Dynamic Kinetic Resolution Of α?Purine Substituted Acids:Access To Chiral Acyclic Purine Nucleosides

Chiral acyclic nucleosides,in which the cyclic carbohydrate moiety of the nucleoside is replaced by a chiral acyclic side chain,have demonstrated significant antivirus and antitumor activities.Thus,it is crucial to develope a simple and effective synthetic strategy.Until now,there are two main methods for constructing chiral acyclic nucleosides.On the one hand,chiral acyclic nucleosides are synthesized by chiral sources or chiral adjuvant induction.On the other hand,chiral acyclic nucleosides are synthesized by asymmetric catalysis.While,there are three methods which contain aza-Michael addition,N-allylation reaction and asymmetric reduction to synthesize chiral acyclic nucleosides by asymmetric catalysis.However,there are few reports on the synthesis of chiral acyclic nucleosides by dynamic kinetic resolution.Therefore,an efficient route to construct chiral acyclic purine nucleoside analogues with high enantioselectivities via dynamic kinetic resolution ofα-purine substituted acids is reported.Initially,the reaction ofα-purine substituted propionic acid and di（1-naphthyl）methanol was selected as a model reaction to construct chiral acyclic nucleoside compounds via dynamic kinetic resolution.A series of conditions were optimized such as the type of chiral catalysts,anhydrides,bases,solvents and temperatures.Finally,the optimal reaction conditions were as follows:chiral isothiourea was used as the catalyst,trimethylacetic anhydride was used as the anhydride,i-Pr₂NEt was used as the base,DMF was used as the solvent,at 15°C for 4 days.Under the optimal conditions,diverse chiral acyclic purine nucleoside analogues were obtained in moderate to good yields（up to 93%）and high enantioselectivities（up to 98%ee）and the absolute configuration of the chiral product was determined by single crystal X-ray diffraction analysis.Subsequently,the reaction was performed on a 1 mmol scale and the derived experiments to synthesize Tenofovir analogue,which showed that the yield and enantioselectivity of the products were well maintained.In summary,an efficient route to construct chiral acyclic purine nucleoside analogues via dynamic kinetic resolution ofα-purine substituted alkanoic acids was reported.A variety of chiral acyclic purine nucleoside analogues were obtained with different substituents at C1’position by this method,and the Tenofovir analogue was obtained in 96%ee.Finally,the new compounds were characterized by ¹H NMR,¹³C NMR,HRMS,and their structures were completely correct.