Sheng Jia, Hassan Abdalla E A, Huang Zhen
Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
J Org Chem. 2008 May 16;73(10):3725-9. doi: 10.1021/jo7025806. Epub 2008 Apr 15.
Several 2',3'-dideoxynucleosides (ddNs) and 2',3'-didehydro-2',3'-dideoxynucleosides (d4Ns) are FDA-approved anti-HIV drugs. Via conveniently synthesized 2,2'-anhydronucleosides, we have developed a novel synthesis of d4Ns by discovering and applying a new telluride-mediated elimination reaction. Our experiment results show that after substitution of 2,2'-anhydronucleosides with a telluride monoanion, a telluride intermediate is formed, and its elimination leads to formation of the olefin products (d4Ns). Our mechanistic study indicates that this telluride-assisted reaction consists of two steps: substitution (or addition) and elimination. By using dimethyl ditelluride (0.1 equiv) as the reagent, d4Ns can be synthesized with yields up to 90% via this telluride-mediated elimination. Our novel strategy has great potential to simplify synthesis of these drugs and to further reduce cost of AIDS treatment and will also facilitate development of novel d4N and ddN analogues.
几种2'，3'-双脱氧核苷（ddNs）和2'，3'-双脱氢-2'，3'-双脱氧核苷（d4Ns）是美国食品药品监督管理局（FDA）批准的抗艾滋病病毒（HIV）药物。通过方便合成的2,2'-脱水核苷，我们发现并应用了一种新的碲化物介导的消除反应，从而开发出了一种合成d4Ns的新方法。我们的实验结果表明，用碲化物单阴离子取代2,2'-脱水核苷后，会形成碲化物中间体，其消除反应会导致烯烃产物（d4Ns）的形成。我们的机理研究表明，这种碲化物辅助反应包括两个步骤：取代（或加成）和消除。通过使用二甲基二碲（0.1当量）作为试剂，通过这种碲化物介导的消除反应可以合成产率高达90%的d4Ns。我们的新策略在简化这些药物的合成以及进一步降低艾滋病治疗成本方面具有巨大潜力，并且还将促进新型d4N和ddN类似物的开发。
