Modular Approaches to Unusual Borylated Heterocycles using Novel Acylborons and alpha-Hydroxy borons as Enabling Tools

项目摘要/摘要 本研究计划的目标是开发合成具有以下特点的杂环化合物的一般方法 用常规方法很难获得的硼基取代模式。杂环化合物，如 吡唑、嘧啶、异恶唑、脂环醚/胺是生物活性化合物中普遍存在的骨架。 包括药用活性物质和天然产品。最通用的方法之一就是 将这些杂环结合到高度官能化的医药重要化合物中依赖于使用 相应的硼化杂环构筑基团。然而，传统的硼化方法 吡唑、嘧啶和异恶唑允许获得一组非常有限的硼基取代模式和/或 对功能群体的耐受性较差。 以酰基硼或α-羟基硼为原料同时安装杂环核和硼 底物代表了一种非常有效的策略来构建难以合成的硼化杂环 用传统方法合成。然而，这一战略的更广泛应用受到以下因素的阻碍 限制获得新的和多功能的酰基硼和α-羟基硼。我们最近开发了 一条新颖而简明的路线，合成各种MIDA酰基硼酸酯和α-羟基硼。高度的模块化和 这一策略的温和条件打开了一些新类别的酰基硼的途径。我们的预赛 研究还表明，其中一些新的酰基硼-α-羟基硼是适合于 硼化杂环化反应。根据我们的初步数据，我们假设新的和 多功能酰基硼将为构建吡唑打开几个令人兴奋的机会， 具有稀有的硼基取代模式的嘧啶、异恶唑、脂环醚/胺。为了测试这一点 假设，我们将追求三个特定的目标，其中，我们将开发一些合成的一般方法 新型关键的酰基硼和α-羟基硼及其在合成硼基吡唑类化合物中的应用， 嘧啶、异恶唑、脂环醚/胺。 我们的初步结果为实现本方案的目标和我们的研究提供了坚实的基础 战略旨在为本科生提供尖端和严谨的研究经验， 史蒂文斯。这些新型的酰基硼、α-羟基硼和硼化杂环的开发将 为合成社区提供新的通用工具，以扩大医学上重要的化学空间 杂环化合物和有机硼化合物。

Project Summary/Abstract The goal of this research proposal is to develop general methods for synthesis of heterocycles possessing boryl-substitution patterns that are difficult to access using conventional approaches. Heterocycles such as pyrazoles, pyrimidines, isoxazoles, alicyclic ethers/amines are ubiquitous frameworks in bioactive compounds including pharmaceutically active agents and natural products. One of the most versatile methods to incorporate these heterocycles in highly functionalized medicinally important compounds relies on the use of the corresponding borylated heterocyclic building blocks. However, conventional approaches to borylated pyrazoles, pyrimidines and isoxazole allow access to a very limited set of boryl-substitution patterns and/or suffer from poor functional group tolerance. The simultaneous installation of heterocyclic core and boron using acylborons or alpha-hydroxy borons as substrates represents a very powerful strategy for construction of borylated heterocycles that are difficult to synthesize using traditional methods. However, broader applications of this strategy have been hampered by limited access to novel and multifunctional acylborons and alpha-hydroxy borons. We have recently developed a novel and concise route to various MIDA acylboronates and alpha-hydroxy borons. The high modularity and mild conditions of this strategy has opened up access to some novel classes of acylborons. Our preliminary studies also suggest that some of these novel acylborons alpha-hydroxy borons are competent substrates for borylative heterocyclization. Based on our preliminary data, we hypothesize that the availability of novel and multifunctional acylborons would unlock several exciting opportunities for construction of pyrazoles, pyrimidines, isoxazoles, alicyclic ethers/amines possessing rare boryl-substitution patterns. To test this hypothesis, we will pursue three specific aims, wherein, we will develop general methods for synthesis of some novel linchpin acylborons and alpha-hydroxy borons and their application for construction of boryl-pyrazoles, pyrimidines, isoxazoles, alicyclic ethers/amines. Our preliminary results provide us a strong foundation to achieve the goals of this proposal and our research strategy is designed to provide cutting-edge and rigorous research experience to undergraduate students at Stevens. The development of these novel acylborons, alpha-hydroxy borons and borylated heterocycles will provide the synthetic community new and versatile tools to expand the chemical space of medicinally important heterocyclic compounds and organoborons.