Diastereoselective Synthesis of (–)-6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic Acid via Morpholinone Derivatives

Abstract

A simple and convenient synthesis of (-)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is described, applying a combination of two synthetic methods: the Petasis reaction and Pomeranz-Fritsch-Bobbitt cyclization. The diastereomeric morpholinone derivative N-(2,2-diethoxyethyl)-3-(3,4-dimethoxyphenyl)-5-phenyl-1,4-oxazin-2-one formed in the Petasis reaction was further transformed into 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid via Pomeranz-Fritsch-Bobbitt cyclization, a classical method of synthesis leading to the tetrahydroisoquinoline core. We review important examples of applications of the Pomeranz-Fritsch process and its modifications in the synthesis of chiral tetrahydroisoquinoline derivatives that have been published in the past two decades.