Diastereoselective Construction of Quaternary Carbons Directed via Macrocyclic Ring Conformation: Formal Synthesis of (-)-Mesembrine Steve Arns, Marie-Eve Lebrun, Christiane M. Grise ´, Irina Denissova, and Louis Barriault* Department of Chemistry, UniVersity of Ottawa, 10 Marie-Curie, Ottawa, Ontario, Canada K1N 6N5 lbarriau@uottawa.ca ReceiVed August 27, 2007 In this article, we report a highly diastereoselective new method for the generation of quaternary carbon centers through an anionic oxy-Cope/alkylation sequence where the diastereoselectivity is induced by the conformation of a macrocyclic tetrasubstituted enolate. The use of our methodology culminated in the formal total synthesis of (-)-mesembrine (34) in 11 steps from known starting materials. Introduction The task of constructing quaternary carbon centers has been and still is one of the most challenging problems faced in organic chemistry, particularly when it is necessary to synthesize these centers with high enantio- or diastereoselectivity. Quaternary carbon centers are prevalent throughout most classes of natural products and pharmaceutical agents; hence, it is to be expected that there are numerous ingenious methods that have been developed to selectively access this structural motif. 1 Despite these advances, the solution to this far-reaching problem has not been completely resolved. One time-honored method used for the construction of quaternary centers is the alkylation of a tetrasubstituted enolate. Classically, the selectivity of this reaction can be achieved through the use of a chiral auxiliary or some other structural feature of the molecule that shields one face of the enolate from electrophilic attack, allowing the production of one diastereomer. Metal catalysis using chiral ligands has also been used to promote the diastereoselective addition of electrophiles to tetrasubstituted enolates. 1g During the course of our investigations into cascading pericyclic reactions, we became interested in how the conforma- tion of the macrocyclic intermediates in these processes dictated the stereochemical outcome of the reactions. 2 Keeping true to this theme, we wondered whether or not macrocyclic conforma- tion could be used to control the diastereoselectivity in other types of reactions, for example, the alkylation of tetrasubstituted enolates. We thought that, if we could generate a chiral tetrasubstituted enolate embedded in a macrocycle that was conformationally constrained, we would be able to stereoselectively construct quaternary carbon centers upon the addition of various elec- trophiles. 3,4 To obtain high selectivity in this process, several criteria must be met. First, it is of paramount importance to control the geometry of the tetrasubstituted enolate. To this end, (1) For recent reviews, see: (a) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (b) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005, 347, 1473. (c) Quaternary Stereocenters: Challenges and Solutions for Organic Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim, Germany, 2005. (d) Ramon, D. J.; Yus, M. Curr. Org. Chem. 2004, 8, 149. (e) Douglas, C. J.; Overmann, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363. (f) Barriault, L.; Denissova, I. Tetrahedron 2003, 59, 10105. (g) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688. (h) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591. (i) Corey, E. J.; Guzman- Perez, A. Angew. Chem., Int. Ed. 1998, 110, 402. (2) (a) Gauvreau, D.; Barriault, L. J. Org. Chem. 2005, 70, 1382. (b) Sauer, E. L. O.; Barriault, L. J. Am. Chem. Soc. 2004, 126, 8569. (c) Sauer, E. L. O.; Hooper, J.; Woo, T.; Barriault, L. J. Am. Chem. Soc. 2007, 129, 2112. (3) Pioneering work of Still demonstrated that the conformation of medium and large macrocycles affords an effective vehicle in which the asymmetric synthesis of stereogenic centers can be achieved. See: (a) Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981. (b) Still, W. C. J. Am. Chem. Soc. 1977, 99, 4186. (c) Still, W. C. J. Am. Chem. Soc. 1979, 101, 2493. (d) Still, W. Curr. Trends Org. Synth., Proc. Int. Conf. 4th 1983, 233. (e) Still, W. C.; Murata, S.; Revial, G.; Yoshihara, K. J. Am. Chem. Soc. 1983, 105, 625. (f) Still, W. C.; Novack, V. J. J. Am. Chem. Soc. 1984, 106, 1148. (g) Still, W. C.; Romero, A. G. J. Am. Chem. Soc. 1986, 108, 2105. (4) von Zezschwitz, P.; Voight, K.; Noltemeyer, M.; de Meijere, A. Synthesis 2000, 1327. 9314 J. Org. Chem. 2007, 72, 9314-9322 10.1021/jo701833v CCC: $37.00 © 2007 American Chemical Society Published on Web 10/24/2007