Iterative Arylation of Amino Acids and Aliphatic Amines via δ‐C(sp³)−H Activation: Experimental and Computational Exploration

Abstract

Directed CÀHfunctionalization has been realized as ac omplementary tool to the traditional approaches for as traightforwarda ccess of non-proteinogenic amino acids; albeit such aprocess is restricted mostly up to the g-position. In the present work, we demonstrate the diverse (hetero)arylation of amino acids and analogous aliphatic amines selectively at the remote d-position by tuning the reactivity controlled by ligands.Anorganopalladium d-C(sp 3 )ÀHactivated intermediate has been isolated and crystallographically characterized. Mechanistic investigations carried out experimentally in conjunction with computational studies shed light on the difference in the mechanistic picture depending on the substrate structure.

Organometallic AlaM reagents for umpolung peptide diversification

“…The installation of a fluorescence imaging probe such as BODIPY (17d) is of particular significance 79 because it complements nucleophilic cysteine arylation methods previously described to attached BODIPY to peptides 80 and avoids the use nitrogen protecting groups required to direct CH activation in the earlier attempts to install fluorescent dyes. 81,82 High chemoselectivity was also observed in the reactions with aromatic chlorides (17e, 16i). A series of substituents such as methyl, methoxy, chloro, carbonyl, and amido groups were tolerated.…”

Organometallic AlaM Reagents for Umpolung Peptide Diversification

“…78 groups required to direct CH activation in the earlier attempts to install fluorescent dyes. 81,82 High chemoselectivity was also observed in the reactions with aromatic chlorides (17e, 16i). A series of substituents such as methyl, methoxy, chloro, carbonyl, and amido groups were tolerated.…”

Pd-catalyzed site-selective C(sp2)–H chalcogenation of amino acids and peptides using a picolinamide auxiliary

“…12–20 Recently, metal-catalyzed C–H activation has emerged as a powerful synthetic methodology for various types of challenging chemical transformations including the structural modification of amino acids/peptides. 21–34 Directing group (DG)-assisted metal-catalyzed C(sp 3 )–H bond functionalizations of amino acids and peptides have been well investigated, 35–53 in contrast to the poorly investigated C(sp 2 )–H activation on aromatic rings of aromatic amino acids and their peptides. 54–59 However, the C–H functionalizations of phenylalanine and phenylglycine have shown significant progress.…”