Synthesis Of Chiral Cyclopropyl Carbocyclic Purine Nuleosides Via Michael-initiated Asymmetric Cyclopropanation

Carbocyclic nucleosides are nucleoside derivatives with most special structures and excellent bioactivities.Especially in the antiviral activities that carbocyclic nucleosides exhibit some superior properties.Carbocyclic nucleosides have attracted considerable attention due to the absence of the labile N-glycosidic bond and have thus far led to the regulatory approval of Abacavir,Carbovir,and Entecavir for the treatment of an infectious viral disease.As for carbocyclic nucleosides containing different sizes of the ring,cyclopropyl carbocyclic purine nucleosides have received increasing interest owing to their fixed conformation and potent biological activities.Among the numerous carbocyclic nucleoside compounds,chiral cyclopropyl carbocyclic purine nucleoside takes up a large ratio of these compounds.Therefore,the search for an efficient route to synthesize chiral purine carbocyclic nucleosides with different functional groups in their side chains remains a critical scientific goal.The traditional route for the synthesis of chiral cyclopropyl purine carbocyclic nucleosides is based on a linear approach,in which the purine moiety is constructed from a chiral cyclopropyl.Nevertheless,the generation of the chiral cyclopropyl often requires an equivalent chiral starting material and multiple steps that often proceed in low total yields.Therefore,how to conveniently and rapidly synthesize chiral cyclopropyl purine carbocyclic nucleosides has become an urgent problem to be solved.Our groups focus on the design,synthesis and selective structure modification of nucleoside drugs and their analogues.It is noteworthy that the process yields the chiral cyclopropyl purine nucleoside analogues that have a chiral quaternary stereocenter,which would normally be challenging for construction with good stereocontrol by other methods.On the basis of our group previous work,we have developed an efficient route to chiral cyclopropyl purine nucleoside analogues via the organocatalytic asymmetry catalysis Michael-initiated ring-closure reactions of α-purine acrylates with α-bromo-carboxylic esters.Through the screening of Michael receptors,nucleophiles,catalysts,bases,solvents,temperatures,and substrate ratios,we developed one novel synthesize method with a chiral quaternary stereocenter cyclopropyl purine carbocyclic nucleosides analogues.Using(DHQD)2AQN as the catalyst,various chiral cyclopropyl purine nucleoside analogues with a chiral quaternary stereocenter were obtained in 72-98% yields,excellent diastereoselectivities,and 93-97% ee.Through simple functional group transformations,diverse chiral cyclopropyl purine nucleosides with hydroxymethyl group or carboxyl group were obtained.The compound library of chiral cyclopropyl purine nucleosides was enriched.This article has developed an efficient route to chiral cyclopropyl purine nucleoside analogues via the organocatalytic Michael-initiated ring-closure reactions.All the resulting structure of the compounds has been characterized by various ways.At the same time,the absolute configuration of the chiral cyclopropyl purine nucleoside product was determined by the single-crystal X-ray diffraction analysis.