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Enantioselective construction of quaternary N-heterocycles by palladium-catalysed decarboxylative allylic alkylation of lactams

Abstract

The enantioselective synthesis of nitrogen-containing heterocycles (N-heterocycles) represents a substantial chemical research effort and resonates across numerous disciplines, including the total synthesis of natural products and medicinal chemistry. In this Article, we describe the highly enantioselective palladium-catalysed decarboxylative allylic alkylation of readily available lactams to form 3,3-disubstituted pyrrolidinones, piperidinones, caprolactams and structurally related lactams. Given the prevalence of quaternary N-heterocycles in biologically active alkaloids and pharmaceutical agents, we envisage that our method will provide a synthetic entry into the de novo asymmetric synthesis of such structures. As an entry for these investigations we demonstrate how the described catalysis affords enantiopure quaternary lactams that intercept synthetic intermediates previously used in the synthesis of the Aspidosperma alkaloids quebrachamine and rhazinilam, but that were previously only available by chiral auxiliary approaches or as racemic mixtures.

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Figure 1: Natural products and pharmaceuticals containing chiral N-heterocycles.
Figure 2: Solvent, N-substituent-group and ligand screen.
Figure 3: Scope of palladium-catalysed decarboxylative alkylation of lactams.
Figure 4: Utility of the lactam products.

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Acknowledgements

This publication is based on work supported by award from the King Abdullah University of Science and Technology (KAUST; no. KUS-11-006-02). The authors thank NIH-NIGMS (R01GM080269-01 and a postdoctoral fellowship to D.E.W.), the Gordon and Betty Moore Foundation, Amgen, Abbott, Boehringer Ingelheim and Caltech for financial support. T.Y. acknowledges the Japan Society for the Promotion of Science for a predoctoral fellowship.

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D.C.B., Y.L., T.Y. and J.K. planned and carried out the experimental work. D.C.B., T.Y., D.E.W. and S.C.V. took part in the initial reaction development and screening experiments. B.M.S. conceived, initiated and directed the project and wrote the manuscript. All authors commented on the manuscript.

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Correspondence to Brian M. Stoltz.

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Behenna, D., Liu, Y., Yurino, T. et al. Enantioselective construction of quaternary N-heterocycles by palladium-catalysed decarboxylative allylic alkylation of lactams. Nature Chem 4, 130–133 (2012). https://doi.org/10.1038/nchem.1222

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