Synthesis of Reversible Sequence-Defined Oligourethane Macrocycles through Click and Declick Thiol-Amine Conjugation with a Meldrum’s Acid-Derived Conjugate Acceptor

Sequence-defined polymers are linear macromolecules whose exact sequence of monomers is both known and precisely controlled with a polydispersity of one. Sequence-defined oligourethanes can be generated in an automated fashion, and the sequence of unknown oligomers can be read back by monitoring a chain end 5-exo-trig cyclization reaction over time via LC-MS. In this work, we demonstrate the ability to reversibly cyclize sequence-defined oligourethanes with a Meldrum's acid-derived conjugate acceptor to generate abiotic sequence-defined macrocycles. By precisely controlling the position and orientation of a functional group around the binding pocket of these macrocycles, a library of abiotic macrocycles of differing sequences and sizes was generated with strings of alanine and phenylalanine side chains. Furthermore, we demonstrate that the cyclization of these compounds can be reversed by "declicking" the conjugate acceptor upon exposure to dithiothreitol, regenerating the original unscathed linear oligourethane for sequencing if desired. Conformational landscapes derived from molecular dynamics simulations of the macrocycles revealed trends in hydrogen bond network, compaction, and heterogeneity in free energy landscapes. We herein report the synthesis and modeling of sequence-defined oligourethane macrocycles paired with "declicking" of the macrocyclization linker to regenerate unscathed linear oligourethanes─a step toward sequenceable sequence-defined macrocycles for supramolecular chemistry purposes.