Switched "On" Transient Fluorescence Output from a Pulsed-Fuel Molecular Ratchet.

We report the synthesis and operation of a molecular energy ratchet that transports a crown ether from solution onto a thread, along the axle, over a fluorophore, and off the other end of the thread back into bulk solution, all in response to a single pulse of a chemical fuel (CClCOH). The fluorophore is a pyrene residue whose fluorescence is normally prevented by photoinduced electron transfer (PET) to a nearby -methyltriazolium group. However, crown ether binding to the -methyltriazolium site inhibits the PET, switching on pyrene fluorescence under UV irradiation.

In Search of Wasserman's Catenane.

We repeat the earliest claimed [2]catenane synthesis, reported by Wasserman over 60 years ago, in order to ascertain whether or not a nontemplate, statistical synthesis by acyloin macrocyclization does indeed form mechanically interlocked rings. The lack of direct experimental evidence for Wasserman's catenane has led to it being described as a "prophetic compound", a technical term used in patents for claimed molecules that have not yet been synthesized. Contemporary synthetic methods were used to reconstruct Wasserman's deuterium-labeled macrocycle and other building blocks on the 10-100 g reaction scale necessary to generate, in principle, ∼1 mg of catenane.

Pumping between phases with a pulsed-fuel molecular ratchet.

The sorption of species from a solution into and onto solids underpins the sequestering of waste and pollutants, precious metal recovery, heterogeneous catalysis, analysis and separation science, and other technologies. The transfer between phases tends to proceed spontaneously in the direction of equilibrium. For example, alkyl ammonium groups mounted on silica nanoparticles are used to chemisorb cucurbituril macrocycles from solution through host-guest binding.

Site-to-site peptide transport on a molecular platform using a small-molecule robotic arm.

Peptides attached to a cysteine hydrazide 'transporter module' are transported selectively in either direction between two chemically similar sites on a molecular platform, enabled by the discovery of new operating methods for a molecular transporter that functions through ratcheting. Substrate repositioning is achieved using a small-molecule robotic arm controlled by a protonation-mediated rotary switch and attachment/release dynamic covalent chemistry. A polar solvent mixtures were found to favour to isomerization of the doubly-protonated switch, transporting cargo in one direction (arbitrarily defined as 'forward') in up to 85% yield, while polar solvent mixtures were unexpectedly found to favour to isomerization enabling transport in the reverse ('backward') direction in >98% yield.

Sequence-Selective Decapeptide Synthesis by the Parallel Operation of Two Artificial Molecular Machines.

We report on the preparation of a decapeptide through the parallel operation of two rotaxane-based molecular machines. The synthesis proceeds in four stages: (1) simultaneous operation of two molecular peptide synthesizers in the same reaction vessel; (2) selective residue activation of short-oligomer intermediates; (3) ligation; (4) product release. Key features of the machine design include the following: (a) selective transformation of a thioproline building block to a cysteine (once it has been incorporated into a hexapeptide intermediate by one molecular machine); (b) a macrocycle-peptide hydrazine linkage (as part of the second machine) to differentiate the intermediates and enable their directional ligation; and (c) incorporation of a Glu residue in the assembly module of one machine to enable release of the final product while simultaneously removing part of the assembly machinery from the product.

Active template rotaxane synthesis through the Ni-catalyzed cross-coupling of alkylzinc reagents with redox-active esters.

The synthesis of unsymmetrical axle [2]rotaxanes through a recently developed Ni-catalyzed C(sp)-C(sp) cross-coupling of redox-active esters (formed directly from carboxylic acids) and organozinc reagents (derived from alkyl bromides) is reported. The method also furnishes, as a minor product, the symmetrical axle [2]rotaxanes resulting from the homo-coupling of the organozinc half-thread. The rotaxanes are formed in up to 56% yield with the ratio of unsymmetrical rotaxane increasing with the cavity size of the macrocycle.

Securing a Supramolecular Architecture by Tying a Stopper Knot.

We report on a rotaxane-like architecture secured by the in situ tying of an overhand knot in the tris(2,6-pyridyldicarboxamide) region of the axle through complexation with a lanthanide ion (Lu ). The increase in steric bulk caused by the knotting locks a crown ether onto the thread. Removal of the lutetium ion unties the knot, and when the axle binding site for the ring is deactivated, the macrocycle spontaneously dethreads.

Rotary and linear molecular motors driven by pulses of a chemical fuel.

Many biomolecular motors catalyze the hydrolysis of chemical fuels, such as adenosine triphosphate, and use the energy released to direct motion through information ratchet mechanisms. Here we describe chemically-driven artificial rotary and linear molecular motors that operate through a fundamentally different type of mechanism. The directional rotation of [2]- and [3]catenane rotary molecular motors and the transport of substrates away from equilibrium by a linear molecular pump are induced by acid-base oscillations.

Sequence-Specific β-Peptide Synthesis by a Rotaxane-Based Molecular Machine.

