| Research Abstract |
Previously we reported a new synthetic method for the preparation of indoles having various kinds of alkyl-and/or alkoxy-substituents at the benzene portion of the indole nucleus, starting from 2- or 3-substituted pyrroles. In the present research project, our new method was applied to an enantioselective synthesis of a variety of bio-active natural products of indole series, and the following successful results were obtained, culminating in a synthesis of an extremely potent anti-tumor antibiotic, duocarmycin SA.
1.Enantiomers of herbindoles A, B and C, cytotoxic constituents of an orange-colored sponge collected near Australia, were synthesized from a chirality-defined Diels-Alder adduct. This study established the absolute structures of the natural herbindoles, which had remained unknown.
2.Absolute structures of cis-, trans- and iso-trans-trikentrins B were also established by enantioselective syntheses of itself and enantiomers, starting from an intermedate of the above herbindole synthesis. These trikentrins are ingredients of another sponge in the ocean near Australia.
3.Antibacterial and antimycotic hapalindole O was synthesized from (R)-(-)-carvone.
4.Stereoselective synthesis of pendolmycin, an inhibitor of EGF-induced phosphatidylinositor turnover, was accomplished by incorporation of an optically active amino-alcohol into the position to be improved.
5.Mitosene derivatives related to mitomycins and FR 900482 were synthesized by condensation of a chiral aldehyde derived from an optically active amino acid and 4-alkoxyindoles obtainable using our indole synthesis.
6.A potent anti-tumor antibiotic, duocarmycin SA was synthesized by resolution of a racemic intermediate. It was shown that the non-natural enantiomer of duocarmycin SA exhibits also very strong anti-tumor activities.
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