Palladium Catalyzed Asymmetric Synthesis Of Five-membered Cyclic Nitrone Compounds

Five-membered cyclic nitrone is the largest member of the cyclic nitrone family.In organic synthesis,cyclic nitrones is an important intermediate for the synthesis of chiral pyrrolidine,pyrrolidine indoles,and many alkaloids,which play an important role in medicinal chemistry.In contrast,their asymmetric synthesis is for a long time limited to stoichiometric diastereoselective transformations and there is a lack of effective catalytic schemes.It is only in the past several years that highly enantioselective catalytic protocols have begun to emerge.As our continued interest in the cyclization of alkenyl oximes for the synthesis of O-and N-heterocycles,as well as our interest in the asymmetric synthesis of nitrones,in this thesis we studied Pd-catalyzed carbocyclization ofγ,δ-alkenyl oxime for the synthesis of five-membered cyclic nitrones.After screening we obtained conditions for the highly enantiocontrol,with the key parameters being the weakly polar solvent,a weak base and a suitably chosen sulfonamide-phosphine ligand developed by Professor Junliang Zhang’s group.A series of alkyloxime and aryl halides with different substituents were investigated at 60℃,5 mol%Pd（dba）₂,6 mol%ligand L18,using 1.2 equiv.Cs₂CO₃as base and methyl tert-butyl ether as solvent under the optimal conditions.The target products were obtained with excellent yield and enantioselectivity（up to 97%）.The optimized conditions is found to be competent for a large variety of substrates,and the enantiocontrol is relatively stable across the board.This work provides the first protocol for the catalytic synthesis of enantioenriched cyclic nitrones by two-component reaction,and is expected to be insightful for other heterocyclization reactions at large.