Synthesis of 7-substituted-5-androstene derivatives promoted by SmI 2

Article abstract of DOI:10.1016/j.steroids.2005.08.008

The 7-substituted-5-androstene derivatives 2a-10a and 2b-10b were prepared by reaction of 3β,17β-di(tert-butyldimethylsilyloxy)-5-androsten-7-one 1 with different organic halides. The resulting 7α- and 7β-isomers were carefully separated by column chromat

Full text of DOI:10.1016/j.steroids.2005.08.008

steroids 7 1 ( 2 0 0 6 ) 96–101
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/steroids
Synthesis of 7-substituted-5-androstene derivatives
promoted by SmI2
Qin Gu, Yun-Hong Zheng, Yuan-Chao Li∗
Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Cong Zhi Road, Zhangjiang
Hi-Tech Park, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The 7-substituted-5-androstene derivatives 2a–10a and 2b–10b were prepared by reaction
of 3␤,17␤-di(tert-butyldimethylsilyloxy)-5-androsten-7-one 1 with different organic halides.
The resulting 7␣- and 7␤-isomers were carefully separated by column chromatography. The
structural assignments of the 7␣- and 7␤-isomers were determined by 13C-NMR.
© 2005 Elsevier Inc. All rights reserved.
Received 31 May 2005
Received in revised form 16 August
2005
Accepted 19 August 2005
Available online 9 November 2005
Keywords:
7-Substituted-5-androstene
derivatives
␣,␤-Unsaturated ketone
SmI2-mediated coupling reaction
1.
Introduction
2.
Experimental
Since Kagan reported the first reliable preparation of SmI2 [1],
it has become widely used in synthetic chemistry for promot-
ing alkylation of carbonyl compounds with organic halides
[2]. The reactions have been mostly performed as Barbier-
type or Reformatsky-type reactions by treatment of a mixture
of organic halides and carbonyl compounds with SmI2 pro-
ducing the corresponding alcohols. Although various ketones
and aldehydes have been used in the SmI2-mediated coupling
reactions with organic halides, there is little information on
the coupling reaction of ␣,␤-unsaturated ketones.
2.1.
General methods and equipment
All melting points were determined on a Buchi 510 melt-
ing point apparatus and are uncorrected. Optical rotations
were recorded on a Jasco-DIP-181 polarimeter. IR spectra were
recorded on a Nicollet Magna FT-IR-750 spectrometer using
KBr pellets. 1H and 13C NMR spectra were run on a Bruker
AM-400 spectrometer using tetramethyl silane as the inter-
nal standard (chemical shifts in ı ppm). Splitting patterns
are designated as “s, d, t, q, and m”; these symbols indi-
cate “singlet, doublet, triplet, quartet, and multiplet”, respec-
tively. Mass spectra and high-resolution mass spectra were
measured on a Finnigan MAT-95 mass spectrometer. Ele-
In the present paper, we report the reactions of androst-
5-en-7-one 1 with various organic halides mediated by SmI2,
and the resulting 7␣- and 7␤-isomers were obtained by column
chromatography.
∗
Corresponding author. Tel.: +86 21 50806600x3502; fax: +86 21 50807288.
E-mail address: ycli@mail.shcnc.ac.cn (Y.-C. Li).
0039-128X/$ – see front matter © 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2005.08.008

steroids 7 1 ( 2 0 0 6 ) 96–101
97
mental analysis was performed at a Carlo Erba 1106 instru-
2.4.
3ˇ,17ˇ-Di(tert-butyldimethylsilyloxy)-7ˇ-
ment. Silica gel 60H (200–300 mesh) manufactured by Qing-
dao Haiyang Chemical Group Co. (China) was used for flash
chromatography.
ethylandrost-5-en-7˛-ol 3a and
3ˇ,17ˇ-di(tert-butyldimethylsilyloxy)-7˛-ethylandrost-5-
en-7ˇ-ol 3b
Tetrahydrofuran (THF) was distilled from sodium under
argon before use. Samarium metal and Nickel(II) iodide (NiI2)
were purchased from Aldrich Chemicals, and were weighed
and stored under an inert atmosphere. Diiodomethane (CH2I2)
was purchased from TCI Chemicals, distilled prior to use, and
stored under argon over copper turnings. Hexamethylphos-
phoramide (HMPA) was purchased from Shanghai Chemical
Under similar conditions as above, 1 (100 mg, 0.19 mmol) was
reacted with ethyl iodide (0.03 mL, 0.38 mmol) to afford a
residue, which was chromatographed on silica. Elution with
petroleum ether/ethyl acetate (20:1) gave 3a (20 mg, 19.0%
yield), which was recrystallized from n-hexane to give an ana-
lytical sample: white solid, mp 72–75 ◦C. [˛]D20 − 30.4 (c 0.90, n-
C6H14). IR (KBr) ꢀmax (cm−1): 3442 (OH), 2956, 2856, 1630 (C C).
1H NMR (CDCl3) ı: 0.00 (d, 6H, J = 3.2 Hz, (CH3)2Si), 0.05 (s, 6H,
(CH3)2Si), 0.73 (s, 3H, 18-CH3), 0.75 (t, 3H, J = 7.2 Hz, 7-CH2CH3),
0.87 (s, 9H, (CH3)3CSi), 0.88 (s, 9H, (CH3)3CSi), 0.94 (s, 3H, 19-
CH3), 3.48–3.53 (m, 1H, 3-H), 3.55 (t, 1H, J = 8.0 Hz, 17-H), 5.08 (s,
1H, 6-H). 13C NMR (CDCl3) ı: −4.5, −4.3, −4.2, 9.6, 11.6, 18.3, 18.4,
18.5, 21.2, 26.2, 26.2, 27.0, 31.1, 32.3, 34.5, 36.8, 37.1, 37.4, 37.5,
42.5, 44.1, 45.0, 46.4, 72.1, 73.6, 81.6, 128.9, 145.7. EIMS m/z: 562
[M]+ (5), 544 [M H2O]+ (8), 534 (42), 533 (100), 515 (18), 487 (22),
75 (21). Analysis calculated for C33H62O3Si2:C, 70.40; H, 11.10.
