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

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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.

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

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Publication details

The article was received on 05 Sep 2019, accepted on 09 Nov 2019 and first published on 11 Nov 2019


Article type: Edge Article
DOI: 10.1039/C9SC04482E
Chem. Sci., 2020, Advance Article
  • Open access: Creative Commons BY-NC license
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    Synthesis of amino acids and peptides with bulky side chains via ligand-enabled carboxylate-directed γ-C(sp3)–H arylation

    L. Liu, Y. Liu and B. Shi, Chem. Sci., 2020, Advance Article , DOI: 10.1039/C9SC04482E

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