Unspecific Peroxygenase Catalyzes Selective Remote‐Site Functionalizations

We describe the discovery of an unspecific peroxygenase (UPO) variant that catalyzes the remote‐site functionalization of halogenated and unsaturated hydrocarbons with high catalytic site‐specificity. UPOs are fungal heme‐thiolate biocatalysts with wide‐ranging oxidative activities, including C─H bond oxygenation, usually with limited regioselectivity. We describe here a wild‐type MroUPO, newly isolated in high yield from a previously uncharacterized strain of Marasmius rotula. This variant, MroUPO‐TN, catalyzes the selective oxygenation of a range of haloalkanes, cyclic haloalkanes and cyclic olefins to generate useful remote‐site haloketones. The regioselectivity for eight‐membered rings reaches 99% with significant enantiomeric excess. Mechanistic studies performed with deuterated substrates and 18O‐labeling experiments have revealed a synergy between intrinsic substrate properties and the highly aliphatic, heme active site. The observed selectivity offers routes to new and useful, bifunctional synthons and pharmacophores, thus providing practical ways to employ these natural and environmentally benign biocatalysts. The high‐yielding fungal peroxygenase, MroUPO‐TN, catalyzes the regioselective remote‐site functionalization of hydrocarbons, providing useful and new synthetic building blocks in an economical and sustainable process. Bromocyclooctane affords 4‐bromocyclooctanone in 80% yield, whereas 1‐haloalkanes are transformed into the corresponding ω‐1 haloketones. Deuterium labeling and 18O‐labeling experiments show that the selectivity for 4‐halocyclooctanones derives from selective, remote site oxygenation.