The National Research Centre for Carbohydrate Synthesis, Jiangxi Normal University , 99 Ziyang Avenue, Nanchang 330022, China.
J Am Chem Soc. 2017 Sep 13;139(36):12736-12744. doi: 10.1021/jacs.7b07020. Epub 2017 Sep 1.
A novel alkyne-activation-based glycosylation protocol using o-(p-methoxyphenylethynyl)phenyl (MPEP) glycoside was established. The glycosyl MPEP donors were shelf-stable and could be prepared efficiently via Sonogashira reaction from the corresponding o-iodophenyl (IP) glycosides. The outstanding stability of IP glycosides as well as their efficient transformations to MPEP glycosides dramatically facilitates the syntheses of MPEP glycosyl donors and IP glycosyl acceptors. Furthermore, they make the MPEP glycosylation protocol applicable to the latent-active oligosaccharide and glycoconjugate synthetic strategy, with IP glycosides as the latent form and MPEP glycosides as the active form, as illustrated by the highly efficient fabrication of Streptococcus pneumoniae type 3 trisaccharide. The phenolic glycoside nature of MPEP glycosides bestows on the new glycosyl donors enhanced stability compared to their thioglycoside counterparts toward activation conditions applied for glycosyl trichloroacetimidate (TCAI) and o-alkynylbenzoate (ABz) donor. Thus, MPEPs can also be utilized in the selective one-pot glycosylation strategy, as exemplified by the syntheses of oligosaccharides via successive glycosylations with glycosyl TCAI, ABz, and EPMP as donors. Despite sharing identical promotion conditions with thioglycoside donors, the odor-free starting material (IP), the stable departure structure of the leaving group (3-iodobenzofuran), and the decreased nucleophilicity of the o-MPEP glycoside help to eliminate the three major shortcomings of the thioglycoside donors (unpleasant odor of starting material, detrimental interference of the cleaved leaving group, and aglycon intra- or intermolecular migration) while maintaining the prominent features of the thioglycoside methodology, including the broad substrate scopes, the mild promotion conditions, the stability of glycosyl donors, and the versatile applications in existing glycoside synthesis strategies. Based on the experimental results, a mechanism for MPEP activation was proposed, which was supported by systematic mechanistic investigations, including trapping of active intermediates, design of a vital disarmed rhamnosyl donor, and isolation and characterization of the departure species of the leaving group.
建立了一种基于炔基活化的新型糖基化方法，使用邻-(对甲氧基苯乙炔基)苯（MPEP）糖苷。糖基 MPEP 供体稳定，可通过相应的邻碘苯（IP）糖苷的 Sonogashira 反应高效制备。IP 糖苷的出色稳定性及其高效转化为 MPEP 糖苷极大地促进了 MPEP 糖苷供体和 IP 糖苷受体的合成。此外，它们使 MPEP 糖基化方法适用于潜伏活性寡糖和糖缀合物合成策略，其中 IP 糖苷为潜伏形式，MPEP 糖苷为活性形式，如图所示，高效制备肺炎链球菌 3 型三糖。MPEP 糖苷的酚糖苷性质与硫代糖苷相比，赋予新的糖苷供体在用于糖基三氯乙酰亚胺（TCAI）和邻炔基苯甲酸酯（ABz）供体的活化条件下更高的稳定性。因此，MPEP 也可以用于选择性一锅法糖基化策略，例如通过连续糖基化用糖基 TCAI、ABz 和 EPMP 作为供体合成寡糖。尽管与硫代糖苷供体具有相同的促进条件，但无臭起始材料（IP）、离去基团（3-碘苯并呋喃）的稳定离去结构以及邻-MPEP 糖苷的亲核性降低有助于消除硫代糖苷供体的三个主要缺点（起始材料的不愉快气味、断裂离去基团的有害干扰以及糖苷配基的内或分子间迁移），同时保持硫代糖苷方法的突出特点，包括广泛的底物范围、温和的促进条件、糖苷供体的稳定性以及在现有糖苷合成策略中的广泛应用。基于实验结果，提出了 MPEP 活化的机制，该机制得到了系统的机制研究的支持，包括活性中间体的捕获、关键无武装鼠李糖供体的设计以及离去基团的离去物种的分离和表征。