Found: C, 70.22; H, 11.10; and 3b (55 mg, 52.1% yield), which
was recrystallized from n-hexane to give an analytical sam-
ple: white solid, mp 142–144 ◦C. [˛]D20 − 13.1 (c 1.33, n-C6H14).
IR (KBr) ꢀmax (cm−1): 3498 (OH), 2933, 2856, 1637(C C). 1H NMR
(CDCl3) ı: 0.01 (d, 6H, J = 2.8 Hz, (CH3)2Si), 0.06 (d, 6H, J = 1.6 Hz,
(CH3)2Si), 0.71 (s, 3H, 18-CH3), 0.87 (s, 9H, (CH3)3CSi), 0.89 (s, 9H,
(CH3)3CSi), 0.95 (t, 3H, J = 7.2 Hz, 7-CH2CH3), 1.04 (s, 3H, 19-CH3),
1.53 (q, 2H, J = 7.2 Hz, 7-CH2CH3), 3.44–3.49 (m, 1H, 3-H), 3.54 (t,
1H, J = 8.0 Hz, 17-H), 5.24 (s, 1H, 6-H). 13C NMR (CDCl3) ı: −4.5,
−4.3, −4.2, 8.7, 11.2, 18.4, 18.5, 19.5, 21.1, 26.2, 26.2, 26.8, 29.8,
31.2, 32.3, 36.9, 37.6, 37.7, 42.8, 43.7, 44.0, 44.6, 46.6, 72.9, 74.8,
81.6, 128.1, 142.3. EIMS m/z: 562 [M]+ (1), 544 [M − H2O]+ (5), 534
˚
Reagent Co. (China), distilled from CaH2, and stored over 4 A
molecular sieves under argon. All reactions were conducted
under an argon atmosphere. All halides were purified by the
appropriate methods before use.
2.2.
Preparation of 0.1 M SmI2 in THF [3]
The samarium metal powder (130 mg, 0.87 mmol) was added
to a dry 25-mL round-bottom flask equipped with stirbar. The
flask was simultaneously flushed with argon and flamed dry.
THF (8 mL) was added to the cooled flask. The vigorously
stirred slurry of samarium metal in THF was cooled to 0 ◦C,
and neat diiodomethane (0.065 mL, 0.80 mmol) was added. The
green slurry was stirred at 0 ◦C for 30 min, then, allowed to
warm to room temperature, and vigorously stirred for an addi-
tional hour. The resulting solution of 0.1 M samarium(II) iodide
was deep blue in color.
2.3.
3ˇ,17ˇ-Di(tert-butyldimethylsilyloxy)-7ˇ-
methylandrost-5-en-7˛-ol 2a and
3ˇ,17ˇ-di(tert-butyldimethylsilyloxy)-7˛-methylandrost-
5-en-7ˇ-ol 2b
(44), 533 (100), 75 (17). Analysis calculated for C33
70.40; H, 11.10. Found: C, 70.53; H, 10.64.
H62O3Si2: C,
HMPA (0.4 mL, 2.29 mmol) was added to a solution of SmI2
in THF (0.1 M, 8 mL). The deep purple solution was stirred
for 15 min at room temperature, and then, a mixture of 1
(100 mg, 0.19 mmol) and methyl iodide (0.025 mL, 0.40 mmol)
in THF (3 mL) was added dropwise at room temperature.
After the initial deep purple color of the SmI2 solution
turned yellow, the reaction was quenched with 0.1N HCl, and
then, extracted with ethyl acetate (30 mL × 3). The combined
extracts were washed sequentially with saturated Na2S2O3,
saturated NaHCO3, and brine, then dried over anhydrous
Na2SO4, and concentrated in vacuo. The crude mixture was
chromatographed with petroleum ether/ethyl acetate (40:1)
to give 2a (17 mg, 16.5% yield), which was recrystallized
from diisopropyl ether to give an analytical sample: white
solid, mp 109–111 ◦C. 1H NMR (CDCl3) ı: 0.01 (d, 6H, J = 1.8 Hz,
(CH3)2Si), 0.04 (s, 6H, (CH3)2Si), 0.72 (s, 3H, 18-CH3), 0.87 (s, 9H,
(CH3)3CSi), 0.88 (s, 9H, (CH3)3CSi), 0.95 (s, 3H, 19-CH3), 1.23
(s, 3H, 7-CH3), 3.47–3.53 (m, 1H, 3-H), 3.57 (t, 1H, J = 7.8 Hz,
17-H), 5.19 (s, 1H, 6-H); and 2b (61 mg, 59.2% yield), which
was recrystallized from diisopropyl ether to give an analyt-
ical sample: white solid, mp 110–112 ◦C (lit. [4] mp 111 ◦C).
1H NMR (CDCl3) ı: 0.01 (d, 6H, J = 2.1 Hz, (CH3)2Si), 0.05 (s,
6H, (CH3)2Si), 0.72 (s, 3H, 18-CH3), 0.87 (s, 9H, (CH3)3CSi), 0.88
(s, 9H, (CH3)3CSi), 1.04 (s, 3H, 19-CH3), 1.13 (s, 3H, 7-CH3),
3.43–3.52 (m, 1H, 3-H), 3.55 (t, 1H, J = 7.8 Hz, 17-H), 5.15 (s, 1H,
6-H).
2.5.
