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.

项目摘要 氚标记的药物正被用来开发现有疗法的更安全的替代品和 提高现有候选药物的安全性。尽管这本小说有很大的希望 分子在新药的开发中，有方法将氘结合到分子支架中 都是原始的。虽然合成有机化学界已经习惯了高度选择性的转变 金属催化的反应为产生新的C-C、C-O和C-N键，重氢装置也应 用完全的立体控制和最小的超过和不足的氚杂质是可能的。不仅具有高度的选择性 氢化很少见，但支持这一领域进展的光谱技术是不够的。我们正在发射 一个整体研究计划，不仅开发高选择性的氚掺入反应，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。通过我们与光谱学领域领先者的合作， 我们已经开始开发分析技术，为准确的表征和 氢化小分子的鉴定。我们的初步研究表明，氢可以安装在 精确地分解成小分子。在许多情况下，同分异构体和同分异构体的杂质非常少，以至于它们 几乎检测不到。我们的研究现在可以扩展到更广泛的有机分子类别。 我们将开发新的铜催化的烯烃选择性重氢和加氢重氢转化。 还有乙炔。这些转变将准确地在小分子中插入氘，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年内 几年来，我们的合成策略和分析方法将解决概述的很大一部分 考虑因素。这将极大地扩大新型氚治疗药物的开发，以解决许多 困扰现代医学的安全性和耐受性问题。 除了氚的掺入，我们还建议开发区域选择性的新反应。 内部芳基炔烃的氢化功能化。铜催化炔烃区域选择性的有效方法 氢化功能化是存在的，但大多局限于末端炔烃和对称的内部炔烃。 因此，在α-取代的苯乙烯的合成中存在主要的空隙。以获取这些分子 从炔烃出发，我们建议开发一种选择性铜催化的芳烃内氢官能化反应 反应。这项研究将受益于我们小组进行的重氢研究，以开发新的铜催化的 炔氢重氢反应。在我们正在进行的调查中获得了前所未有的区域选择性 将作为开发所提议的铜催化的a-选择性内芳基炔的起点 氢化功能化反应。