α-Hydroxylation at C-15 and C-16 in Cholesterol: Synthesis of (25R)-5α-Cholesta-3β,15α,26-triol and (25R)-5α-Cholesta- 3β,16α,26-triol from Diosgenin

Article abstract of DOI:10.1021/ol036257u

(Matrix presented) (25R)-5α-Cholesta-3β,16α,26-triol 7b and (25R)-5α-cholesta-3β,15α,26-triol 10b were synthesized, via (25R)-5α-cholesta-3β,16β26-triol 5a, from diosgenin 3 in 52% yield over six steps and 47% yield over eight steps, respectively. An efficient method for inversion of a C-16β hydroxyl to the C-16α position and a short method for transposition of a C-16β hydroxyl to the C-15α position via the unexpected β-reduction of a C-15 ketone in a steroid are reported.

Full text of DOI:10.1021/ol036257u

ORGANIC
LETTERS
2
004
Vol. 6, No. 2
69-271
r-Hydroxylation at C-15 and C-16 in
Cholesterol: Synthesis of
2
(
25R)-5r-Cholesta-3â,15r,26-triol and
25R)-5r-Cholesta-3â,16r,26-triol from
Diosgenin
(
,†
†
†
†
John R. Williams,* Hua Gong, Nathan Hoff, Olaoluwa I. Olubodun, and
Patrick J. Carroll
‡
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122-2585,
and Department of Chemistry, UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
john.r.williams@temple.edu
Received November 18, 2003
ABSTRACT
(25R)-5r-Cholesta-3â,16r,26-triol 7b and (25R)-5r-cholesta-3â,15r,26-triol 10b were synthesized, via (25R)-5r-cholesta-3â,16â,26-triol 5a, from
diosgenin 3 in 52% yield over six steps and 47% yield over eight steps, respectively. An efficient method for inversion of a C-16â hydroxyl
to the C-16r position and a short method for transposition of a C-16â hydroxyl to the C-15r position via the unexpected â-reduction of a C-15
ketone in a steroid are reported.
Oxysterols constitute a class of oxygenated derivatives of
cholesterol with remarkably diverse, important biological
actions. Steroids oxygenated at C-15R lower 3-hydroxy-3-
Few synthetic efforts have been devoted to C-15 and C-16
D-ring hydroxylation. Remote functionalization has afforded
1
5
6
C-15 keto and C-15R-hydroxy steroids. Hydroboration-
oxidation of cholesta-7,14-dien-3â-ol afforded the C-15R
methylglutaryl-CoA reductase activity and affect sphingolipid
7
1
hydroxyl. Marino functionalized D rings of steroids with a
metabolism, platelet aggregation, and protein prenylation.
C-15â hydroxyl by alkyl cyanocuprate addition to a 1,3-
A large number of oxysterols also occur as marine natural
8
2
diene mono-â-epoxide system. De Riccardis found that
products. Among those with 15R-hydroxylation is the shark-
3
reduction of the C-15 carbonyl is stereoselective, affording
the C-15R hydroxyl group when C-16 and C-17 are sp2
repelling pavoninin-5 (1b). 16R-Hydroxylation is found in
4
aragusterol H (2), which shows antiproliferative activity
toward KB cells with an IC50 of 6.48 µg/mL.
(
1) Schroepfer, G. J., Jr. Physiol. ReV. 2000, 80, 361.
(2) Minale, L.; Ricco, R.; Zollo, F. In Prog. Chem. Org. Nat. Prod.;
Herz, W., Kirby, G. W., Moore, R. E., Steglich, W., Tamm, Ch., Eds.;
Springer-Verlag: New York, 1993, 62, 75.
(
3) (a) Tachibana, K.; Sakaitani, M.; Nakanishi, K. Science 1984, 226,
7
03. (b) Tachibana, K.; Sakaitani, M.; Nakanishi, K. Tetrahedron 1985,
4
1, 1027.
(
4) Miyaoka, H.; Shinohara, M.; Shimomura, M.; Mitome, H.; Yano,
A.; Iguchi, K.; Yamada, Y. Tetrahedron 1997, 53, 5403.
5) Breslow, R.; Baldwin, S.; Flechtner, T.; Kalicky, P.; Liu, S.;
Washburn, W. J. Am. Chem. Soc. 1973, 95, 3251.
6) For a recent reference, see: Yang, J.; Gabriele, B.; Belvedere, S.;
(
(
Huang, Y.; Breslow, R. J. Org. Chem. 2002, 67, 5057.
(7) Taylor, E. J.; Djerassi, C. J. Org. Chem. 1977, 42, 3571.
(8) Marino, J. P.; Abe, H. J. Am. Chem. Soc. 1981, 103, 2907.
†
Temple University.
University of Pennsylvania.
‡
1
0.1021/ol036257u CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/30/2003

