Bridged scaffold editing of carbocycles and heterocycles.

Abstract

Bridged frameworks are widely recognized as privileged motifs in natural products and pharmaceuticals, and their distinctive three-dimensional architectures often underpin target recognition and bioactivity. However, their preparation remains a formidable challenge, with most strategies relying on either linear multi-step syntheses or structurally specialized substrates. Here we report a bridged scaffold editing strategy for heterocycles and carbocycles, which employs formaldehyde and ureas in a distinct multicomponent reaction, toward modular and efficient construction of diverse bridged polycycles. Notably, this protocol enables concurrent C(sp²)-H and unactivated C(sp³)-H functionalization, for directly assembling bridged polycyclic products from planar or quasi-planar cyclic substrates through regio- and diastereoselective multiple bond formations. Experimental and computational studies collectively elucidate the plausible reaction pathways underlying these transformations. By offering rapid and general access to three-dimensional polycyclic skeletons, this approach expands the molecular editing toolbox and provides a versatile platform for generating structurally unique compounds with potential applications in drug discovery.