101(P-38) Duocarmycin SAの全合成研究(ポスター発表の部)
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(+)-Duocarmycin SA (1), which is a potent antitumor antibiotic bears a characteristic structural features in which the tricyclic ring system containing cyclopropane are connected with the trimethoxyindole part. Due to both of the unique structure and biological activity, 1 had been attracted by many organic chemists and total syntheses had been already reported by several research groups. Herein, we will report synthetic studies of 1 by two independent routes using two different kind methods for constructing the nitrogen containing heterocycles as key steps. For the first route, the epoxide (17) which is the substrate for the ring closure reaction was synthesized from commercially available 4-amino-3-nitrophenol (14) by 5 steps in good overall yield. The reaction of 17 with BuLi in THF gave the desired 5-membered ring (18) for 82% yield as a single isomer via 5-exo selective ring closure reaction of the carbanion intermediate. Acetylation of 18, followed by regioselective nitration reaction provided 19. The substrate for Sonogashira coupling reaction was synthesized by reduction of nitro group and bromination. However, the bromide (21) was completely recovered in the all reaction conditions. At this point, as we thought that this low reactivity might be the serious steric hindrance, we turned our attention to the other synthetic route. For the second route, 2-amino-5-nitrophenol (23) was converted to the iodide (26) by benzyl ether formation, regioselective iodination, and mesylamide formation. Application of Negishiis coupling conditions to the iodide (26) with methyl propiolate afforded the unexpected indole (28) via tandem coupling and cyclization reaction. The nitro group of 28 was converted to the iodide (34) by 3 steps and it was coupled with propargyl alcohol by Sonogashira coupling reaction provided the acetylene (35). The partial reduction of the triple bond in the presence of Lindler catalyst and the resulting alcohol was subjected to intramolecular Mitsunobu reaction and deprotection gave 38 in almost perfect overall yield. The epoxidation of 38 and the reductive epoxide opening reaction provided the alcohol (40), which was converted to 41 by the reported procedure. The spectral data of 40 and 41 were identified with reported data and the formal synthesis of 1 was accomplished. Now, asymmetric total synthesis of 1 is under going in our laboratory.
- 2003-09-01
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