DNA-Compatible α-Aminoamide Synthesis for a DNA-Encoded Library

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Biochemistry

Background:

• Multicomponent reactions (MCRs) are efficient synthetic tools.
• DNA-compatible chemistry is crucial for developing DNA-encoded libraries (DELs).
• The Ugi reaction is a prominent MCR for synthesizing alpha-aminoamides.

Purpose of the Study:

• To develop the first direct solution-phase on-DNA Ugi three-component reaction.
• To achieve selective synthesis of alpha-aminoamides under mild, DNA-compatible conditions.
• To expand the utility of MCRs in the context of DNA-based synthesis.

Main Methods:

• Optimization of the on-DNA Ugi reaction conditions.
• Utilizing DNA-conjugated anilines, aldehydes, and isocyanides as substrates.
• Characterization of reaction products and assessment of selectivity.

Main Results:

• Successful implementation of the first direct solution-phase on-DNA Ugi reaction.
• Selective synthesis of alpha-aminoamides with minimized competing pathways.
• Demonstrated broad substrate scope with DNA-conjugated anilines, aldehydes, and isocyanides.

Conclusions:

• The developed method provides selective access to alpha-aminoamides on DNA.
• This work broadens the scope of DNA-compatible MCRs.
• The reaction enables the synthesis of privileged alpha-aminoamide scaffolds for DELs.