Reactions involving both hydrophobic and hydrophilic molecules present a significant challenge due to the difficulties associated with finding solvents that are capable of effectively accommodating reactants with contrasting solubility properties. Solvent-free conditions offer a potential alternative, albeit that under conventional neat conditions, immiscible reactants often remain poorly mixed at the molecular level, resulting in low reactivity. Here, we demonstrate that mechanochemistry could potentially offer a practical solution to overcome this immiscibility issue. Specifically, we discovered that mechanical agitation by ball milling enables highly efficient Fischer glycosylation reactions of hydrophilic unprotected sugars with a wide range of hydrophobic long-chain aliphatic alcohols, offering straightforward access to various glycolipid derivatives. This type of direct glycosylation has been recognized as a challenging transformation due to the inefficient mixing of the immiscible substrate pairs under conventional conditions. Thus, the present study highlights the promising potential of a mechanochemical approach to tackle longstanding challenges associated with immiscibility in the synthesis of value-added amphipathic small molecules.
Kubota et al. (Tue,) studied this question.