Diversity-oriented Synthesis Of Acyclic Nucleosides Via Ring-opening Of Vinyl Cyclopropanes With Purines

The structure of purine N9 alkylation products and their derivatives are very similar to natural nucleosides, therefore, they can be involved in the synthesis of viral DNA, interfering with protein synthesis, and inhibit the growth of viral. So purine N9 alkylation derivatives are recognized as potential bioactive compounds. The N7 position of purine, specifically the N7 position of guanine, are susceptible to be attacked by alkylating reagents, and fall down from the DNA chain, leading to the DNA damage. Some carcinogens can cause DNA damage by the alkylation of N7 position of purine in the DNA chain, thereby inducing cancer. Therefore, the purine N7 alkylation and derivatives are important marker of the carcinogenic process, the synthesis of purine N7 alkylation and their derivatives are of great significance to the pharmacy and toxicology.According to the known literature, as a 5 carbon synthons, vinyl cyclopropane can efficiently build complex organic molecules in organic synthesis. Currently, the opening mode of double-activation vinyl cyclopropane is divided into 1,3 ring opening and 1,5 ring opening. In the presence of Lewis acid, more 1,3 ring opening products can be obtained; when low valence state metal is used as catalyst, more 1,5 ring opening products can be obtained. As vinyl cyclopropane has multiple active sites, we designed to synthesis a series of acyclic nucleoside analogue by nucleophilic addition reaction between double activated vinyl cyclopropane and purine, and investigated the reaction conditions. It has not been reported that vinyl cyclopropane is used to have specific reaction on special active site by adjusting the reaction conditions.In this paper, we applied different catalysts in the reaction between purine and double active vinyl cyclopropane, and successfully obtained highly regioselective of 1,3 ring-opening products and 1,5 ring-opening products. Under the catalysis of palladium(0), purine N9 alkylation products can be obtained through 1,5 ring opening; under the catalysis of AlCl3, purine N9 alkylation products can be obtained through 1,3 ring opening; under the catalysis of MgI2, purine N7 alkylation products can be obtained through 1,3 ring opening. These reactions had less steps and good regionalselectivity, and greatly enriched the types of purine acyclic nucleosides.This paper opens up a new way for synthesis of acyclic nucleoside analogue drugs and purine N7 alkylation productions, and the mechanism of the reaction is briefly discussed. All the target compounds were characterized by 1H NMR, 13 C NMR and HRMS.