Stereoselective Synthesis of Morpholine Derivatives by Aziridine-Epoxide Heterocoupling

Stereoselective Synthesis of Morpholine Derivatives by Aziridine-Epoxide Heterocoupling

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Morpholine derivatives have properties that are desirable in medicinal chemistry, and this motif has been applied in anti-cancer, anti-inflammatory, anti-viral, and anti-hyperlipidemic drugs. However, the stereocontrolled synthesis of substituted morpholines remains challenging. The Delaney lab has developed a modular synthesis of morpholine derivatives based on heterocoupling of aziridines and epoxides. The approach involves two-steps: the selective addition of an aziridine to an epoxide to form an aziridine-alcohol, and an acid-mediated cyclization of the aziridinyl alcohol to form a morpholine. We hypothesized that the cyclization reaction proceeds by an SN1 mechanism, and that a phenyl group on the aziridine stabilizes a carbocationic intermediate. To test this hypothesis, substituted phenyl aziridine derivatives with differing electronic ring character were synthesized and submitted to the acid-mediated cyclization process. Mechanistic insights and yields resulted from these studies will be presented.