Hiroki Kumamoto1, Misato Fukano1, Tomohiko Nakano1, Keito Iwagami1, Chiaki Takeyama1, Satoru Kohgo2, Shuhei Imoto3, Masayuki Amano4, Nobuyo Kuwata-Higashi4, Manabu Aoki5, Hiroshi Abe6, Hiroaki Mitsuya7, Kiyoshi Fukuhara1, Kazuhiro Haraguchi8. 1. School of Pharmacy, Showa University , 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. 2. Center for Clinical Sciences, National Center for Global Health and Medicine , 1-21-1 Toyama, Shinjuku, Tokyo 162-8655, Japan. 3. Faculty of Pharmaceutical Sciences, Sojo University , 4-22-1 Ikeda, Kumamoto 860-0082, Japan. 4. Department of Infectious Diseases and Hematology, Kumamoto University School of Medicine , Kumamoto 860-8556, Japan. 5. Department of Medical Technology, Kumamoto Heath Science University , 325 Izumimachi, Kumamoto 861-5598, Japan. 6. Department of Chemistry, Graduate School of Science, Nagoya University , Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. 7. Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States. 8. Nihon Pharmaceutical University , 10281 Komuro, Inamachi, Kita-adachi-gun, Saitama 362-0806, Japan.
Abstract
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.
A method for the diastereoselective synthen class="Chemical">sis 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 carbocyclicguanosine 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.
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