Structural characterization of N-acyl-homoserine lactones from bacterial quorum sensing using LC-MS/MS analyses after Paternò-Büchi derivatization in solution.

Bacterial quorum sensing is a chemical language allowing bacteria to interact through the excretion of molecules called autoinducers, like N-acyl-homoserine lactones (AHLs) produced by Gram-negative Burkholderia and Paraburkholderia bacteria known as opportunistic pathogens. The AHLs differ in their acyl-chain length and may be modified by a 3-oxo or 3-hydroxy substituent, or C = C double bonds at different positions. As the bacterial signal specificity depends on all of these chemical features, their structural characterization is essential to have a better understanding of the population regulation and virulence phenomenon. This study aimed at enabling the localization of the C = C double bond on such specialized metabolites while using significantly lower amounts of biological material. The approach is based on LC-MS/MS analyses of bacterial extracts after in-solution derivatization by a photochemical Paternò-Büchi reaction, leading to the formation of an oxetane ring and subsequently to specific fragmentations when performing MS/MS experiments. The in-solution derivatization of AHLs was optimized on several standards, and then the matrix effect of bacterial extracts on the derivatization was assessed. As a proof of concept, the optimized conditions were applied to a bacterial extract enabling the localization of C = C bonds on unsaturated AHLs.

Total Synthesis of Cyclotripeptidic Natural Products Anacine, Aurantiomide C, Polonimides A and C, and Verrucine F.

The total synthesis of cyclotripeptidic natural products possessing a central piperazino[2,1-b]quinazolin-3,6-dione core is described through an original strategy involving the pivotal cyclocondensation of an electrophilic homoserine lactone intermediate. The alkylidene group was spontaneously installed by autoxidation during the cyclocondensation process, while the propionamide side chain was introduced through the nickel-catalyzed aminocarbonylation of a bromoethyl intermediate. This last reaction is unprecedented on such highly functionalized intermediates. Finally, we explored structural modifications and interconversions of the natural products. Overall, this work led to anacine, aurantiomide C, polonimides A and C, and verrucine F.

Tandem Hock and Friedel-Crafts reactions allowing an expedient synthesis of a cyclolignan-type scaffold.

The Hock cleavage, which is compatible with tandem processes, was applied to the synthesis of 1-aryltetralines through a one-pot transformation from readily available benzyl(prenyl)malonate substrates. After the photooxygenation of the prenyl moiety, the resulting hydroperoxide was directly engaged in a Hock cleavage by adding a Lewis acid. The presence of an aromatic nucleophile in the reaction mixture and that of a benzyl moiety on the substrate resulted in tandem Friedel-Crafts reactions to form the 1-aryltetraline products. These compounds share a close analogy to the cyclolignan natural products. Experimental observations and a DFT study support the involvement of an aldehyde intermediate during the Friedel-Crafts reactions, rather than an oxocarbenium.

Mode-of-action of the natural herbicide radulanin A as an inhibitor of photosystem II.

BACKGROUND: Radulanin A is a natural 2,5-dihydrobenzoxepin synthesized by several liverworts of the Radula genus. Breakthroughs in the total synthesis of radulanin A paved the way for the discovery of its phytotoxic activity. Nevertheless, its mode-of-action (MoA) has remained unknown so far and thus was investigated, in Arabidopsis thaliana. RESULTS: Radulanin A phytotoxicity was associated with cell death and partially depended on light exposure. Photosynthesis measurements based on chlorophyll-a fluorescence evidenced that radulanin A and a Radula chromene inhibited photosynthetic electron transport with IC50 of 95 and 100 µm, respectively. We established a strong correlation between inhibition of photosynthesis and phytotoxicity for a range of radulanin A analogs. Based on these data, we also determined that radulanin A phytotoxicity was abolished when the hydroxyl group was modified, and was modulated by the presence of the heterocycle and its aliphatic chain. Thermoluminescence studies highlighted that radulanin A targeted the QB site of the Photosystem II (PSII) with a similar MoA as 3-(3,4-dichloropheny)-1,1-dimethylurea (DCMU). CONCLUSION: We establish that radulanin A targets PSII, expanding QB sites inhibitors to bibenzyl compounds. The identification of an easy-to-synthesize analog of radulanin A with similar MoA and efficiency might be useful for future herbicide development. © 2023 Society of Chemical Industry.

Tandem InCl3-Promoted Hydroperoxide Rearrangements and Nucleophilic Additions: A Straightforward Entry to Benzoxacycles.

The acid-catalyzed rearrangement of organic peroxides is generally associated with C-C-bond cleavages (Hock and Criegee rearrangements), with the concomitant formation of an oxocarbenium intermediate. This article describes the tandem process between a Hock or Criegee oxidative cleavage and a nucleophilic addition onto the oxocarbenium species (in particular a Hosomi-Sakurai-type allylation), under InCl3 catalysis. It was applied to the synthesis of 2-substituted benzoxacycles (chromanes and benzoxepanes), including a synthesis of the 2-(aminomethyl)chromane part of sarizotan, and a total synthesis of erythrococcamide B.

