Studies on Design and Synthesis of Glycoconjugate Drugs with Targeting

由于含糖生物分子中糖残基的生物学意义已被迅速认识，合理设计和开发立体控制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去基的新型高效糖基化方法的一部分，我们现在发现，结合亚磷酸二乙酯的糖基供体不仅具有优异的货架稳定性，而且在糖基化反应中具有以下明显的优势。(1)以BF_3-OEt_2为启动子，即使在-78℃的温度下，苯基保护的glycopyranosyl二乙基亚磷酸酯也能与多种受体醇偶联，对O-2上不参与基的糖苷化表现出迄今为止已知的最高的1,2-反式β选择性。(2) tmsotf介导的含C-2…More参与基团的亚磷酸糖基糖化是一种非常温和和通用的立体控制构建1,2-反式-糖苷键的方法。(3)利用2-脱氧甘氨酰基二乙基亚磷酸酯，在一定催化量的TMSOTf存在下，开发了一种直接构建2-脱氧- β -糖苷键的方法，其中2-脱氧-d -葡萄糖和2-脱氧- l -鼠李糖酰基给体与伯醇的糖苷化已被发现具有迄今为止已知的最高β -选择性。(4)在tmsotf存在的情况下，利用4,6- o -苄基保护的甘露吡喃二乙基亚磷酸酯，实现了直接糖苷化立体控制构建1,2 -顺式- β -甘露苷，这是一个长期存在的棘手问题，尽管该方法仅限于伯醇。(5)在2,6-二叔丁基碘化吡啶和四丁基碘化铵的存在下，以苯基保护的甘氨酰二乙基亚磷酸为糖基供体，在足够温和的酸不稳定醇条件下，建立了高度立体控制的1,2-顺式- α糖苷化反应。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