Synthesis of amino acids and peptides with bulky side chains via ligand-enabled carboxylate-directed γ-C(sp3 )-H arylation

Chemical Science
Lei LiuBing-Feng Shi

Abstract

Amino acids and peptides with bulky side chains are of significant importance in organic synthesis and modern medicinal chemistry. The efficient synthesis of these molecules with full enantiocontrol and high diversity remains challenging. Herein we report a Pd-catalyzed ligand-enabled γ-C(sp3)-H arylation of tert-leucine and its derived peptides without using an external directing group (DG) via a less favored six-membered palladacycle. Structurally diverse bulky side chain amino acids and peptides were accessed in a step-economic fashion and the reaction could be conducted on a gram scale with retention of chirality. The resulting amino acids can be used as chiral ligands in Co(iii)-catalyzed enantioselective C(sp3)-H amidation. It is worth noting that the weakly coordinating carboxylate DG outcompetes the strongly coordinating bidentate DG of the peptide backbone, providing the products of γ-C(sp3)-H arylation of Tle residue exclusively. This protocol represents the first example of late stage C(sp3)-H functionalization of peptides using a weakly coordinating directing group.

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Citations

Apr 7, 2020·Angewandte Chemie·Kiron Kumar GhoshManuel van Gemmeren
May 10, 2020·Angewandte Chemie·Han Seul ParkJin-Quan Yu
Sep 9, 2020·Angewandte Chemie·Francesca GhiringhelliManuel van Gemmeren
Oct 30, 2020·Chemical Communications : Chem Comm·Bei-Bei ZhanBing-Feng Shi
Jan 12, 2021·Chemistry, an Asian Journal·Animesh Das, Biplab Maji
Jan 15, 2021·The Journal of Organic Chemistry·Peng-Peng NiuYu-Peng He
Jun 8, 2021·Chemical Science·Jayabrata DasDebabrata Maiti
Jun 8, 2021·Chemical Science·Marcos San Segundo, Arkaitz Correa
Jul 20, 2021·Journal of the American Chemical Society·Alexander UttryManuel van Gemmeren
Nov 9, 2021·Journal of the American Chemical Society·Yan-Hua LiuBing-Feng Shi

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