Studies On Asymmetric Baeyer-villiger Oxidation Of Quaternary 1,3-Cyclobutanedione

As a special type of?-lactone,chiral 5,5-disubstituted tetronic acid derivatives are common structure units in natural products and bioactive molecules,and are widely used in medicine,pesticide and other fields.Therefore,the development of efficient methods to enantioselectively construct these motifs is of great research significance.To the date,the synthesis of chiral 5,5-disubstituted tetronic acids mainly depends on the multi-step reaction starting from the chiral substrates.Catalytic asymmetric methods to synthesis these motifs,using achiral substrates,has not been documented yet.In view of the wide application of asymmetric Baeyer-Villiger(B-V)oxidation reaction in the synthesis of chiral lactones,this thesis aims to develop a novel asymmetric catalytic method to construct enantioenriched 5,5-disubstituted quaternary tetronic acid derivatives via desymmetric B-V oxidation of prochiral cyclic ketones.Starting from quaternary 1,3-cyclobutanedione,we first evaluated a series of chiral phosphoric acid catalyst and revealed a spirocyclic chiral phosphoric acid as the best catalyst for this reaction.In the following,the effect of oxidant on the reaction outcome was investigated and the commercially available cumene peroxide(CHP)afforded the best enantioselectivity.The reaction showed relatively higher reactivity and ee values in halohydrocarbon solvents than in other common solvents and1,2-dichloroethane is the most suitable one.Lowering the reaction temperature could effectively improve the enantioselectivity of the reaction,but led to diminished reactivity.After several trials,we finally chose-20 ~oC as the best reaction temperature.Under the above optimized conditions,a series of 2,2-dialkyl-1,3-cyclobutanediones could be enantioselectively oxidized to give the desired chiral 5,5-disubstituted quaternary tetronic acid derivatives in up to 98%yield and 93%ee values,where as2-aryl-1,3-cyclobutanedione afforded inferior result,in term of both yield and ee values.It is worth noting that previous reports on desymmetric B-V oxidation reaction only explored asymmetric B-V oxidation of prochiral cyclic monoketone substrates.The reaction developed in current thesis represents the first desymmetric B-V oxidation of 1,3-diketone substrate and the first highly enantioselective B-V oxidation of quaternary cyclobutanones,which obviously broadened the substrate scope of asymmetric B-V oxidation reaction.