Next-generation C-H functionalization methods for organic synthesis and their applications to biological inquiry

下一代有机合成C-H官能化方法及其在生物学研究中的应用

• 批准号: 10625618
• 负责人: JONATHAN A ELLMAN
• 金额: $ 5.84万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625618
• 关键词: 3-Dimensional; Aldehydes; Amines; Architecture; Biological; Complex; Coupling; Dihydropyridines; Enzyme Inhibitor Drugs; Enzymes; Funding; G-Protein-Coupled Receptors; Hydrogen Bonding; Imines; In Situ; Lactams; Ligands; Light; Mediating; Medical; Messenger RNA; Methods; Molecular; Natural Products; Nitrogen; Organic Chemistry; Organic Synthesis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phosphotransferases; Piperazines; Preparation; Process; Production; Purines; Reaction; Research; Stereoisomer; Structure; drug candidate; inhibitor; morpholine; next generation; novel strategies; piperidine; programs; receptor; transcriptome

PROJECT SUMMARY/ABSTRACT Catalytic C-H bond functionalization has emerged as a powerful approach in synthetic organic chemistry for the discovery and production of new pharmaceuticals. The next generation C-H bond functionalization methods described in this proposal will enable the rapid assembly of pharmaceutically relevant compounds from simple and readily available inputs. In one program, we will access complex molecular architectures in a single step from simple precursors by the sequential three-component coupling of a C-H bond and two different types of coupling partners. Because many different coupling partners are effective for conventional C-H bond additions to one coupling partner, sequential three-component reactions utilitizing different combinations of coupling partners should provide access to an enormous diversity of motifs relevant to drug and natural product synthesis. Preliminary results obtained with MIRA funding have established the feasibility and utility of this approach. In a second program, we will apply reversible light-mediated C-H bond activation to obtain the most stable from the most accessible heterocycle stereoisomer. Saturated heterocycles such as piperidines, morpholines, piperazines, and lactams are prevalent in drugs and drug candidates but are often most efficiently prepared as the less stable stereoisomer. However, light-mediated processes can enable their highly stereoselective conversion to the more stable stereoisomer as we recently demonstrated for piperidines with MIRA funding. In a third program, we will broadly develop nitrogen heterocycle synthesis by imidoyl C-H functionalization. Imines derived from readily available aldehydes and primary amines are centrally important intermediates in organic synthesis. With MIRA funding, we developed a new approach for the efficient preparation of purine bioisosteres by imidoyl C-H activation of imines followed by in situ annulation with different coupling partners. Purine bioisosteres are found in large numbers of drugs and drug candidates, especially those that interact with biomolecular targets that have purine recognition motifs such as receptors, kinases, and mRNA. We will leverage our methods for the synthesis of purine bioisosteres to target the transcriptome and will apply imidoyl C-H activation and annulation to prepare other important heterocycles. With MIRA funding we advanced new enzyme inhibitor discovery approaches and potent and selective inhibitors to challenging enzyme targets. In proposed research, we will directly apply C-H functionalization to biological inquiry. For example, our methods for the synthesis and elaboration of dihydropyridines enable the rapid preparation of amine-containing structures with three-dimensional display of functionality and stereoselective introduction of multiple stereogenic centers, features increasingly sought after in medicinal chemistry endeavors. These approaches will be applied to the discovery of potent and selective ligands to challenging biomolecular targets relevant to the treatment of unmet medical conditions, including the identification of CNS penetrant, highly selective ligands to aminergic GPCRs.

项目概要/摘要 催化 C-H 键官能化已成为合成有机化学中的一种强大方法，用于 新药物的发现和生产。下一代C-H键功能化方法 该提案中描述的将能够从简单的方法快速组装药学相关化合物 和随时可用的输入。在一个程序中，我们将一步访问复杂的分子结构 由简单的前体通过 C-H 键和两种不同类型的连续三组分偶联而成 耦合伙伴。因为许多不同的偶联伙伴对于传统的 C-H 键加成都是有效的 对于一个偶联伙伴，利用不同偶联组合的连续三组分反应 合作伙伴应提供与药物和天然产物合成相关的多种多样的主题。 MIRA 资助获得的初步结果已经证实了该方法的可行性和实用性。在一个 第二个项目，我们将应用可逆光介导的C-H键激活来获得最稳定的 最容易获得的杂环立体异构体。饱和杂环如哌啶、吗啉、 哌嗪和内酰胺在药物和候选药物中普遍存在，但通常最有效的制备方法是 较不稳定的立体异构体。然而，光介导的过程可以使其具有高度立体选择性 转化为更稳定的立体异构体，正如我们最近在 MIRA 资助下证明的哌啶。在 第三个项目，我们将广泛开发通过亚氨基C-H官能化合成氮杂环。亚胺 衍生自容易获得的醛和伯胺，是有机合成中最重要的中间体 合成。在 MIRA 的资助下，我们开发了一种有效制备嘌呤生物等排体的新方法 通过亚胺基 C-H 活化亚胺，然后与不同的偶联伙伴原位成环。嘌呤 生物等排体存在于大量药物和候选药物中，特别是那些与 具有嘌呤识别基序的生物分子靶标，例如受体、激酶和 mRNA。我们将利用 我们的嘌呤生物等排体合成方法以转录组为目标，并将应用亚氨基 C-H 活化和成环以制备其他重要的杂环。在 MIRA 的资助下，我们开发了新的酶 抑制剂发现方法以及针对具有挑战性的酶靶标的有效和选择性抑制剂。在提议的 研究中，我们将直接将C-H功能化应用于生物学探究。例如，我们的方法 二氢吡啶的合成和加工能够快速制备含胺结构 功能的三维显示和多个立体中心的立体选择性引入， 药物化学领域越来越受追捧的功能。这些方法将应用于 发现与未满足治疗相关的具有挑战性的生物分子靶标的有效和选择性配体 医疗条件，包括鉴定中枢神经系统渗透剂、胺能 GPCR 的高选择性配体。