The asymmetric O-alkylation of secondary aliphatic alcohols remains a substantial challenge in chemistry. Such a challenge largely stems from the steric demand of each reactant, in addition to the relatively low nucleophilicity of alcohols. Here, we report the development of a base-free, Cu-catalysed propargylic substitution reaction that enables the efficient, asymmetric O-propargylation of secondary aliphatic alcohols. Mechanistic studies implied key factors to slow down the undesired decomposition process of electrophiles in this reaction, which opened up the possibility of using secondary aliphatic alcohols as nucleophilic substrates. This asymmetric O-alkylation reaction proceeds under almost neutral conditions, tolerates a broad scope of functional groups and shows remarkable chemoselectivities. This method is amenable to the modification of natural products and commercial drugs. The products obtained could be readily elaborated to various classes of enantioenriched α,α′-disubstituted ethers that are difficult to access by other methods.

仲脂族醇的不对称O-烷基化仍然是化学上的重大挑战。除了相对低的醇亲核性之外，这种挑战很大程度上源于每种反应物的空间需求。在这里，我们报告了无碱，铜催化的炔丙基取代反应的发展，该反应使仲脂肪醇的高效，不对称的O-炔丙基化成为可能。机理研究表明，关键因素减缓了该反应中亲电试剂的不良分解过程，从而打开了使用仲脂族醇作为亲核底物的可能性。这个不对称的O-烷基化反应在几乎中性的条件下进行，可耐受各种官能团并显示出显着的化学选择性。该方法适用于天然产物和商业药物的改性。所获得的产物可以容易地制成各种类型的对映体富集的α，α'-二取代的醚，难以通过其他方法获得。