1β-hydroxylation in 5β-steroids: An efficient synthesis of 1β,3α-dihydroxy-5β-cholan-24-oic acid

Article abstract of DOI:10.1081/SCC-100104006

An efficient method for the oxyfunctionalization at C-1 in 5β-steroid (A/B-cis) is described as exemplified by conversion of lithocholic acid (3α-hydroxy-5β-cholan-24-oic acid) to 1β,3α-dihydroxy-5β-cholan-24-oic acid. The key reactions used are regioselective functionalization at C-2 in the 5β-steroid nucleus, stereoselective epoxidation of intermediary α,β-conjugated ketone with dimethyldioxirane, and subsequent reductive cleavage of the resulting β-epoxy-ketone with PhSeNa.

Full text of DOI:10.1081/SCC-100104006

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1β-HYDROXYLATION IN 5β-
STEROIDS: AN EFFICIENT
SYNTHESIS OF 1β,3α-
DIHYDROXY-5β-CHOLAN-24-
OIC ACID
a
a
Takeru Yamaguchi , Ryusei Nakamori , Takashi
b
c
Iida & Toshio Nambara
a
College of Humanities and Sciences, Nihon
University , Setagaya, Sakurajosui, Tokyo,
1
56-8550, Japan
b
College of Humanities and Sciences, Nihon
University , Setagaya, Sakurajosui, Tokyo,
1
56-8550, Japan
c
Hoshi University , Shinagawa, Ebara, Tokyo,
40-1165, Japan
1
Published online: 09 Nov 2006.
To cite this article: Takeru Yamaguchi , Ryusei Nakamori , Takashi Iida & Toshio
Nambara (2001) 1β-HYDROXYLATION IN 5β-STEROIDS: AN EFFICIENT SYNTHESIS
OF 1β,3α-DIHYDROXY-5β-CHOLAN-24-OIC ACID, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
31:8, 1213-1219, DOI: 10.1081/SCC-100104006
To link to this article: http://dx.doi.org/10.1081/SCC-100104006

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SYNTHETIC COMMUNICATIONS, 31(8), 1213–1219 (2001)
1
b-HYDROXYLATION IN 5b-STEROIDS:
AN EFFICIENT SYNTHESIS OF
b,3a-DIHYDROXY-5b-CHOLAN-24-OIC ACID
1
1
Takeru Yamaguchi, Ryusei Nakamori, Takashi Iida,
1
1,*
2
and Toshio Nambara
1
College of Humanities and Sciences, Nihon University,
Setagaya, Sakurajosui, Tokyo 156-8550, Japan
2
Hoshi University, Shinagawa, Ebara,
Tokyo 140-1165, Japan
ABSTRACT
An efficient method for the oxyfunctionalization at C-1
in 5ꢀ-steroid (A/B-cis) is described as exemplified by conver-
sion of lithocholic acid (3ꢁ-hydroxy-5ꢀ-cholan-24-oic acid) to
1
ꢀ,3ꢁ-dihydroxy-5ꢀ-cholan-24-oic acid. The key reactions
used are regioselective functionalization at C-2 in the 5ꢀ-
steroid nucleus, stereoselective epoxidation of intermediary
ꢁ
,ꢀ-conjugated ketone with dimethyldioxirane, and sub-
sequent reductive cleavage of the resulting ꢀ-epoxy-ketone
with PhSeNa.
In continuation of a program of synthesis of biologically and physio-
logically important bile acid metabolites, the need for a supply of 1ꢀ-
1
–5
hydroxylated 5ꢀ-bile acids
examine literature preparations of the compounds. The method, reported
as authentic specimens prompted us to
,7
6
*
Corresponding author.
1
213
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1
214
YAMAGUCHI ET AL.
7
by Thoma et al., which involves selective dehydrobromination of 2,4-
dibromo-3-oxo derivatives of 5ꢀ-bile acids, epoxidation of the resulting
ꢁ
,ꢀ-enones with alkaline hydrogen peroxide, and reductive cleavage of the
1
ꢀ,2ꢀ-epoxy-3-ketones with chromous acetate, is somewhat complicated
and inelegant, and renders low yields. The result implies that oxyfunctionali-
zation at C-1 in 5ꢀ-steroids (normal series; A/B-cis) is less straightforward
than in the more stable 5ꢁ-steroids (allo series; A/B-trans).
We report here a regio-and stereoselective method for the preparation
of 1ꢀ-hydroxylated 5ꢀ-steroids, as exemplified by conversion of lithocholic
acid (3ꢁ-hydroxy-5ꢀ-cholan-24-oic acid; 2) to 1ꢀ,3ꢁ-dihydroxy-5ꢀ-cholan-
2
4-oic acid (1).
As outlined in Scheme 1, the key intermediate is the ꢁ,ꢀ-
conjugated enone ester 6a, which was prepared regioselectively in three
steps from the 3-oxo acid (3) of 1, based on the preferential formylation
8
at C-2 of 3-oxo-5ꢀ-steroids with A/B-cis junction. Thus, the steps
involve: 1) conversion of 3 into the 2-hydroxymethylene derivative 4 with
sodium methoxide and ethyl formate; 2) dehydrogenation of 4 with
Scheme 1.

