Asymmetric Conjugate Addition Reactions With Chiral Oxadiazinones: Unusual Conformational Properties Of The Oxadiazinones

A series of Ephedra based oxadiazinones have been prepared, acylated, and examined in the asymmetric conjugate addition reaction with Grignard reagents in the presence of copper(I) bromide-dimethyl sulfide complex. The highest diastereoselectivity that was obtained in the conjugate addition reaction was observed with the (1R,2S)-ephedrine based N-4-methyloxadiazinone (5:1 d.r.) favoring the formation of the (S)-configuration of the conjugate addition product. Efforts to enhance the level of diaster-eoselection via increasing the steric volume of the stereo-directing N-4-substituent of the oxadiazinone (N-4- = p-methoxyphenyl or -isopropyl) led to an observed decrease in the level of diastereoselection. A computational study was conducted to examine the conformations adopted by the N-4-methyloxadiazinone vs. the N-4-isopropyl-oxadiazinone that yielded the lower diastereoselectivity. An argument is made for the stereoelectronic properties of the N-4-substituent being the cause of both the moderate diastereoselectivity and the unexpected facial preference for the conjugate addition. (C) 2021 Elsevier Ltd. All rights reserved.