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

新型酰基硼和α-羟基硼能够实现生物活性分子和蛋白质缀合物的模块化、区域和立体控制合成

基本信息

批准号：
10668428
负责人：
Abhishek Sharma
金额：
$ 36.18万
依托单位：
STEVENS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

项目摘要

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.

项目概要/摘要我的研究实验室的长期目标是建立能够综合以前的难以获得的区域/立体定义的有机硼最终能够像乐高积木一样构建富含 C(sp3) 的有机硼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区块有望为目标化合物类别提供通用途径，这对于优化其生物活性。正交官能化乙烯基或芳香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。相比之下，策略构建多功能和立体定义的酰基硼/烷基硼结构单元及其应用富含 C(sp3) 的分子支架和生物共轭物的模块化合成仍有待探索。这本提案中描述的研究项目将为实现上述更广泛的目标提供一个平台建立通用的酰基硼/α-羟基硼基范式，以开放多种途径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。酰基硼代表了一类尚未被开发的有机硼，其存在和显着的合成实用性直到最近才开始出现。我们之前报道过一种不对称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-羟基硼是获得正交功能化、区域和立体定义的有机硼的强大中间体。基于我们已发表的工作和初步数据，我们将开发合成和合成的通用方法几种新型多功能酰基硼和α-羟基硼的应用最终提供使用现有方法难以制备的对映体富集的有机硼。我们将展示这些新颖的构建模块在安装罕见替代模式方面的独特优势生物活性分子，并实现药物中发现的手性框架的模块化合成方法重要的化合物。在互补的研究方向上，我们将开发一类新的相互正交生物共轭剂有望允许 i) 同时探测多种蛋白质- 蛋白质相互作用和 ii) 均质且稳定的生物共轭物的制备。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Generation and Application of Homoallylic α,α-Diboryl Radicals via Diboron-Promoted Ring-Opening of Vinyl Cyclopropanes: cis-Diastereoselective Borylative Cycloaddition.

通过二硼促进乙烯基环丙烷开环产生同烯丙基α,α-二硼基自由基：顺式非对映选择性硼基环加成。

DOI：
发表时间：
2024-01-08
期刊：
影响因子：
0
作者：
Vyas, Het;Gangani, Ashvin J;Mini, Aiswarya;Lin, Shengjia;Chu, Jia;Agee, Caitlyn O;Gabriel, Justin;Williamson, R Thomas;Zhang, Yong;Sharma, Abhishek
通讯作者：
Sharma, Abhishek

Boron-Promoted Deprotonative Conjugate Addition: Geminal Diborons as Soft Pronucleophiles and Acyl Anion Equivalents.

硼促进的去质子共轭加成：偕二硼作为软亲核试剂和酰基阴离子等价物。