A General Methodology for the Enantioselective Synthesis of 1-Substituted Tetrahydroisoquinoline Alkaloids

Starting from tricyclic lactam 2, which is easily accessible by cyclocondensation of delta-oxoester 1 with (R)-phenylglycinol, a three-step synthetic route to enantiopure 1-substituted tetra-hydroisoquinolines, including 1-alkyl-, 1-aryl-, and 1-benzyl-tetrahydroisoquinoline alkaloids, as well as the tricyclic alkaloid (-)-crispine A, has been developed. The key step is a stereoselective alpha-amidoalkylation reaction using the appropriate Grignard reagent.