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Asymmetric, Organocatalytic 1,4-Addition of Pyridinyl Acetates with Crystallization-Enabled Diastereoconvergency

Year: 2025

Type: article

Abstract: Azaarenyl acetates represent promising building blocks for the synthesis of stereochemically complex scaffolds containing pharmaceutically relevant heterocycles. Current methods that employ azaarenyl acetates as nucleophiles in enantioselective transformations generally rely on metal catalysts and are compatible only with 2-azaarenyl acetates, limiting the diversity of electron-deficient heterocycles that can be installed. We have developed the first enantioselective organocatalytic method for the 1,4-addition of 4-azaarenyl acetates into trisubstituted electrophilic alkenes. The resulting products─possessing three contiguous stereocenters─are obtained in moderate to high diastereo- and enantioselectivities. Mechanistic studies suggest a scenario in which two of the stereocenters are under kinetic control, while the β-keto amide stereocenter undergoes a thermodynamically controlled crystallization-induced diastereomer transformation.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.5c17000

Authors: Katelyn M. Kitzinger, Susanna N. Angles, Yuki Kojima, Jeffrey S. Johnson

Institution: University of North Carolina at Chapel Hill

Language: English

Topic: Asymmetric Synthesis and Catalysis

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: green