Chemoenzymatic one-pot process for the synthesis of tetrahydroisoquinolines

Abstract

1,2,3,4-Tetrahydyroisoquinolines form a valuable scaffold for a variety of bioactive second-ary metabolites and commercial pharmaceuticals. Due to the harsh or complex conditions of the con-ventional chemical synthesis of this molecular motif, alternative mild reaction pathways are in de-mand. Here we present an easy-to-operate chemoenzymatic one-pot process for the synthesis of tetra-hydroisoquinolines starting from benzylic alcohols and an amino alcohol. We initially demonstrate the oxidation of 12 benzylic alcohols by a laccase/TEMPO system to the corresponding aldehydes, which are subsequently integrated in a phosphate salt mediated Pictet–Spengler reaction with m-tyramine. The reaction conditions of both individual reactions were analyzed separately, adapted to each other, and a straightforward one-pot process was developed. This enables the production of 12 1,2,3,4-tetra-hydyroisoquinolines with yields of up to 87% with constant reaction conditions in phosphate buffer and common laboratory glass bottles without the supplementation of any additives.