Abstract

Site-specific functionalization of unprotected native peptides and biomolecules remains a useful transformation in synthetic design and chemical biology, yet until recently, advancements in transition metal-catalyzed methods, which have prevailed in organic synthesis, have been relatively ineffective when applied to large and structurally complex biomolecules. Here, the mechanistically distinct, Ni/photoredox-catalyzed arylation of unprotected, native thiols (e.g., cysteine residues) is reported - a process initiated through a visible light-promoted, hydrogen atom transfer (HAT) event under ambient conditions. Sub-stoichiometric loadings of the dual-catalyst system (≤5 mol%) are employed, granting excellent site-specificity, broad substrate scope, and low chemical waste. Reaction scalability (from μg to grams) has been achieved through modest reagent adjustments, and high throughput experimentation (HTE) demonstrates the ease of reaction setup, enabling prompt screening of aryl halide coupling partners and conditions. Scores of thiol substrates and aryl entities were examined and effectively conjugated, suggesting further diverse, practical applications.

Highlights

  • Transition metal-catalyzed cross-couplings are an undisputable staple in synthetic chemistry, yet granting widespread substrate and functional group tolerance to such a critical class of reactions remains an overarching goal of much synthetic effort

  • We present the rst application of a Ni/photoredox, dual-catalyzed cross-coupling on unprotected, biologicallyderived thiols with wide scope in both thiol and aryl halide partners

  • The designed Ni/photoredox thioarylation reaction does not require transition-metal reagents, large excess of aryl halide (>20 equiv.), nor elaborate ligand design, and may well serve research communities interested in quickly accessing native, protected and/or unprotected, thioarylated small biomolecules, serving as a practical complement to Pdcatalyzed processes that have proven effective for protein bioconjugation

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Summary

Introduction

Transition metal-catalyzed cross-couplings are an undisputable staple in synthetic chemistry, yet granting widespread substrate and functional group tolerance to such a critical class of reactions remains an overarching goal of much synthetic effort.

Results
Conclusion
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