Preparation of 4-Arylpyridine-2,6-Dicarboxylic Acids via Microwave-assisted Suzuki Coupling

Protein crystallography is a useful tool to elucidate protein structures to the atomic level. X-ray crystallography requires high-quality diffracting crystals, which can be difficult to obtain, especially for proteins. Proteins are fragile, sensitive to external changes, highly heterogenous and large. In addition, protein-protein interactions are weak and scattered over a large surface area. To bring the large, heterogenous protein molecules into an ordered arrangement is a challenge. Several approaches have been explored to better promote protein crystal formation; for instance small molecules, polymers, and metal ions. Recently, organo-lanthanide complexes have been reported to work well. Lanthanide complexes have two advantages over the other approaches: 1) if a lanthanide complex is successfully incorporated into a protein, the derivatized protein will luminesce under UV light, and 2) lanthanide complexes possess large anomalous factors which are useful in X-ray crystallography. Only two classes of organo-lanthanide complexes have been reported for use in protein crystallography; one is based on cyclen and the other is based on dipicolinic acid. Herein, we wish to present our preparation of eight derivatives of dipicolinic acid using microwave-assisted Suzuki coupling. We found that the Suzuki reaction worked best at 140 oC for 40 minutes and the best conditions for the hydrolysis of the diesters were 14 equivalents of LiOH in 3:1 MeOH/H2O. Six of the compounds exhibited limited solubility, whereas 4-(4-carboxyphenyl)pyridine-2,6-dicarboxylic acid and 4-(4-aminophenyl)pyridine-2,6-dicarboxylic acid showed improved solubility. Sterically hindered boronic acids reacted less efficiently and highly electron-poor boronic acids did not react at all. The eight compounds will be used in the preparation of lanthanide complexes, which will be screened against nine proteins.