Scheme 1. Synthesis of (25R)-5R-Cholesta-3â,16R,26-triol, 7b, and (25R)-5R-Cholesta-3â,15R,26-triol, 10b.
9
hybridized. Recently, we reported two methods for the
some of the silyl protecting groups. We also tried elimination
of the 16-mesylate with other reaction conditions, but the
yield of alkene was still poor. Dehydration of the 16â alcohol
with phosphorus oxychloride showed good regioselectivity
to give the C-16 olefin 6 in 90% yield. From 6, we can
synthesize both the C-16R and C-15R hydroxy steroids 7b
and 10b, respectively, as shown in Scheme 1.
transposition of C-16â hydroxyl to the 15R position, as well
as a successful synthesis of the aglycone of 26-O-deacetyl
pavoninin-5 (1a) via the 15R-hydroxy-16-ketone, using the
13
1
0
Barton deoxygenation reaction on the 16-alcohol. In this
paper, we report a more efficient method for executing this
transposition via allylic oxidation and subsequent stereospe-
cific reduction. A good method for epimerization of steroidal
C-16â hydroxyl to the C-16R position is also reported.
Tigogenin, [(25R)-5R-spirostan-3â-ol] 4, obtained in quan-
titative yield by catalytic reduction of diosgenin 3, was
reacted with zinc and hydrochloric acid using our improved
To introduce the C-16R hydroxyl group we first tried the
1
4
Mitsunobu reaction, to invert the C-16â hydroxy stereo-
chemistry in 5b. Unfortunately, no reaction was observed
even when we used trimethylphosphine instead of triph-
enylphosphine to reduce steric congestion. We also tried
Dodge’s methodology, which varies the acid component.15
Introduction of the C-16R hydroxyl by oxidation of the
conditions to yield (25R)-5R-cholesta-3â,16â,26-triol 5a in
0,11
8
5% yield.1 Selective protection of the triol 5a with tert-
butyldimethylsilyl chloride (TBDMSCl) and DBU gave the
C-16â hydroxy to the 16-one followed by KBH afforded
4
1
2
3
â,26-bissilyloxy ether, 5b, in 93% yield. Kim et al.
reported the synthesis of a C-16 ene in good yield from a
6-mesylate using NaI in DMF at 120 °C. However, when
we treated the 16-mesylate of 5b with NaI, the 16-ene 6
was obtained in poor yield, probably because NaI removed
in poor yield a mixture of C-16R and C-16â hydroxy
1
6
compounds in a 1:9 ratio. An ene reaction on a (Z)-16-
pregnene has afforded a bisnorchol-16-en-22-ol, which upon
hydroboration-oxidation gave the C-16R-hydroxy steroid.9
1
(
13) Giner, J. L.; Margot, C.; Djerassi, C. J. Org. Chem. 1989, 54, 369.
(
9) Izzo, I.; Filippo, M. D.; Napolitano, R.; De Riccardis, F. Eur. J. Org.
Chem. 1999, 3505.
10) Williams, J. R.; Chai, D.; Bloxton, J. D., II; Gong, H.; Solvibile,
W. R. Tetrahedron 2003, 59, 3183.
(14) For reviews see: (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes,
D. L. Org. Prep. Procd. Int. 1996, 28, 127.
(15) Dodge, J. A.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994, 59,
234.
(
(
(
11) Williams, J. R.; Chai, D.; Wright, D. Steroids 2002, 67, 1041.
12) Kim, H. S.; Oh, S. H. Biol. Med. Org. Chem. Lett. 1993, 3, 1339.
(16) Ronchetti, F.; Russo, G. J. Labelled Compd. Radiopharm. 1978,
14, 687.
270
Org. Lett., Vol. 6, No. 2, 2004

