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

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.