Studies in asymmetric β-lactone synthesis: extensions of the chiral nucleophile catalyzed aldol-lactonization (NCAL) reaction and new transformations of chlorinated β-lactones

Abstract

Expansion of Wynberg's procedure for the asymmetric synthesis of β-lactones has been extended to the use of in situ generated ketene. Reaction with dichlorinated aldehydes in the presence of quinidine yielded β-lactone products in good yield (40-85%) and excellent enantioselectivity (93-98% ee). The first nucleophile catalyzed aldol-lactonization (NCAL) reaction with unactivated aldehydes was also developed leading to novel β-lactone fused carbocycles. The racemic bicyclic β-lactones were obtained in moderate yield (36-68%) employing Et₃N as the nucleophile. Employing quinidine as the nucleophilic catalyst provided a bicyclic β-lactone in excellent enantioselectivity (90% ee). Several transformations of the resulting optically active dichlorinated β-lactones were accomplished to further extend the utility of these products. In addition, 4-(trichloromethyl)-2-oxetanone was transformed into a variety of amino acid precursors. The first synthesis of the natural amino acid, 2-amino-5-methyl-6-hydroxyhex-4-enoic acid was accomplished employing this amino acid synthon derived from 4-(trichloromethyl)-2-oxetanone.