Synthesis Of Chiral Acyclic Nucleoside Analogues Via Asymmetric Hydrogenation Of Olefins By Using Rhodium Catalysts

The synthetic nucleosides could control or prevent various viral replication very well in the body due to their similar structures to the nature nucleosides.Among all kinds of nucleoside drugs,chiral acyclic nucleosides hold a signif icant position.Generally speaking,chiral acyclic nucleosides c an be synthesized via three methods,including chiral pool strategy,chiral auxiliary strategy and asymmetric catalysis.However,the former two methods suffer from some drawbacks,such as the limited chiral pool and the multiple-step synthesis process.Transition metal-catalyzed asymmetric hydrogenation has been established as one of the most powerful tools for preparing enantiomerically pure compounds in organic synthesis as its virtue of the high efficiency,atom-economy,and cost-effectiveness.However,the hydrogenation of unsaturated substrates bearing a N-containing heterocyclic group remains a great challenge because of the strong coordinating ability of the nitrogen moiety,which often results in catalyst deactivation.Successful examples in the hydrogenation of such type of substrates are rare.This study mainly focuses on the asymmetric hydrogenation of ?-purine nucleobase substituted acrylates.The resulting new hydrogenated products have similar structure to some antiviral drugs used in clinic,and might have some unique biological activity.Firstly,a series of purine nucleobase substituted acrylates were designed through the purine addition of propiolic acid esters and Huck coupling reaction of iodobenzene and acrylates.Subsequently,we systematically studied the rhodium-catalyzed asymmetric hydrogenation of ?-purine nucleobase substituted acrylates by screening the catalysts,solvents,temperature,hydrogen pressure and so on.It was found that a wide range of mono-and disubstituted acrylates were successfully hydrogenated under very mild conditions in high yields with good to excellent enantioselectivities(up to 99% ee).Finally,this asymmetric hydrogenation reaction was performed at the gram scale,which is advantageous for practical applications.The absolute configuration of the chiral product was characterized by single-crystal X-ray analysis of its corresponding alcohol derivative.At the same time,the proposed coordination model has also been given.By using this chiral acyclic nucleoside as the starting material,a Tenofovir analogue was successfully prepared.In a word,we have developed a new method for the synthesis of chiral acyclic nucleosides,which provides a facile access to Tenofovir analogues.In addition,the N-containing heterocyclic purine ring was proposed as the coordinating functional group(CFG)to facilitate the asymmetric hydrogenation process,which will pave the way for the asymmetric hydrogenation of other more challenging unsaturated substrates bearing heterocyclic groups.