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

基本信息

批准号：
10797141
负责人：
JONATHAN A ELLMAN
金额：
$ 12.52万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

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.

项目摘要/摘要催化C-H键功能化已成为合成有机化学的强大方法新药的发现和生产。下一代C-H键功能化方法该提案中描述的将使简单的药物相关化合物快速组装并随时可用的输入。在一个程序中，我们将在一个步骤中访问复杂的分子体系结构从简单的前体来通过C-H键的顺序三组分耦合和两种不同类型的类型的耦合耦合伙伴。因为许多不同的耦合伙伴对于常规的C-H键添加有效对于一个耦合伙伴，顺序的三组分反应利用了不同的耦合组合合作伙伴应提供与药物和天然产品合成相关的大量主题的访问。通过MIRA资金获得的初步结果已经确定了这种方法的可行性和实用性。在第二个程序，我们将应用可逆的光介导的C-H键激活，从最容易访问的杂环立体异构体。饱和杂环，例如哌啶，吗啡，哌嗪和lactams在药物和候选药物中很普遍，但通常是最有效的准备稳定的立体异构体。但是，光介导的过程可以使其高度立体选择性正如我们最近通过Mira资助为piperidines所展示的那样，转换为更稳定的立体异构体。在第三个程序，我们将通过Imidoyl C-H功能化广泛发展氮杂环合成。爱意源自随时可用的醛和原代胺是有机物中重要的中间体合成。通过Mira资助，我们开发了一种新的方法来有效制备嘌呤生物蛋白酶通过Imidoyl C-H的激活，与不同的耦合伴侣一起进行原位环状。嘌呤在大量药物和候选药物中发现了生物同体，尤其是那些与之相互作用的药物具有嘌呤识别基序（例如受体，激酶和mRNA）的生物分子靶标。我们将利用我们合成嘌呤生物固定剂以靶向转录组的方法，并将应用Imidoyl C-H 激活和环状以准备其他重要的杂环。通过Mira资助，我们提高了新酶抑制剂发现方法以及有效的抑制剂，可挑战酶靶标。提议研究，我们将直接将C-H功能化应用于生物学查询。例如，我们的方法二氢吡啶的合成和阐述可以使含胺结构的快速制备功能和立体选择性引入多个立体生成中心的三维显示，在药物化学努力中，人们越来越多地追求的特征。这些方法将应用于发现有效和选择性的配体，以挑战与未得到的治疗相关的生物分子靶标医疗状况，包括鉴定CNS渗透物，高度选择性的配体对AMINEGIC GPCR。