Synthesis Of Carbocyclic Nucleosides By Asymmetric Transfer Hydrogenation Via Dynamic Kinetic Resolution

Diseases caused by viral infections,such as hepatitis B,hepatitis C and AIDS,have plagued humankind for millennia and constitute a major global health problem.At present,clinically available drugs can only inhibit virus replication.However,these diseases couldn't be cured completely.More importantly,the virus become drug-fast after long-term use of the drugs.Therefore,there is an urgent need to develop novel antiviral drugs.On the other hand,carbocyclic nucleosides show good antiviral or antitumor activities,for example Entecavir(anti-HBV),Abacavir(anti-HIV)and Carbovir(anti-HIV).Many different synthetic approaches for these compounds often required multi-steps or fine asymmetric control,which often had very high wastage in the process.Using rac-a-base cycloalkanone as the raw material.Through the optimization of the reaction conditions,it was determined that HCOOH/Et3N(1:1)was hydrogen source under the dosage of 1 mol%of catalyst with dioxane as solvent.The source can obtain a chiral five-membered carbocyclic nucleoside at a normal temperature and pressure of 96%of the isolated yield and 97%of the enantioselectivity.The reaction substrate has a wide range of applications and can achieve hydrogenation of a plurality of a-base cyclopentanones.Subsequently,the catalytic reaction was prepared in a magnified amount(1.16 g,5 mmol)to achieve gram-level synthesis,and the absolute configuration of the hydrogenated product was determined by single crystal diffraction.Finally,the ?-base cyclopentanol was further derivatized to synthesize a series of chiral carbocyclic nucleoside compounds having a fluorine atom,a sulfur atom,N3 or an amino group on a five-membered carbocyclic ring.In this dissertation,an asymmetric transfer hydrogenation of rac-?-(purin-9-yl)cyclopentones via dynamic kinetic resolution for the construction of carbocyclic nucleosides was developed,and a possible catalytic mechanism was proposed,which provided a new idea for the synthesis of chiral carbocyclic nucleosides.