The bisected s-trans conformation-controlled highly stereoselective addition of Grignard reagents to C-cyclopropylaldonitrone. An efficient synthesis of 1-phenyl-2-[(S)-1-aminoalkyl]-N,N-diethylcyclopropanecarboxamides, a new class of potent NMDA receptor antagonists

Abstract

An efficient synthesis of 1-phenyl-2-[(S)-1-aminoethyl]- and 1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamides [1a (PEDC) and 1b (PPDC), respectively], potent NMDA receptor antagonists having a cyclopropane structure, was achieved. We have shown for the first time that C-cyclopropylaldonitrone preferentially exists in the bisected s-trans conformation, due to the characteristic stereoelectronic effects of the cyclopropane ring, by X-ray crystallographic analysis, NMR studies, and theoretical calculations. Based on these findings, the highly stereoselective addition reaction of Grignard reagents to C-cyclopropylaldonitrone 6 was developed, and the reaction was successfully used as the key step for the preparation of the NMDA receptor antagonists 1a and 1b as well as for a newly designed isopropyl-type congener 1c. The facial selectivity of the addition of Grignard reagents can be explained by the attack of the reagents from the less hindered side of the substrate in the predicted bisected s-trans conformation. This Grignard reaction is the first example of a highly stereoselective addition to a nitrone via a non-chelation controlled pathway.