Divergent On-DNA Transformations from DNA-Linked Piperidones.

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Chemical Biology

Background:

• DNA-encoded libraries (DELs) are powerful tools for drug discovery.
• Efficient synthesis of diverse chemical scaffolds is crucial for DELs.
• Piperidine derivatives are common in drug molecules.

Purpose of the Study:

• To develop novel DNA-linked transformations for constructing diverse chemotypes.
• To synthesize DNA-conjugated piperidine intermediates and derivatives.
• To create focused scaffold-based DNA-encoded libraries with drug-like properties.

Main Methods:

• Development of a novel procedure for DNA-conjugated piperidine synthesis under basic conditions.
• Application of subsequent reactions to generate privileged scaffolds like 4-aminopiperidine, fused [1,2,4]triazolo[1,5-a]pyrimidine, and quinoline derivatives.
• Utilizing DNA-linking strategies for library construction.

Main Results:

• Successful development of highly efficient and divergent transformations.
• First reported synthesis of a DNA-conjugated piperidine intermediate.
• Generation of multiple privileged scaffolds from the piperidine core.
• Demonstration of DNA-encoded library construction with druglike properties.

Conclusions:

• The developed transformations provide a versatile platform for scaffold-based DEL construction.
• This approach facilitates the generation of focused libraries with potential therapeutic applications.
• The methodology expands the synthetic toolbox for DNA-encoded chemistry.