Epidemiology of injuries at the 2023 UCI cycling world championships using the International Olympic Consensus: a protocol for a prospective cohort study.

The sport of cycling consists of several individual sporting disciplines. Indeed, the world governing body for cycling, Union Cycliste Internationale (UCI), oversees the various cycling disciplines, with each of these disciplines having a number of subcategories. While several sports have undertaken prospective injury surveillance studies to understand the risks of their sport, plan event medical support and develop prevention programmes, limited high-quality studies have been undertaken within cycling. Indeed, this is the first prospective study of cycling injuries, particularly when considering the whole sport of cycling together. This current study will therefore aim to describe the incidence, severity, burden and nature of injuries within elite cycling in those athletes participating across 13 championship events at the inaugural World Championships, Glasgow, August 2023. Injury and exposure definitions will be in line with the IOC Consensus for injury surveillance in cycling. Injury incidence will be reported per 1000 athlete match hours or per number of athletes/cyclists and injury severity will be assessed via estimated median or mean days lost to training/competition. Meanwhile injury burden will be assessed via days of absence/1000 athlete match hours (or per number of athletes exposed) and all these results will be compared between male and female cyclists. This paper will also report the most common specific injuries for male and female cyclists (per 1000 hours of participation or per number of athletes exposed). Statistical differences will be tested for incidence or severity measures between sexes and will be compared to other sports.

Controlling piezoresistance in single molecules through the isomerisation of bullvalenes.

Nanoscale electro-mechanical systems (NEMS) displaying piezoresistance offer unique measurement opportunities at the sub-cellular level, in detectors and sensors, and in emerging generations of integrated electronic devices. Here, we show a single-molecule NEMS piezoresistor that operates utilising constitutional and conformational isomerisation of individual diaryl-bullvalene molecules and can be switched at 850 Hz. Observations are made using scanning tunnelling microscopy break junction (STMBJ) techniques to characterise piezoresistance, combined with blinking (current-time) experiments that follow single-molecule reactions in real time. A kinetic Monte Carlo methodology (KMC) is developed to simulate isomerisation on the experimental timescale, parameterised using density-functional theory (DFT) combined with non-equilibrium Green's function (NEGF) calculations. Results indicate that piezoresistance is controlled by both constitutional and conformational isomerisation, occurring at rates that are either fast (equilibrium) or slow (non-equilibrium) compared to the experimental timescale. Two different types of STMBJ traces are observed, one typical of traditional experiments that are interpreted in terms of intramolecular isomerisation occurring on stable tipped-shaped metal-contact junctions, and another attributed to arise from junction‒interface restructuring induced by bullvalene isomerisation.

Ethene-1,1-disulfonyl Difluoride (EDSF) for SuFEx Click Chemistry: Synthesis of SuFExable 1,1-Bissulfonylfluoride Substituted Cyclobutene Hubs.

We present the synthesis of 1,1-bis(fluorosulfonyl)-2-(pyridin-1-ium-1-yl)ethan-1-ide, a bench-stable precursor to ethene-1,1-disulfonyl difluoride (EDSF). The novel SuFEx reagent, EDSF, is demonstrated in the preparation of 26 unique 1,1-bissulfonylfluoride substituted cyclobutenes via a cycloaddition reaction. The regioselective click cycloaddition reaction is rapid, straightforward, and highly efficient, enabling the generation of highly functionalized 4-membered ring (4MR) carbocycles. These carbocycles are valuable structural motifs found in numerous bioactive natural products and pharmaceutically relevant small molecules. Additionally, we showcase diversification of the novel cyclobutene cores through selective Cs2 CO3 -activated SuFEx click chemistry between a single S-F group and an aryl alcohol, yielding the corresponding sulfonate ester products with high efficiency. Finally, density functional theory calculations offer mechanistic insights about the reaction pathway.

Shapeshifting bullvalene-linked vancomycin dimers as effective antibiotics against multidrug-resistant gram-positive bacteria.

