Diazaphospholenes: A new class of catalyst for asymmetric reductions

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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.********