Issue 1, 2020

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

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

Supplementary files

Article information

Article type
Edge Article
Submitted
05 sen 2019
Accepted
09 noy 2019
First published
11 noy 2019
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2020,11, 290-294

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, 11, 290 DOI: 10.1039/C9SC04482E

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements