Synthesis Of Chiral Acyclic Nucleosides By Three-component Dynamic Kinetic Resolution Of Purines,Aldehydes And Anhydrides

Chiral acyclic nucleosides,as the analogues of nucleosides,could connect diverse chiral groups with different stereo configurations in their side chains.Thus,chiral acyclic nucleosides exhibit outstandingly potential antiviral activities.The traditional approach to synthesize chiral acyclic nucleosides is based on chiral pool strategy,which exhibit several disadvantages such as long steps,low total yields,and difficult to obtain chiral starting materials.To date,there are only few reports to synthesize chiral acyclic nucleosides via asymmetric catalysis including asymmetric aza-Michael addition and N-allylation reactions.To our knowledge no example of enantioselective construction of chiral acyclic nucleoside via dynamic kinetic resolution reaction has been reported.Owing to the two?N9-H and N7-H?tautomeric forms in purine,the competitive nucleophilicity of N9 or N7 may result in regioselectivity issues.An efficient route to construct chiral acyclic purine nucleosides containing a hemiaminal ester moiety is reported via three-component dynamic kinetic resolution of purines,aldehydes,and acid anhydrides.Notable features of this method include simple raw materials and mild reaction conditions.It is worth suggesting that this reaction is highly regioselective,and only N9 substituted chiral acyclic nucleosides were obtained.Initially,6-chloropurine,acetaldehyde,and acetic anhydride were selected as reactants for the three-component dynamic kinetic resolution reaction.We carried out the reaction by screening of catalyst structures,bases,solvents,substrate proportions,temperatures and so on.Finally the optimized reaction conditions were as follows:4-azepanyl-derived pyridine catalyst as the chiral catalyst,Na₂CO₃ as the base,toluene as the solvent,4?MS as the additive,at 25 ^oC for 72 hours.In the presence of chiral4-azepanyl-derived pyridine catalyst as the acyl-transfer catalyst,a series of aldehydes,substituted purines,and acid anhydrides were shown to be suitable,affording chiral acyclic purine nucleosides in a regioselective manner with good yields?up to 93%yield?and excellent enantioselectivities?up to 95%ee?.Then,a scale up reation was performed,and the results were obtained without any loss of yield or enantioselectivity.At the same time,the absolute configuration of the product was determined by X-ray single crystal diffraction of the product.Finally,a series of control experiments were carried out to explore the mechanism of the regioselectivity in this reaction.In summary,we have reported an efficient route to construct chiral acyclic purine nucleosides with extremely high regioselectivity,and explored the mechanism of the regioselectivity in the reaction.According to the literature research,the unrepresented compounds in this paper have been characterized by¹H NMR,¹³C NMR and HRMS,and the results are correct.