Flavin Hydroperoxide and Semiquinone: Structures and Biomimetic Activity

Abstract

Flavins are unique natural redox cofactors that can switch between an oxidized, a radical half-reduced, and a fully reduced state. In nature, the interplay between these redox states is orchestrated by the surrounding flavoenzymes and unlocks a myriad of unique chemical transformations. One of the most archetypical flavin properties is the activation of molecular oxygen from air by the reduced cofactor, which proceeds via the half-reduced semiquinone radical and leads to a flavin hydroperoxide, the key species in flavin-mediated oxygenations. While central to many natural and biomimetic catalytic processes, both flavin semiquinone and hydroperoxide are transient reactive species and, therefore, have so far evaded structural characterization at the molecular level, including single-crystal diffraction. We close this gap and disclose solid-state structures of both isolated key intermediates, linking their reactivity to enzymatic transformations. The biomimetic oxygenation of tetrahydrocarbazoles, which constitute the core structure of many biologically active natural products, was achieved in high yields using a flavin hydroperoxide. Orthogonal activation of the same substrates was achieved by embedding the flavin semiquinone in a catalytic cycle. A total of seven distinct product classes were accessed, all resembling structures occurring in natural products. Our findings clearly link the reactivity of isolated flavin species to well-studied flavoenzymes. We expect these results to promote the application of flavin catalysts as oxygenation agents at both laboratory and industrial scales.