Synthetic cascades are enabled by combining biocatalysts with artificial metalloenzymes

Enzymic catalysis and homogeneous catalysis offer complementary means to address synthetic challenges, both in chem. and in biol.  Despite its attractiveness, the implementation of concurrent cascade reactions that combine an organometallic catalyst with an enzyme has proven challenging because of the mutual inactivation of both catalysts.  To address this, we show that incorporation of a d6-piano stool complex within a host protein affords an artificial transfer hydrogenase (ATHase) that is fully compatible with and complementary to natural enzymes, thus enabling efficient concurrent tandem catalysis.  To illustrate the generality of the approach, the ATHase was combined with various NADH-, FAD- and haem-dependent enzymes, resulting in orthogonal redox cascades.  Up to three enzymes were integrated in the cascade and combined with the ATHase with a view to achieving (i) a double stereoselective amine deracemization, (ii) a horseradish peroxidase (HRP)-coupled readout of the transfer hydrogenase activity towards its genetic optimization, (iii) the formation of L-pipecolic acid from L-lysine, and (iv) regeneration of NADH to promote a monooxygenase-catalyzed oxyfunctionalization reaction