Utility and Application of Unsaturated Acylammonium Salts in Organic Synthesis

在化学系化学合成计划的资助下，贝勒大学的丹尼尔·罗莫教授正在开发顺序发生的、快速建立有机分子结构复杂性的“级联”反应。作为共同派，加州大学戴维斯分校的迪恩·塔尼洛教授正在研究在ROMO实验室开发的反应中提供选择性的机械细节。现代有机合成研究致力于开发在一次操作中产生多个碳-碳、碳-氧和碳-氮键的反应过程，并控制碳周围原子的三维排列。这种方法显著提高了各种分子的合成效率，包括生物活性天然产物和具有药用价值的化合物，并提供了以前无法访问的分子结构。在这个项目中，Romo博士利用有机小分子作为催化剂来激活底物，从而以高选择性启动各种类型的键结构。他正在探索一种新的活化模式，这种模式已经被证明对开发新型的级联反应非常有用，并极大地影响了有机合成的效率。在研究组工作的本科生，特别是那些与他发起的“贝勒本科生微型制药计划”相关的本科生，正在获得团队合作和领导经验，对与制药行业相关的化学研究的各个方面的品味，新的研究技能，以及最先进的设备经验，最终为可发表的研究做出贡献。ROMO正在追求一种基于容易生成的手性不饱和酰胺盐的新颖而广泛的有机合成设计原则，对不断增长的可伸缩、不对称有机催化领域产生重大影响。他正在研究的有机级联过程包括通常由Michael加成(与碳、氮和硫亲核试剂)启动的串联反应，这些反应导致高度实用的、对映选择性的合成路线，生成生物活性天然产品和药物中常见的碳环和杂环。鉴于有机串联催化的重要性，本研究中涉及的各种不饱和酰基铵盐中间体的机理研究将与Tantillo教授合作进行。这些合作研究提供了对这些手性中间体的激活模式和对映体选择性的更好的理解。以含有β-内酯的天然产物为靶标，证明了所开发的合成方法的实用性。这些又作为蛋白质组探针，带有适当的记者标签，用于与德国慕尼黑理工大学的斯蒂芬·西伯教授在化学/生物学界面上进行基础研究。贝勒本科生微型医药项目使本科生能够通过设计、合成和测试新的衍生品来了解制药行业，以实现一个共同的目标，即识别用于潜在癌症治疗的先导化合物，包括神经母细胞瘤。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

With this award, funded by the Chemical Synthesis Program of the Chemistry Division, Prof. Daniel Romo of Baylor University is developing "cascade" reactions that occur sequentially and rapidly build up structural complexity in organic molecules. As co-PI, Professor Dean Tanillo of the University of California, Davis, is studying the mechanistic details that provide for selectivity in the reactions developed in the Romo lab. Modern day organic synthesis research seeks to develop reaction processes that generate multiple carbon-carbon, carbon-oxygen, and carbon-nitrogen bonds in a single operation, and with control of the 3-dimensionnal arrangement of atoms around carbon. This approach significantly increases the efficiency of the synthesis of a variety of molecules, including bioactive natural products and compounds of pharmaceutical interest, and provides access to molecular architectures not previously accessible. In this project, Dr. Romo is utilizing small organic molecules that serve as catalysts to activate substrates leading to initiation of various types of bond constructions with high selectivity. He is exploring a new activation mode that is already proving broadly useful for the development of novel cascade reactions, and greatly impacting efficiency in organic synthesis. Undergraduates working in the research group and in particular those associated with the "Baylor Undergraduate MiniPharma Program" that he initiated, are gaining teamwork and leadership experience, a taste of various aspects of chemical research relevant to the pharmaceutical industry, new research skills, and experience with state-of-the-art equipment, ultimately contributing to publishable research.Prof. Romo is pursuing a novel and broad design principle for organic synthesis based on readily generated chiral unsaturated acylammonium salts, significantly impacting the growing field of scalable, asymmetric organocatalysis. The organocascade processes he is studying include tandem reactions typically initiated by Michael additions (with carbon, nitrogen, and sulfur nucleophiles) that lead to highly practical, enantioselective synthetic routes to carbocycles and heterocycles commonly found in bioactive natural products and pharmaceuticals. Given the importance for organocascade catalysis, mechanistic studies of the various unsaturated acylammonium salt intermediates accessed in this research will be undertaken in collaboration with Prof. Tantillo. These collaborative studies are providing a greater understanding of the mode of activation and enantioselectivity observed with these chiral intermediates. The utility of the developed synthetic methods is being demonstrated by targeting natural products bearing beta-lactones. These in turn serve as proteomics probes with appropriate reporter tags for fundamental studies at the chemistry/biology interface with Prof. Stephan Sieber (Tech Univ of Munich, Germany). The Baylor Undergraduate MiniPharma Program enables undergraduates to get a 'taste' of the pharmaceutical industry by designing, synthesizing, and testing novel derivatives toward a common goal of identifying lead compounds for potential cancer treatment, including glioblastoma.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.