Multistep Synthesis of Designed MurF Inhibitors and Enantioselective Ruthenium Catalyzed Alkynylation of Aldehydes

Abstract

Antibiotic resistance is rising to dangerously high levels in all parts of the world. New resistance mechanisms are emerging and spreading globally, threatening our ability to treat common infections. Peptidoglycan is a main component of bacterial cell wall that is essential for bacterial survival and involves specific enzymes i.e., Muramyl ligases (Mur) to catalyze its synthesis. As these enzymes have no human analogs, they have proved to be a captivating target for antibacterial drug discovery. In this study proposed new inhibitor of MurF ligase have been designed and successfully synthesized by developing more facile and convergent synthetic protocol. Synthesis was divided into two parts; in first part individual components were synthesized by employing sulfonamide and Heck cross coupling reactions which were combined by amide coupling in second part providing good to excellent yields. In second part of this study, we have developed an atom economical synthesis of chiral propargylic alcohol that has diverse biological applications. We investigated ruthenium catalyzed alkynylation of aldehydes employing various chiral phosphine ligands. Among other ruthenium sources, [RuCp(MeCN)3]PF6 and RuO2 worked really well in this reaction. More flexible and sterically hindered ligands like (R,R)-DTBM-DIOP showed better results. Different aldehydes with electron-donating as well as electron-withdrawing substituents were explored in this reaction giving moderate to good results i.e., 62–90 % yield and 53:47–80:20 enantionmeric ratio (er).