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

## TL;DR

This paper describes a new method to create complex bicyclic ketones using light-driven chemistry and mild cyclization, enabling efficient and stereocontrolled synthesis of drug-like structures.

## Contribution

A photoredox-enabled synthesis of trans-fused bicyclic ketones with exclusive stereocontrol via 6-endo-trig radical additions and mild aldol cyclizations.

## Key findings

- Two complementary photoredox conditions trigger radical cyclization to α-branched cyclic ketones.
- Mechanistic studies and DFT calculations confirm radical pathways and regioselectivity.
- The method enables ring-size diversity and access to trans-hydrindanone architectures.

## Abstract

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.

A photoredox-enabled synthesis of trans-fused [n.3.0] bicyclic ketones via 6-endo-trig radical additions and mild aldol cyclizations, offering stereocontrolled access to densely functionalized bicyclic scaffolds.