Synthetic Study on Antitumor Compounds Starting from Carbohydrates

开发高活性、低毒的新型抗癌化疗药物是医学领域的重要课题。本研究的主要目的是从现成的碳水化合物开始，建立具有高抗肿瘤活性的化合物的合成途径。为此，研究了从d -葡萄糖开始的7- deoxyypancatstatin和FR 65814的全合成，这两种化合物有望成为新的抗癌化疗药物的先导化合物。7-去氧甘草汀的全合成。7-脱氧葡萄碱和葡萄碱都是菲那西酮类生物碱，从植物的顶部分离出来，据报道在几种抗癌测试系统中显示出高活性。由于它们的天然丰度较低以及分离的实际复杂性，因此迫切需要发展这些化合物的合成方法。利用铁链的碳环化反应，从d -葡萄糖中有效地合成了7-去氧甘草汀的氨基环己烷部分。与6-溴丙二酸缩合后，通过pd催化环化反应生成非那恶酮。立体选择性氢化并通过环氧化物引入羟基，得到7-去氧潘甲他汀。7-脱氧葡萄碱的前体也被转化为另一种天然生物碱，7-脱氧反式二氢葡萄碱。由此，建立了以d -葡萄糖为起始点立体选择性合成7-去氧潘克拉他汀的途径。进一步的合成研究正在进行中。FR65814的合成研究。FR65814是从青霉菌发酵液中分离得到的一种新型免疫抑制剂。FR 65814与富马吉尔尔的结构相似性使其有望成为抗肿瘤药物。FR65814的合成是由d -葡萄糖经Ferrier碳环化反应制备的高氧环己烷环。经酮羰基立体选择性还原后，FR 65814侧链被Claisen重排有效引入。该产物被转化为烷基醇衍生物，有望成为全合成FR 65814的有力前体。少

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