Asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters to functionalized chiral allylic alcohols via dynamic kinetic resolution

An iridium catalyzed asymmetric hydrogenation of racemic exocyclic gamma,delta-unsaturated beta-ketoesters via dynamic kinetic resolution to functionalized chiral allylic alcohols was developed. With the chiral spiro iridium catalysts Ir-SpiroPAP, a series of racemic exocyclic gamma,delta-unsaturated beta-ketoesters bearing a five-, six-, or seven-membered ring were hydrogenated to the corresponding functionalized chiral allylic alcohols in high yields with good to excellent enantioselectivities (87 to >99% ee) and cis-selectivities (93 : 7 to >99 : 1). The origin of the excellent stereoselectivity was also rationalized by density functional theory calculations. Furthermore, this protocol could be performed on gram scale and at a lower catalyst loading (0.002 mol%) without the loss of reactivity and enantioselectivity, and has been successfully applied in the enantioselective synthesis of chiral carbocyclic delta-amino esters and the beta-galactosidase inhibitor isogalactofagomine.

Automated summary

An iridium-catalyzed asymmetric hydrogenation process was developed to convert racemic exocyclic gamma,delta-unsaturated beta-ketoesters into functionalized chiral allylic alcohols via dynamic kinetic resolution. The protocol exhibited high yields, good to excellent enantioselectivities (87 to >99% ee), and cis-selectivities (93 : 7 to >99 : 1), and was successfully applied in the enantioselective synthesis of chiral carbocyclic delta-amino esters and the beta-galactosidase inhibitor isogalactofagomine with a lower catalyst loading on gram scale.