A Library of Spirooxindoles Based on a Stereoselective Three-Component Coupling Reaction

• Published in: Journal of the American Chemical Society Vol. 126; no. 49; pp. 16077 - 16086
• Main Authors: Lo, Michael M.-C, Neumann, Christopher S, Nagayama, Satoshi, Perlstein, Ethan O, Schreiber, Stuart L
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 15-12-2004
• Subjects: Aldehydes - chemistry; Alkynes - chemistry; Chemistry; Combinatorial Chemistry Techniques - methods; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Indoles - chemical synthesis; Lactams - chemistry; Magnetic Resonance Spectroscopy - methods; Organic chemistry; Preparations and properties; Spiro Compounds - chemical synthesis; Stereoisomerism; Stereoselectivity; Organic synthesis; Nitrogen heterocycle; Chemical compound library; Combinatorial chemistry; Bicyclic compound; Aromatic compound; Biological activity; Spiran; Chemical coupling
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja045089d

A collection of structurally complex and chemically diverse small molecules is a useful tool to explore cell circuitry. In this article, we report the split-pool synthesis of more than 3000 spirooxindoles on high capacity macrobeads. The key reaction to assemble the spirooxindole core stereoselectively is a Lewis acid variant of the Williams' three-component coupling. After formation, the skeleton was elaborated using Sonogashira couplings, amide forming reactions, and N-acylations of γ-lactams. The final library was analyzed by sampling individual macrobeads and by using binomial confidence limits. It was determined that at least 82% of the library compounds should have better than 80% purity. To demonstrate the utility of our discovery process, a high-throughput chemical genetic modifier screen was performed using stock solutions of the resultant products. A number of positives were identified as enhancers of the cellular actions of latrunculin B, an actin polymerization inhibitor. Through resynthesis, we confirmed one of the positives and demonstrated that, in yeast cells, it has an EC50 in the sub-micromolar range.