Copper-catalyzed Synthesis Of Chiral Azacyclic Nucleoside Analogues VIA Asymmetric [3+2] Cycloaddition

With the development of science and technology, nucleoside drugs have walked into more and more ordinary people’s life gradually. Due to cyclic nucleotide and its analogues show important antiviral and anticancer activity in clinical treatment, chemical and pharmaceutical scientists have shown strong interest in the synthesis of novel cyclic nucleoside analogues all over the world. At present, the synthesis of cyclic nucleoside analogues are mainly including two parts: build a sugar skeleton with specific spatial configuration at first and then link the sugar moiety with various base. However, complicated synthetic method and harsh stereoselective control make it a challenging job.Asymmetric [3+2] cycloadditon reactions of poor-electronic olefins with azomethine ylides, one kind of pericyclic reaction, are powerful and classical synthetic methodology to creat five-membered heterocyclic rings with regio- and stereocontrolled. Novel approach was employed to synthesis chiral azacyclic nucleoside analogues by the method of asymmetric [3+2] cycloaddition with β–nucleobase substituted acrylates as material. Because of pyrrolidine is similar with furan and cyclopentyl on the structure, so cyclic nucleoside analogues may have specifical biological activities if those compounds contain structure of pyrrolidine, which can be used for clinic treatment as a kind of potential novel nucleoside drugs. The straightforward preparation of azacyclic nucleoside analogues by 1,3-dipolar cycloaddition have advantages of simple reaction, mild conditions and high yield, and have potential value in industrial application.Chapter 1: Summarized the structure of nucleoside and introduced biological activity of nucleotide analogues, the research of various synthesis of cyclic nucleoside analogues the status quo, the development and application of asymmetric [3+2] cycloaddition reactions with azomethine ylides in recent years.Chapter 2: A lot of reaction conditions of asymmetric [3+2] cycloaddition catalysed by Cu(I) complex carefully was studied. moreover, reaction factors like ligand, metal, solvent, base and temperature are optimized. Research has achieved excellent results. In the presence of 1 mol% of Cu/N-P complex, the corresponding azacyclic nucleoside analogues were obtained more than 99% of the ee value, more than 95:5 of the enantioselective and the yield up to 99%. There’s also further research suggesting that other β-heteroaryl acrylates including pyrimidine-, benzimidazole-, imidazole-, benzotriazole-, and indole-substituted acrylates also suitable dipolarophiles for the reaction, affording the desired pyrrolidine derivatives with excellent results.Chapter 3: The structure of the reaction products were comfirmed by HRMS, 13 C NMR, 1H NMR, and its spectra are list as follows. The absolute configuration of azacyclic nucleoside analogue was determined by the single-crystal X-ray diffraction analysis of the p-tosylprotected azacyclic nucleoside analogue.This paper have reported a novel way for the synthesis of azacyclic nucleoside analogues. Abundant chiral azacyclic nucleoside analogues that we have synthesis will rich nucleoside drug molecular library greatly.