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.

Keywords

• 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid
• Petasis reaction
• Pomeranz–Fritsch–Bobbitt cyclization
• 3,5-substituted 1,4-oxazin-2-one