High-Precision Synthesis and Analysis of Deuterated Cycloalkene Isotopomers

在化学系化学合成项目的支持下，W。弗吉尼亚大学的迪安·哈曼（Dean Harman）和布鲁克斯·佩特（Brooks Pate）正在研究制造和鉴定具有不同三维结构的分子的方法，这些分子在氢（H）及其同位素氘（D =带有额外中子的氢原子）与特定碳原子的连接上有所不同。哈曼教授正在使用一种金属络合物来模板化氘在有机分子中的可控加成。佩特教授正在开发分子旋转共振光谱技术，以确定分子之间的结构差异，只有不同的附着氢和氘。虽然氢和氘表现出类似的广泛反应模式，但碳-氘键比碳-氢键略强，这种差异可以用来改变反应发生的速度。通过在分子的特定部分中安装氘而不是氢，分子的生物活性可以适于提供增加药物寿命、减少剂量和改善安全裕度的机会。有机化学家用来鉴定分子结构的常用技术不足以确定氢和氘在单个碳原子上的连接。分子共振光谱学正在开发，以解决这一限制。这些活动将为不同群体的研究生和本科生提供跨学科的教育。Harman教授和Pate教授还积极寻求机会，通过参与外联活动，增加代表性不足的群体对化学的参与。由于氘动力学同位素效应，氢原子被氘取代的化合物可以显示出显著降低的代谢率。为了实现将可获得的同位素体构建模块纳入现有或潜在药物的活性药物成分的目标，Harman教授正在开发用于精确合成常见环烯烃的同位素体和立体同位素异构体的策略。芳香族分子结合钨配合物的基本反应性正在研究中，以使精确，顺序添加个别氘原子的芳香环。通过这个过程，可以产生高纯度的各种特定异构体，仅通过氘原子的数量，位置和三维位置进行区分。制备同位素体和立体同位素异构体结构单元的关键挑战是无法通过常规表征方法准确确定其分子几何形状和纯度程度。Pate教授正在通过开发对映体富集同位素的分子共振光谱技术来解决这一限制，这是一种他设计用于高通量分析的方法。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作用，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，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

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.