Iridium-Catalyzed Asymmetric Hydrogenation of Tetrasubstituted Exocyclic Olefins: An Efficient Access to Dexmethylphenidate

An Ir-catalyzed enantioselective hydrogenation of challenging tetrasubstituted exocyclic olefins is dis-closed. This new catalytic system tolerates a broad substrate scope and affords valuable chiral cyclic & beta;- amino esters possessing two vicinal stereocenters in high yields and excellent enantioselectivities and dia-stereoselectivities (up to 94% yield, 96% ee, 99:1 dr). Control experiments and deuterium-labeling reac-tions reveal an iminium hydrogenation mechanism upon Bronsted acid-promoted tautomerization of the C=C double bond to cycliciminium intermediates. Density functional theory calculations showcase that the excellent selectivities are derived from C-H & BULL;& BULL;& BULL;& pi; interaction between the substrate and the chiral ligand. Application in gram-scale preparation of dexmethylphenidate with up to 1500 turnover num-ber is also demonstrated, showing the promising potential of Ir-catalyzed enantioselective hydrogena-tion in drug synthesis.