Piperidines are an important class of heterocycles, and constitute a privileged core in bioactive sp3–rich frameworks such as alkaloid natural products. Whilst there are many routes towards these compounds, a strategy that would provide a variety of skeletally distinct analogs from simple starting materials would be highly desirable. In this work, a readily available cyclic carbamate functions as a general precursor to a range of functionalized piperidine products via a new Pd-catalyzed annulation reaction of activated carbonyl compounds. Structural diversity in the final products is derived from the type of substrate employed and monocyclic, bicyclic and spirocyclic piperidines are generated from simple β-keto esters. An asymmetric variant utilizes privileged phosphoramidite ligands and provides a rapid and efficient means to access these heterocycles with high to excellent levels of enantiocontrol. Finally, these richly functionalized compounds are amenable to further chemoselective elaboration, including an unprecedented Rh-catalyzed, imine-directed C-H amidation.

Pd-catalyzed synthesis of highly functionalized piperidines

254th National Meeting (2017)

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