We recently reported that the novel NO-releasing O2-glycosylated diazeniumdiolates of structure 1 showed promising anti-parasitic activity against Leishmania major.1 While preparing some 2-deoxyglucose analogs for lead optimization, we have observed the facile displacement of acetate by bromide from the 4-position of peracetylated 2-deoxyglucose 2, as shown in Scheme 1, providing a convenient synthesis of 4-brominated 2,4-dideoxyglucose derivatives that would otherwise be difficult to access by currently preferred, directed synthetic routes. Scheme 1 In an effort to prepare compound 4a, peracetylated 2-deoxyglucose 2 was treated with HBr in glacial acetic acid. A tar assumed to be bromide 3 was formed and immediately reacted with diazeniumdiolate salt 5 to generate a product expected to be 4a. However, this easily crystallized, sharp-melting product was characterized by elemental analysis values that were vastly different from our expectation. Further examination revealed the presence of only two methyl singlets in the proton NMR, and mass spectrometry pointed to the presence of a bromine atom in the molecular ion isotopic cluster. Detailed analysis of the 1H NMR spectral properties showed that the halide had replaced the C4 acetoxy group with retention of configuration. Further work-up afforded 7a in 38% yield. The product 7a was deacetylated with methoxide in methanol to produce 7b. An alternate bromination procedure using BiBr3 and trimethylsilyl bromide gave 4-α-bromo-2,4-dideoxyglucosyl bromide diacetate 6, presumably the same glycosylating agent produced in the HBr/HOAc reaction. The reaction with BiBr3 was rapid, efficient, and gave a higher yield of 6 than the HBr procedure. Diazeniumdiolates generate up to two moles of NO upon hydrolysis under various conditions. Replacement of the C4 acetoxy group of compound 4b by bromine had little effect (only about three-fold) on hydrolysis rates at pH values of 14, 7.4, and 3.8–4.6 (Table 1), a key predictor of anti-leishmanial activity.1 Table 1 Half-lives of Hydrolysis at 37°C for Diazeniumdiolated Glycosides of Structure Et2NN(O)=NOR In conclusion, we have discovered a novel and simple BiBr3/TMS bromide-mediated preparation of compound 6, an extremely useful intermediate in the preparation of the 2-deoxy sugars primed for further functionality at C4. In particular, compounds 7a and 7b offer an electrophilic center at C4, making it potentially useful for further reaction with nucleophiles, including peptide chains or additional saccharides.

中文翻译：

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在 O2-糖基化二氮烯二醇的合成过程中，溴在非异头位置意外掺入

我们最近报道了结构 1 的新型释放 NO 的 O2-糖基化二氮烯二醇酯对主要利什曼原虫显示出有希望的抗寄生虫活性。1 在制备一些用于铅优化的 2-脱氧葡萄糖类似物时，我们观察到溴化物从过乙酰化 2-脱氧葡萄糖 2 的 4-位，如方案 1 所示，提供了 4-溴化 2,4-二脱氧葡萄糖衍生物的方便合成，否则很难通过目前优选的定向合成路线获得。方案1 为了制备化合物4a，在冰醋酸中用HBr处理过乙酰化2-脱氧葡萄糖2。假定为溴化物 3 的焦油形成并立即与二氮烯二醇盐 5 反应生成预期为 4a 的产物。然而，这很容易结晶，快速熔化产品的特征是元素分析值与我们的预期大不相同。进一步检查显示，质子 NMR 中仅存在两个甲基单峰，质谱分析表明分子离子同位素簇中存在溴原子。1H NMR 光谱特性的详细分析表明，卤化物取代了 C4 乙酰氧基，保留了构型。进一步后处理以 38% 的产率得到 7a。产物7a在甲醇中用甲醇盐脱乙酰以产生7b。使用 BiBr3 和三甲基甲硅烷基溴的替代溴化程序产生 4-α-溴-2,4-二脱氧葡糖基溴二乙酸酯 6，推测与 HBr/HOAc 反应中产生的糖基化剂相同。与 BiBr3 的反应快速、有效、并给出比 HBr 程序更高的 6 产率。Diazeniumdiolates 在各种条件下水解时产生多达 2 摩尔的 NO。用溴取代化合物 4b 的 C4 乙酰氧基对 pH 值 14、7.4 和 3.8-4.6（表 1）的水解速率几乎没有影响（仅约三倍），这是抗利什曼原虫活性的关键预测因子。 1 表 1 结构为 Et2NN(O)=NOR 的二氮烯二醇化糖苷在 37°C 下水解的半衰期 总之，我们发现了一种新颖且简单的 BiBr3/TMS 溴化物介导的化合物 6 制备，这是一种非常有用的中间体制备 2-脱氧糖，为 C4 的进一步功能做好准备。特别是，化合物 7a 和 7b 在 C4 处提供了一个亲电中心，使其有可能用于与亲核试剂的进一步反应，