Kinetic Selection in the Out‐of‐Equilibrium Autocatalytic Reaction Networks that Produce Macrocyclic Peptides

Autocatalytic reaction networks are instrumental for validating scenarios for the emergence of life on Earth and for synthesizing life de novo. Here, we demonstrate that dimeric thioesters of tripeptides with the general structure (Cys‐Xxx‐Gly‐SEt)2 form strongly interconnected autocatalytic reaction networks that predominantly generate macrocyclic peptides up to 69 amino acids long. Some macrocycles of 6–12 amino acids were isolated from the product pool and were characterized by NMR spectroscopy and single‐crystal X‐ray analysis. We studied the autocatalytic formation of macrocycles in a flow reactor in the presence of acrylamide, whose conjugate addition to thiols served as a model “removal” reaction. These results indicate that even not template‐assisted autocatalytic production combined with competing removal of molecular species in an open compartment could be a feasible route for selecting functional molecules during the pre‐Darwinian stages of molecular evolution. A chemical system is presented where polymerization of peptide monomers results in predominantly macrocyclic oligomers. Using this system, we make a clear demonstration of how the combination of autocatalysis, diversity of products, and out‐of‐equilibrium conditions results in the selection of complex products.