The present report describes a stereoselective synthesis of 1,4-dihydro-4-phenyl isoquinolinones 5 based on a stereoselective Friedel–Crafts type cyclization. Cyclization precursors 1 were prepared in two steps, from the readily available (S)-mandelic acid, in 60–80% overall yield. The stereoselective electrophilic cyclization was accomplished in 20–86% yield and with 20–97% ee. In the course of this work, the presence of the amide carbonyl was found to be particularly important to guarantee a stereospecific process during the electrophilic aromatic substitution.

Highly diastereoselective protonation of chiral lactam enolates of 4-substituted-1,4-dihydroisoquinolin-3-ones is reported. Protonation and alkylation processes of these lactam enolates derived from phenylglycinol occur with opposite diastereofacial selectivity. This diastereoselective protonation has been applied to the asymmetric synthesis of (4S)-N-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline 9 obtained in up to 97% ee.

Enantiomerically pure 1,4-dihydroisoquinolin-3-one 1 was prepared in four steps with an overall yield of 60%. Alkylation of the corresponding lactam enolate has been studied and has proven to be highly diastereoselective. Thus, 4-substituted-1,4-dihydroisoquinolin-3-ones 7a-d were obtained in high chemical yields with up to 97% diastereoisomeric excesses.