Site-Selective delta-C(sp(3))-H Alkylation of Amino Acids and Peptides with Maleimides via a Six-Membered Palladacycle

The site-selective functionalization of unactivated C(sp(3))-H bonds remains one of the greatest challenges in organic synthesis. Herein, we report on the site-selective delta-C(sp(3))-H alkylation of amino acids and peptides with maleimides via a kinetically less favored six-membered palladacycle in the presence of more accessible gamma-C(sp(3))-H bonds. Experimental studies revealed that C-H bond cleavage occurs reversibly and preferentially at gamma-methyl over delta-methyl C-H bonds while the subsequent alkylation proceeds exclusively at the six-membered palladacycle that is generated by delta-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(sp(3))-H activation.