3ˇ,17ˇ-Di(tert-butyldimethylsilyloxy)-7ˇ-
butylandrost-5-en-7˛-ol 4a and
3ˇ,17ˇ-di(tert-butyldimethylsilyloxy)-7˛-butylandrost-5-
en-7ˇ-ol 4b
Under similar conditions as above, 1 (100 mg, 0.19 mmol) was
reacted with n-butyl iodide (0.05 mL, 0.44 mmol) to afford a
residue, which was chromatographed on silica. Elution with
petroleum ether/ethyl acetate (15:1) gave 4a (13 mg, 11.7%
yield): colorless oil, [˛]2D0 − 23.6 (c 0.90, n-C6H14). IR (KBr) ꢀmax
(cm−1): 3473 (OH), 2928, 1651 (C C). 1H NMR (CDCl3) ı: −0.01
(d, 6H, J = 2.4 Hz, (CH3)2Si), 0.04 (s, 6H, (CH3)2Si), 0.71 (s, 3H, 18-
CH3), 0.85 (t, J = 6.9 Hz, 3H, 7-(CH2)3CH3), 0.86 (s, 9H, (CH3)3CSi),
0.87 (s, 9H, (CH3)3CSi), 0.92 (s, 3H, 19-CH3), 3.44–3.50 (m, 1H,
3-H), 3.54 (t, 1H, J = 7.8 Hz, 17-H), 5.09 (s, 1H, 6-H). 13C NMR
(CDCl3) ı: −4.8, −4.6, −4.5, 11.3, 14.0, 18.0, 18.1, 18.2, 20.9, 23.2,
25.8, 25.9, 26.7, 27.1, 30.8, 32.0, 36.5, 36.8, 37.2, 37.9, 41.7, 42.2,
43.8, 44.7, 46.1, 71.8, 72.8, 81.3, 129.0, 145.0. EIMS m/z: 590 [M]+
(1), 572 [M − H2O]+ (18), 533 (100), 515 (77), 307 (19), 75 (52).
HREIMS calculated for C35H66O3Si2 590.4550, found 590.4565;
and 4b (63 mg, 56.9% yield): colorless oil, [˛]2D0 − 39.6 (c 1.20,
n-C6H14). IR (KBr) ꢀmax (cm−1): 3477 (OH), 2926, 1672 (C C).
1H NMR (CDCl3) ı: 0.01 (d, 6H, J = 2.4 Hz, (CH3)2Si), 0.06 (s, 6H,
(CH3)2Si), 0.70 (s, 3H, 18-CH3), 0.87 (s, 9H, (CH3)3CSi), 0.89 (s,

98
steroids 7 1 ( 2 0 0 6 ) 96–101
(c 0.80, n-C6H14). IR (KBr) ꢀmax (cm−1): 3466 (OH), 2931, 2856,
1659 (C C). 1H NMR (CDCl3) ı: 0.00 (d, 6H, J = 2.7 Hz, (CH3)2Si),
0.05 (s, 6H, (CH3)2Si), 0.73 (s, 3H, 18-CH3), 0.73 (d, 3H, J = 6.9 Hz,
7-CH(CH3)2), 0.87 (s, 9H, (CH3)3CSi), 0.88 (s, 9H, (CH3)3CSi), 0.94
(s, 3H, 19-CH3), 0.97 (d, J = 6.9 Hz, 3H, 7-CH(CH3)2), 3.45–3.53
(m, 1H, 3-H), 3.54 (t, 1H, J = 8.1 Hz, 17-H), 5.28 (s, 1H, 6-H). 13C
NMR (CDCl3) ı: −4.9, −4.6, −4.5, 11.3, 16.1, 18.0, 18.1, 18.2, 18.8,
21.0, 25.8, 25.9, 27.1, 30.8, 32.0, 34.1, 36.6, 36.9, 37.3, 37.8, 42.5,
43.9, 44.9, 46.5, 71.8, 74.8, 81.3, 122.9, 146.0. EIMS m/z: 576 [M]+
(<1), 561 [M − CH3]+ (24), 558 [M − H2O]+ (19), 533 (100), 515 (37),
401 (25), 75 (26). HREIMS calculated for C34H63O3Si2 [M − 1]+
575.4316, found 575.4331; and 5b (37 mg, 34.2% yield): colorless
oil, [˛]2D0 − 8.6 (c 1.00, n-C6H14). IR (KBr) ꢀmax (cm−1): 3481 (OH),
2928, 2854, 1663 (C C). 1H NMR (CDCl3) ı: 0.01 (s, 6H, (CH3)2Si),
0.07 (s, 6H, (CH3)2Si), 0.71 (s, 3H, 18-CH3), 0.88 (s, 9H, (CH3)3CSi),
0.89 (s, 9H, (CH3)3CSi), 0.91 (d, J = 6.6 Hz, 3H, 7-CH(CH3)2), 0.97
(d, J = 6.6 Hz, 3H, 7-CH(CH3)2), 1.03 (s, 3H, 19-CH3), 3.44–3.52
(m, 1H, 3-H), 3.56 (t, 1H, J = 7.8 Hz, 17-H), 5.19 (s, 1H, 6-H). 13C
NMR (CDCl3) ı: −4.9, −4.6, −4.5, 11.1, 18.1, 18.2, 18.5, 18.8, 21.0,
21.2, 25.8, 25.9, 27.2, 30.9, 32.0, 33.4, 36.5, 37.1, 37.4, 42.9, 43.6,
43.8, 45.4, 45.8, 72.8, 76.0, 81.1, 123.9, 144.3. EIMS m/z: 576 [M]+
(<1), 561 [M − CH3]+ (23), 558 [M − H2O]+ (25), 533 (100), 401 (13),
73 (11). HREIMS calculated for C34H63O3Si2 [M − 1]+ 575.4316,
found 575.4325.
9H, (CH3)3CSi), 0.92 (t, J = 7.2 Hz, 3H, 7-(CH2)3CH3), 1.04 (s, 3H,
19-CH3), 3.45–3.51 (m, 1H, 3-H), 3.55 (t, 1H, J = 8.0 Hz, 17-H), 5.23
(s, 1H, 6-H). 13C NMR (CDCl3) ı: −4.8, −4.6, −4.5, 10.9, 14.2, 18.1,
18.2, 19.2, 20.7, 23.8, 25.8, 25.9, 26.0, 26.5, 30.9, 32.0, 36.5, 36.9,
37.3, 37.4, 42.5, 43.4, 43.6, 44.4, 46.2, 72.6, 74.5, 81.3, 128.3, 141.6.
