Diazaphospholenes: A new class of catalyst for asymmetric reductions

手性胺在药物活性成分中很常见，估计高达40%的药物含有至少一个手性胺中心。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。在拆分中，制备手性但外消旋（含有两种对映异构体）胺，并通过使用酶或与手性对映纯酸形成盐来分离对映异构体。拆分是浪费的，因为一半的胺是不需要的对映体。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材料选择性地获得手性胺的一种对映异构体。现有的手性还原催化剂是基于贵金属和有毒金属如铑或铱与手性配体的组合，其通常也是昂贵的。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磷杂环戊二烯催化剂。这些简单的催化剂可以在不使用金属的情况下进行还原，以制备手性胺。 转向无金属还原化学对制药工业很重要，因为采购金属催化剂的费用，然后从产品中去除金属残留物使催化不对称还原的使用复杂化。尽管催化还原具有优于拆分反应的优点，但由于使用贵金属的上述复杂性，拆分反应仍然主导手性胺的工业合成。我们已获得手性二氮磷杂环戊二烯的临时专利保护。虽然我们的催化剂已经显示出与其他无金属催化剂相匹配或超过的化学选择性和效率，但我们仍在继续改进。在该提案中，我们展示了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被证明可以进行的转化的底物范围。这两个目标将提高我们的催化剂对商业化的吸引力，并被潜在的工业合作伙伴采用。

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.********