Installation of d3-methyl group to drugs by continuous-flow solid-phase synthesis
The d3-methyl group, which combines the "magic methyl effect" and the deuterium effect, is highly sought after by medicinal chemists, resulting in the development of various d3-methyl reagents derived from low-cost, readily available CD<sub>3</sub>OD. However, a universally applicable, cost-effective, easily accessible and handleable, highly active, and recyclable d3-methyl reagent remains elusive. Herein, we design a thianthrene-based organic polymer (TT-OP) that shows the ability of capturing and releasing the d3-methyl reagent. This polymer demonstrates excellent loading capacity, scalability, and stability. Utilizing this developed heterogeneous d3-methyl reagent (TT-OP-CD<sub>3</sub>), we achieve selective d3-methylation of over 35 biologically active molecules d3-at oxygen, nitrogen, sulfur, and carbon sites-transformations that are very challenging to be realized by other methods. Finally, we establish an automated platform for high-throughput, scalable d3-methylation of pharmaceutical molecules by integrating solid-phase synthesis with continuous-flow, demonstrating its sustainability and practicality for drug synthesis.
Authors
- Wei Ou (ORCID: https://orcid.org/0000-0002-3878-2592)
- Ying Tao (ORCID: https://orcid.org/0000-0003-4810-5998)
- Hao Hou (ORCID: https://orcid.org/0000-0002-3664-5885)
- Qingzhu Xu (ORCID: https://orcid.org/0000-0001-8156-4219)
- Chenliang Su (ORCID: https://orcid.org/0000-0002-8453-1938)
- Lei Yu (ORCID: https://orcid.org/0000-0001-5659-7289)
- Bin Liu (ORCID: https://orcid.org/0000-0002-4685-2052)
- Wei Liu (ORCID: https://orcid.org/0000-0002-0789-2270)
- Jie Wang (ORCID: https://orcid.org/0000-0002-1078-2056)
- Qiyuan Wang (ORCID: https://orcid.org/0000-0001-5976-3270)
- Taoran Chen
Institutions
- City University of Hong Kong (HK)
- Shenzhen University (CN)
- San’an Optoelectronics (China) (CN)
- Shenzhen Technology University (CN)
- Yangzhou University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1038/s41467-025-65810-z
- Citations
- 2
- Primary Topic
- Innovative Microfluidic and Catalytic Techniques Innovation
- Type
- article
- Field-Weighted Citation Impact
- 1.35
Funders
- City University of Hong Kong
- Ministry of Education, Culture, Sports, Science and Technology
- National Natural Science Foundation of China
- Department of Education of Guangdong Province
- National Key Research and Development Program of China
- Basic and Applied Basic Research Foundation of Guangdong Province