Development Of C-6’ Modified Quinine Derived Phase-transfer Catalysts And Their Application In Asymmetric α-hydroxyl Reactions

a-hydroxyl keto ester is a kind of very important and common molecular structure unit, and widely exists in natural compounds, drugs and functional fine chemical intermediates. Hydroxylation of p-keto ester structure is the key step for synthesizing function compound. The existing literature reported that direct oxidation of dicarbonyl compounds by chiral catalysts was the most convenient way for a-hydroxylation of β-dicarbonyl compounds. However, there are still many practical problems in the present literature method, such as low catalytic activity,low selectivity, complicate catalyst preparation process, low oxidant stability, security problems, high cost and environment polluting and so on. All these problems need to be solved.In this paper, based on good catalytic effect of cinchona alkaloid derived phase transfer catalysts for a-hydroxylation of β-keto esters. We focused on exploring new quinine derived phase transfer catalysts and screened their performance on a-hydroxylation of β-dicarbonyl compounds. Firstly, we use quinine as skeleton and got demethyl quinine. Furthermore, we modified C-6’of demethyl quinine and got 6’-hydroxyl,6-’methoxyl,6-`isopropoxy, 6-’cyclohexoxyl,6-`TIPSO modified compounds(Q-1 to Q-5). Then we modified N atom with substituted benzyl and got corresponding catalysts Qn-1 to Qn-15. After that we use commercially available hydroperoxide cumene as oxidant and p-keto ester and β-keto amide structure as substrate for asymmetric catalytic oxidation.After screening of a series of quinine quaternary ammonium C-6’ phase transfer catalyst, we found that C-6`substituted group has big influence on the on selectivity. The bigger the steric hindrance of C-6`group, the lower the ee for the corresponding products. Ultimately, we determine the C-6`hydroxyl quinine as the main skeleton and research for quaternary ammonium salts. We found F atoms and trifluorine substituted benzyl bromide has a great influence for selectivity of asymmetric hydroxyl of β-dicarbonyl compound. Through combination and screening, we determine the 6-hydroxyl-N-(4’-fuluorine-2’-trifluoromethyl quinine quaternary ammonium salts as the optimal catalyst. With the optimal conditions:15℃, 50% K2HPO4, CHP as oxidant; The corresponding hydroxylated β-dicarbonyl compounds product got up to 95% yield and up to 87%ee.Finally,based on these newly developed catalysts, we further researched photo induced catalytic reaction for a-hydroxylation of (3-keto esters by using air as oxidant resources. We explore structure-activity relationship between the catalyst and the substrate and found that C-6`9 dihydroxyl quinine quaternary ammonium salts revealed high activity for asymmetric reaction. Besides, stereoselectivity can be further improved by adjusting electronic properties.All in all, we gave a guidance for future investigation on C-6` hydroxyl cinchona alkaloid derived catalysts for photo catalysis.