Synthesize Penciclovir Analogues By Ring-opening Of Aminocyclopropanes With Purines

Acyclic purine nucleosides have displayed significant antivirus activities,making modification of the acyclic side chain a research hotspot.Acyclovir,containing a N-glycosidic bond,is the earliest acyclic nucleoside drug for the treatment of antiherpes.When a hydroxymethyl group is introduced into the 3?position of Acyclovir,a new acyclic drug Ganciclovir is generated,which is used to treat cytomegalovirus（CMV）.As for Ganciclovir,when the ether oxygen at 2?position is substituted by a methylene,it becomes the Penciclovir,another drug for the treatment of various herpesvirus infections.With regard to the Adefovir,when a methyl group was linked to its 2?position,a new chiral acyclic nucleoside Tenofovir is emerged,which exhibits more potent than Adefovir in the treatment of hepatitis B virus（HBV）.Therefore,developing an efficient method to construct acyclic purine nucleosides with different side chains is highly desirable.There are many synthetic methods for acyclic nucleosides,such as alkylation,N-allylation,aza-Michael etc.But there are very few examples of the use of cyclopropane to synthesize acyclic nucleosides.In 2015,our group reported the ring-opening of vinyl cyclopropanes with purines to afford acyclic purine nucleoside analogues,in which the strong Lewis acid AlCl₃ was employed in an equivalent and only vinyl group could be linked at C1?position.Due to the limitations of vinyl,we replaced vinyl cyclopropane with D-A aminocyclopropane to increase product’s diversity.In this paper,we use Lewis acid Sc（OTf）₃ to realize the ring opening of D-A aminocyclopropane,and the alkylation product is realized at the 9 position of the purine.The yield of the product is up to 90%,and the amino is introduced at the 1’position.The product is reduced to obtain Penciclovir analogue.In the paper,we conducted a control experiment and found that the group on the 6th purine has a significant influence on the selectivity of the product.We also tried the asymmetric catalytic reaction of the reaction,but unfortunately we did not get good results.However,this method provides a new idea for the construction of Penciclovir analogue and enriches the diversity of acyclic nucleosides.In this paper,we provide a new way for the efficient synthesis of acyclic nucleosides,and the experimental operation is simple,rapidly,and the post-treatment is simple.The obtained target product molecules were all certified by HRMS,¹H-NMR,and ¹³C-NMR.Oxindole compounds are widely present in natural products,and most of the products have pharmaceutically active activities such as bactericidal anti-inflammatory,antiviral,antitumor and so on.In this paper,we studied the intermolecular rearrangement of oxindole by using the chiral pyridyl oxynitride catalysts designed by our group.Under this type of catalysts,we screened the solvent,temperature,molecular sieve and other conditions to obtain an ee value of up to 94%.The successful implementation of this reaction expands the applicability of the catalyst.