Metal-free stereoretentive click coupling of chiral metallocenes in water

Click chemistry has revolutionised molecular construction by enabling rapid, modular, and reliable bond formation. Here, we reported a stereoretentive strategy of frustrated triaryl carbenium ion pair-catalysed click reactions in water of chiral metallocene alcohols coupling with diverse nucleophiles via an SN1-type dehydrative pathway, enabling the formation of C–S, C–O, C–Se, C–N, C–C, and C–P bonds in minutes with exceptional chirality retention under mild, aqueous conditions. Integrated experimental and density functional theory calculations revealed that the rigid sandwich architecture of the metallocene framework stabilised the ion-pair intermediate through non-directional dispersion interactions, restricting carbocation conformational flexibility and suppressing backside nucleophilic attack. This strategy provided a general and efficient platform for the stereospecific incorporation of chiral metallocene motifs into functional molecules, including amino acids, peptides, and proteins.