Two Complementary Approaches to Site-Selective HAT and ET Reactions

位点选择性 HAT 和 ET 反应的两种互补方法

• 批准号: 2350270
• 负责人: Thomas Lectka
• 金额: $ 59.5万
• 依托单位: Johns Hopkins University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2350270&HistoricalAwards=false
• 关键词: Two; Complementary; Approaches; Site; Selective

With support from the Chemical Synthesis Program in the Division of Chemistry, Professor Thomas Lectka of Johns Hopkins University will study new ways to selectively modify one specific carbon-hydrogen or carbon-carbon bond in a large complex molecular scaffold. In recent years, organic chemists have sought to synthesize new derivatives of complex natural products of medicinal value through reactions at one particular site among many possible sites in a molecule. There are major challenges for site selectivity in such important late stage modifications with the potential to afford derivatives of practical value to chemistry, biology, and medicine. The Lectka research team will approach such site selectivity through two different strategies. The first strategy employs hydrogen bonds to guide reactivity in well-structured substrates, leading to site-selective functionalization reactions. In the second strategy, undesirable sites in a complex substrate are deactivated through the binding of a metal ion to the fragment that needs to be neutralized. The proposed research activities will provide a strong training platform for the professional development of graduate students and research experiences for undergraduate students. Professor Lectka and his research team will partner with the JHU Women in Science and Engineering (WISE) program, the Pioneer Program for high school students, and the Goucher Prison Education Partnership Program in outreach to the broader local and national communities.Under this award, the Lectka research team will involve directing intermolecular hydrogen atom transfer (HAT) and, in some cases, electron transfer (ET) to specific sites within a variety of complex molecules through two fundamental and complementary strategies. The first strategy will employ hydrogen bonds to guide HAT and ET in well-structured substrates through functional group direction, leading to site-selective functionalization reactions to form new carbon-fluorine and carbon-carbon bonds diastereoselectively and potentially enantioselectively. In the second strategy, undesirable sites in a complex substrate will be deactivated through the binding of a metal ion to the fragment that needs to be neutralized. In the case of an electrophilic reaction, positive charge repulsion, induced steric effects, and electron withdrawal will provide the necessary deactivation and proof of principle. This new approach contrasts with the traditional approach to site selectivity involving the use of highly engineered reagents, catalysts, or enzymes to react exclusively at a desired site. Site selective functionalization in complex molecular settings is a current great challenge in chemistry motivated by the desire to be able to study and modify natural products and practical pharmaceutical targets without having to individually prepare each analogue from basic building blocks. A new, complementary approach to siteselectivity would thus be of great import to fields such as medical and biological chemistry.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.

在化学合成计划中的化学分区的支持下，约翰·霍普金斯大学的托马斯·莱克特卡教授将研究新方法，在大型复杂的分子支架中选择性地修改一种特定的特定碳 - 氢或碳碳键。 近年来，有机化学家试图通过一个特定位点的反应在一个分子中的许多位点中通过反应来综合具有药用价值的复杂天然产物的新衍生物。 在如此重要的晚期修改中，现场选择性面临着主要的挑战，具有对化学，生物学和医学实用价值的衍生品的潜力。 Lectka研究团队将通过两种不同的策略来达到此类现场选择性。 第一种策略采用氢键来指导结构良好的底物中的反应性，从而导致位点选择性功能化反应。 在第二个策略中，复杂底物中的不良位点通过金属离子与需要中和的片段的结合而被停用。拟议的研究活动将为研究生的专业发展和本科生的研究经验提供强大的培训平台。 Lectka教授及其研究团队将与JHU科学与工程学（WISE）计划，高中生的先驱计划以及Goucher监狱教育伙伴关系计划与更广泛的本地和国家社区的宣传。两种基本和互补策略。 第一种策略将采用氢键通过功能组方向在结构良好的底物中引导HAT和ET，从而导致位点选择性的功能化反应，形成新的碳氟和碳碳键映射，并有潜在地进行对映射。 在第二个策略中，将通过金属离子与需要中和的片段结合而停用复杂底物中的不良位点。 在电力反应的情况下，正电荷排斥，诱导的空间效应和电子撤回将提供必要的失活和原理证明。 这种新方法与传统的现场选择性方法形成鲜明对比，该方法涉及使用高度工程的试剂，催化剂或酶在所需的现场进行反应。 在复杂分子环境中的现场选择性功能化是在化学方面的当前巨大挑战，其渴望能够研究和修改天然产物和实用药物目标的愿望而无需单独从基本的构件中准备每个模拟。 因此，一种新的，互补的现场方法将对诸如医学和生物化学等领域具有很大的意义。该奖项反映了NSF的法定任务，并且使用基金会的知识分子优点和更广泛的影响审查标准，被认为值得通过评估来获得支持。