Intermolecular carbene S-H insertion catalysed by engineered myoglobin-based catalysts

The first example of a biocatalytic strategy for the synthesis of thioethers via an intermolecular carbene S-H insertion reaction is reported. Engineered variants of sperm whale myoglobin were found to efficiently catalyze this C-S bond forming transformation across a diverse set of aryl and alkyl mercaptan substrates and alpha-diazoester carbene donors, providing high conversions (60-99%) and high numbers of catalytic turnovers (1100-5400). Furthermore, the enantioselectivity of these biocatalysts could be tuned through mutation of amino acid residues within the distal pocket of the hemoprotein, leading to myoglobin variants capable of supporting asymmetric S-H insertions with up to 49% ee. Rearrangement experiments support a mechanism involving the formation of a sulfonium ylide generated upon attack of the thiol substrate to a heme-bound carbene intermediate.