Rapid Synthesis of Topologically Complex Molecules with Tungsten Dearomatization Agents

用钨脱芳构剂快速合成拓扑复杂分子

• 批准号: 9897642
• 负责人: Walter Dean Harman
• 金额: $ 36.69万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897642
• 关键词: 3-Dimensional; Affinity; Alcohols; Alkenes; Amines; Architecture; Benzene; Binding Sites; Biological; Carbon; Chemicals; Chemistry; Clinical; Complex; Coupled; Cyclohexanes; Development; Disease; Electrons; Evaluation; Exclusion; Foundations; Generations; Goals; Hydrogenation; Lead; Libraries; Ligands; Medicine; Methodology; Methods; Molecular; Oxides; Pattern; Pharmacologic Substance; Preparation; Process; Property; Public Health; Reaction; Research; Shapes; Site; Space Explorations; Specificity; Tungsten; alkyl group; carboxylate; chemical reaction; cyclohexene; design; diene; electron donor; functional group; improved; molecular shape; nucleophilic addition; overpopulation; receptor; scaffold; screening; small molecule libraries; stereochemistry; success; three dimensional structure

Project Summary/Abstract The development of a new pharmaceutical agent often requires screening thousands of compounds. Such compounds are typically derived from high-throughput syntheses, which tend to focus on simple transformations. For this reason, so called “flat” compounds, made from aromatic rings coupled together, predominate medchem libraries. However, molecules in these libraries stand in contrast to most naturally occurring, biologically active compounds, which have well-defined three-dimensional structures, rich in carbon stereocenters, adapted for specific and selective interactions with receptors. Since more complex molecules are better able to optimally fill space in their binding sites, molecular complexity strongly correlates with clinical success. Thus, a limited scope of synthetic methods used in discovery chemistry has led to an overpopulation of certain types of molecular shapes and properties to the exclusion of others. The challenge is to generate new classes of compounds with both diversity and complexity in a manner that is accessible to medicinal chemists. Such methodologies would open new, more prolific chemical space for exploration in both traditional SAR studies and the generation of fragment libraries. This proposal describes an approach to building cyclohexanes with multiple stereocenters derived from simple benzene precursors. The otherwise inert benzene scaffold is chemically enabled through its dihapto-coordination to a tungsten complexing agent. In the proposed study, we will assess the ability of {WTp(NO)(PMe3)} to activate electrophilic addition and nucleophilic addition reactions with a high degree of regio- and stereochemical control. Aim 1 focuses on the conversion of the 2-benzene complex to chiral 2-1,3-cyclohexadiene complexes. Aim 2 explores the conversion of these 2-1,3-cyclohexadienes to highly functionalized 2-cyclohexene complexes. Aim 3 is concerned with elaboration of these cyclohexene complexes into a wide variety of cyclohexanes, decorated with amine, alcohol, and carboxylate functionalities. Aim 4 evaluates the effects of a single substituent on an 2-benzene substrate. And finally, whereas the first four sections of this proposal explore the potential of creating molecular diversity using nucleophiles, Aim 5 focuses on the strategic use of carbon electrophiles. This dearomatization methodology will open more fertile chemical space-- fragment libraries that feature a diverse range of complex three-dimensional architectures with many of the functional groups common to proven pharmaceuticals. This approach not only increases the chances for finding new lead-like compounds for pharmaceutical development with increased affinity for a targeted binding site, but more importantly, increased specificity for that site.

项目概要/摘要 新药剂的开发通常需要筛选数千种化合物。这样的 化合物通常源自高通量合成，其往往侧重于简单的转化。 因此，由芳香环耦合在一起制成的所谓“扁平”化合物在医学化学中占主导地位 图书馆。然而，这些文库中的分子与大多数天然存在的、具有生物活性的分子形成鲜明对比。 化合物，具有明确的三维结构，富含碳立构中心，适用于 与受体的特异性和选择性相互作用。由于更复杂的分子能够更好地填充 结合位点的空间，分子复杂性与临床成功密切相关。因此，范围有限 发现化学中使用的合成方法导致某些类型的分子数量过多 形状和属性，排除其他。挑战在于生成新类别的化合物 以药物化学家可以理解的方式兼顾多样性和复杂性。此类方法将 开辟新的、更多产的化学空间，用于传统 SAR 研究和生成 片段库。该提案描述了一种构建具有多个立构中心的环己烷的方法 衍生自简单的苯前体。原本呈惰性的苯支架通过其化学活性得以实现 与钨络合剂的双键配位。在拟议的研究中，我们将评估以下人员的能力： {WTp(NO)(PMe3)} 以高度激活亲电加成和亲核加成反应 区域和立体化学控制。 目标 1 重点是将 2-苯配合物转化为手性 2-1,3-环己二烯配合物。目标2 探索了这些 2-1,3-环己二烯 向高度官能化 2-环己烯 复合物的转化。 目标 3 涉及将这些环己烯配合物加工成多种环己烷， 用胺、醇和羧酸酯官能团装饰。目标 4 评估单个取代基的影响 在 2-苯底物上。最后，虽然该提案的前四个部分探讨了 使用亲核试剂创造分子多样性，目标 5 重点关注碳亲电子试剂的战略使用。这 脱芳构化方法将开辟更丰富的化学空间——具有多样化特征的片段库 一系列复杂的三维架构，具有许多经过验证的常见功能组 药品。这种方法不仅增加了寻找新的类先导化合物的机会 药物开发对目标结合位点的亲和力增加，但更重要的是， 该网站的特殊性。