Mogemark Mickael, Elofsson Mikael, Kihlberg Jan
Organic Chemistry, Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden, and AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden.
J Org Chem. 2003 Sep 19;68(19):7281-8. doi: 10.1021/jo034581x.
A route for solid-phase synthesis of the alpha-Gal epitopes Gal(alpha1-3)Gal(beta1-4)Glc and Gal(alpha1-3)Gal(beta1-4)GlcNAc is described. These trisaccharide antigens are responsible for hyperacute rejection in xenotransplantation of porcine organs. Optimization of the solid-phase synthesis relied on use of fluorinated protective groups for the carbohydrate building blocks and use of a fluorinated linker. This allowed convenient on-resin analysis of the reactions with gel-phase (19)F NMR spectroscopy. Conditions were established which allowed reductive ring-opening of 4,6-O-benzylidene acetals to be performed on the solid phase with high regioselectivity to furnish the corresponding 6-O-benzyl ethers. It was found that glycosylations could be conveniently carried out by using thioglycosides as donors with N-iodosuccinimide and trifluoromethanesulfonic acid as the promoter system. With use of these conditions a challenging alpha-glycosidic linkage was successfully installed with complete stereoselectivity in the final glycosylation. It was also established that fluorinated benzoates, benzyl ethers, and benzylidene acetals display almost identical chemical properties as their nonfluorinated counterparts, a finding that is essential for future use of fluorinated protective groups in solid-phase oligosaccharide synthesis.
本文描述了α - 半乳糖表位Gal(α1 - 3)Gal(β1 - 4)Glc和Gal(α1 - 3)Gal(β1 - 4)GlcNAc的固相合成路线。这些三糖抗原是猪器官异种移植中超急性排斥反应的原因。固相合成的优化依赖于对碳水化合物构建单元使用氟化保护基团以及使用氟化连接体。这使得通过凝胶相（19）F NMR光谱对反应进行方便的树脂上分析成为可能。建立了相关条件，使得4,6 - O - 亚苄基缩醛的还原开环能够在固相上以高区域选择性进行，以提供相应的6 - O - 苄基醚。研究发现，通过使用硫代糖苷作为供体，以N - 碘代琥珀酰亚胺和三氟甲磺酸作为促进剂体系，可以方便地进行糖基化反应。在这些条件下，在最后的糖基化反应中成功地以完全的立体选择性安装了具有挑战性的α - 糖苷键。还确定了氟化苯甲酸酯、苄基醚和亚苄基缩醛与其非氟化对应物表现出几乎相同的化学性质，这一发现对于氟化保护基团在固相寡糖合成中的未来应用至关重要。