5b-STEROIDS
1215
2
,3-dichloro-5,6-dicyano-benzoquinone (DDQ); and 3) subsequent defor-
1
mylation and methyl esterification of the resulting Á -2-formyl-3-ketone 5
with chlorotris(triphenyl phosphine) rhodium. Each step proceeds through
easily prepared, well-defined intermediates, and affords a pure product 6a in
reasonable yields.
Dimethyldioxirane, a new class of powerful organic oxidant and/or
oxygen-transfer reagent, has been shown to carry out a variety of syntheti-
9
,10
cally useful transformations.
was subjected to the oxidation with dimethyldioxirane in CHCl at room
Indeed, when the conjugated enone ester 6a
3
temperature for 1 h, the reaction proceeded stereoselectively to give the
expected 1ꢀ,2ꢀ-epoxy-3-oxo ester 7a in an excellent isolated yield (82%).
Although the reagent is not commercially available, mild and neutral con-
ditions, as well as easy work-up after the reaction, are especially attractive,
since no unfavorable side reactions such as hydrolysis of the C-24 ester
group occur, in contrast with the conventional epoxidation of ꢁ,ꢀ-enones
with alkaline hydrogen peroxide.
Reductive cleavage of the 1ꢀ,2ꢀ-epoxy-3-ketone 7a to the correspond-
ing 1ꢀ-hydroxy-3-oxo ester 8a was successfully achieved by organoselenium-
1
1
mediated reduction with PhSeNa, which is generated by simply mixing
diphenyl diselenide and NaBH in ethanol in the presence of a catalytic
4
amount of acetic acid, and led to ꢀ-hydroxylation at C-1. The organosele-
nium-mediated reduction is rapid (20 m) and clean, and raised the isolated
yield of 8a to 78%.
Although LiAlH4 and chromous acetate have been traditionally
employed for the reductive cleavage of steroidal epoxides, the former
reduced the C-24 ester group of 7a, while the latter produced the desired
8
a in a fairly low yield.
The final step of stereoselective reduction of 8a to its corresponding
C-3 equatorial alcohol (1a) initially appeared simply to require reduction by
NaBH , tert-butylamine-borane complex or metallic K/tert-amyl alcohol,
which normally reduce saturated 3-ketones stereoselectively to C-3 equator-
4
1
2
ial products 2. However, with 8a, the reducing reagents unexpectedly
yielded the 3ꢀ-hydroxy epimer in considerable amounts, probably owing
to shielding of the ꢀ-face of the molecule by the axial 1ꢀ-hydroxy substitu-
ent. Ultimately, selective reduction to 1a was successful when the reagent
was Zn(BH ) . With this reagent, 8a underwent stereoselective reduction at
4
2
C-3, and after hydrolysis of the C-24 ester group, yielded the desired 1ꢀ,3ꢁ-
dihydroxy acid (1) in a good isolated yield. Thus, the overall yield of good
quality of 1 from 2 was at least ca. 18%.
In conclusion, the highly regio-and stereoselective reactions found
in this study suggest their utility for the preparation of other bioactive
1
ꢀ-hydroxylated steroids and vitamin D analogs in the 5ꢀ-series.

