Enantioselective α-Hydroxylation Of β-Keto Esters By Phase-transfer Catalysis

a-Funcationalization ofβ-keto ester is a highly straighfouwand and strategically simple method for the synthesis of a large number of interesting molecules and synthetic building blocks, especially, the a-hydroxylation products is a common structural motif in a variety of natural products and Pharmaceuticals. Although several examples of catalytic enantioselective a-hydroxylation ofβ-keto esters have already been reported, the most direct preparation method is to use an asymmetric catalytic, currently, there are still challenging issues that need to be addressed, such as low active of catalyst, low selectivity, safety of oxidant, efficiency and ease of catalyst preparation, and reaction scale-up. These problems limit the application of these strategies.Herein, firstly, we developed the green and efficient system using cinchonine derived phase-transfer catalyst to promote a direct a-hydroxylation ofβ-keto esters. After screening a series of catalysts which the C9-OH was protected by esterification reaction, we found that the most important functional groups to achieve higher ee were the anthracene group at the bridgehead nitrogen of cinchonine and the chiral secondary alcohol protected by a bulky1-adamantyl group. The scope of the method was next probed using variousβ-keto esters, giving the corresponding products in35-95%yield with58-90%ee. Finally, this new methodology was successfully scaled-up to a gram-quantity with85%yield and87%of enantioselectivity. Based on the similarity and difference with the phenomenon of literature, in this paper, we speculate the model of the catalyst-substrate complex.In order to further improve environment friendly of enantioselective a-Hydroxylation of β-keto esters by phase-transfer catalysis, we changed oxidation route, using air as the green oxygen source for the asymmetric transformation. After screening a series of catalysts which the C9-OH was protected by esterification reaction, we found that the most effective catalyst was Qn-1which derived from quinidine. After a further reaction optimization, good to excellent selectivities have been obtained for a range ofβ-keto esters under mild conditions. Furthermore, the green, inexpensive and operated simply a-hydroxylations can be used for smallβ-keto esters, gave the corresponding products in92-99%yield with58-64%ee. Evenmore. this improved α-oxidation method forβ-oxo esters was successfully scaled up to a gram-quantity in99%yield with64%of enantioselectivity, and the recycling of catalyst effect is remarkable, it is suitable for use in industrial processes.