Utility and Application of Unsaturated Acylammonium Salts

不饱和酰胺盐的用途和应用

• 批准号: 2154430
• 负责人: Daniel Romo
• 金额: $ 53.5万
• 依托单位: Baylor University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2154430&HistoricalAwards=false
• 关键词: Utility; Application; Unsaturated; Acylammonium; Salts

With the support of the Chemical Synthesis (SYN) program in the Division of Chemistry, Professor Daniel Romo of Baylor University is studying the development of reaction processes that generate carbon-carbon and carbon-heteroatom bonds in a single operation. These methods will significantly increase the efficiency of bioactive natural product and pharmaceutical synthesis. In the proposed research, the development of complex cascade or domino reactions are targeted that build up structurally complexity very rapidly. Organocatalysis involves the use of small, chiral organic molecules to activate substrates and initiate various bond constructions. Despite recent advances in covalent organocatalysts, there is a paucity of general substrate activation modes, with only limited types revealing multiple reactive sites in a single catalytic cycle. This research, in collaboration with a computational chemist, will continue exploration of a novel activation mode that is already proving broadly useful for the development of novel organo-cascade reactions that greatly impacts efficiency in organic synthesis. In addition, the methods being developed are expected to enable biological studies of complex naturally-occurring compounds with potential activity as anticancer and antibiotic agents. Undergraduate students, in particular those associated with the Baylor Undergraduate MiniPharma Program, working on these projects are gaining teamwork and leadership experience, a taste of various aspects of pharmaceutical research, new specialized research skills, and experience with state-of-the-art equipment. In addition, the Baylor University Advanced Instrumentation workshop provides an opportunity for faculty and students from local primarily undergraduate institutions to visit Baylor University to gain hands-on experience with these advanced synthetic methods and state-of-the-art equipment.Through this award, Professor Daniel Romo from Baylor University is pursuing a novel and broad design principle based on readily generated chiral unsaturated acylammonium ions, adding an important foray into the growing field of scalable, asymmetric organocatalysis. The organo-cascade processes to be studied include the development of (i) a dynamic kinetic resolution involving a previously described Diels-Alder-lactonization cascade and (ii) a Giese-type radical-initiated cyclization. These approaches have the potential to provide new, practical, enantioselective synthetic routes into both carbocycles and heterocycles commonly found in bioactive natural products. Mechanistic studies of the reactions of the chiral unsaturated acylammonium salts will be undertaken in collaboration with Professor Dean Tantillo (UC Davis). It is anticipated that these collaborative studies will provide insight into mechanistic pathways and problematic substrates and provide a greater understanding of the mode of activation and of enantioselection observed in these reactions. The methods being developed will be applied to the stereocontrolled synthesis of natural products including beta-lactone natural products with great potential for structure-activity relationship studies. In particular, several of these are being targeted as proteomic probes in a chemical biology collaboration with Professor Stephan Sieber of the Technical University of Munich, Germany.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.

在化学系化学合成（SYN）项目的支持下，贝勒大学的丹尼尔罗莫教授正在研究在单一操作中产生碳-碳和碳-杂原子键的反应过程的发展。这些方法将大大提高生物活性天然产物和药物合成的效率。在拟议的研究中，复杂的级联或多米诺骨牌反应的发展是有针对性的，建立结构上的复杂性非常迅速。 有机催化涉及使用小的手性有机分子来活化底物并引发各种键结构。尽管共价有机催化剂的最新进展，有一个缺乏一般的底物活化模式，只有有限的类型揭示多个反应位点在一个单一的催化循环。这项研究与计算化学家合作，将继续探索一种新的激活模式，这种模式已经被证明对开发新型有机级联反应非常有用，这极大地影响了有机合成的效率。此外，正在开发的方法有望使复杂的天然化合物的生物学研究具有潜在的抗癌和抗生素活性。本科生，特别是那些与贝勒大学生微型制药计划，在这些项目上工作获得团队合作和领导经验，制药研究的各个方面的味道，新的专业研究技能，并与国家的经验最先进的设备。此外，贝勒大学先进仪器研讨会为来自当地主要本科院校的教师和学生提供了一个访问贝勒大学的机会，以获得这些先进合成方法和最先进设备的实践经验。通过这个奖项，贝勒大学的丹尼尔罗莫教授正在追求一种新颖而广泛的设计原理，该原理基于容易生成的手性不饱和酰胺离子，加入了一个重要的进军日益增长的领域的规模，不对称有机催化。要研究的有机级联过程包括开发（i）涉及先前描述的Diels-Alder内酯化级联的动态动力学拆分和（ii）Giese型自由基引发的环化。 这些方法有可能提供新的，实用的，对映选择性的合成路线到碳环和杂环中常见的生物活性天然产物。手性不饱和酰基铵盐反应的机理研究将与Dean Tantillo教授（加州大学戴维斯分校）合作进行。预计这些合作研究将提供深入了解的机制途径和有问题的基板，并提供了更好的理解模式的激活和在这些反应中观察到的对映选择。这些方法的建立将为天然产物的立体控制合成提供新的思路，包括β-内酯类天然产物的立体控制合成，具有很大的构效关系研究潜力。 特别是，其中几个正在与德国慕尼黑工业大学的Stephan Sieber教授进行化学生物学合作，作为蛋白质组学探针。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。