d r ost-5-en -7â-ol (9b) a n d
3â,17â-Dim eth oxy-7â-m eth yla n d r ost-5-en -7r-ol (10b). A so-
lution of methylmagnesium iodide prepared from magnesium
(0.69 g, 0.028 mol), methyl iodide (1.8 mL, 0.029 mol), and
anhydrous ether (30 mL) was cooled to -8 °C, and at this
temperature, a solution of 7b (2.35 g, 7.07 mmol) in dry THF
(30 mL) was added dropwise over 20 min. Stirring was continued
at -8 °C for 1 h. The reaction was quenched with saturated
ammonium chloride (25 mL) and the mixture partitioned
between water and ether. The aqueous layer was extracted with
ethyl acetate (15 mL × 3). The combined extracts were washed
2
0
7
b (6.20 g, 69% yield): mp 142-143 °C; [R]
CHCl
D
1
-150.8 (c 0.85,
-
1
3
); IR vmax (KBr) 2975, 2863, 1666 cm ; H NMR (CDCl
3
)
δ 0.76 (s, 3H), 1.18 (s, 3H), 3.19 (m, 2H), 3.33 (s, 3H), 3.37 (s,
1
3
3
3
1
3
H), 5.69 (s, 1H); C NMR (CDCl ) δ 11.6, 17.3, 20.8, 25.6, 27.5,
6.2, 36.6, 38.7, 43.2, 45.0, 50.0, 55.9, 57.8, 78.9, 89.7, 125.9,
+
+
65.6, 202.0; MS (m/z) 332 [M] (100), 317 [M - CH
M - CH
3
]
(6), 300
+
[
3
OH] (22). Anal. Calcd for C21
H
32
O
3
: C, 75.86; H, 9.70.
Found: C, 76.08; H, 9.63.
â,17â-Dih yd r oxy-5-a n d r osten -7-on e (8). Sodium hydrox-
ide (10%, 60 mL) was added to the suspension of 7a (20.13 g,
.052 mol) in methanol (500 mL). After the mixture was stirred
2 4
with brine, dried over anhydrous Na SO , and concentrated in
3
vacuo. The residue was chromatographed with chloroform/
methanol 250/1 to give 9b (1.13 g, 46% yield), which was
recrystallized from ethyl acetate to give an analytical sample
0
[mp 140-141 °C; [R]20
-56.1 (c 1.68, CHCl
); IR vmax (KBr)
3467, 2969, 2931, 2819, 1677 cm ; H NMR (CDCl ) δ 0.77 (s,
3H), 1.03 (s, 3H), 1.12 (s, 3H), 3.06 (m, 1H), 3.22 (t, J ) 7.69
Hz, 1H), 3.34 (s, 6H), 5.18 (s, 1H); 13C NMR (CDCl
at room temperature for 2 h, glacial acetic acid (26 mL) was
added. Most of the methanol was evaporated, and a white solid
was precipitated by the addition of water (1500 mL). The solid
was collected by filtration and dried to give 8 (14.09 g, 89% yield).
Crystallization from methanol afforded an analytical sample:
mp 201-204 °C (lit. mp 201 °C).
3
D
3
-
1 1
3
3
) δ 11.3, 19.0,
20.7, 23.6, 26.2, 27.7, 27.9, 37.2, 37.3, 37.6, 38.1, 43.0, 43.3, 45.2,
1
5
+
46.8, 55.6, 57.8, 72.9, 80.0, 90.2, 131.2, 140.3; MS (m/z) 348 [M]
+
â,17â-Bis(ter t-b u t yld im et h ylsilyloxy)-5-a n d r ost en -7-
(2), 333 [M - CH
3
]
(100); Anal. Calcd for C22
H
36
O
3
: C, 75.82;
on e (7c). Imidazole (4.20 g, 0.062 mol) and tert-butyldimethyl-
silyl chloride (6.29 g, 0.042 mol) were added to a solution of 8
H, 10.41. Found: C, 76.07; H, 10.53] and 10b (1.23 g, 50% yield)
as a white powder: [R]20
-71.5 (c 0.63, CHCl ); IR vmax (KBr)
3508, 3382, 2935, 1652 cm ; H NMR (CDCl ) δ 0.76 (s, 3H),
0.92 (s, 3H), 1.21 (s, 3H), 3.06 (m, 1H), 3.21 (t, J ) 8.06 Hz,
1H), 3.33 (s, 6H), 5.20 (s, 1H); 13C NMR (CDCl
) δ 11.6, 18.0,
20.8, 27.1, 27.6, 27.9, 30.5, 36.9, 37.0, 37.4, 38.1, 42.0, 43.3, 45.3,
46.2, 55.6, 57.8, 69.9, 79.6, 90.3, 130.6, 142.7; MS (m/z) 348 [M]
D
3
-
1
1
(4.00 g, 0.013 mol) in dry DMF (200 mL). The mixture was
3
stirred at room temperature for 20 h and then poured into water
(800 mL). The precipitate was collected by filtration to give 7c
3
(
6.54 g, 93% yield). Recrystallization from acetone afforded an
2
0
+
analytical sample: mp 185-186 °C; [R]
IR vmax (KBr) 2950, 2856, 1674 cm ; H NMR (CDCl
D
-82.6 (c 1.15, CHCl
3
);
-1
1
(8), 333 [M - CH ]
+
(100); HRMS calcd for C22H36O 348.26649,
3
) δ -0.0015
3
3
(s, 6H), 0.05 (s, 6H), 0.71 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 1.19
found 348.26650.
