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: 10364728
• 负责人: Walter Dean Harman
• 金额: $ 30.77万
• 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/10364728
• 关键词: 3-Dimensional; Affinity; Alcohols; Alkenes; Amines; Architecture; Benzene; Binding Sites; 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.

项目总结/摘要 开发一种新的药物制剂通常需要筛选数千种化合物。等 化合物通常来源于倾向于集中于简单转化的高通量合成。 由于这个原因，所谓的“平面”化合物，由芳环偶联在一起，占主导地位的medchem 图书馆.然而，这些文库中的分子与大多数天然存在的生物活性分子相反， 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 在其结合位点的空间中，分子复杂性与临床成功密切相关。因此，有限的范围 在发现化学中使用的合成方法导致了某些类型的分子的过剩 形状和属性，以排除其他。挑战在于产生新的化合物类别， 多样性和复杂性，以一种药物化学家可以理解的方式。这种方法将 在传统的SAR研究和新一代的SAR研究中， 片段文库。该建议描述了一种构建具有多个立构中心的环己烷的方法 由简单的苯前体衍生。在其他方面惰性的苯支架通过其化学活性而被化学激活。 与钨络合剂双半配位。在拟议的研究中，我们将评估 {WTp（NO）（PMe3）}，以高的亲电性和亲核性活化亲电加成和亲核加成反应。 区域和立体化学控制。 目的1主要研究手性邻苯二甲酸配合物转化为手性邻苯二甲酸-1，3-环己二烯配合物.目的2 探索了这些β 2 - 1，3-环己二烯向高度官能化的β 2-环己烯络合物的转化。 目的3涉及将这些环己烯络合物加工成各种各样的环己烷， 用胺、醇和羧酸酯官能团修饰。目标4评估了单个取代基的影响 在一个β 2-苯底物上。最后，尽管本提案的前四部分探讨了 利用亲核试剂创造分子多样性，目标5侧重于碳亲电试剂的战略用途。这 脱芳构化方法将打开更肥沃的化学空间-片段库，具有不同的 一系列复杂的三维架构，其中许多功能组已被证明是常见的 大药厂这种方法不仅增加了发现新的类铅化合物的机会， 药物开发增加了对靶向结合位点的亲和力，但更重要的是，增加了 该位点特异性。