Densely-functionalized bicyclic cyclopentanones by combined photoinduced 6- endo-trig Giese additions and mild aldol cyclizations

Polycyclic scaffolds are central to numerous natural products and pharmaceuticals, motivating concise, stereocontrolled routes to their construction. We report a photoredox-enabled synthesis of trans-fused n.3.0 bicyclic ketones (n = 4, 5, 10) from malonate-derived enol ethers. α-Brominated intermediates, formed by acylation with 2-bromo-2-methylpropanoyl bromide, undergo radical cyclization under two complementary conditions: (i) acridinium orange (AOH+) with Hantzsch ester (HE) at 455 nm, or (ii) photoexcited HE alone at 365 nm. Both modes trigger 6-endo-trig Giese addition, C-O bond fragmentation, and hydrogen-atom transfer to α-branched cyclic ketones that ring-close under mild Brønsted or Lewis acid activation to trans-fused products with exclusive junction control. Mechanistic studies (Stern-Volmer, UV-Vis, electrochemistry) support two activation pathways-AOH+* quenching by HE or direct HE excitation-each generating the same radical intermediates in fine. DFT calculations validate mechanistic pathways and regioselectivity in favor of philicity matching of the electrophilic radical and the polar electron-rich enol ether. The method accommodates ring-size diversity, accesses trans-hydrindanone architectures, and outcompetes 5-exo-trig spirocyclization.