1
3
(
s, 3H), 3.56 (m, 2H), 5.66 (d, J ) 1.28 Hz, 1H); C NMR (CDCl
3
)
3â,17â-Bis(ter t-bu tyldim eth ylsilyloxy)-7r-m eth ylan dr ost-
5-en -7â-ol (9c) a n d 3â,17â-Bis(ter t-bu tyld im eth ylsilyloxy)-
7â-m eth yla n d r ost-5-en -7r-ol (10c). A solution of methylmag-
nesium iodide prepared from magnesium (4.0 g, 0.16 mol),
methyl iodide (10 mL, 0.16 mol), and anhydrous ether (130 mL)
was cooled to 0 °C, and at this temperature, a solution of 7c
δ -4.9, -4.7, -4.5, 11.3, 17.3, 18.1, 20.9, 25.8, 30.9, 31.7, 36.0,
3
2
6.4, 38.4, 42.6, 43.6, 44.5, 45.3, 50.2, 71.2, 80.9, 125.6, 166.3,
+
+
02.4; MS (m/z) 532 [M] (4), 475 [M - t-Bu] (100), 399 (96).
Anal. Calcd for C31
H, 10.45.
2 3
H56Si O : C, 69.86; H, 10.59. Found: C, 69.94;
(6.54 g, 0.012 mol) in dry THF (100 mL) was added dropwise
over 30 min. Stirring was continued at 0 °C for 1 h. The reaction
was quenched with saturated ammonium chloride (100 mL) and
the mixture partitioned between water and ether. The aqueous
layer was extracted with ethyl acetate (70 mL × 3). The
(
14) George, A.; Boswell, Tr. U.S. Patent 3,282,969, 1966; Chem.
Abstr. 1967, 66, 11129b.
15) Schering A.-G. Ger. Patent 873,699, 1953; Chem. Abstr. 1958,
2, P7367b.
(
5
J . Org. Chem, Vol. 68, No. 4, 2003 1605

combined extracts were washed with brine, dried over anhydrous
Na SO , and evaporated in vacuo. The crude mixture was
chromatographed with cyclohexane/ethyl acetate 50/1 to give 9c
(KBr) 2952, 1734 cm-1; 1H NMR (CDCl
J ) 6.95 Hz, 3H), 0.96 (s, 3H), 2.02 (s, 3H), 2.03 (s, 3H), 4.57
(m, 2H), 5.09 (s, 1H); 13C NMR (CDCl
3
) δ 0.80 (s, 3H), 0.94 (d,
2
4
3
) δ 12.4, 19.4, 21.1, 21.3,
(
2.98 g, 44% yield), which was recrystallized from diisopropyl
21.6, 22.7, 26.4, 27.9, 28.1, 31.1, 36.1, 36.3, 37.1, 38.0, 39.6, 43.4,
2
0
ether to give an analytical sample [mp 111 °C; [R]
1
D
-27.8 (c
50.8, 51.9, 73.8, 82.8, 130.1, 138.4, 170.7, 171.4; MS (m/z) 388
); IR vmax (KBr) 3527, 2956, 2854 cm 1; 1H NMR
-
+
+
.13, CHCl
3
[M] (<1), 328 [M - CH OOH] (100); HRMS calcd for C24H36O4
3
(
6
(
CD
3
OD) δ -0.09 (d, J ) 3.30 Hz, 6H), -0.10 (d, J ) 1.46 Hz,
388.25806, found 388.25770.
