Stereoselective Synthesis of 2鈥?Fluoro-6鈥?methylene Carbocyclic Adenosine via Vince Lactam

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• 作者：Uma S. Singh ; Ram C. Mishra ; Ravi Shankar ; Chung K. Chu
• 刊名：Journal of Organic Chemistry
• 出版年：2014
• 出版时间：May 2, 2014
• 年：2014
• 卷：79
• 期：9
• 页码：3917-3923
• 全文大小：327K
• 年卷期：v.79,no.9(May 2, 2014)
• ISSN：1520-6904

文摘

2鈥?Fluoro-6鈥?methylene carbocyclic adenosine (FMCA) is a potent and selective inhibitor of wild type as well as drug-resistant hepatitis B virus (HBV) mutants. FMCA demonstrated excellent anti-HBV activity against both adefovir-resistant and lamivudine-resistant double (rtL180M/rtM204V) mutants as well as in lamivudine/entecavir triple mutants (L180M+S202G+M204V) in vitro. Its monophosphate prodrug (FMCAP) demonstrated a greater than 12-fold increase of anti-HBV activity in comparison to that of the nucleoside without elevation of cellular toxicity. In the preliminary in vivo study in chimeric mice harboring the lamivudine/entecavir triple mutant, FMCAP effectively reduced HBV viral load, while entecavir was not effective. Therefore, it was of great interest to develop an efficient synthetic procedure to support the preclinical investigation. In this article, a new approach for the synthesis of FMCA from a readily available starting material (Vince lactam) in 16 steps is described. An efficient and practical methodology for stereospecific preparation of a versatile carbocyclic key intermediate, d-2鈥?fluoro-6鈥?methylene cyclopentanol 14, has been developed from diazotization, elimination, stereoselective epoxidation, fluorination, and oxidation鈥搑eduction sequence of the Vince lactam in 14 steps. The utility of d-2鈥?fluoro-6鈥?methylene cyclopentanol 14 is demonstrated in the preparation of FMCA using the Mitsunobu coupling to introduce the adenine base to synthesize the final nucleoside.