posted on 2022-10-10, 16:05authored byZican 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.