Molecular Editing of Flavins for Catalysis

Abstract

The diverse activity of flavoenzymes in organic transformations has fascinated researchers for a long time. However, when applied outside an enzyme environment, the isolated flavin cofactor only shows largely reduced activity. This highlights the importance of embedding the reactive flavin’s isoalloxazine core in defined surroundings. The latter include crucial non-covalent interactions with amino acid side chains or backbone as well as controlled access to reactants such as molecular oxygen. Nevertheless, molecular flavins are increasingly applied in the organic laboratory as valuable organocatalysts. Chemical modification of the parent isoalloxazine structure is of particular interest in this context in order to achieve reactivity and selectivity in transformations, which are so far only known with flavoenzymes or even unprecedented. This review aims to give a systematic overview of the reported designed flavin catalysts and highlights the impact of each structural alteration. It is intended to serve as a source of information when comparing the performance of known catalysts, but also when designing new flavins. Over the last decades, molecular flavin catalysis has emerged from proof-of-concept reactions to increasingly sophisticated transformations. This stimulates anticipating new flavin catalyst designs for solving contemporary challenges in organic synthesis.

Reduced Molecular Flavins as Single-Electron Reductants after Photoexcitation

“…The general usefulness of reduced flavin catalysts is highlighted by recent reductive catalytic reactions with flavoenzymes and a deazaflavin . We found it remarkable that in organic synthesis molecular flavins are extensively applied for oxidations, for example, using commercially available (−)-riboflavin, but they are not applied for reductions. Therefore, we aimed for finding a strategy to use molecular flavins in the reductive 5- exo -trig cyclization of barbituric acid derivatives, which had previously only been reported with superstoichiometric metal reductants (Figure B). , …”

Highly Chemoselective Catalytic Photooxidations by Using Solvent as a Sacrificial Electron Acceptor

“…The unique catalytic properties of 3‐Cl were demonstrated by comparison with neutral deazaflavin 2 b and riboflavin tetraacetate (RFTA), which is a prominent flavin derivative used in photooxidation reactions [17b–d] . As expected, with 2 b and RFTA, the photooxidation of 4 b occurred in good to excellent yield under an oxygen atmosphere.…”

“…However, although flavins have been shown to be selective in a few cases, the procedure for oxidizing the benzyl position in the presence of a heteroatom, such as sulfur in sulfides or nitrogen in an amino group, has not been described to date (Scheme 2). [17b,21] Similar to other photocatalysts, the need for oxygen during flavin recovery causes chemoselectivity problems.…”

A Self‐Assembling Flavin for Visible Photooxidation

“…Flavins can catalyze a range of reactions [3c,22] . Previous work on the use of a gelling flavin derivative for aerobic hydrogenation of olefins showed that the gel phase provided enhanced catalysis compared to the equivalent non‐gelled catalyst due to the formation of reaction cavities [10b] .…”