Boronic Acid Chemistry as a Modern Platform in Catalysis, Stereocontrolled Synthesis and Bioconjugation

硼酸化学作为催化、立体控制合成和生物共轭的现代平台

• 批准号: RGPIN-2017-05086
• 负责人: Hall, Dennis
• 金额: $ 10.13万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=710111
• 关键词: Boronic; Acid; Chemistry; Modern; Platform

With discoveries like pharmaceutical drugs, insecticides, polymers, and food additives, organic synthesis stands as a powerful science that helped our modern society enjoy a dramatic increase in life expectancy and standard of living in the past century. Boronic acids are stable and relatively non-toxic boron-containing organic compounds that have undergone huge developments only over the past two decades. Continued growth in their synthetic and biological applications will occur only if supported by a judicious exploration of their properties and reactivity. With this view, new projects will be undertaken in the following directions: 1. Synthetic methodology development, with a focus on stereoselective synthesis to enable the selective preparation of "mirror image" forms of chiral (unsymmetrical) compounds, an endeavor of critical importance in the pharmaceutical industry. To this end, we will address the challenge of preparing highly functionalized heteroatom-containing chiral alkylboronic esters, and optimize methods for their stereoselective catalytic cross-coupling as a means to streamline the synthesis of chiral drugs. 2. New catalytic processes: We will examine new applications of boronic acids as mild and 'green' catalysts for direct elimination and substitutions of readily available alcohols, thus bypassing the use of toxic alkyl halides in these important classes of reactions. The discovery of borate-based catalytic leaving groups for primary alcohols is a high-risk-high-reward objective that would address many green chemistry “priority areas” of pharmaceutical chemistry. 3. Novel bioorthogonal conjugation chemistry with native peptides: Boronate formation with rigid diols provides a bioorthogonal “click” reaction with non-toxic components. Using two different approaches: phage display selection of peptide libraries, and rational design of heteropolycyclic boronate adducts, we will identify short and unique natural peptide sequences with a tight binding affinity to ortho-formyl arylboronic acids. Such peptides could be incorporated readily into a protein of interest due to its genetic encodability, thus providing a simple, fast and biocompatible conjugation system with labeled boronic acids that would be of great utility for investigating protein function in living systems in real time.

随着药物、杀虫剂、聚合物和食品添加剂等的发现，有机合成成为一门强大的科学，帮助我们的现代社会在过去的世纪中大幅提高了预期寿命和生活水平。硼酸是稳定且相对无毒的含硼有机化合物，仅在过去二十年中才经历了巨大的发展。只有在对其性质和反应性进行明智探索的支持下，它们的合成和生物应用才会持续增长。根据这一观点，将在以下方向开展新的项目：1.合成方法学开发，重点是立体选择性合成，以选择性制备手性（不对称）化合物的“镜像”形式，奋进在制药行业至关重要。为此，我们将解决制备高度官能化的含杂原子的手性烷基硼酸酯的挑战，并优化其立体选择性催化交叉偶联的方法，以简化手性药物的合成。2.新的催化工艺：我们将研究硼酸作为温和和“绿色”催化剂的新应用，用于直接消除和取代容易获得的醇，从而绕过在这些重要类别的反应中使用有毒的烷基卤化物。 伯醇的硼酸酯基催化离去基团的发现是一个高风险高回报的目标，它将解决药物化学的许多绿色化学“优先领域”。 3.与天然肽的新型生物正交缀合化学：与刚性二醇的硼酸酯形成提供了与无毒组分的生物正交“点击”反应。使用两种不同的方法：通过噬菌体展示肽库的选择和杂环硼酸酯加合物的合理设计，我们将鉴定出对邻甲酰基芳基硼酸具有紧密结合亲和力的短且独特的天然肽序列。这样的肽由于其遗传可编码性而可以容易地掺入到感兴趣的蛋白质中，从而提供了具有标记的硼酸的简单、快速和生物相容性的缀合系统，其对于真实的时间研究生命系统中的蛋白质功能将是非常有用的。