Mechanical bonding of rigid MORFs using a tetratopic rotaxane.

The preparation of highly rigid cobalt(II)- and copper(II)-organic frameworks incorporating a tetralactam [2]rotaxane as a ligand is described. The interlocked ligand is functionalized with two pairs of carboxylate groups placed at each counterpart, thus limiting its dynamics within the crystal. The solid structure of the metal-organic rotaxane frameworks showed different, unprecedented polycatenation modes of grids, depending on the employed metal, providing great rigidity to the structures. This rigidity has been evaluated by using single crystal X-ray diffraction analyses of the cobalt(II)-organic frameworks embedded in different solvents, observing that the lattices remain unchanged. Thus, this research demonstrates that rigid and robust materials with permanent porosity can be achieved using dynamic ligands.

Mechanically Planar-to-Point Chirality Transmission in [2]Rotaxanes.

Herein we describe an effective transmission of chirality, from mechanically planar chirality to point chirality, in hydrogen-bonded [2]rotaxanes. A highly selective mono-N-methylation of one (out of four) amide N atom at the macrocyclic counterpart of starting achiral rotaxanes generates mechanically planar chirality. Followed by chiral resolution, both enantiomers were subjected to a base-promoted intramolecular cyclization, where their interlocked threads were transformed into new lactam moieties. As a matter of fact, the mechanically planar chiral information was effectively transferred to the resulting stereocenters (covalent chirality) of the newly formed heterocycles. Upon removing the entwined macrocycle, the final lactams were obtained with high enantiopurity.

Modulating the shuttling motion of [2]rotaxanes built of p-xylylenediamine units through permethylation at the benzylic positions of the ring.

In this study, we show the effect of the gem-dimethyl substitution at the four benzylic carbons of the ring on the internal dynamics of two-station [2]rotaxanes. Such structural modification of the polyamide macrocycles promotes a drastic change of the internal dynamics as shown by variable-temperature (VT) 1H NMR experiments. We determined that the shuttling rates of the octamethylated macrocycle along a series of symmetrical threads were significantly faster compared to the non-substituted ring. This effect was particularly pronounced in the fumaramide-based system, in which the rate was 27 times faster than that of the model system.

Intramolecular Cyclization of Azido-Isocyanides Triggered by the Azide Anion: An Experimental and Computational Study.

This work describes the unprecedented intramolecular cyclization occurring in a set of α-azido-ω-isocyanides in the presence of catalytic amounts of sodium azide. These species yield the tricyclic cyanamides [1,2,3]triazolo[1,5-a]quinoxaline-5(4H)-carbonitriles, whereas in the presence of an excess of the same reagent, the azido-isocyanides convert into the respective C-substituted tetrazoles through a [3 + 2] cycloaddition between the cyano group of the intermediate cyanamides and the azide anion. The formation of tricyclic cyanamides has been examined by experimental and computational means. The computational study discloses the intermediacy of a long-lived N-cyanoamide anion, detected by NMR monitoring of the experiments, subsequently converting into the final cyanamide in the rate-determining step. The chemical behavior of these azido-isocyanides endowed with an aryl-triazolyl linker has been compared with that of a structurally identical azido-cyanide isomer, experiencing a conventional intramolecular [3 + 2] cycloaddition between its azido and cyanide functionalities. The synthetic procedures described herein constitute metal-free approaches to novel complex heterocyclic systems, such as [1,2,3]triazolo[1,5-a]quinoxalines and 9H-benzo[f]tetrazolo[1,5-d][1,2,3]triazolo[1,5-a][1,4]diazepines.

Control of the assembly of a cyclic hetero[4]pseudorotaxane from a self-complementary [2]rotaxane.

