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Analysis of two homologous groups of fungal pericyclases demonstrates how they can catalyse either an Alder-ene reaction—which has not previously been found in nature—or a hetero-Diels–Alder reaction.

ATP acts as a co-substrate in enzyme catalysed reactions, but can also specifically bind metal ions. Here, the authors show that ATP interacts with copper ions and forms a Cu(II)-ATP complex that efficiently catalyses Diels-Alder reactions, and determine ATP residues that are essential for this activity.

Strained organic compounds have long fascinated the chemistry community. Heterocyclic allenes are particularly interesting strained intermediates, but their use in synthetic chemistry is rather scarce. Now, an experimental and computational study of azacyclic allenes demonstrates that heteroatom-containing cyclic allenes can be harnessed for the construction of complex molecular scaffolds, including those that bear multiple stereogenic centres.

Theory suggests that many chemical reactions (not simply, as is often thought, redox reactions) might be catalysed by an applied electric field; experimental evidence for this is now provided from single-molecule studies of the formation of carbon–carbon bonds in a Diels–Alder reaction.

Water-soluble macrocycles are useful in drug delivery and other applications, yet controlling their host–guest interactions under physiological conditions remains challenging. Here, the authors employ reversible Diels-Alder cycloaddition reactions to control complexation between β-cyclodextrin hosts and anthracene-derived guests in water.

This approach leverages the rapid, bio-orthogonal inverse electron demand Diels–Alder reaction between a radiolabeled tetrazine and a trans-cyclooctene–bearing antibody to enable pretargeted positron emission tomography imaging and endoradiotherapy in a murine model of cancer.

Genomic analyses of DNA from modern individuals show that, about 800 years ago, pre-European contact occurred between Polynesian individuals and Native American individuals from near present-day Colombia, while remote Pacific islands were still being settled.

Despite five decades of research, the alkaloid (+)-brevianamide A has remained an elusive target for chemical synthesis. Now, it has been shown that the total synthesis of (+)-brevianamide A can be achieved in seven steps and 7.2% overall yield to give 750 mg of the target compound.

The synthesis of acenaphthylene-containing polycyclic aromatic hydrocarbons has traditionally required multiple sequential synthetic steps, limiting structural diversity. Herein, the authors present a tandem C−H penta- and hexaannulation reaction of aryl alkyl ketone with acetylenedicarboxylate.

In this review, we summarize the use of Diels–Alder reaction in the synthesis of arylene-based polymers, including polyphenylenes and ladder polymers, as well as graphene nanoribbons. These polymer materials are structurally related to each other, but rarely discussed all together in a same context. The importance and versatility of the Diels–Alder polymerization is highlighted for the synthesis of such polymers with various potential applications, for example, as polymer electrolyte membrane and organic semiconductors.

Different agonists produce equilibria of at least four distinct active states of the G-protein-bound M2 muscarinic acetylcholine receptor, each with a different ability to activate G proteins.

Combining cycloaddition and carbon–carbon cross-coupling offers a way of simplifying the enantioselective preparation of chemical building blocks, natural products and medicines such as the antipsychotic asenapine.

Unlike traditional chiral metal complexes, which typically contain chiral ligands, in chiral-at-metal complexes chirality originates from a stereogenic metal center bound to achiral ligands. Herein, the authors use an unsymmetric tridentate ligand to construct a Werner-type tetrahedral chiral-at-zinc complex which displays high configurational stability and catalyzes an oxa-Diels-Alder reaction with high yield and enantioselectivity.

The complete biosynthesis of the fungal indole alkaloid malbrancheamide, which culminates in an intramolecular [4+2] hetero-Diels–Alder cyclization to produce the bicyclo[2.2.2]diazaoctane scaffold, has now been discovered. Chemical synthesis and protein structural analysis were used to provide mechanistic insight into this enzyme-dependent diastereo- and enantioselective cycloaddition.

Pericyclase enzymes are an expanding family of enzymes. Here, the authors identify the norbornene synthase SdnG, a pericyclase for the intramolecular Diels-Alder reaction between a cyclopentadiene and an olefinic dienophile to form the sordaricin norbornene structure, and reconstitute the sordaricin biosynthesis.

C-terminal α-amidated peptides are attractive therapeutic targets, but preparative methods to access amidated pharmaceuticals are limited both on lab and manufacturing-scale. Here, the authors report a straightforward and scalable approach to the C-terminal α-amidation of peptides and proteins from cysteine-extended polypeptide precursors.

Healable materials are typically repaired by heat, which can affect the properties of the substance. Here the authors report a dynamic covalent polymer network in which light can switch the healing abilities on or off, allowing healing at defined locations without affecting the polymer as a whole.

Cascade reactions allow step-economical generation of molecular complexity. Now, a butatriene equivalent, TMSCH₂C ≡ CCH₂OH, is used to couple two powerful and convergent cycloadditions — the homologous Diels–Alder ([5 + 2]) and the Diels–Alder ([4 + 2]) reactions –– through a vinylogous Peterson elimination, en route to a series of kinase inhibitors inspired by staurosporine.

