High-Precision Synthesis and Analysis of Deuterated Cycloalkene Isotopomers

氘代环烯同位素异构体的高精度合成与分析

• 批准号: 2100345
• 负责人: Walter Harman
• 金额: $ 50万
• 依托单位: University of Virginia Main Campus
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2100345&HistoricalAwards=false
• 关键词: Precision; Synthesis; Analysis; Deuterated; Cycloalkene

With the support of the Chemical Synthesis Program in the Division of Chemistry, Professors W. Dean Harman and Brooks Pate of the University of Virginia are studying ways to make and identify molecules with distinct three-dimensional structures that differ in the attachment of hydrogen (H) and its isotope deuterium (D = a hydrogen atom with an extra neutron) to specific carbon atoms. Professor Harman is using a metal complex to template the controlled addition of deuterium to organic molecules. Professor Pate is developing molecular rotational resonance spectroscopy techniques to identify the structural distinctions between molecules that only differ in the attachment of hydrogen and deuterium. While hydrogen and deuterium exhibit similar broad reactivity patterns, carbon-deuterium bonds are slightly stronger than carbon-hydrogen bonds and this difference can be used to alter how a fast a reaction occurs. By installing deuterium instead of hydrogen in specific portions of a molecule, the biological activity of the molecule can be adapted to provide opportunities for increased drug lifetime, reduced dosing, and improved safety margins. Common techniques used by organic chemists to identify the structures of molecules are insufficient for determining the attachment of a hydrogen and a deuterium at a single carbon atom. Molecular resonance spectroscopy is being developed to address this limitation. These activities will provide an interdisciplinary education for a diverse group of graduate and undergraduate students. Professors Harman and Pate are also actively pursuing opportunities to increase participation in chemistry by underrepresented groups through engagement in outreach activities.Owing to the deuterium kinetic isotope effect, compounds in which hydrogen atoms have been replaced with deuterium can show dramatically reduced rates of metabolism. To progress toward the goal of having accessible isotopologue building blocks for incorporation into the active pharmaceutical ingredient of existing or potential drugs, Professor Harman is developing strategies for the precise synthesis of isotopologues and stereoisotopomers of common cycloalkenes. The fundamental reactivity of aromatic molecules bound to tungsten complexes is being investigated to enable the precise, sequential addition of individual deuterium atoms to aromatic rings. Through this process, a variety of specific isomers can be generated in high purity, solely differentiated by the number, position, and three-dimensional location of the deuterium atoms. A key challenge to making isotopologue and stereoisotopomer building blocks is the inability to accurately determine their molecular geometry and extent of purity through conventional characterization methods. Professor Pate is addressing this limitation through the development of molecular resonance spectroscopy techniques for enantio-enriched isotopomers, an approach that his designed to accommodate high-throughput analysis. With the good synergy between the development of synthetic chemistry and of new complementary analytical techniques, this research will provide a strong, interdisciplinary training environment for graduate and undergraduate students.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学系化学合成计划的支持下，弗吉尼亚大学的W.Dean Harman教授和Brooks Pate教授正在研究如何制造和识别具有不同三维结构的分子，这些分子具有不同的三维结构，即氢(H)及其同位素重氢(D=带有额外中子的氢原子)与特定碳原子的附着性。哈曼教授正在使用一种金属络合物来模板化有机分子中可控的氚加成。佩特教授正在开发分子旋转共振光谱学技术，以识别分子之间的结构差异，这些分子之间的区别只是在氢和氢的结合上不同。虽然氢和氢表现出类似的广泛反应模式，但碳-氚键略强于碳-氢键，这种差异可用于改变反应发生的速度。通过在分子的特定部分安装氘而不是氢，可以调整分子的生物活性，以提供延长药物寿命、减少剂量和提高安全裕度的机会。有机化学家用来确定分子结构的常用技术不足以确定氢和氢在单个碳原子上的结合。分子共振光谱学就是为了解决这一局限而开发的。这些活动将为不同的研究生和本科生群体提供跨学科教育。哈曼教授和佩特教授还积极寻求机会，通过参与外联活动，增加未被充分代表的群体对化学的参与。由于氢的动力学同位素效应，氢原子被氢原子取代的化合物的新陈代谢速度会显著降低。为了实现在现有或潜在药物的活性药物成分中加入可获得的同位异构体的目标，哈曼教授正在开发精确合成常见环烯烃的同位异构体和立体同位异构体的策略。人们正在研究与钨络合物结合的芳香族分子的基本反应性，以便能够精确地、顺序地将单个重氢原子加到芳香环上。通过这一过程，可以高纯度地产生各种特定的异构体，仅根据氘原子的数量、位置和三维位置来区分。制造同位素和立体同分异构体的一个关键挑战是无法通过传统的表征方法准确确定它们的分子几何形状和纯度程度。佩特教授正在通过开发富含对映体的同位素异构体的分子共振光谱技术来解决这一局限性，他设计的这种方法是为了适应高通量分析。随着合成化学和新的互补分析技术的发展之间的良好协同，这项研究将为研究生和本科生提供一个强大的跨学科培训环境。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。