1
216
YAMAGUCHI ET AL.
EXPERIMENTAL
Melting points (m.p.) were determined on an electric micro hot stage
and are uncorrected. IR spectra were obtained on a Bio Rad FTS-7 FT-IR
spectrometer (Philadelphia, PA) as KBr disks. UV spectra were measured
1
on a HITACHI U-2000A spectrophotometer in ethanol solution. H NMR
spectra were obtained on a JEOL JNM-EX 270 instrument at 270 MHz,
with CDCl containing Me Si as the solvent, unless otherwise specified;
3
4
chemical shifts are expressed in ꢂ (ppm) relative to Me Si. Analytical TLC
4
was performed on precoated silica gel plates (20 cm ꢀ 20 cm, 0.25 mm layer
thickness; Merck, Darmstadt, Germany) using EtOH-hexane-acetic acid
(
50:50:1ꢁ10:40:2, v/v/v) as the developing solvent. Lithocholic acid was
purchased from Tokyo Kasei Kogyo Co. (Tokyo, Japan); it was converted
to the 3-oxo derivative (3) by the usual method.
A solution of dimethyldioxirane in CHCl was prepared as described
3
1
3
by Singh and Murray and was standardized by iodometric titration; the
concentration was 0.25 M.
2
-Hydroxymethylene-3-oxo-5b-cholan-24-oic Acid (4)
To a stirred solution of 3 (1.0 g) (prepared from 2 by the Jones oxida-
tion) and sodium methoxide (600 mg) in dry pyridine (40 mL) was added
dropwise ethyl formate (12 mL), and the mixture was stirred at room tem-
perature under N for 8 h. The reaction was quenched by adding an excess
2
of water and then acidified with 10% HCl. The reaction product was
extracted with EtOAc. The combined extracts were washed with 10% HCl
and saturated brine, dried over Drierite, and evaporated to give the title
compound 4, which was recrystallized from acetone-hexane as a colorless
ꢂ
1
ꢂ
ꢃ1
amporphous solid: yield, 886 mg (82%); m.p. 180 ꢁ183 C. IR, ꢃ
cm :
max
1
712 (C ¼ O). UV ꢄ : 288 nm (", 7400, EtOH). H NMR (CDCl þ 20%
6 3 3
max
3
DMSO-d ) ꢂ: 0.66 (s, 3H, 18-CH ), 0.90 (d, 3H, J ¼ 6.2 Hz, 21-CH ), 1.05
(
(
s, 3H, 19-CH ), 8.29 (s, 1H, 2-CHOH). MS (as the methyl ester), m/z: 416
3
8%, M), 398 (14%, MꢃH O), 388 (25%, MꢃCO), 387 (32%, MꢃCHO),
2
3
18 (72%, MꢃringA).
2
-Formyl-3-oxo-5b-chol-1-en-24-oic Acid (5)
To a solution of the 2-hydroxymethylene-3-oxo acid 4 (1.0 g) in dry
benzene (40 mL) was added DDQ (600 mg), and the resulting mixture was
stirred at room temperature for 5 m. The solvent was evaporated under

