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- Title
Site‐Selective δ‐C(sp<sup>3</sup>)−H Alkylation of Amino Acids and Peptides with Maleimides via a Six‐Membered Palladacycle.
- Authors
Zhan, Bei‐Bei; Li, Ya; Xu, Jing‐Wen; Nie, Xing‐Liang; Fan, Jun; Jin, Liang; Shi, Bing‐Feng
- Abstract
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.
- Subjects
AMINO acids; MALEIMIDES; PALLADACYCLES; CARBON-hydrogen bonds; ORGANIC synthesis; SCISSION (Chemistry)
- Publication
Angewandte Chemie, 2018, Vol 130, Issue 20, p5960
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201801445