Asymmetric iron catalyzed hydrogenation of ketones

The development of chemical transformations that are not only efficient and selective but also comply with green chemistry guidelines has become a key focus in synthetic chemistry in recent years. Catalytic reactions that employ benign earth-abundant metals like iron are prime candidates towards this effort. Specifically iron catalysis has seen an over-exponential increase in research output over the last decade. The reduction of ketones is of considerable importance specifically in the pharmaceutical industry where it is most commonly performed with hydride donor reagents which generates large amounts of waste and necessitates extra work-up and purification steps. However, the use of hydrogen gas as reductant (hydrogenation) is 100% atom economical, therefore minimizing waste and the need for purification. Herein, the development of a mild and selective iron catalyzed asymmetric hydrogenation of ketones to form chiral alcohol products is proposed. The proposal builds on groundbreaking work reported earlier in the Milstein group. Milstein et al. have successfully employed well defined iron pincer complexes to reduce ketones and carbon dioxide by employing hydrogen gas as the reductant with unprecedented efficiency and under mild reaction conditions. This reaction shall now be rendered asymmetric to access highly valuable chiral alcohols important e.g. in the pharmaceutical industry. The mode of action is proposed to include a novel metal ligand interaction which comprises of an aromatization-dearomatization step and leads to unique reactivity. A selection of appropriate chiral ligands will be prepared to investigate through which factors (sterics/electronics) the enantioselectivity can be best affected. To date, comparable reactions can only be performed with expensive and environmentally harmful precious metals or under the generation of large amounts of waste and by-products which poses a serious drawback for the chemical industry. A successful research outcome will provide a base-metal catalyzed, byproduct-free, environmentally benign way to access highly sought-after chiral alcohols with a clear potential for industrial applicability.

In this project, the development of a new iron-based catalyst system was achieved. The catalyst was able to react with important substrates like molecular hydrogen, oxygen, sulfur, alcohols and alkynes in an unprecedented mode of action. The responsibility of todays chemists to develop chemical reactions that are not only highly efficient but also consistent with green chemistry guidelines is undeniable. In addition, the construction of complex molecules by the use of smaller, easily available substrates like molecular hydrogen or oxygen or simple alcohols or alkynes is an important goal in synthetic organic chemistry. In order to be environmentally conscious and applicable to industry-scale production, syntheses of these products have to be as concise and reliable as possible, generating a minimum amount of waste or hazardous by-products. Therefore, the discovery of new transformations and reaction-modes that fulfill these requirements is a primary objective of synthetic chemistry. Catalytic reactions involving transition metals are strong candidates for this effort, as by definition the catalyst is regenerated at the end of the reaction and can thus potentially be re-used. This minimizes the amount of hazardous waste produced and states an important green chemistry principle. Not surprisingly, metal-catalyzed processes have already found broad use in the industrial production of chemicals. However, the transition metals employed are in most cases rare and thus expensive elements like rhodium, iridium, platinum, palladium or ruthenium and their high price along with their significant toxicity are serious drawbacks. The element iron on the other hand is the second most abundant metal in the earth crust. With its very low cost and toxicity it is the ideal metal for the development of new, ecologically and economically favorable catalytic transformations.