Installation of d3-methyl group to drugs by continuous-flow solid-phase synthesis

Wei Ou, Hao Hou, Ying Tao, Qiyuan Wang, Taoran Chen, Jie Wang, Wei Liu, Qingzhu Xu, Lei Yu, Bin Liu and Chenliang Su ()
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Wei Ou: Shenzhen University, International Collaborative Laboratory of 2D Materials for Optoelectronics Science and Technology of Ministry of Education, Institute of Microscale Optoelectronics
Hao Hou: Shenzhen University, International Collaborative Laboratory of 2D Materials for Optoelectronics Science and Technology of Ministry of Education, Institute of Microscale Optoelectronics
Ying Tao: Shenzhen University, International Collaborative Laboratory of 2D Materials for Optoelectronics Science and Technology of Ministry of Education, Institute of Microscale Optoelectronics
Qiyuan Wang: Yangzhou University, College of Chemistry and Chemical Engineering
Taoran Chen: Shenzhen University, International Collaborative Laboratory of 2D Materials for Optoelectronics Science and Technology of Ministry of Education, Institute of Microscale Optoelectronics
Jie Wang: Shenzhen University, International Collaborative Laboratory of 2D Materials for Optoelectronics Science and Technology of Ministry of Education, Institute of Microscale Optoelectronics
Wei Liu: Shenzhen University, International Collaborative Laboratory of 2D Materials for Optoelectronics Science and Technology of Ministry of Education, Institute of Microscale Optoelectronics
Qingzhu Xu: Yangzhou University, College of Chemistry and Chemical Engineering
Lei Yu: Yangzhou University, College of Chemistry and Chemical Engineering
Bin Liu: City University of Hong Kong, Department of Materials Science and Engineering
Chenliang Su: Shenzhen University, International Collaborative Laboratory of 2D Materials for Optoelectronics Science and Technology of Ministry of Education, Institute of Microscale Optoelectronics

Nature Communications, 2025, vol. 16, issue 1, 1-8

Abstract: Abstract 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 CD3OD. 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-CD3), 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.

Date: 2025
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DOI: 10.1038/s41467-025-65810-z

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