Novel Borazines: Syntheses and Elaboration

新型环硼嗪：合成和精制

基本信息

批准号：
9488516
负责人：
GARY A MOLANDER
金额：
$ 25.16万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9488516
关键词：
Agrochemicals Alkenes Alkynes Amination Amines Architecture Area Benzene Benzofurans Binding Biological Biological Testing Carbon Characteristics Chemicals Chemistry Collection Coupling Development Dimensions Electrostatics Family Glare Goals Hand Histone Deacetylase Hybrids Hydrogen Bonding Indoles Investigation Isoquinolines Isoxazoles Libraries Methods Modeling Modernization Molecular Naphthalenes Nature Nitrogen Pattern Pharmaceutical Preparations Pharmacologic Substance Pharmacology Process Property Proteins Proxy Reaction Reagent Research Resort Rest Route Site Structure System Time Transition Elements Work analog base benzimidazole benzothiophene catalyst design drug candidate drug discovery fascinate flexibility invention materials science novel novel strategies novel therapeutics programs public health relevance pyridine quinoline

项目摘要

DESCRIPTION (provided by applicant): The invention of novel reactive building blocks and their incorporation into unique substructural platforms present outstanding opportunities to explore and create new chemical space. The overarching goal of our research program is to facilitate the construction of organic molecules by developing such new reagents and subsequently exploiting the novel reactivity patterns for those reagents as a means to access new chemical architectures. Herein are described investigations that we propose will serve to open vast new possibilities for novel molecular designs incorporating borazine isosteres of a variety of important aromatic and heteroaromatic systems. Relatively simple aromatic/heteroaromatic compounds, and particularly biaryls, dominate libraries of compounds typically generated by pharmaceutical companies because they can preferentially bind to a number of proteins, thus making them ideal platforms for the design of potent and highly specific drugs. Although these structural motifs have served well in the discovery of a wide-range of pharmacologically active materials, there is a growing recognition that current "undruggable" targets may not be undruggable at all, but rather the recalcitrance observed may be reflective of the limited range of chemical space accessed in current collections. The proposed research seeks to open new chemical space within the aromatic/heteroaromatic domain. Nearly all of the borazine substructures proposed to be created are unique, and neither the reactivity nor the physicochemical properties of the compounds proposed have ever been studied in a systematic manner. Despite being known for more than five decades, the borazine class of heteroaromatics has rarely been studied in the context of drug discovery, presumably because of their relatively limited synthetic accessibility. It is this glaring deficiency of reliable, effcient, and flexible routes to diverse azaborines that the research proposed seeks to redress. The synthetic methods described, combined with "classical" approaches to a variety of borazines, will provide extraordinary access to novel chemical space. More importantly, the ability to manipulate these platforms further in unprecedented ways will allow these systems to be more fully decorated by facile methods, in many cases in a highly selective, sustainable manner without resorting to transition metal-catalyzed reactions or directing groups. The borazines thus represent a fascinating hybrid between aromatic and heteroaromatic reactivity patterns and those of classical organoborons and amines that has not been previously exploited, and we will take maximum advantage of this in the development of unprecedented transformations.

描述（由适用提供）：新颖的反应性构建块及其在独特的子结构平台中发明的发明提供了探索和创造新化学空间的出色机会。我们的研究计划的总体目标是通过开发这种新试剂并随后利用这些试剂的新反应性模式来促进有机分子的构建，以此作为访问新化学体系结构的手段。这里描述了我们建议的研究，这些研究将为编码各种重要的芳香族和异性系统的新型分子设计开放新的可能性。相对简单的芳族/异源化合物，尤其是双芳基化合物，主要由制药公司生成的化合物库，因为它们可以优先与多种蛋白质结合，从而使其成为潜在和高度特定药物的理想平台。尽管这些结构基序在发现广泛的药物活性材料方面非常有效，但人们越来越认识到目前的“不可能”靶标可能根本不需要不良，但是观察到的顽固性可能反映出当前集合中的化学空间范围有限。拟议的研究旨在在芳香/异源域内开放新的化学空间。几乎所有提议创建的硼嗪子结构都是独特的，并且所提出的化合物的反应性和物理特性都没有系统地研究。尽管五十多年来一直闻名，但在药物发现的背景下，硼嗪类的异源性类别很少被研究，这大概是因为它们相对有限的合成可及性。这项研究提出的是，正是可靠，高效和灵活的途径的明显缺陷，拟议中的研究试图纠正。所描述的合成方法，结合了各种硼嗪的“经典”方法，将为新的化学空间提供非凡的访问。更重要的是，以前所未有的方式进一步操纵这些平台的能力将使这些系统可以通过便捷的方法更加完全装饰，在许多情况下，以高度选择性，可持续的方式而无需诉诸于过渡金属捕获的反应或指导群体。因此，硼嗪代表了芳香和异性反应性模式与古典有机杆和胺之间的迷人杂种，这些杂种以前尚未探索过，我们将在前所未有的变换发展中最大程度地利用这一点。