The asymmetric hydrogenation of aromatic γ- and δ-keto esters into optically active hydroxy esters or diols under the catalysis of a novel DIPSkewphos/3-AMIQ-Ru complex was studied. Under the optimized conditions (8 atm H , Ru complex/t-C H OK=1:3.5, 25 °C) the γ- and δ-hydroxy esters (including γ-lactones) were obtained quantitatively with 97-99 % ee. When the reaction was conducted under somewhat harsh conditions (20 atm H , [t-C H OK]=50 mm, 40 °C), the 1,4- and 1,5-diols were obtained predominantly with 95-99 % ee. The reactivity of the ester group was notably dependent on the length of the carbon spacer between the two carbonyl moieties of the substrate. The reaction of β- and ϵ-keto esters selectively afforded the hydroxy esters regardless of the reaction conditions. This catalyst system was applied to the enantioselective and regioselective (for one of the two ester groups) hydrogenation of a γ-ϵ-diketo diester into a trihydroxy ester.
The DIPSkewphos/PICA derivative-Ru(II) complexes catalyzed asymmetric hydrogenation of significantly sterically hindered 2',3',4',5',6'-pentamethylacetophenone, which was not reduced with NaBH 4 at 25 8C, with a substrate-to-catalyst molar ratio (S/ C) of 2000 under 50 atm of H 2 in a base-containing 2-propanol to afford the alcohol in 99 % ee quantitatively. A series of polysubstituted aromatic ketones was smoothly reacted with an S/C of 300-10,000 under 10-50 atm of H 2 , yielding the alcoholic products in up to 99 % ee. The catalyst system achieved an industrial-scale (50 kg) hydrogenation of 2',6'-dichloro-3'-fluoroacetophenone, affording the alcohol in 96 % isolated yield and in 98 % ee. The obtained alcoholic product is known as a key intermediate for the synthesis of the medicine crizotinib.
The asymmetric hydrogenation of aromatic γ‐ and δ‐keto esters into optically active hydroxy esters or diols under the catalysis of a novel DIPSkewphos/3‐AMIQ–RuII complex was studied. Under the optimized conditions (8 atm H2 , Ru complex/t‐C4H9OK=1:3.5, 25 °C) the γ‐ and δ‐hydroxy esters (including γ‐lactones) were obtained quantitatively with 97–99 % ee. When the reaction was conducted under somewhat harsh conditions (20 atm H2 , [t‐C4H9OK]=50 mm, 40 °C), the 1,4‐ and 1,5‐diols were obtained predominantly with 95–99 % ee. The reactivity of the ester group was notably dependent on the length of the carbon spacer between the two carbonyl moieties of the substrate. The reaction of β‐ and ϵ‐keto esters selectively afforded the hydroxy esters regardless of the reaction conditions. This catalyst system was applied to the enantioselective and regioselective (for one of the two ester groups) hydrogenation of a γ‐ϵ‐diketo diester into a trihydroxy ester.
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