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Antibiotic discovery and development is challenging as chemical scaffolds of synthetic origin often lack the required pharmaceutical properties, and the discovery of novel ones from natural sources is tedious. Herein, we report the discovery of new cystobactamids with a significantly improved antibacterial profile in a detailed screening of myxobacterial producer strains. Some of these new derivatives display antibacterial activities in the low-μg mL⁻¹ range against Gram-negative pathogens, including clinical isolates of Klebsiella oxytoca, Pseudomonas aeruginosa, and fluoroquinolone-resistant Enterobacteriaceae, which were not observed for previously reported cystobactamids. Our findings provide structure–activity relationships and show how pathogen resistance can be overcome by natural scaffold diversity. The most promising derivative 861-2 was prepared by total synthesis, enabling further chemical optimization of this privileged scaffold.

From Nature's toolbox: A concise study with myxobacterial producer strains yielded novel cystobactamid derivatives that display superior activity against Gram-negative pathogens. The most promising derivative was obtained by total synthesis, and will serve as a starting point for the further optimization of these gyrase inhibitors and their development as antibacterial drugs. SAR=structure–activity relationship.

There is a strong need to better diagnose infections at deep body sites through noninvasive molecular imaging methods. Herein, we describe the synthesis and characterization of probes based on siderophore conjugates with catechol moieties and a central DOTAM scaffold. The probes can accommodate a metal ion as well as an antibiotic moiety and are therefore suited for theranostic purposes. The translocation of the conjugates across the outer and inner cell membranes of E. coli was confirmed by growth recovery experiments with enterobactin-deficient strains, by the antibacterial activity of ampicillin conjugates, and by confocal imaging using a fluorogen-activating protein–malachite green system adapted to E. coli. The suitability of the probes for in vivo imaging was demonstrated with a Cy5.5 conjugate in mice infected with P. aeruginosa.

Trojan horses: A siderophore motif was coupled to functional imaging and/or antibiotic moieties via a DOTAM scaffold. The conjugates are internalized into Gram-positive as well as Gram-negative pathogenic bacteria and can be used for multiple theranostic applications, such as the in vivo imaging of infections.

In this review article recent isotopic labelling experiments are presented that served in the elucidation of the complex mechanisms of terpene biosynthesis. The article is structured by first presenting the recent advances in the biosynthesis of terpene monomers, followed by sections on monoterpenes, sesquiterpenes and diterpenes. This overview covers a personal selection of eminent examples from the accumulated literature since 2010.

This review summarises the results of recent mechanistic investigations on enzymes involved in the biosynthesis of terpene precursors and on terpene cyclases by isotopic labelling experiments. The accumulated knowledge from these experiments is discussed against the background of insights obtained by quantum chemical calculations.

Inspired by the unique character of enzymes, we developed novel chiral SPO (secondary-phosphine-oxide) ligand (SPO-Wudaphos) which can enter into both ion pair and H-bond noncovalent interactions. The novel chiral SPO-Wudaphos exhibited excellent results in the asymmetric hydrogenation of α-methylene-γ-keto carboxylic acids, affording the chiral γ-keto acids with up to over 99 % ee. A series of control experiments and DFT calculations were conducted to illustrate the critical roles of both the ion pair and H-bond noncovalent interactions.

Two different interactions: Just like enzymes which can enter into multiple cooperative noncovalent interactions with substrates, the chiral secondary-phosphine-oxide (SPO) Wudaphos ligand can engage in ion pair and H-bonding interactions. The chiral SPO-Wudaphos ligand gave excellent results in the rhodium-catalyzed asymmetric hydrogenation of α-methylene-γ-keto carboxylic acids.

An efficient iodine-mediated regioselective tandem approach for the synthesis of symmetric and asymmetric iodo-substituted indenes and stereoselective cyclopenta [b]pyridine/thiophenes from easily accessible enediynes that proceeds by in situ formation of an iodonium intermediate followed by a regioselective 5-endo-dig cyclization has been described. The intramolecular electrophilic iodocyclization was selectively triggered by a distribution of electronic density along the alkyne bond. Subsequently, the iodo-substituted indenes were diversified by employing palladium-catalyzed cross-coupling reactions and the coupled products were further confirmed by X-ray crystallographic studies.

An efficient iodine-mediated regioselective tandem approach for the synthesis of symmetric and asymmetric iodo-substituted indenes and stereoselective cyclopenta [b]pyridine/thiophenes using easily accessible enediynes has been described. The intramolecular electrophilic iodocyclization was selectively triggered by a distribution of electronic density along the alkyne bond. Subsequently, the iodo-substituted indenes were diversified by employing palladium-catalyzed cross-coupling reactions.

In 2001, two years before the disclosure of the CERT-associated Cer transfer machinery, N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)alkanamides (HPAs) were described as the first, and to date unique, family of intracellular Cer trafficking inhibitors. The dodecanamide derivative, HPA-12, turned out to be a benchmark as a cellular inhibitor of CERT-mediated de novo sphingomyelin biosynthesis. In only 15 years after its first disclosure, this compound has prompted a growing number of biological and chemical studies. Its initial chemical development closely paralleled the study of the CERT protein. It was only after its structural revision in 2011 that HPA-12 received broad attention from the synthetic chemistry community, leading to novel analogues with enhanced protein binding. This Minireview aims at presenting an exhaustive report of the syntheses of HPA-12 and analogues. Biological activities of this CERT inhibitor and structure–activity relationships are also presented to afford a comprehensive overview of the chemistry and biology of the HPA series.

