Asymmetric Synthesis Of 2,2-Disubsituted Pyrrolidine Derivatives

2,2-disubstituted pyrrolidine is a common structural motif that is widely present in active natural products and drug molecules.Most asymmetric synthesis of pyrrolidines containing quaternary carbon at C2 position employed chiral compounds as starting materials.However,these methods have obvious drawbacks,such as waste of chiral starting materials.Therefore,it is still urgent to develop more efficient mtheod for synthesis of chiral 2,2-disubstituted pyrrolidine derivatives.With the development of asymmetric synthetic technology,the preparation of chiral compounds by catalytic asymmetric method has been paid more and more attention.Based on previous research work,we present herein that 2,2-disubstituted pyrrolidines with quaternary carbon center at C2 position were successfully synthesized by catalytic asymmetric decarboxylative allylation reactions.By investigating the influence parameters of the key asymmetric reactions involving transition metal catalysis,chiral ligand,reaction medium,temperature and additives,the reaction procedded with good enantioselectivity.After screening reaction conditions,products was obtained on gram scale and could be applied directly to the synthesis of cephalotaxine and its derivatives,providing support for further activity screening.Staring from proline,the precursor 2-benzoylpyrrolidine-1-carboxylate derivatives could be easily obtained via successive reactions with Boc anhydride,N,O-dimethylhydroxylamine hydrochloride and aryl magnesium bromide.The optimal reaction conditions for this catalytic asymmetric decarboxylative allylation was as follows:using 5 mmol% Pd(dba)2 as the catalyst,12 mmol%(R)-BINAP as the chiral ligand in the presence of Li HMDS.The ee value of the product was up to 81%.As-e ries of chiral 2,2-disubstituted pyrrolidine derivatives were obtained via this asym-m etric catalytic reactions.