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

项目摘要/摘要 催化C-H键功能化已成为合成有机化学中的一种强有力的方法 新药的发现和生产。新一代C-H键功能化方法 这项建议中描述的将使药物相关化合物能够从简单的 和随时可用的输入。在一个程序中，我们将在一个步骤中访问复杂的分子结构 通过C-H键和两种不同类型的C-H键的顺序三组分耦合从简单的前体 配对搭档。因为许多不同的偶联伙伴对于传统的C-H键加成是有效的 对于一个偶联伙伴，顺序的三组分反应利用不同的偶联组合 合作伙伴应提供各种与药物和天然产物合成有关的主题。 利用米拉基金获得的初步结果证实了这一办法的可行性和实用性。在一个 第二个计划，我们将应用可逆光介导的C-H键激活，以获得最稳定的 最易获得的杂环立体异构体。饱和杂环，如哌啶类、吗啡类、 哌嗪和内酰胺类药物普遍存在于药物和候选药物中，但通常最有效的制备方法是 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，就像我们最近在米拉资助下为哌啶类药物所展示的那样。在……里面 第三个项目，我们将广泛开发亚胺基C-H官能化合成氮杂环。亚胺 来源于容易获得的醛和伯胺是有机化合物中最重要的中间体 综合。在米拉的资助下，我们开发了一种有效地制备嘌呤生物等位体的新方法。 通过亚胺的亚胺酰基C-H活化，然后与不同的偶联对进行原位环化。嘌呤 在大量的药物和候选药物中发现了生物等位基因，特别是那些与 具有嘌呤识别基序的生物分子靶标，如受体、激酶和信使核糖核酸。我们将利用 我们合成以转录组为靶点的嘌呤生物等位基因的方法，并将应用亚胺酰C-H 活化和环化以制备其他重要的杂环。在米拉的资助下，我们推出了新的酶 发现抑制剂的方法和有效的和选择性的抑制剂来挑战酶靶标。在建议中 研究，我们将直接将C-H功能化应用于生物探究。例如，我们针对 二氢吡啶的合成和精制使含胺结构的快速制备成为可能 功能的三维展示和多个立体产生中心的立体选择性引入， 在药物化学努力中越来越受追捧的特征。这些方法将应用于 发现有效和选择性的配体来挑战与未满足的治疗相关的生物分子靶点 医疗条件，包括鉴定中枢神经系统穿透性、对胺能GPCRs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.