Direct Catalytic Asymmetric Syntheses Of Oxindole-based δ-Hydroxy-β-ketoesters

δ-Hydroxy-β-ketoesters are useful building blocks for the syntheses of biologically important natural products and pharmaceutical precursors.The development of efficient synthetic methods of β-hydroxy-β-ketoesters has drawn wide attention from the synthetic community.General methods reported to access δ-hydroxy-β-ketoesters include reactions of dianions generated from β-ketoesters by using two or more equivalents of strong base(s)or reactions of preformed silyl dienol ethers or alkyl dienol ether derivatives with carbonyl compounds.These methods require either severe conditions or tedious protection and deprotection procedures.Only a handful of reports are available on the direct nucleophilic addition of β-ketoesters to synthesize δ-hydroxy-β-ketoesters under mild conditions.For example,the direct aldol reactions of β-ketoesters catalyzed by 1,8-diazabicyclo [5.4.0] undec-7-ene(DBU)or other bases that form the carbon-carbon bond at the γ-position of the β-ketoesters to provideδ-hydroxy-β-ketoester derivatives have been reported.Although enantiomerically enriched δ-hydroxy-β-ketoesters were obtained by resolutions of the racemic aldol products using homochiral amines,catalytic asymmetric processes are desired.Direct organocatalytic asymmetric syntheses of δ-hydroxy-β-ketoesters was accomplished via regio-and enantioselective aldol reactions of β-ketoesters with isatins catalyzed by cinchona alkaloid thiourea derivatives in this thesis.The C-C bond formation of the reactions occurred only at the γ-position of the β-ketoesters.Both enantiomers of the products were obtained by the use of pseudoenantiomers of the cinchona-derived catalysts.Reaction progress monitoring and product stability analyses under the conditions that included the catalyst indicated that the γ-position reaction products were formed kinetically.A possible mechanism is proposed based on the experimental results.It is a very simple and highly efficient method that provides an atomically economical synthetic route to the new diversely functionalizedδ-hydroxy-β-ketoesters bearing 3-alkyl-3-hydroxyoxindole cores relevant to the development of bioactive molecules.