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

使用新型酰基硼和α-羟基硼作为实现工具的异常硼化杂环的模块化方法

• 批准号: 10114821
• 负责人: Abhishek Sharma
• 金额: $ 46.26万
• 依托单位: STEVENS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10114821
• 关键词: Amidines; Amines; Boron; Chemicals; Communities; Cyclic Ethers; Data; Development; Ethers; Family; Foundations; Generations; Goals; Heterocyclic Compounds; Hydrazines; Hydroxyl Radical; Isoxazoles; Libraries; Methods; Natural Products; Pattern; Pharmacologic Substance; Physical condensation; Positioning Attribute; Preparation; Public Health; Pyrazoles; Pyrimidines; Reaction; Research; Research Proposals; Route; Structure; Testing; X-Ray Crystallography; base; design; drug discovery; experience; functional group; innovation; novel; oxidation; piperidine; tetrahydrofuran; tool; undergraduate student

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.

项目总结/摘要 本研究的目标是开发具有以下性质的杂环化合物的一般合成方法： 使用常规方法难以获得的硼基取代模式。杂环如 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 包括药物活性剂和天然产物。最通用的方法之一， 将这些杂环引入高度官能化的医学上重要的化合物依赖于使用 相应的硼基化杂环结构单元。然而，硼基化的常规方法 吡唑、嘧啶和异恶唑允许获得非常有限的一组硼基取代模式和/或 具有差官能团耐受性。 使用酰基硼或α-羟基硼作为杂环核和硼的同时安装， 底物代表了构建硼基化杂环的非常有力的策略， 使用传统方法合成。然而，这一战略的更广泛应用受到以下因素的阻碍： 限制获得新的和多官能的酰基硼和α-羟基硼。我们最近开发了 一种新颖而简洁的制备各种MIDA酰基硼酸盐和α-羟基硼的路线。高模块化和 该策略的温和条件已经打开了获得某些新类别的酰基硼的途径。我们的初步 研究还表明，这些新的酰基硼中的一些α-羟基硼是 硼化杂环化根据我们的初步数据，我们假设，新的和 多官能酰基硼将开启几个令人兴奋的构建吡唑的机会， 嘧啶、异恶唑、具有罕见硼基取代模式的脂环醚/胺。为了验证这一 假设，我们将追求三个具体目标，其中，我们将开发用于合成一些 新的关键酰基硼和α-羟基硼及其在构建硼基吡唑中的应用， 嘧啶、异恶唑、脂环醚/胺。 我们的初步结果为我们实现本建议和我们的研究目标提供了坚实的基础 战略旨在为本科生提供尖端和严格的研究经验， 史蒂文斯这些新的酰基硼、α-羟基硼和硼化杂环的开发将 提供合成社区新的和多功能的工具，以扩大化学空间的医学重要 杂环化合物和有机硼。