New Strategies for the Solid-Phase Synthesis of Highly Functionalized, Small Molecules: Sequential Nucleophilic Substitutions on Polymer-Bound Polyelectrophiles

Abstract

Publisher Summary The screening of large and diverse arrays of compounds prepared on insoluble supports is one of the most efficient approaches for fast identification of lead compounds for novel, small molecule enzyme inhibitors, or other ligands for proteins. Parallel solid-phase synthesis is particularly well suited for the preparation of such arrays of diverse compounds, since multistep synthetic sequences on insoluble supports can be conducted on fully automated synthesizers. The advantages of using nucleophilic reagents for library production can be exploited by performing sequential nucleophilic substitutions on a polymer-bound polyelectrophile. A suitable polyelectrophile would be a polymer-bound compound with two or more leaving groups that could be orthogonally displaced by different nucleophiles. The sequential nucleophilic substitutions on support-bound polyelectrophiles gives quick access to highly functionalized, pharmacophore-rich small molecules. Because no protective groups are required, the scope of these syntheses is broad and a multitude of different pharmacophoric patterns can be generated by using exclusively simple, commercially available reagents. The use of 2,3-dichloropropionic acid and 4,5-difluoro-2-nitrobenzoic acid is discussed in the chapter to illustrate the scope and limitations of this strategy for the preparation of lead-like compound arrays.