Post-translational modifications (PTMs) greatly expand the structures and functions of proteins in nature 1,2 . Although synthetic protein functionalization strategies allow mimicry of PTMs 3,4 , as well as formation of unnatural protein variants with diverse potential functions, including drug carrying 5 , tracking, imaging 6 and partner crosslinking 7 , the range of functional groups that can be introduced remains limited. Here we describe the visible-light-driven installation of side chains at dehydroalanine residues in proteins through the formation of carbon radicals that allow C-C bond formation in water. Control of the reaction redox allows site-selective modification with good conversion efficiencies and reduced protein damage. In situ generation of boronic acid catechol ester derivatives generates RH2C • radicals that form the native (β-CH2-γ-CH2) linkage of natural residues and PTMs, whereas in situ potentiation of pyridylsulfonyl derivatives by Fe(II) generates RF2C • radicals that form equivalent β-CH2-γ-CF2 linkages bearing difluoromethylene labels. These reactions are chemically tolerant and incorporate a wide range of functionalities (more than 50 unique residues/side chains) into diverse protein scaffolds and sites. Initiation can be applied chemoselectively in the presence of sensitive groups in the radical precursors, enabling installation of previously incompatible side chains. The resulting protein function and reactivity are used to install radical precursors for homolytic on-protein radical
Molecular
editing such as insertion, deletion, and single atom
exchange in highly functionalized compounds is an aspirational goal
for all chemists. Here, we disclose a photoredox protocol for the
replacement of a single fluorine atom with hydrogen in electron-deficient
trifluoromethylarenes including complex drug molecules. A robustness
screening experiment shows that this reductive defluorination tolerates
a range of functional groups and heterocycles commonly found in bioactive
molecules. Preliminary studies allude to a catalytic cycle whereby
the excited state of the organophotocatalyst is reductively quenched
by the hydrogen atom donor, and returned in its original oxidation
state by the trifluoromethylarene.
Sulfonyl chlorides are inexpensive reactants extensively explored for functionalization, but never considered for radical hydrosulfonylation of alkenes. Herein, we report that tris(trimethylsilyl)silane is an ideal hydrogen atom donor enabling highly effective photoredox‐catalyzed hydrosulfonylation of electron‐deficient alkenes with sulfonyl chlorides. To increase the generality of this transformation, polarity‐reversal catalysis (PRC) was successfully implemented for alkenes bearing alkyl substituents. This late‐stage functionalization method tolerates a remarkably wide range of functional groups, is operationally simple, scalable, and allows access to building blocks which are important for medicinal chemistry and drug discovery.
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