Nucleofuge Generating Glycosidations by the Remote Activation of Hydroxybenzotriazolyl Glycosides

Hydroxybenzotriazole
is routinely used in peptide chemistry for
reducing racemization due to the increased reactivity. In this article,
very stable hydroxybenzotriazolyl glucosides were identified to undergo
glycosidation. The reaction was hypothesized to go through the remote
activation by the Tf2O at the N3-site of HOBt followed
by the extrusion of the oxocarbenium ion that was attacked by the
glycosyl acceptor. Further, equilibration of the zwitterionic benzotriazolyl
species makes the leaving group noncompetitive and generates the nucleofuge
that has been reconverted to the glycosyl donor. The reaction is mild,
high yielding, fast and suitable for donors containing both C2-ethers
and C2-esters as well. The regenerative-donor glycosidation strategy
is promising as it enables us to regenerate the glycosyl donor for
further utilization. The utility of the methodology for the oligosaccharide
synthesis was demonstrated by the successful synthesis of the branched
pentamannan core of the HIV1−gp120 complex.

羟基苯并三唑（Hydroxybenzotriazole，下文简称HOBt）常规应用于肽化学领域，用于降低因反应活性提升而引发的消旋化副反应。本文中，研究人员成功鉴定出稳定性优异的羟基苯并三唑基葡萄糖苷，其可参与糖苷化反应。研究推测该反应经由以下路径进行：三氟甲磺酸酐（Tf₂O）作用于HOBt的N3位实现远程活化，随后脱去氧鎓离子，该离子可被糖苷受体进攻。进一步而言，两性离子苯并三唑基物种的平衡过程可使离去基团失去竞争性，并生成可重新转化为糖基供体的亲核离去基团。该反应条件温和、产率优异、反应速率快，同时适用于同时含有C2-醚基与C2-酯基的糖基供体。这种再生型供体糖苷化策略极具应用前景，因其能够实现糖基供体的再生以供后续循环利用。该方法在寡糖合成中的实用性已通过人类免疫缺陷病毒1型gp120（HIV1−gp120）复合物分支型五甘露糖核心的成功合成得到验证。