Diastereoselective Synthesis of 6‿(Z)- and 6‿(E)-Fluoro Analogues of Anti-hepatitis B Virus Agent Entecavir and Its Evaluation of the Activity and Toxicity Profile of the Diastereomers

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• 作者：Hiroki Kumamoto ; Misato Fukano ; Tomohiko Nakano ; Keito Iwagami ; Chiaki Takeyama ; Satoru Kohgo ; Shuhei Imoto ; Masayuki Amano ; Nobuyo Kuwata-Higashi ; Manabu Aoki ; Hiroshi Abe ; Hiroaki Mitsuya ; Kiyoshi Fukuhara ; Kazuhiro Haraguchi
• 刊名：Journal of Organic Chemistry
• 出版年：2016
• 出版时间：April 1, 2016
• 年：2016
• 卷：81
• 期：7
• 页码：2827-2836
• 全文大小：515K
• ISSN：1520-6904

文摘

A method for the diastereoselective synthesis of 6″-(Z)- and 6″-(E)-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-exo-dig cyclization of the selenides 6 and 15 having the phenylsulfanylethynyl structure as a radical accepting moiety. In the radical reaction of the TBS-protected precursor 6, (Z)-anti-12 was formed as a major product. On the other hand, TIPS-protected 15 gave (E)-anti-12. The sulfur-extrusive stannylation of anti-12 furnished a mixture of geometric isomers of the respective vinylstannane, whereas benzoyl-protected 17 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 (E)- and (Z)-3 after deprotection. Evaluation of the anti-HBV activity of 3 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.