Bifunctional Asymmetric Catalysis: A Tandem Nucleophile/Lewis Acid Promoted Synthesis of -Lactams Stefan France, Harald Wack, Ahmed M. Hafez, Andrew E. Taggi, Daniel R. Witsil, and Thomas Lectka* Department of Chemistry, Johns Hopkins UniVersity, 3400 North Charles Street, Baltimore, Maryland 21218 lectka@jhunix.hcf.jhu.edu Received March 1, 2002 ABSTRACT We describe a superior procedure for the catalytic, asymmetric synthesis of -lactams using a bifunctional catalyst system consisting of a chiral nucleophile and an achiral Lewis acid. Bifunctional catalysis, in particular the combination of a Lewis acid working in tandem with a Lewis base or nucleophile, has been an appealing goal in organic chemistry for many years. Although bifunctional metal/organic systems always look good in theory, very often they do not function as intended. One of the most common reasons is the interference of a self-quenching reaction in which the Lewis base and Lewis acid combine to form a catalytically inactive adduct. In the past few years, however, considerable progress has been made in the development of bifunctional systems for organic synthesis wherein a weak Lewis base is used to work in concert with a Lewis acid. 1 Recently, a bifunctional system for the acceleration of the Baylis-Hillman reaction was reported wherein the authors combined a metal salt with a catalytic nucleophile, such as dabco. 2 Remarkably, the nucleophile and Lewis acid proved to be compatible with each other under the conditions of the reaction. In this contribution, we wish to report a system in which an achiral Lewis acid works in concert with a chiral nucleophile to effect a highly enantio- and diastereoselective catalytic reaction (Scheme 1). We hope that our results will point the way to the design of new systems for asymmetric catalysis with practical benefit for selectivity and yield. We have published several studies on the catalytic, asymmetric synthesis of -lactams, where we exploit a catalyzed reaction of nucleophilic ketenes and electrophilic imines 3 developed in our labs. 4 The enantioselectivity of this reaction is dependent on the use of a chiral nucleophile (in particular various synthetic cinchona alkaloid derivatives 5a,b). The major limitation of this protocol has been the (1) (a) Groger H. Chem. Eur. J. 2001, 7, 5247-5251. (b) Rowlands, G. J. Tetrahedron 2001, 57, 1865-1882. (c) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1236-1256. (d) Steinhagen, H.; Helmchen, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 2339-2342. For an example of Lewis acid/Brønsted acid bifunctional catalysis, see: (e) Josephsohn, N. S.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 11594-11599. (2) Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R. J. Org. Chem. 2002, 67, 510-514. (3) As a result of this role reversal, this process is mechanistically distinct from the classical Staudinger reaction. ORGANIC LETTERS 2002 Vol. 4, No. 9 1603-1605 10.1021/ol025805l CCC: $22.00 © 2002 American Chemical Society Published on Web 04/09/2002