Preparation of fused beta-lactams through Weinreb amide alpha-anions

Graphical Abstract Preparation of fused ‐lactams through Weinreb amide ‐anions William M. Hewitt, Michael Egger † , Nathaniel B. Zuckerman ‡ and Joseph P. Konopelski* Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064 USA † Present address: tesa SE, Quickbornstr. 24, 20253 Hamburg, Germany ‡ Present address: Lawrence Livermore National Laboratory, 7000 East Avenue #283, Livermore, CA 94551 USA Abstract: Enantiomerically pure ‐lactams bearing a Weinreb amide functionality at the C3 position have been shown to be excellent substrates for ‐alkylation reactions, generating C3 quaternary centers with predictable absolute stereochemistry. In addition, oxidative coupling of C3/C4 dianions affords entry to fused ,‐bislactam systems. Introduction Azetidin‐2‐ones (‐lactams) are among the most highly investigated heterocyclic ring systems. Beyond the obvious impact on antibiotic research and treatment, 1 ‐lactams have expressed biological activity in cholesterol absorption 2 and as a target of viral proteases. 3 As synthetic organic reagents, 4,5 ‐lactams offer a well‐defined stereochemical relationship between the adjacent sp 3 centers and an amide carbonyl that is reactive by virtue of the 4‐membered ring strain. In peptide chemistry ‐lactams have been employed as turn mimics 6,7 and as precursors to ‐amino acids 8,9 and their related polymers 10 (‐ foldamers 11,12 ) that have been the focus of much study. New synthetic methods for the preparation of this ring system continue to appear in the literature with great frequency. 13,14 Recently, we presented a new route to enantiomerically pure (EP) ‐lactams, such as 1 and 2, from readily available ‐amino acids in a process that is efficient both in the use of photochemistry for the key reaction and in the dearth of chromatographic separations (Scheme 1). 15 In addition, the ‐lactam Weinreb amide functionality is able to effectively undergo reactions with Grignard and alkyllithium reagents without opening of the ‐lactam ring due to the steric presence of the N‐Tr group. Herein we report our continuing studies on this ‐lactam system, with the goal of articulating reaction pathways toward synthetic building blocks offering myriad (orthogonal) functionalities around the EP four‐ membered ring. The specific focus of the present studies was on functionalization of the C3 center. In particular, we have found that alkylation reactions occur with predictable stereochemistry at this activated carbon. In addition, we present our results on the oxidative coupling of the dianion formed