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

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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.