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.

项目摘要/摘要： 合成化学对社会的影响不能被夸大。有机化的化学改变了我们的世界 从赋予避孕药的发明到创造妇女的生殖权利到创造 使我们能够养活全球的农药。医学上的创新与 由于大多数药物是有机化学家合成的，有机化学的进步。长期以来已经 认识到小分子的整体形状是控制其生物学的最基本因素 效果。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纽带领域中的许多创新 形成诸如不对称离子配对，有机催化，C – H激活，刘易斯酸/碱，Brønsted等过程 酸/碱，减少/氧化，交叉偶联反应等等。尽管取得了这些成就， 与理想相比，最新的状态在许多方面仍然缺乏。尽管概述了每个唯一激活模式 以上允许在许多情况下实现高化学，映射和对映体选择性 发生的债券形成事件发生的底物通常必须承担能够结合或存在的功能组 被手性催化剂激活。特别是，将惰性C – H键转换为碳的能力 在没有指导群体的情况下，在特定位置的碳键是非常需要的 药物发现过程。 为了应对这一挑战，我们的工作重点是开发新的去质子化替代 允许在杂环中通常不可辨的位置的序列直接功能化。 具体而言，我们发现刘易斯基地可以从较强的有机锂试剂中提取li阳离子，允许 高碱基的离子对要生产，而杂环中通常偏远和惰性C – H键 去质子化。其次，我们开发了一种新的手性磷酸配体，以实现 映体ver剂与消极供体试剂的交叉耦合。该提议试图合并这些概念 通过开发不对称的去质子化交叉耦合序列，该序列通常允许无法访问 碳中心要功能化。该建议的具体目标包括：（1） 有机矿试剂和刘易斯基地，合并后允许在生物碱中惰性C – H键 被质子化； （2）开发新的手性膦配体，使启用negishi启用negishi 与外围供体试剂的交叉偶联反应； （3）不对称去质子化的发展 交叉耦合序列，允许在单个中直接化生物学相关的生物碱 合成操作。