Synthesis of a malaria candidate glycosylphosphatidylinositol (GPI) structure: A strategy for fully inositol acylated and phosphorylated GPIs
Synthesis of a malaria candidate glycosylphosphatidylinositol (GPI) structure: A strategy for fully inositol acylated and phosphorylated GPIs
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DOI：
10.1021/ja038807p
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发表时间：
2004-06-23
影响因子：
15
通讯作者：
Fraser-Reid, B
中科院分区：
文献类型：
--
作者：
Lu, J;Jayaprakash, KN;Fraser-Reid, B
合成了一种存在于疟疾病原体恶性疟原虫细胞表面的糖基磷脂酰肌醇（GPI）膜锚的同源物。该GPI是少量在肌醇的O-2处携带脂肪酰基的这种膜锚的实例。虽然酰基在GPI的生物合成中起着至关重要的作用，但它很少在成熟分子中存在。其他值得注意的例子是哺乳动物GPIs CD 52和AchE。在肌醇部分的三个连续位置处存在庞大的官能团产生了非常拥挤的环境，这对进行选择性化学操作造成了困难。因此，轴向长链酰基和相邻的磷酸甘油基复合物的安装充满了障碍。在成功合成疟疾候选物和原型结构中，这些障碍的关键解决方案涉及环状原酸酯的立体电子控制打开。反应以非常好的产率进行，主要形成所需的轴向非对映体，在长链酰基衍生物的情况下甚至更是如此。以甲基α-D-吡喃葡萄糖苷为原料，采用Bender和Budhu的仿生方法合成了肌醇前体。对于聚糖阵列，利用了以下事实：（a）在用三氟甲磺酸镱和N-碘代琥珀酰亚胺处理后，正戊烯基原酸酯供体被快速且化学特异性地活化，以及（B）与受体偶联仅提供α-偶联产物。从相应的α-甘露糖苷获得GPI的α-氨基葡糖苷组分的策略采用了Deshong的新叠氮化物置换方法。因此，聚糖阵列的所有单元都是从β-D-甘露糖-n-戊烯基原酸酯获得的，这可以很容易地从D-甘露糖在三个简单的高产率步骤中制备。上述1和2位的“拥挤环境”可以通过酰基迁移到天然产物中相邻的顺式-O-3-羟基而得到缓解。然而，我们的合成中间体和原型的研究表明，O-2酰基是相当稳定的，这种迁移不容易发生。
A congener of the glycosylphosphatidylinositol (GPI) membrane anchor present on the cell surface of the malaria pathogen Plasmodium, falciparum has been synthesized. This GPI is an example of a small number of such membrane anchors that carry a fatty acyl group at O-2 of the inositol. Although the acyl group plays crucial roles in GPI biosynthesis, it rarely persits in mature molecules. Other notable examples are the mammalian GPIs CD52 and AchE. The presence of bulky functionalities at three contiguous positions of the inositol moiety creates a very crowded environment that poses difficulties for carrying out selective chemical manipulations. Thus installations of the axial long-chain acyl group and neighboring phosphoglyceryl complex were fraught with obstacles. The key solution to these obstacles in the successful synthesis of the malarial candidate and prototype structures involved stereoelectronically controlled opening of a cyclic ortho ester. The reaction proceeds in very good yields, the desired axial diastereomer being formed predominantly, even more so in the case of long-chain acyl derivatives. The myoinositol precursor was prepared from methyl alpha-D-glucopyranoside by the biomimetic procedure of Bender and Budhu. For the glycan array, advantage was taken of the fact that (a) n-pentenyl ortho ester donors are rapidly and chemospecifically activated upon treatment with ytterbium triflate and N-iodosuccinimide and (b) coupling to an acceptor affords alpha-coupled product exclusively. A strategy for obtaining the GPI's alpha-glucosaminide component from the corresponding a-mannoside employed Deshong's novel azide displacement procedure. Thus all units of the glycan array were obtained from a beta-D-manno-n-pentenyl ortho ester, this being readily prepared from D-mannose in three easy, high-yielding steps. The "crowded environment" at positions 1 and 2, noted above, could conceivably be relieved by migration of the acyl group to the neighboring cis-O-3-hydroxyl in the natural product. However, study of our synthetic intermediates and prototypes indicate that the O-2 acyl group is quite stable, and that such migration does not occur readily.