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; 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 新药剂的开发通常需要筛选数千种化合物。这样的 化合物通常来自高通量合成，这些合成倾向于简单转换。 因此 库。但是，这些库中的分子与最自然发生的，生物学活性的形成鲜明对比 具有富含碳立体中心的三维结构的化合物，适用于 与接收者的特定和选择性互动。由于更复杂的分子能够更好地填充 分子复杂性在其结合位点的空间与临床成功密切相关。那是有限的范围 在发现化学中使用的合成方法导致某些类型的分子过度人口 将他人排除在外的形状和属性。面临的挑战是与 多样性和复杂性都以医学化学家可以使用的方式。这样的方法会 在传统的SAR研究和产生中，开放新的，更丰富的化学空间，用于探索 碎片库。该建议描述了用多个立体中心构建环形的方法 源自简单的苯前体。否则惰性的苯支架是通过其化学启用的 与钨络合剂配合的dihapto协调。在拟议的研究中，我们将评估 {wtp（no）（pme3）}以高度激活亲电的添加和核螺旋添加反应 区域和立体化学控制。 AIM 1专注于2-苯苯络合物到手性2-1,3-循环己二烯复合物的转化。目标2 探索这些2-1,3-循环的转化为高度功能化的2-环己烯复合物。 AIM 3与将这些环己烯配合物详细说明有关 用胺，酒精和羧酸盐功能装饰。 AIM 4评估单个亚字符的效果 在2-苯苯基板上。最后，尽管该提案的前四个部分探讨了 AIM 5使用核致化学物质创建分子多样性，重点是碳电力的战略使用。这 Dearomatization方法论将开放更多肥沃的化学空间 - 碎片图书馆具有潜水员 许多功能组的复杂三维体系结构范围很常见 药品。这种方法不仅增加了寻找类似铅的化合物的机会 药物开发具有增加对靶向结合位点的亲和力，但更重要的是， 该站点的特异性。