Catalytic Generation of Nucleophiles at Main Group Centres for Stereoselective Transformations

在立体选择性转化的主要基团中心催化生成亲核试剂

• 批准号: RGPIN-2017-04297
• 负责人: Speed, Alexander
• 金额: $ 2.4万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=665695
• 关键词: Catalytic; Generation; Nucleophiles; Main; Group

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.

提案摘要***有机合成通过提供制备用于医药、材料和农业的精细化学品的手段来提高我们的生活质量。有机化学的转化通常由于缺乏通用性而变得复杂，或者伴随着不需要的副产物的形成，因此用于精细化学转化的新催化剂的开发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采用由地球丰富的主族元素合成的催化剂的方法，通过为过渡金属衍生的催化剂提供补充反应性，使合成更便宜、更安全，并使目前未知的转化变得容易实现。***我们是探索两个有希望的主题，这两个主题都基于主基团中心开发新类别的亲核试剂，其反应特性与现有技术不同且得到改进。其中一个主题涉及这样一种假设，即由于 BAC 卡宾的空间体积减小，双（氨基）环亚丙基 (BAC) 卡宾支持的硼阳离子将比已知的硼阳离子表现出更高的反应性。我们已经证明，BAC 卡宾硼阳离子能够氢化先前报道的硼阳离子无法接触的底物。我们将研究用于不对称催化的手性 BAC 卡宾负载硼阳离子的合成，包括氢化、羟醛反应和狄尔斯-阿尔德反应，这些反应对于包括药物在内的精细化学品的合成至关重要。我们的第二个主题涉及这样的假设：杂原子与二氮杂磷烯的络合提高了杂原子的亲核性。我们已经证明二氮杂磷烯醇盐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杂磷烯，并探索其催化活化和氢化物以外的亲核试剂加成到共轭受体和羰基化合物的能力。二氮杂磷烯缺乏路易斯酸性，使其与质子官能团和路易斯碱性官能团相容，减少了对保护基团的需求，并可能允许开发功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对合成化学产生重大影响。诸如我的团队正在开发的催化剂，它们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，从而可以减少精细化学合成中的步骤。这种精简将节省大量环境和资金，因为精细化学合成，尤其是制药，是一个每年价值数千亿美元的行业。