Buchler Glossary

Asymmetric Hydrogenation

Hydrogenation is a reduction reaction which results in an addition of hydrogen (often as H2). If an organic compound is hydrogenated, it becomes more “saturated” with hydrogen atoms. Asymmetric hydrogenation of unsaturated double bonds (C=C, C=N, C=O) is one of the most desired atom-economic strategies in order to obtain chiral compounds from prochiral precursors. Many important pharmaceuticals and agrochemicals are produced on large scale via asymmetric hydrogenation.

Asymmetric Hydrogenation

Enantioselective hydrogenation of ketones, imines, substituted olefines has emerged as a popular facile route to approach enantiopure secondary alcohols, amines and substituted aliphatic compounds as essential intermediates for the construction of biologically active molecules. The catalytic activity and stereoselectivity are highly influenced by the ligands, chiral catalysts employed in the reaction. The enantioselectivity of a chiral catalyst relies on its ability to distinguish the prochiral centres or faces of substrates. For this purpose in particular Cinchona alkaloids have been widely used as chiral skeletons and organocatalysts in asymmetric organic synthesis due to their structural properties, bearing 5 chiral centers, the quinuclidine nitrogen included.

Cinchona alkaloids in Enantioselective Hydrogenation

A series of cinchona alkaloid-based NNP ligands, have been employed for the asymmetric hydrogenation of ketones. Cinchona alkaloid based ruthenium complexes and various aromatic and heteroaromatic ketones were smoothly reacted. Valuable chiral alcohols with an extremely high 99.9% ee could be obtained. Over the last few decades, the asymmetric hydrogenation of C=O double bonds was generally affected by a variety of chiral transition metal catalysts. In particular Ru, Rh, Ir, Pd and Pt catalysts have proven to be highly active and enantioselective catalysts. For the asymmetric hydrogenation of activated ketones over Pt/Al2O3 and Pd/TiO2 often basic Cinchona alkaloids are applied as chiral modifiers. Most of substrates, even heteroaromatic ketone, were converted to corresponding chiral alcohols in excellent enantioselectivities.

9-Epiamino (9-deoxy) cinchona alkaloids, derived from natural cinchona alkaloids, were applied in asymmetric transfer hydrogenation in both iridium and rhodium catalytic systems using i-propanol as the hydrogen source. A series of aromatic ketones was examined, and good to excellent conversions and enantioselectivities were observed. The best results were achieved using 9-Epiamino(9-deoxy)cinchonine as the ligand and [Ir(COD)Cl]2 as the metal precursor.

The stereoselective reduction of imines with trichlorosilane is a well-established procedure for the synthesis of enantio-enriched amines. This reaction is catalyzed by chiral Lewis bases.

Among the metal-free methodologies available for the enantioselective reduction of imines, the use of trichlorosilane in combination with Cinchona alkaloids represents one of the most successful ways.

Furthermore the asymmetric hydrogenation of tetrasubstituted olefins provides direct access to very useful biological molecules and intermediates. In this case, hydrogenation is also induced by cinchona alkaloid derivatives.

You can find a lot of examples for enantioselective hydrogenation in our free of charge Chiral Catalyst Search Data Base.

Example from Literature

Cinchona-alkaloid-derived NNP ligand for Iridium-catalyzed asymmetric hydrogenation of ketones. ( Zhang et al.; Org. Lett., 2021, 24(1), 415-419.)

Enantioselective Hydrogenation

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