Chemical conjugation between hydrophilic and hydrophobic components is difficult because of their extremely different solubility. Herein, we report a new versatile method with a solid‐phase‐assisted disulfide ligation to overcome the difficulty of conjugation attributed to solubility. The method involves two steps in a one‐pot process: 1) loading of a hydrophobic molecule onto a resin in an organic solvent, and 2) release of the solid‐supported hydrophobic molecule as a conjugate with a hydrophilic molecule into an aqueous solvent. This strategy allows the use of a suitable solvent system for the substrates in each step. Conjugates of a water‐insoluble drug, plinabulin, with hydrophilic carriers that could not be prepared by solution‐phase reactions were obtained in moderate yields (29–45 %). This strategy is widely applicable to the conjugation of compounds with solubility problems.

中文翻译：

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固相辅助二硫键合连接亲水和疏水成分的有效方法

亲水性和疏水性成分之间的化学共轭是困难的，因为它们的溶解度极为不同。本文中，我们报道了一种新的通用方法，该方法具有固相辅助的二硫键连接，可以克服由于溶解性引起的结合困难。该方法涉及一个一锅法过程中的两个步骤：1）将疏水性分子负载到有机溶剂中的树脂上，以及2）将与亲水性分子结合的固体负载疏水性分子释放到水性溶剂中。该策略允许在每个步骤中为基材使用合适的溶剂系统。以中等产率（29–45％）获得了水不溶性药物匹林布林与无法通过溶液相反应制备的亲水性载体的结合物。