We report on the synthesis and operation of a three-barrier, rotaxane-based, artificial molecular machine capable of sequence-specific β-homo (β) peptide synthesis. The machine utilizes nonproteinogenic β-amino acids, a class of amino acids not generally accepted by the ribosome, particularly consecutively. Successful operation of the machine via native chemical ligation (NCL) demonstrates that even challenging 15- and 19-membered ligation transition states are suitable for information translation using this artificial molecular machine.

The synthesis and biological evaluation of a kabiramide C fragment modified with a WH2 consensus actin-binding motif as a potential disruptor of the actin cytoskeleton.

The F-actin depolymerisation potency of a fragment of kabiramide C was increased when modified with a WH2 consensus actin-binding motif LKKV. Despite its low affinity for actin monomers, a shorter analogous fragment not bearing LKKV was identified as a potent inhibitor of actin polymerisation and a promoter of its depolymerisation, resulting in a loss of actin stress fibres in cells.

Diastereoselective carbocyclization of 1,6-heptadienes triggered by rhodium-catalyzed activation of an olefinic C-H bond.

The use of α,ω-dienes as functionalization reagents for olefinic carbon-hydrogen bonds has been rarely studied. Reported herein is the rhodium(I)-catalyzed rearrangement of prochiral 1,6-heptadienes into [2,2,1]-cycloheptane derivatives with concomitant creation of at least three stereogenic centers and complete diastereocontrol. Deuterium-labeling studies and the isolation of a key intermediate are consistent with a group-directed C-H bond activation, followed by two consecutive migratory insertions, with only the latter step being diastereoselective.

Multiple rhodium-catalyzed cleavages of single C-C bonds.

The Rh(I)-catalyzed intramolecular hydroacylation of cis and trans asymmetrically substituted alkylidenecyclobutanes proceeds according to three mechanistic pathways. As shown by deuterium-labeling experiments, the mechanism accounting for the rearrangement of the cis isomers includes the cleavage of three carbon-carbon bonds and a remarkable transannular 3-exo-trig carbometalation.

Reversible aryl migrations in metallated ureas: controlled inversion of configuration at a quaternary carbon atom.

Deprotonation with strong bases of N-vinyl ureas carrying an N'-aryl substituent leads to migration of the N'-aryl group from N to C via an allyllithium; with weaker bases and electron-deficient aryl rings the direction of the migration reverses, and aryl substituents α to the urea N atom may migrate from C to N.

Quaternary centres bearing nitrogen (α-tertiary amines) as products of molecular rearrangements.

Quaternary centres bearing a nitrogen substituent (α-tertiary amines and their derivatives) are found in a variety of bioactive molecules but pose a major challenge in synthesis, particularly when enantiomeric purity is required. Approaches comparable to those used for tertiary alcohols are typically hampered by the poor electrophilicity of imines, requiring powerful nucleophiles that may also act as bases. A set of powerful alternative approaches make use of the rearrangement of readily available precursors, often (but not always) with formation of a new tertiary carbon to nitrogen bond.

Geometry-selective synthesis of E or Z N-vinyl ureas (N-carbamoyl enamines).

N-Vinyl ureas are emerging as a valuable class of compounds with both nucleophilic and electrophilic reactivity. They may be made by capturing the enamine tautomer of an imine with an isocyanate, a reaction which in general leads to the E isomer of the vinyl urea. Deprotonation of such a vinyl urea, or of an allyl urea, generates a dipole stabilized Z-allyl anion which may be protonated to return the Z-vinyl urea.

Sequential double α-arylation of N-allylureas by asymmetric deprotonation and N→C aryl migration.

On lithiation with lithium amides, N-allyl-N'-aryl ureas undergo rearrangement with transfer of the aryl ring from N to the allylic α carbon. From the α-arylated products, a further aryl transfer under the influence of a chiral lithium amide allows the enantioselective construction of 1,1-diarylallylamine derivatives. Stereoselectivity in these reactions results from the enantioselective formation of a planar chiral allyllithium under kinetic control.

Tandem beta-alkylation-alpha-arylation of amines by carbolithiation and rearrangement of N-carbamoyl enamines (vinyl ureas).

Organolithiums add in an umpolung fashion to the beta-carbon of N-carbamoyl enamines (N-vinyl ureas). The reaction proceeds with syn diastereospecificity and provides urea-stabilized, configurationally defined organolithiums. Facilitated by coordinating solvents (THF or DMPU), these undergo intramolecular attack on an N'-aryl group, resulting in retentive arylation of the organolithium and hence overall addition of an alkyl or aryl group to both carbon atoms of the urea-substituted alkene.

N to C aryl migration in lithiated carbamates: alpha-arylation of benzylic alcohols.

We report a new mode of reactivity displayed by lithiated O-benzyl carbamates carrying an N-aryl substituent: upon lithiation, the N-aryl group is transferred cleanly from N to C. An arylation of the carbamate results, providing a route to alpha,alpha-arylated secondary or tertiary alcohols. We also report density functional theory calculations supporting the proposal that arylation proceeds through a dearomatizing attack on the aromatic ring, a significantly lower energy pathway than the 1,2-acyl transfer observed with related N-alkyl carbamates.