Utility and Application of Chiral, Unsaturated Acylammoniums

手性不饱和酰胺的效用和应用

• 批准号: 1546973
• 负责人: Daniel Romo
• 金额: $ 30万
• 依托单位: Baylor University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1546973&HistoricalAwards=false
• 关键词: Utility; Application; Chiral; Unsaturated; Acylammoniums

Through this award, funded by the Chemical Synthesis Program, Prof. Daniel Romo from Texas A&M University is turning to bioinspired organocascade or domino processes that generate multiple bonds and stereocenters in a single operation, significantly increasing the efficiency of bioactive natural product and pharmaceutical synthesis. Organocatalysis involves the use of small, chiral organic molecules to activate substrates and initiate various bond constructions. Generic substrate activation modes, and their implementation in reaction design, have led to an explosion in covalent organocatalysts over the past decade, using judicious combinations of catalytic activation modes. However, there is a paucity of general substrate activation modes, with only limited types revealing multiple reactive sites in a single catalytic cycle. This research will explore a new activation mode that could prove broadly useful for the development of novel organocascade reactions. Undergraduates, working in the Texas A&M Undergraduate MiniPharma Program, will study certain aspects of the proposed methods gaining teamwork and leadership experience, a taste of various aspects of pharmaceutical research, new research skills, and experience with state-of-the-art equipment ultimately contributing to publishable research.This research pursues a novel and broad design principle based on readily generated chiral unsaturated acylammonium salts, significantly impacting the growing field of scaleable, asymmetric organocatalysis. The organocascade processes focus on cycloadditions, enabling highly practical, enantioselective synthetic routes to carbocycles and heterocycles commonly found in bioactive natural products and pharmaceuticals. In addition, the synthesis of recyclable, supported-isothiourea catalysts and mechanistic studies of unsaturated acylammonium intermediates, given their established and increasing importance for organocascade catalysis, are undertaken in collaboration with Prof. Dean Tantillo (UC Davis). The utility of the developed synthetic methods is demonstrated by targeting the synthesis of natural products with compelling bioactivities enabling further fundamental studies at the chemistry/biology interface with Prof. Stephan Sieber (Tech Univ of Munich, Germany). Hypothesis-driven, novel reaction development and empirical laboratory synthetic methods for reaction discovery are employed to reach these objectives.

通过这项由化学合成计划资助的奖项，德克萨斯农工大学的Daniel Romo教授正在转向生物启发的有机级联或多米诺过程，这种过程在一次操作中产生多个键和立体中心，显著提高了生物活性天然产品和药物合成的效率。有机催化涉及使用小的手性有机分子来激活底物并启动各种键结构。通用底物活化模式及其在反应设计中的实施，在过去十年中导致了共价有机催化剂的爆炸性增长，使用了合理的催化活化模式组合。然而，一般的底物活化模式很少，仅有有限的类型在一个催化循环中显示多个反应位点。这项研究将探索一种新的活化模式，该模式可能被证明对开发新型的有机级联反应具有广泛的实用价值。在德克萨斯农工大学本科生Mini Pharma项目工作的本科生，将学习建议方法的某些方面，获得团队合作和领导经验，对制药研究的各个方面的品味，新的研究技能，以及最终有助于发表研究的最先进设备的经验。这项研究追求一种新颖而广泛的设计原理，基于容易产生的手性不饱和酰胺盐，显著影响不断增长的可伸缩、不对称有机催化领域。有机级联工艺专注于环加成反应，使合成碳环和杂环的路线变得非常实用，对映选择性很高，通常存在于生物活性天然产品和药物中。此外，可回收的负载型异硫脲催化剂的合成和不饱和酰基铵中间体的机理研究是与加州大学戴维斯分校的Dean Tantillo教授合作进行的，因为它们在有机级联催化中已经确立并日益重要。开发的合成方法的实用性通过以合成具有令人信服的生物活性的天然产品为目标，使与德国慕尼黑理工大学的Stephan Sieber教授在化学/生物学界面上进行进一步的基础研究成为可能。为了实现这些目标，人们采用了假设驱动的、新颖的反应开发和用于反应发现的经验实验室合成方法。

项目成果

Quantitative chemoproteomic profiling reveals multiple target interactions of spongiolactone derivatives in leukemia cells

定量化学蛋白质组学分析揭示了白血病细胞中海绵内酯衍生物的多个靶点相互作用

• DOI: 10.1039/c7cc04990k
• 发表时间: 2017
• 期刊: Chemical Communications
• 影响因子: 4.9
• 作者: Wright, M. H.;Tao, Y.;Drechsel, J.;Krysiak, J.;Chamni, S.;Weigert-Munoz, A.;Harvey, N. L.;Romo, D.;Sieber, S. A.
• 通讯作者: Sieber, S. A.