Synthetic Study on Antitumor Compounds Starting from Carbohydrates

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The development of new chemotherapeutic agent against cancer prossessing high activity and low toxicity is a highly important task in medical science. The major objective of this research is to establish the synthetic route to the compounds having high anti-tumor activity starting from readily available carbohdyrates.Toward this end, total synthesis of 7-deoxypancratistatin and FR 65814, both are expected to be novel lead compounds for new chemotherapeutic agents against cancer, starting from D-glucose is investigated.1. Total Synthesis of 7-Deoxypancratistatin.7-Deoxypancratistatin and pancratistatin, both are phenanthridone alkaloids, were isolated from the roof of the plant and has been reported to show high activity in several anticancer test systems. Due to their low natural abundance as well as practical complications in separation, the development of synthetic method for these compounds are highly desired. The aminocyclohexane portion of 7-deoxypancratistatin was effectively con … More structed in an optically pure form from D-glucose utilizing ferrier's carbocyclization reaction. After condensation with 6-bromopiperonic acid, the resulting bromo-enamide was converted into phenanthridone by means of Pd-catalyzed cyclization. Stereoselective hydrogenation and introduction of hydroxy group via epoxide afforded 7-deoxypancratistatin. The precursor of 7-deoxypancratistatin was aiso converted into another natural alkaloid, 7-deoxy-trans-dihydronarciclasine. Thus, stereoselective synthetic pathway to 7-deoxpancratistatin starting from D-glucose was established. Further synthetic study toward pancratistatin is underway.2. Synthetic Study of FR65814.FR65814 is a novel immunosuppressant isolated from culture broth of Penicillium. The structural resaemblance of FR 65814 to fumagillol makes this compound promising for anti-tumor agent. For the synthesis FR65814, its highly oxygenated cyclohexane ring was prepared by Ferrier's carbocyclization reaction from D-glucose. After stereoselective reduction of the ketone carbonyl, the side chain of FR 65814 was effectively introduced by Claisen rearrangement. The product was converted into ally alcohol derivative, which is expected to be a potent precursor for the total synthesis of FR 65814. Less