Identification of BACE-1 inhibitors through directed C(sp3)–H activation on 5-oxo-pyrrolidine-3-carboxylic acid derivatives

Lorenzo Baldini; Elena Lenci; Cristina Faggi; Andrea Trabocchi

doi:10.1039/D3OB02117C

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Identification of BACE-1 inhibitors through directed C(sp³)–H activation on 5-oxo-pyrrolidine-3-carboxylic acid derivatives†

Lorenzo Baldini,

^a Elena Lenci,

^a Cristina Faggi^a and Andrea Trabocchi

*^a

Author affiliations

* Corresponding authors

^a Department of Chemistry “Ugo Schiff”, University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy
E-mail: andrea.trabocchi@unifi.it

Abstract

Convenient synthesis of stereochemically dense 5-oxo-pyrrolidines was obtained from succinic anyhdride and imines by combining the Castagnoli–Cushman reaction with directed Pd-catalyzed C(sp³)–H functionalization, taking advantage of the developing carboxylic group properly derivatized with 8-aminoquinoline as a directing group. These fully substituted 5-oxopyrrolidines were found to be able to inhibit BACE-1 enzyme with sub-micromolar activity, thanks to the interaction of the key aryl appendage introduced by C(sp³)–H activation within BACE-1 S2′ subsite.

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Article information

DOI: https://doi.org/10.1039/D3OB02117C
Article type: Paper
Submitted: 29 Dec 2023
Accepted: 08 Mar 2024
First published: 08 Mar 2024
This article is Open Access

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Org. Biomol. Chem., 2024,22, 2754-2763

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Identification of BACE-1 inhibitors through directed C(sp³)–H activation on 5-oxo-pyrrolidine-3-carboxylic acid derivatives

L. Baldini, E. Lenci, C. Faggi and A. Trabocchi, Org. Biomol. Chem., 2024, 22, 2754 DOI: 10.1039/D3OB02117C

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Organic & Biomolecular Chemistry