title: Stapled Peptides by Late-Stage C(sp3)-H Activation.
abstract: Despite the importance of stapled peptides for drug discovery, only few practical processes to prepare cross-linked peptides have been described; thus the structural diversity of available staple motifs is currently limited. At the same time, C-H activation has emerged as an efficient approach to functionalize complex molecules. Although there are many reports on the C-H functionalization of amino acids, examples of post-synthetic peptide C-H modification are rare and comprise almost only C(sp2)-H activation. Herein, we report the development of a palladium-catalyzed late-stage C(sp3)-H activation method for peptide stapling, affording an unprecedented hydrocarbon cross-link. This method was first employed to prepare a library of stapled peptides in solution. The compatibility with various amino acids as well as the influence of the size (i,i+3 and i,i+4) and length of the staple were investigated. Finally, a simple solid-phase procedure was also established.
authors.affiliation: Institute for Research in Biomedicine (IRB-Barcelona), Baldiri Reixac 10, 08028, Barcelona, Spain.
authors.forename: Anaïs F M
authors.initials: AF
authors.lastname: Noisier
authors.affiliation: Institute for Research in Biomedicine (IRB-Barcelona), Baldiri Reixac 10, 08028, Barcelona, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: García
authors.affiliation: Institute for Research in Biomedicine (IRB-Barcelona), Baldiri Reixac 10, 08028, Barcelona, Spain.|Pharmaceutical Chemistry Department, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, 41 Victor Babes St., 400012, Cluj-Napoca, Romania.
authors.forename: Ioana A
authors.initials: IA
authors.lastname: Ionuţ
authors.affiliation: Institute for Research in Biomedicine (IRB-Barcelona), Baldiri Reixac 10, 08028, Barcelona, Spain.|CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Baldiri Reixac 10, 08028, Barcelona, Spain.|Department of Organic Chemistry, University of Barcelona, Barcelona Science Park, Baldiri Reixac 10, 08028, Barcelona, Spain.|School of Chemistry and Physics, University of KwaZulu-Natal, Durban, 4001, South Africa.
authors.forename: Fernando
authors.identifier: 0000-0002-8946-0462
authors.initials: F
authors.lastname: Albericio
keywords: C−H activation; macrocycles; palladium; peptides; stapled peptides