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

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，在过去的一个世纪里，它帮助我们的现代社会大幅提高了预期寿命和生活水平。硼酸是一种稳定且相对无毒的含硼有机化合物，仅在过去二十年中才有了巨大的发展。只有在明智地探索其性质和反应性的支持下，它们的合成和生物应用才会持续增长。有鉴于此，将在下列方向进行新的项目：合成方法的发展，重点是立体选择性合成，以选择性制备“镜像”形式的手性（不对称）化合物，这是制药工业中至关重要的一项努力。为此，我们将解决制备高功能化含杂原子手性烷基硼酯的挑战，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. 新的催化过程：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现成的醇，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。以硼酸盐为基础的伯醇催化离去基的发现是一个高风险高回报的目标，它将解决许多绿色化学的药物化学“优先领域”。3. 与天然肽的新型生物正交偶联化学：硼酸盐与刚性二醇的形成提供了与无毒成分的生物正交“点击”反应。利用噬菌体展示选择肽库和合理设计杂多环硼酸加合物两种不同的方法，我们将鉴定出与邻甲酰基芳基硼酸紧密结合的短而独特的天然肽序列。由于其遗传可编码性，这种肽可以很容易地结合到感兴趣的蛋白质中，从而提供了一种简单，快速和生物相容性的标记硼酸偶联系统，这将对实时研究生命系统中的蛋白质功能有很大的帮助。

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.