The alarming rise in superbugs that are resistant to drugs of last resort, including vancomycin-resistant enterococci and staphylococci, has become a significant global health hazard. Here, we report the click chemistry synthesis of an unprecedented class of shapeshifting vancomycin dimers (SVDs) that display potent activity against bacteria that are resistant to the parent drug, including the ESKAPE pathogens, vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-resistant S. aureus (VRSA). The shapeshifting modality of the dimers is powered by a triazole-linked bullvalene core, exploiting the dynamic covalent rearrangements of the fluxional carbon cage and creating ligands with the capacity to inhibit bacterial cell wall biosynthesis. The new shapeshifting antibiotics are not disadvantaged by the common mechanism of vancomycin resistance resulting from the alteration of the C-terminal dipeptide with the corresponding d-Ala-d-Lac depsipeptide. Further, evidence suggests that the shapeshifting ligands destabilize the complex formed between the flippase MurJ and lipid II, implying the potential for a new mode of action for polyvalent glycopeptides. The SVDs show little propensity for acquired resistance by enterococci, suggesting that this new class of shapeshifting antibiotic will display durable antimicrobial activity not prone to rapidly acquired clinical resistance.

Intramolecular Tricarbonyl-Ene Reactions and α-Hydroxy-ß-Diketone Rearrangements Inspired by the Biosynthesis of Polycyclic Polyprenylated Acylphloroglucinols.

Structurally unique natural products pose biosynthetic puzzles whose solution can inspire new chemical reactions. Herein, we propose a unified biosynthetic pathway towards some complex meroterpenoids-the hyperireflexolides, biyoulactones, hybeanones and hypermonones. This hypothesis led to the discovery of uncatalyzed, intramolecular carbonyl-ene reactions that are spontaneous at room temperature. We also developed an anionic cascade reaction featuring an α-hydroxy-ß-diketone rearrangement and an intramolecular aldol reaction to access four distinct natural product scaffolds from a common intermediate.

Two Steps to Bicyclo[4.2.0]octadienes from Cyclooctatetraene: Total Synthesis of Kingianic Acid A.

Synthetic approaches to bicyclo[4.2.0]octadiene natural products frequently employ the synthesis of linear tetraenes to initiate a biosynthetic 8π/6π-electrocyclization cascade. This work forges a functionalized bicyclo[4.2.0]octadiene in two steps from cyclooctatetraene. The versatility of this method is demonstrated through natural product synthesis, including the first total synthesis of kingianic acid A and formal syntheses of kingianins A, D, and F and cryptobeilic acid D ethyl ester. The unexpected formation of an E,E,Z,E-tetraene byproduct is rationalized through density functional theory modeling.

Guest-Dependent Isomer Convergence of a Permanently Fluxional Coordination Cage.

A fluxional bis-monodentate ligand, based on the archetypal shape-shifting molecule bullvalene, self-assembles with M2+ (M=Pd2+ or Pt2+ ) to produce a highly complex ensemble of permanently fluxional coordination cages. Metal-mediated self-assembly selects for an M2 L4 architecture while maintaining shape-shifting ligand complexity. A second level of simplification is achieved with guest-exchange; the binding of halides within the M2 L4 cage mixture results in a convergence to a cage species with all four ligands present as the "B isomer". Within this confine, the reaction graph of the bullvalene is greatly restricted, but gives rise to a mixture of 38 possible diastereoisomers in rapid exchange. X-ray crystallography reveals a preference for an achiral form consisting of both ligand enantiomers. Through a combination of NMR spectroscopy and DFT calculations, we elucidate the restricted isomerisation pathway of the permanently fluxional M2 L4 assembly.

Ambimodal Pericyclic Rearrangements of Dialkenyl-Bullvalenes Give Tetrahydro-1,8-ethenoheptalenes.

The fluxional structure of bullvalene is expanded by the discovery of a [5,5]-sigmatropic rearrangement of dialkenyl substituted derivatives. This gives rise to tetrahydro-1,8-ethenoheptalenes (THEH), representing the first examples of this tricyclic scaffold. Variation of the substitution pattern alters the product distribution, including one thermodynamically balanced between THEH and bullvalene isomers. DFT calculations are used to explore the thermodynamic landscape and reaction mechanism revealing a pretransition state bifurcation leading to a concerted ambimodal rearrangement pathway.

Illustration of a computational pipeline for evaluating cyclodextrin host-guest complex formation through conformational capture of bullvalene.