EIMS m/z: 590 [M]+ (2), 572 [M − H2O]+ (38), 533 (100), 515 (56),
440 (22), 75 (24). HREIMS calculated for C35H66O3Si2 590.4551,
found 590.4554.
2.6.
3ˇ,17ˇ-Di(tert-butyldimethylsilyloxy)-7ˇ-(6-
chlorohexyl)androst-5-en-7˛-ol 6a and
3ˇ,17ˇ-di(tert-butyldimethylsilyloxy)-7˛-(6-
chlorohexyl)androst-5-en-7ˇ-ol 6b
Under similar conditions as above, 1 (100 mg, 0.19 mmol) was
reacted with 1-chloro-6-iodohexane (0.06 mL, 0.40 mmol) to
afford a residue, which was chromatographed on silica. Elu-
tion with petroleum ether/ethyl acetate (25:1) gave 6a (15 mg,
12.3% yield): colorless oil, [˛]2D0 − 33.9 (c 0.83, n-C6H14). IR
(KBr) ꢀmax (cm−1): 3464 (OH), 2929, 2856, 1647 (C C). 1H NMR
(CDCl3) ı: 0.01 (d, 6H, J = 3.2 Hz, (CH3)2Si), 0.05 (d, 6H, J = 3.2 Hz,
(CH3)2Si), 0.73 (s, 3H, 18-CH3), 0.87 (s, 9H, (CH3)3CSi), 0.88 (s, 9H,
(CH3)3CSi), 0.94 (s, 3H, 19-CH3), 3.47–3.51 (m, 1H, 3-H), 3.53 (t,
2H, J = 6.8 Hz, 7-(CH2)5CH2Cl), 3.55 (t, 1H, J = 8.0 Hz, 17-H), 5.10
(s, 1H, 6-H). 13C NMR (CDCl3) ı: −4.8, −4.6, −4.5, 11.3, 18.1, 18.2,
20.9, 24.7, 25.8, 25.9, 26.8, 26.8, 29.4, 30.8, 32.0, 32.6, 36.5, 36.7,
37.1, 38.0, 41.7, 42.2, 43.8, 44.7, 45.1, 46.1, 71.8, 72.8, 81.3, 128.8,
145.2. EIMS m/z: 654 [M]+ (<1), 533 (100), 515 (24), 75 (15). HREIMS
calculated for C37H69ClO3Si2 652.4474, found 652.4491; and 6b
(39 mg, 31.9% yield): colorless oil, [˛]2D0 − 18.3 (c 0.90, n-C6H14).
IR (KBr) ꢀmax (cm−1): 3458 (OH), 2929, 2856, 1640 (C C). 1H NMR
(CDCl3) ı: 0.01 (d, 6H, J = 2.8 Hz, (CH3)2Si), 0.06 (d, 6H, J = 1.6 Hz,
(CH3)2Si), 0.71 (s, 3H, 18-CH3), 0.88 (s, 9H, (CH3)3CSi), 0.89 (s, 9H,
(CH3)3CSi), 1.04 (s, 3H, 19-CH3), 3.45–3.50 (m, 1H, 3-H), 3.54 (t,
2H, J = 6.8 Hz, 7-(CH2)5CH2Cl), 3.56 (t, 1H, J = 8.0 Hz, 17-H), 5.23
(s, 1H, 6-H). 13C NMR (CDCl3) ı: −4.8, −4.6, −4.5, 10.9, 18.1, 18.2,
19.2, 20.7, 23.6, 25.8, 25.9, 26.5, 26.9, 29.9, 30.9, 32.0, 32.6, 36.5,
36.9, 37.3, 42.5, 43.4, 43.6, 44.4, 45.1, 46.2, 72.5, 74.4, 81.3, 128.2,
141.9. EIMS m/z: 636 [M − H2O]+ (<1), 533 (100), 515 (6), 401 (10),
75 (10), 73 (11). HREIMS calculated for C37H69ClO3Si2 652.4474,
found 652.4482.
2.8.
