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.

Public Health Relevance

Pharmaceutical drug discovery depends heavily on accessing unexplored chemical space. Borazines are a class of molecules that possess highly promising pharmacological properties, and embedding such subunits within organic molecules provides extraordinary opportunities to develop novel drug candidates. Unfortunately, current methods for the synthesis of these building blocks are extremely limited. The proposed research outlines unique ways to access borazines more efficiently, allowing access to novel platforms that hold promise in increasing molecular diversity in drug discovery efforts.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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University of Pennsylvania
Schools of Arts and Sciences
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Compton, Jordan S; Saeednia, Borna; Kelly, Christopher B et al. (2018) 3-Boryl-2,1-borazaronaphthalene: Umpolung Reagents for Diversifying Naphthalene Isosteres. J Org Chem 83:9484-9491
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