Cyclodextrins have a diverse range of applications, including as supramolecular hosts, as enzyme active-site analogs, in improving drug solubility and delivery, and in molecular selection. We have investigated their ability to form stable complexes with bullvalenes, unusual organic cage molecules that spontaneously interconvert between numerous degenerate isomers. The shape-shifting nature of substituted bullvalenes raises the potential for dynamic adaptive binding to biological targets. We tested whether ß- and γ-cyclodextrins can capture particular bullvalene isomers and whether the preferred binding mode(s) differ between isomers. We first applied our computational host-guest interaction potential energy profiling to determine the best binding mode(s) of unsubstituted bullvalene and each isomer of methylenehydroxybullvalene to ß- and γ-cyclodextrin. Subsequent molecular dynamics simulations of the predicted host-guest complexes showed that while unsubstituted bullvalene has a single, albeit ill-defined, binding mode with either cyclodextrin, each isomer of methylenehydroxybullvalene has two possible modes of binding to ß-cyclodextrin but only a single, nebulous mode of binding to γ-cyclodextrin. Experimental determination of the binding free energy of each methylenehydroxybullvalene-cyclodextrin complex showed that methylenehydroxybullvalene is more likely to bind to ß-cyclodextrin than to γ-cyclodextrin, despite its smaller cavity. Together, our results suggest that ß-cyclodextrin, but not γ-cyclodextrin, shows promise for conformational capture of mono-substituted bullvalenes. More broadly, our computational pipeline should prove useful for rapid characterization of cyclodextrin host-guest complexes, avoiding the need for costly synthesis of guest molecules that are unlikely to bind stably, as well as providing detailed atomic-level insight into the nature of complexation.

Stereomutation of Substituted Bullvalenes.

The stereomutation of substituted bullvalenes is an inevitable consequence of the valence isomerism that automerizes this unique fluxional hydrocarbon. The introduction of external stereogenicity in the substituents expands the reaction graphs and leads to a wealth of complex diastereochemical relationships. In this communication, we explore these possibilities and prepare a range of stereochemically rich substituted bullvalenes. This includes a series of disubstituted bullvalenes with two external stereocenters as a platform for fluxional, shape-diverse compound libraries. We also prepare a tethered bisbullvalene with central stereogenicity in the tether as an ensemble of 900 unique isomers that are completely stereomutable.

Biomimetic Synthesis Enables the Structure Revision of Littordials E and F and Drychampone B.

Structural reassignments for littordial E, littordial F, and drychampone B are proposed on the basis of consideration of their biosynthetic origin. The key step in the proposed biosynthesis of each of these meroterpenoids is an intermolecular hetero-Diels-Alder reaction between an o-quinone methide and caryophyllene or humulene. Biomimetic total synthesis of the natural products gave sufficient material to allow their structure revision by NMR studies.

Highly Active Gas Phase Organometallic Catalysis Supported Within Metal-Organic Framework Pores.

Metal-organic frameworks (MOFs) can act as a platform for the heterogenization of molecular catalysts, providing improved stability, allowing easy catalyst recovery and a route toward structural elucidation of the active catalyst. We have developed a MOF, 1, possessing vacant N,N-chelating sites which are accessible via the porous channels that penetrate the structure. In the present work, cationic rhodium(I) norbornadiene (NBD) and bis(ethylene) (ETH) complexes paired with both noncoordinating and coordinating anions have been incorporated into the N,N-chelation sites of 1 via postsynthetic metalation and facile anion exchange. Exploiting the crystallinity of the host framework, the immobilized Rh(I) complexes were structurally characterized using X-ray crystallography. Ethylene hydrogenation catalysis by 1·[Rh(NBD)]X and 1·[Rh(ETH)2]X (X = Cl and BF4) was studied in the gas phase (2 bar, 46 °C) to reveal that 1·[Rh(ETH)2](BF4) was the most active catalyst (TOF = 64 h-1); the NBD materials and the chloride salt were notably less active. On the basis of these observations, the activity of the Rh(I) bis(ethylene) complexes, 1·[Rh(ETH)2]BF4 and 1·[Rh(ETH)2]Cl, in butene isomerization was also studied using gas-phase NMR spectroscopy. Under one bar of butene at 46 °C, 1·[Rh(ETH)2]BF4 rapidly catalyzes the conversion of 1-butene to 2-butene with a TOF averaging 2000 h-1 over five cycles. Notably, the chloride derivative, 1 [Rh(ETH)2]Cl displays negligible activity in comparison. XPS analysis of the postcatalysis sample, supported by DFT calculations, suggest that the catalytic activity is inhibited by the strong interactions between a Rh(III) allyl hydride intermediate and the chloride anion.

Photochemical Cyclopropanation of Cyclooctatetraene and (Poly-)unsaturated Carbocycles.

We report on the use of visible light to conduct carbene-transfer reactions of donor/acceptor diazoalkanes with cyclooctatetraene and polyunsaturated carbocycles to give the corresponding cyclopropanes in excellent yields with excellent stereoselectivities. This photochemical protocol proved to be superior to conventional metal-catalyzed cyclopropanation reactions and now provides platform chemicals containing a cyclic conjugated all-cis triene. The cyclopropane is an important structural feature to prevent 6π electrocyclization. Instead, the triene moiety can now be selectively functionalized in cycloaddition reactions.

