Molecular flavin catalysts for C–H functionalisation and derivatisation of dehydroamino acids

Abstract

In nature, the isoalloxazine heterocycle of flavin cofactors undergoes reversible covalent bond formation with a variety of different reaction partners. These intermediates play a crucial role inter alia as the signalling states and in selective catalysis reactions. In the organic laboratory, covalent adducts with a new carbon–carbon bond have been observed with photochemically excited flavins but have, so far, only been regarded as dead-end side products. We have identified a series of molecular flavins that form adducts resulting in a new C–C bond at the C4a-position through allylic C–H activation and dehydroamino acid oxidation. Typically, these reactions are of radical nature and a stepwise pathway is assumed. We could demonstrate that these adducts are no dead-end and that the labile C–C bond can be cleaved by adding the persistent radical TEMPO leading to flavin regeneration and alkoxyamine-functionalised substrates. Our method allows for the catalytic oxidation of dehydroamino acids (16 examples) and we show that the acylimine products serve as versatile starting points for diversification. The present results are envisioned to stimulate the design of further catalytic reactions involving intermediates at the flavin C4a-position and their reactivity towards metal complexes or other persistent organic radicals. Our method for dehydrobutyrine derivatisation is orthogonal to the currently used methods (i.e., nucleophilic attack or radical addition) and offers new perspectives for peptide natural product diversification.