Reaction Condition Optimization And Mechanistic Studies Of Palladium-catalyzed Asymmetric Coupling Cyclization Of Alkenyl Oxime For The Synthesis Of Chiral Cyclic Nitrone

Nitrone is a very important functional group,which not only exists in natural products,but also has important applications in organic synthesis,biomedicine,analytical chemistry and other fields.However,until recently,asymmetric synthesis of nitroketone was limited to diastereoselective synthesis,and catalytic reactions for asymmetric synthesis of nitrone compounds remained scarce.The development of simple and efficient asymmetric synthesis of nitroketone is one of the problems to be solved.In recent years,our group has been focused on palladium-catalyzed cyclization of alkenyl oxime with organohalides to produce N-and O-heterocycles.Recently,we developed an efficient catalytic asymmetric synthesis of chiral five-membered cyclic nitrone.Due to the importance of 6-membered N-heterocycles,it is of great significance to develop synthetic methods for 6-membered cyclic nitrone and further study the reaction mechanism of this transformation.In this paper,we studied the palladium-catalyzed cyclization coupling reaction between unsaturated oxime and aryl halides and its mechanism.Using 2,2-dimethyl-1-phenylhexyl-4-enyl-1-ketoxime 1a as the starting material,we screened chiral ligands,solvents and other reaction parameters,and established highly enantioselective conitions:use of chiral tert-butylsulfonamido-phosphine ligand in weakly polar solvents such as hydrocarbons and ethers and weak inorganic base such as Cs₂CO₃ is key to the high enantiocontrol.In the second part,the dependence of cyclization pathway of alkenyl oxime on reaction conditions was revealed through the reactions of isotope-labeled substrates and product derivatization.The results suggest that both outer-sphere anti-aminopalladation and inner-sphere syn-migratory insertion mechanisms exist,in which weak coordination solvent,chiral phosphine sulfonamide ligand and weak base favor the trans-aminopalladation,which corresponds to high enantioselective control.Finally,the free energy profile of the reaction and the origin of enantioselectivity control are revealed by DFT calculation.The development of a simple and efficient asymmetric catalytic synthesis of nitrone and the study of the reaction mechanism provide an important reference for the subsequent asymmetric catalytic synthesis of annular nitrone and palladiation cyclization of alenyl oxime amine.