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Site‐Selective δ‐C(sp 3 )−H Alkylation of Amino Acids and Peptides with Maleimides via a Six‐Membered Palladacycle
Author(s) -
Zhan BeiBei,
Li Ya,
Xu JingWen,
Nie XingLiang,
Fan Jun,
Jin Liang,
Shi BingFeng
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201801445
Subject(s) - alkylation , chemistry , stereochemistry , peptide , selectivity , cleavage (geology) , palladium , bond cleavage , amino acid , medicinal chemistry , catalysis , organic chemistry , biochemistry , geotechnical engineering , fracture (geology) , engineering
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 δ‐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 γ‐C(sp 3 )−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(sp 3 )−H activation.