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

Starting from tricyclic lactam 2, which is easily accessible by cyclocondensation of δ‐oxoester 1 with (R)‐phenylglycinol, a three‐step synthetic route to enantiopure 1‐substituted tetrahydroisoquinolines, including 1‐alkyl‐, 1‐aryl‐, and 1‐benzyltetrahydroisoquinoline alkaloids, as well as the tricyclic alkaloid (–)‐crispine A, has been developed. The key step is a stereoselective α‐amidoalkylation reaction using the appropriate Grignard reagent. Tricyclic (R)‐phenylglycinol‐derived lactam 2 has proven to be a versatile scaffold that provides general access to enantiopure 1‐substituted tetrahydroisoquinoline derivatives as well as more complex alkaloids, for example, (–)‐crispine A, bearing the tetrahydroisoquinoline moiety.