Issue 41, 2024

Synthesis of chiral α-amino acids via Pd(ii)-catalyzed enantioselective C–H arylation of α-aminoisobutyric acid

Abstract

Non-natural chiral α,α-disubstituted α-amino acids (α,α-AAs) constitute an attractive α-aminoisobutyric acid (Aib) replacement for improving bioavailability of linear peptides as therapeutics due to the ability of these amino acids to induce the peptides to form helical structures. Enantioselective β-C(sp3)–H arylation of Aib could potentially provide a versatile one-step strategy for accessing diverse α,α-AAs, but the installation and removal of external directing groups was found in our previously reported work to reduce the efficiency of this approach. Herein we report a Pd(II)-catalyzed enantioselective C–H arylation of N-phthalyl-protected Aib enabled by a N-2,6-difluorobenzoyl aminoethyl phenyl thioether (MPAThio) ligand, affording α,α-AAs with up to 72% yield and 98% ee. Use of this newly developed chiral catalyst has also significantly improved enantioselective C(sp3)–H arylation of cyclopropanecarboxylic acids by expanding the substrate scope to heterocyclic coupling partners and increasing enantioselectivity to 99% ee.

Graphical abstract: Synthesis of chiral α-amino acids via Pd(ii)-catalyzed enantioselective C–H arylation of α-aminoisobutyric acid

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Article information

Article type
Edge Article
Submitted
11 Aug 2024
Accepted
16 Sep 2024
First published
18 Sep 2024
This article is Open Access

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

Chem. Sci., 2024,15, 17092-17096

Synthesis of chiral α-amino acids via Pd(II)-catalyzed enantioselective C–H arylation of α-aminoisobutyric acid

Z. Zhang, T. Zhang, Y. Ouyang, P. Lu, J. X. Qiao and J. Yu, Chem. Sci., 2024, 15, 17092 DOI: 10.1039/D4SC05378H

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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