Novel Acylborons and Alpha-hydroxy Borons to Enable Modular, Regio- and Stereocontrolled Synthesis of Bioactive Molecules and Protein Conjugates

项目概要/摘要 我的研究实验室的长期目标是建立一种策略， 难以接近的区域/立体限定的有机硼，最终能够构建富含C（sp3）的乐高样结构。 生物活性分子和蛋白质缀合物。使用可互换建筑的模块化合成策略 块预计能够实现到目标化合物类的通用路线，这对于 优化其生物活性。单官能化的乙烯基或芳族卤代有机硼具有 在许多天然产物的模块化合成路线中发挥了关键作用。相反， 构建多官能和立体定向的酰基硼/烷基硼结构单元及其用于 富含C（sp3）的分子支架和生物缀合物的模块化合成仍然未被探索。的 本建议书所述的研究项目将提供一个平台，通过以下方式实现上述更广泛的目标： 建立一种通用的酰基硼/α-羟基硼基范例， 独特的有机硼在药物化学和化学生物学中具有广泛的应用。 酰基硼代表一类未被探索的有机硼，其存在和显着的合成 实用性只是最近才开始出现。我们以前报道过一种不对称的二硼基 构建稀有酰基硼的方法，包括α，β-不饱和酰基硼的第一个实例。 我们最近的初步数据表明，α，β-不饱和酰基硼和α-羟基硼 是获得正交官能化的、区域和立体定向的有机硼的有力中间体。 在我们已发表的工作和初步数据的基础上，我们将开发合成和 几种新型多官能酰基硼和α-羟基硼的应用， 提供了使用现有方法难以制备的对映体富集的有机硼。我们将 证明了这些新的构建模块的独特优势， 生物活性分子，并使模块化的合成方法，以手性框架中发现的药用 重要的化合物。在一个互补的研究方向，我们将开发一个新的类相互 正交生物缀合剂，预期其允许i）同时探测多种蛋白质- 蛋白质相互作用和ii）制备均质和稳定的生物缀合物。

Project Summary/Abstract The long-term goal of my research laboratory is to establish strategies that allow the synthesis of previously inaccessible regio-/stereodefined organoborons to ultimately enable the lego-like construction of C(sp3)-rich bioactive molecules and protein conjugates. Modular synthetic strategies using interchangeable building blocks are expected to enable a generalized route to the targeted compound class which is crucial for optimizing its biological activity. Orthogonally functionalized vinylic or aromatic halo-organoborons have played a critical role in many modular synthetic routes to natural products. In contrast, strategies to construct multifunctional and stereodefined acylborons/alkyl boron building blocks and their applications for modular synthesis of C(sp3)-rich molecular scaffolds and bioconjugates remain underexplored. The research projects described in this proposal will provide a platform to achieve the above broader goal by establishing a versatile acylboron/alpha-hydroxy boron-based paradigm to open-up access to several unique organoborons having broad applications in medicinal chemistry and chemical biology. Acylborons represent an underexplored class of organoborons whose existence and remarkable synthetic utility is beginning to emerge only recently. We previously reported an unsymmetrical diboron-based approach to construct rare acylborons including the first example of an alpha,beta-unsaturated acyl boron. Our recent preliminary data suggests that alpha,beta-unsaturated acyl borons and alpha-hydroxy borons are powerful intermediates to access orthogonally functionalized, regio- and stereodefined organoborons. Building upon our published work and preliminary data, we will develop general methods for synthesis and application of several new types of multifunctional acylborons and alpha-hydroxy borons to ultimately provide enantioenriched organoborons that would be difficult to prepare using existing methods. We will demonstrate the unique benefit of these novel building blocks to install rare substitution patterns on bioactive molecules and to enable a modular synthetic approach to chiral frameworks found in medicinally important compounds. In a complementary research direction, we will develop a new class of mutually orthogonal bioconjugation agents that are expected to allow i) simultaneous probing of multiple protein- protein interactions and ii) preparation of homogeneous and stable bioconjugates.