Late-stage peptide C–H alkylation for bioorthogonal C–H activation featuring solid phase peptide synthesis

Alexandra Schischko, Nikolaos Kaplaneris, Torben Rogge, Giedre Sirvinskaite, Jongwoo Son and Lutz Ackermann ()
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Alexandra Schischko: Georg-August-Universität Göttingen
Nikolaos Kaplaneris: Georg-August-Universität Göttingen
Torben Rogge: Georg-August-Universität Göttingen
Giedre Sirvinskaite: Georg-August-Universität Göttingen
Jongwoo Son: Georg-August-Universität Göttingen
Lutz Ackermann: Georg-August-Universität Göttingen

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11395-3

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