Lewis Base Ligands Designed to Control Carbon-Carbon Bond Formation

旨在控制碳-碳键形成的路易斯碱配体

• 批准号: 10713775
• 负责人: Andy Alexander Thomas
• 金额: $ 36.72万
• 依托单位: TEXAS A&M 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/10713775
• 关键词: Achievement; Acids; Address; Alkaloids; Binding; Biological; Carbon; Catalysis; Cations; Chemistry; Clinic; Contraceptive Agents; Coupling; Development; Event; Exhibits; Goals; Hydrogen Bonding; Ions; Ligands; Link; Location; Medicine; Nitrogen; Organic Chemistry; Organic Synthesis; Pesticides; Phosphines; Positioning Attribute; Process; Property; Reaction; Reagent; Reproductive Rights; Shapes; Societies; Synthesis Chemistry; Therapeutic; Transition Elements; Woman; Work; base; catalyst; deprotonation; design; drug discovery; falls; functional group; human disease; innovation; invention; operation; oxidation; small molecule

PROJECT SUMMARY/ABSTRACT: The impact of synthetic chemistry on society cannot be overstated. Organic chemistry has changed our world in momentous ways, from giving women reproductive rights through the invention of contraceptives, to creating pesticides that allow us to feed the globe. It is axiomatic that innovations in medicine are invariably linked to advancements in organic chemistry as most medicines are synthesized by organic chemists. It has long been recognized that the overall shape of a small molecule is the most fundamental factor that controls its biological effects. It is fortunate that rapid developments in asymmetric synthesis have paved the way for therapeutics to reach the clinic. These triumphs can be attributed to the many innovations in the realms of enantioselective bond forming processes such as asymmetric ion pairing, organocatalysis, C–H activation, Lewis acid/base, BrØnsted acid/base, reductions/oxidations, cross-coupling reactions and many more. Despite these achievements, the state of the art still falls short in many ways from the ideal. Although each of the unique activation modes outlined above allow for high chemo-, diastero- and enantio-selectivities to be achieved, in many cases for the desired bond forming event to occur the substrate must often bear a functional group that is capable of binding or being activated by a chiral catalyst. In particular, the ability to enantioselectively convert inert C–H bonds into carbon- carbon bonds at specific locations without the aid of directing groups is highly desirable because it would further the drug discovery process. To address this challenge, our work has focused on the development of new deprotonation substitution sequences which allow for typically untargetable positions within heterocycles to be directly functionalized. Specifically, we have found that Lewis bases can extract Li cations from strong organolithium reagents allowing highly basic ion pairs to be produced and in turn for typically remote and inert C–H bonds in heterocycles to be deprotonated. Secondly, we have developed a new class of chiral phosphine ligands that enable enantioconvergent cross-couplings with racemic donor reagents. This proposal seeks to merge these concepts by developing asymmetric deprotonation cross-coupling sequences that can allow for typically inaccessible carbon centers to be functionalized. Specific goals of this proposal include: (1) the development of both organolithium reagents and Lewis bases that when combined allow for typically inert C–H bonds in alkaloids to be deprotonated; (2) the development of new chiral phosphine ligands that enable enantioconvergent Negishi cross-coupling reactions with racemic donor reagents; and (3) the development of asymmetric deprotonation cross-coupling sequences that allow for biologically relevant alkaloids to be directly functionalized in a single synthetic operation.

项目总结/摘要： 合成化学对社会的影响怎么强调都不过分。有机化学改变了我们的世界 从发明避孕药具赋予妇女生育权， 杀虫剂，让我们养活地球仪。不言而喻，医学创新总是与 有机化学的进步，因为大多数药物是由有机化学家合成的。人们早就 认识到小分子的整体形状是控制其生物学特性的最基本因素。 方面的影响.幸运的是，不对称合成的快速发展为治疗铺平了道路， 到达诊所。这些胜利可以归因于对映选择性键领域的许多创新 形成过程，如不对称离子配对、有机催化、C-H活化、刘易斯酸/碱、布朗斯台德 酸/碱、还原/氧化、交叉偶联反应等等。尽管取得了这些成就， 但是现有技术在许多方面仍然与理想状态有福尔斯差距。尽管概述的每种独特的激活模式 以上的化合物允许实现高的化学选择性、对映选择性和对映选择性，在许多情况下，对于所需的 为了发生键形成事件，基底必须经常带有能够结合或 通过手性催化剂活化。特别地，对映选择性地将惰性C-H键转化为碳-H键的能力是有利的。 在没有导向基团的帮助下，在特定位置的碳键是非常期望的，因为它将进一步 药物发现过程。 为了应对这一挑战，我们的工作集中在开发新的去质子化取代 这些序列允许杂环内通常不可靶向的位置被直接官能化。 具体地，我们已经发现，刘易斯碱可以从强有机锂试剂中提取Li阳离子， 产生高碱性离子对，进而在杂环中形成典型的远程和惰性C-H键， 去质子化的其次，我们开发了一类新的手性膦配体， 与外消旋供体试剂的对映会聚交叉偶联。这项建议试图合并这些概念 通过开发不对称去质子化交叉偶联序列， 碳中心被官能化。本建议的具体目标包括：（1）发展 有机锂试剂和刘易斯碱，当组合时，允许生物碱中的典型惰性C-H键， 去质子化;（2）开发新的手性膦配体，使对映收敛Negishi 与外消旋供体试剂的交叉偶联反应;和（3）不对称去质子化的发展 交叉偶联序列，其允许生物学相关的生物碱在单一的寡核苷酸中直接官能化， 合成操作