Highly Selective Cu-Catalyzed Reactions for Precision Deuteration and Alkyne Hydrofunctionalization

用于精密氘化和炔烃氢官能化的高选择性铜催化反应

• 批准号: 10501457
• 负责人: Joseph Clark
• 金额: $ 37.05万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501457
• 关键词: Address; Alkenes; Alkynes; Chemistry; Collaborations; Communities; Deuterium; Development; Foundations; Investigation; Label; Medicine; Methods; Modern Medicine; Modernization; Molecular; Organic Chemistry; Pharmaceutical Preparations; Positioning Attribute; Reaction; Research; Safety; Scientist; Spectrum Analysis; Styrenes; Techniques; Therapeutic; Transition Elements; analytical method; chemical reaction; design; drug candidate; improved; novel; novel therapeutics; programs; scaffold; small molecule; success

Project Summary Deuterium labeled medicines are being used to develop safer alternatives to existing therapeutics and improve the safety of current drug candidates. Despite the tremendous promise that novel deuterated small molecules have in the development of new medicines, methods to incorporate deuterium into molecular scaffolds are primitive. While the synthetic organic chemistry community has grown accustom to highly selective transition metal-catalyzed reactions for the creation of new C–C, C–O and C–N bonds, deuterium installation should also be possible with full stereocontrol and minimal over- and under-deuteration impurities. Not only is highly selective deuteration rare, but spectroscopic techniques to support advances in this field are inadequate. We are launching a holistic research program to not only develop highly selective reactions for deuterium incorporation but pioneer the expansion of analytical techniques required to support the development and use of these reactions among the broader scientific community. Through our established collaboration with leaders in the spectroscopy field, we have started to develop analytical techniques that provide the foundation for accurate characterization and identification of deuterated small molecules. Our preliminary studies indicate that deuterium can be installed precisely into small molecules. In many cases, isotopomer and isotopologue impurities are so minimal that they are nearly undetectable. Our research is now positioned for expansion into broader classes of organic molecules. We will develop new Cu-catalyzed transformations for the selective deuteration and hydrodeuteration of alkenes and alkynes. These transformations will precisely insert deuterium in a small molecule and be compatible with compounds that contain functionality commonly found in small molecule drugs. We anticipate that in the next 5 years, our synthetic strategies and analytical methods will address significant portions of the outlined considerations. This will drastically expand the development of novel deuterated therapeutics to address many of the safety and tolerability problems plaguing modern medicine. Beyond deuterium incorporation, we are proposing to develop new reactions for the regioselective hydrofunctionalization of internal aryl alkynes. Powerful methods for regioselective Cu-catalyzed alkyne hydrofunctionalization exist but are mostly limited to terminal alkynes and symmetrical internal alkynes. Consequently, there exists a major void in the synthesis of a-substituted styrenes. To access these molecules from alkynes, we are proposing to develop a-selective Cu-catalyzed internal aryl alkyne hydrofunctionalization reactions. The research will benefit from deuteration studies performed in our group to develop new Cu-catalyzed alkyne hydrodeuteration reactions. The unprecedented regioselectivities obtained in our ongoing investigations will serve as the starting point for developing the proposed Cu-catalyzed a-selective internal aryl alkyne hydrofunctionalization reactions.

项目概要 氘标记药物被用来开发现有疗法的更安全替代品 提高当前候选药物的安全性。尽管小说有着巨大的希望，但它却被贬低了 分子在新药开发中具有将氘纳入分子支架的方法 是原始的。虽然合成有机化学界已经习惯了高度选择性的转变 用于创建新的 C-C、C-O 和 C-N 键的金属催化反应，氘的安装也应该 可以实现完全立体控制和最小化的过量和不足氘化杂质。不仅选择性高 氘很少见，但支持该领域进展的光谱技术还不够。我们正在推出 一个整体研究计划，不仅开发氘并入的高度选择性反应，而且是先驱 支持这些反应的开发和使用所需的分析技术的扩展 更广泛的科学界。通过我们与光谱领域领导者建立的合作， 我们已经开始开发分析技术，为准确表征和 氘代小分子的鉴定。我们的初步研究表明可以安装氘 精确地分解成小分子。在许多情况下，同位素异构体和同位素异构体杂质非常少，以至于它们 几乎无法检测到。我们的研究现在定位于扩展到更广泛的有机分子类别。 我们将开发新的铜催化转化用于烯烃的选择性氘化和加氢氘化 和炔烃。这些转化将精确地将氘插入小分子中并与 含有小分子药物中常见功能的化合物。我们预计在未来 5 年 多年来，我们的综合策略和分析方法将解决概述的重要部分 考虑因素。这将极大地扩展新型氘化疗法的开发，以解决许多问题 困扰现代医学的安全性和耐受性问题。 除了掺入氘之外，我们还建议开发新的区域选择性反应 内部芳基炔烃的氢官能化。区域选择性铜催化炔烃的强大方法 存在氢官能化，但主要限于末端炔烃和对称内部炔烃。 因此，α-取代苯乙烯的合成存在很大的空白。访问这些分子 我们建议从炔烃中开发α-选择性铜催化的内芳基炔烃氢官能化 反应。该研究将受益于我们小组进行的氘化研究，以开发新的铜催化 炔烃加氢氘化反应。我们正在进行的研究中获得了前所未有的区域选择性 将作为开发拟议的铜催化α-选择性内芳基炔的起点 加氢官能化反应。