Diazaphospholenes: A new class of catalyst for asymmetric reductions

二氮杂磷烯：一类新型不对称还原催化剂

• 批准号: 523283-2018
• 负责人: Speed, Alexander
• 金额: $ 9.11万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Idea to Innovation
• 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=665697
• 关键词: Diazaphospholenes; new; class; catalyst; asymmetric

Chiral amines are common in pharmaceutical active ingredients, with up to 40 percent of pharmaceuticals estimated to contain at least one chiral amine centre. The synthesis of chiral amines for modern pharmaceuticals relies on two predominant technologies, resolution, or asymmetric catalytic reduction. In a resolution, a chiral but racemic (containing both enantiomers) amine is prepared, and the enantiomers are separated, either through the use of enzymes or formation of salts with chiral enantiopure acids. Resolution is wasteful, since half the amine is the undesired enantiomer. Asymmetric catalytic reduction reduces waste, since a chiral catalyst can selectively access one enantiomer of a chiral amine from an achiral starting material. Existing chiral reduction catalysts are based on precious and toxic metals such as rhodium or iridium, in combination with chiral ligands, which are also frequently expensive. We are requesting funds to further develop our recently discovered chiral diazaphospholene catalysts. These simple catalysts can perform reductions without the use of metals, to make chiral amines. Moving to metal-free reductive chemistry is of importance for the pharmaceutical industry, since the expense of procuring metal catalysts, then removing metal residues from products complicates the use of catalytic asymmetric reduction. Despite the advantages catalytic reductions have over resolution reactions, resolution reactions still dominate the industrial synthesis of chiral amines, due to the above stated complications of using precious metals.. We have secured provisional patent protection for our chiral diazaphospholenes. While our catalysts already show chemoselectivity and efficiency that matches or exceeds that demonstrated by other metal-free catalysts, we continue to work on improvements. In this proposal, we show how we will improve the selectivity of the catalyst to levels that approach or exceed those of metal-containing catalysts, while expanding the substrate scope of transformations our catalyst is demonstrated to do. Both of these goals will enhance the attractiveness of our catalyst for commercialization, and uptake by potential industrial partners.********

手性胺在药物活性成分中很常见，据估计，高达40%的药物至少含有一个手性胺中心。用于现代药物的手性胺的合成依赖于两种主要技术，拆分或不对称催化还原。在一种拆分方法中，制备了手性但外消旋(包含两种对映体)的胺，并通过使用酶或与手性对映体酸形成盐来分离对映体。拆分是浪费的，因为一半的胺是不受欢迎的对映体。不对称催化还原减少了浪费，因为手性催化剂可以从非手性起始物质中选择性地访问手性胺的一个对映体。现有的手性还原催化剂是以贵金属和有毒金属(如Rh或Ir)与手性配体相结合的，手性配体通常也很昂贵。我们正在申请资金，以进一步开发我们最近发现的手性二氮杂膦催化剂。这些简单的催化剂可以在不使用金属的情况下进行还原，以制造手性胺。转向无金属还原化学对制药工业很重要，因为购买金属催化剂的费用，然后从产品中去除金属残留物使催化不对称还原的使用变得复杂。尽管催化还原比拆分反应具有优势，但由于上述使用贵金属的复杂性，拆分反应仍然主导着手性胺的工业合成。我们已经为我们的手性重氮膦烯获得了临时专利保护。虽然我们的催化剂已经显示出与其他不含金属的催化剂相同或超过的化学选择性和效率，但我们仍在继续改进。在这项建议中，我们将展示如何将催化剂的选择性提高到接近或超过含金属催化剂的水平，同时扩大我们的催化剂所做的转化的底物范围。这两个目标都将提高我们的商业化催化剂的吸引力，并为潜在的工业伙伴所接受。