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Chemoenzymatic ortho-quinone methide formation

revised on 26.10.2019 and posted on 29.10.2019 by Tyler Doyon, Jonathan Perkins, Summer A. Baker Dockrey, Evan O. Romero, Kevin Skinner, Paul M. Zimmerman, Alison Narayan
Generation of reactive intermediates and interception of these fleeting species in a cascade is a common strategy employed by Nature. However, formation of these species under mild conditions using traditional synthetic techniques can present a challenge. Here, we demonstrate the utility of biocatalysis in generating ortho-quinone methide intermediates under aqueous conditions and at reduced temperatures. Specifically, we applied an α-ketoglutarate-dependent non-heme iron enzyme, CitB, in the selective modification of benzylic C–H bonds of ortho-cresol substrates to afford a benzylic alcohol product which, under the reaction conditions, is in equilibrium with the corresponding ortho-quinone methide. Interception of the ortho-quinone methide by a nucleophile or a dienophile allows for one-pot conversion of benzylic C–H bonds into C–C, C–N, C–O, and C–S bonds in a chemoenzymatic cascade.


T32 GM 008597

NIH R35GM128830


Email Address of Submitting Author


University of Michigan


United States

ORCID For Submitting Author


Declaration of Conflict of Interest

No conflict of interest

Version Notes

version 3.0