Diastereoselective Pictet-Spengler Based Synthesis of a Chiral Tetrahydroisoquinoline D1 Potentiator.

Abstract

A practical synthesis of a D1 potentiator chiral tetrahydroisoquinoline has been accomplished employing diastereoselective Pictet-Spengler methodology to access the required trans-stereochemistry. A dynamic kinetic resolution by crystallization gives high yields of a N-(phenylsulfonyl)alkyloxazolidinone that is converted to an acyl iminium ion when exposed to a variety of Lewis acids resulting in a highly diastereoselective Pictet-Spengler cyclization. An eight-step linear synthesis that starts with commercially available R-2-bromophenylalanine affords the chiral tetrahydroisoquinoline 1 in 54% overall yield.