Biocatalytic Redox Cascade Enabled Site-Selective Direct β-Alkylation of Cyclopentanones

Abstract

Abstract Alkylation of carbonyl compounds is among the most widely practiced transformations in organic synthesis. While extensive methods exist for functionalization at the ipso and α-positions, direct β-alkylation remains a significant challenge, especially for cyclic ketones. Furthermore, catalyst-controlled site selectivity in the β-alkylation of α-aryl- or alkyl-substituted cyclic ketones is rarely achieved using existing methods. Herein, we report a highly site-selective direct β-C(sp3)–H alkylation of α-nonacyl-substituted cyclopentanones via photobiocatalysis. Through mechanism-driven enzyme repurposing, a single flavin-dependent ‘ene’-reductase (ERED) orchestrates two mechanistically distinct transformations, desaturation and Giese-type radical addition, in one redox cascade. Precise enzyme control over site selectivity in the desaturation step ensures site-specific installation of diverse alkyl groups at the β-position adjacent to the α-substituent, providing trans-α,β-disubstituted cyclopentanones with excellent diastereoselectivity. A site-divergent alkylation is also achieved through synergistic tuning of enzyme catalyst and light activation, underscoring the catalytic versatility of EREDs and their potential in streamlining complex molecule synthesis.

The authors' abstract, as published at the source. Journal of the American Chemical Society, 2026 · DOI ↗