Iterative one-pot synthesis of oligosaccharides
Iterative one-pot synthesis of oligosaccharides
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DOI：
10.1002/anie.200460176
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发表时间：
2004-01-01
影响因子：
16.6
通讯作者：
Ye, XS
中科院分区：
文献类型：
--
作者：
Huang, XF;Huang, LJ;Ye, XS
传统的寡糖合成是一个耗时的过程，主要是由于繁琐的保护基团操作和中间体分离。为了减少合成和纯化步骤的数量，已经开发了许多创新方法，例如自动化固相合成，[1]正交糖基化，[2]迭代糖基化，[3]和化学选择性糖基化，[4]其中基于反应性的一锅法特别值得注意。[5]基于反应性的一锅法是指其中允许具有降低的异头反应性的糖基供体在单个反应烧瓶中顺序反应的方法。大寡糖可以以这种方式组装，而无需繁琐的中间体纯化或端基离去基团的调整，如岩藻糖基GM 1 [5a] LeY [5c]和Globo H [5d]等复杂寡糖的全合成以及寡糖文库的组装所证明的。[5b然而，为了获得具有合适的异头反应性的结构单元，必须进行广泛的保护基团操作和/或糖苷配基调节。[5]这种对结构单元的过度合成操作使合成过程复杂化并降低了总体效率。为了克服现有方法的局限性，我们已经研究了设计一种独立于不同糖基供体反应性的通用一锅法的可能性。这可以通过预活化供体来实现，[6]其在不存在受体的情况下产生反应性中间体（方案1）。在将第二结构单元添加到预活化供体后，将形成二糖，其在还原末端具有相同的可活化糖苷配基。该过程可以在相同的反应容器中重复，从而允许寡糖的快速组装。然而，成功的迭代一锅法合成必须满足几个先决条件：1）所用的启动子必须是化学计量的，以活化广泛的糖基供体，并被供体完全消耗，以防止随后的结构单元活化; 2）预活化后产生的中间体必须稳定，直到加入受体，但对快速高产糖基化反应具有反应性;和3）由活化形成的副产物必须不干扰糖基化。经过大量的实验检查各种促进剂，[7]糖苷配基离去基团，[8]和添加剂的影响，[9]通过使用对甲苯基硫代糖苷作为结构单元，对甲苯磺酰基三氟甲磺酸酯，（p-TolSOTf），[10]由对甲苯磺酰氯原位形成（p-TolSCl）和作为化学计量促进剂的三氟甲磺酸银（AgOTf）在脱水剂MSAW 300存在下反应。观察到供体的化学选择性糖基化与供体和受体的反应性无关，以令人满意的产率产生带有异头苯硫甲苯基部分的二糖（表1）。在60 ℃下，将一当量的p-TolSCl引入武装供体1、AgOTf和MS-AW 300在乙醚中的混合物中，导致糖基供体的瞬时完全活化。[11]将受体4加入到预活化的供体中，在几分钟内迅速形成二糖9，由于异头效应，以87%的产率分离出α异头物（表1，条目1）。活化产生的对甲苯基二硫化物不会干扰糖基化。
Traditional oligosaccharide synthesis is a time-consuming process, primarily due to tedious protective group manipulation and intermediate separation. To reduce the number of synthetic and purification steps, many innovative methodologies have been developed, such as automated solid-phase synthesis,[1] orthogonal glycosylation,[2] iterative glycosylation,[3] and chemoselective glycosylation,[4] among which the reactivity-based one-pot method is particularly noteworthy.[5] The reactivity-based one-pot method refers to one in which glycosyl donors with decreasing anomeric reactivities are allowed to react sequentially in a single reaction flask. Large oligosaccharides can be assembled in this fashion without tedious purification of intermediates or adjustment of anomeric leaving groups, as witnessed by total syntheses of complex oligosaccharides such as fucosyl GM1,[5a] LeY,[5c] and Globo H,[5d] as well as assembly of oligosaccharide libraries.[5b, e] However, to obtain building blocks with suitable anomeric reactivities, extensive protective group manipulations and/or aglycon adjustments must be carried out.[5] This excessive synthetic manipulation on building blocks complicates the synthetic process and decreases overall efficiency. To overcome limitations of existing approaches, we have investigated the possibility of designing a general one-pot method independent of differential glycosyl donor reactivities. This can be achieved by pre-activating the donor,[6] which generates a reactive intermediate in the absence of the acceptor (Scheme1). Upon addition of the second building block to the pre-activated donor, a disaccharide will be formed with an identical activatable aglycon at the reducing end. This process can be repeated in the same reaction vessel allowing rapid assembly of oligosaccharides. Several prerequisites, however, must be satisfied for a successful iterative one-pot synthesis: 1) the promoter utilized must be stoichiometric in activation of a wide range of glycosyl donors and be completely consumed by the donor to prevent activation of following building blocks; 2) the intermediate generated after pre-activation must be stable till addition of acceptor, yet reactive for rapid high-yielding glycosylations; and 3) side products formed from activation must not interfere with glycosylations. After much experimentation examining the effects of various promoters,[7] aglycon leaving groups,[8] and additives,[9] general reaction conditions were established by using p-tolyl thioglycosides as building blocks, p-toluenesulfenyl triflate (p-TolSOTf),[10] formed in situ from p-toluenesulfenyl chloride (p-TolSCl) and silver triflate (AgOTf), as the stoichiometric promoter, in the presence of the dehydrating reagent MSAW300. Chemoselective glycosylation of donors was observed independent of the reactivities of donors and acceptors, producing disaccharides bearing an anomeric pthiotolyl moiety in satisfactory yields (Table 1). Introduction of one equivalent of p-TolSCl to a mixture of armed donor 1, AgOTf, and MS-AW300 in diethyl ether at À608C led to instantaneous complete activation of the glycosyl donor.[11] Addition of the acceptor 4 to the preactivated donor rapidly formed disaccharide 9 in just a few minutes, which was isolated in 87% yield as the α anomer due to the anomeric effect (Table 1, entry 1). The p-tolyl disulfide generated from activation did not perturb the glycosylation.