The methylation states of Lysa nd Arg represent aparticularly challenging set of targets to distinguish selectively in water using synthetic receptors.T od ate,t rimethyllysine (Kme3) is the only post translational modification (PTM) of the eight possible methylation states of Lysand Arg that can be recognized selectively.H ere,w er eport the first synthetic receptor capable of selectively recognizing asymmetric dimethylarginine (Rme2a). This was achieved by using ab iased dynamic combinatorial chemistry (DCC) library to generate ar eceptor mimicking the 5-sided box-like shape of Rme2 reader proteins,afeature that has been hypothesized to impart selectivity.A dditionally,w es ynthesized at hioether-linked analogue of the resulting receptor to provide an ovel scaffold with maintained selectivity but greater stability.T his work introduces strategies that can be applied towards achieving selectivity based on subtle differences in hydrophilic guests in aqueous solutions.

The methylation states of Lys and Arg represent a particularly challenging set of targets to distinguish selectively in water using synthetic receptors. To date, trimethyllysine (Kme3) is the only post translational modification (PTM) of the eight possible methylation states of Lys and Arg that can be recognized selectively. Here, we report the first synthetic receptor capable of selectively recognizing asymmetric dimethylarginine (Rme2a). This was achieved by using a biased dynamic combinatorial chemistry (DCC) library to generate a receptor mimicking the 5‐sided box‐like shape of Rme2 reader proteins, a feature that has been hypothesized to impart selectivity. Additionally, we synthesized a thioether‐linked analogue of the resulting receptor to provide a novel scaffold with maintained selectivity but greater stability. This work introduces strategies that can be applied towards achieving selectivity based on subtle differences in hydrophilic guests in aqueous solutions.