Studies on Design and Synthesis of Glycoconjugate Drugs with Targeting

由于糖类生物分子中糖残基的生物学意义被迅速认识，合理设计和开发立体控制的糖苷化反应不仅在碳水化合物化学中，而且在药物化学中也越来越重要。作为开发利用含磷离开基团的新的高效糖苷化方法的计划的一部分，我们现在发现，含有亚磷酸二乙酯的糖基供体不仅表现出良好的货架稳定性，而且在糖苷化反应中具有以下明显的优势。(1)以BF_3-OEt_2为促进剂，在-78ﾟC条件下，以BF_3-OEt_2为促进剂，实现了苯基保护的乙二乙基亚磷酸酯与多种受体醇的偶联反应，表现出迄今已知的与O-2上非参与基团的1，2-反式β-选择性。(2)TMSOTf介导的糖基亚磷酸盐在C-2…上的糖苷化反应对于立体控制的1，2-反式-β-糖苷键的构建，MORE是一种非常温和和普遍的方法。(3)2-脱氧-D-葡萄糖和2-脱氧-L-鼠李糖基供体与伯醇的糖苷化反应是迄今已知的最高的β-选择性。(4)通过在TMSOTf存在下开发4，6-O-亚苄基甘露糖二乙酯，实现了1，2-顺式-β-甘露糖苷的直接糖苷化，尽管该方法仅限于伯醇，但这是一个长期存在的棘手问题。(5)在2，6-二叔丁基碘化吡啶和四丁基碘化铵存在下，以苄基保护的氨基二乙基亚磷酸酯为糖基供体，发展了一种高度立体控制的1，2-顺式-α-糖苷化反应。较少

Due to the rapidly recognized biological significance of saccharide residues of carbohydrate-containing biomolecules, the rational design and development of stereocontrolled glycosidation reactions are of growing importance not only in carbohydrate chemistry but also in medicinal chemistry.As part of a program to develop novel and efficient glycosidation methods capitalizing on the phosphorus-containing leaving groups, we have now found that glycosyl donors incorporating diethyl phosphite exhibit not only excellent shelf-stabilities but also the following distinct advantages in the glycosidation reactions. (1) Coupling of benzyl-protected glycopyranosyl diethyl phosphites with a variety of acceptor alcohols can be effected by the aid of BF_3-OEt_2 as a promoter even at -78ﾟC to exhibit the highest 1,2-trans-beta-selectivity known to date for glycosidations with a non-participating group on O-2. (2) TMSOTf-mediated glycosidation of glycosyl phosphites bearing participating groups at C-2 … More constitutes an extremely mild and general method for the stereocontrolled construction of 1,2-trans-beta-glycosidic linkages. (3) A direct method for the construction of 2-deoxy-beta-glycosidic linkages has been developed by using 2-deoxyglycopyranosyl diethyl phosphites in the presence of a catalytic amount of TMSOTf, wherein glycosidations of 2-deoxy-D-gluco- and 2-deoxy-L-rhamnopyranosyl donors with primary alcohols have been found to exhibit the highest beta-selectivity known to date. (4) A direct glycosidation for the stereocontrolled construction of 1 , 2-cis-beta-mannnosides, a long-standing and formidable problem, has been achieved by exploiting 4,6-O-benzylidene-protected mannopyranosyl diethyl phosphites in the presence ofTMSOTf, though the method is limited to primary alcohols. (5) A highly stereocontrolled 1,2-cis-alpha-glycosidation under conditions mild enough for acid-labile alcohols has been developed by using benzyl-protected glycopyranosyl diethyl phosphites as glycosyl donors in the presence of 2,6-di-tert-butylpyridinium iodide and tetrabutylammonium iodide. Less