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

项目总结/摘要 催化C-H键官能化已经成为合成有机化学中的一种强有力的方法， 发现和生产新的药物。下一代C-H键功能化方法 该提议中所描述的方法将能够从简单的化合物中快速组装药学相关的化合物。 和容易获得的输入。在一个程序中，我们将在一个步骤中访问复杂的分子结构 从简单的前体通过C-H键和两种不同类型的 伴侣因为许多不同的偶联配偶体对于常规的C-H键加成是有效的 对于一个偶联配偶体，利用偶联的不同组合的顺序三组分反应 合作伙伴应提供获得与药物和天然产品合成有关的各种图案的机会。 利用MIRA资金获得的初步结果确定了这一方法的可行性和实用性。中 第二个程序，我们将应用可逆的光介导的C-H键活化，以获得最稳定的 最易接近的杂环立体异构体。饱和杂环如哌啶，吗啉， 哌嗪和内酰胺在药物和药物候选物中普遍存在，但通常最有效地制备为 立体异构体越不稳定。然而，光介导的过程可以使它们的高度立体选择性 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 第三个计划，我们将广泛发展通过亚胺基C-H官能化的氮杂环合成。亚胺 衍生自容易获得的醛和伯胺是有机合成中重要的中间体。 合成.在MIRA的资助下，我们开发了一种有效制备嘌呤生物电子等排体的新方法 通过亚胺的亚氨酰基C-H活化，随后与不同的偶联配偶体原位成环。嘌呤 生物电子等排体存在于大量的药物和药物候选物中，尤其是那些与 具有嘌呤识别基序的生物分子靶标，如受体、激酶和mRNA。我们将利用 我们合成嘌呤生物电子等排体的方法靶向转录组， 活化和成环以制备其它重要的杂环。在MIRA的资助下， 抑制剂发现方法和有效的和选择性的抑制剂，以挑战酶的目标。在建议的 研究中，我们将直接将C-H功能化应用于生物学研究。例如，我们为 二氢吡啶的合成和精制使得能够快速制备含胺结构， 功能性的三维显示和多个立体中心的立体选择性引入， 在药物化学领域越来越受欢迎。这些方法将应用于 发现了与治疗未满足要求相关的挑战性生物分子靶点的有效和选择性配体 医学状况，包括CNS渗透剂的鉴定，胺能GPCR的高选择性配体。

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.