Novel Borazines: Syntheses and Elaboration

 描述(由申请人提供)：新型反应性积木的发明及其与独特的子结构平台的结合为探索和创造新的化学空间提供了绝佳的机会。我们研究计划的总体目标是通过开发这种新的试剂并随后利用这些试剂的新的反应模式作为获得新的化学结构的手段来促进有机分子的构建。在这里，我们提出的研究将为结合各种重要的芳香族和杂芳族体系的硼氮异构体的新型分子设计开辟广阔的新可能性。相对简单的芳香族/杂芳族化合物，特别是联芳基，主导着通常由制药公司产生的化合物库，因为它们可以优先与一些蛋白质结合，从而使它们成为设计有效和高度特异性药物的理想平台。尽管这些结构基序在发现广泛的药理活性物质方面发挥了很好的作用，但越来越多的人认识到，目前“无法下药”的靶标可能根本不是不可下药的，而是观察到的顽固性可能反映了当前收集的化学空间范围有限。这项拟议的研究试图在芳香族/杂芳族领域开辟新的化学空间。几乎所有被提议创建的硼氮亚结构都是独一无二的，而且所提议的化合物的反应性和物理化学性质都没有被系统地研究过。尽管人们已经知道了50多年，但在药物发现的背景下，很少有人研究硼氮杂环族化合物，这可能是因为它们的合成可及性相对有限。正是这种明显的不足，可靠，有效和灵活的路线，以不同的氮硼化合物，这项研究建议寻求纠正。所描述的合成方法，与各种硼氮杂环丙烷的“经典”方法相结合，将提供进入新的化学空间的非凡途径。更重要的是，能够以前所未有的方式进一步操纵这些平台，将使这些系统能够更充分地用简单的方法装饰，在许多情况下，以高度选择性和可持续的方式，而不需要求助于过渡金属催化的反应或导向基团。因此，硼氮类化合物代表了芳香族和杂芳族反应性模式以及那些以前从未被开发过的经典有机硼和胺的迷人的混合体，我们将在开发前所未有的转化过程中最大限度地利用这一点。

 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.