SYNTHESIS OF ANTITUMOR AGENTS AND RELATED CHEMISTRY

描述：（主要研究者摘要） 本研究的明确目标包括： 1.为了完成一个高度收敛的，相对较短的全合成， 抗癌剂软海绵素B，它对几种药物具有强效活性 耐药的人实体瘤异种移植物，但受到缺乏进一步研究的限制。 NCI临床前研究的进展。 2.为了进一步开发6，8-二氧杂双环（3.2.1）辛烷的有效合成， 分子间缩醛化/分子内二烯复分解，用于应用 唾液酸合成（KDN、N-乙酰神经氨酸（Neu 5Ac）和KDO）。的 这些目标中的最后一个将需要开发一种区分 在复分解去对称化中的对映体乙烯基之间。 3.探索桥连6，8-二氧杂双环（3.2.1）辛烷的转化 1，7-二氧杂螺（5.5）癸烷螺缩酮的衍生物，其普遍存在 昆虫信息素、抗癌和抗生素天然结构成分 产品. 4.目的：探索番荔枝内酯类化合物的合成新方法， 催化闭环复分解以构建双（四氢呋喃）核， 例如鳞霉素的全合成。快速访问 对映体纯的C2-对称核将提供容易获得的几种 这类中的其它有效的抗肿瘤剂，其显示出十倍于 8次幂到10次幂是阿霉素对几种 肿瘤细胞系 5.在战略层面上，利用对称和新颖的战略， 简化复杂的目标，并提供短而 其有效合成。

DESCRIPTION: (Principal Investigator's Abstract) Explicit goals of this research include: 1. To complete a highly convergent, relatively short total synthesis of the anticancer agent halichondrin B, which is potently active against several resistant human solid tumor xenografts, but is limited by scarcity from further advancement in NCI preclinical studies. 2. To further develop a powerful synthesis of 6,8-dioxabicyclo(3.2.1)octanes by intermolecular acetalization/intramolecular diene metathesis, for application to sialic acid syntheses (KDN, N-acetylneuraminic acid (Neu5Ac), and KDO). The last of these targets will require development of a means to distinguish between enantiotopic vinyl groups in the metathesis desymmetrization. 3. To explore the conversion of bridged 6,8-dioxabicyclo(3.2.1)octane derivatives to 1,7-dioxaspiro(5.5)decane spiroketals, which are ubiquitous structural components in insect pheromones, anticancer and antibiotic natural products. 4. To develop a new synthetic approach to the annonaceous acetogenins using catalytic ring closing metathesis to construct the bis(tetrahydrofuran) core, exemplified by a total synthesis of squamotacin. Quick access to the enantiomerically pure, C2-symmetric core will provide ready access to several additional potent antitumor agents in this class, which show potency ten to the 8th power to ten to the 10th power times that of adriamycin against several tumor cell lines. 5. To exploit, at the strategic level, symmetry and novel strategies for symmetry-breaking to simplify complex targets and to provide short and efficient syntheses thereof.