Regio- and stereoselective ruthenium-catalyzed hydrovinylation of 1,3-dienes: Application to the generation of a 20(S) steroidal side chain

Article abstract of DOI:10.1021/ol030031+

(Matrix presented) The addition of ethylene to 1,3-dienes and 1-vinylcycloalkenes, catalyzed by two ruthenium complexes, proceeds in a regioselective fashion to afford 3-methyl-1,4-dienes as products. For a steroidal-based 1-vinylcycloalkene, the addition

Full text of DOI:10.1021/ol030031+

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1567-1569
Regio- and Stereoselective
Ruthenium-Catalyzed Hydrovinylation of
1,3-Dienes: Application to the
Generation of a 20(S) Steroidal Side
Chain
Zhengjie He, Chae S. Yi,* and William A. Donaldson*
Department of Chemistry, Marquette UniVersity,
P.O. Box 1881, Milwaukee, Wisconsin 53201-1881
william.donaldson@marquette.edu
Received February 27, 2003
ABSTRACT
The addition of ethylene to 1,3-dienes and 1-vinylcycloalkenes, catalyzed by two ruthenium complexes, proceeds in a regioselective fashion
to afford 3-methyl-1,4-dienes as products. For a steroidal-based 1-vinylcycloalkene, the addition is stereospecific, giving a product with a
20(S) configuration.
Transition metal-catalyzed hydrovinylation1 holds tremen-
dous potential as a generally useful C-C bond-forming
reaction, since it uses a cheap feedstock (ethylene) and
proceeds in an “atom economical” fashion.2 This reaction
has largely focused on 1-arylethylenes as substrates since
the products, 3-aryl-1-butenes, may be transformed into
useful analgesics (e.g., ibuprofen, naproxen). While a number
of recent reports describe highly enantioselective hydrovi-
nylation of styrenes,3 further development of this reaction
as a general synthetic tool will require broadening the scope
of applicable substrates. Only limited examples of the
hydrovinylation of cyclic dienes have been reported.4 In the
course of examining the ruthenium-catalyzed coupling of
ethylene with alkynes, one of our labs recently reported the
use of two ruthenium catalytic systems 1 and 2 for the
coupling of ethylene with alkynes and alkenes.5 We herein
report the ruthenium-catalyzed hydrovinylation of unsym-
metrically substituted 1,3-dienes. Reaction of 1,3-dienes
Figure 1. Ruthenium catalyst structures.
3a-h with excess ethylene, in the presence of either catalyst
1 or 2 gave predominantly the corresponding 3-methyl-1,4-
dienes 4a-h, the products resulting from 1,2-hydrovinylation
(Table 1).6 The structural assignment for 4 was based on its
1H NMR spectral data. In particular, signals at ca. δ 5.9 (ddd,
1H), 5.05 (m, 2H), and 1.2 ppm (d, 3H) are characteristic of
the vinyl and methyl groups of a 3-substituted-1-butenyl
(1) (a) Jolly, P. W.; Wilke, G. In Applied Homogeneous Catalysis with
Organometallic Compounds; Cornils, B., Herrmann, W. A., Eds.; Wiley-
VCH: New York, 2000; pp 1024-1072. (b) Goossen, L. J. Angew. Chem.,
Int. Ed. 2002, 41, 3775-3778.
(2) (a) Trost, B. M. Science 1991, 254, 1471-1477. (b) Trost, B. M.
Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281.
10.1021/ol030031+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/04/2003

