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: 10661088
• 负责人: Joseph Clark
• 金额: $ 37.02万
• 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/10661088
• 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 氘标记的药物正被用于开发现有治疗方法的更安全的替代品， 提高现有候选药物的安全性。尽管这部小说有着巨大的前景， 分子在新药开发中将氘掺入分子支架的方法 是原始的。虽然合成有机化学界已经习惯于高度选择性的过渡 金属催化的反应产生新的C-C，C-O和C-N键，氘装置还应 可以完全立体控制和最小的过氘和欠氘杂质。不仅是高度选择性的 氘很少，但支持这一领域进展的光谱技术是不够的。我们正在启动 一个全面的研究计划，不仅开发高选择性的反应，氘掺入，但先驱 扩大所需的分析技术，以支持这些反应的发展和使用， 更广泛的科学界。通过我们与光谱领域的领导者建立的合作关系， 我们已经开始开发分析技术，为准确表征提供基础， 鉴定氘代小分子。我们的初步研究表明，氘可以安装在 精确地转化为小分子。在许多情况下，同位素异构体和同位素物杂质是如此的少，以至于它们可以被分离。 几乎无法察觉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烯烃的选择性氘代和加氢氘代反应 和炔。这些转换将精确地将氘插入小分子中，并与 含有小分子药物中常见的功能的化合物。我们预计，在未来5年， 年，我们的综合战略和分析方法将解决概述的重要部分， 注意事项。这将极大地扩展新型氘代治疗剂的开发，以解决许多 现代医学的安全性和耐受性问题。 除了氘掺入，我们还建议开发新的反应， 内部芳基炔的氢官能化。区域选择性铜催化炔的有效方法 存在加氢官能化，但主要限于末端炔和对称内部炔。 因此，在α-取代苯乙烯的合成中存在主要的空白。去接触这些分子 从炔，我们建议开发选择性铜催化的内芳基炔氢官能化 反应.该研究将受益于我们小组进行的氘代研究，以开发新的铜催化的 炔加氢氘代反应。在我们正在进行的调查中获得的前所未有的区域选择性 将作为开发所提出的Cu催化的α-选择性内芳基炔的起点 氢官能化反应。