3ˇ,17ˇ-Di(tert-butyldimethylsilyloxy)-7ˇ-
benzylandrost-5-en-7˛-ol 7a and
3ˇ,17ˇ-di(tert-butyldimethylsilyloxy)-7˛-benzylandrost-
5-en-7ˇ-ol 7b
A mixture of 1 (100 mg, 0.19 mmol) and benzyl chloride
(0.05 mL, 0.43 mmol) in THF (5 mL) was added dropwise to
a solution of SmI2 in THF (0.1 M, 8 mL) at room tempera-
ture. After the initial dark blue color of the SmI2 solution
turned yellow, the reaction was quenched with 0.1N HCl, and
then, extracted with ethyl acetate (30 mL × 3). The combined
extracts were washed sequentially with saturated Na2S2O3,
saturated NaHCO3, and brine, dried over anhydrous Na2SO4,
and concentrated in vacuo. The crude mixture was chro-
matographed with petroleum ether/ethyl acetate (25:1) to give
7a (45 mg, 38.4% yield): colorless oil, [˛]2D0 − 16.6 (c 1.13, n-
C6H14). IR (KBr) ꢀmax (cm−1): 3462 (OH), 2928, 1674 (C C), 1603,
1495 (Ph). 1H NMR (CDCl3) ı: 0.02 (s, 6H, (CH3)2Si), 0.04 (s, 6H,
(CH3)2Si), 0.48 (s, 3H, 18-CH3), 0.75 (s, 3H, 19-CH3), 0.88 (s,
9H, (CH3)3CSi), 0.89 (s, 9H, (CH3)3CSi), 2.75 (d, 1H, J = 12.9 Hz,
7-CH2Ph), 2.95 (d, 1H, J = 12.9 Hz, 7-CH2Ph), 3.43–3.52 (m, 1H,
3-H), 3.61 (t, 1H, J = 7.8 Hz, 17-H), 5.22 (s, 1H, 6-H), 7.16–7.26 (m,
5H, Ph). 13C NMR (CDCl3) ı: −4.8, −4.6, −4.4, 11.4, 17.1, 18.1,
18.2, 20.9, 25.9, 27.5, 31.0, 32.0, 36.2, 36.9, 36.9, 38.9, 42.0, 44.0,
45.4, 46.8, 47.7, 71.6, 72.6, 81.5, 126.2, 127.7, 127.7, 131.2, 137.6,
144.7. EIMS m/z: 606 [M − H2O]+ (37), 533 (100), 515 (64), 73 (50).
HREIMS calculated for C38H62O2Si2 [M − H2O]+ 606.4288, found
606.4282, and 7b (54 mg, 46.0% yield): colorless oil, [˛]2D0 − 57.8
(c 1.08, n-C6H14). IR (KBr) ꢀmax (cm−1): 3483 (OH), 2956, 2856,
1669 (C C), 1601, 1495 (Ph). 1H NMR (CDCl3) ı: 0.03 (s, 6H,
(CH3)2Si), 0.07 (s, 6H, (CH3)2Si), 0.76 (s, 3H, 18-CH3), 0.89 (s,
9H, (CH3)3CSi), 0.90 (s, 9H, (CH3)3CSi), 1.04 (s, 3H, 19-CH3), 2.70
(d, 1H, J = 12.8 Hz, 7-CH2Ph), 2.88 (d, 1H, J = 12.8 Hz, 7-CH2Ph),
3.46–3.54 (m, 1H, 3-H), 3.60 (t, 1H, J = 8.0 Hz, 17-H), 4.67 (s, 1H,
6-H), 7.14–7.17 (m, 2H, Ph), 7.22–7.27 (m, 3H, Ph). 13C NMR
2.7.
3ˇ,17ˇ-Di(tert-butyldimethylsilyloxy)-7ˇ-
isopropylandrost-5-en-7˛-ol 5a and
3ˇ,17ˇ-di(tert-butyldimethylsilyloxy)-7˛-
isopropylandrost-5-en-7ˇ-ol 5b
NiI2 (5 mg, 0.016 mmol) and HMPA (0.4 mL, 2.29 mmol) were
added to a solution of SmI2 in THF (0.1 M, 8 mL). The deep pur-
ple solution was stirred for 15 min at room temperature, and
then, a mixture of 1 (100 mg, 0.19 mmol) and isopropyl bro-
mide (0.04 mL, 0.42 mmol) in THF (3 mL) was added dropwise
at room temperature. After the initial deep purple color of the
SmI2 solution turned yellow, the reaction was quenched with
0.1N HCl, and then extracted with ethyl acetate (30 mL × 3).
The combined extracts were washed sequentially with satu-
rated Na2S2O3, saturated NaHCO3 and brine, dried over anhy-
drous Na2SO4, and concentrated in vacuo. The crude mixture
was chromatographed with petroleum ether/ethyl acetate
(30:1) to give 5a (8 mg, 7.4% yield) as a colorless oil: [˛]2D0 − 22.2

steroids 7 1 ( 2 0 0 6 ) 96–101
99
5.48 (s, 1H, 6-H), 7.29–7.37 (m, 5H, Ph). 13C NMR (CDCl3) ı: −4.8,
−4.6, −4.5, 11.3, 17.9, 18.1, 18.2, 20.9, 25.8, 25.9, 27.0, 30.7, 32.0,
36.5, 36.7, 37.1, 37.8, 42.4, 43.7, 44.4, 45.9, 71.5, 71.8, 73.3, 76.4,
81.3, 126.2, 127.6, 127.6, 128.3, 138.3, 144.5. EIMS m/z: 654 [M]+
(2), 636 [M − H2O]+ (22), 533 (100), 515 (20), 401(16), 91 (39), 73
(CDCl3) ı: −4.8, −4.7, −4.4, 11.0, 18.1, 18.4, 19.3, 20.9, 25.9, 25.9,
26.6, 31.0, 32.1, 36.7, 37.3, 37.7, 42.5, 43.1, 43.5, 43.6, 43.9, 46.5,
72.9, 74.1, 81.4, 126.2, 127.8, 129.0, 131.0, 137.5, 141.0. EIMS m/z:
624 [M]+ (<1), 606 [M − H2O]+ (44), 533 (100), 515 (8), 474 (14),
401 (15), 73 (13). HREIMS calculated for C38H64O3Si2 624.4394,
found 624.4385.
(27). HREIMS calculated for C39H
66O4Si2 [M]+ 654.4500, found
654.4463; and 9b (60 mg, 48.8% yield), which was recrystallized
from n-hexane to give an analytical sample: white solid, mp
114–116 ◦C. [˛]D20 − 32.1 (c 1.90, n-C6H14). IR (KBr) ꢀmax (cm−1):
3440 (OH), 2956, 2856, 1667 (C C). 1H NMR (CDCl3) ı: 0.01 (s, 6H,
(CH3)2Si), 0.08 (s, 6H, (CH3)2Si), 0.69 (s, 3H, 18-CH3), 0.88 (s, 9H,
(CH3)3CSi), 0.90 (s, 9H, (CH3)3CSi), 1.05 (s, 3H, 19-CH3), 3.42 (d,
1H, J = 9.0 Hz, 7-CH2OBn), 3.46–3.55 (m, 2H, 3-H, 17-H), 3.56 (d,
1H, J = 9.0 Hz, 7-CH2OBn), 4.52 (d, 1H, J = 12.6 Hz, CH2Ph), 4.60 (d,
1H, J = 12.6 Hz, CH2Ph), 5.31 (s, 1H, 6-H), 7.30–7.38 (m, 5H, Ph).
