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Design of Glycosidation Reactions Directed toward Efficient Synthesis of Biologically Active Oligosaccharide Chains

面向高效合成生物活性寡糖链的糖苷化反应设计

基本信息

批准号：
07457517
负责人：
HASHIMOTO Shunichi
金额：
$ 1.34万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457517/
关键词：
Oligosaccharide Chain Phosphorus Leaving Group Protection Reactivity Diethyl Phosphite Stereoselectivity Glycosidation

项目摘要

The rapidly growing significance of oligosaccharide chains as constituents of biologically important compounds such as antitumor antibiotics, glycolipids, and glycoproteins has sparked considerable interest in the rational design and development of stereocontrolled glycosidation reactions directed toward the block synthesis.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 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 also 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.The phosphoroamidates, which have proven to be compatible with a variety of protective group interchange conditions, play a pivotal role as the "disarmed" donors in the block synthesis of oligosaccharides based on the "armed/disarmed" concept, while the diphenylphosphinimidates, phosphorodiamidimidothioates, and diethyl phosphites can serve as the "armed" donors.

寡糖链作为抗肿瘤抗生素、糖脂和糖蛋白等重要生物学化合物的组成部分，其重要性迅速增长，引发了人们对针对嵌段合成的立体控制糖苷化反应的合理设计和开发的极大兴趣。含磷离去基团，我们现在发现掺入亚磷酸二乙酯的糖基供体不仅表现出优异的储存稳定性，而且在糖苷化反应中具有以下明显的优势。 (1) 在 BF_3·OEt_2 作为促进剂的帮助下，即使在-78℃下，苄基保护的吡喃葡萄糖基二乙基亚磷酸酯与各种受体醇的偶联也能实现，从而表现出迄今为止已知的与 O-2 上非参与基团的糖苷化的最高 1,2-反式-β-选择性。 (2) C-2 处带有参与基团的糖基亚磷酸酯的 TMSOTf 介导的糖苷化构成了一种用于立体控制构建 1,2-反式-β-糖苷键的极其温和且通用的方法。 (3)还开发了一种直接构建2-脱氧-β-糖苷键的方法，通过在催化量的TMSOTf存在下使用2-脱氧吡喃糖基二乙基亚磷酸酯，其中已发现2-脱氧-D-葡萄糖-和2-脱氧-L-吡喃鼠李糖基供体与伯醇的糖苷化表现出最高的迄今为止已知的β-选择性。酰胺磷酸酯已被证明与各种保护基团交换条件兼容，在基于“武装/解除武装”概念的寡糖嵌段合成中作为“解除武装”供体发挥着关键作用，而二苯基亚膦酸酯、二酰胺硫代磷酸酯和亚磷酸二乙酯可以发挥作用作为“武装”捐助者。