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.

A Diazo-Hooker Reaction, Inspired by the Biosynthesis of Azamerone.

Motivated by the biosynthesis of azamerone, we report the first example of a diazo-Hooker reaction, which involves the formation of a phthalazine ring system by the oxidative rearrangement of a diazoketone. Computational studies indicate that the diazo-Hooker reaction proceeds via an 8π-electrocyclization followed by ring contraction and aromatization. The biosynthetic origin of the diazoketone functional group was also chemically mimicked using a related natural product, naphterpin, as a model system.

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.

Biomimetic Total Synthesis of the Rubiginosin Meroterpenoids.

Total synthesis of the Rhododendron meroterpenoids rubiginosins A and G, which both contain unusual 6-6-6-4 ring systems, has been achieved using a bioinspired cascade approach. Stepwise synthesis of these natural products, and the related 6-6-5-4 meroterpenoids fastinoid B and rhodonoid B, from naturally occurring chromene precursors is also reported.

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.

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.

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.

3D Anionic Silicate Covalent Organic Framework with srs Topology.

The synthesis of 3D covalent organic frameworks (COFs) adopting novel topologies is challenging, and so far 3D COFs have only been reported for nets based on building blocks with tetrahedral geometry. We demonstrate the targeted synthesis of an anionic 3D COF crystallizing in a three-coordinated srs net by exploiting a recently developed linkage for the formation of anionic silicate COFs based on hypercoordinate silicon nodes. The framework, named SiCOF-5, was synthesized by reticulating dianionic hexacoordinate [SiO6]2- nodes with triangular triphenylene building blocks and adopts a two-fold interpenetrated srs-c net with an overall composition of Na2[Si(C18H6O6)] (where C18H6O6 is triphenylene-2,3,6,7,10,11-hexakis(olate)). A key requirement for the crystallization of SiCOF-5 was the careful control over the nucleation and growth rate by gradual generation of the silicon source during the course of the reaction.

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.