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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=710962
• 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方法来提高我们的生活质量。有机化学中的转化通常由于缺乏通用性而变得复杂，或者伴随着不期望的副产物的形成，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，该方法采用从地球丰富的主族元素合成的催化剂，通过为过渡金属衍生的催化剂提供互补反应性，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，这两个开发新的类亲核试剂的基础上，具有不同的和改进的反应性配置文件，以目前的技术的主群中心。其中一个主题涉及这样的假设，即由双（氨基）亚环丙基（BAC）卡宾支持的borenium阳离子将显示出比已知borenium阳离子更大的反应性，因为BAC卡宾的空间体积减小。我们已经证明，BAC卡宾borenium阳离子能够氢化底物，这是以前报道的borenium阳离子无法达到的。我们将研究手性BAC卡宾负载的Borenium阳离子的合成，用于不对称催化，包括氢化，羟醛和Diels-桤木反应，所有这些都在精细化学品（包括药物）的合成中至关重要。我们的第二个主题涉及杂原子与二氮磷杂环烯络合会提高杂原子的亲核性的假设。我们已经证明，二氮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磷杂环戊二烯，并探索它们进行催化活化和与氢化物以外的亲核试剂加成的能力。二氮杂磷杂环戊二烯的刘易斯酸性的缺乏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要，并且潜在地允许开发用于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对合成化学产生重大影响。催化剂，如那些正在开发的在我的小组，表现出增强的官能团耐受性，或允许目前无法实现的转换，允许步骤被削减精细化学合成。这种精简将导致重大的环境和财政节省，因为精细化学品合成，特别是制药，代表了一个每年价值数千亿美元的行业。