H), 0.59 (s, 3H), 0.73 (s, 18H), 0.91 (s, 3H), 0.94 (s, 3H), 3.34
3
â, 17â-Dim eth oxy-7â-m eth yla n d r ost-5-en e (11b) was
m, 1H), 3.44 (t, J ) 8.05 Hz, 1H), 4.97 (d, J ) 1.46 Hz, 1H); 13
C
isolated by chromatography with cyclohexane/ethyl acetate
NMR (CD
2
7
CH
C
1
CHCl
3
OD) δ -4.1, -3.9, -3.7, 12.2, 19.5, 19.9, 22.4, 24.1,
20
8
v
3
0/1: white powder (85% yield); [R]
D
-17.6 (c 1.31, CHCl
max (KBr) 2946, 2875, 1677 cm ; H NMR (CDCl ) δ 0.75 (s,
H), 0.91 (d, J ) 6.97 Hz, 3H), 0.94 (s, 3H), 3.02 (m, 1H), 3.16
3
); IR
6.9, 27.9, 32.6, 33.7, 38.5, 38.9, 39.0, 43.9, 44.2, 45.1, 46.5, 48.9,
4.0, 74.3, 83.4, 133.5, 141.7; MS (m/z) 548 [M] (2), 533 [M -
-1
1
3
+
+
+
3
]
(36), 491 [M - C(CH
3
)
3
]
(33), 473 (100). Anal. Calcd for
13
(
t, J ) 7.33 Hz, 1H), 3.34 (s, 6H), 5.05 (s, 1H); C NMR (CDCl
δ 11.8, 19.3, 21.2, 22.7, 26.1, 27.8, 28.1, 36.2, 37.2, 38.1, 38.5,
9.5, 43.5, 51.0, 52.4, 55.5, 57.8, 80.0, 90.6, 129.1, 139.4; MS (m/
3
)
32
H
60Si
2
O
3
: C, 70.00; H, 11.02. Found: C, 70.07; H, 11.00] and
2
1
0
0c (3.17 g, 47% yield) as a white powder: [R]
D
-41.6 (c 1.15,
3
-
1
3
); IR vmax (KBr) 3479, 2956, 2856 cm ; H NMR (CDCl
3
)
+
+
+
z) 332 [M] (12), 317 [M - CH
HRMS calcd for C22 332.27177, found 332.27180.
â,17â-Dih ydr oxy-7â-m eth yla n dr ost-5-en e (11c). The resi-
3
]
(4), 300 [M - CH
3
OH] (100);
δ 0.01 (d, J ) 2.93 Hz, 6H), 0.03 (s, 6H), 0.71 (s, 3H), 0.86 (s,
8H), 0.94 (s, 3H), 1.21 (s, 3H), 3.53 (m, 2H), 5.17 (s, 1H); 13
NMR (CDCl
36 2
H O
1
C
3
3
) δ -4.8, -4.6, -4.4, 11.3, 18.0, 18.1, 18.2, 20.8, 25.9,
due was chromatographed with cyclohexane/ethyl acetate 3/1,
followed by crystallization with ethyl acetate to give the white
2
7
7.4, 30.6, 30.9, 32.0, 36.8, 37.3, 42.3, 42.4, 43.7, 44.7, 46.3, 70.0,
+
1.9, 81.4, 130.2, 143.5; MS (m/z) 548 [M] (<1), 491 [M -
2
0
+
crystal (99% yield): mp 185-187 °C; [R]
D
-5.1 (c 1.23, CHCl
IR vmax (KBr) 3266, 2935, 1637 cm ; H NMR (CDCl ) δ 0.76
s, 3H), 0.95 (d, J ) 6.59 Hz, 3H), 0.97 (s, 3H), 3.51 (m, 1H),
3
);
C(CH
3
)
3
] (54),473 (100); HRMS calcd for C32
H
60Si
2
O
3
548.40927,
-
1
1
3
found 548.40940.
(
3
Gen er a l Con d ition s for th e Deoxygen a tion of 9a -c a n d
1
3
.61 (t, J ) 8.42 Hz, 1H), 5.07 (t, J ) 2.20 Hz, 1H); C NMR
) δ 11.2, 19.4, 21.1, 22.6, 26.2, 30.6, 31.8, 35.8, 36.3, 36.9,
7.2, 39.7, 42.1, 43.5, 50.9, 52.0, 71.5, 81.7, 129.2, 139.3; MS (m/
1
0a -c (11a -c). A mixture of 9 and 10 (1.0 mmol) was dissolved
(CDCl
3
in methylene chloride (20 mL) and cooled to 0 °C. Triethylsilane
3
(1.0 mL, 6.00 mmol) was added to the solution, and then boron
+
+
z) 304 [M] (12), 286 [M - H
C H O
20 32 2
2
O] (100). Anal. Calcd for
: C, 78.90; H, 10.59. Found: C, 79.05; H, 10.48.
trifluoride etherate (1.2 mL, 10.00 mmol) was added dropwise.
After the mixture was stirred for 10 min, 10% sodium carbonate
(
10 mL) was added. The aqueous layer was extracted with
methylene chloride. The combined methylene chloride was
washed with brine, dried over anhydrous Na SO , and evapo-
Su p p or tin g In for m a tion Ava ila ble: The X-ray diffrac-
2
4
tion analytical data and an ORTEP diagram of 11c and the
proton NMR spectra of 6a , 7a -c, 10a -c, and 11a -c. This
material is available free of charge via the Internet at
http://pubs.acs.org.
rated in vacuo to afford a residue from which 11a -c were
obtained after chromatography.
3
â,17â-Dia cetoxy-7â-m eth yla n d r ost-5-en e (11a ) was iso-
lated by chromatography with cyclohexane/ethyl acetate 20/1:
2
0
white powder (79% yield); [R]
D
-26.4 (c 0.85, CHCl
3
); IR vmax
J O020290X
1
606 J . Org. Chem., Vol. 68, No. 4, 2003