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香槟分校化学系的Martin Burke教授的研究。 伯克教授和他的学生正在开发组装含有非平面“sp3”碳原子的分子构建模块的新方法。这种方法有可能实现一种简单的，基于构建块的方法，用于制造具有明确定义的三维形状的许多不同类型的分子。此类分子具有许多潜在应用，包括用作药物、生物探针、诊断剂、农用化学品、材料、分子技术、香料、甜味剂和许多其它家用产品。该研究的一个目标是开发新的钯配体，以允许构建块的三维形状转化为最终产品的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访问的构建模块集合整合到一个全自动化平台中，用于按需合成自然界中发现的大家族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。 伯克教授的小组也处于有利地位，为来自科学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的新方法的开发主要包括许多不同类型的小分子的基于自动构建块的构建的可行路线图。所提出的研究旨在开发用于偶联具有一个或多个立体异构sp3-杂化碳原子的未活化的手性仲非外消旋硼酸的此类方法。靶向新膦配体，其通过有利于在sp3-杂化碳处的金属转移和还原消除同时消除或最小化不期望的β-氢化物消除反应来促进这种偶联。这些方法的能力进行评估，使全自动全合成的一个完整的家庭复杂的天然产物从预组装的手性积木。这项研究产生了新的策略和方法，使手动和自动合成许多不同类型的手性Csp 3丰富的小分子。该研究计划还有助于培养有机合成前沿的研究生和本科生。

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.