Stereochemically controlled hydrogen bond donors play essential roles in the pharmaceutical industry. Consequently, organic molecules that bear difluoromethyl (CF₂H) groups at chiral centres are emerging as pivotal components in pharmaceuticals owing to their distinct hydrogen-bonding property. However, a general approach for introducing CF₂H groups in an enantioselective manner has remained elusive. Here we show that enantioconvergent difluoromethylation of racemic alkyl electrophiles, through alkyl radical intermediates, represents a strategy for constructing CF₂H-containing stereocentres. This strategy is enabled by using copper catalysts bound with a chiral diamine ligand bearing electron-deficient phenyl groups, and a nucleophilic CF₂H-zinc reagent. This method allows the high-yield conversion of a diverse range of alkyl halides into their alkyl-CF₂H analogues with excellent enantioselectivity. Mechanistic studies reveal a route involving asymmetric difluoromethylation of alkyl radicals and crucial non-covalent interactions in the enantiodetermining steps. This copper-catalysed difluoromethylation process opens an avenue for the efficient preparation of CF₂H-containing pharmaceuticals.

立体化学控制的氢键供体在制药行业中发挥着至关重要的作用。因此，由于其独特的氢键特性，在手性中心带有二氟甲基 （CF₂H） 基团的有机分子正在成为药物中的关键成分。然而，以对映选择性方式引入 CF₂H 基团的通用方法仍然难以捉摸。在这里，我们表明，通过烷基自由基中间体的外消旋烷基亲电试剂的对映趋同二氟甲基化代表了构建含 CF₂H 的立体中心的策略。通过使用与带有缺电子苯基团的手性二胺配体结合的铜催化剂和亲核 CF₂H-锌试剂，可实现该策略。该方法允许将各种烷基卤化物高产率转化为具有优异对映选择性的烷基-CF₂H 类似物。机理研究揭示了一种涉及烷基自由基不对称二氟甲基化和对映决定步骤中关键非共价相互作用的途径。这种铜催化的二氟甲基化过程为高效制备含 CF₂H 的药物开辟了一条途径。