Synthesis Of Chiral Phthalazine Catalyst And Application In Asymmetric Halolactionization

Objective:Most of the lactones containing α-methyl-γ-butyrolactone ring structure have chiral centers and exhibit a wide range of biological activities.At present,the catalyst for selective synthesis of halogenated α-methylene-γ-butyrolactones with dienoic acid as substrate is scarce.In this study,a chiral phthalazine catalyst derived from amino acids was designed and synthesized,and it is expected that the catalyst can be used in asymmetric halolactonization of dienoic acids bearing a 7-member ring moiety to synthesize α-methylene-γ-butyrolactones with excellent stereoselectivity.Method:Firstly,a series of chiral phthalazine catalysts derived from amino acids were designed and synthesized.Then,the bromolactonization reaction condition was optimized,and a series of dienoic acid substrates were synthesized.Then,the catalyst was used to conduct asymmetric halolactonization reaction of dienoic acid substrates,and the product were subjected to in vitro cytotoxic evaluation.Finally,the reaction mechanism was explored.Result:1.Through screening eight chiral phthalazine catalysts derived from amino acids,3c was determined to be the most suitable catalyst for the efficient and selective synthesis of bromo-α-methylene-γ-butyrolactones;2.The optimal conditions for the reaction were optimized,that is,at-78℃,with toluene as solvent,and 10 mol% of catalyst;3.A series of halogenated α-methylene-γ-butyrolactoneswere synthesized with hight yield(up to 99% yield)and excellent stereoselectivity(up to 99.8% ee)by sixteen examples of asymmetric halolactonizations;4.Bioassay results showed that compound 2c and ent-2c had significant cytotoxic activity on H1975 non-small cell lung cancer cells bearing L858R/T709 M mutant and A431 wild type cells in vitro.5.Mechanism studies have shown that the phthalazine structure in catalyst play an important role in asymmetric halolactonization.Conclusion:This project has successfully synthesized an amino-acid-derived chiral phthalazine catalyst,which can efficiently catalyze the conversion of dienoic acid bearing a 7-member ring moiety into halogenated α-methylene-γ-butyrolactones with high yield and excellent stereoselectivity.