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Solid-phase synthesis of a 4-substituted gamma-lactam library
Anne L Vergnon1, Richard S Pottorf, Michael P Winters
1Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C. 8 Clarke Drive, Cranbury, New Jersey 08512, USA.
Journal of Combinatorial Chemistry
|November 9, 2004
Summary
Researchers synthesized 12,000 pyrrolidin-2-one derivatives using solid-phase synthesis for high-throughput screening. This library of gamma-lactam compounds offers potential for drug discovery targeting diverse protein receptors.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Drug Discovery
Background:
- Pyrrolidin-2-one (gamma-lactam) derivatives exhibit diverse biological activities, acting as ligands for receptors like integrin, CCR5, and CCK.
- The development of efficient synthetic routes is crucial for generating compound libraries for screening.
Purpose of the Study:
- To develop a solid-phase synthesis for pyrrolidin-2-one derivatives.
- To create a large library of these compounds for high-throughput screening against various protein targets.
Main Methods:
- Solid-phase synthesis involving acylation of resin-bound amines with N-Fmoc-protected amino acids.
- Ring formation via reaction of deprotected amines with beta-monomethyl itaconate.
- Final steps included saponification, amide formation, and resin cleavage.
Main Results:
- Successfully synthesized a library of 12,000 pyrrolidin-2-one derivatives.
- Products were obtained in good yields as high-purity diastereomeric mixtures.
- The developed synthesis allows for exploration of pyrrolidin-2-one ring formation.
Conclusions:
- The solid-phase synthesis is effective for producing diverse pyrrolidin-2-one derivatives.
- The generated library is suitable for high-throughput screening in drug discovery programs.
- This approach facilitates the exploration of gamma-lactam chemical space for novel therapeutic agents.