TOTAL SYNTHESIS OF KINAMYCINS AND LOMAIVITICINS

运动霉素和洛马霉素的全合成

• 批准号: 7215159
• 负责人: K. C. NICOLAOU
• 金额: $ 48.17万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215159
• 关键词: 9,10-anthraquinone; Acids; Alkylation; Anthraquinones; Applications Grants; Area; Biological; Biological Factors; Biomimetics; Carbon; Chemotherapy-Oncologic Procedure; Cleaved cell; Crowding; Development; Dihydroxyacetone; Dimerization; Esters; Evaluation; Generations; Monitor; Numbers; Pliability; Process; Production; Research; Screening procedure; Technology; Work; analog; antitumor agent; cytoskyrin A; drug discovery; tetrahydrothiophene

DESCRIPTION (provided by applicant): This grant application describes the proposed total syntheses of a number of potent antitumor agents of natural origin, namely lomaiviticins A and B, cytoskyrin A, amphidinolide N and caribenolide I, as well as a number of related molecules for biological screening. The proposed total synthesis of the lomaiviticins would involve the dimerization of an advanced a-halo enone intermediate to generate the C2-symmetric polycyclic framework. Further elaboration of the sterically crowded central core would then be facilitated by the temporary incorporation of a bridging cyclic tether. Two alternative such tethers have been devised, namely a tetrahydrothiophene and a carbocycle bearing a pendant ester group, increasing the flexibility of the overall strategy. Once the required structural motifs are installed, either of these bridges could be oxidatively cleaved to reveal the necessary functionalities for completion of the target molecules. For cytoskyrin A, a biomimetic cascade process to furnish the cage-like framework of the target molecule has been experimentally demonstrated. Involving the acid-catalyzed dimerization of an anthraquinone derivative followed by a bis-enolization/ double intramolecular Michael addition sequence, careful monitoring of this cascade allows for the selective generation of the central core of not only cytoskyrin A, but also that of a number of other structurally related biologically active natural products. This cascade process would be amenable to the production of not only these natural products themselves, but also to that of specifically targeted analogs, which would be screened for antitumor activity. The proposed syntheses of amphidinolide N and caribenolide I feature a unified, highly convergent strategy involving the sequential asymmetric alkylation of a chiral 1,3-dihydroxyacetone equivalent to establish the complete carbon framework of the target molecules, followed by a highly selective macrolactonization to generate the 26-membered ring in each case. The significance of the proposed work will lie specifically in the area of cancer chemotherapy research, and in the development of new synthetic strategies and technologies for general use in the drug discovery and development process.

描述（由申请人提供）：本授权申请描述了许多天然来源的有效抗肿瘤剂，即洛麦维他菌素A和B、细胞骨架素A、两性霉素N和卡立宾菌素I，以及许多用于生物筛选的相关分子的建议全合成。所提出的洛麦替星的全合成将涉及高级α-卤代烯酮中间体的二聚化以产生C2-对称多环骨架。空间拥挤的中央核心的进一步加工将通过临时结合桥接环状系链来促进。已经设计了两种替代的这样的系链，即四氢噻吩和带有侧酯基的碳环，增加了整体策略的灵活性。一旦安装了所需的结构基序，这些桥中的任何一个都可以被氧化裂解，以揭示完成靶分子所必需的功能。对于cytoskyrin A，提供靶分子的笼状框架的仿生级联过程已被实验证明。涉及酸催化的二聚化的蒽醌衍生物，然后由一个双烯醇化/双分子内迈克尔加成序列，仔细监测这级联允许选择性产生的中心核心不仅cytoskyrin A，但也有一些其他结构相关的生物活性的天然产物。这种级联过程不仅适用于生产这些天然产物本身，而且适用于生产特定靶向类似物，并对这些类似物进行抗肿瘤活性筛选。建议的amphidinobenzene N和caribenobenzene I的合成具有统一的，高度收敛的策略，涉及顺序的手性1，3-二羟基丙酮等价物的不对称烷基化，以建立完整的碳框架的目标分子，然后由一个高度选择性的macrolactonization生成的26元环在每种情况下。拟议工作的意义将具体在于癌症化疗研究领域，以及开发新的合成策略和技术，用于药物发现和开发过程。