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Abstract
Methods for the late-stage diversification of structurally complex peptides hold enormous potential for advances in drug discovery, agrochemistry and pharmaceutical industries. While C–H arylations emerged for peptide modifications, they are largely limited to highly reactive, expensive and/or toxic reagents, such as silver(I) salts, in superstoichiometric quantities. In sharp contrast, we herein establish the ruthenium(II)-catalyzed C–H alkylation on structurally complex peptides. The additive-free ruthenium(II)carboxylate C–H activation manifold is characterized by ample substrate scope, racemization-free conditions and the chemo-selective tolerance of otherwise reactive functional groups, such as electrophilic ketone, bromo, ester, amide and nitro substituents. Mechanistic studies by experiment and computation feature an acid-enabled C–H ruthenation, along with a notable protodemetalation step. The transformative peptide C–H activation regime sets the stage for peptide ligation in solution and proves viable in a bioorthogonal fashion for C–H alkylations on user-friendly supports by means of solid phase peptide syntheses.
Highlights
Methods for the late-stage diversification of structurally complex peptides hold enormous potential for advances in drug discovery, agrochemistry and pharmaceutical industries
Arylation protocols have enabled the synthesis of substituted peptides, they are inherently limited to the introduction of the aryl motif. Such arylative approaches require reactive aryliodonium and aryldiazonium salts, are operative under basic conditions or employ stoichiometric quantities of costly and toxic silver(I) salts, significantly compromising the step- and atom-economical nature of the C–H activation approach (Fig. 1a). We have addressed these major shortcomings of C–H functionalization by developing peptide C–H alkylation[45,46,47,48] on structurally complex peptides (Fig. 1b)
An air- and water-tolerant ruthenium(II) catalyst set the stage for the chemo-selective late-stage diversification of amino acids and peptides
Summary
Methods for the late-stage diversification of structurally complex peptides hold enormous potential for advances in drug discovery, agrochemistry and pharmaceutical industries. These conventional cross-couplings can lead to the racemization of the peptidic scaffold, and yield stoichiometric amount of undesired byproducts In response to these limitations, metal-catalyzed C‒H activation[12,13,14,15,16,17,18] has emerged as a more atom- and step-economical tool toward decorated peptides[19,20,21], with considerable potential for the late-stage diversification of peptides of relevance to agrochemical and pharmaceutical industries[22,23,24,25,26,27,28,29,30]. A key asset of our strategy is represented by the peptide C–H alkylation by solid phase peptide synthesis (SPPS)[52,53,54], setting the stage for the operationally simple assembly of structurally complex peptides in an iterative manner on user-friendly resin support
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