Synthesis Of Chiral Acyclonucle Osides And Acyclonucleotides Asymmetrically Catalyzed By L-Proline Derivatives

Nucleoside and nucleotide compounds play important roles in anti-tomor, anti-virus and anti-AIDS drugs, and they accounted for a considerable proportion of drugs which have been used in clinical antiviral.In many nucleoside and nucleotide drugs, chiral acyclic nucleoside and nucleotide compounds play a unique role, because of their efficacy in anti-herpes, virus and anti-retrovirus. Forthermore, most of these compounds are currently recognized as potential antiviral drugs.So far, athough chiral acyclic nucleoside and nucleotide drugs which can treat three diseases above have been widely developed and applied, these drugs still face some problems, such as high production cost, low efficacy, side effect and so on. Therefore, it is still an important task to explore a convinent new method to efficiently synthesize a variety of new drugs for pharmaceutical chemists.Over the last decade, Small organic molecule catalysis has been a rapid development, following the metal and enzymatic catalysis, and it has been widely used in organic synthesis. Especially, Aza-Michael addition reaction of small organic molecule asymmetric catalysis are well developed and it has a good application in construction of optically active C-N bond in the organic synthesis.View of this, in this paper, based on the concept of"chiral organic small molecule asymmetric catalysis", a variety of organic small molecules were designed and synthesized, to achieve asymmetric synthesis of chiral acyclic nucleosides and nucleotides from the low-cost and non-chiral side chains and purine bases.We synthesized several derivatives of L-proline(chiral catalysts of small organic molecules), and through screening of the catalyst, we firstly synthesized acyclonucleosides by an organocatalytic asymmetric aza-Michael addition reaction from achiral purine bases andα,β-unsaturated aldehydes in 82-89% yield and up to 99% ee. The isolated chrial acyclonucleosides are readily converted to acyclonucleotides. In the experiment, we found that reaction solvent has a great influence on the enantioselectivity, and a small amounts of auxiliary agent(benzoic acid)significantly increased reaction rate. Application of this protocol allows the efficient synthesis of biologically important chiral acyclonucleoside and acyclonucleotide analogues from achiral starting materials without the use of expensive and toxic metal complexes.With the optimal reaction conditions in hand, we got 15 new chiral acyclonucleosides. Furthermore, these novel chiral acyclonucleoside analogues can be used as key intermediates for synthesis of not only (S)-DHPA and its analogues, but also of (R)-PMPA like chiral acyclonucleotide analogues. This method opens a new route to the synthesis of many useful optically pure derivatives from achiral starting materials and will be of broad interest to synthetic chemists.