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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要本研究计划的目标是开发合成具有以下性质的杂环的通用方法使用传统方法难以获得硼基取代模式。杂环化合物如吡唑、嘧啶、异恶唑、脂环族醚/胺是生物活性化合物中普遍存在的框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化合物合并到高度功能化的重要药用化合物中依赖于使用相应的硼化杂环结构单元。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/或官能团耐受性差。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化杂环的非常强大的策略，而硼化杂环很难使用传统方法合成。然而，该策略的更广泛应用受到了阻碍获得新型多功能酰基硼和 α-羟基硼的机会有限。我们最近开发了一种生产各种 MIDA 酰基硼酸酯和 α-羟基硼的新颖而简洁的路线。高度模块化和这种策略的温和条件开辟了获得一些新型酰基硼的途径。我们的初步研究还表明，其中一些新型酰基硼 α-羟基硼是硼基杂环化。根据我们的初步数据，我们假设新颖的和多功能酰基硼将为吡唑的构建带来一些令人兴奋的机会，嘧啶、异恶唑、脂环族醚/胺具有罕见的硼基取代模式。为了测试这个假设，我们将追求三个具体目标，其中，我们将开发合成某些物质的通用方法新型关键酰基硼和α-羟基硼及其在构建硼基吡唑中的应用，嘧啶、异恶唑、脂环族醚/胺。我们的初步结果为我们实现本提案和研究的目标提供了坚实的基础该战略旨在为本科生提供前沿和严谨的研究经验史蒂文斯。这些新型酰基硼、α-羟基硼和硼化杂环的开发将为合成界提供新的多功能工具，以扩大具有重要药用价值的化学空间杂环化合物和有机硼。