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

NSF化学部的化学合成计划支持伊利诺伊大学厄巴纳-香槟分校化学系马丁·伯克教授的研究。伯克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”碳原子的分子构件。这种方法有可能实现一种简单的、基于积木的方法来制造许多不同类型的分子，使其具有明确的三维形状。这类分子有许多潜在的应用，包括用作药物、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。这项研究的目标之一是开发新的钯配体，以促进这种组装反应，使构建块的三维形状可以转化为最终产品的形状。该项目还旨在将这些新的偶联方法和易于获得的积木集合纳入一个全自动化平台，用于按需合成自然界中发现的一大类生物活性分子的小分子。这项研究非常适合各级科学家的教育。伯克教授的团队也处于有利地位，可以为来自科学界代表性不足的群体的学生提供最高水平的教育和培训。立体起源的SP3碳原子的定点和立体特异性交叉偶联的新方法的开发，在很大程度上构成了实现许多不同类型小分子的自动化构建的可行路线图。所提出的研究旨在开发这样的方法来偶联具有一个或多个立体生成的SP3杂化碳原子的未活化的手性次级非外消旋硼酸。新的膦配体是通过促进SP3杂化碳上的金属易位和还原消除，同时消除或减少不希望发生的β-氢化物消除反应来促进这种偶联反应的目标。对这些方法的能力进行了评估，以实现从预先组装的手性构建块全自动合成整个复杂的天然产品家族。这项研究产生了新的策略和方法，使许多不同类型的富含Csp3的手性小分子的手动和自动合成成为可能。该研究项目还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.