Enantioselective α-Hydroxylation Of β-Dicarbonyl Compounds Catalyzed By Cinchona Alkaloid Derivatives

Chirality is one of the important attributes of nature and it is closely related to the fields of study in chemistry, biology, pharmacy, engineering etc. Enormous demands for chiral compounds in the area of industrial community promoted the development of chiral science rapidly. The optically active a-hydroxy-β-dicarbonyl compounds represented a functional and common structural motif. Direct asymmetric a-hydroxylation of β-dicarbonyl compounds is the most convenient and efficient way to obtain this type of structure.Firstly, cinchona alkaloids quinine and quinidine were used as the leading organocatalysts, structural modifications of cinchona alkaloids in the C-2’and C-6’positions were proceed. Then the organo-catalytic a-hydroxylation of 5-chloro methyl 1-oxo-2, 3-dihydro-lH-indene-2-carboxylate was used as the model reaction.21 kinds of cinchona alkaloid derivatives were synthetized and screened. The structure-function relationship between the catalyst and the model reaction was investigated. After catalyst screening, catalyst QD-3 derived from quinidine, which has two-hydroxy groups at C-9 and C-6’ positions, and a Br atom at C-2’positon, was proved to be an efficent catalyst for the a-hydroxylation. The a-hydroxylation product was obtaind with 92% ee and 98% yield. A gram-scale reaction proceeded smoothly with maintained efficiency (96% yield) and enantioselectivity (91% ee). In this reaction system, the S-products were obtained by using cumyl hydroperoxide as oxidant, with good enantioselectivities (80%-90% ee) and high yields (87%-99%). The R-products were obtained by using 30% H2O2 as oxidant, with 36%-87% ee and 35%-96% yields. The catalytic system can be also applied to the asymmetric a-hydroxylation of β-keto amides and the products were obtained with 51%-94% yields and 38%-92% ee. At last, the reaction mechanism was discussed and the paper explained that the high reactivity of reaction was possiblely due to the hydrogen bondings among catalyst, substrate and oxidant.Secondly, by using hydroquinine as catalyst, the hydrazine-induced enantioselective a-hydroxylation of β-keto esters with molecular oxygen was developed. A wide variety of β-keto esters could undergo this a-hydroxylation to give the products with 55%-85%ee in 67%-95% yields. Here is the activation process of molecular oxygen:radical cation was formed in the presence of hydrazine and base, then it can react with molecular oxygen. Hydrogen peroxide was then generated and the a-hydroxylation of the substrate was proceeded.Thirdly, through the visible-light driven oxidition strategy, an enantioselective photo-organocatalytic a-hydroxylation of β-dicarbonyl compounds using molecular oxygen has been realized, and the atom economy is 100%. We designed, synthetized and screened the cinchona alkaloid derived phase transfer catalysts. PTC 31 which is derived from cinchonine with a substituted phenyl group at C-2’position was an efficient catalyst for a-hydroxylation of β-keto esters and β-keto amides (30 examples). The products was obtained with up to 90% ee and 71%-99% yields. Besides, a new cinchona-derived N-oxide asymmetric phase-transfer catalyst PTC-Cn-7 derived from cinchonine was synthetized and it has the properties of recovery and reuse. By using PTC-Cn-7 as catalyst, the enantioselective photo-organocatalytic a-hydroxylation of β-keto esters and β-keto amides (23 examples) was achieved with up to 82% ee and 99% yield. The catalyst could be reused six times for such a reaction with 78% ee and 91% yield. After that, an assumed mechanism was proposed, the oxidation reaction may go through a singlet oxygen process and peroxide intermediates oxidation process.