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Cooperative catalysis by carbenes and Lewis acids in a highly stereoselective route to γ-lactams

Nature Chemistry volume 2, pages 766–771 (2010)Cite this article

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Abstract

Enzymes are a continuing source of inspiration for the design of new chemical reactions that proceed with efficiency, high selectivity and minimal waste. In many biochemical processes, different catalytic species, such as Lewis acids and bases, are involved in precisely orchestrated interactions to activate reactants simultaneously or sequentially. This type of ‘cooperative catalysis’, in which two or more catalytic cycles operate concurrently to achieve one overall transformation, has great potential in enhancing known reactivity and driving the development of new chemical reactions with high value. In this disclosure, a cooperative N-heterocyclic carbene/Lewis acid catalytic system promotes the addition of homoenolate equivalents to hydrazones, generating highly substituted γ-lactams in moderate to good yields and with high levels of diastereo- and enantioselectivity.

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Figure 1: Opportunities with NHCs and metals.
Figure 2: Cooperative catalysis between a Lewis acid and an NHC.
Figure 3: N–N bond cleavage and further functionalization.

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Acknowledgements

Support for this work was generously provided by National Institute of General Medical Sciences (RO1 GM73072), GlaxoSmithKline, AstraZeneca and the Alfred P. Sloan Foundation. B.C.D. thanks the Fonds Quebecois de la Recherche sur la Nature et les Technologies for a postdoctoral fellowship. Funding for the Northwestern University Integrated Molecular Structure Education and Research Center (IMSERC) has been furnished in part by the National Science Foundation (CHE-9871268). T. Reynolds and J. Roberts provided X-ray crystallography support.

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  1. Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, 60208, Illinois, USA

    Dustin E. A. Raup, Benoit Cardinal-David, Dane Holte & Karl A. Scheidt

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Contributions

K.A.S. conceived the idea and wrote the manuscript. D.E.A.R., B.C.-D. and D.H. performed the experiments. All the authors analysed the data. K.A.S., D.E.A.R. and B.C.-D contributed to discussions and edited the manuscript.

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Correspondence to Karl A. Scheidt.

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Raup, D., Cardinal-David, B., Holte, D. et al. Cooperative catalysis by carbenes and Lewis acids in a highly stereoselective route to γ-lactams. Nature Chem 2, 766–771 (2010). https://doi.org/10.1038/nchem.727

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