A Stereocontrolled Synthesis of (+)-Febrifugine via Azide and Azide-Free Pathways

(+)-Febrifugine, a natural antimalarial compound with a promising therapeutic profile, has become a hot target for synthetic chemists seeking to optimize its biological activity and expand its therapeutic applications. In this research, we present a stereocontrolled synthesis of (+)-febrifugine using both azide and azide-free approaches. Starting from the commercially available chiral pool precursor, d-glucose, the synthesis was completed in 20 steps for both approaches. Key reactions included the Zn-mediated Bernet-Vasella reaction, Horner-Wadsworth-Emmons reaction, and cyclization for constructing the chiral substituted piperidine ring. Additionally, α-bromoketone alkylation of quinazolinone was employed to assemble the (+)-febrifugine core structure.