Research On Asymmetric Organocatalytic Oxidation Based On Drug Skeleton

The α-hydroxy β-keto esters is an important structural motif in a variety of natural products, pharmaceutical products and key intermediates, such as vindoline, doxycycline, hamigeran A and indoxacarb etc. The most convenient method to synthesize this unit is through direct enantioselective oxidation of β-keto esters. However, the efficient methods are limited. There remains a great need to explore new organocatalysts which have more advantages including ease of preparaion, economy and efficiency.Cinchona alkaloids are an important class of asymmetric organic catalysts, cinchonine has been used to catalyze asymmetric α-hydroxylation of5-chloro-1-oxo-indan-2-carboxylic acid methyl ester by Dupont group to afford the corresponding product in85%yield and50%ee. And the Dupont group manufacture hundreds of tons of Indoxacarb annually. This is the largest industrial applications of asymmetric organocatalytic reaction.The hydrogen bonding between the proton of hydroxy group at C-9of Cinchonine and the ester group of the substrate control the configuration of the product. So we transform the hydroxyl group for the amino group using the isosteric theory. And then we synthetize a series of derivatives Cn-2～Cn-10. But the result of catalyzing a-hydroxylation of5-chloro-1-oxo-indan-2-carboxylic acid methyl ester is not satisfactory. The yields are no more than49%and the enantioselectivities are no more than31%ee.Through screening twenty-three aryloxy aminopropanol organocatalysts deriving from β-blocker inhibitor S-timolol for asymmetric a-hydroxylation of5-chloro-1-oxo-indan-2-carboxylic acid methyl ester,(R)-1-(tert-butylamino)-3-(3,4.5-trimethoxy phenoxy)propan-2-ol (A22) was the most effective catalyst. Then we optimized the reaction conditions and found that the best reaction conditions:20mol%of A22as catalyst,3-fold excess of tert-butyl hydrogen peroxide as the oxidant. hexane as solvent, reacting at15℃for48h. Under this condition, A22could enantioselectively catalyze a-hydroxylation of5-chloro-1-oxo-indan-2-carboxylic acid methyl ester to afford the corresponding product in97%conversion and41%ee. Investigating the scope of the substrates, we found that the ee value is88%using the4-methoxy-1-oxo-indan-2-carboxylic acid methyl ester as the substrate and the yield is up to96%.