Late-stage peptide C–H alkylation for bioorthogonal C–H activation featuring solid phase peptide synthesis
Schischko, Alexandra ; Kaplaneris, Nikolaos ; Rogge, Torben ; Sirvinskaite, Giedre ; Son, Jongwoo ; Ackermann, Lutz
Citable Link (URL):http://resolver.sub.uni-goettingen.de/purl?gs-1/16571
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.
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