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Abstract：
β-l-5-((E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) uracil (l-BHDU, 17) is a potent and selective inhibitor of the varicella-zoster virus (VZV). l-BHDU (17) has demonstrated excellent anti-VZV activity and is a preclinical candidate to treat chickenpox, shingles (herpes zoster), and herpes simplex virus 1 (HSV-1) infections. Its monophosphate prodrug (POM-l-BHDU-MP, 24) demonstrated an enhanced pharmacokinetic and antiviral profile. POM-l-BHDU-MP (24), in vivo, effectively reduced the VZV viral load and was effective for the topical treatment of VZV and HSV-1 infections. Therefore, a viable synthetic procedure for developing POM-l-BHDU-MP (24) is needed. In this article, an efficient approach for the synthesis of l-BHDU (17) from a readily available starting material is described in 7 steps. An efficient and practical methodology for both chiral pure l- & d-dioxolane 11 and 13 were developed via diastereomeric chiral amine salt formation. Neutralization of the amine carboxylate salt of l-dioxolane 10 provides enantiomerically pure l-dioxane 11 (ee ≥ 99%). Optically pure 11 was utilized to construct the final nucleoside l-BHDU (17) and its monophosphate ester prodrug (POM-l-BHDU-MP, 24). Notably, the reported process eliminates expensive chiral chromatography for the synthesis of chiral pure l- & d-dioxolane, which offers avenues for the development and structure-activity relationship studies of l- & d-dioxolane-derived nucleosides.
摘要：
β-1-5-（（E）-2-溴乙烯基）-1-（（2S，4S)-2-(羟甲基)-1,3-(二氧戊环-4-基)尿嘧啶(1-BHDU,17）是水痘带状疱疹病毒（VZV）的有效和选择性抑制剂。l-BHDU（17）已显示出优异的抗VZV活性，是治疗水痘的临床前候选药物，带状疱疹（带状疱疹），和单纯疱疹病毒1（HSV-1）感染。其单磷酸酯前药（POM-l-BHDU-MP，24）显示出增强的药代动力学和抗病毒谱。POM-l-BHDU-MP(24),在体内，有效降低了VZV病毒载量，对VZV和HSV-1感染的局部治疗有效。因此,需要开发POM-1-BHDU-MP(24)的可行合成程序。在这篇文章中,在7个步骤中描述了从容易获得的起始材料合成I-BHDU(17)的有效方法。通过形成非对映体手性胺盐，开发了一种有效且实用的手性纯1-和d-二氧戊环11和13的方法。1-二氧戊环10的胺羧酸盐的中和提供对映体纯的1-二恶烷11(ee≥99%)。光学纯11用于构建最终的核苷1-BHDU（17）及其单磷酸酯前药（POM-1-BHDU-MP，24).值得注意的是,报道的方法消除了昂贵的手性色谱合成手性纯1-和d-二氧戊环，这为l-和d-二氧戊环衍生核苷的开发和结构-活性关系研究提供了途径。
