Cobalt-Catalyzed Asymmetric Hydrogenation Enables Concise Synthesis of Chiral β-Methyl Ketones and β,β'-Dimethyl Ketones.

The introduction of a stereogenic methyl group, particularly in the form of chiral β-methyl ketones, represents a privileged strategy in drug discovery and natural product synthesis due to its pronounced influence on biological activity and physicochemical properties. Despite notable progress, existing asymmetric approaches to these motifs often rely on precious metal catalysts or suffer from drawbacks such as poor chemoselectivity, high cost, or excessive catalyst loadings. Herein, we report the first highly efficient cobalt-catalyzed asymmetric hydrogenation of readily accessible β-methyl conjugated enones. This method delivers a broad range of chiral β-methyl ketones with excellent chemoselectivity and enantioselectivity (70-99% yields, 91 to >99% ee). The protocol extends smoothly to symmetric β,β'-dimethyl dienones, affording the corresponding chiral β,β'-dimethyl ketones with exceptional diastereo- and enantiocontrol (generally >20:1 dr, > 99% ee). Synthetic utility is demonstrated by gram-scale reactions at low catalyst loading (TON = 1000), the concise asymmetric synthesis of (R)-(-)-dihydro-ar-turmerone, and the efficient construction of a novel spiroketal-based chiral biphosphine ligand. Mechanistic studies integrated with DFT calculations support a Co(II)-only catalytic cycle and reveal that the cationic pathway, along with combined steric and entropic effects, governs the high stereoselectivity. This sustainable cobalt-catalyzed hydrogenation offers a powerful and environmentally benign alternative to precious metal-based methods for accessing enantioenriched β-methylated ketone scaffolds.