Hemoproteins have recently emerged
as promising biocatalysts for
promoting a variety of carbene transfer reactions including cyclopropanation
and Y–H insertion (Y = N, S, Si, B). For these and synthetic
carbene transfer catalysts alike, achieving high chemoselectivity
toward cyclopropanation in olefin substrates bearing unprotected Y–H
groups has proven remarkably challenging due to competition from the
more facile carbene Y–H insertion reaction. In this report,
we describe the development of a novel artificial metalloenzyme based
on an engineered myoglobin incorporating a serine-ligated Co-porphyrin
cofactor that is capable of offering high selectivity toward olefin
cyclopropanation over N–H and Si–H insertion. Intramolecular
competition experiments revealed a distinct and dramatically altered
chemoselectivity of the Mb(H64V,V68A,H93S)[Co(ppIX)] variant in carbene
transfer reactions compared to myoglobin-based variants containing
the native histidine-ligated heme cofactor or other metal/proximal
ligand substitutions. These studies highlight the functional plasticity
of myoglobin as a “carbene transferase” and illustrate
how modulation of the cofactor environment within this metalloprotein
scaffold represents a valuable strategy for accessing carbene transfer
reactivity not exhibited by naturally occurring hemoproteins or transition
metal catalysts
