The principal objectives of the next grant period are: (1) Continued development of efficient synthetic pathways for the mitomycins, FR-900482, and their epoxide analogs. These compounds are expected to show antitumor activities by cross-linking DNAs. (2) Completion of the total syntheses of discorhabdins A and C, unique marine natural products with antitumor activity. (3) Development of an efficient synthetic route for an antitumor antibiotic (-)-safracin B, which is amenable to preparation of a variety of analogs. (4) Efficient synthesis of oligothiazoline-type natural products including thiangazole, didehydromirabazole A, and their analogs. These compounds belong to a completely new family of biologically active compounds.It is hoped that compounds prepared from this project would exhibit unique antitumor and/or anti-HIV activities. (5) Development of an efficient synthetic protocol for indole alkaloids including tabersonine and catharanthine. Efficient synthesis of catharanthine and its analogs will enable the preparation of a variety of hitherto inaccessible analogs of vinblastine, a potent antitumor agent currently used clinically. (6) Completion of the total synthesis of gelsemine, a synthetically challenging alkaloid with CNS activity.
