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

项目摘要/摘要 我的研究实验室的长期目标是建立战略，允许综合以前的 难以进入的区域/立体定义的有机硼最终实现富含C(SP3)的乐高结构 生物活性分子和蛋白质结合物。使用可互换建筑的模块化综合策略 块应该支持通向目标复合类的通用路由，这对于 优化其生物活性。正交官能化的乙烯或芳香族卤代有机硼 在许多合成天然产品的模块化合成路线中发挥了关键作用。相比之下，战略以 构筑多功能和立体定义的酰基硼/烷基硼构筑基块及其应用 富含C(SP3)的分子支架和生物结合物的模块化合成仍未得到充分的探索。这个 本提案中描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 建立一个通用的基于酰基硼/α-羟基硼的范例，以打开对几个 独特的有机硼化合物，在药物化学和化学生物学中有广泛的应用。 酰基硼代表了一类未被开发的有机硼，它的存在和非凡的合成 公用事业是最近才开始出现的。我们之前报道了一种不对称的双硼化合物 构建稀有酰基硼的方法，包括第一个α，β-不饱和酰基硼的例子。 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、区域和立体定义的有机硼的强大中间体。 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 几种新型多功能酰基硼和α-羟基硼在最终生产中的应用 提供用现有方法难以制备的富对映体有机硼。我们会 展示了这些新构建块在其上安装稀有替换模式的独特优势 生物活性分子，并使模块化合成方法能够在药物中发现手性骨架 重要的化合物。在相辅相成的研究方向上，我们将发展出一类新的相互 有望允许i)同时探测多个蛋白质的正交生物偶联剂- 蛋白质相互作用和II)制备均一和稳定的生物偶联物。

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.