Two Complementary Approaches to Site-Selective HAT and ET Reactions

在化学系化学合成计划的支持下，约翰·霍普金斯大学的托马斯·莱特卡教授将研究新的方法，选择性地修饰大型复杂分子支架中的一个特定碳氢或碳-碳键。近年来，有机化学家试图通过在分子中许多可能的位置中的一个特定位置进行反应，合成具有药用价值的复杂天然产品的新衍生物。在这种重要的后期修饰中，有可能为化学、生物和医学提供具有实用价值的衍生物，因此在位点选择性方面存在重大挑战。Lectka研究团队将通过两种不同的策略来实现这种站点选择。第一种策略使用氢键来引导结构良好的底物中的反应活性，从而导致位置选择性的官能化反应。在第二种策略中，通过将金属离子与需要中和的片段结合来使复杂底物中的不希望看到的位置失活。拟开展的研修活动将为研究生的专业发展和本科生的研修体验提供有力的培养平台。Lectka教授和他的研究团队将与JHU女性科学与工程(WISE)计划、高中生先锋计划和Goucher监狱教育伙伴计划合作，向更广泛的地方和国家社区推广。根据这一奖项，Lectka研究团队将通过两种基本和互补的策略，引导分子间氢原子转移(HAT)，在某些情况下，电子转移(ET)到各种复杂分子中的特定位置。第一种策略将利用氢键通过官能团方向在结构良好的底物上引导HAT和ET，导致位置选择性的官能化反应，以非对映选择性和潜在的对映选择性地形成新的碳-氟和碳-碳键。在第二种策略中，通过将金属离子与需要中和的片段结合来使复杂底物中的不希望看到的位置失活。在亲电反应的情况下，正电荷排斥、诱导的立体效应和电子撤回将提供必要的失活和原理证明。这种新的方法与传统的位置选择性方法形成对比，传统方法涉及使用高度工程化的试剂、催化剂或酶来专门在所需的位置进行反应。在复杂的分子环境中的位置选择性官能化是当前化学中的一个巨大挑战，其动机是能够研究和修饰天然产物和实用的药物靶标，而不必从基本的构建块单独制备每个类似物。因此，一种新的、补充的选址方法将对医疗和生物化学等领域非常重要。这一奖项反映了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。

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.