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

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.