13C NMR (CDCl3) ı: −4.5, −4.2, −4.1, 11.1, 18.4, 18.5, 19.3, 21.0,
26.2, 26.2, 27.0, 31.1, 32.3, 36.7, 37.6, 37.6, 42.2, 42.7, 43.9, 44.5,
46.4, 72.7, 73.7, 74.3, 74.6, 81.6, 127.6, 127.8, 127.9, 128.6, 138.6,
143.2. EIMS m/z: 654 [M]+ (1), 636 [M − H2O]+ (20), 533 (100),
401(16), 91 (33), 73 (23). Analysis calculated for C39H66O4Si2:
C, 71.50; H, 10.15; found: C, 71.35; H, 10.38.
2.9.
3ˇ,17ˇ-Di(tert-butyldimethylsilyloxy)-7ˇ-
allylandrost-5-en-7˛-ol 8a and
3ˇ,17ˇ-di(tert-butyldimethylsilyloxy)-7˛-allylandrost-5-
en-7ˇ-ol 8b
Under similar conditions to those for the preparation of 7a
and 7b, 1 (100 mg, 0.19 mmol) was reacted with allyl bro-
mide (0.04 mL, 0.46 mmol) to afford a residue, which was chro-
matographed on silica. Elution with petroleum ether/ethyl
acetate (30:1) gave 8a (55 mg, 51.0% yield): colorless oil, [˛]D20
−
20.3 (c 0.93, n-C6H14). IR (KBr) ꢀmax (cm−1): 3446 (OH), 3065
(C C), 2929, 2854, 1639 (C C). 1H NMR (CDCl3) ␦: 0.01 (d,
6H, J = 1.2 Hz, (CH3)2Si), 0.05 (s, 6H, (CH3)2Si), 0.71 (s, 3H, 18-
CH3), 0.87 (s, 9H, (CH3)3CSi), 0.88 (s, 9H, (CH3)3CSi), 0.91 (s,
3H, 19-CH3), 3.44–3.53 (m, 1H, 3-H), 3.56 (t, 1H, J = 8.0 Hz,
17-H), 5.01 (d, 1H, J = 17.2 Hz, 7-CH2CH CH2), 5.06 (d, 1H,
J = 10.0 Hz, 7-CH2CH CH2), 5.18 (s, 1H, 6-H), 5.56–5.67 (m, 1H,
7-CH2CH CH2). 13C NMR (CDCl3) ı: −4.8, −4.6, −4.5, 11.3, 17.9,
18.1, 18.2, 20.9, 25.8, 25.9, 27.1, 31.0, 32.0, 36.5, 36.8, 37.1, 38.5,
42.2, 43.8, 44.9, 46.2, 46.2, 71.8, 72.0, 81.4, 118.0, 128.1, 134.6,
145.3. EIMS m/z: 574 [M]+ (1), 556 [M − H2O]+ (13), 533 (100),
515 (31), 424 (16), 401 (11), 57 (17). HREIMS calculated for
2.11. 3ˇ,17ˇ-Di(tert-butyldimethylsilyloxy)-7ˇ-(2-
ethoxy-2-oxoethyl)androst-5-en-7˛-ol 10a and
3ˇ,17ˇ-di(tert-butyldimethylsilyloxy)-7˛-(2-ethoxy-2-
oxoethyl)androst-5-en-7ˇ-ol 10b
HMPA (0.4 mL, 2.29 mmol) was added to a solution of SmI2
in THF (0.1 M, 8 mL). The deep purple solution was stirred
for 15 min at room temperature, then cooled to −78 ◦C, and
stirred at this temperature for 30 min. A mixture of 1 (100 mg,
0.19 mmol) and ethyl bromoacetate (0.04 mL, 0.36 mmol) in
THF (3 mL) was added dropwise, and the reaction mixture
was stirred at −78 ◦C for 20 min. The mixture was then
warmed to 0 ◦C gradually and stirred at this temperature
for 2 h. The reaction was quenched with 0.1N HCl, and
then, extracted with ethyl acetate (30 mL × 3). The combined
extracts were washed sequentially with saturated Na2S2O3,
saturated NaHCO3, and brine, dried over anhydrous Na2SO4,
and concentrated in vacuo. The crude mixture was chro-
matographed with petroleum ether/ethyl acetate (15:1) to give
10a (21 mg, 18.0% yield): colorless oil, [˛]2D0 − 19.5 (c 0.83, n-
C6H14). IR (KBr) ꢀmax (cm−1): 3462 (OH), 2928, 1732, 1714 (C O).
