Synthesis Of 1,4-dihydro-2H-3,1-benzoxazin-2-one Derivatives Through Catalytic Asymmetric Chlorocyclization

Compounds having the skeleton of 1,4-dihydro-2H-3,1-benzoxazin-2-one have attracted considerable attention from medicinal and organic chemists.Many of these compounds have been reported to exhibit important biological activities,such as HIV-1 reverse transcriptase inhibitory and progesterone receptor antagonistic activities.Although a series of strategies for the construction of the 1,4-dihydro-2H-3,1-benzoxazin-2-one have been reported,there are few reports on the asymmetric synthesis of these compounds.Hence,developing new catalytic system to obtain these compounds with high optical purity is quite necessary for the further study of biological activities.This subject has developed a synthesis method of the chiral 1,4-dihydro-2H-3,1-benzoxazin-2-one derivatives via the halocyclization of carbamates catalyzed by organocatalysts.Morever,the optimal catalyst applied in this method is a novel Cinchonidine-based chiral ester.We have also demonstrated the synthetic utility of this methodology.As a novel class of potent,selective,and orally active progesterone receptor antagonists,the 6-aryl-1,4-dihydro-benzoxazin-2-one was obtained without any loss of ee.The conversion of the carbamate group to the thiocarbamate was also achieved with good stereochemical integrity to generate the 1,4-dihydro-benzoxazin-2-thione.Further study showed the novel catalyst also has good applicability for the asymmetric synthesis of 4H-3,1-benzoxazin.