Catalytic Generation of Nucleophiles at Main Group Centres for Stereoselective Transformations

有机合成通过提供手段来制备用于医药、材料和农业的精细化学品，从而提高了我们的生活质量。有机化学中的转化往往因缺乏通用性而变得复杂，或者伴随着不希望的副产物的形成，因此开发用于精细化学转化的新型催化剂一直是一个活跃的研究领域。我在达尔豪西大学的新研究小组正在开发一种方法，使用从地球上丰富的主族元素合成的催化剂，通过向来自过渡金属的催化剂提供互补的反应性，使合成更便宜、更安全，并使目前未知的转化变得容易。*我们正在探索两个有前途的主题，这两个主题都在主族中心的基础上开发新的亲核剂，这些主族中心与当前技术的反应性曲线不同且得到改进。一个主题涉及一种假设，即双(氨基)环丙叉卡宾(BAC)卡宾支持的硼阳离子将表现出比已知的硼阳离子更大的反应活性，因为BAC卡宾的空间体积减少。我们已经证明了BAC卡宾硼阳离子能够使以前报道的硼阳离子不能接触到的底物氢化。我们将研究手性BAC卡宾负载的硼阳离子的合成，用于不对称催化，包括氢化反应、Aldol反应和Diels-Alder反应，这些反应在包括药物在内的精细化学品的合成中都是至关重要的。我们的第二个主题涉及一个假设，即杂原子与二氮杂膦的络合作用提高了杂原子的亲核性。我们已经证明了二氮杂磷烯醇氧化物可以催化亚胺还原和共轭还原反应。我们将合成具有不同结构的手性二氮磷茂化合物，并探索它们催化活化和将氢化物以外的亲核试剂加成到共轭受体和羰基化合物上的能力。重氮膦烯的Lewis酸度不足使它们与质子型官能团和Lewis碱性官能团相容，减少了对保护基的需求，并有可能开发出官能化分子合成的新策略。我们将从这两个主题发展的概念将通过发现新的反应性在合成化学中产生重大影响。催化剂，如我的团队正在开发的那些，表现出增强的官能团耐受性，或允许目前无法获得的转化，允许在精细化学合成中削减步骤。这种精简将带来重大的环境和财务节约，因为精细化学合成，特别是制药，代表着一个每年价值数千亿美元的行业。

Summary of Proposal ***Organic synthesis raises our quality of life by providing means to prepare fine chemicals used in medicine, materials and agriculture. Transformations in organic chemistry are often complicated by a lack of generality, or accompanied by the formation of undesired side products, consequently the development of new catalysts for fine chemical transformations continues to be an area of active investigation. My new research group at Dalhousie University is developing methodology employing catalysts synthesized from earth abundant main group elements to make synthesis cheaper, safer, and to make currently unknown transformations accessible, by providing complementary reactivity to catalysts derived from transition metals.***We are exploring two promising themes, both of which develop new classes of nucleophiles based on main group centres with different and improved reactivity profiles to current technologies. One theme involves the hypothesis that borenium cations supported by bis(amino)cyclopropylidene (BAC) carbenes will display greater reactivity than known borenium cations because of the diminished steric bulk of BAC carbenes. We have already demonstrated that BAC carbene borenium cations are capable of hydrogenating substrates that are inaccessible to previously reported borenium cations. We will investigate the synthesis of chiral BAC carbene-supported borenium cations for asymmetric catalysis, including hydrogenation, aldol, and Diels- Alder reactions, all of vital importance in the synthesis of fine chemicals including pharmaceuticals. Our second theme involves the hypothesis that complexation of a heteroatom to a diazaphospholene raises the heteroatom's nucleophilicity. We have demonstrated that diazaphospholene alkoxides can catalyze imine reduction and conjugate reduction reactions. We will synthesize chiral diazaphospholenes with diverse architectures, and explore their ability to conduct catalytic activation and addition of nucleophiles other than hydride to conjugate acceptors and carbonyl compounds. The lack of Lewis acidity of diazaphospholenes renders them compatible with protic functional groups and Lewis basic functional groups, reducing the need for protecting groups, and potentially allowing the development of new strategies for functionalized molecule synthesis. The concepts we will develop from both themes will result in major impacts in synthetic chemistry through discovery of new reactivity. Catalysts such as those being developed in my group, that exhibit enhanced functional group tolerance, or allow transformations that are not currently accessible, allow steps to be cut in fine chemical synthesis. This streamlining will result in major environmental and financial savings, since fine chemical synthesis, especially pharmaceuticals, represent an industry worth hundreds of billions of dollars per year.