J . Org. Chem. 1998, 63, 6999-7001
6999
A High ly â-Ster eoselective Ca ta lytic Ep oxid a tion of
∆5-Un sa tu r a ted Ster oid s w ith a Novel Ru th en iu m (II) Com p lex
u n d er Aer obic Con d ition s
Venkitasamy Kesavan and Srinivasan Chandrasekaran*
Department of Organic Chemistry, Indian Institute of Science, Bangalore-560 012, India
Received May 1, 1998
Catalytic â-stereoselective epoxidation of ∆5-unsaturated steroid derivatives has been effected by
a novel ruthenium(II) bioxazoline complex under aerobic conditions. The reactions are regio- and
stereoselective. The reaction conditions provide the corresponding 5â,6â-epoxides with high degree
of stereoselectivity (88-96%) in very good yields, while oxidation of steroid derivatives with peracids
leads to 5R,6R-epoxides as the major products. The overall conformation of the steroid nucleus is
nearly planar in the cholesteryl ester, while it is bent at the junction between the rings A and B
in the 5â,6â-epoxide. This change from pseudo-trans- to cis-stereochemistry of the A-B ring junction
provides more room for the catalyst to approach from the â-face of the steroidal skeleton.
There has been considerable interest in recent years
in the synthesis of 5â,6â-epoxides of ∆5-unsaturated
steroids1-3 particularly since this functionality is present
in a number of biologically active steroids.4 Moreover,
epoxides are extremely useful for further elaboration
since their facile ring opening allows the introduction of
various substituents in a stereospecific manner. Due to
the presence of the C(10)-angular methyl group on the
â-face of the steroid skeleton, epoxidations of ∆5-unsatur-
ated steroids with peracids5 or dioxiranes6 invariably
yield the 5R,6R-epoxides as the major products. Synthe-
sis of â-epoxides of ∆5-unsaturated steroids has been
accomplished via the formation of halohydrins in two or
three steps in moderate yields.7 Earlier attempts to effect
stereoselective â-epoxidation involved the introduction of
a bulky 3R-halo substituent that would block the entry
of the reagent from the R-face.8 Miura9 reported epoxi-
dation of cholesteryl acetate by iodosobenzene in the
presence of chromium, manganese, or iron tetramesi-
tylporphyrin with a high degree of selectivity (70-90%)
but in very poor yields (15-25%). Under very high
dilution, â-epoxidation of steroids has been achieved with
chromyl acetate in moderate yields, but this procedure
is complicated by the formation of side products.10
Reports are available on the successful â-epoxidation of
steroids using ruthenium tetramesitylporphyrin catalyst.
The major drawbacks of this methodology are that the
synthesis of the catalyst is not always easy and the
reactions generally required a few days for reasonable
conversion for most of the steroids studied.11 Reagent
12a
systems involving KMnO4-CuSO4
and modification
thereof12b have been shown to provide 5â,6â-epoxides in
good yields and with good selectivity.
The homogeneous transition metal-catalyzed epoxida-
tion of alkenes13 and the use of oxoruthenium complexes
as catalysts for oxidations of organic substrates14 have
been the subject of intense study in recent years. With
regard to aerobic oxidation catalyzed by transition metal
complexes, several reactions involving the combined use
of molecular oxygen with reducing agents have been
reviewed.15 Since ruthenium porphyrin complexes are
not that easily accessible, it was of interest to use the
ruthenium(II) bioxazoline complex 1, which has a square
(1) (a) Salvador, J . A. R.; Sa´emelo, M. L.; Campos Neves, A. S.
Tetrahedron. Lett. 1996, 37, 687. (b) Hanson, J . R.; Hitchcock, P. B.;
Liman, M. D.; Nagaratnam, S.; Manickavasagar, R. J . Chem. Res.,
Synop. 1995, 220.
(2) Galagovsky, L. R.; Gros, E. G. J . Chem. Res., Synop. 1993, 137.
(3) Marchon, J . C.; Ramasseul, R. J . Chem. Res., Synop. 1992, 104.
(4) (a) Glotter, E.; Kirson, I.; Lavie, D.; Abraham, A. Bio-organic
chemistry; Van Tamelen, E. E., Ed.; Academic Press: New York, 1979;
Vol. 2, p 57. (b) Tschesche, R.; Schwang, H. H.; Legler, G. Tetrahedron
1966, 22, 1121.
(5) Kirk, D. N.; Hartshon, M. P. Steroid Reaction Mechanism;
Elsevier: London, 1968; Chapter 3, p 70.
(6) Bovicelli, P.; Lupattelli, P.; Mincione, E. J . Org. Chem. 1992,
57, 2182.
planar structure around the ruthenium core analogous
to ruthenium porphyrin systems.11 Recently we have
shown that this ruthenium(II) complex 1 is an efficient
catalyst for epoxidation of alkenes with a high degree of
selectivity.16 Therefore we decided to explore the ef-
ficiency of this catalyst for stereoselective epoxidation of
∆5-unsaturated steroids and our successful results of this
investigation are presented in this paper.
(7) Matthews, G. J .; Hassner, A. The Organic Reactions in Steroid
Chemistry; Fried, J ., Edwards, J . A., Eds.; Van Nostrand: New York,
1972; Vol. 2, p 2.
(8) Shiota, M.; Ogihara, T.; Watanabe, Y. Bull. Chem. Soc. J pn.
1964, 34, 40. (b) Hanson, J . R.; Truneh, A. J . Chem. Soc., Perkin Trans.
1 1988, 2001.
(11) Marchon, J . C.; Ramasseul, R. Synthesis 1989, 389.
(12) (a) Syamala, M. S.; Das, J .; Baskaran, S.; Chandrasekaran, S.
J . Org. Chem. 1992, 57, 1928. (b) Salvador, J . A. R.; Sae Melo, M. L.;
Campor Neves, A. S. Tetrahedron Lett. 1996, 37, 687.
(13) J orgensen, K. A. Chem. Rev. 1989, 89, 431.
(14) Griffith, W. P. Chem. Soc. Rev. 1992, 21, 179.
(15) Mukaiyama, T.; Yamada, T. Bull. Chem. Soc. J pn. 1995, 68,
17.
(9) Muto, T.; Umehara, J .: Masumori, H.; Miura, T.; Kimura, M.
Chem. Pharm. Bull. 1985, 33, 4749.
(10) Galagovsky, L. R.; Eurton, G.; Gros, E. G. Z. Naturforsch. 1989,
14b, 806.
(16) Kesavan, V.; Chandrasekaran, S. J . Chem. Soc., Perkin Trans
1 1997, 3115.
S0022-3263(98)00829-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/16/1998