Study On The Synthesis Of Elvucitabin Andα-Elvucitabin

Elvucitabine is now in phase Ⅱ clinical trials in the development as an antiviral drug indicated for the treatment of HBV and HIV. Elvucitabine is a nucleoside analogue with unnatural L-configuration designed with the goal of reducing the long-term adverse effects observed with the commonly encountered D-nucleoside analogues that are thought to due to mitochondrial toxicity.During the development of elvucitabine as an antiviral drug for the treatment of HBV and HIV, its a-anomer, a-elvucitabine, was needed for the assignment of the impurities in the elvucitabine sample.Firstly, virus diseases, antiviral drugs, antiviral HIVdrugs, antiviral HBV drugs, the research history of elvucitabine, Appel reaction, Barton-McCombie, anomer were introduced.Secondly, the reaction of retrosynthetic analysis was also proposed,10-step new synthetic protocol to elvucitabine starting from L-xylose by Ketal reaction, ethers hydrolysis reaction, Alcoholysis reaction, and then after ethers hydrolysis reaction, happened Alcoholysis reaction with CICH2COCI, coupled with the cytosine moiety, hydrolysis reactionos, occurred rection with chlorine atom, olefination reaction, ester hydrolysis reaction, with an overall yield of20%was developed. The key steps included TMSOTf-mediated stereocontrolled β-glycosidation and exquisite choice of chloroacetyl group for the protection of hydroxyl group as well as the corresponding deprotection under a mild condition.Finally, total synthesis of a-elvucitabine was achieved in26%overall yield by a concise9-steps procedure through the stereo selective synthesis starting from L-lyxose, with TMSOTf-medicated stereocontrolled a-N-glycosidation and olefination through Barton-McCombie deoxygenation being the key steps. Structures of the intermediates were confirmed by1H NMR, the stereochemistry of the product was determined by NOESY. the possible mechanism was also proposed.