With the C-16 olefin in hand, treatment of 6 with borane-
dimethyl sulfide, followed by oxidation with alkaline hy-
drogen peroxide, afforded the C-16R hydroxy steroid 7a in
7
5% yield. (25R)-5R-Cholesta-3â,16R,26-triol, 7b, was
obtained by desilylation of 7a using 49% aqueous HF in
99% yield.
The 3â,15R,26-triol 10b was synthesized by allylic oxida-
tion of the olefin 6 with Na
2
Cr
cinimide to give the ∆ -15-oxo compound 8 in 70% yield.
This represents a considerable improvement over the CrO
dimethylpyrazole oxidation method, which gave 8 in a yield
2
O
7
‚2H
2
O and N-hydroxysuc-
16
3
/
Figure 1. X-ray structure of (25R)-5R-cholesta-3â,15R,26-triol,
10b.
1
7
of 50%. Reduction of the enone 8 under Luche conditions
afforded the allylic alcohol 9 in 98% yield. The 500 MHz
1
3
H NMR of 9 in CDCl showed H-15 as a doublet with
In conclusion, we report short and efficient methods for
R-hydroxylation at C-15 and C-16 in cholesterol. Namely,
the syntheses of (25R)-5R-cholesta-3â,16R,26-triol 7b and
coupling constant J ) 9.8 Hz at δ 4.50 ppm. Catalytic
hydrogenation of the 16-olefin in 9 afforded only the
saturated C-15R alcohol 10a in 98% yield. Desilylation of
(25R)-5R-cholesta-3â,15R,26-triol 10b from diosgenin 3 in
10a, using HF in dichloromethane, afforded (25R)-5R-
5
2% yield over six steps and 47% yield over eight steps,
cholesta-3â,15R,26-triol 10b in excellent yield. The R-con-
figuration of the 15-hydroxy group was confirmed by an
X-ray structure (see Figure 1). This represents an efficient
method for transposing the C-16â hydroxyl to the 15R
position in 60% yield over four steps. At first glance, the
reduction of enone 8 to the 15R alcohol 9 may seem
unexpected. However, molecular modeling using Spartan 4
respectively.
Acknowledgment. Financial support for this research was
provided by a grant from the Temple University Research
Incentive Fund, GlaxoSmithKline, Pfizer, Bristol-Myers
Squibb, and Merck. N.H. and O.O. were supported in part
by the Howard Hughes Medical Institute grant to the
Undergraduate Biological Sciences Education Program at
Temple University. We thank Dr. Jeffrey Honovich of Drexel
University for the high-resolution mass spectra.
2
shows that when C-16 and C-17 are sp hybridized, C-22 of
the cholesterol side chain can move down such that the side
chain can protect the C-15 carbonyl from R attack. The top
face of 8 is less hindered, which results in â delivery of the
hydride to give the 15R alcohol. Furthermore the enone
system flattens ring D in 8, decreasing the protective effect
of the C-18 methyl.
Supporting Information Available: Full experimental
details for the synthesis of 4, 5a,b, 6, 7a,b, 8, 9, and 10a,b
and selected spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(17) (a) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226. (b) Gemal, A.
L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
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