Research On New Catalysts For Asymmetric α-Hydroxylation Of β-Keto Esters

Theα-hydroxy1-β-keto ester moiety is an important structure. Till now, the most convineint approach to obtainα-hydroxyl-β-keto esters is asymmetrically oxidizingβ-keto esters catalyzed by chiral acid or chiral base. Currently asymmetric oxidation ofβ-keto esters is catalyzed by cinchona alkaloids cinchonine in the yield of 68%-85%, ee 44%-50% in large scale. Therefore it is vitally important both in theoretical study and industrial application to continue developing cheap and efficient chiral organocatalysts with novel frameworks.During screening of chiral drugs, our lab found thatβ-amino alcohol compounds lappaconitine and the analogue of chiral drug timolol (R)-1-(tert-butylamino)-3-(naphthalen-2-yloxy)propan-2-ol (Cat.1) can catalyze asymmetricα-hydroxylation ofβ-keto esters. Therefore, we optimized the reaction conditions catalyzed by amino alcohol compounds at frist. We found that the best reaction conditions:10 mol% lappaconitine as Br(?)nsted base, chloroform as solvent,5-fold excess of tert-butyl hydrogen peroxide as the oxidant, reacting at 15℃for 72 h. Under this condition,β-ketoesters asymmetricα-hydroxylation reaction reaches the highest ee value of 85% and the highest yield is 95%. We also developed the types of the substrate. On the following, the system catalyzed byβ-amino alcohol compound Cat.1 was optimized. We found the best reaction conditions:30 mol% Cat.1 as catalyst,20 mol%β-cyclodextrin as cocatalyst, hexane as solvent,3-fold excess of tert-butyl hydrogen peroxide as the oxidant, reacting at 15℃for 48 h. The reaction conversion rate is 93% and the ee value is 42%. Investigating the scope of the substrates, we found that the ee value is 57% using the methyl 6-methoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate as the substrate and the yield up to 92%. However, Cat.1 can't catalyze theα-hydroxylation of the chainβ-keto esters andβ-dicarbonyl compounds.In the paper,19β-amino alcohol compounds were designed and synthesized based on 'leading compound' ofβ-amino alcohol Cat.1, including 16 new compounds. We found that the group of the aromatic ether is essential. The group of the aromatic ether with big steric hindrance is not conducive to the catalytic reaction. The aromatic group can also effect the catalytic reaction by the electronic effect. The ability of the catalyst which contains basic rigid ring was influenced by the electronic effect, steric effect and the orientation space between the center of nitrogen atom and hydroxyl groups.