Published on Web 11/01/2005
Regiospecific and Stereoselective Syntheses of (()-Reserpine
and (-)-Reserpine
Gilbert Stork,* Peng Cho Tang,† Michael Casey,‡ Burton Goodman,§ and
Masahiro Toyota
Contribution from the Department of Chemistry, Columbia UniVersity,
New York, New York 10027
Received August 22, 2005; E-mail: gjs8@columbia.edu
Abstract: Full details of three approaches to an entirely regio- and stereoselective synthesis of the well-
known target reserpine are described, culminating in a total synthesis which efficiently meets these
requirements.
Introduction
at C-3 was a major product, but it was accompanied by
considerable quantities of an unwanted regioisomer.
Natural products of some complexity have played a major
role in stimulating the design of new synthetic methods and in
the evolution of the strategy and tactics of organic synthesis.
For some chemists, the attractiveness of many of these
substances as targets of synthesis is their bioactivity. For others,
the structural challenge is the incentive to attempt their
construction. For both reasons, almost half a century since its
synthesis was first achieved,1 the indole alkaloid reserpine (1)
has been,2,3 and will probably continue to be, a very attractive
target to test novel approaches to its construction.
Imaginative and original as all these total syntheses of
reserpine were, however, problems of regio- and stereochemistry
still remained. In some syntheses, including the historic initial
one,1a,4 the C-3 center was initially produced regiospecifically
but, exclusively or to a significant extent, as the epimer
corresponding to isoreserpine (2). In others, the correct epimer
† Hengrui Pharmaceutical Ltd., Shanghai.
Our plan for a regiospecific, as well as stereoselective,
construction of reserpine was based on the anticipation that the
kinetic closure of a regiospecifically produced iminium ion, 3,
would lead to the formation of the (desired) less stable
arrangement at C-3 (vide infra). The requirement for regiospeci-
‡ University College, Dublin.
§ Deceased Dec 28, 2004.
Osaka Prefecture University.
(1) (a) Woodward, R. B.; Bader, F. E.; Bickel, H.; Kierstead, R. W. Tetrahedron
1958, 2, 1. Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead,
R. W. J. Am. Chem. Soc. 1956, 78, 2023; 2657. (b) For practical improve-
ments, see: Novak, L.; Jilek, J. O.; Kakac, B.; Protiva, M. Tetrahedron
Lett. 1959, 5, 10. Protiva, M.; Jilek, J. O.; Ernest, I.; Novak, L. Tetrahedron
Lett. 1959, 11, 12.
(2) (a) Pearlman, B. A. J. Am. Chem. Soc. 1979, 101, 6398; 6404. (b) Wender,
P. A.; Schaus, J. M.; White, A. W. J. Am. Chem. Soc. 1980, 102, 6157;
Heterocycles 1987, 25, 263. (c) Martin, S. F.; Grzejszczak, S.; Ru¨eger, H.;
Williamson, S. A. J. Am. Chem. Soc. 1985, 107, 4072. Martin, S. F.; Ru¨eger,
H.; Williamson, S. A.; Grzejszczak, S. J. Am. Chem. Soc. 1987, 109, 6124.
(d) Gomez, A. M.; Lopez, J. C.; Fraser-Reid, B. J. Org. Chem. 1994, 59,
4048; 1995, 60, 3859. (e) Chu, C.-S.; Liao, C.-C.; Rao, P. D. Chem.
Commun. 1996, 1537. (f) Hanessian, S.; Pan, J. W.; Carnell, A.; Bouchard,
H.; Lesage, L. J. Org. Chem. 1997, 62, 465. (g) Mehta, G.; Reddy, D. S.
J. Chem. Soc., Perkin Trans. 1 2000, 1399. (h) Sparks, S. M.; Shea, K. J.
Org. Lett. 2001, 3, 2265. Sparks, S. M.; Gutierrez, A. J.; Shea, K. J. J.
Org. Chem. 2003, 68, 5274.
(3) For syntheses of the closely related deserpidine, see: (a) Szantay, C.; Blasko,
G.; Honty, K.; Baitz-Gacz, E.; Tamas, J.; To¨ke, L. Liebigs Ann. Chem.
1983, 1292. (b) Naito, T.; Hirata, Y.; Miyata, O.; Ninomiya, I.; Inoue, M.;
Kamiichi, K.; Doi, M. Chem. Pharm. Bull. 1989, 37, 901. (c) Baxter, E.
W.; Labaree, D.; Ammon, H. L.; Mariano, P. S. J. Am. Chem. Soc. 1990,
112, 7682. Many routes to reserpine, although abandoned for one reason
or another, deserve attention. Cf., inter alia, Isobe, M.; Fukami, N.;
Nishikawa, T.; Goto, T. Heterocycles 1987, 25, 521.
(4) The original Woodward synthesis of reserpine goes through the initial
formation of isoreserpine, its C-3 epimer, via a borohydride reduction in
methanol which presumably involves axial addition of hydride to a pre
chair iminium intermediate. A variety of modified reduction conditions of
an iminium intermediate have been explored in the hope of producing
reserpine directly, rather than via its C-3 epimer. Catalytic hydrogenation
(cf. Gottfredsen, W. O.; Vangedal, S. Acta Chem. Scand. 1956, 10, 1414)
also gives isoreserpine, but zinc-aqueous acid processes have been reported
to yield reserpine selectively. (a) For instance, Weisenborn et al. (Weisen-
born, F. L.; Diassi, P. A. J. Am. Chem. Soc. 1956, 78, 2022) reported the
formation of reserpine, in unspecified yield, by zinc-aqueous acetic acid
reduction. (b) Velluz et al. (Velluz, L.; Muller, G.; Joly, R.; Nomine´, G.;
Mathieu, J.; Allais, A.; Warnant, J.; Valls, J.; Bucourt, R.; Jolly, J. Bull.
Soc. Chim. Fr. 1958, 673) reported a 75% yield of reserpine, using zinc
and aqueous perchloric acid on the 18-trimethoxybenzoate of the relevant
iminium ion, and the same procedure, using the 18-acetate, was reported
(Protiva, M.; Jilek, J. O.; Ernest, I.; Novak, L. Tetrahedron Lett. 1959, 12)
to give a “3:1 mixture of reserpine to isoreserpine”. Martin (J. Am. Chem.
Soc. 1987, 109, 6124) reports, however, that his group’s attempts to
duplicate the favorable results reported earlier for these zinc-acid reductions
gave, by contrast, ratios of 1:1.7-2.0 in faVor of isoreserpine. See also:
Wenkert, E.; Roychaudhuri, D. K. J. Am. Chem. Soc. 1958, 89, 1613.
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