Utility and Application of Unsaturated Acylammonium Salts

在化学系化学合成（SYN）项目的支持下，贝勒大学的Daniel Romo教授正在研究在一次操作中产生碳-碳和碳杂原子键的反应过程的发展。这些方法将显著提高生物活性天然产物和药物合成的效率。在提出的研究中，复杂的级联反应或多米诺骨牌反应的发展是快速建立结构复杂性的目标。有机催化包括使用小的手性有机分子来激活底物并引发各种键结构。尽管共价有机催化剂最近取得了进展，但普遍的底物激活模式缺乏，只有有限的类型在单个催化循环中显示多个反应位点。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新型有机级联反应的发展广泛有用，这种反应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具有潜在抗癌和抗生素活性的复杂天然化合物的生物学研究成为可能。本科生，特别是那些与贝勒本科迷你制药项目有关的学生，在这些项目中工作，可以获得团队合作和领导经验，体验药物研究的各个方面，新的专业研究技能，以及使用最先进设备的经验。此外，贝勒大学先进仪器研讨会为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，以获得这些先进的合成方法和最先进的设备的实践经验。通过这一奖项，贝勒大学的Daniel Romo教授正在追求一种基于易于生成的手性不饱和乙酰氨基铵离子的新颖而广泛的设计原则，为不断发展的可扩展、不对称有机催化领域增添了重要的突破。要研究的有机级联过程包括：(i)涉及先前描述的diels - alder -内酯化级联的动态动力学解析和（ii）吉斯型自由基引发的环化。这些方法有可能为生物活性天然产物中常见的碳环和杂环提供新的、实用的、对映选择性的合成途径。手性不饱和酰基铵盐的反应机理研究将与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对机制途径和有问题的底物的深入了解，并提供对这些反应中观察到的激活模式和对映体选择的更好理解。所开发的方法将应用于立体控制合成天然产物，包括β -内酯天然产物，具有很大的构效关系研究潜力。特别是，在与德国慕尼黑工业大学的Stephan Sieber教授的化学生物学合作中，其中一些正成为蛋白质组学探针的目标。该奖项反映了美国国家科学基金会的法定使命，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。

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.