Asymmetric Hydrogenation of Substituted Pyridines

Asymmetric hydrogenation has been applied to a large range of prochiral substrates as a cost-efficient and sustainable method for the production of enantiopure compounds. However, aromatic and heteroaromatic substrates among which pyridines are of special interests due to the large occurrence of chiral piperidines in biologically active compounds (Figure 1) have remained a challenge for this technology. Two inherent characteristics from the substrate and the product make the hydrogenation of pyridines difficult: i) the harsh conditions needed to break the aromaticity of pyridines adversely affect the enantioselectivities, ii) both pyridines and piperidines can coordinate to the catalyst and act as an inhibitor. So far, the best strategy to cope with these difficulties was via quaternization of the pyridines.1 Taking advantage of the high throughput facilities present at DSM Innovative Synthesis (Geleen, Netherlands), where up to 96 hydrogenations can be performed in parallel, an extensive screening was carried out towards a catalyst for the enantioselective hydrogenation of quaternized substituted pyridines. Two novel catalytic systems were identified, the first one using iridium as a metal with two monodentate ligands (one chiral and one achiral) and the second one using rhodium with a bidentate ligand for more demanding substrates (Scheme 1). Mechanistic studies relying on kinetic measurements and the use of deuterium as well as a substrate scope will be presented.