A Linchpin Synthesis of 6-Hydroxyceramides from Aziridine Aldehydes.

A chemoselective N-oxidation/Meisenheimer rearrangement protocol was developed to generate vinylaziridine scaffolds from aziridine aldehydes. A subsequent Lewis acid-mediated aziridine ring opening with carboxylic acid nucleophiles followed by N-O bond cleavage furnishes a human skin 6-hydroxyceramide natural product in short order. The utility of this methodology is demonstrated by the preparation of a number of unnatural 6-hydroxyceramide analogues. This modular approach enables the expedient synthesis of poorly understood skin lipids, which may find application in therapeutics and cosmetics.