1H NMR (CDCl3) ı: 0.01 (d, 6H, J = 3.2 Hz, (CH3)2Si), 0.05 (s,
6H, (CH3)2Si), 0.72 (s, 3H, 18-CH3), 0.88 (s, 18H, 2 × (CH3)3CSi),
0.94 (s, 3H, 19-CH3), 1.26 (t, 3H, J = 7.2 Hz, OCH2CH3), 2.36 (d,
1H, J = 15.2 Hz, 7-CH2CO), 2.79 (d, 1H, J = 15.2 Hz, 7-CH2CO),
3.50–3.60 (m, 2H, 3-H, 17-H), 4.15 (q, 2H, J = 7.2 Hz, OCH2CH3),
5.35 (s, 1H, 6-H). 13C NMR (CDCl3) ı: −4.8, −4.6, −4.5, 11.2,
14.2, 17.9, 18.1, 18.2, 20.8, 25.9, 25.9, 27.1, 30.9, 32.0, 36.6, 37.0,
37.0, 40.7, 42.3, 43.8, 44.3, 45.4, 45.8, 60.5, 70.3, 71.7, 81.3, 126.4,
144.5, 172.4. EIMS m/z: 602 [M − H2O]+ (6), 545 (100), 244 (6), 73
(10). HREIMS calculated for C35H62O4Si2 [M − H2O]+ 602.4187,
found 602.4180; and 10b (71 mg, 60.9% yield): colorless oil,
[˛]2D0 − 22.2 (c 2.15, n-C6H14). IR (KBr) ꢀmax (cm−1): 3512 (OH),
2929, 2854, 1732, 1709 (C O). 1H NMR (CDCl3) ı: 0.01 (d, 6H,
J = 2.4 Hz, (CH3)2Si), 0.04 (s, 6H, (CH3)2Si), 0.72 (s, 3H, 18-CH3),
0.87 (s, 18H, 2 × (CH3)3CSi), 1.05 (s, 3H, 19-CH3), 1.28 (t, 3H,
J = 7.2 Hz, OCH2CH3), 2.41 (d, 1H, J = 14.4 Hz, 7-CH2CO), 2.60 (d,
1H, J = 14.4 Hz, 7-CH2CO), 3.41–3.49 (m, 1H, 3-H), 3.52 (t, 1H,
C34H62O3Si2 574.4238, found 574.4209; and 8b (51 mg, 47.3%
yield): colorless oil, [˛]2D0 − 13.8 (c 1.1, n-C6H14). IR (KBr) ꢀmax
(cm−1): 3469 (OH), 3074 (C C), 2928, 2852, 1639 (C C). 1H
NMR (CDCl3) ı: 0.01 (d, 6H, J = 2.4 Hz, (CH3)2Si), 0.06 (s, 6H,
(CH3)2Si), 0.72 (s, 3H, 18-CH3), 0.88 (s, 9H, (CH3)3CSi), 0.89 (s,
9H, (CH3)3CSi), 1.04 (s, 3H, 19-CH3), 3.42–3.50 (m, 1H, 3-H)), 3.54
(t, 1H, J = 8.0 Hz, 17-H), 5.09 (d, 1H, J = 17.2 Hz, 7-CH2CH CH2),
5.13 (d, 1H, J = 9.2 Hz, 7-CH2CH CH2), 5.15 (s, 1H, 6-H), 5.88–5.97
(m, 1H, 7-CH2CH CH2). 13C NMR (CDCl3) ı: −4.9, −4.6, −4.5,
10.9, 18.1, 18.2, 19.1, 20.8, 25.8, 25.9, 26.5, 30.9, 32.0, 36.6, 37.2,
37.4, 41.9, 42.4, 43.4, 43.4, 43.8, 46.1, 72.6, 73.9, 81.3, 118.2,
128.5, 134.6, 141.7. EIMS m/z: 574 [M]+ (<1), 556 [M − H2O]+
(10), 533 (100), 424 (8), 401 (14), 73 (10). HREIMS calculated for
C
34H62O3Si2 574.4237, found 574.4241.
2.10. 3ˇ,17ˇ-Di(tert-butyldimethylsilyloxy)-7ˇ-
benzyloxymethylandrost-5-en-7˛-ol 9a and
3ˇ,17ˇ-di(tert-butyldimethylsilyloxy)-7˛-
benzyloxymethylandrost-5-en-7ˇ-ol 9b
Under similar conditions to those for the preparation of 7a
and 7b, 1 (100 mg, 0.19 mmol) was reacted with chloromethyl
benzyl ether (0.06 mL, 0.43 mmol) to afford a residue, which
was chromatographed on silica. Elution with petroleum
ether/ethyl acetate (25:1) gave 9a (16 mg, 13.0% yield): color-
less oil, [˛]D20 − 23.8 (c 2.20, n-C6H14). IR (KBr) ꢀmax (cm−1): 3471
(OH), 2955, 2856, 1664 (C C). 1H NMR (CDCl3) ı: 0.01 (d, 6H,
J = 3.6 Hz, (CH3)2Si), 0.06 (s, 6H, (CH3)2Si), 0.69 (s, 3H, 18-CH3),
0.87 (s, 9H, (CH3)3CSi), 0.89 (s, 9H, (CH3)3CSi), 0.94 (s, 3H, 19-
CH3), 3.20 (d, 1H, J = 9.2 Hz, 7-CH2OBn), 3.49 (d, 1H, J = 9.2 Hz,
7-CH2OBn), 3.49–3.57 (m, 2H, 3-H, 17-H), 4.53 (s, 2H, CH2Ph),

100
steroids 7 1 ( 2 0 0 6 ) 96–101
tial hydroxymethylation reagent [6,7], was difficult to convert
into the corresponding Grignard reagent. However, coupling
of this compound with 1 mediated by SmI2 afforded 9a and
9b with a stereo ratio of 1:3.75 in 61.8% overall yield. When
the secondary alkyl halide (i-PrBr) reacted with 1, a catalytic
amount of NiI2 (2%) [8] was added to improve the reducing
ability of SmI2, and the adducts (5a and 5b) were produced
in 41.6% overall yield. Chemoselective reaction was carried
out with ␻-chloro hexyl iodide; however, the reaction did not
take place with chloride, and the 7-chlorohexyl substituted
androstene was produced in a relatively low yield (44%). The
SmI2-mediated Reformatsky-type reaction of ethyl bromoac-
etate with 1 was performed in the presence of HMPA [9], the
two isomers were obtained with a stereo ratio of 1:3.38 in 78.9%
overall yield. This reaction appears to provide another useful
alternative to normal Zn-promoted Reformatsky reactions.
The above results clearly show that different types of
organic halides can couple with androst-5-en-7-one 1 when
mediated by SmI2 to afford the 7-substituted-5-androstene
derivatives. This method will make 7-substituted derivatives
of steroids more widely available than before.
J = 8.0 Hz, 17-H), 4.13–4.25 (m, 2H, OCH2CH3), 5.24 (s, 1H, 6-H).
13C NMR (CDCl3) ı: −4.9, −4.7, −4.6, −4.5, 11.0, 14.3, 18.1, 18.2,
19.1, 20.7, 25.8, 25.9, 26.4, 30.8, 32.0, 36.6, 37.3, 37.4, 41.4, 42.0,
42.4, 43.5, 44.5, 46.0, 60.7, 72.4, 72.7, 81.4, 126.8, 142.5, 173.6.