The synthesis of a ditopic interlocked building-block and its self-assembly into a cyclic dimer is reported herein. Starting from a thread with two recognition sites, a three-component clipping reaction was carried out to construct a bistable [2]rotaxane. A subsequent Suzuki cross-coupling reaction allowed the connection of a second ring to that of the rotaxane, affording a self-complementary ditopic system. NMR studies were carried out to identify a cyclic hetero[4]pseudorotaxane as the main supramolecular structure in solution. Its assembly is the result of a positive cooperativity operating in the hydrogen-bonding-driven assembly of this mechanically interlocked supramolecule, as revealed by computational studies. The increase of the polarity of the solvent allows the disruption of the intercomponent interactions and the disassembly of the hetero[4]pseudorotaxane into the two interlocked units. The disassembly of the cyclic dimer was also achieved through a Diels-Alder reaction over the fumaramide binding site of the thread, triggering the translational motion of the entwined macrocycle to an adjacent glycylglycine-based station and precluding the supramolecular dimerization. The competitive molecular recognition of a guest molecule by one of the self-templating counterparts of the dimer also led to the controlled disassembly of the hetero[4]pseudorotaxane.

Reactivity of Glutaconamides Within [2]Rotaxanes: Mechanical Bond Controlled Chemoselective Synthesis of Highly Reactive α-Ketoamides and their Light-Triggered Cyclization.

Glutaconamide-based [2]rotaxanes are efficiently oxidized to the respective interlocked α-ketoamides, whereas their non-interlocked threads afford hydroxycyclohexene tetraamides under similar reaction conditions. These results showcase the mechanically interlocking of highly reactive substrates as a powerful tool for controlling their chemical behavior. Inside the macrocycle and under irradiation with light, the α-ketoamide threads convert, in a divergent manner, into the corresponding interlocked hydroxy-ß-lactams or oxazolidinones by two modes of Norrish/Yang type-II intramolecular cyclizations, processes that are efficiently chemocontrolled by the mechanical bond.

Main Determinants Affecting the Antiproliferative Activity of Stilbenes and Their Gut Microbiota Metabolites in Colon Cancer Cells: A Structure-Activity Relationship Study.

trans-Resveratrol can be catabolized by the gut microbiota to dihydroresveratrol, 3,4'-dihydroxy-trans-stilbene, lunularin, and 4-hydroxydibenzyl. These metabolites can reach relevant concentrations in the colon. However, not all individuals metabolize RSV equally, as it depends on their RSV gut microbiota metabotype (i.e., lunularin producers vs. non-producers). However, how this microbial metabolism affects the cancer chemopreventive activity of stilbenes and their microbial metabolites is poorly known. We investigated the structure-antiproliferative activity relationship of dietary stilbenes, their gut microbial metabolites, and various analogs in human cancer (Caco-2 and HT-29) and non-tumorigenic (CCD18-Co) colon cells. The antiproliferative IC50 values of pterostilbene, oxy-resveratrol, piceatannol, resveratrol, dihydroresveratrol, lunularin, 3,4'-dihydroxy-trans-stilbene, pinosylvin, dihydropinosylvin, 4-hydroxy-trans-stilbene, 4-hydroxydibenzyl, 3-hydroxydibenzyl, and 4-trans-stilbenemethanol were calculated. IC50 values were correlated with 34 molecular characteristics by bi- and multivariate analysis. Little or no activity on CCD18-Co was observed, while Caco-2 was more sensitive than HT-29, which was explained by their different capacities to metabolize the compounds. Caco-2 IC50 values ranged from 11.4 ± 10.1 µM (4-hydroxy-trans-stilbene) to 73.9 ± 13.8 µM (dihydropinosylvin). In HT-29, the values ranged from 24.4 ± 11.3 µM (4-hydroxy-trans-stilbene) to 96.7 ± 6.7 µM (4-hydroxydibenzyl). At their IC50, most compounds induced apoptosis and arrested the cell cycle at the S phase, pterostilbene at G2/M, while 4-hydroxy-trans-stilbene and 3,4'-dihydroxy-trans-stilbene arrested at both phases. Higher Connolly values (larger size) hindered the antiproliferative activity, while a lower pKa1 enhanced the activity in Caco-2, and higher LogP values (more hydrophobicity) increased the activity in HT-29. Reducing the styrene double bond in stilbenes was the most critical feature in decreasing the antiproliferative activity. These results (i) suggest that gut microbiota metabolism determines the antiproliferative effects of dietary stilbenes. Therefore, RSV consumption might exert different effects in individuals depending on their gut microbiota metabotypes associated with RSV metabolism, and (ii) could help design customized drugs with a stilbenoid and (or) dibenzyl core against colorectal cancer.

