Yagong Wang ,  Hangke Ma ,  Ivan Hu ,  Jin Liang ,  Bingxin Chen ,  Lijun Xue ,  Kexin Yang ,  Yun Jin Hu

Organic Letters 

DOI: 10.1021/acs.orglett.5c04043

Abstract

We present a metal-free photochemical strategy for the synthesis of on-DNA β-hydroxy sulfides, which are essential pharmacophores with limited access via existing DNA-encoded library (DEL) methodologies. This innovative hydrothiolation features a broad substrate scope with both thiols and olefins. Its operational simplicity and excellent DNA compatibility enable the efficient construction of diverse DELs, significantly expanding the accessible chemical space for drug discovery and providing a new tool for identifying novel therapeutics.

Summary

This study introduces a novel metal-free, photoinduced method for synthesizing β-hydroxy sulfides on DNA. The approach leverages visible light to drive the reaction, avoiding the use of metal catalysts that can be harmful to DNA. The protocol is characterized by its operational simplicity, broad substrate scope, and excellent compatibility with DNA, making it highly suitable for constructing diverse DNA-encoded libraries (DELs). This method significantly expands the chemical space accessible for drug discovery and offers a powerful tool for identifying new therapeutic agents.

Highlights

• Metal-Free and Photoinduced: The method is metal-free and utilizes visible light, avoiding conditions harmful to DNA.
• Broad Substrate Scope: The reaction tolerates a wide range of thiols and olefins, including both aromatic and aliphatic substrates.
• Operational Simplicity: The protocol is straightforward, requiring only readily available starting materials and mild reaction conditions.
• DNA Compatibility: The method is highly compatible with DNA, enabling efficient construction of DELs without significant DNA damage.
• Expands Chemical Space: This approach significantly broadens the chemical space accessible for DEL-based drug discovery.

Conclusion

The development of a metal-free, photochemical β-hydrothiolation for the on-DNA synthesis of β-hydroxy sulfides represents a significant advancement in the field of DNA-encoded library synthesis. This operationally simple protocol demonstrates excellent functional group tolerance and DNA compatibility, enabling the efficient construction of a diverse DNA-encoded library from readily available thiols and disulfides. The method provides a powerful and versatile tool that significantly expands the accessible chemical space for DEL-based drug discovery, offering a new avenue for identifying novel therapeutic agents.