Studies toward Rapid Synthesis of Oligosaccharides on Solid Phase

低聚糖和糖共轭化合物的固相合成是研究其生物学功能的重要手段。糖苷化反应是低聚糖固相合成中最重要的问题。因此，我们开发了新的有效的硫代糖苷的糖苷化方法，通过NBS和强酸性盐的组合或使用由PHIO-Lewis酸制备的高价碘试剂。我们还发现，N-苯基硒邻苯二甲酰亚胺(PhSeNPhth)-Mg(ClO_4)_2在温和的条件下也能有效地促进与硫代糖苷的糖苷化反应。由于PhSeNPhth-Mg(ClO_4)_2的糖苷化反应几乎是在中性条件下进行的，因此酸敏感的三叔丁基可以作为保护基团。结果表明，给体6-位上的三甲基显著提高了α-选择性。6位含三氯乙氧基团(TROC)的苯基化给电子体也实现了高的α-选择性。用于固相合成低聚糖的实际羟基保护基团和连接基的数量有限。我们最近开发了对叠氮基-间氯苯甲基(Cl-Azb)，它对DDQ很稳定，但在叠氮基团转化为相应的亚氨基磷孢烷后，很容易被2，3-二氯-5，6-二氰基苯甲酚(DDQ)氧化裂解。CL-azb在固相合成中表现出较好的性能。我们先前描述的对酰氨基苯基具有比MPM基更高的酸稳定性，但很容易被DDQ裂解。因此，对戊二胺基苯基被开发为一种连接物，它可以很容易地从对硝基苯基上衍生出来，并且很容易被DDQ裂解。对酰氨基苯苷也被用作连接剂，它可以很容易地从对硝基苯苷中得到，并且很容易被硝酸铈铵(CAN)氧化裂解。

Solid phase synthesis of oligosaccharides and glycoconjugates has been strongly required for the investigation of their biological functions. Glycosidation reaction is most important issue for the solid phase synthesis of oligosaccharides. We, therefore, developed novel and effective glycosidation methods with thioglycosides by combination of NBS and strong acid salts or by using hypervalent iodine reagents prepared from PhIO-Lewis acids. We also found that N-phenylselenophthalimide (PhSeNPhth) -Mg (ClO_4) _2 also effectively promotes glycosidation with thioglycosides under mild conditions. Since the glycosidation using PhSeNPhth-Mg (ClO_4) _2 proceeded under almost neutral conditions, acid-sensitive trityl group was able to use as a protecting group. Trityl group at 6-position of the donor was found to remarkably increase alpha-selectivity. High alpha-selectivity was also achieved by use of a benzylated donor possessing trichloroethoxycarbonyl (Troc) group at the 6-position.There have been only limited numbers of practical protecting groups of hydroxyl functions and linkers for solid phase synthesis of oligosaccharides. We recently developed p-azido-m-chlorobenzyl group (Cl-Azb) which is stable to DDQ but can be readily cleaved by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) oxidation after conversion of the azide group into the corresponding iminophosporane. Cl-Azb showed good performance for the solid phase synthesis.We previously described p-acylaminobenzyl groups have higher acid stability than the MPM group but are readily cleaved with DDQ.The p-glutarylaminophenyl function was thus developed as a linker which can be readily derived from p-nitrobenzyl function and can be easily cleaved by DDQ.The p-acylaminophenyl glycoside was also utilized as a linker which can be readily obtained from p-nitrophenyl glycoside and can be readily cleaved by ammonium cerium (IV) nitrate (CAN) oxidation.