Lunularin Producers versus Non-producers: Novel Human Metabotypes Associated with the Metabolism of Resveratrol by the Gut Microbiota.

We describe here for the first time the consistent observation of two metabotypes associated with resveratrol metabolism by the human gut microbiota, that is, lunularin (LUNU)-producers and LUNU non-producers. In healthy volunteers (n = 195), resveratrol was reduced to dihydroresveratrol, which only in the LUNU-producer metabotype was sequentially dehydroxylated at the 5-position to yield LUNU and the 3-position to produce 4-hydroxydibenzyl. These metabolites (also 3,4'-dihydroxy-trans-stilbene in some LUNU-producers) were detected in the urine and (or) feces of 74% of volunteers after consuming resveratrol, while 26% lacked these dehydroxylase activities. The LUNU non-producer metabotype was more prevalent in females (P < 0.05) but independent of individuals' BMI and age. A 4-styrylphenol reductase in both metabotypes converted stilbenes to their corresponding dibenzyls, while no 4-dehydroxylation in stilbenes or dibenzyls was observed. 4-Hydroxy-trans-stilbene, pinosylvin, dihydropinosylvin, 3-hydroxydibenzyl, and 3-hydroxy-trans-stilbene were not detected in vivo or in vitro. Further research on LUNU metabotypes, their associated gut microbiota, and their impact on health is worthwhile.

Ring-to-Thread Chirality Transfer in [2]Rotaxanes for the Synthesis of Enantioenriched Lactams.

The synthesis of chiral mechanically interlocked molecules has attracted a lot of attention in the last few years, with applications in different fields, such as asymmetric catalysis or sensing. Herein we describe the synthesis of orientational mechanostereoisomers, which include a benzylic amide macrocycle with a stereogenic center, and nonsymmetric N-(arylmethyl)fumaramides as the axis. The base-promoted cyclization of the initial fumaramide thread allows enantioenriched value-added compounds, such as lactams of different ring sizes and amino acids, to be obtained. The chiral information is effectively transmitted across the mechanical bond from the encircling ring to the interlocked lactam. High levels of enantioselectivity and full control of the regioselectivity of the final cyclic compounds are attained.

Mechanically interlocked molecules in metal-organic frameworks.

Mechanically interlocked molecules (MIMs) have great potential in the development of molecular machinery due to their intercomponent dynamics. The incorporation of these molecules in a condensed phase makes it possible to take advantage of the control of the motion of the components at the macroscopic level. Metal-organic frameworks (MOFs) are postulated as ideal supports for intertwined molecules. This review covers the chemistry of the mechanical bond incorporated into metal-organic frameworks from the seminal studies to the latest published advances. We first describe some fundamental concepts of MIMs and MOFs. Next, we summarize the advances in the incorporation of rotaxanes and catenanes inside MOF matrices. Finally, we conclude by showing the study of the rotaxane dynamics in MOFs and the operation of some stimuli-responsive MIMs within MOFs. In addition to emphasising some selected examples, we offer a critical opinion on the state of the art of this research field, remarking the key points on which the future of these systems should be focused.

Violations to the principle of least motion: the shortest path is not always the fastest.

