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: 9924794
• 负责人: Walter Dean Harman
• 金额: $ 2.01万
• 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/9924794
• 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.

项目摘要/摘要 开发一种新的药剂通常需要对数千种化合物进行筛选。是这样的 化合物通常来自高通量的合成，这往往集中在简单的转化上。 出于这个原因，所谓的“扁平”化合物，由芳香环连接在一起制成，在医学上占主导地位。 图书馆。然而，这些文库中的分子与大多数自然产生的、具有生物活性的分子形成了鲜明的对比 化合物，具有明确的三维结构，富含碳立体中心，适用于 与受体的特异性和选择性相互作用。因为更复杂的分子更能以最佳方式填充 在其结合部位的空间，分子复杂性与临床成功密切相关。因此，有限的范围 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，而不包括其他。挑战是生成新的化合物类别， 多样性和复杂性，以一种药物化学家可以理解的方式。这种方法论将 开辟新的、更多产的化学空间，用于传统的SAR研究和新一代 片段库。该方案描述了一种构建具有多个立体中心的环己烷的方法 从简单的苯前体中提取。其他惰性的苯支架通过其化学方法实现 与钨络合剂的二次配位作用。在拟议的研究中，我们将评估 {Wtp(NO)(PMe3)}以高度的亲电加成和亲核加成反应 区域和立体化学控制。 目的1研究-2-苯络合物向手性-2-1，3-环己二烯络合物的转化。目标2 探索了这些2-1，3-环己二烯转化为高官能化的-2-环己烯络合物。 目标3涉及将这些环己烯络合物精制成各种环己烷， 装饰着胺、酒精和羧酸盐的官能团。目标4评估单一取代基的影响 在-2-苯底物上。最后，鉴于本提案的前四个部分探讨了 目标5利用亲核试剂创造分子多样性，重点是碳亲电体的战略使用。这 脱芳烃方法学将开辟更肥沃的化学空间--具有多样化特征的片段文库 一系列复杂的三维体系结构，具有许多经过验证的常见功能组 制药公司。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 该站点的专一性。