Cyclization Strategies and Methodologies Toward the Synthesis of Complex Natural Products

在化学系化学合成（SYN）项目的支持下，印第安纳州大学（IU-Bloomington）的大卫威廉姆斯教授将开发用于构建复杂生物活性分子的新方法和策略。 这些概念之所以重要，主要有两个原因。 有必要设计更有效的程序来组装分子的复杂性，同时找到环境友好的试剂和反应。 其次，需要扩大结构化学的范围，以确定具有生物活性的新支架，既作为化学生物学的工具，又作为药物化学的潜在热门甚至先导化合物。 将探索多步合成途径以制备生物活性天然产物;该项目特别关注反应性化合物的金属催化环化反应，这是可能导致在单个反应中形成两个或更多个环的特征。 该项目的教育方面是面向广泛发展学生作为有机化学领域的问题解决者。 从这个实验室的经验大多数毕业生在制药和生物技术行业就业。 社会效益将包括征聘代表性不足的个人和妇女并使其参与研究的各个方面。 暑期研究机会也将提供给本科参与者在这个研究项目。该研究项目旨在为合成方法，特别是环化反应策略奠定新的基础。 过渡金属催化的应变环丙烷和环丙烯的反应将被探索为复杂的，生物活性的天然产物的合成的新途径的设计中的一个关键要素。 拟议的活动预计将推进知识的合成取代环丙烷和有效地将这些反应性的积木到复杂的分子结构。 这些调查也将审查的倾向重组的小环金属杂环，形成更稳定的π-烯丙基金属中间体在环化过程中。 项目的目标是设计一个以分子内[3+2]和[2+2+1]环化结束的反应级联。 通过考察催化剂及其配体所施加的电子和空间因素，对反应范围和立体选择性进行了研究。 提出了新的合成策略，有效地构建了三环氰乙烷和梭壳烷，并完成了daphnicyclidin A的合成。 该项目是印第安纳州大学化学系STEM（科学，技术，工程和数学）承诺的重要组成部分，重点是通过IU ACS桥接方案为妇女和代表性不足的个人提供机会。 通过与生物学、动物科学、神经科学和医学等相关学科的科学家进行有计划的合作，预计将产生更广泛的科学影响。 总体而言，该项目旨在推进基础有机化学方法和战略，并为学生提供现代合成化学培训的上级平台。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemical Synthesis (SYN) Program in the Division of Chemistry, Professor David Williams of Indiana University (IU-Bloomington) will develop new methods and strategies for the construction of complex, bio-active molecules. These concepts are important for two principal reasons. There is a need to devise more efficient procedures for the assembly of molecular complexity while finding environmentally benign reagents and reactions. Secondly, there is need to expand the limits of structural chemistry to identify new scaffolds that are biologically active, both as a tools for chemical biology and as potential hit or even lead compounds for medicinal chemistry. Multi-step synthesis pathways will be explored for the preparation of bio-active natural products; this project is especially focused on metal-catalyzed cyclization reactions of reactive compounds as a feature that may lead to the formation of two or more rings in a single reaction. Educational aspects of this project are geared to broadly develop students as problem-solvers in the field of organic chemistry. Most of the graduates from this laboratory experience are employed in the pharmaceutical and biotechnology industries. Societal benefits will include the recruitment and participation of under-represented individuals and women in all aspects of the research. Summer research opportunities will also be available for undergraduate participants in this research project. This research project seeks to forge new ground in synthetic methodology and particularly in strategies for cyclization reactions. Transition metal-catalyzed reactions of strained cyclopropanes and cyclopropenes will be explored as a key element in the design of new pathways for the synthesis of complex, bio-active natural products. The proposed activities are expected to advance knowledge regarding the synthesis of substituted cyclopropanes and the effective incorporation of these reactive building blocks into complex molecular architectures. These investigations will also examine the propensity for reorganization of small ring metallacycles to form more stable pi-allyl metal intermediates in cyclization processes. Project objectives seek to devise a reaction cascade concluding with intramolecular [3+2] and [2+2+1] cyclizations. Studies are also planned on reaction scope and stereoselectivity through the examination of electronic and steric factors imposed by the catalyst and its ligands. New synthesis strategies are proposed for the efficient construction of tricyclic cyathanes and fusicoccanes, as well as for completion of the synthesis of daphnicyclidin A. The project is a significant component of the Indiana University Department of Chemistry STEM (Science, Technology, Engineering and Mathematics) commitment with an emphasis on access for women and underrepresented individuals through the IU ACS Bridging Program. Broader scientific impacts are expected through planned collaborations with scientists in allied disciplines including biology, animal sciences, neuroscience and medicine. Overall, this project aims to advance fundamental organic chemistry methodology and strategy and to provide a superior platform for student training in modern synthetic chemistry.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.