Catalytic Generation of Nucleophiles at Main Group Centres for Stereoselective Transformations

有机合成提供了制备用于医药、材料和农业的精细化学品的手段，从而提高了我们的生活质量。有机化学中的转化往往由于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催化剂仍然是一个积极研究的领域。我在达尔豪斯大学的新研究小组正在开发一种方法，利用从地球上丰富的主族元素合成的催化剂，使合成更便宜、更安全，并通过提供从过渡金属中提取的催化剂的互补反应性，使目前未知的转化变得容易实现。***我们正在探索两个有前景的主题，这两个主题都基于具有不同和改进的反应性概况的主要基团中心开发新的亲核试剂类别。其中一个主题涉及到一个假设，即由双（氨基）环丙烯（BAC）碳支持的硼离子将比已知的硼离子表现出更大的反应性，因为BAC碳的空间体积减小了。我们已经证明，BAC碳硼离子能够氢化底物，这是以前报道的硼离子无法达到的。我们将研究手性BAC碳负载的硼离子的不对称催化合成，包括氢化，醛醇和Diels- Alder反应，这些反应在精细化学品包括药物的合成中都是至关重要的。我们的第二个主题涉及到杂原子与二氮磷烯的络合提高杂原子的亲核性的假设。我们已经证明了重氮磷烷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烯，并探索其催化活化和除氢化物以外的亲核试剂加成共轭受体和羰基化合物的能力。二氮磷烯缺乏刘易斯酸性使得它们与质子官能团和刘易斯碱性官能团相容，减少了对保护基团的需求，并有可能开发出功能化分子合成的新策略。我们将从这两个主题中发展的概念将通过发现新的反应性对合成化学产生重大影响。像我的团队正在开发的那些催化剂，表现出增强的官能团耐受性，或者允许目前无法实现的转化，可以减少精细化学合成的步骤。由于精细化学合成，特别是制药，是一个每年价值数千亿美元的行业，因此这种精简将导致重大的环境和财政节约。

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.