1,3-diene.7 Any unreacted starting material or the isomerized
1,3-diene product could be chemically separated from the
desired 1,4-diene 4 by treatment of the reaction mixture with
phenyl triazodione (PTAD); the PTAD undergoes cycload-
dition with the conjugated dienes, and the desired product 4
can be cleanly separated from these cycloaddition products.
Hydrovinylation of dienes bearing aryl substituents (3a,b)
as well as 1-vinylcycloalkenes (3c-h) proceeded with
excellent 1,2-addition regioselectivity. For certain substrates
bearing a resident stereocenter (e.g., 3d,f,g), hydrovinylation
was not stereoselective, giving a 1:1 mixture of diastereo-
meric products. In contrast, hydrovinylation of the steroidal
diene 3h proceeded with excellent regio- and stereoselec-
tivity, giving a single diastereomer 4h in good isolated yield.
Since assignment of the C20 configuration of the product
4h was not possible on the basis of NMR spectral data, a
crystalline derivative was sought. To this end, hydroboration/
oxidation of 4h proceeded only at the vinyl group to afford
the primary alcohol 5 (Scheme 1). Oxidation of 5 with Jones
Table 1. Ru-Catalyzed Hydrovinylation of 1,3-Dienes
Scheme 1
reagent, followed by treatment of the crude product with
diazomethane, gave a separable mixture of ester 68 and
spirocyclic lactone 7.9 Crystals of 7 suitable for X-ray
diffraction analysis revealed the relative configurations within
the molecule;10 since the precursor 3h was prepared from
optically pure estrone,11 the absolute configurations at the
C17 and C20 stereocenters of 7 were assigned as (R) and
(S), respectively. Thus, the hydrovinylation product 4h has
the 20(S) configuration, which is opposite to the configura-
tion of most naturally occurring steroids [i.e., 20(R)].
Recently, a nonnatural 20(S) vitamin D3 analogue has been
reported that selectively induces bone formation.12 While
there are many strategies for the preparation of the 20(R)
side chain,13 there is a general lack of stereoselectiVe routes
to side chains with the 20(S) configuration.14
a From ref 5b. b Mixture of diastereomers (1:1). c Single diastereomer.
functionality. In certain cases, the reaction was terminated
prior to complete consumption of starting material 3, as
prolonged contact with the catalyst led to isomerization of
the initially formed 4 to the more stable conjugated 3-methyl-
(3) (a) Bayersdorfer, R.; Ganter, B.; Englert, U.; Keim, W.; Vogt, D. J.
Organomet. Chem. 1998, 552, 187-194. (b) Albert, J.; Cadena, M.; Granell,
J.; Muller, G.; Ordinas, J. I.; Panyella, D.; Puerta, C.; Sanudo, C.; Valerga,
P. Organometallics 1999, 18, 3511-3518. (c) Englert, U.; Haerter, R.;
Vasen, D.; Salzer, A.; Eggerling, E. B.; Vogt, D. Organometallics 1999,
18, 4390-4398. (d) Wegner, A.; Leitner, W. J. Chem. Soc., Chem. Commun.
1999, 1583-1584. (e) Bosmann, A.; Francio, G.; Jenssen, E.; Solinas, M.;
Leitner, W.; Wasserscheid, P. Angew. Chem., Int. Ed. 2001, 40, 2697-
2699. (f) Francio, G.; Faraone, F.; Leitner, W. J. Am. Chem. Soc. 2002,
124, 736-737. (g) Nomura, N.; Jin, J.; Park, H.; RajanBabu, T. V. J. Am.
Chem. Soc. 1998, 120, 459-460. (h) Nandi, M.; Jin, J.; RajanBabu, T. V.
J. Am. Chem. Soc. 1999, 121, 9899-9900. (i) Park, H.; RajanBabu, T. V.
J. Am. Chem. Soc. 2002, 124, 734-735.
(4) (a) Beger, J.; Duschek, C.; Gericke, C. J. Prakt. Chem. 1974, 316,
952-962. (b) Buono, G.; Siv, C.; Peiffer, G.; Triantaphylides, C.; Denis,
P.; Mortreux, A.; Petit, F. J. Org. Chem. 1985, 50, 1781-1782. (c) Hilt,
G.; du Mesnil, F.-X.; Luers, S. Angew. Chem., Int. Ed. 2001, 40, 387-
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(5) (a) Yi, C. S.; Lee, D. W.; Chen, Y. Organometallics 1999, 18, 2043-
2045. (b) Yi, C. S.; He, Z.; Lee, D. W. Organometallics 2001, 20, 802-
804.
(7) Isomerization (over longer reaction periods) is observed with both
catalysts 1 and 2. Thus, at least for catalyst 1, this isomerization cannot be
attributed to the presence of acid.
(8) Both the 20(S)- and 20(R)-isomers of the methyl ether corresponding
to benzyl ether 6 have been previously prepared. The close similarity of
their literature NMR spectral data does not allow for an unambiguous
assignment. Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1978, 100,
3435-3443.
(9) Formation of γ-lactones from 4-penten-1-ols or δ-lactones from
5-hexen-1-ols via oxidation with chromium reagents has been previously
reported. (a) Chakraborty, T. K.; Chandrasekaran, S. Tetrahedron Lett. 1984,
25, 2895-2896. (b) Schlecht, M. F.; Kim, H. Tetrahedron Lett. 1985, 26,
127-130. (c) Rathore, R.; Vankar, P. S.; Chandrasekaran, S. Tetrahedron
Lett. 1986, 27, 4079-4082.
(10) Bennett, D. W.; Siddiquee, T. A.; Murphy, K. L.; Haworth, D. T.;
He, Z.; Donaldson, W. A. J. Chem. Cryst. Submitted for publication. CCDC
number 201892.
(6) Neither 1,4-diphenyl-1,3-butadiene or 2,5-dimethyl-2,4-hexadiene
reacted with ethylene in the presence of either 1 or 2.
(11) De Riccardis, F.; Meo, D.; Izzo, I.; Di Filippo, M.; Casapullo, A.
Eur. J. Org. Chem. 1998, 1965-1970.
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Org. Lett., Vol. 5, No. 9, 2003

