Synthesis and X‐ray crystal structures of chiral, nonracemic 5,6‐dihydro‐4H‐1,3,4‐oxadiazines

Abstract

A series of chiral, nonracemic oxadiazines have been prepared from (1R,2S)-ephedrine, (1R,2S)-norephedrine, and L-phenylalaninol. The synthesis of the Ephedra-based oxadiazines was accomplished by a process of N-nitrosation, reduction, acylation, and acid-catalyzed cyclization. The trans-and cis-diastereomeric oxadiazines derived from (1R,2S)-ephedrine were analyzed by 1 H NMR spectroscopy and by single crystal X-ray crystallographic analysis. The stereochemistry of the (1R,2S)-norephedrine-derived oxadiazines was assigned based on 1 H NMR spectroscopy and by analogy with the X-ray crystal structure of the (1R,2S)-ephedrine-based oxadiazines. In addition, L-phenylalaninol was used as a template to prepare a series of oxadiazines substituted at the N 4 -nitrogen with an isopropyl group. This was accomplished by a reductive alkylation of L-phenylalaninol with acetone and subsequent hydrazide formation. These hydrazides were reacted with methanesulfonyl chloride to yield the corresponding oxadiazines by a base-mediated cyclization.