5b-STEROIDS
1217
reduced pressure, and the reaction product was dissolved in CH Cl2
2
(
20 mL). The insoluble material was filtered off, and the mother liquor
was evaporated to give a residue. Chromatography of the residue on a
column of silica gel (30 g) and elution with CH Cl -acetone (98:2, v/v)
afforded the title compound 5, which was recrystallized from EtOAc-
2
2
ꢂ
hexane as a colorless amorphous solid: yield, 660 mg (67%); m.p. 188 ꢁ
ꢂ
ꢃ1
1
1
1
1
3
91 C. IR ꢃ
cm : 1735, 1704, 1684 (C ¼ O). H NMR ꢂ: 0.71 (s, 3H,
3 3
max
8-CH ), 0.92 (d, 3H, J ¼ 6.2 Hz, 21-CH ), 1.30 (s, 3H, 19-CH ), 7.65 (s, 1H,
3
-H), 10.09 (s, 1H, 2-CHO). MS (as the methyl ester), m/z: 414 (10%, M),
86 (100%, MꢃCO), 318 (35%, MꢃringA).
Methyl 3-Oxo-5b-chol-1-en-24-oate (6a)
1
To a solution of the 2-formyl-Á acid 5 (500 mg) in dry benzene
(
50 mL) was added freshly prepared chlorotris(triphenylphosphine)-rho-
dium (1.0 g), and the resulting mixture was refluxed under N for 3 h. The
2
solvent was evaporated, and the reaction product was dissolved in methanol
(
10 mL). After removal of the insoluble material by filtration, the filtrate was
esterified with diazomethane. The methylated product, which was shown by
TLC to consist essentially of a single component, was purified by a column
of silica gel (20 g). Elution with benzene-EtOAc (95:5, v/v) afforded the title
compound 6a, which was recrystallized from EtOAc-hexane as a colorless
ꢂ
ꢂ
7
ꢂ
ꢂ
thin plate: yield, 365 mg (76%); m.p. 141 ꢁ143 C (lit. 144 ꢁ145 C).
ꢃ1
1
IR ꢃ
cm : 1735, 1679 (C ¼ O). H NMR ꢂ: 0.69(s, 3H, 18-CH ), 0.91
3 3 3
max
3
(
5
d, 3H, J ¼ 6.2 Hz, 21-CH ), 1.19 (s, 3H, 19-CH ), 3.66 (s, 3H, COOCH ),
.89 (d, 1H, J ¼ 10.0 Hz, 2-H), 6.83 (d, 1H, J ¼ 10.0 Hz, 1-H). MS, m/z: 386
(
100%, M), 355 (25%, MꢃOCH ), 271 (71%, MꢃS.C.).
3
Methyl 1b,2b-Epoxy-3-oxo-5b-cholan-24-oate (7a)
1
To a solution of the 3-oxo-Á ester 6a (300 mg) in CH Cl (10 mL) was
2
2
added a solution of dimethyldioxirane (0.25 M, 6 mL; 1.5 mmol) in CHCl3,
and the mixture was stirred at room temperature for 1 h. Evaporation of the
solvent yielded the 1ꢀ,2ꢀ-epoxy-3-oxo ester 7a, which was recrysatllized
ꢂ
from methanol as colorless needles: yield, 256 mg (82%); m.p. 111 ꢁ
ꢂ
7
ꢂ
ꢂ
ꢃ1
1
1
0
3
15 C (lit. 123 ꢁ124 C). IR ꢃ
cm : 1740, 1713 (C ¼ O). H NMR ꢂ:
3 3
max
.85 (s, 3H, 18-CH ), 0.68 (d, 3H, J ¼ 7.0 Hz, 21-CH ), 1.27 (s, 3H, 19-CH ),
3
.26 (d, 1H, J ¼ 4.1 Hz, 1ꢁ-H), 3.39 (d, 1H, J ¼ 4.1 Hz, 2ꢁ-H), 3.64

