Project of the month, May 2008

Phosphoric Acid Catalyzed Transfer Hydrogenations

Hydrogenation of carbon-carbon or carbon-heteroatom double bonds in the presence of a chiral catalyst is the method of choice to generate tertiary stereocenters in industrial applications. For decades, the concept of asymmetric hydrogenation has been associated with the use of transition metal complexes with chiral ligands. More recently, the explosion of asymmetric organocatalysis has prompted many research groups to investigate alternatives not relying on the use of metals. 1,4-Dihydropyridines such as Hantzsch esters are powerful reducing agents which can be easily prepared in one step. The use of organocatalysis in the reduction of double bonds with Hantzsch esters has been very succesful, resulting in protocols for highly enantioselective hydrogenation of α,β-unsaturated aldehydes, N-aryl imines, α-imino esters, nitroolefins, quinolines and other heterocycles.^[1] From a fundamental point of view, this approach is particularly interesting since it closely resembles the mode of action of the NAD(P)⁺/NAD(P)H redox couple in biological processes. Besides that, this recent developments provide a robust method for the enantioselective reduction of imines which proved to be very challenging substrates for transition metal catalysis.

In this project, DFT is used to investigate the mode of action of the phosphoric acid catalysts in the reduction of carbon-nitrogen double bonds. Enantioselectivity is also adressed by comparison of the calculated relative energies for the transition states to opposite enantiomers for different substrates to the experimentally determined enantiomeric excess of the products.

[1] Recent reviews: (a) S.-L. You, Chem. Asian J. 2007, 2, 820-827; (b) S. J. Connon, Org. Biomol. Chem. 2007, 5, 3407-3417.

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