Endoperoxide containing drugs such as artemisinin are the frontline treatment for malaria. Unfortunately malaria parasites are developing resistance to current antimalarial drugs and new classes of theraputics are needed. 1,2,4-dioxazinanes are a relatively unknown heterocycle that has potential biological activity. We report the diastereoselective synthesis of 1,2,4-dioxazinanes via a catalyst free, one-pot cascade reaction. A wide range of peroxyquinols, aldehydes and amines were successfully combined to create novel 1,2,4-dioxazinanes as single diastereomers in high yields. The reaction mechanism is proposed to proceed via peroxyhemiaminal formation followed by an aza-Michael desymmetrization reaction. These novel 1,2,4-dioxazinanes show cytotoxicity towards a number of cancer cell lines.

Synthesis of 1,2,4-dioxazinanes via aza-Michael desymmetrization

253rd National Meeting (2017)

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