Research led by scholars at Southern University of Science and Technology (SUSTech) has led to a more efficient method for synthesizing the fundamental scaffolds for bioactive medication and therapeutic products.

SUSTech Assistant Professor Tiezheng Jia (Chemistry) has led his research group to publish a paper in the high-impact academic journal ACS Catalysis (IF = 12.2). Their article, titled, “Copper-Catalyzed Intermolecular Difunctionalization of Styrenes with Thiosulfonates and Arylboronic Acids via a Radical Relay Pathway,” was selected as the Supplementary cover of Volume 10, No. 4.

Sulfones are prevalent scaffolds in natural products, synthetic bioactive molecules, and marketed therapeutics. A study of the drug-likeness analysis found that alkyl aryl sulfones are among the top five drug skeletal fragments. Sulfones also find widespread applications in materials and agricultural industries. They also serve as essential intermediates in organic synthesis, as exemplified by the well-known Julia-Lythgoe olefination. Therefore, methods for the construction of sulfones have attracted significant attention.

The researchers developed an efficient construction method using commercially available ingredients. They opted for the use of methyl thiosulfonates as a source of sulfonyl radicals because it simplifies the preparation process. There is also no need for column chromatography separation and purification, and the reaction is atom-economically favored.

Their process prevents the major two-component side reaction between aryl sulfonyl radicals and boronic acids, successfully resulting in the efficient preparation of 2,2-diaryl-ethyl sulfones. This reaction feathers mild conditions and broad functional group tolerance, attesting to the late-stage functionalization of bioactive natural products. Their study shows that there is a copper-catalyzed free radical relay process.

Figure 1. Synthesis of 2,2-diaryl-ethyl sulfones via a difunctionalization strategy of styrenes

The researchers provided a hypothesis for a reaction mechanism (Figure 2). Their proposal follows the traditional copper-catalyzed pathway, but the sulfonyl radicals are obtained through the solvent-involved transfer of free radicals.

Figure 2. Proposed mechanism

Benefiting from our research, 2,2-diaryl-ethyl sulfones, a prevalent drug scaffold, could be synthesized from commercially available materials in the presence of cheap and abundant copper catalysts.

Professor Tiezheng Jia was the correspondent author of the paper. The first author was SUSTech-Harbin Institute of Technology master student Qingjin Liang (Chemistry and Chemical Engineering). Significant contributions also came from the University of Pennsylvania Professor Patrick Walsh (Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry).

The research received financial supports from the Shenzhen Science and Technology Innovation Commission and the SUSTech Start-up fund. The researchers also thank Dr. Yang Yu (SUSTech), Dr. Zhou Tang (SUSTech), and the US National Science Foundation.

Article link: https://pubs.acs.org/doi/10.1021/acscatal.9b04887