Diastereoselective Synthesis of 6″‑(<i>Z</i>)- and 6″‑(<i>E</i>)‑Fluoro Analogues of Anti-hepatitis B Virus Agent Entecavir and Its Evaluation of the Activity and Toxicity Profile of the Diastereomers

Abstract

A method for the diastereoselective synthesis of 6″-(<i>Z</i>)- and 6″‑(<i>E</i>)-fluorinated analogues of the anti-HBV agent entecavir has been developed. Construction of the methylenecyclopentane skeleton of the target molecules has been accomplished by radical-mediated 5-<i>exo</i>-<i>dig</i> cyclization of the selenides <b>6</b> and <b>15</b> having the phenylsulfanylethynyl structure as a radical accepting moiety. In the radical reaction of the TBS-protected precursor <b>6</b>, (<i>Z</i>)-<i>anti</i>-<b>12</b> was formed as a major product. On the other hand, TIPS-protected <b>15</b> gave (<i>E</i>)-<i>anti</i>-<b>12</b>. The sulfur-extrusive stannylation of <i>anti</i>-<b>12</b> furnished a mixture of geometric isomers of the respective vinylstannane, whereas benzoyl-protected <b>17</b> underwent the stannylation in the manner of retention of configuration. Following XeF₂-mediated fluorination, introduction of the purine base and deoxygenation of the resulting carbocyclic guanosine gave the target (<i>E</i>)- and (<i>Z</i>)-<b>3</b> after deprotection. Evaluation of the anti-HBV activity of <b>3</b> revealed that fluorine-substitution at the 6″-position of entecavir gave rise to a reduction in the cytotoxicity in HepG2 cells with retention of the antiviral activity