In 2001, two years before the disclosure of the CERT-associated Cer transfer machinery, N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)alkanamides (HPAs) were described as the first family of intracellular Cer trafficking inhibitors. The dodecanamide derivative, HPA-12, turned out to be a benchmark as a cellular inhibitor of CERT-mediated de novo sphingomyelin biosynthesis. This Minireview aims to present an exhaustive report of the chemistry and biology of the HPA series (see figure).

Presented herein is a mild, facile, and efficient iron-catalyzed synthesis of substituted allenes from propargyl carboxylates and Grignard reagents. Only 1–5 mol % of the inexpensive and environmentally benign [Fe(acac)₃] at −20 °C was sufficient to afford a broad range of substituted allenes in excellent yields. The method tolerates a variety of functional groups.

Iron clad: The title reaction is effective for the synthesis of substituted allenes using a low catalyst loading at −20 °C. The mild reaction conditions tolerated not only terminal acetylenes but also functional groups such as acetal, silyl ether, and ethyl carboxylate. A high degree of chirality-transfer was observed and the reaction conditions are compatible with radical probes.

A diverse set of highly substituted 4-aminoquinolines was synthesized from ynamides, triflic anhydride, 2-chloropyridine, and readily accessible amides in a mild one-step procedure.

Diverse products: Electrophilically activated amides easily react with sulfonyl ynamides to yield a diverse range of substituted 4-aminoquinolines. The ynamides can be easily modified by Sonogashira processes or generated from dichloroenamide precursors. Any substituent can thus be introduced at the C3 position of the quinoline. 2-ClPy=2-chloropyridine, Tf₂O=triflic anhydride.

Vue d’artiste du projet de distillerie de Hunter Laing à Ardnahoe, face à l’île de Jura. ©DR

A catalytic asymmetric dearomatization of 2-naphthols with azodicarboxylates has been accomplished by using a N,N′-dioxide-scandium(III) complex as a chiral catalyst. A number of optically active β-naphthalenone compounds with a nitrogen-containing quaternary carbon stereocenter were obtained in up to 99 % yield and up to 99 % ee under mild reaction conditions. The reaction could be scaled up to a gram-scale with the yield and ee maintained. Based on these experiments and on previous reports, a possible transition state was proposed.

Animate you aminations! A catalytic asymmetric dearomatization of 2-naphthols with azodicarboxylates has been accomplished by using a N,N′-dioxide–scandium(III) complex as a chiral catalyst (see scheme). A number of optically active β-naphthalenone compounds with a nitrogen-containing quaternary carbon stereocenter were obtained under mild reaction conditions.

The white backlight in displays is generated by optimizing the proportions of individual emitters with different wavelengths by variations in materials composition, phase, and structure. Color pixels usually result from the separation of white light or the excitation with multiwavelength or multipulse sources. However, it is a challenge to develop a material that comprises a single structure and emits over the full visible spectrum, but where the emission wavelengths can be controlled by a simple excitation source. Herein, we report an upconversion nanostructure that incorporates several lanthanide ions in the same core@shell@shell structure. The combination of multiple narrow spectral bands results in the emission of white light. The emission colors can be tuned by changing the excitation power density, which manipulates the photon transfer pathways. Applications such as flat-panel displays and imaging have been demonstrated.

Seeing the light: An upconversion nanostructure comprises several lanthanide ions integrated in a single system. The balance of numerous narrow emission bands covering the full visible spectrum results in white-light emission. The emission colors can be determined by changing the excitation power density (see picture), which manipulates the photon transfer pathways to bring potential applications such as multicolor displays or imaging.

A two-step synthesis of structurally diverse pyrrole-containing bicyclic systems is reported. ortho-Nitro-haloarenes coupled with vinylic N-methyliminodiacetic acid (MIDA) boronates generate ortho-vinyl-nitroarenes, which undergo a “metal-free” nitrene insertion, resulting in a new pyrrole ring. This novel synthetic approach has a wide substrate tolerance and it is applicable in the preparation of more complex “drug-like” molecules. Interestingly, an ortho-nitro-allylarene derivative furnished a cyclic β-aminophosphonate motif.

Old dog, new tricks: A two-step synthesis of structurally diverse pyrrole-containing bicyclic systems is reported. ortho-Nitro-haloarenes coupled with vinylic N-methyliminodiacetic acid (MIDA) boronates generate ortho-vinyl-nitroarenes, which undergo a “metal-free” nitrene insertion, resulting in a new pyrrole ring. This approach has a wide substrate tolerance and it is applicable in the preparation of more complex “drug-like” molecules. Interestingly, an ortho-nitro-allylarene derivative furnished a cyclic β-aminophosphonate motif.