1
218
YAMAGUCHI ET AL.
(
s, 3H, COOCH ). MS, m/z: 402 (16%, M), 384 (26%, MꢃH O), 371 (10%,
3
2
MꢃOCH ), 353 (40%, MꢃH OꢃOCH ), 287 (47%, MꢃS.C.).
3
2
3
Methyl 1b-Hydroxy-3-oxo-5b-cholan-24-oate (8a)
Acetic acid (36 mL) was added to a solution of PhSeNa, prepared by
the reduction of diphenyl diselenide (600 mg) with NaBH (185 mg) in etha-
ꢂ
4
1
1
ꢂ
nol (12 mL), and the mixture was stirred at 0 ꢁ5 C for 30 min. The result-
ing solution was added at once to a solution of the 1ꢀ,2ꢀ-epoxy ketone 7a
(200 mg) in ethanol (4 mL) under N and stirred for 20 min at 0 ꢁ5 C. The
reaction mixture was diluted with water, neutralized with 10% H SO , and
ꢂ
ꢂ
2
2 4
evaporated. The combined CH Cl layer was washed with water, dried with
2
2
Drierite, and evaporated, and the residue was chromatographed on silica gel
8 g). Elution with benzene-EtOAc (9:1, v/v) and recrystallization of the title
compound 8 from EtOAc-hexane as colorless thin plates: yield, 156 mg
(
ꢂ
ꢂ
1
7
ꢂ
ꢂ
ꢃ1
(
1
78%); m.p. 178 ꢁ180 C (lit. 179 ꢁ181 C). IR ꢃmax. cm : 3418 (OH),
3
722, 1706 (C ¼ O). H NMR ꢂ: 0.69 (s, 3H, 18-CH ), 0.91 (d, 3H,
3 3 3
J ¼ 6.5 Hz, 21-CH ), 1.15 (s, 3H, 19-CH ), 3.67 (s, 3H, COOCH ).4.16
(
brm, 1H, J ¼ 2.2 Hz, 1ꢁ-H). MS, m/z: 386 (100%, M), 355 (25%,
MꢃOCH ꢃH O), 271 (44%, MꢃH O–S.C.).
3
2
2
1
b,3a-Dihydroxy-5b-cholan-24-oic Acid (1)
To a stirred solution of Zn(BH ) in Et O (2.5 mL, 4.8 mmol), a sol-
4
2
2
ution of 1ꢀ-hydroxy-3-oxo ester 8a (100 mg) in C H -Et O (6 mL, 1:1, v/v)
6
6
2
was added dropwise under N . After further stirring for 30 min at room
2
temperature, the mixture was poured into water, dried with Drierite, and
evaporated to dryness. Crystallization of the residue from EtOAc-hexane
gave the 1ꢀ,3ꢁ-dihydroxy ester (1a) as colorless thin plates: yield, 75 mg
ꢂ
ꢂ
7
ꢂ
ꢂ
ꢃ1
(
75%); m.p. 195 ꢁ198 C (lit. 203 ꢁ205 C). IR ꢃmax. cm : 3425 (OH),
1
1
2
1
720, (C ¼ O). H NMR ꢂ: 0.65 (s, 3H, 18-CH ), 0.90 (d, 3H, J ¼ 6.2 Hz,
3
1-CH ), 1.05 (s, 3H, 19-CH ), 3.67 (s, 3H, COOCH ), 3.94 (brm, 1H,
3
3
3
ꢁ-H), 4.13 (m, 1H, J ¼ 5.1 Hz, 3ꢀ-H). MS (as the methyl ester-trimethylsilyl
ether derivative), m/z: 535 (2%, MꢃCH ), 460 (85%, MꢃTMSOH), 370
3
(
6%, Mꢃ2TMSOH).
The ester 1a was hydrolyzed by the usual methanolic potassium
hydroxide. Recrystallization of the product, from EtOH-hexane gave the
ꢂ
ꢂ
desired acid 1 as a colorless amorphous solid: yield, 94%; m.p. 272 ꢁ275 C
7
ꢂ
ꢂ
ꢃ1
1
(
lit. 274 ꢁ278 C). IR ꢃ
cm : 3267 (OH), 1713 (C ¼ O). H NMR
max

5b-STEROIDS
1219
(
2
CDCl þ 20% DMSO-d ) ꢂ: 0.64 (s, 3H, 18-CH ), 0.92 (d, 3H, J ¼ 6.2 Hz,
3
6
3
1-CH ), 1.03 (s, 3H, 19-CH ).
3 3
ACKNOWLEDGMENTS
This work was supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports and Culture of
Japan. Masami Kitamura and Masako Ishibashi contributed able technical
assistance.
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Received May 15, 2000