(438c) Enantioselective Synthesis of (S)-1,2,3,4-Tetrahydroisoquinoline Carboxylic Acids Via D-Amino Acid Oxidase Mediated Chemo-Enzymatic Cascade Reaction

Optically pure 1,2,3,4-tetrahydroisoquinolines (THIQs) are an important class of building blocks for the synthesis of natural products and synthetic pharmaceuticals. Deracemization employing oxidoreductase is an attractive method to prepare chiral THIQs, because of its high yield and excellent enantioselectivity. However, current applications of this method are limited to the non-carboxyl substituted THIQs, such as 1-alkyl-, benzyl- and aryl- substituted THIQs. The preparation of chiral carboxyl-substituted THIQs is still challenging for the lack of suitable oxidoreductase.

Herein, a D-amino acid oxidase from Fusarium solani M-0718 (FsDAAO) with broad substrate scope and excellent enantioselectivity was exploited through genome mining. It was applied in the kinetic resolution of a number of racemic 1- and 3-carboxyl substituted THIQs with different substitutions on the phenyl ring to yield the corresponding (S)-enantiomers with excellent ee (up to >99%) for the first time. By using FsDAAO in combination with ammonia-borane in one-pot, deracemization of these racemic carboxyl-substituted THIQs was achieved with conversions up to >98% and >99% ee. Noteworthily, preparative-scale deracemization of racemic 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid and 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid was demonstrated with good yield (82% and 73%, respectively) and ee >99%. Our study provides a novel and general method for the synthesis of enantiomeric pure 1,2,3,4-tetrahydroisoquinoline carboxylic acids. This method is expected to provide access to chiral carboxyl-substituted 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydro-ß-carbolines.