Synthesis and Biosynthesis of Pyran and Spiroketal Structural Units

描述(由申请人提供)：我们的整个项目对聚酮类天然产物的进化和化学治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类化合物中发现的特殊结构特征，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，我们实验室以前开发的阳离子环丙烷方法将提供AmBruticin J，抗真菌药物AmBruticin S的假定生物合成中间体。该材料将用于探索AmBruticin J到AmBruticin S的化学和生化转化。与罗尔夫·穆勒(萨尔兰大学)合作进行的生化研究将提供包括环氧酶AmbJ在内的几种PKS后蛋白质的作用的基本信息。此外，合成AmBruticin J所需的中间体将被转化为几种标记的SNAC酯，用于生产生物体和分离蛋白的饲料研究。对投料研究的分析将提供关于这些含有环丙烷的聚酮的独特生物合成的重要信息。研究计划第二节提出了适用于合成无环多酮片段、吡喃结构单元和螺酮的新方法--乙醚转移。与环丙烷方法一样，乙醚转移是一种有效的过程，它通过一种独特的碳阳离子中间体进行，并迅速将简单的起始材料修改为立体化学复杂的合成碎片。该方法的应用包括有效地合成多酮类化合物、薯蓣皂苷A和B以及新胡萝卜素内酯。对新薄荷内酯聚酮核心进行了生物学和构象研究，作为模拟设计的先导。

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.