Designed, Flavin-Based Multistate Catalysis

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Flavoenzymes catalyze highly diverse transformations ranging from oxygenations with oxygen and carbohydrate transfer to oxidations as well as reductions both upon and without visible light excitation. However, these reactions are mediated by the same isoalloxazine reactive site of the flavin adenine dinucleotide (FAD) cofactor. The latter easily changes between oxidation states and covalent substrate adduct states, each of which is characterized by distinct reactivity. In enzymes, control over divergent activity as well as selectivity relies on non-covalent contacts of the isoalloxazine and the substrates with the peptide surrounding. Most flavin activity, therefore, is lost when the isolated cofactor is removed from the peptide surrounding. On the other hand, artificial flavoenzymes are sensitive towards solvent choice and modifications of the isoalloxazine for non-natural reactivity. In this research programme, designed molecular flavin catalysts are proposed in order to make the full spectrum of natural as well as non-natural flavin reactivity accessible. Our key strategy relies on precise tuning of the isoalloxazine reactive center and its three-dimensional ‘outer-sphere’ by means of non-covalent interaction sites, thereby controlling catalyst reactivity and selectivity. Three distinct reactivity areas have been selected based on enzyme activity and the aim for synthetic utility: i) Activation of oxygen from air for hydroxylation and halogenation reactions, ii) organocatalytic glycosylation and oxidative coupling reactions, and iii) decarboxylative peptide conjugation and stapling as well as olefin coupling via visible light excitation of the flavin. Switching between these areas of reactivity - with an identical flavin catalyst - will be accomplished through changing external parameters such as air versus argon atmosphere, oxidative versus reductive conditions, and irradiation versus reaction in the dark. This strategy lays the foundation for multistate reaction sequences, in which a single flavin-based catalyst performs various different transformations consecutively. These multistate catalysts will be applied in stereo-, site-, and chemoselective editing of increasingly complex natural products. Here, the outlined diverse reactivity allows for a variety of modifications including modulation of secondary structure and polarity, attachment of labels, and binding site changes. Recent work in diversification of natural product antibiotics revealed synergistic effects of multiple instead of isolated alterations. In this context, the selective modification of multiple sites - or consecutive editing of a single site - with one designed flavin catalyst is anticipated to be beneficial for accessing biologically relevant complex molecules.