Utility and Application of Unsaturated Acylammonium Salts in Organic Synthesis

不饱和酰铵盐在有机合成中的用途及应用

• 批准号: 1800411
• 负责人: Daniel Romo
• 金额: $ 47.96万
• 依托单位: Baylor University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1800411&HistoricalAwards=false
• 关键词: Utility; Application; Unsaturated; Acylammonium; Salts

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.

贝勒大学（Baylor University）的丹尼尔·罗莫（Daniel Romo）教授获得了由化学部化学合成项目资助的这一奖项，他正在开发“级联”反应，这种反应顺序发生，并迅速建立起有机分子的结构复杂性。作为联合负责人，加州大学戴维斯分校的迪恩·塔尼洛教授正在研究在罗莫实验室开发的反应中提供选择性的机理细节。现代有机合成研究寻求发展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药物感兴趣的化合物，并提供了以前无法获得的分子结构。在这个项目中，Romo博士利用小有机分子作为催化剂来激活底物，从而引发高选择性的各种类型的键结构。他正在探索一种新的激活模式，这种模式已经被证明对新型级联反应的发展非常有用，并极大地影响了有机合成的效率。在研究小组工作的本科生，特别是那些与他发起的“贝勒本科生迷你制药计划”有关的本科生，正在获得团队合作和领导经验，品尝与制药工业相关的化学研究的各个方面，新的研究技能和使用最先进设备的经验，最终为可发表的研究做出贡献。Romo正在寻求一种新颖而广泛的设计原则，用于基于易于生成的手性不饱和酰基铵盐的有机合成，这对不断增长的可扩展、不对称有机催化领域产生了重大影响。他正在研究的有机级联过程包括串联反应，通常由Michael添加（与碳，氮和硫亲核试剂）引发，从而产生高度实用的，对映选择性的合成途径，以获得生物活性天然产物和药物中常见的碳环和杂环。鉴于有机级联催化的重要性，本研究将与Tantillo教授合作进行各种不饱和酰基铵盐中间体的机理研究。这些合作研究对这些手性中间体的活化模式和对映体选择性有了更深入的了解。所开发的合成方法的实用性正在通过靶向含有β -内酯的天然产物来证明。这些反过来作为蛋白质组学探针，与Stephan Sieber教授（慕尼黑工业大学，德国）在化学/生物学界面进行基础研究。贝勒本科迷你制药项目使本科生能够通过设计、合成和测试新的衍生物来“体验”制药行业，以确定潜在癌症治疗的先导化合物，包括胶质母细胞瘤。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。

项目成果

Synthesis of agelastatin A and derivatives premised on a hidden symmetry element leading to analogs displaying anticancer activity

• DOI: 10.1016/j.tet.2021.132340
• 发表时间: 2021-08-17
• 期刊: TETRAHEDRON
• 影响因子: 2.1
• 作者: Xue，Haoran;Svatek，Haleigh;Romo，Daniel
• 通讯作者: Romo，Daniel

Simplified immunosuppressive and neuroprotective agents based on gracilin A

• DOI: 10.1038/s41557-019-0230-0
• 发表时间: 2019-04-01
• 期刊: NATURE CHEMISTRY
• 影响因子: 21.8
• 作者: Abbasov, Mikail E.;Alvarino, Rebeca;Romo, Daniel
• 通讯作者: Romo, Daniel

Enantioselective, Organocatalytic Strategy for the Oxazolomycin Core: Formal Synthesis of (+)-Neooxazolomycin

• DOI: 10.1021/acs.orglett.0c03511
• 发表时间: 2020-12-04
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Chaheine, Christian M.;Gladen, Paul T.;Romo, Daniel
• 通讯作者: Romo, Daniel