The ribosome builds proteins by joining together amino acids in an order determined by messenger RNA. Here, we report on the design, synthesis, and operation of an artificial small-molecule machine that travels along a molecular strand, picking up amino acids that block its path, to synthesize a peptide in a sequence-specific manner. The chemical structure is based on a rotaxane, a molecular ring threaded onto a molecular axle. The ring carries a thiolate group that iteratively removes amino acids in order from the strand and transfers them to a peptide-elongation site through native chemical ligation. The synthesis is demonstrated with ~10(18) molecular machines acting in parallel; this process generates milligram quantities of a peptide with a single sequence confirmed by tandem mass spectrometry.

The first crystal structure of an oligoproline adopting an all-trans polyproline II (PPII) helix is presented. The high-resolution structure provides detailed insight into the dimensions and conformational properties of oligoprolines that are important for, e.g., their use as "molecular rulers" and "molecular scaffolds". The structure also showed that the amides interact with each other within a PPII helix and that water is not necessary for PPII helicity.

Switch it on! The activity of an organocatalytic group incorporated within a rotaxane architecture can be controlled by switching the position of the macrocycle. The system was used to mediate the progress of the Michael addition of an aliphatic thiol to trans‐cinnamaldehyde.

We report on an improved strategy for the preparation of artificial molecular machines that can pick up and assemble reactive groups in sequence by traveling along a track. In the new approach a preformed rotaxane synthon is attached to the end of an otherwise fully formed strand of building blocks. This "rotaxane-capping" protocol is significantly more efficient than the "final-step-threading" method employed previously and enables the synthesis of threaded molecular machines that operate on extended oligomer, and potentially polymer, tracks. The methodology is exemplified through the preparation of a machine that adds four amino acid building blocks from a strand in sequence, featuring up to 20-membered ring native chemical ligation transition states.

The activation mode of a rotaxane-based organocatalyst with both secondary amine and squaramide catalytic units can be switched with acid or base, affording different products from a mixture of three building blocks.

The reactivity of a rotaxane that acts as an aminocatalyst for the functionalization of carbonyl compounds through HOMO and LUMO activation pathways has been studied. Its catalytic activity is explored for C-C and C-S bond forming reactions through iminium catalysis, in nucleophilic substitutions and additions through enamine intermediates, in Diels-Alder reactions via trienamine catalysis, and in a tandem iminium-ion/enamine reaction. The catalyst can be switched "on" or "off", effectively controlling the rate of all of these chemical transformations, by the in situ change of the position of the macrocycle between two different binding sites on the rotaxane thread.

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