Utility and Application of Chiral, Unsaturated Acylammoniums

通过这个由化学合成项目资助的奖项，来自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，在一次操作中产生多个键和立体中心，显著提高生物活性天然产物和药物合成的效率。有机催化包括使用小的手性有机分子来激活底物并引发各种键结构。通用底物激活模式及其在反应设计中的应用，在过去的十年中导致了共价有机催化剂的爆炸式增长，使用了明智的催化激活模式组合。然而，一般的底物激活模式缺乏，只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激活模式，可以证明对新型有机级联反应的发展广泛有用。在德州农工大学迷你制药项目工作的本科生，将学习拟议方法的某些方面，获得团队合作和领导经验，体验药物研究的各个方面，新的研究技能，以及使用最先进设备的经验，最终为可发表的研究做出贡献。本研究基于易于生成的手性不饱和酰基铵盐，寻求一种新颖而广泛的设计原理，对可扩展的、不对称的有机催化领域产生重大影响。有机级联过程侧重于环加成，实现高度实用的对映选择性合成途径，以合成生物活性天然产物和药物中常见的碳环和杂环。此外，考虑到不饱和酰基铵中间体在有机级联催化方面的重要性，我们与Dean Tantillo教授（加州大学戴维斯分校）合作进行了可回收的、负载的异硫脲催化剂的合成和不饱和酰基铵中间体的机理研究。开发的合成方法通过靶向合成具有引人注目的生物活性的天然产物来证明其实用性，从而在化学/生物学界面上与Stephan Sieber教授（德国慕尼黑工业大学）进行进一步的基础研究。假设驱动，新的反应发展和经验实验室合成方法的反应发现被用来达到这些目标。

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.