Aziridine–Epoxide Heterocoupling: A Straightforward Approach to Stereoselective Synthesis of Complex Morpholine Derivatives

The morpholine motif is valued in medicinal chemistry, but C-substituted morpholine derivatives remain challenging to access. Here we report a general strategy to address that challenge: annulative heterocoupling of aziridines and epoxides to synthesize highly substituted, N-unprotected morpholine derivatives via aziridinyl alcohols. Due to the accessibility of complex, stereodefined aziridines and epoxides, this approach allows for facile and combinatorial synthesis of substituted morpholine derivatives with handles for further elaboration. Stereochemical outcomes are dictated by the preset stereogenic centers in the strained-ring coupling partners. Our method expands access to morpholine derivatives bearing multiple substituents α to oxygen and densely substituted morpholine derivatives bearing up to six C substituents. Moreover, our formal 3 + 3 synthetic approach can be used to join two complex molecules through the carbon atoms of a morpholine ring, affording rapid access to diverse molecular skeletons for use in medicinal chemistry and diversity-oriented synthesis.