Total synthesis of (+)-vinblastine: control of the stereochemistry at C18'.
Vinblastine has been widely known as a prominent agent in cancer chemotherapy, and in order to search for more potent drugs, various analogs have been derived from natural products. However, because modifications of natural products have limited classes of derivatives, an efficient synthetic route toward vinblastine has been required.Herein a stereocontrolled total synthesis of (+)-vinblastine is described. The synthesis of the upper half features a stereoselective construction of the tertiary alcohol through a 1,3-dipolar cycloaddition of nitrile oxide and a Baeyer-Villiger oxidation, a facile indole formation utilizing a radical cyclization of o-alkenylthioanilide, and a macrocyclization of 2-nitrobenzenesulfonamide. The crucial coupling of the upper half with synthetic vindoline was successfully performed to furnish the coupling product in nearly quantitative yield, and subsequent transformations provided (+)-vinblastine.
Yokoshima
Satoshi
S
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. yokosima@mol.f.u-tokyo.ac.jp
Tokuyama
Hidetoshi
H
Fukuyama
Tohru
T
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D013237:Stereoisomerism; D014747:Vinblastine / Q000138:chemical synthesis* / Q000737:chemistry
D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine