Organocatalytic Asymmetric Synthesis Of Dihydrobenzoxazinones Bearing Trifluoromethylated Quaternary Stereocenters:Scope And Mechanism

Trifluoromethylated heterocycles have showed a great diversity of superior biological properties mainly due to the incorporation of trifluoromethyl group which can improve chemical and metabolic stability, lipophilicity, and membrane permeability of the molecules. The catalytic asymmetric construction of CF3-containing quaternary stereocenters in heterocyclic systems remains highly desirable. This dissertation first summarizes the research progress of asymmetric catalytic Friedel-Crafts alkylation reaction, and then uses this group for the development of chiral spirocyclic phosphoric acid, explores its the application and mechanism of asymmetric catalytic synthesis of benzoxazinones derivatives bearing trifluoromethylated quaternary stereocenters, the main innovative results obtained are as follows:1. A new approach of a chiral spirocyclic phosphoric acid catalytic asymmetric reactions of highly enantioselective synthesis of benzoxazinones derivatives bearing trifluoromethylated quaternary stereocenters was developed. Benzoxazinonepyrrole derivatives bearing trifluoromethy and pyrrole derivatives as raw material, through the screening of catalysts and reaction conditions such as solvent, Under the optimal reaction conditions of 5mol%(R)-6,6’-di-2,4, 6-triisopropyl-phenyl-SPINOL-phosphoric acid, toluene,25℃, nineteen optically active benzoxazinonepyrroles were obtained in high yields (up to 96%) with excellent enantioselectivities (up to 94%). The absolute configuration of substrate was confirmed to be (R) by X-ray.2. Through the experimental research and the results of theoretical calculation, a significant effect of fluoride was found, we proposed that triple hydrogen-bond interactions hold the transition structure rigidly to activate substrates and induce chirality in asymmetric phosphoric acid catalysis, and the yield will decrease dramatically without the CF3 moiety. Based on the results of theoretical calculation, in the transition structure, we found the chiral phosphoric acid catalyst concurrently activates both the nucleophilic group and the electrophilic group through a classical double hydrogen-bonding catalyst-substrate interaction, and an unexpected attractive non-classical arene C-H…F hydrogen bonding. The findings further enrich chiral phosphoric acid chemical and asymmetric synthesis chemistry.