Modular Synthesis of Natural Products via Site- and Stereoretentive Couplings of Secondary Csp3 Boronic Acids

美国国家科学基金会化学部的化学合成项目支持伊利诺伊大学厄巴纳-香槟分校化学系Martin Burke教授的研究。Burke教授和他的学生们正在开发新的方法来组装含有非平面sp3碳原子的分子积木。这种方法有可能使一种简单的、基于构建块的方法成为可能，用于制造具有明确三维形状的许多不同类型的分子。这些分子有许多潜在的应用，包括作为药物、生物探针、诊断、农用化学品、材料、分子技术、香水、甜味剂和许多其他家用产品。这项研究的一个目标是为钯开发新的配体，以一种允许构建块的三维形状转化为最终产品形状的方式促进这种组装反应。该项目还旨在将这些新的偶联方法和易于获取的构建块集合整合到一个全自动平台中，用于按需合成自然界中发现的一大家族生物活性分子。这项研究非常适合各级科学家的教育。伯克教授的小组也处于有利地位，可以为来自科学领域代表性不足的群体的学生提供最高水平的教育和培训。立体sp3碳原子的位点特异性和立体特异性交叉偶联新方法的发展在很大程度上包括了许多不同类型小分子的基于自动化构建块的构建的可行路线图。所提出的研究旨在开发具有一个或多个立体sp3杂化碳原子的非活化手性二级非外消旋硼酸的偶联方法。新的膦配体通过促进sp3杂化碳的金属转化和还原消除来促进这种偶联，同时消除或最小化不需要的β -氢化物消除反应。这些方法被评估为能够从预组装的手性构建块中全自动合成整个家族的复杂天然产物的能力。这项研究产生了新的策略和方法，使人工和自动合成许多不同类型的手性富含csp3的小分子成为可能。该研究项目也有助于培养有机合成前沿领域的研究生和本科生。

The Chemical Synthesis Program of the NSF Chemistry Division supports the research of Professor Martin Burke in the Department of Chemistry at The University of Illinois at Urbana-Champaign. Professor Burke and his students are developing new methods for assembling molecular building blocks that contain non-planar "sp3" carbon atoms. Such methods have the potential to enable a simple, building block-based approach for making many different types of molecules with well-defined three-dimensional shapes. Such molecules have many potential applications, including serving as medicines, biological probes, diagnostics, agrochemicals, materials, molecular technologies, perfumes, sweeteners, and many other household products. One goal of the research is to develop new ligands for palladium that promote such assembly reactions in a manner that allows the three-dimensional shapes of the building blocks to be translated into the shapes of the final products. The project also aims to incorporate these new coupling methods and a readily accessible collection of building blocks into a fully automated platform for on-demand small molecule synthesis of a large family of biologically active molecules found in nature. This research is well suited for the education of scientists at all levels. Professor Burke's group is also well positioned to provide the highest level of education and training for students from groups that are underrepresented in science. The development of new methods for site- and stereospecific cross-coupling of stereogenic sp3 carbon atoms largely comprise an actionable roadmap toward automated building block-based construction of many different types of small molecules. The proposed studies aim to develop such methods for coupling unactivated chiral secondary non-racemic boronic acids that possess one or more stereogenic sp3-hybridized carbon atoms. New phosphine ligands are targeted that promote such couplings by favoring transmetalation and reductive elimination at sp3-hybridized carbons while eliminating or minimizing undesired beta-hydride elimination reactions. These methods are evaluated for their capacity to enable fully automated total synthesis of an entire family of complex natural products from pre-assembled chiral building blocks. This research yields new strategies and methods that enable both the manual and automated synthesis of many different types of chiral Csp3-rich small molecules. This research program also contributes to the training of graduate and undergraduate students at the frontiers of organic synthesis.