On-DNA C-H functionalization of electron-rich arenes for DNA-encoded libraries

Area of Science:

• Medicinal Chemistry
• Organic Chemistry
• Chemical Biology

Background:

• DNA-encoded libraries (DELs) are valuable for pharmaceutical hit discovery.
• Current DEL synthesis is limited by the lack of transformations compatible with DNA in aqueous conditions.
• Increasing structural diversity in DELs is crucial for identifying novel drug candidates.

Purpose of the Study:

• To develop a general C-H functionalization method for electron-rich arenes on DNA.
• To overcome limitations in DEL structural diversity.
• To enable late-stage functionalization for analogue synthesis.

Main Methods:

• Development of a novel selenoxide reagent for aqueous C-H functionalization.
• Regio- and chemoselective formation of arylselenonium salts on DNA conjugates.
• Utilizing arylselenonium salts as versatile intermediates for subsequent reactions.

Main Results:

• Successful implementation of C-H functionalization on DNA-encoded molecules.
• Demonstration of regio- and chemoselective arylselenonium salt formation in aqueous media.
• Access to diverse analogues via transition-metal-mediated and photochemical transformations (C-C, C-I, C-S bond formation).

Conclusions:

• The developed method significantly enhances the structural diversity of DNA-encoded libraries.
• Arylselenonium salts serve as versatile linchpins for generating numerous analogues.
• This advancement expands the utility of DELs in drug discovery and chemical biology.