Synthesis of (R)- and (S)-2,3-methanovaline as the hydrochloride salts, through manipulation of the N-phthaloyl group of an (S)-leucine derivative for the recall of stereochemistry

Abstract

(S)-N-Phthaloyl-4-bromoleucine methyl ester was prepared from (S)-leucine. Treatment of the phthalimide with sodium borohydride in methanol gave the corresponding diastereomeric α-methoxyamides. The new stereochemical centre gave rise to diastereoselectivity in the base-induced cyclisation of the methoxyamides. It was also exploited to distinguish and separate the stereoisomers of the methanovaline derivatives produced in those reactions. Deprotection of the cyclised species then completed the synthesis of the hydrochloride salts of the enantiomers of methanovaline, illustrating the way in which an N-phthaloyl protecting group may be manipulated to recall the stereochemistry of an α-amino acid in asymmetric synthesis.