American Chemical Society
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Visible Light-Mediated, Diastereoselective Epimerization of Morpholines and Piperazines to More Stable Isomers

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journal contribution
posted on 2022-10-10, 16:05 authored by Zican Shen, María A. Vargas-Rivera, Elizabeth L. Rigby, Shuming Chen, Jonathan A. Ellman
We report a photocatalyzed epimerization of morpholines and piperazines that proceeds by reversible hydrogen atom transfer (HAT) and provides an efficient strategy for editing the stereochemical configurations of these saturated nitrogen heterocycles, which are prevalent in drugs. More stable morpholine and piperazine isomers are obtained from the more synthetically accessible but less stable stereoisomers, and a broad scope is demonstrated in terms of substitution patterns and functional group compatibility. The observed distributions of diastereomers correlate well with the relative energies of the diastereomer pairs as determined by density functional theory (DFT) calculations. Mechanistic studies, including luminescence quenching, deuterium labeling reactions, and determination of reversibility support a thiyl radical-mediated HAT pathway for the epimerization of morpholines. Investigation of piperazine epimerization established that the mechanism is more complex and led to the development of thiol-free conditions for the highly stereoselective epimerization of N,N′-dialkyl piperazines for which a previously unrecognized radical chain HAT mechanism is proposed.