A vitamin B2-photocatalysed approach to methionine analogues Oliver Knowles, Linus O. Johannissen, Giacomo E. M. Crisenza, Sam Hay, David Leys, David J. Procter University of Manchester, UK Sulfide functionality is ubiquitous in important biological structures, such as amino acid residues, cofactors and vitamins. As such, the ability to selectively functionalise sulfides is crucial in synthetic biological chemistry. Recent advances in photoredox catalysis have enabled functionalization selectively at the α-position of sulfides, through radical-based C–H alkylation processes. Here, sequential oxidation of the sulfur atom – by an excited-state photocatalyst – and base-assisted deprotonation at an adjacent site, generates α-sulfur-radicals, which can be intercepted by appropriate radical traps. 1 This approach has been applied both to the synthesis of simple sulfide- containing scaffolds, 2 and for bioconjugation via the functionalization of methionine residues in enzymes. 3 We envisioned exploiting this strategy for the production of sought-after, but elusive, methionine derivatives, whose synthesis often requires forcing reaction conditions and involves unstable intermediates. Thus, using an inexpensive and commercially available flavin photocatalyst (riboflavin, vitamin B 2 ), we first developed a simple and efficient method for the α-selective C–H functionalization of sulfides, in water, using a variety of electron- deficient alkene partners. Crucially, the use of riboflavin bypasses the need for an external base for deprotonation. Our method allows the two-step synthesis of novel methionine analogues by radical addition to unsaturated amino acid derivatives. Furthermore, our protocol facilitates the chemoselective modification of existing peptide side- chains to yield non-natural methionine residues, within polypeptides ( residue exchange strategy ). The mechanism of the bio-inspired flavin photocatalysis has been probed by experimental and DFT studies. 4 References 1. Hasegawa et al. , J. Org. Chem. 2002 , 53 , 5435–5442.Alfonzo, S. M. Hande, ACS Catal. 2020 , 10 , 12590–12595. 2. Kim et al ., J. Am. Chem Soc. 2020 , 142 , 21260–21266.O. J. Knowles et al ., Manuscript Submitted .
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