The structural complexities and biological activities of naturally-occurring lactams have inspired organic chemists to devise new ways of synthesizing densely substituted lactam cores. Herein, we report the development of a practical, catalytic method for accessing structurally complex γ-lactams and symmetrically fused bis-γ-lactam cores from imines and 2,5-bis(trimethylsilyloxy)furan. By analogy to the anhydride Mannich reaction (AMR) and the Mukaiyama aldol reaction, we call this method the Mukaiyama AMR. In the presence of catalytic Lewis acid and a stoichiometric excess of imine electrophiles, the bis-silyl ketene acetal nucleophile performs sequential Mukaiyama Mannich additions, a transannular acylation, and an amidation to form bis-γ-lactams as a single diastereomer. Preliminary screens of bulkier disulfonimide catalysts show excellent selectivity for single Mannich addition lactam products. We envision that further optimization of these silicon Lewis acid precursors will impart enantioselectivity to the Mukaiyama AMR via asymmetric counteranion directed catalysis (ACDC). In order to demonstrate the utility of the Mukaiyama AMR, progress towards the total syntheses of lactam natural products is also reported.

Stereoselective synthesis of fused bis-γ-lactams by catalytic Mukaiyama Mannich reaction of imines and 2,5-bis(trimethylsilyloxy)furan

255th National Meeting (2018)

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