The flat molecular structures commonly found in medicines can limit their properties.
A new light-powered chemical technique could give scientists more freedom to design drug molecules with complex three-dimensional shapes. Researchers at the University of Hong Kong (HKU) have developed a way to produce molecular structures that could serve as alternatives to benzene rings, which are widely used in medicines but can sometimes limit their properties.
Led by Professor Jian He from HKU’s Department of Chemistry, the team developed specialized copper(I) photosensitizers that use visible light to construct bicyclo[2.1.1]hexanes, or BCHs. Published in Nature Chemistry, the research addresses two major challenges in producing these structures: the limited range of compatible starting materials and unwanted chemical reactions that interfere with synthesis.
Why Drug Designers Are Looking Beyond Benzene
Benzene rings are common in pharmaceutical compounds because their chemical stability makes them reliable frameworks for arranging other molecular components. However, their flat shape and relatively lipophilic nature can contribute to poor water solubility or unfavorable interactions with biological targets, potentially limiting the performance of certain drug candidates.
BCHs offer a compact, three-dimensional alternative that can fulfill a similar structural role while giving molecules a different shape. Incorporating these structures could allow medicinal chemists to adjust properties such as solubility, selectivity, and metabolic stability. However, producing a broad variety of BCH compounds has remained difficult using existing synthetic techniques.
Using Visible Light to Build More Complex Molecules
One way to make BCHs is to combine bicyclo[1.1.0]butanes, known as BCBs, with alkenes. BCBs contain highly strained molecular rings that can be transformed into more complex structures. Unfortunately, conventional reactions often work with only certain starting materials and can suffer from unstable catalysts or unwanted polymerization, which causes molecules to join into chains rather than form the desired products.
To overcome these limitations, the HKU researchers developed a new class of copper(I) photosensitizers. When exposed to visible light, these compounds absorb energy and transfer it to a starting material, helping drive the formation of BCH structures. By adjusting the energy properties of the copper complexes, the team reduced competing reactions and expanded the types of molecules that could participate.
The researchers also demonstrated control over the placement of chemical groups on the BCH framework. They successfully produced BCH compounds on a gram scale and modified the resulting structures with additional functional groups, demonstrating the method’s versatility for future medicinal chemistry research.
Professor He explained, “The heteroleptic copper(I) photosensitizers developed by our team provide a new approach to the efficient and selective synthesis of BCHs. By modulating the triplet energy levels of copper complexes, we have effectively suppressed polymerization side reactions and expanded the substrate scope to include electron-deficient alkenes, enynes, dienes, and even aliphatic alkenes. This opens new opportunities for sustainable chemical production and the development of more diverse drug candidates.”
Reference: “Modulating endergonic triplet photosensitization for cycloadditions between bicyclo[1.1.0]butanes and alkenes” by Wing Yi Tang (鄧詠誼), Jun Guo (郭军), Shaowei Nie (聂少尉), Jingyu Yang (杨靖宇), Chong-Lei Ji (吉崇磊), Xue-Zhi Wang (王学智), Hongzhi Zhou (周鸿志), Yuanhui Liu (柳元辉), Xu Sun (孙旭), Meng-Ying Sun (孙梦滢), Yao Zhang (张瑶), Dongyi Liu (刘冬艺), Zekun Li (李泽坤), Juan Du (杜鹃), Jun Yang (杨军) and Jian He (何健), 18 August 2026, Nature Chemistry.
DOI: 10.1038/s41557-026-02233-3
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