Synthesis and Biosynthesis of Pyran and Spiroketal Structural Units

描述（由申请人提供）：我们的整体项目对聚酮类天然产物的进化和化疗潜力的基本问题感兴趣。利用有机合成的力量，我们试图了解在聚酮中发现的特定结构特征，它们对构象的影响，以及构象对生物活性的重要性。这项工作的一个基本主题是开发适用于合成聚酮天然产物中发现的立体化学复杂结构片段的实用方法。在研究期间，我们实验室之前开发的阳离子环丙烷方法将提供ambruticin J的途径，ambruticin J是抗真菌剂ambruticin s的假定生物合成中间体。这种材料将用于探索ambruticin J到ambruticin s的化学和生化转化。与Rolf Muller （Saarland大学）合作进行的研究将提供关于几种pks后蛋白的作用的基本信息，包括环氧化酶AmbJ。此外，ambruticin J合成所需的中间体将被转化为几种标记的SNAC酯，用于与生产生物以及分离蛋白质的饲养研究。饲养研究的分析将为这些含环丙烷聚酮的独特生物合成提供重要信息。研究计划的第二部分提出了新的方法，醚转移，适用于合成无环聚酮片段，吡喃结构单元和螺旋酮。与环丙烷方法一样，醚转移是一种高效的过程，通过独特的碳阳离子中间体进行，并迅速将简单的起始材料修饰成立体化学复杂的合成片段。该方法的应用包括高效地合成了聚酮、聚海绵蛋白A和聚海绵蛋白B以及新果内酯。新榄内酯聚酮核心的生物学和构象研究被提议作为类似物设计的先驱。

DESCRIPTION (provided by applicant): Our overall program is interested in fundamental issues regarding the evolution and chemotherapeutic potential of polyketide natural products. Using the power of organic synthesis, we seek to learn about the specific structural features found in polyketides, their effect on conformation, and the importance of conformation on biological activity. An underlying theme of this work is the development of practical methods applicable to the synthesis of stereochemically complex structural fragments found in polyketide natural products. During the research period, cationic cyclopropane methodology previously developed in our lab will provide access to ambruticin J, the putative biosynthetic intermediate to the antifungal agent ambruticin S. This material will be used to explore both chemical as well as biochemical conversion of ambruticin J to ambruticin S. The biochemical studies, performed in collaboration with Rolf Muller (University of Saarland) will provide fundamental information regarding the role of several post-PKS proteins including the epoxidase, AmbJ. In addition, intermediates necessary for ambruticin J synthesis will be converted to several labelled SNAC esters for feeding studies with the producing organism as well as isolated proteins. Analysis of the feeding studies will provide important information with regard to the unique biosynthesis of these cyclopropane containing polyketides. Section II of the Research Plan proposes new methodology, ether-transfer, applicable to the synthesis of acyclic polyketide fragments, pyran structural units and spiroketals. Like the cyclopropane methodology, ether-transfer is an efficient process that proceeds through a unique carbocationic intermediate and rapidly modifies simple starting materials into stereochemically complex synthetic fragments. Applications of the methodology include an efficient synthesis of the polyketides, diospongin A and B as well as neopeltolide. Biological and conformational studies on the neopeltolide polyketide core are proposed as a precursor to analogue design. PUBLIC HEALTH RELEVANCE: Our overall program is interested in fundamental issues regarding the evolution and chemotherapeutic potential of polyketide natural products. An underlying theme of this application is the development of practical methods applicable to the synthesis of complex structural fragments found in polyketide natural products. Synthetic and biosynthetic studies will investigate natural products shown to possess antifungal and anticancer activity.