Enantioselective Bromolactonization Of ?,?-Unsaturated Keto Acids

Objective:Compounds containing a lactone ring skeleton have strong research value in drug development,and the current asymmetric catalytic synthesis of lactone compounds is mainly carried out using active olefins as a substrate.In this research,it is expected that asymmetric bromolactonization using ?,?-unsaturated keto acid and other deactived olefinic acids as substrates can be used to synthesize chiral lactones in a simple,efficient and highly stereoselective mode,and apply it to derivatization research.Methods:Firstly,the type of catalyst which can effectively catalyze the asymmetric bromo lactoneization of ?,?-unsaturated keto acid is selected by screening,and the catalyst structure is optimized.Then,the reaction conditions are optimized,including the bromination reagent,the reaction solvent,The reaction temperature and the amount of catalyst were investigated.Then,the synthesis of a series of ?,?-unsaturated keto acid substrates and their asymmetric bromolactoneization were studied to investigate the applicability of the catalysts to different structural types of substrates.Some products were selected for derivatization research;finally,the possible reaction mechanism was explored.Results:1.The cinchona alkaloid derived bifunctional urea catalysts was screened to accelerate the asymmetric bromolactoneization of the deactived olefinic acid such as ?,?-unsaturated keto-acid,which is highly stereoselective.2.The optimal conditions for the reaction were optimized,that is,at 15?,with toluene as solvent,NBS as bromination reagent,and 15 mol % of catalyst;3.24 examples of ?,?-unsaturated keto-acid substrates(1a?1x)were synthesized,and a series of new lactoneization products(2a?2x)were obtained by asymmetric bromolactoneization.the reactions proceeded with excellent yield and good to excellent enantioselectivity;4.Derivatization of the asymmetric bromolactonization product was carried out for 1h,and the ethoxylated derivative 11 and the azide derivative 12 were obtained in high yield,and the derivatization reaction did not destroy the chiral center;5.The Catalyst investigation results shows that,unlike typical urea catalysts that require electron-deficient substituents to enhance the hydrogen bond strength,it is interesting to realize that electron-rich ureas are essential for high enantioselectivity in this case.Conclusion:This project has successfully developed a synthetic method based on a bifunctional amino-urea catalyst for the asymmetric bromolactonization of ?,?-unsaturated keto acids,with high yield(up to 99% yield)and high enantioselectivity(up to 99% ee).obtained 24 novel lactone compounds,and the obtained bromolactonization product can be widely used in derivatization research.