Boronate Ester Bullvalenes.

Boronate ester bullvalenes are now accessible in two to four operationally simple steps. This unlocks late-stage diversification through Suzuki cross-coupling reactions to give mono-, di-, and trisubstituted bullvalenes. Moreover, a linchpin strategy enables preprogrammed installation of two different substituents. Analysis of solution phase isomer distributions and single-crystal X-ray structures reveals that isomer preference in the crystal lattice is due to general shape selectivity.

Total synthesis of endiandric acid J and beilcyclone A from cyclooctatetraene.

The endiandric acids are classic targets in natural product synthesis. The spectacular 8π/6π-electrocylisation/intramolecular Diels-Alder (8π/6π/IMDA) reaction cascade at the heart of their biosynthesis has inspired practitioners and students of pericyclic chemistry for nearly forty years. All previous synthetic approaches have sought to prepare a linear tetraene and thereby initiate the cascade. In this communication we demonstrate the use of cyclooctatetraene to rapidly intercept the 8π/6π/IMDA cascade at the cyclooctatriene stage. Endiandric acid J and beilcyclone A are prepared for the first time in six and five steps, respectively. The strategy features a tactical overall anti-vicinal difunctionalisation of cyclooctatetraene through SN2' alkylation of cyclooctatetraene oxide followed by an intriguing tandem Claisen rearrangement/6π-electrocyclisation from the corresponding vinyl ether. This rapidly constructs an advanced bicyclo[4.2.0]octadiene aldehyde intermediate. Olefinations and intramolecular Diels-Alder cycloadditions complete the syntheses. This establishes a short and efficient new path to the endiandric acid natural products. DFT modelling predicts thermal racemisation of bicyclo[4.2.0]octadiene intermediates, dashing hopes of enantioselective synthesis.

The simplest Diels-Alder reactions are not endo-selective.

There is a widespread perception that the high level of endo selectivity witnessed in many Diels-Alder reactions is an intrinsic feature of the transformation. In contrast to expectations based upon this existing belief, the first experimental Diels-Alder reactions of a novel, deuterium-labeled 1,3-butadiene with commonly used mono-substituted alkenic dienophiles (acrolein, methyl vinyl ketone, acrylic acid, methyl acrylate, acrylamide and acrylonitrile) reveal kinetic endo : exo ratios close to 1 : 1. Maleonitrile, butenolide, α-methylene γ-butyrolactone, and N-methylmaleimide behave differently, as does methyl vinyl ketone under Lewis acid catalysis. CBS-QB3 calculations incorporating solvent and temperature parameters give endo : exo product ratios that are in near quantitative agreement with these and earlier experimental findings. This work challenges the preconception of innate endo-selectivity by providing the first experimental evidence that the simplest Diels-Alder reactions are not endo-selective. Trends in behaviour are traced to steric and electronic effects in Diels-Alder transition structures, giving new insights into these fundamental processes.

Network Analysis of Substituted Bullvalenes.

Substituted bullvalenes are dynamic shape-shifting molecules that exist within complex reaction networks. Herein, we report the synthesis of di- and trisubstituted bullvalenes and investigate their dynamic properties. Trisubstituted bullvalenes share a common major isomer which shows kinetic metastability. A survey of the thermodynamic and kinetic landscapes through computational analysis together with kinetic simulation provides a map of the internal dynamics of these systems.

Total Synthesis of Naphterpin and Marinone Natural Products.

A concise and divergent strategy for the synthesis of the naphterpin and marinone meroterpenoid families has been developed. The approach features a succession of pericyclic reactions-an aromatic Claisen rearrangement, a retro-6π-electrocyclization, and two Diels-Alder reactions-which facilitated the first total synthesis of naphterpin itself in five steps from 2,5-dimethoxyphenol, alongside similar syntheses of 7-demethylnaphterpin and debromomarinone. Late-stage oxidation and bromination reactions were also investigated, leading to the first total syntheses of naphterpins B and C and isomarinone.

Synthesis and Analysis of Substituted Bullvalenes.

Herein we detail a practical synthesis of bullvalene and a variety of mono- and disubstituted analogues through cobalt-catalysed [6+2] cycloaddition of cyclooctatetraene to alkynes, followed by photochemical di-π-methane rearrangement. The application of isomer-network analysis, coupled with quantum-chemical calculations, provides a powerful automated tool for predicting the properties of bullvalene isomer networks.