Stereoselective oxidative C3–N bond dehydrogenation and aromatization of 1-carboxyl substituted tetrahydroisoquinolines employing pipecolate oxidase

Abstract

The dehydrogenation of C–N bond in 1,2,3,4-tetrahydroisoquinolines (THIQs), especially 1-substituted THIQs, is a type of fascinating transformation owing to its utility in synthetic organic chemistry. Yet, the existing reports are limitedly known as C1–N semi-dehydrogenation and dehydroaromatization. Herein, we describe a biocatalytic strategy for stereoselective oxidative C3–N dehydrogenation and aromatization of 1-substituted THIQs. This redox biotransformation enables the efficient kinetic resolution of a range of racemic 1-carboxyl substituted THIQs by employing a putative pipecolate oxidase from Schizosaccharomyces octosporus yFS286 (SoPIPOX), providing straightforward access to aromatized isoquinolines and unreacted (R)-enantiomers with excellent enantioselectivity and regioselectivity under mild conditions. Mechanistic studies reveal that the SoPIPOX-mediated successive dehydrogenation process proceeds via the initial unusual C3–N dehydrogenation followed by spontaneous further dehydrogenative aromatization of the resultant imine intermediate. This work lays the foundation for repurposing pipecolate oxidase for the synthesis of versatile N-heterocycles analogues.