Highly Efficient Asymmetric Hydrogenation Catalyzed by Iridium Complexes with Tridentate Chiral Spiro Aminophosphine Ligands

CONSPECTUS: Catalytic asymmetric hydrogenation is one of the most reliable, powerful, and environmentally benign methods for the synthesis of chiral molecules with high atom economy and has been successfully applied in the industrial production of pharmaceuticals, agrochemicals, and fragrances. The key to achieving highly efficient and highly enantioselective hydrogenation reactions is the design and synthesis of chiral catalysts.Our recent studies involving iridium complexes of bidentate chiral spiro aminophosphine ligands (Ir-SpiroAP) have revealed that adding another coordinating group on the nitrogen atom to form a tridentate ligand can provide catalysts with markedly higher stability, enantioselectivity, and efficiency. Specifically, chiral IrSpiroAP catalysts bearing an added pyridine group (designated IrSpiroPAP) exhibit high activity and excellent enantioselectivity in the asymmetric hydrogenation of a wide range of carbonyl compounds, including aryl ketones, fi- and (5-ketoesters, a,fi-unsaturated ketones and esters, and racemic a-substituted lactones, as well as highly electron-deficient alkenes such as a,fi-unsaturated malonates and analogues. The efficiency of the Ir-SpiroPAP catalysts is extremely high: in the hydrogenation of aryl ketones, turnover numbers reach 4.5 million, which is the highest value reported to date for a molecular catalyst. Moreover, when a thioether or a bulky triarylphosphine group is added to afford tridentate ligands designated SpiroSAP and SpiroPNP, respectively, the resulting iridium catalysts show high efficiency and enantioselectivity for asymmetric hydrogenation of fi-alkyl-fi-ketoesters and dialkyl ketones, which are challenging substrates. Furthermore, chiral spiro catalysts containing an added oxazoline moiety (Ir-SpiroOAP) show high enantioselectivity for asymmetric hydrogenation of a-keto amides and racemic a-aryloxy lactones. The above-described catalysts have been used for enantioselective synthesis of chiral pharmaceuticals and other bioactive compounds.We have shown that chiral spiro ligands that combine a rigid skeleton with tridentate coordination stabilize iridium catalysts. The careful tailoring of the substituents on the ligand creates a chiral environment around the active metal center of the catalyst that can precisely discriminate between the two faces of a substrate carbonyl group. These factors are key for controlling the activity, enantioselectivity, and turnover numbers of asymmetric hydrogenation catalysts. We expect that catalysts based on iridium, and other transition metals, coordinated by tridentate chiral ligands with a rigid skeleton will find more applications in asymmetric hydrogenation and other asymmetric transformations.

Automated summary

Catalytic asymmetric hydrogenation is a reliable, powerful, and environmentally friendly method for synthesizing chiral molecules. Our recent studies have shown that the design and synthesis of chiral catalysts can greatly improve the efficiency and selectivity of hydrogenation reactions. By adding additional coordinating groups, the stability and efficiency of the catalyst can be significantly increased.