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发现的出现，有机合成成为一门强大的科学，在过去的一个世纪里帮助我们的现代社会享受到了预期寿命和生活水平的显著提高。硼酸是一种稳定且相对无毒的含硼有机化合物，在过去20年里才经历了巨大的发展。只有在对它们的性质和反应性进行明智探索的情况下，它们在合成和生物应用方面的持续增长才会发生。根据这一观点，将在以下方向开展新的项目：1.合成方法学的开发，重点是立体选择性合成，以便能够选择性地制备“镜像”形式的手性(不对称)化合物，这在制药业中至关重要。为此，我们将解决制备高功能化的含杂原子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，作为一种简化手性药物合成的手段。2.新的催化方法：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，从而避免在这些重要的反应类别中使用有毒的卤代烷。伯醇的硼酸盐基催化离开基团的发现是一个高风险、高回报的目标，将解决药物化学的许多绿色化学“优先领域”。3.与天然多肽的新型生物正交结合化学：与刚性二醇形成硼酸盐提供了与无毒成分的生物正交“点击”反应。通过两种不同的方法：噬菌体展示选择多肽库和合理设计杂多环硼酸加合物，我们将鉴定与邻甲酰基芳基硼酸具有紧密结合亲和力的短小而独特的天然多肽序列。由于其遗传可编码性，这些多肽可以很容易地被结合到感兴趣的蛋白质中，从而提供了一种简单、快速和生物相容的与标记的硼酸的结合系统，这对于实时研究生命系统中的蛋白质功能将是非常有用的。

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.