Palladium-Catalyzed Formal Insertion Of Carbenoids Into N,o-aminals:Direct Access To ?-Alkoxy-?-Amino Acid Esters

?-Alkoxy-?-amino acid esters are a class of important structure motifs.They are not only frequently found in a wide range of natural products,bioactive compounds and functional materials,but also are valuable synthetic building blocks that can be transformed into many other functional groups via simple transformation.In contrast,the straightforward and general methods for the synthesis of such kind of compounds bearing a quaternary carbon-center at the ?-position have rarely been achieved,although their unique structural and diverse biologic properties have been noted.Accordingly,the development of more general and straightforward synthetic methods toward these compounds is in high demand.Herein,we present an efficient palladium-based catalyst system between N,O-aminal and ?-diazoacetate to syntheses ?-alkoxy-?-amino acid esters.The results are as follows:1.We have reported a method to construct ?-alkoxy-?-amino acid esters via palladium-catalyzed formal insertion of carbenoids into N,O-aminals.After screening the reaction conditions,including solvent,catalyst,ligand,counterion,feeding ratio and other metals,the optimum condition is chosen.Then we examined the scope of ?-diazoacetate and N,O-aminals.The deried products were characterized by NMR,HRMS and X-ray crystal.2.The reaction proceeded smoothly on a gram scale under the standerd conditions,affording the product in 85% yield.The two benzyl groups contained in the desired product could removed to form a ?-lactam or demethylated to synthesize the corresponding ?-hydroxy-?-amino acid ester.Preliminary validation of this mechanism indicated that Pd(0)was oxidative added to the N,O-aminal to form a palladium complex,which is then reacted with ?-diazoesters to form a Pd-carbene intermediate.The nucleophile alkoxy anion attacks the intermediate,then undergoes reductive elimination to give the drsired products and Pd(0).