Enantioselective α-hydroxylation Of β-keto Esters By Phase-transfer Catalysis

α-Funcationalization of β-keto ester is a highly direct 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 of β-keto esters have already been reported, there are still challenging issues that need to be addressed. For example, safety of oxidant, efficiency and ease of catalyst preparation, and reaction scale-up.In this thesis, we developed a green and efficient system using cinchonine derived phase-transfer catalyst (PTC) to promote a direct a-hydroxylation of β-keto esters. After screening the28catalysts we found that the most important functional groups to achieve higher ee were the benzyl group at the bridgehead nitrogen of cinchonine and the chiral secondary alcohol moiety at C9position of the alkaloid. Equally important, we found that1-Ad moiety in the substrates not only enhanced the reaction yield but also affected the stereochemical outcome of the reaction.1-Indanone derived1-Ad β-keto esters, in the presence of commercially available cumyl hydroperoxide and the cinchonine based ammonium salt, gave the corresponding products in69-91%yield with65-74%ee. In addition, this kind of substrates was easier to access via a transesterification than tert-butyl ester which was widely used in asymmetric phase-transfer reation. Finally, this new methodology was successfully scaled-up to a gram-quantity without any loss of enantioselectivity.The research of catalytic C-O bond formation in the presence of PTC and cumyl hydroperoxide allowed us to propose a model of the catalyst-substrate complex and we hypothesized that there are three sites of interaction may be exist:i) ion pairing interaction; ii) hydrogen bonding interaction; iii) π-π interaction. The model of the intermediate could account for the importance of hydroxy group at C9position of the catalyst and also could explain the different enantioselectivity when modifing the substituent at the aromatic ring of the substrates or the substituent at the benzyl moiety of the catalysts in the a-hydroxylation of β-keto esters.Inspired by the model of the catalyst-substrate complex, the biphase reaction system may perform a similar effectiveness when changing another oxidation route, particularly using air as the green oxygen source for the asymmetric transformation. So an enantioselective phase-transfer catalyzed photooxygenation of β-keto esters was developed after screening the light sources, solvents, reaction temperatures, substrate concentrations, sensitizers and catalysts, and finally good to excellent results (up to93%yield and up to75%ee) had been obtained for a range of β-keto esters. To the best of our knowledge, using photooxygenation in chiral phase-transfer conditon has never been reported. More importantly, these green a-hydroxylations are inexpensive and operated simply. All materials in this process are catalytic amount and the protocols tolerate different light sources. Finally, we have discussed a plausible reaction mechanism to explain how the hydroperoxide intermediate transformed to the final product, and also proved that the atom economy of the reaction is100%.Based on the hypothesized model of the catalyst-substrate complex, a series of new phase-transfer catalysts, bearing a modified amino group at the C9postion of cinchona alkaloid, had been designed and the purpose was to increase the enantioselectivity by reinforcing the hydrogen bond performance between the C9postion of catalysts and the ester group of substrates. However, after tring much different synthetic strategies, the designed new catalysts had not been achieved. On the basis of analyzing failure cases, the main reason is that the designed amino group may reduce the nucleophilicity of the bridgehead nitrogen of quinuclidine ring or the structure of cinchona derived ammonium salts are readily decomposed during the Mitsunobu reaction conditon, so further investigations on structure design are currently underway.