Synfacts 2020; 16(08): 0890
DOI: 10.1055/s-0040-1707088
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Zoliflodacin

Philip Kocienski
Further Information

Publication History

Publication Date:
21 July 2020 (online)



Zoliflodacin is an oral antibiotic with a unique mode of inhibition against type II ­topoisomerases with binding sites in bacterial gyrase. It has entered phase 3 clinical trials for the treatment of gonorrhea (P. A. Bradford, A. A. Miller, J. O’Donnell, J. P. Mueller ACS Infect. Dis. 2020, 6, 1332). Zoliflodacin also has activity against Gram-positive, Gram-negative, and atypical pathogens including multidrug-resistant strains.



In 2015, Basarab and co-workers reported the discovery of this DNA gyrase inhibiting spiropyrimidinetrione fused to a benzisoxazole scaffold. In the key spirocyclization reaction, intermediate (2R,6R)-morpholine L underwent a 1,5-hydrogen shift to generate intermediate M that ­epimerized before cyclization to the spiropyrimidinedione in zoliflodacin (dr = 9:1).