| Research Abstract |
The antitumor alkaloid camptothecin has attracted much attention over the years since its isolation in 1966. Camptothecin has a long, rich history as a potential anticancer agent, and it has recently reemerged as one of the most important lead compounds among the antitumor natural products. Several syntheses of camptothecin have accomplished, resulting in the development of numerous new synthetic strategies and methodologies. Camptothecin proved to be a rather difficult target as is event by the length of many of the early syntheses.
We have investigated in order to develop a new and effective synthesis of camptothecin and analogs. First, we succeeded in the synthesis of the racemate of camptothecin using the enamine annulation method, which was developed by us. Using this method l0-methoxy and l0-hydroxycamptothecins were prepared. Shortening steps of this strategy was further studied and a domino reaction, double enamine annelation reaction, was devised.
Domino reactions forming multip
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le bonds in a stereo- and regio-selective manner by one procedure is one of the most ideal process in organic synthesis. The domino reaction is also called as cascade and tandem reaction. As the result of the further investigations, we could developed several types of domino reactions, which are useful for natural products synthesis. One of them is the intramolecular double Michael reaction. Thus, treatment of an indole derivative having an alpha, beta-unsaturated ester function at the C-2 position and an unsaturated amide group at the C-3 position with TBSOTf in the presence of triethylamine provided the indoloquinolizidine derivative. Tacamonine, an indole alkaloid, having important biological activities was straightforwardly synthesized by this method. The indoloquinolizidine derivative prepared by the intramolecular double Michael reaction could be converted into camptotecin analogs.
Recently, the a, b, c, d part of camptothecin was directly constructed by the intramolecular Diels-Alder reaction of a 1-azadiene. It is expected that a facile synthesis of camptothecin and analogs would be accomplished by this methodology. Less
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