The reaction between two molecules is usually envisioned as following a least-motion path with both molecules travelling minimum distances to meet each other. However, the reaction path of lowest activation energy is not only determined by practicality but mainly by the orbital symmetry of the involved reactants and the efficiency of their mutual interaction. The term non-least-motion was born to design those reactions in which reactants follow, in their route to products, pathways longer than those intuitively expected. In this review we summarize the theoretical and experimental studies that describe and rationalize reactions following non-least-motion paths, starting with the dimerizations of carbenes and followed by additional processes of these and other reactive species (silylenes, carbynes) such as insertions into single bonds and additions to π-bonds. Other examples involving less reactive partners are also included.

Mechanically Interlocked Profragrances for the Controlled Release of Scents.

The synthesis of a series of interlocked profragrances and the study of the controlled release of the corresponding scents are reported. The structures of the profragrances are based on a [2]pseudorotaxane scaffold with a fumaramate thread derived from perfumery alcohols and a tetrabenzylamido ring. The delivery of the scents was accomplished by sequential thermal dethreading and further enzymatic hydrolysis. Alternatively, the dethreading can be achieved by increasing the polarity of the solvent or photochemical isomerization. The temperature of dethreading can be modulated by the steric demand of the ends of the thread, which allows the selection of different precursor structures depending on the desired rates of delivery. The inputs and outputs for the controlled release of the interlocked profragrances correspond to those of YES or AND logic gates.

Unraveling the computed non-least motion pathway for the homodimerization of superchameleonic isocyanides: the peculiar nonsymmetrical (F-NC)2 reactant complex.

Isocyanides are commonly qualified as chameleonic compounds because of their reactions with both nucleophiles and electrophiles. In some instances, their chameleonic behavior changes to superchameleonic when they are involved in homodimerization processes, with the two initially identical isocyanide units adopting different roles along the reaction coordinate. We present here a detailed analysis of the computed non-least motion pathway that two isocyanides, the superchameleonic F-NC and, for the sake of comparison, the standard Me-NC, follow when reacting with themselves by comparing the evolution of a series of representative geometrical and electronic parameters along the respective reaction coordinates. This study shows that the two F-NC units are notoriously distinguishable from each other in all the parameters under scrutiny. Furthermore, we envisage that the superchameleonic character of F-NC seems to be most likely due to a minimal electrostatic interaction between the two entities at the earliest stage of the reaction. We also show that MeO-NC, MeS-NC and Me3P[double bond, length as m-dash]N-NC might be postulated as new examples of superchameleonic isocyanides.

Unmasking the elusive 1,4-diazabutatrienes: the stabilizing role of the N-substituents.

The geometrical and electronic properties of a representative set of diversely-substituted 1,4-diazabutatrienes are analyzed by theoretical and statistical methods. The influence of the substituents on the stabilization of these exotic azacumulenes has been estimated through a homodesmotic reaction and compared with related heterocumulenes. The 1,4-diazabutatrienes are stabilized by π-donor or σ-acceptor substituents and, in some cases, by the combination of one donor with one acceptor substituents at both N termini, a fact that might be associated with the ideally linear geometry of the heterocumulenic core for keeping the optimal orbital overlapping between its atoms.

In Search of 1,4-Diazabutatrienes, the Elusive Isocyanide Homodimers: The Superchameleonic F-NC.

Isocyanides might dimerize forming 1,4-diazabutatrienes, never isolated but eventually proposed as reaction intermediates. We herein disclose a computational study on the homo- and heterodimerization of isocyanides, in particular on the influence of the substituents onto the structural and energetics parameters of these processes. As a result, we have identified some reaction partners that are predicted to give stable 1,4-diazabutatrienes by surpassing low energy barriers. Of special significance is the homodimerization of F-NC, in which this species is revealed as an excellent acceptor and, quite surprisingly, also as a suitable donor.

Copper-Linked Rotaxanes for the Building of Photoresponsive Metal Organic Frameworks with Controlled Cargo Delivery.

