Xue Jundi, Han Ziyi, Li Gen, Emmanuel Khalisha A, McManus Cynthia L, Sui Qiang, Ge Dongmian, Gao Qi, Cai Li
Shanghai University of Engineering Science, 333 Long Teng Road, Shanghai 201620, China.
China State Institute of Pharmaceutical Industry, 285 Gebaini Rd, Shanghai 201203, China.
Beilstein J Org Chem. 2020 Aug 10;16:1955-1962. doi: 10.3762/bjoc.16.162. eCollection 2020.
Lipid A, the hydrophobic domain of lipopolysaccharide (LPS), is a strong immunostimulator and therefore a valuable target for the development of novel immunomodulators. Various lipid A derivatives have been chemically synthesized in order to reduce toxicity while retaining the immunostimulatory activity. In this work, we describe a novel approach to the frequently problematic synthesis of monophosphorylated mono- and disaccharide lipid X using a combination of established chemistry and a novel 2-naphthylmethyl ether (Nap) protecting group for "permanent" protection of hydroxy groups. Of particular note is the fact that the key Nap protecting group is able to remain in the molecule until the final global deprotection step. Our synthetic strategy is not only efficient in regards to the yield of the various chemical transformations, but also robust in regards to the potential application of this route to the production of other lipid A analogs.
脂多糖（LPS）的疏水结构域脂质A是一种强大的免疫刺激剂，因此是开发新型免疫调节剂的重要靶点。为了在保留免疫刺激活性的同时降低毒性，人们已经化学合成了各种脂质A衍生物。在这项工作中，我们描述了一种新颖的方法，用于解决单磷酸化单糖和二糖脂质X合成中经常出现的问题，该方法结合了成熟的化学方法和一种新型的2-萘甲基醚（Nap）保护基，用于羟基的“永久性”保护。特别值得注意的是，关键的Nap保护基能够在分子中保留到最后的全局脱保护步骤。我们的合成策略不仅在各种化学转化的产率方面效率高，而且在将该路线应用于生产其他脂质A类似物的潜在应用方面也很稳健。
