Total asymmetric syntheses of (1S,2S)-norcoronamic acid, and of (1R,2R)- and (1S,2S)-coronamic acids from the diastereoselective cyclization of 2-(N-benzylideneamino)-4-chlorobutyronitriles

Abstract

(3R)-2-(N-Benzylideneamino)-4-chloro-3-methylbutyronitrile 3, prepared from the commercially available methyl (2S)-3-hydroxy-2-methyl propionate 5 (96% ee), readily underwent potassium carbonate induced cyclization to provide, after acid hydrolysis (6 N HCl) and chromatography, the (1S,2S)-norcoronamic acid 1a with 88% diastereoselectivity and > 95% enantiomeric excess. From (2R)-2-(hydroxymethyl)butyl acetate 23 (> 88% ee) obtained by enzymatic enantioselective hydrolysis with lipase PS, was prepared the (3S)-2-(N-benzylideneamino)-3-(chloromethyl)valeronitrile 29, which after base-induced cyclization (K2CO3) and acid (6 N HCl) or basic (0.8 N NaOH) hydrolysis led to the non-natural (1R,2R)-coronamic acid 18 (> 88% ee). Also from this same acetate (2R)-23 was prepared the (3R)-3-(chloromethyl)-2-[(diphenylmethylene)amino]pentanenitrile 37, which provided the (1S,2S)-coronamic acid 17 (> 88% ee) after base-induced cyclization (K2CO3 or LDA) and acid hydrolysis (6 N HCl). It is noteworthy that these short synthetic sequences, which do not require any expensive chiral auxiliary or optically active precursors, do not alter the enantiomeric purity of the stereogenic centers of these 2,3-methanoamino acids. However, the E diastereoselectivity of these cyclizations was not improved by using bulky N-(diphenylmethylene)amino substituent, contrary to results of some molecular mechanic calculations (MAD).