Synthetic Ketoreductase Mimics (SyKe)

Main funder

Funds granted by main funder (€)

246 585,00

Funding program

Postdoctoral Researcher, AoF (Academy of Finland)

Project timetable

Project start date: 01/09/2018

Project end date: 31/08/2021


Selective reduction of carbonyl groups remains one of the fundamental challenges in synthetic chemistry. In Nature this transformation is catalyzed by ketoreductase enzymes. The active site of the enzyme consists of a hydrogen bond network creating an oxyanion hole for the ketone and bringing the hydride source (NADH) to appropriate distance. Conversely, synthetic asymmetric ketone reduction relies mainly on two methodologies: oxazaborolidine-mediated hydroboration and ruthenium-catalyzed hydrogenation.
The goal of prosed project is to use synthetic oxyanion hole (SOX) catalysts for enantioselective ketone reduction. The ketone functionality will be activated by bidentate hydrogen bonding analogous to oxyanion holes. In order to stereoselectively deliver the hydride to the activated ketone, we propose to coordinate a main-group element hydride with a Lewis basic functionality tethered to the hydrogen bond catalyst. The binding of the Lewis base not only gives full control of the active site of the catalysts, but also increases the hydricity of the reductant. Lewis base activation of main-group element hydrides has been widely applied, especially in silane activation. The corresponding hydroborane activation however, has not attracted same attention despite the recent success in related frustrated Lewis pair (FLP) catalysis as well as classic precedence of oxazaborolidine-mediated hydroboration (CBS-reduction). Although hydrogen bond activation of carbonyls and Lewis base activation of main-group element hydrides have been studied extensively, the combination has not been applied in to the asymmetric ketone reduction.
The bifunctional foldamer catalysts could be further used in the related allylboration. As in the proposed reduction, the ketone would be bound by hydrogen bonding, while the Lewis base would be used to activate allylborane. Nucleophilic attack by the allyl fragment to the activated ketone would generate a chiral quaternary alcohol.
Finally we propose to catalytically generate the active borohydride using dihydrogen. Incorporating an electron-deficient borane to the proximity of a sterically encumbered Lewis base leads to the formation of a (frustrated) Lewis pair, which have been successfully used to metal-free heterolytic splitting of dihydrogen. Combining foldamer hydrogen bond activation of carbonyls with FLP activation of dihydrogen for asymmetric hydrogenation of ketones would be a major breakthrough.

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Last updated on 2018-14-06 at 14:45