An efficient, concise synthetic approach to γ-aminobutyric acid (GABA) derivatives bearing bicyclo[2.2.2]octane and bicyclo[2.2.1]heptane rings

Abstract

An efficient, concise 5-step synthetic approach to γ-aminobutyric acid (GABA) derivatives bearing bridged bicyclo[2.2.2]octane and bicyclo[2.2.1]heptane rings was developed, which consists of Diels-Alder cycloaddition to construct the bridged bicyclic rings with a nitrile functionality, hydrogenation, LDA-mediated S_N2 alkylation to introduce acetate moiety at the α-position of nitrile, reduction of the nitrile functionality to amino group followed by intramolecular formation of lactam and finally acidic hydrolysis of lactam to give the desired GABA derivatives (1 and 19 as HBr salts). The reaction conditions of Diels-Alder cycloaddition and LDA-mediated S_N2 alkylation were intensively optimized to improve the yields. The stereochemistry of the S_N2 reaction involved in the bicyclo[2.2.1]heptane ring system was unambiguously elucidated by single-crystal X-ray diffraction. This synthetic approach possesses advantages of less reaction steps, high overall yields and avoidance of toxic reagents, and may find wide applications in the synthesis of other GABA derivatives with similar bicyclic or polycyclic rings.

Graphical abstract

Keywords:

• Diels-Alder cycloaddition
• bridged bicyclic ring
• S_N2 alkylation
• γ-aminobutyric acid (GABA)
• stereochemistry

Acknowledgements

The authors want to thank Ms Xiaotong Lin and Ms Yanlan Qin for performing NMR and HR-MS determinations, respectively.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Guangdong Basic and Applied Basic Research Foundation under Grants 2021A1515010197 and 2023A1515012259; Zhongshan Municipal Natural Science Foundation under Grants 200805173640573 and 210730214049987; and Creative Research Group of Zhongshan City (Lingnan Pharmaceutical Research and Innovation team) under Grant CXTD2022011.