Jose Berna

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

Azodicarboxamides as template binding motifs for the building of hydrogen-bonded molecular shuttles.

Azodicarboxamides (R(2)NCON=NCONR(2)) are shown to act as new templates for the assembly of unprecedented azo-functionalized hydrogen-bond-assembled [2]rotaxanes. Moreover, these binding sites can be reversibly and efficiently interconverted with their hydrazo forms through a hydrogenation-dehydrogenation strategy of the nitrogen-nitrogen bond. This novel chemically switchable control element has been implemented in stimuli-responsive molecular shuttles that work through a reversible azo/hydrazo interconversion, producing large amplitude net positional changes with a good discrimination between the binding sites of the macrocycle in both states of the shuttle. These molecular shuttles are able to operate by two different mechanisms: in a discrete mode through two reversible and independent chemical events and, importantly, in a continuous regime through a catalyzed ester bond formation reaction in which the shuttle acts as an organocatalyst. In this latter, the incorporation of both states of the shuttle into this simple chemical reaction network promotes a dynamic translocation of the macrocycle between two nitrogen and carbon-based stations of the thread allowing an energetically uphill esterification process to take place.

Comparative inhibitory activity of the stilbenes resveratrol and oxyresveratrol on African swine fever virus replication

Stilbenols are polyphenolic phytoalexins produced by plants in response to biotic or abiotic stress. These compounds have received much attention because of their significant biological effects. One of these is their antiviral action, which has previously been documented for two members of this class, namely resveratrol and oxyresveratrol. Here we tested the antiviral effect of these two compounds on African swine fever virus, the only member of the newly created family Asfarviridae and a serious limitation to porcine production worldwide. Our results show a potent, dose-dependent antiviral effect of resveratrol and oxyresveratrol in vitro. Interestingly, this antiviral activity was found for these synthetic compounds and also for oxyresveratrol extracted from new natural sources (mulberry twigs). The antiviral effect of these two drugs was demonstrated at concentrations that do not induce cytotoxicity in cultured cells. Moreover, these antivirals achieved a 98-100% reduction in viral titers. Both compounds allowed early protein synthesis but inhibited viral DNA replication, late viral protein synthesis and viral factory formation.

Amide-based molecular shuttles (2001-2006)*

Stimuli-responsive molecular shuttles are rotaxanes in which the macrocycle can be translocated from one position on the thread to a second site in response to an external trigger. Here, we present a brief overview of the contributions of the Leigh group to the field from 2001 to 2006. In this short period of time, molecular shuttles have moved from little more than laboratory curiosities to truly functional molecular machines.

Small-molecule recognition for controlling molecular motion in hydrogen-bond-assembled rotaxanes.

Di(acylamino)pyridines successfully template the formation of hydrogen-bonded rotaxanes through five-component clipping reactions. A solid-state study showed the participation of the pyridine nitrogen atom in the stabilization of the mechanical bond between the thread and the benzylic amide macrocycle. The addition of external complementary binders to a series of interlocked bis(2,6-di(acylamino)pyridines) promoted restraint of the back and forward ring motion. The original translation can be restored through a competitive recognition event by the addition of a preorganized bis(di(acylamino)pyridine) that forms stronger ADA-DAD complexes with the external binders.

Tripod–Tripod Coupling of Triazides with Triphosphanes. The Synthesis, Characterization, and Stability in Solution of New Cage Compounds: Chiral Macrobicyclic Triphosphazides

Rare intracyclic PN3 units of Z configuration are present in the three arms of the unprecedented, rigid macrobicycles of propellerlike topology (1) formed by self-assembly of triazides and CH3C(CH2PPh2)3 (triphos).

Stereocontrolled Synthesis of β-Lactams within [2]Rotaxanes: Showcasing the Chemical Consequences of the Mechanical Bond

The intramolecular cyclization of N-benzylfumaramide [2]rotaxanes is described. The mechanical bond of these substrates activates this transformation to proceed in high yields and in a regio- and diastereoselective manner, giving interlocked 3,4-disubstituted trans-azetidin-2-ones. This activation effect markedly differs from the more common shielding protection of threaded functions by the macrocycle, in this case promoting an unusual and disfavored 4-exo-trig ring closure. Kinetic and synthetic studies allowed us to delineate an advantageous approach toward β-lactams based on a two-step, one-pot protocol: an intramolecular ring closure followed by a thermally induced dethreading step. The advantages of carrying out this cyclization in the confined space of a benzylic amide macrocycle are attributed to its anchimeric assistance.

Hydroxylation of p-substituted phenols by tyrosinase: Further insight into the mechanism of tyrosinase activity

A study of the monophenolase activity of tyrosinase by measuring the steady state rate with a group of p-substituted monophenols provides the following kinetic information: k(cat)(m) and the Michaelis constant, K(M)(m). Analysis of these data taking into account chemical shifts of the carbon atom supporting the hydroxyl group (δ) and σ(p)(+), enables a mechanism to be proposed for the transformation of monophenols into o-diphenols, in which the first step is a nucleophilic attack on the copper atom on the form E(ox) (attack of the oxygen of the hydroxyl group of C-1 on the copper atom) followed by an electrophilic attack (attack of the hydroperoxide group on the ortho position with respect to the hydroxyl group of the benzene ring, electrophilic aromatic substitution with a reaction constant ρ of -1.75). These steps show the same dependency on the electronic effect of the substituent groups in C-4. Furthermore, a study of a solvent deuterium isotope effect on the oxidation of monophenols by tyrosinase points to an appreciable isotopic effect. In a proton inventory study with a series of p-substituted phenols, the representation of [Formula: see text] / [Formula: see text] against n (atom fractions of deuterium), where [Formula: see text] is the catalytic constant for a molar fraction of deuterium (n) and [Formula: see text] is the corresponding kinetic parameter in a water solution, was linear for all substrates. These results indicate that only one of the proton transfer processes from the hydroxyl groups involved the catalytic cycle is responsible for the isotope effects. We suggest that this step is the proton transfer from the hydroxyl group of C-1 to the peroxide of the oxytyrosinase form (E(ox)). After the nucleophilic attack, the incorporation of the oxygen in the benzene ring occurs by means of an electrophilic aromatic substitution mechanism in which there is no isotopic effect.

Redox divergent conversion of a [2]rotaxane into two distinct degenerate partners with different shuttling dynamics

The submolecular translational movement in novel hydrogen-bonded [2]rotaxanes containing benzylic amide macrocycles and two azo/hydrazodicarboxamide binding sites was analyzed by dynamic NMR spectroscopy. The results show that the activation free energies of the macrocycle shuttling in these systems depend on the oxidation level of both nitrogen-based binding sites embedded in the thread; the shuttling motion being more rapid in [2]rotaxanes at the lower oxidation level bis(hydrazo)-based rotaxanes. Moreover, by means of a fully controllable chemical switching, these two-station [2]rotaxanes are able to swap over three different dynamic states, which differ in macrocycle shuttling velocity: a) faster in a bis(hydrazo) [2]rotaxane, the lower oxidation state; b) moderate in a bis(azo) [2]rotaxane, the higher oxidation state; and c) practically stopped at the azodicarboxamide station of an azo/hydrazo [2]rotaxane, the intermediate oxidation state. Thus, from this latter resting state, two “fans” of different velocity can be turned on and off by simple chemical redox processes.

Dampened circumrotation by CH···π interactions in hydrogen bonded [2]rotaxanes.

Establishment of CH···π interactions between the aliphatic axis and the benzylic amide macrocycle of hydrogen-bonded [2]rotaxanes causes a measurable interference in the pirouetting submolecular motion of these interlocked molecules.