Synthesis and Biosynthesis of Pyran and Spiroketal Structural Units

描述（由申请人提供）：我们的总体计划是关于聚酮化合物天然产物的演变和化疗潜力的基本问题。利用有机合成的力量，我们试图了解聚酮化合物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化合物天然产物中立体化学复杂结构片段的实用方法。在研究期间，我们实验室先前开发的阳离子环丙烷方法将提供获得安布鲁特星J的途径，安布鲁特星J是抗真菌剂安布鲁特星S的假定生物合成中间体。该材料将用于探索安布霉素J向安布霉素S的化学和生物化学转化。与Rolf Muller（萨尔兰大学）合作进行的生化研究将提供有关几种PKS后蛋白质（包括环氧酶AmbJ）作用的基本信息。此外，合成安地霉素J所需的中间体将转化为几种标记的SNAC酯，用于生产生物体以及分离的蛋白质的饲养研究。喂养研究的分析将提供重要的信息，关于这些环丙烷含聚酮化合物的独特的生物合成。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，吡喃结构单元和螺缩酮。与环丙烷方法一样，醚转移是一种有效的过程，通过独特的碳阳离子中间体进行，并将简单的起始材料快速修饰成立体化学复杂的合成片段。该方法的应用包括有效合成的聚酮化合物，diospongin A和B以及neopeltolide。生物学和构象的neopeltolide聚酮核心的研究提出了类似物设计的先驱。

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.