Mitsunobu reaction: assembling C-N bonds in chiral traditional Chinese medicine

The synthesis of chiral molecules has long been a central focus and challenge in medicinal chemistry research. The Mitsunobu reaction, developed by Japanese chemist Mitsunobu in 1967, is a widely utilized bimolecular nucleophilic substitution reaction that plays a vital role in synthesizing chiral natural products. In this reaction, alcohols react with nucleophilic reagents in the presence of a phosphine ligand to form an intermediate phosphonium salt. This intermediate enables the formation of various chemical bonds. The purpose of this review is to explore the applications of the Mitsunobu chemistry in constructing pivotal carbon-nitrogen bonds in traditional Chinese medicines (TCMs). Emphasis will be placed on the preparative synthetic applications of the Mitsunobu strategy as a key step in the total synthesis of naturally occurring biologically active products.