Abstract The lack of effective methods to perform direct β-selective glycosylation reactions with 2-deoxy-1,4-dithio-D-erythro-pentofuranosides has long been a significant stumbling block for the multi-gram synthesis of 4’-thio-2’-deoxy nucleosides. In addition, previously reported methods for the preparation of appropriately substituted 2-deoxy-1,4-dithio-D-erythro-pentofuranosides have proven problematic for large scale synthesis. To address these issues, herein we describe the modification and optimization of previously reported methods to allow for the convenient large scale synthesis of benzyl substituted 2-deoxy-1,4-dithio-D-erythro-pentofuranosides. Furthermore, we describe the development of reaction conditions for β-selective glycosylation reactions of benzyl substituted 2-deoxy-1,4-dithio-D-erythro-pentofuranosides with both N4-benzoylcytosine and 5-aza-cytosine to enable the practical multi-gram syntheses of the clinical candidates 4'-thio-2'-deoxycytidine (T-dCyd) and 5-aza-4’-thio-2’-deoxycytidine (aza-T-dCyd). Taken together, these new synthetic developments have made possible the preclinical and early clinical development of these important anticancer agents at the National Cancer Institute.

中文翻译：

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用苄基取代的 2-deoxy-1,4-dithio-D-erythro-pentofuranosides 开发 β-选择性糖基化反应：实现 4'-Thio-2'-deoxycytidine (T-dCyd) 和 5 的实际多克合成-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd) 支持临床开发

摘要 长期以来，缺乏与 2-deoxy-1,4-dithio-D-erythro-pentofuranosides 进行直接 β-选择性糖基化反应的有效方法一直是多克合成 4'-thio-2 的重要障碍。 '-脱氧核苷。此外，先前报道的制备适当取代的 2-deoxy-1,4-dithio-D-erythro-pentofuranosides 的方法已证明对大规模合成存在问题。为了解决这些问题，我们在本文中描述了对先前报道的方法的修改和优化，以方便地大规模合成苄基取代的 2-脱氧-1,4-二硫代-D-赤型-戊呋喃糖苷。此外，我们描述了苄基取代的 2-deoxy-1 的 β-选择性糖基化反应的反应条件的发展，4-dithio-D-erythro-pentofuranosides 与 N4-benzoylcytosine 和 5-aza-cytosine，使临床候选物 4'-thio-2'-deoxycytidine (T-dCyd) 和 5-aza 的实际多克合成成为可能-4'-thio-2'-脱氧胞苷 (aza-T-dCyd)。综上所述，这些新的合成发展使美国国家癌症研究所的这些重要抗癌药物的临床前和早期临床开发成为可能。