We have prepared a photoresponsive metal-organic framework by using an amide-based [2]rotaxane as linker and copper(II) ions as metal nodes. The interlocked linker was obtained by the hydrogen bond-directed approach employing a fumaramide thread as template of the macrocyclic component, this latter incorporating two carboxyl groups. Single crystal X-ray diffraction analysis of the metal-organic framework, prepared under solvothermal conditions, showed the formation of stacked 2D rhombohedral grids forming channels decorated with the interlocked alkenyl threads. A series of metal-organic frameworks differing in the E/Z olefin ratio were prepared either by the previous isomerization of the linker or by postirradiation of the reticulated materials. By dynamic solid state 2H NMR measurements, using deuterium-labeled materials, we proved that the geometry of the olefinic axis of the interlocked struts determined the obtention of materials with different independent local dynamics as a result of the strength of the intercomponent noncovalent interactions. Moreover, the usefulness of these novel copper-rotaxane materials as molecular dosing containers has also been assayed by the diffusion and photorelease of p-benzoquinone, evaluated in different solvents and temperatures.

Lewis Acid-Mediated Formation of 1,3-Disubstituted Spiro[cyclopropane-1,2'-indanes]: The Activating Effect of the Cyclopropane Walsh Orbital.

By virtue of its alkylidenecyclopropane moiety, 2-(cyclopropylidenemethyl)benzaldehyde reacts with a range of amines and thiols under Lewis acid catalysis. These reactions yield 1,3-bis(arylamino) and 1,3-bis(arylthio and alkylthio)indanes, respectively, which are spirolinked to the cyclopropane ring at carbon 2. The reaction mechanism, and the peculiar contribution of the cyclopropane ring, have been scrutinized via DFT calculations.

Enhancing the selectivity of prolinamide organocatalysts using the mechanical bond in [2]rotaxanes.

The synthesis of a pair of switchable interlocked prolinamides and their use as organocatalysts in three different enamine-activated processes are reported. A diacylaminopyridine moiety was incorporated into the thread for directing [2]rotaxane formation further allowing the association of complementary small molecules. The rotaxane-based systems were tested as organocatalysts in asymmetric enamine-mediated processes, revealing a significantly improved catalytic ability if compared with the non-interlocked thread. The presence of an electron-withdrawing nitro group at the macrocycle helps to achieve high conversions and enantioselectivities. These systems are able to interact with N-hexylthymine as a cofactor to form supramolecular catalysts displaying a divergent catalytic behaviour. The presence or absence of the cofactor controls the chemoselectivity in competitive reactions.

Cyclization of interlocked fumaramides into ß-lactams: experimental and computational mechanistic assessment of the key intercomponent proton transfer and the stereocontrolling active pocket.

A detailed mechanistic study of the diastereoselective CsOH-promoted cyclization of interlocked fumaramides to give ß-lactams is described. The mechanistic analysis comprises the experimental evaluation of the structure-reactivity relationship for a wide range of fumaramides [2]rotaxanes (Hammet-plots), KIE studies with deuterium-labelled interlocked fumaramides and computational analysis of two alternative mechanistic pathways for the cyclization process. The obtained results confirm that: (a) the rate-determining step is the deprotonation of the N-benzyl group of the thread by the amidate group of the macrocycle generated by the external base, (b) the polyamide macrocycle plays an important role not only as activating element but also as the stereodifferenciating factor responsible for the observed diastereoselection and (c) the higher flexibility of the adamantyl core speeds up the cyclization process in diadamantyl-derived rotaxanes.

Interlocking the Catalyst: Thread versus Rotaxane-Mediated Enantiodivergent Michael Addition of Ketones to ß-Nitrostyrene.

Fumaramide threads bearing one l-prolinamide fragment have been designed as templates for promoting the efficient formation of novel Leigh's [2]rotaxanes. Both threads and rotaxanes are shown to catalyze the asymmetric addition of ketones to ß-nitrostyrene in an enantio- and diastereoselective manner. Interestingly, the enantioselective course of these processes is reversed simply by changing from thread to rotaxane as catalyst. DFT computations have allowed to rationalize the stereodivergence shown by the interlocked and noninterlocked catalysts.