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.

We find that a bulky pyridine-based catalyst promotes carbonate-forming reactions that ratchet the displacement of the macrocycle away from the reactive sites on the track. Under reaction conditions where both attachment and cleavage of the Fmoc groups occur through different processes, and the cleavage reaction occurs at a rate independent of macrocycle location, net directional rotation of the molecular motor continues for as long as unreacted fuel remains. We anticipate that autonomous chemically-fuelled molecular motors will find application as engines for molecular nanotechnology. 2, 19,20

Active metal template synthesis is a powerful new strategy for the construction of rotaxanes, catenanes and other mechanically interlocked molecular structures. The key feature is that the metal plays a dual role during the assembly of the interlocked architecture, acting as both a template for entwining or threading the components and as a catalyst for capturing the interlocked final product by covalent bond formation. Unlike traditional "passive" metal template methods to rotaxanes and catenanes, permanent recognition motifs are not required on each of the components to be interlocked (i.e., the assembly can be traceless) and the template can often be used in sub-stoichiometric quantities. Since its inception in 2006, a rapidly growing number of different metal-catalysed reactions have proven suitable for the active metal template synthesis of both rotaxanes and catenanes, including the copper(i)-catalysed terminal alkyne-azide cycloaddition (the CuAAC "click" reaction), palladium- and copper-catalysed alkyne homocouplings and heterocouplings, and palladium-catalysed oxidative Heck couplings and Michael additions. In addition to simple rotaxanes and catenanes, the synthetic strategy has been used to construct switchable molecular shuttles with weak intercomponent interactions (a requirement for fast shuttling) and to provide insight into the mechanisms of transition metal-catalysed reactions. In this tutorial review we highlight the utility and potential of the early examples of the active metal template strategy in mechanically interlocked molecule synthesis.

We discuss the stereogenic units that have been investigated in interlocked molecules, their application, absolute stereochemistry and propose future directions.

A synthetic approach to rotaxane architectures is described in which metal atoms catalyze covalent bond formation while simultaneously acting as the template for the assembly of the mechanically interlocked structure. This "active-metal" template strategy is exemplified using the Huisgen-Meldal-Fokin Cu(I)-catalyzed 1,3-cycloaddition of azides with terminal alkynes (the CuAAC "click" reaction). Coordination of Cu(I) to an endotopic pyridine-containing macrocycle allows the alkyne and azide to bind to metal atoms in such a way that the metal-mediated bond-forming reaction takes place through the cavity of the macrocycle--or macrocycles--forming a rotaxane. A variety of mono- and bidentate macrocyclic ligands are demonstrated to form [2]rotaxanes in this way, and by adding pyridine, the metal can turn over during the reaction, giving a catalytic active-metal template assembly process. Both the stoichiometric and catalytic versions of the reaction were also used to synthesize more complex two-station molecular shuttles. The dynamics of the translocation of the macrocycle by ligand exchange in these two-station shuttles could be controlled by coordination to different metal ions (rapid shuttling is observed with Cu(I), slow shuttling with Pd(II)). Under active-metal template reaction conditions that feature a high macrocycle:copper ratio, [3]rotaxanes (two macrocycles on a thread containing a single triazole ring) are also produced during the reaction. The latter observation shows that under these conditions the mechanism of the Cu(I)-catalyzed terminal alkyne-azide cycloaddition involves a reactive intermediate that features at least two metal ions.

Research on mechanically interlocked molecules has advanced substantially over the last five decades. A large proportion of the published work focusses on the synthesis of these challenging targets, and the subsequent control of the relative position of the covalent sub-components, to generate novel molecular devices and machines. In this Feature Article we instead review some of the less discussed consequences of mechanical bonding for the chemical behaviour of catenanes and rotaxanes, and their application in synthesis, including striking recent examples of molecular machines which carry out complex synthetic tasks.

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