General Access to the Vinca and Tacaman Alkaloids Using a Rh(II)-Catalyzed Cyclization/Cycloaddition Cascade Dylan B. England and Albert Padwa* Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322 chemap@emory.edu ReceiVed January 15, 2008 The total synthesis of several members of the Vinca and tacaman classes of indole alkaloids has been accomplished. The central step in the synthesis consists of an intramolecular [3+2]-cycloaddition reaction of an R-diazo indoloamide which delivers the pentacyclic skeleton of the natural product in excellent yield. The acid lability of the oxabicyclic structure was exploited to establish the trans-D/E ring fusion of (()-3H-epivincamine (3). Finally, a base induced keto-amide ring contraction was utilized to generate the E-ring of the natural product. A variation of the cascade sequence of reactions used to synthesize (()-3H-epivincamine was also employed for the synthesis of the tacaman alkaloids (()-tacamonine and (()-apotacamine. Introduction The development of synthetic methods for constructing indole alkaloids has attracted much attention for several decades due to the important pharmacological properties and diverse struc- tures of this class of natural products. 1-8 In particular, both the Vinca and tacaman families of indole alkaloids occupy a central place in natural product chemistry because of their wide range of complex structural variation. 9,10 These two families are characterized by the presence of a common pentacyclic frame- work 1, containing either a cis- or trans-fused D/E ring system (Figure 1). 11 Prototypical examples of the Vinca alkaloids include (+)-vincamine (2), as well as its epimer, (()-3H-epivincamine (3) which have been isolated from several plants of the Vinca genus. 12 Members of the Vinca family all exhibit strong vasodilation activity which brings about an enhancement of the overall cerebral blood flow. 13 Thus, these compounds along with their semi-synthetic derivatives have recently been the subject of intense pharmacological and synthetic studies. 14 The structur- ally related tacaman alkaloids represented by tacamine (4), tacamonine (5), and apotacamine (6) were isolated from the Central African plant Tabernaemontana eglandulosa Stapf. 15 (1) (a) Openshaw, H. T.; Robinson, R. J. Nature 1946, 157, 438. (b) Bonjoch, J.; Sole ´, D. Chem. ReV. 2000, 100, 3455. (c) Ohshima, T.; Xu, Y.; Takita, R.; Shimizu, S.; Zhong, D.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14546. (d) Mori, M.; Nakanishi, M.; Kajishima, D.; Sato, Y. J. Am. Chem. Soc. 2003, 125, 9801. (2) Saxton, J. E. In The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Academic Press: San Diego, CA, 1998; Vol. 51, pp 1-197. (3) Stork, G.; Dolfini, J. E. J. Am. Chem. Soc. 1963, 85, 2872. (4) Barton, J. E. D.; Harley-Mason, J. Chem. Commun. 1965, 298. (5) Kutney, J. P.; Abdurahman, N.; LeQuesne, P.; Piers, E.; Vlattas, I. J. Am. Chem. Soc. 1966, 88, 3656. (6) Harley-Mason, J.; Kaplan, M. Chem. Commun. 1967, 915. (7) Wenkert, E.; Liu, S. J. Org. Chem. 1994, 59, 7677. (8) (a) Banwell, M. G.; Smith, J. A. J. Chem. Soc., Perkin Trans. 1, 2002, 2613. (b) Banwell, M. G.; Lupton, D. W. Org. Biomol. Chem. 2005, 3, 213. (9) Saxton, J. E. Nat. Prod. Rep. 1996, 13, 327. (10) van Beek, T. A.; Lankhorst, P. P.; Verpoorte, R.; Baerheim, Svendsen, A. Tetrahedron Lett. 1982, 23, 4827. (11) Cava, M. P.; Tjoa, S. S.; Ahmed, Q. A.; Da Rocha, A. I. J. Org. Chem. 1968, 33, 1055. (12) (a) Atta-ur-Rahman, Sultana, M. Heterocycles 1984, 22, 841. (b) Node, M.; Nagasawa, H.; Fuji, K. J. Org. Chem. 1990, 55, 517. (13) Taylor, W. I., Farnsworth, N. R., Eds. The Vinca Alkaloids; Marcel Dekker: New York, 1973. 2792 J. Org. Chem. 2008, 73, 2792-2802 10.1021/jo8001003 CCC: $40.75 © 2008 American Chemical Society Published on Web 03/05/2008