Site-Selective δ-C(sp3 )-H Alkylation of Amino Acids and Peptides with Maleimides via a Six-Membered Palladacycle.

Abstract

The site-selective functionalization of unactivated C(sp3 )-H bonds remains one of the greatest challenges in organic synthesis. Herein, we report on the site-selective δ-C(sp3 )-H alkylation of amino acids and peptides with maleimides via a kinetically less favored six-membered palladacycle in the presence of more accessible γ-C(sp3 )-H bonds. Experimental studies revealed that C-H bond cleavage occurs reversibly and preferentially at γ-methyl over δ-methyl C-H bonds while the subsequent alkylation proceeds exclusively at the six-membered palladacycle that is generated by δ-C-H activation. The selectivity can be explained by the Curtin-Hammett principle. The exceptional compatibility of this alkylation with various oligopeptides renders this procedure valuable for late-stage peptide modifications. Notably, this process is also the first palladium(II)-catalyzed Michael-type alkylation reaction that proceeds through C(sp3 )-H activation.