Diverse-Target Synthesis: Direct Access to the Bioactive Xenicane Family Tree

描述(申请人提供)：本研究方案的目标是合成具有生物活性的杂环烷小分子天然产物，以便于进一步研究了解癌症和细菌疾病的生物学。在过去的二十年里，由于对小分子天然产物(SMNPs)的研究，大量的抗癌和抗菌药物被开发出来。由于缺乏来自不可再生、生长缓慢的生物体的材料，需要对SMNPs进行全化学合成以进行严格的生物学评估。一条短而简明的合成路线将为研究提供材料，以帮助理解疾病的生物学并确定疾病治疗的新方式。在这项提案中，将使用一种结合了目标和多样性方法的战略，以直接获得半有效的抗癌和抗细菌Xicane SMNPs谱系树。该合成的关键步骤包括Oppolzer氢化硼化/跨金属环合，使用SHI环氧化的动态动力学拆分，Diels-Alder/Retro Diels-Alder反应，以及钛自由基和Lewis酸介导的跨环反应。拟议研究与公共卫生的相关性：癌症和细菌疾病的生物学尚未完全了解。新的生物活性化合物的合成和评价对于药物开发和疾病治疗新方法的确定是必要的。该提案中的合成路线将使人们能够获得一系列具有生物活性的天然产品，这些产品可以作为工具，促进进一步研究，以了解癌症和细菌疾病的生物学，从而努力推动现代医学的发展。

DESCRIPTION (provided by applicant): The goal of this research proposal is to synthesize the biologically active xenicane small molecule natural products in order to facilitate further research to understand the biology of cancer and bacterial diseases. A significant number of anticancer and antibacterial drugs have been developed over the past twenty years primarily due to the studies of small molecule natural products (SMNPs). Owing to the paucity of material from non-renewable, slow-growing organisms the total chemical synthesis of SMNPs is required for rigorous biological evaluation. A short and concise synthetic route to a suite of structurally diverse and biologically active SMNPs would provide material for research to help understand the biology of diseases and determine new modalities for disease treatment. In this proposal a strategy that incorporates both a target- and diversity-oriented approach will be used to gain direct access to the semi-validated anticancer and antibacterial xenicane family tree of SMNPs. Key steps in this synthesis include Oppolzer hydroboration/transmetallation cyclization, dynamic kinetic resolution using the Shi epoxidation, Diels- Alder/retro Diels-Alder reaction, and titanium radical and Lewis acid mediated transannulations. Relevance of proposed research to public health: The biology of cancer and bacterial diseases is not yet fully understood. The synthesis and evaluation of new biologically active compounds is needed for drug development and determination of new methods for disease treatment. The synthetic route in this proposal would give access to a suite of bioactive natural products which can serve as tools to facilitate further research to understand the biology of cancer and bacterial diseases in an effort to advance modern medicine.