Department of Biochemistry and Molecular Biology, University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, United States.
J Org Chem. 2013 Jun 21;78(12):5970-86. doi: 10.1021/jo4006602. Epub 2013 Jun 11.
β-D-mannosyl phosphomycoketide (C32-MPM), a naturally occurring glycolipid found in the cell walls of Mycobacterium tuberculosis, acts as a potent antigen to activate T-cells upon presentation by CD1c protein. The lipid portion of C32-MPM contains a C32-mycoketide, consisting of a saturated oligoisoprenoid chain with five chiral methyl branches. Here we develop several stereocontrolled approaches to assemble the oligoisoprenoid chain with high stereopurity (>96%) using Julia-Kocienski olefinations followed by diimide reduction. By careful choice of olefination sites, we could derive all chirality from a single commercial compound, methyl (2S)-3-hydroxy-2-methylpropionate (>99% ee). Our approach is the first highly stereocontrolled method to prepare C32-MPM molecule with >96% stereopurity from a single >99% ee starting material. We anticipate that our methods will facilitate the highly stereocontrolled synthesis of a variety of other natural products containing chiral oligoisoprenoid-like chains, including vitamins, phytol, insect pheromones, and archaeal lipids.
β-D-甘露糖基磷酸酰化甘露糖酯（C32-MPM）是一种天然存在于结核分枝杆菌细胞壁中的糖脂，作为一种有效的抗原，在由 CD1c 蛋白呈递时可激活 T 细胞。C32-MPM 的脂质部分含有一个 C32-酰化甘露糖酯，由一个饱和的寡异戊二烯链组成，带有五个手性甲基支链。在这里，我们开发了几种立体控制方法，使用 Julia-Kocienski 烯烃化反应，然后进行二酰亚胺还原，以高立体纯度（>96%）组装寡异戊二烯链。通过仔细选择烯烃化位点，我们可以从单一商业化合物（（2S）-3-羟基-2-甲基丙酸甲酯（>99%ee）中获得所有的手性。我们的方法是第一个从单一>99%ee 的起始原料以>96%的立体纯度制备 C32-MPM 分子的高度立体控制方法。我们预计，我们的方法将促进各种含有手性寡异戊二烯样链的其他天然产物的高度立体控制合成，包括维生素、植醇、昆虫信息素和古菌脂质。
