Methods for rapid preparation of densely functionalized and stereochemically complex N-heterocyclic scaffolds are in demand for exploring potential bioactive chemical space. This work describes experimental and computational studies to better understand the features of aziridinium ylides as intermediates for the synthesis of highly substituted dehydromorpholines. The development of this chemistry has enabled the extension of aziridinium ylide chemistry to the concomitant formation of both a C-N and a C-O bond in a manner that preserves the stereochemical information embedded in the substrate. Additionally, we have uncovered several key insights that describe the importance of steric effects, rotational barriers around the C-N bond of the aziridinium ylide, and non-covalent interactions (NCIs) on the ultimate reaction outcome. These critical insights will assist in the further development of this chemistry to generate N-heterocycles that will further expand complex amine chemical space.
Keywords: aziridine; aziridinium ylide; carbene; morpholine; non-covalent interactions; tunability.