Reversing Benzene Bioisosterism through Photocatalytically Divergent Double Strain-Release Skeletal Remodeling
Year: 2026
Type: preprint
Abstract: Highly functionalized two-dimensional molecular frameworks are vital in drug discovery, but their regioselective synthesis remains challenging. Here, we present a photocatalytic method that reverses the conventional paradigm of replacing planar aromatic rings with three-dimensional C(sp3)-rich bioisosteres. Instead, this technique converts bicyclo[1.1.0]butanes (BCBs) back into highly functionalized benzenes. This process creates a reversible link between three-dimensional and planar chemical spaces via divergent double-strain-release steps. By tuning the photocatalyst to favor either energy transfer or electron transfer pathways, distinct regioselective skeletal rearrangements were achieved from common BCB precursors. The method works with many functional groups and substitution patterns, enabling direct synthesis of densely functionalized benzenes that are otherwise difficult to produce regioselectively. Combined experimental and computational data revealed the reaction mechanisms in which photoinduced energy or electron transfer produces intermediates that undergo strain release and radical rearrangement in sequence. These results demonstrate strain-release skeletal remodeling as a way to switch between three-dimensional and planar chemical spaces, providing a complementary strategy to traditional benzene bioisosterism.
Source: ChemRxiv
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7214113618