Utility and Application of Chiral, Unsaturated Acylammoniums

通过该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骨牌工艺，在一次操作中生成多个键和立体中心，从而显着提高生物活性天然产物和药物合成的效率。有机催化涉及使用小的手性有机分子来激活底物并引发各种键构建。过去十年中，通过明智地组合催化活化模式，通用底物活化模式及其在反应设计中的实施导致了共价有机催化剂的爆炸式增长。然而，通用的底物活化模式很少，只有有限的类型在单个催化循环中揭示多个反应位点。这项研究将探索一种新的激活模式，该模式可能对新型有机级联反应的开发具有广泛的用途。 在德克萨斯农工大学本科小型制药项目中工作的本科生将研究所提出方法的某些方面，获得团队合作和领导经验、药物研究各个方面的体验、新的研究技能以及最终有助于可发表研究的最先进设备的经验。这项研究追求一种基于容易生成的手性不饱和酰基铵盐的新颖而广泛的设计原理，对不断发展的可扩展、不对称有机催化领域产生了重大影响。 有机级联工艺侧重于环加成，为生物活性天然产物和药物中常见的碳环和杂环提供高度实用的对映选择性合成路线。此外，由于不饱和酰铵中间体对于有机级联催化的重要性日益增加，可回收负载型异硫脲催化剂的合成和不饱和酰铵中间体的机理研究是与 Dean Tantillo 教授（加州大学戴维斯分校）合作进行的。 通过针对具有引人注目的生物活性的天然产物的合成，证明了所开发的合成方法的实用性，从而能够与 Stephan Sieber 教授（德国慕尼黑工业大学）在化学/生物学界面进行进一步的基础研究。 采用假设驱动的新颖反应开发和反应发现的经验实验室合成方法来实现这些目标。

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.