Pd-Catalyzed C(sp3)-H Functionalizations Directed by Free Alcohols and Boc-Protected Amines

由游离醇和 Boc 保护的胺引导的 Pd 催化 C(sp3)-H 官能化

基本信息

批准号：
10606508
负责人：
Daniel Aaron Strassfeld
金额：
$ 6.95万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10606508
关键词：
Acceleration Acids Address Alcohols Amides Amines Binding Biological Carbamates Charge Chemical Structure Chemistry Compensation Complex Development Environment Equilibrium Excision Failure Family Future Goals Growth Health Human Hydrogen Bonding Hydroxyl Radical Knowledge Ligands Mentorship Metals Methodology Methods Modification Molecular National Institute of General Medical Sciences Outcome Palladium Pharmaceutical Chemistry Postdoctoral Fellow Production Pyridones Reaction Research Research Design Research Institute Role Site Structure Synthesis Chemistry Transition Elements Validation Work alcohol free base carbene carboxylate carboxylation catalyst chelation dehydrogenation deprotonation design driving force functional group methyl group novel novel therapeutics professor small molecule small molecule therapeutics success tool

项目摘要

PROJECT SUMMARY/ABSTRACT Subtle structural modifications have the potential to dramatically alter the biological activity of small molecules. Consequently, the development of synthetic methods that allow for selective molecular editing has the potential to greatly accelerate the design and synthesis of novel therapeutics. Transition-metal catalyzed C– H functionalization is a particularly compelling approach, as it circumvents the requirement for prior activation at the site of functionalization. However, C–H activation typically requires a high degree of preorganization of the agostic interaction between the metal and the target bond, usually through coordination of the metal to a directing group. Unfortunately, efforts to use common functional groups and commonly used protecting groups to direct C(sp3)–H activation have met with limited success. Instead, specially designed directing groups are often necessary, limiting the synthetic utility of existing C–H functionalization methodologies. In the proposed research, ligands will be designed to enable the use of common, weakly coordinating L-type donors, such as alcohols and carbamates, as directing groups for C(sp3)–H activation. We hypothesized that two main factors are responsible for the failure of existing ligands to promote these reactions: the intrinsically weak binding of these functional groups to Pd, and the focus on L,X chelates in recent ligand design efforts, which are expected to disfavor agostic complex formation with L-type directing groups due to the lack of charge balance within the complex. Thus, we propose to design novel bis-anionic ligands, structures that are currently underexplored in C–H activation chemistry, containing an internal base that can participate in C–H activation via concerted metalation-deprotonation. In order to compensate for the weak coordination of the desired directing groups to Pd, the proposed ligands will be designed to stabilize substrate-Pd complexes through the secondary coordination sphere by serving as H-bond acceptors or donors matched to the desired directing group. In Aim 1, which is strongly supported by preliminary results, we will develop ligands that can enable alcohol-directed C(sp3)–H functionalizations through two reaction manifolds: C–H dehydrogenation reactions to form allylic alcohols, which are exceedingly versatile synthetic intermediates, and direct C(sp3)–H arylations. Aim 2 will extend this ligand design strategy to develop α-arylations of Boc-amines, with a particular focus on methylene C–H activation in saturated N-Boc azacycles. The successful realization of these aims will provide powerful new synthetic methodologies, directly facilitating the design and synthesis of novel therapeutics. In addition, validation of the underlying hypotheses and ligand design strategy will afford a conceptual advance that will contribute to the continued development of the field of C–H activation. The proposed work will be carried out under the mentorship of Professor Jin-Quan Yu, a preeminent scholar in the field of transition-metal catalyzed C–H functionalization. The intellectual environment in the Yu lab and The Scripps Research Institute is ideally suited to enable the successful execution of these aims.

项目概要/摘要微妙的结构修饰有可能显着改变小分子的生物活性经过测试，允许选择性分子编辑的合成方法的发展已经取得进展。极大地加速新型疗法的设计和合成的潜力。 H 功能化是一种特别引人注目的方法，因为它规避了预先激活的要求然而，C-H 激活通常需要高度的预组织。金属和目标键之间的无控制相互作用，通常通过金属与定向键的配位来实现不幸的是，努力使用常见的官能团和常用的保护基团来指导。 C(sp3)–H 的激活效果有限，相反，专门设计的导向基团通常是有效的。必要的，限制了现有C-H官能化方法的合成效用。在拟议的研究中，配体将被设计为能够使用常见的弱配位 L 型供体，例如醇和氨基甲酸酯，作为 C(sp3)–H 激活的指导基团。现有配体未能促进这些反应的两个主要因素是：本质上这些官能团与 Pd 的结合较弱，并且在最近的配体设计工作中重点关注 L,X 螯合物，由于缺乏电荷，预计不利于与 L 型导向基团形成无望复合物因此，我们建议设计新颖的双阴离子配体，即目前的结构。在 C-H 活化化学中尚未得到充分探索，包含可以通过以下方式参与 C-H 活化的内部碱基：协调的金属化-去质子化，以补偿所需定向的弱协调。基团到 Pd 上，所提出的配体将被设计为通过次级稳定基底-Pd 复合物在目标 1 中，通过充当与所需指导基团相匹配的氢键受体或供体来实现配位范围。初步结果有力支持了这一点，我们将开发能够实现醇定向的配体通过两个反应流形进行 C(sp3)–H 官能化：C–H 脱氢反应形成烯丙基醇，这是一种用途极其广泛的合成中间体，并且可以直接进行 C(sp3)–H 芳基化反应。扩展该配体设计策略以开发 Boc 胺的 α-芳基化，特别关注亚甲基饱和 N-Boc 氮杂环中的 C-H 激活这些目标的成功实现将提供强大的新功能。合成方法学，直接促进新疗法的设计和合成。基本假设和配体设计策略的研究将提供概念上的进步，这将有助于 C-H激活领域的持续发展。拟议的工作将在杰出学者于金泉教授的指导下进行于实验室的智力环境和过渡金属催化的C-H功能化领域。斯克里普斯研究所非常适合成功实现这些目标。