Development of automated synthesis of oligosaccharides based on solid-phase methodology

基于固相方法的寡糖自动化合成的发展

• 批准号: 11558080
• 负责人: FUKASE Koichi
• 金额: $ 9.02万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11558080/
• 关键词: Solid-phase synthesis; automated synthesis; oligosaccharide synthesis; protective group; glycosylation; linker; catch-and-release

Solid-phase synthesis of oligosaccharides was investigated in order to develop automated synthesis of oligosaccharides. The most fundamental problem in solid-phase oligosaccharide synthesis is heterogeneity of polymer supports that causes insufficient glycosylation on solid support. Two new methods were developed for efficient solid-phase synthesis of oligosaccharides in the present study.The one is a new catch-and-release method of isolation for products using a specific reaction. Desired compounds possessing the 4-azido-3-chlorobenzyl group were selectively isolated from a crude mixture by means of the facile reaction between the azido group and polymer-supported phosphine. This method was successfully applied to the solid-phase synthesis of an oligosaccharide elicitor. Glcβ1-3Glcβ1-3 (Glcβ1-6)Glcβ1-3Glc was synthesized via elongation of saccharide chain on solid-support, cleavage of the protected oligosaccharide from the resin, catch-and-release isolation, and final deprotection.The other is selection of reactive region on polymer supports by using Sonogashira coupling reaction of glycosyl acceptors having an alkyne function with iodobenzamide on supports. Alkynylmethyl glycoside or alkyne ester was used as linker parts. These linkers were cleaved by treatment of Co_2(CO)_8 and TFA. The latter linker was also cleaved under basic conditions. The glycosylation reaction smoothly proceeded on the selected area of the supports to give the desired glycosides in quantitative yields.Automated synthesis of oligosaccharides was carried out by using commercially available multipurpose synthesizer.

为了实现寡糖合成的自动化，对寡糖的固相合成进行了研究。固相寡糖合成中最基本的问题是聚合物载体的不均匀性，这导致固相载体上的糖基化不足。本研究发展了两种固相合成低聚糖的新方法：一种是利用特定反应分离产物的捕获-释放法;通过叠氮基与聚合物负载的膦之间的简单反应，从粗混合物中选择性地分离具有4-叠氮基-3-氯苄基的所需化合物。该方法已成功地应用于寡糖诱导剂的固相合成。Glcβ1-3Glcβ1-3（Glcβ1-6）Glcβ1-3Glc的合成是通过在固相载体上延长糖链，从树脂上切割保护的寡糖，捕获-释放分离，最后脱保护，另一个是通过具有炔功能的糖基受体与载体上的碘苯甲酰胺的Sonogashira偶联反应选择聚合物载体上的反应区域。炔基甲基糖苷或炔酯用作接头部分。这些连接子被Co_2（CO）_8和TFA处理而断裂。后一个接头也在碱性条件下裂解。糖基化反应在载体的选定区域上顺利进行，以定量产率得到所需的糖苷。

项目成果

Kenji Egusa, Yoshihiko Nakai, Koichi Fukase, Shoichi Kusumoto: "Stereoselective Glycosylation and Oligosaccharide Synthesis on Solid Support Using a 4-Azido-3-chlorobenzyl Group for Temporary Protection"Synlett. 2000. 27

Kenji Egusa、Yoshihiko Nakai、Koichi Fukase、Shoichi Kusumoto：“使用 4-叠氮基-3-氯苄基进行临时保护的固体支持物上的立体选择性糖基化和寡糖合成”Synlett。

Koichi Fukase: "Novel Oxidatively Removable linker and Its Application to -Selective Solid-phase Oligosaccharide synthesis on a Macroporous Polystyrene Support"Synlett. 1999\7. 1074-1078 (1999)

Koichi Fukase：“新型氧化可去除连接体及其在大孔聚苯乙烯载体上选择性固相寡糖合成中的应用”Synlett。

Yoshiyuki Fukase, Koichi Fukase, and Shoichi Kusumoto: "Propargyloxycarbonyl and Propargyl Groups for Protection of Amino, Hydroxy, and Carboxy Function"Peptide Science, ed. By N. Fujii, The Japanese Peptide Society. 93 (2000)

Yoshiyuki Fukase、Koichi Fukase 和 Shoichi Kusumoto：“用于保护氨基、羟基和羧基功能的丙炔氧基羰基和丙炔基基团”肽科学，编辑。

Koichi Fukase et al,: "A Novel Oxidatively Removable Linker and Its Application to α-Selective Solid-phase Oligosaccharide Synthesis on a Macroporous Polystyrene Support"Synlett. 7. 1074-1078 (1999)

Koichi Fukase 等人：“一种新型氧化可去除连接体及其在大孔聚苯乙烯载体上的 α-选择性固相寡糖合成中的应用”Synlett。 7. 1074-1078 (1999)

kenji Egusa: "A new catch-and-release purification method using a 4-azido-3-chlorobenzyl group"Synlett. 2001\6. 777-780 (2001)

kenji Egusa：“一种使用 4-叠氮基-3-氯苄基的新捕获和释放纯化方法”Synlett。