Van Leusen Imidazole Synthesis for One-Bead-One-Compound DNA-Encoded Libraries

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• One-bead-one-compound (OBOC) DNA-encoded libraries (DELs) are powerful tools for high-throughput screening.
• Identifying novel pharmaceutical targets requires efficient methods for hit discovery.

Purpose of the Study:

• To develop solid-phase and DNA-compatible conditions for the three-component Van Leusen reaction (imidazole formation) within OBOC DELs.
• To validate the scope of reagents for potential library synthesis and demonstrate high-throughput screening capabilities.

Main Methods:

• Implementation of the Van Leusen reaction under solid-phase and DNA-compatible conditions.
• High-throughput validation of aldehydes, amines, and tosylmethyl isocyanides (TosMICs) using all potential building blocks.
• Assessment of reaction yields to determine reagent suitability for library construction.

Main Results:

• Successful development of conditions for imidazole formation in OBOC DELs.
• Validation of 251 aldehydes, 380 amines, and 19 TosMICs, with 65 aldehydes, 194 amines, and 15 TosMICs meeting a 50% yield cutoff.
• Aliphatic TosMICs demonstrated good performance in solid-phase synthesis, yielding more drug-like products.

Conclusions:

• The developed Van Leusen reaction conditions are suitable for OBOC DEL synthesis.
• The validated reagent scope provides a foundation for creating diverse chemical libraries.
• Solid-phase synthesis with aliphatic TosMICs is a promising strategy for generating drug-like imidazole compounds.