Novel Para-Substituted Benzyl Ethers for Hydroxyl Group Protection
Novel Para-Substituted Benzyl Ethers for Hydroxyl Group Protection
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用于羟基保护的新型对位取代苄基醚
DOI：
10.1021/ja9836085
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发表时间：
1999
影响因子：
15
通讯作者：
O. Hindsgaul
中科院分区：
文献类型：
--
作者：
L. Jobron;O. Hindsgaul
观察到对羟基苄基醚在碱性条件下很容易分解生成游离醇，这使得在碳水化合物化学中作为保护基团的新型可溶液裂解的苄基醚得以发展。O-苄基是碳水化合物化学中最常用的持久性保护基团，在Pd和PtO2等不溶催化剂上，在多步低聚糖合成的最后一步，它几乎总是被去除。这些裂解过程除了对杂质引起的催化剂中毒敏感外，还严重限制了在固相低聚糖合成中使用苄基，在树脂上去除它是可取的。因此，我们正在研究使用可被可溶性试剂裂解的修饰的苄基。在这里，我们描述了新的对乙酰氧基苄基(PAB)和2-(三甲基硅基)乙氧基甲氧基苄基(对-扫描电子显微镜-苄基)。合成了三氯亚氨酸酯3和溴化物4作为引入PAB基团的试剂，如方案1所示。1的伯羟基在室温下用5%三氟乙酸和5%三异丙基硅烷的溶液在CH2Cl2中选择性地三羟基化，然后用5%的三氟乙酸和5%的三异丙基硅烷裂解得到2。在1，8-二氮杂双环的存在下，用三氯乙腈处理2。0]Undec-7-ene以95%的产率合成了三氯乙酰亚氨酸酯3。用四溴化碳(2.2当量)和三苯基膦(4.4当量)在乙醚中反应得到溴4，产率为95%。伯羟基5与三氯乙酰亚胺3在三氟甲磺酸(TfOH)或三氟甲磺酸(Tf2O)1催化下在CH2Cl2中反应，以67%的产率得到保护化合物6(方案2)。在正己烷/CH2Cl2(1/1)中，用三氟甲磺酸银(AgOTf)与溴化物4反应，以78%的产率合成了同样的化合物。如方案2所示，在苄基醚的存在下，PAB醚基可以选择性地以定量的产率裂解。用Naome处理6得到酚氧化物7，如果需要，可以用闪蒸色层析法分离。然而，加热7至65℃会导致PAB基团的损失，可能是通过形成亚甲基苯二酚，如8所示。或者，可以用温和的氧化剂，如2，3-二氯-5，6-二氰基-1，4-苯二酚(DDQ)、2-FeCl3、3-碘苯二乙酸酯、4和CELITE 5上的碳酸银去除苯酚7(条件和产率见表1)。
The observation that p-hydroxybenzyl ethers readily decompose under basic conditions to yield the free alcohol has allowed the development of novel solution-cleavable benzyl ethers as protecting groups in carbohydrate chemistry. The O-benzyl group is the most commonly used “persistent” protecting group in carbohydrate chemistry, where it is almost always removed at the last step of multistep oligosaccharide synthesis by hydrogenolysis over insoluble catalysts such as Pd and PtO2. Those cleavage procedures, besides being sensitive to catalyst poisoning by impurities, severely limit the use of the benzyl group in solid-phase oligosaccharide synthesis, where its removal on the resin would be desirable. We are therefore investigating the use of modified benzyl groups which are cleavable by soluble reagents. Here we describe the novel p-acetoxybenzyl (PAB) and 2-(trimethylsilyl) ethoxymethoxybenzyl (p-SEM-benzyl) groups. The trichloracetimidate 3 and the bromide 4 were prepared as reagents for the introduction of the PAB group as shown in Scheme 1. The primary hydroxyl group of 1 was selectively tritylated followed by acetylation of the phenol and cleavage of the trityl group using a solution of 5% trifluoroacetic acid and 5% triisopropylsilane in CH2Cl2 at room temperature to give 2. Treatment of 2 with trichloroacetonitrile in the presence of 1, 8-diazabicyclo [5.4. 0] undec-7-ene gave the trichloroacetimidate 3 in 95% yield. The bromide 4 was obtained after treatment of 2 with carbon tetrabromide (2.2 equiv) and triphenylphosphine (4.4 equiv) in diethyl ether to give a 95% yield. Reaction of the primary hydroxyl group of 5 with the trichloroacetimidate 3 employing trifluoromethanesulfonic acid (TfOH) or trifluoromethanesulfonic anhydride (Tf2O) 1 as a catalyst in CH2Cl2 gave the protected compound 6 in 67% yield (Scheme 2). The same compound was produced in 78% yield on reaction of 5 with the bromide 4 by using silver trifluoromethanesulfonate (AgOTf) in hexane/CH2Cl2 (1/1). The PAB ether group can be selectively cleaved in quantitative yield in the presence of benzyl ethers as shown in Scheme 2. Treatment of 6 with NaOMe yields the phenoxide 7 which can be isolated by flash chromatography if desired. Heating of 7 to 65 C, however, results in the loss of the PAB group, presumably by formation of a methylene quinone as shown in 8. Alternatively, the phenoxide 7 can be removed by mild oxidizing agents such as 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ), 2 FeCl3, 3 iodobenzene diacetate, 4 and silver carbonate on Celite5 (for conditions and yields, see Table 1).