Stephen M. Goldup

Sequence-Specific Peptide Synthesis by an Artificial Small-Molecule Machine

Ribosomal Rotaxane? The ribosome is an extraordinarily sophisticated molecular machine, assembling amino acids into proteins based on the precise sequence dictated by messenger RNA. Lewandowski et al. (p. 189) have now taken a step toward the preparation of a stripped-down synthetic ribosome analog. Their machine comprises a rotaxane—a ring threaded on a rod—in which the ring bears a pendant thiol that can pluck amino acids off the rod; the terminal nitrogen then wraps around to form a peptide bond and liberate the thiol for further reaction. The system was able to link three amino acids in order from the preassembled rod. A macrocycle threaded on a rod can catalytically insert several amino acids placed along its path into a peptide chain. 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 ~1018 molecular machines acting in parallel; this process generates milligram quantities of a peptide with a single sequence confirmed by tandem mass spectrometry.

Chemical consequences of mechanical bonding in catenanes and rotaxanes: isomerism, modification, catalysis and molecular machines for synthesis.

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.

A Chemically-Driven Molecular Information Ratchet

A chemically driven molecular information ratchet is described. The equilibrium macrocycle distribution in a [2]rotaxane is driven away from its 50:50 population of thread binding sites to a 33:67 ratio by benzoylation under the influence of a chiral catalyst. The reaction corresponds to a dynamic kinetic resolution of rotaxane co-conformers that interconvert through shuttling.

An autonomous chemically fuelled small-molecule motor

Molecular machines are among the most complex of all functional molecules and lie at the heart of nearly every biological process. A number of synthetic small-molecule machines have been developed, including molecular muscles, synthesizers, pumps, walkers, transporters and light-driven and electrically driven rotary motors. However, although biological molecular motors are powered by chemical gradients or the hydrolysis of adenosine triphosphate (ATP), so far there are no synthetic small-molecule motors that can operate autonomously using chemical energy (that is, the components move with net directionality as long as a chemical fuel is present). Here we describe a system in which a small molecular ring (macrocycle) is continuously transported directionally around a cyclic molecular track when powered by irreversible reactions of a chemical fuel, 9-fluorenylmethoxycarbonyl chloride. Key to the design is that the rate of reaction of this fuel with reactive sites on the cyclic track is faster when the macrocycle is far from the reactive site than when it is near to it. 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 9-fluorenylmethoxycarbonyl 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 in molecular nanotechnology.

An Unusual Nickel-Copper-Mediated Alkyne Homocoupling Reaction for the Active-Template Synthesis of [2]Rotaxanes

We report on an unusual Ni-/Cu-mediated alkyne homocoupling reaction, directed through the cavity of a bidentate macrocyclic ligand by chelated metal ions to furnish [2]rotaxanes in excellent (up to 95%) yields. This is the first active metal template reaction to employ an octahedral coordination geometry metal ion, Ni(II), and the study provides some interesting mechanistic insights into the mixed bimetallic reaction mechanism. The mixed-metal catalyst system was discovered serendipitously when Cu(I) was added to a Ni(II)-catalyzed alkyne homocoupling reaction in an attempt to facilitate chloride-acetylide ligand exchange. The role of Cu(I) in the reaction is, in fact, quite different from that originally intended. The effectiveness of having both nickel and copper present can be rationalized by the nature of a pi-activated, sigma-bonded, bimetallic intermediate in which the substitution of Ni(II) for one Cu(I) ion in the classic bimetallic Glaser reaction mechanism apparently aids reductive elimination of the acetylide ligands. The system may prove useful for the development of general mixed-metal protocols for catalytic alkyne coupling reactions as well as being a highly effective route to rotaxanes with bis-acetylene threads, which are potentially useful for materials applications (insulated molecular wires) and in molecular machines (rigid, nonfolding axles).

Active-Metal Template Synthesis of a Molecular Trefoil Knot

Tying the knot: The marriage of catalysis and coordination chemistry enables two CuI ions (red; see picture) to work in partnership for the synthesis of a molecular trefoil knot. One ion entangles an acyclic building block to create a loop in the ligand, and the other gathers the ligands reactive end-groups, threads the loop, and catalyzes the covalent capture of the knotted architecture by an alkyne–azide “click” reaction.

A three-compartment chemically-driven molecular information ratchet

We describe a three-compartment rotaxane information ratchet in which the macrocycle can be directionally transported in either direction along an achiral (disregarding isotopic labeling) track. Chiral DMAP-based catalysts promote a benzoylation reaction that ratchets the displacement of the macrocycle, transporting it predominantly to a particular end compartment determined by the handedness of the catalyst.

Macrocycle Size Matters: “Small” Functionalized Rotaxanes in Excellent Yield Using the CuAAC Active Template Approach

By shrinking the macrocycle in the CuAAC active template reaction not only is it demonstrated to be possible to use smaller macrocycles, but, surprisingly, that smaller macrocycles lead to higher yields of rotaxane product. The synthesis of “small” functionalized [2]rotaxanes showcases this as a method for the production of materials with potential applications in molecular electronics, drug delivery, sensing, and enantioselective catalysis.

Cadiot–Chodkiewicz Active Template Synthesis of Rotaxanes and Switchable Molecular Shuttles with Weak Intercomponent Interactions

Weak interaction, switchable, rotaxane-based molecular shuttles, in which the positional fidelity of the macrocycle is conferred by a single hydrogen bond in each state, are constructed through the high-yielding and selective active template heterocoupling of different functionalized alkynes using the Cadiot–Chodkiewicz reaction

An efficient approach to mechanically planar chiral rotaxanes.

We describe the first method for production of mechanically planar chiral rotaxanes in excellent enantiopurity without the use of chiral separation techniques and, for the first time, unambiguously assign the absolute stereochemistry of the products. This proof-of-concept study, which employs a chiral pool sugar as the source of asymmetry and a high-yielding active template reaction for mechanical bond formation, finally opens the door to detailed investigation of these challenging targets.