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.

通过该奖项，由化学合成计划资助，来自德克萨斯州A＆M大学的Daniel Romo教授正在转向生物启发的OrganoScade或Domino工艺，这些过程在单个操作中产生多个键和立体中心，从而显着提高了生物活性自然产品和药品合成的效率。有机催化涉及使用小的手性有机分子激活底物并启动各种键结构。通用底物激活模式及其在反应设计中的实现，在过去十年中，使用催化激活模式的明智组合在过去十年中导致了共价有机催化剂的爆炸。但是，一般底物激活模式很少，只有有限的类型在单个催化循环中揭示了多个反应性位点。这项研究将探索一种新的激活模式，该模式可能对新的OrganoScade反应的发展非常有用。 在德克萨斯州A＆M本科生微型狂法计划中工作的本科生将研究提出的方法获得团队合作和领导经验的某些方面，对药品研究的各个方面的品味，新的研究技能，新的研究技能以及最先进的设备的经验最终促进了一项可促进的研究。可伸缩的，不对称的有机刻分析场。 OrganoCascade的过程集中在环加成上，从而使高度实用的对映选择性合成途径可以与生物活性天然产物和药品中常见的型碳循环和杂环。此外，鉴于它们与Dean Tantillo教授（UC Davis）合作，进行了不饱和酰基氨基中间体的合成，鉴于其确定的和日益严重的催化性，对不饱和酰基氨基中间体的机械研究的合成以及对有机助力催化的重要性的合成。 通过靶向具有强大生物活性的天然产物的合成，可以在化学/生物学界面与斯蒂芬·西伯（Stephan Sieber）（德国慕尼黑的科技大学）在化学/生物学界面上进行进一步的基础研究，从而证明了开发的合成方法的实用性。 采用假设驱动的，新的反应发展和经验实验室合成方法来达到这些目标。

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.