Carbon isotope exchange mediated by vanadium complexes

钒配合物介导的碳同位素交换

• 批准号: 10711850
• 负责人: Konstantin Bukhryakov
• 金额: $ 34.65万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711850
• 关键词: Alkenes; Area; Biology; C14 isotope; Carbon; Carbon Isotopes; Chemistry; Clinical Drug Development; Collection; Complex; Development; Drug Kinetics; Ethylenes; Isotope Labeling; Isotopes; Label; Mediating; Medicine; Metabolic; Methods; Natural Products; Pharmaceutical Preparations; Pharmacologic Substance; Positron-Emission Tomography; Procedures; Process; Protocols documentation; Source; Transition Elements; Vanadium; Work; catalyst; dehydrogenation; design; drug candidate; functional group; innovation; isotope incorporation; methyl group; methyl iodide; pre-clinical; tool

Project Summary The proposed studies focus on the design, synthesis, and development of a range of vanadium- based catalysts to perform carbon isotope exchange via =*CH2 (*C = 11C, 13C, and 14C) group transfer between terminal olefins. Carbon isotope exchange is an emerging area that allows incorporating carbon- 14 isotope directly into target compounds for metabolic and pharmacokinetic studies. Furthermore, the integration of carbon-11 into pharmaceuticals is an indispensable tool in positron emission tomography. The innovation of the proposed work is the development of olefin metathesis catalysts based on the first-row transition metal, vanadium, to take advantage highly polarized V=C bond. These V alkylidenes feature enabled regioselective formation of metallacyclobutane, resulting in reversible =CH2 transfer between terminal olefins without formation of cross-products and ethylene, which is supported by our preliminary results and DFT studies. Therefore, V-catalyze carbon isotope exchange can serve as a new platform to incorporate labeled carbon atoms into a wide range of pharmaceuticals and natural products without developing new multi-step synthetic strategies. The proposed approach uses accessible labeled iodomethane (*CH3I) as a carbon isotope source and can be applied to compounds containing various common functional groups. The method will be expanded to alkyl-containing bioactive molecules utilizing a tandem dehydrogenation/olefin metathesis strategy. Therefore, the first example of carbon isotope exchange involving the methyl group will be introduced. The utility of the new concepts, catalysts, and protocols will be emphasized through applications to the concise synthesis of isotopically labeled pharmaceuticals and natural products.

项目摘要 拟议的研究着重于一系列钒的设计，合成和开发 基于=*CH2（*C = 11C，13C和14C）的基于碳同位素交换的催化剂 在末端烯烃之间。碳同位素交换是一个新兴区域，允许碳 - 14同位素直接进入代谢和药代动力学研究的目标化合物。此外， 将碳11整合到药物中是正电子发射断层扫描中必不可少的工具。这 拟议工作的创新是基于第一行的烯烃回忆催化剂的开发 过渡金属，钒，以利用优势高度极化V = C键。这些V烷基烯具有 启用了金属环丁烷的区域选择性形成，导致可逆= CH2转移 末端烯烃没有形成跨产品和乙烯的形成，这是我们的初步支持的 结果和DFT研究。因此，V催化碳同位素交换可以作为新平台 将标记的碳原子纳入无需使用的碳原子和无天然产品 制定新的多步合成策略。提出的方法使用可访问的标签 碘甲烷（*CH3I）作为碳同位素源，可以应用于包含各种的化合物 共同的官能团。该方法将扩展到利用A的含烷基生物活性分子 串联脱氢/烯烃的复合策略。因此，碳同位素的第一个例子 将引入涉及甲基的交换。新概念，催化剂和 协议将通过应用于同位素标记的简明合成来强调 药品和天然产品。