EIMS m/z: 620 [M]+ (<1), 602 [M − H2O]+ (7), 563 (43), 545 (100),
469 (58), 429 (48), 399 (28), 73 (30), 57 (34). HREIMS calculated
for C35
H
64O5Si2 [M]+ 620.4293, found 620.4300.
3.
Results and discussion
Treatment of 3␤,17␤-di(tert-butyldimethylsilyloxy)-5-andros-
ten-7-one 1, which was prepared according to the literature
[4], with different organic halides promoted by SmI2 afforded
7-␣ and 7-␤ isomers. Results shown in Table 1 suggest that only
the 1,2-addition products of the ␣,␤-unsaturated ketone 1 were
obtained. The Barbier-type reaction between ␣,␤-unsaturated
ketone 1 and primary alkyl halides can be greatly acceler-
ated by addition of an excess of hexamethylphosphoramide
(HMPA) [3,5], and the resulting 7-␣ and 7-␤ isomers (2a–6a and
2b–6b) were obtained in 41.6–75.7% yield. Reaction of some
active halides (benzyl chloride and allylic bromide) with 1
mediated by SmI2 in the absence of HMPA gave almost equal
amounts of 7a and 7b in 84.4% overall yield, and 8a and
8b in 98.3% overall yield. Benzyloxymethyl chloride, a poten-
The stereochemical assignments of the 7␣- and 7␤-isomers
were determined by 13C-NMR. It has been reported that the
chemical shift of the carbinyl carbon depends on the orienta-
tion of the hydroxyl group; i.e. an axial hydroxyl group shields
Table 1 – SmI2-mediated coupling reaction between 1 and various organic halidesa
Entry
R
X
Conditions
Overall yield (%)
Product a (yield %)d
Product b (yield %)d
a/b (7␣-OH/7␤-OH)
1
2
3
4
5
6
7
8
9
Me
Et
n-Bu
i-Pr
Cl(CH2)6
PhCH2
CH2 CHCH2
PhCH2OCH2
CH2COOEt
I
I
I
Br
I
Cl
Br
Cl
Br
rt, 2.5 hb
rt, 4 hb
75.7
71.1
68.6
41.6
44.2
84.4
98.3
61.8
78.9
2a (16.5)
3a (19.0)
4a (11.7)
5a (7.4)
6a (12.3)
7a (38.4)
8a (51.0)
9a (13.0)
10a (18.0)
2b (59.2)
3b (52.1)
4b (56.9)
5b (34.2)
6b (31.9)
7b (46.0)
8b (47.3)
9b (48.8)
10b (60.9)
1:3.59
1:2.74
1:4.86
1:4.62
1:2.59
1:1.20
1:0.93
1:3.75
1:3.38
rt, 5 hb
rt, 1 hb,c
rt, 4 hb
rt, 0.5 h
rt, 1 min
rt, 1 h
−78–0 ◦C, 4 hb
a
Reaction performed in THF with SmI2/RX/1 = 4:2:1, [SmI2] = 0.1 M.
The reaction was carried out in the presence of HMPA (5 vol.% of the SmI2/THF solution).
NiI2 (2 mol.% of the SmI2) was added.
Isolated yield.
b
c
d
Table 2 – 13C chemical shifts of C-7 in 7␣-OH and 7␤-OH isomers
Steroid
7-OH position
7-C chemical shift in 13C-NMR
Steroid
7-OH position
7-C chemical shift in 13C-NMR
3a
3b
4a
4b
5a
5b
6a
6b
␣
␤
␣
␤
␣
␤
␣
␤
73.6
74.8
72.8
74.5
74.8
76.0
72.8
74.4
7a
7b
8a
8b
9a
9b
10a
10b
␣
␤
␣
␤
␣
␤
␣
␤
72.6
74.1
72.0
73.9
71.5
74.3
70.3
72.7

steroids 7 1 ( 2 0 0 6 ) 96–101
101
Chichester: John Wiley & Sons; 1994. p. 211–
the ␣-carbon atom more than does the corresponding equato-
367.
rial substituent [10]. For example, the axial 7␣-hydroxy isomer
3a and the equatorial 7␤-hydroxy isomer 3b showed 13C-NMR
signals for C-7 at ı 73.6 and ı 74.8, respectively. Determination
of the 7␣- and 7␤-isomers according to their 13C-NMR signals
for C-7 are summarized in Table 2.
In conclusion, we have developed a new, convenient
approach to 7-substituted-5-androstene derivatives mediated
by SmI2. Under SmI2-Barbier or SmI2-Reformatsky conditions,
an ␣,␤-unsaturated ketone—androst-5-en-7-one 1 is suitable
for the reactions, and various 7-substituted derivatives can
be readily prepared. Mild conditions, homogeneous reactions,
and simple operations make this method attractive.
[4] Zheng Y-H, Li Y-C. Novel stereoselective synthesis of
7␤-methyl-substituted 5-androstene derivatives. J Org
Chem 2003;68(4):1603–6.
[5] Inanaga J, Ishikawa M, Yamaguchi M. A mild and
convenient method for the reduction of organic halides by
using a SmI2-THF solution in the presence of
hexamethylphosphoric triamide (HMPA). Chem Lett
1987:1485–6.
[6] Imamoto T, Takeyama T, Yokoyama M. A new method for
the hydroxymethylation of carbonyl compounds.
Tetrahedron Lett 1984;25(30):3225–6.
[7] Imamoto T, Hatajima T, Takiyama N, Takeyama T, Kamiya
Y, Yoshizawa T. Reactions of carbonyl compounds with
benzyl chloromethyl ether of diiodomethane in the
presence of samarium(II) iodide or metallic samarium.
New routes to 1,2-diols, iodohydrins and cyclopropanols. J
Chem Soc, Perkin Trans I 1991:3127–35.
r e f e r e n c e s
[8] Machrouhi F, Hamann B, Namy JL, Kagan HB. Improved
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[9] Utimoto K, Matsubara S. Samarium diiodide-mediated
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