SYNTHETIC/MECHANISTIC INVESTIGATIONS OF ANTITUMOR AGENTS

安卡环素类化合物的合成和机理研究 抗肿瘤剂是该提议的一个目的。一种有效 对安卡环素家族的几个成员的对映选择性策略 抗肿瘤抗生素的概述。总体战略的关键是 本发明涉及包含以下的四环环体系的对映选择性组装： 通过Diels-Alder环加成反应将抗生素的糖苷配基部分转化为糖苷配基。的 Diels-Alder反应的二烯组分有效地制备， 从（-）-奎尼酸开始的光学活性形式。后 环系统的建设，新的方法， 描述了关键氧官能团的立体控制引入。 接下来，L-玫瑰糖的合成， 寡糖部门的许多angucycline抗生素概述。 寡糖的立体控制组装方法及其应用 在合成抗肿瘤抗生素长春霉素B2中的应用 然后描述PI-080。胸苷酸的收敛合成 合成酶抑制剂BE-7585 A也被概述。最后，实验 旨在探索空气与地球的潜在关系 将抗生素水霉素的二氢醌形式氧化成其 抗肿瘤活性也进行了讨论。 该提案的第二个主要目标是FR的全合成- 66979一种抗癌剂，它能诱导DNA-DNA交联， 进行了I期临床试验。取得成功的核心要素 这种抗肿瘤剂的对映选择性合成是金属催化的 不对称碳-氢插入反应， 含有杂环。据报道，DNA-DNA交联形成 通过一个类似于丝裂素的中间体。一种综合办法， 描述了推定的烷基化物质的产生。最后， 旨在探测该中间体的反应性的实验 也进行了讨论。 最终，这些调查将导致新的发展。 合成方法以及临床应用， 抗癌药物的开发。

Synthetic and mechanistic investigations of the angucycline class of antitumor agents is one objective of this proposal. An efficient enantioselective strategy to several members of the angucycline family of antitumor antibiotics is outlined. Key to the general strategy is the enantioselective assembly of the tetracyclic ring system comprising the aglycone portion of the antibiotics via a Diels-Alder cycloaddition. The diene component of the Diels-Alder reaction is efficiently prepared in optically active form starting from (-)-quinic acid. Following the construction of the ring system, novel approaches for the stereocontrolled introduction of key oxygen functionality are described. Next the synthesis of L-rhodinose a monosaccharide common to the oligosaccharide sector of many angucycline antibiotics is outlined. Methodology for the stereocontrolled assembly of oligosaccharides and its application to the synthesis of the antitumor antibiotics vineomycin B2 and PI-080 is then described. A convergent synthesis of the thymidylate synthase inhibitor BE-7585A is also outlined. Finally, experiments directed towards exploring the potential relationship of the air oxidation of the dihydroquinone form of the antibiotic aquayamycin to its antitumor activity are also discussed. The second major objective of this proposal is the total synthesis of FR- 66979, an anticancer agent which induces DNA-DNA cross-links and has undergone phase I clinical trials. Central to the success of the enantioselective synthesis of this antitumor agent is a metal-catalyzed asymmetric carbon-hydrogen insertion reaction to produce a nitrogen containing heterocycle. DNA-DNA cross-link formation reportedly occurs via a mitosene-like intermediate. A synthetic approach towards the generation of the putative alkylating species is described. Finally, experiments directed towards probing the reactivity of this intermediate is also discussed. Ultimately these investigations will lead to the development of new synthetic methodologies as well as clinical application in the development of anticancer agents.