Homogeneous Pt-group metal-based complexes make up the majority of C-H bond activation catalysts, but they are characterized by high cost and low abundance. Here, the authors report atomically dispersed titanium-aluminum-boron nanopowder for low-temperature catalytic activation of aliphatic C-H bonds via the element-specific cooperative mechanistic roles.

Enzymatic Diels–Alder reactions are of high synthetic interest, but mechanistic insights remain scarce. Now, a structure of the Diels–Alderase CghA in complex with its product is reported, a catalytic mechanism proposed and the enzyme is engineered to form the energetically disfavoured exo adduct.

Two coordination cages have been devised that undergo covalent modification during a cascade of two orthogonal Diels–Alder reactions. This results in increased lipophilicity for the second cage, enabling its phase transfer and separation from the first. The trigger, relay and inhibition features of this cascade system mimic key aspects of natural post-translational modification cascades.

The strained C₆H₆ isomer 1,2,3-cyclohexatriene and its derivatives participate in a host of reaction modes which demonstrate their potential for selective chemical transformations and provide an unconventional entryway to complex scaffolds.

Two glycosylated enzymes, EupfF and PycR1, have now been characterized and shown to independently catalyse the tandem intermolecular [4 + 2] cycloaddition in the biosynthesis of bistropolone-sesquiterpenes. Through analysis of enzyme–substrate co-crystal structures, together with computational and mutational studies, the origins of their catalytic activity and stereoselectivity were elucidated.

LepI is an S-adenosylmethionine-dependent pericyclase that catalyses the dehydration, hetero-Diels–Alder reaction and retro-Claisen rearrangement reactions that occur in the formation of the 2-pyridone natural product leporin C. Now, the mechanistic details that underpin this range of catalytic reactions have been uncovered from the crystal structures of LepI and LepI in complex with ligands.

WebNetwork analysis to determine the maximally bridged ring (or rings) of molecules is used as part of a strategy for the syntheses of architecturally complex natural chemicals; this strategy is demonstrated via the synthesis of the diterpenoid alkaloids weisaconitine D and liljestrandinine.

The taxane diterpene family is structurally complex and exhibits a wide range of biological activities, best exemplified by the successful drug Taxol. Here, two of the least oxidized taxanes in the family, ‘taxadienone’ and taxadiene, are prepared by total synthesis on a gram scale. The concise synthetic route described herein provides a scalable, enantioselective entry to the taxane family of natural products.

Performing live-cell microscopy experiments with high spatial and temporal resolution requires fluorophores with highly optimized properties. This Review examines the progress in developing synthetic small-molecule fluorophores and how these in combination with innovative labeling strategies can advance chemical biology.

Covalent cross-linking can be used to improve the mechanical properties of fibers, but can be complicated to prepare and process. Here, the authors report fibers prepared with dynamic covalent bonds, which can reversibly dissociate to enable processing, while maintaining improved mechanical properties in the final material.

Analysis of ancient DNA from four individuals who lived in Vanuatu and Tonga between 2,300 and 3,100 years ago suggests that the Papuan ancestry seen in present-day occupants of this region was introduced at a later date.

A low-cost robotic platform using mainly optical detection to quantify yields of products and by-products allows the analysis of multidimensional chemical reaction hyperspaces and networks much faster than is possible by human chemists.

The biogenesis and stereochemical origin of many natural products remain unknown. Now the biosynthetic pathway of brevianamide A is elucidated. An isomerase is discovered that can catalyse pinacol rearrangement without a cofactor and determine the stereochemistry of the bicyclo[2.2.2]diazaoctane ring.

Natural products citrinalin B and cyclopiamine B, which contain basic nitrogen atoms that are susceptible to oxidation during synthesis, can be synthesized by the selective introduction and removal of functional groups.

Arynes are often generated using strong bases or fluoride sources, limiting functional group tolerance. Now, stable triaryloxonium salts are transformed into arynes and subsequently trapped using cycloaddition reactions by treatment with potassium phosphate at room temperature. This functional group-tolerant method proceeds by an elimination, unimolecular, conjugate base-like elimination mechanism to form the aryne.

Minimally invasive materials that match tissues mechanical properties are needed for biomedical applications. Here, the authors report on brush-like polymers which can be injected and cured in situ, resulting in elastomeric implants which mechanically blend with surrounding tissue and show minimal foreign body response.

Chemoselective dual functionalization of proteins is an invaluable tool to introduce two distinct payloads to proteins. Here, the authors present N-alkylpyridinium reagents as soft electrophiles for chemoselective dual modification of cysteine residues in peptides or proteins via a 1,6-addition reaction.

How chemotherapeutic nucleoside 6-thio-2’-deoxyguanosine (6-thiodG) targets telomerase to inhibit telomere maintenance in cancer cells and tumors was unclear. Here, the authors show that telomere length and telomerase status determine 6-thio-dG sensitivity and uncover the molecular mechanism by which 6-thio-dG selectively inhibits telomerase synthesis of telomeric DNA.

Supramolecular catalytic assemblies attract enormous interest due to their activity that rivals natural enzymes. Using ab initio molecular dynamics, the authors show that a gold catalyst in a Ga₄L₆12^- nanocage, while impeded by reorganization energy, is accelerated by hosting a catalytic water molecule.