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.

项目概要/摘要： 有机化学改变了我们的世界，这一点怎么强调都不为过。 从通过避孕药具的发明赋予妇女生殖权利到创造 不言而喻的是，医学创新总是与农药相关。 有机化学的进步，因为大多数药物都是由有机化学家合成的。 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 幸运的是，不对称合成的快速发展为治疗学铺平了道路。 这些胜利可以归功于对映选择性键领域的许多创新。 形成过程，如不对称离子对、有机催化、C-H 活化、路易斯酸/碱、布朗斯台德 尽管取得了这些成就，但酸/碱、还原/氧化、交叉偶联反应等等。 尽管概述了每种独特的激活模式，但现有技术在许多方面仍与理想存在差距。 上述允许实现高化学选择性、非对映选择性和对映选择性，在许多情况下对于所需的 要发生键形成事件，基材通常必须带有能够结合或被 特别是，能够将惰性 C-H 键对映选择性地转化为碳键。 在没有指导基团帮助的情况下在特定位置形成碳键是非常可取的，因为它会进一步 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取代 允许直接功能化杂环内通常不可靶向的位置的序列。 具体来说，我们发现路易斯碱可以从强有机锂试剂中提取锂阳离子，从而允许 产生高碱性离子对，进而产生杂环中典型的远程和惰性 C-H 键 去质子化。其次，我们开发了一种新型手性膦配体，能够 该提案旨在合并这些概念。 通过开发不对称去质子交叉偶联序列，可以允许通常难以接近的 该提案的具体目标包括：（1）两者的发展。 有机锂试剂和路易斯碱结合后可在生物碱中形成典型的惰性 C-H 键， 去质子化；（2）开发新的手性膦配体，使对映体收敛 与种族供体试剂的交叉偶联反应；以及（3）不对称去质子化的发展； 交叉偶联序列允许生物相关的生物碱在单个序列中直接功能化 合成操作。