Regio-and Enantioselective [3+2] Cycloaddition Of ?-purine Substituted Acrylates With Allenes:an Approach To Chiral Carbocyclic Nucleosides

Carbocyclic nucleosides are nucleoside derivatives with most special structures and excellent bioactivites.Since the discovery of the natural carbocyclic nucleoside Aristeromycin which exhibits significant antiviral activities,numerous synthetic carbocyclic nucleosides with potential bioactivities have been synthesized.In particular,chiral carbocyclic nucleosides Abacavir and Entecavir have been approved by the FDA for the treatment of infectious viral diseases.In addition,the absolute configuration of the chiral center in carbocyclic nucleosides has been proven to play a pivotal role on their relevant bioactivities.Considering that chiral carbocyclic nucleoside comprises an all-carbon carbocycle with multiple stereocenters,it is challenging to construct enantioenriched carbocyclic nucleosides.Thus,developing a new method to synthesize chiral carbocyclic nucleosides would be highly desirable.To the best of our knowledge,N-heteroaromatic-substituted olefins have never been explored in such asymmetric[3+2]cycloaddition with allenes.Considering that chiral cyclopentyl purine nucleoside analogues bearing a quaternary stereocenter and a C=C double bond could be constructed by employing?-purine substituted acrylates as the electron-deficient olefins,herein,we now report the chiral phosphine catalyzed regio-and enantioselective[3+2]cycloaddition between 2,3-butadienoates and?-purine substituted acrylates,generating chiral cyclopentyl purine nucleoside analogues containing a quaternary stereocenter in an?-addition manner.In summary,we have reported a regio-and enantioselective[3+2]cycloaddition of N-heteroaromatic substituted acrylates with 2,3-butadienoates catalyzed by a chiral spirocyclic phosphine.Diverse chiral carbocyclic nucleoside analogues bearing a quaternary stereocenter and a C=C double bond were generated in an?-addition manner with good yields?up to 90%yield?and excellent enantioselectivities?up to 97%ee?.In addition,?-purine-containing disubstituted acrylate and?-benzimidazole substituted acrylate are also suitable substrates in this[3+2]annulation reaction.The cycloadducts could undergo functional group transformations to afford potentially useful chiral carbocyclic nucleosides.We obtained the optimal conditions by screening a variety of conditions.With it in hand,we got 26new chiral cyclopentane nucleoside we cultive a single crystal and determine the absolute configuration by crystal diffraction experiment.The resulting structure of the compounds has been characterized by ¹H NMR,¹³C NMR and HRMS.