To demonstrate the synthetic potential of this diastereo-
selective hydrovinylation reaction, alcohol 5 was transformed
into unsaturated alcohol 9a via a three-step protocol (Scheme
2). Structure 9a is a hybrid between estrone and the Roche
Scheme 3
Scheme 2
â-hydride and subsequent ligand exchange with a 1,3-diene,
regenerates species 10, and affords the product 1,4-diene.
The stereoselective formation of 4h may be rationalized on
the preferential formation of π-allyl intermediate 13 (Scheme
3) in which Ru is trans to the sterically bulky angular methyl
group and the allylic methyl group occupies the anti position
in order to avoid steric interaction with the C12 methylene
(steroid numbering).
In summary, regio- and stereoselective hydrovinylation of
1,3-dienes 3 has been achieved by using Ru catalysts 1 or
2. Further developments in the scope of this reaction as well
as synthetic applications will be reported in due course.
vitamin D3 analogue, Ro 26-9228 (9b), which is reported to
increase bone mineral density in rats.12a Additionally, func-
tionalized estrone analogues structurally similar to 9a are
described as agents for the modulation of cell growth and
differentiation.12d
The hydrovinylation of 1,3-dienes with either 1 or 2 is
proposed to involve a ruthenium hydride species 10 in which
the less substituted olefin of the diene is coordinated to Ru
(Scheme 3).15 Insertion of the conjugated diene into the
Ru-H bond generates the 1-methyl-π-allyl intermediate 11
in a reversible fashion. Ethylene insertion into the σ-allyl
species 12, with retention of configuration, followed by
Acknowledgment. Financial support for this work was
provided by the National Institutes of Health (GM-42641 to
W.A.D. and GM-55987 to C.S.Y.). High-resolution mass-
spectral determinations were made at the Washington
University Mass Spectrometry Resource, an NIH Research
Resource (Grant P41RR0954). W.A.D. acknowledges stimu-
lating discussions with Prof. T. V. RajanBabu.
(12) (a) Kabat, M. M.; Garofalo, L. M.; Daniewski, A. R.; Hutchings,
S. D.; Liu, W.; Okabe, M.; Radinov, R.; Zhou, Y. J. Org. Chem. 2001, 66,
6141-6150. (b) Sicinski, R. R.; Rotkewicz, P.; Kolinski, A.; Sicinska, W.;
Prahl, J. M.; Smith, C. M.; DeLuca, H. F. J. Med. Chem. 2002, 45, 3366-
3380. (c) Shevde, N. K.; Plum, L. A.; Clagett-Dame, M.; Yamamoto, H.;
Pike, J. W.; DeLuca, H. F. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 13487-
13491. (d) Hesse, R. H.; Setty, S. K. S.; Ramgopal, M.; Kugabalusooriar,
S. Patent WO 2000068246, 2000; CAN 133 350395, 2000.
(13) For a review, see: Gui-Dong, Z.; Okamura, W. H. Chem. ReV. 1995,
95, 1877-1952. For a more recent synthesis, see: Yan, J.; Herndon, J. W.
J. Org. Chem. 1998, 63, 2325-2331 and references therein.
(14) 20(S) vitamin D3 precursors have been prepared by ozonolytic
degradation of ergocalciferol, followed by a base-catalyzed epimerization
and separation of the 20(R)- and 20(S)-diastereomers: Hijikuro, D. T.;
Takahashi, T. J. Am. Chem. Soc. 2001, 123, 3716-3722. For a route to the
20(S) side chain that uses stoichiometric palladium, see ref 8.
Supporting Information Available: Details of experi-
mental procedures, characterization, and analytical data for
the products. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) Notably, the Ru-H species 10 has been proposed as an intermediate
in the coupling of alkynes with ethylene using catalyst 1 (see ref 5a).
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