Asymmetric synthesis of a stereopentade fragment toward latrunculins.

Latrunculins are marine toxins used in cell biology to block actin polymerization. The development of new synthetic strategies and methods for their synthesis is thus important in order to improve, modulate or control this biological value. The total syntheses found in the literature all target similar disconnections, especially an aldol strategy involving a recurrent 4-acetyl-1,3-thiazolidin-2-one ketone partner. Herein, we describe an alternative disconnection and subsequent stereoselective transformations to construct a stereopentade amenable to latrunculin and analogue synthesis, starting from (+)-ß-citronellene. Key stereoselective transformations involve an asymmetric Krische allylation, an aldol reaction under 1,5-anti stereocontrol, and a Tishchenko-Evans reduction accompanied by a peculiar ester transposition, allowing to install key stereogenic centers of the natural products.

Total Synthesis of (+)-Cinereain and (-)-Janoxepin through a Fragment Coupling/Retro-Claisen Rearrangement Cascade.

Total syntheses of (+)-cinereain and (-)-janoxepin, two fungal cyclotripeptides featuring a complex heterocyclic core and interesting phytotoxic and antimalarial activities, have been achieved in a convergent manner. A key step in this synthesis is a one-pot cascade initiated by the cyclocondensation of two fragments-a hindered 2-vinylcyclopropane-1-acyl fluoride and an electron-deficient cyclic amidine-to release a reactive spiro[2-vinylcyclopropane-1,5'-pyrimidine-4',6'-dione]. This intermediate underwent a spontaneous retro-Claisen rearrangement that was rationalized by DFT calculations. The cascade directly afforded a 2,5-dihydrooxepin-fused heterotricyclic product, and the challenging oxepin ring was finally forged by the palladium-catalyzed ß-hydride elimination of an allylic fluoride intermediate.

Total Synthesis of Phytotoxic Radulanin A Facilitated by the Photochemical Ring Expansion of a 2,2-Dimethylchromene in Flow.

The radulanins are biologically active bibenzyl natural products featuring a synthetically challenging 2,5-dihydro-1-benzoxepine core. In contrast with previous reports exhibiting lengthy strategies, we demonstrate the shortest synthesis of radulanin A to date, featuring a largely unexplored photochemical ring expansion reaction of a 2,2-dimethylchromene precursor. This work was adapted to a continuous-flow setup for larger-scale preparation, in view of biological investigations into the herbicidal properties of this natural product.

Sinunanolobatone A, an Anti-inflammatory Diterpenoid with Bicyclo[13.1.0]pentadecane Carbon Scaffold, and Related Casbanes from the Sanya Soft Coral Sinularia nanolobata.

A novel diterpenoid, sinunanolobatone A (1), featuring an unprecedented bicyclo[13.1.0]pentadecane carbon framework, along with two new casbane diterpenoids (2 and 3), and five known related ones (4-8) were isolated from the Sanya soft coral Sinularia nanolobata. The structures of the new compounds were established by detailed spectroscopic analysis, X-ray diffraction analysis, chemical reactions, or a quantum chemical computation method. A plausible biosynthetic pathway of 1 was proposed. In bioassay, the novel compound 1 showed significant inhibitory activity against lipopolysaccharide (LPS) induced inflammation in BV-2 microglial cells.

Synthesis of a Biomimetic Tetracyclic Precursor of Aspochalasins and Formal Synthesis of Trichoderone A.

Aspochalasins are leucine-derived cytochalasins. Their complexity is associated with a high degree of biosynthetic oxidation, herein inspiring a two-phase strategy in total synthesis. We thus describe the synthesis of a putative biomimetic tetracyclic intermediate. The constructive steps are an intramolecular Diels-Alder reaction to install the isoindolone core of cytochalasins, whose branched precursor was obtained from a stereoselective Ireland-Claisen rearrangement performed from a highly unsaturated substrate. This also constitutes a formal synthesis of trichoderone A.

Assessing the Role of Developmental and Environmental Factors in Chemical Defence Variation in Heliconiini Butterflies.

Chemical defences in animals are both incredibly widespread and highly diverse. Yet despite the important role they play in mediating interactions between predators and prey, extensive differences in the amounts and types of chemical compounds can exist between individuals, even within species and populations. Here we investigate the potential role of environment and development on the chemical defences of warningly coloured butterfly species from the tribe Heliconiini, which can both synthesize and sequester cyanogenic glycosides (CGs). We reared 5 Heliconiini species in captivity, each on a single species-specific host plant as larvae, and compared them to individuals collected in the wild to ascertain whether the variation in CG content observed in the field might be the result of differences in host plant availability. Three of these species were reared as larvae on the same host plant, Passiflora riparia, to further test how species, sex, and age affected the type and amount of different defensive CGs, and how they affected the ratio of synthesized to sequestered compounds. Then, focusing on the generalist species Heliconius numata, we specifically explored variation in chemical profiles as a result of the host plant consumed by caterpillars and their brood line, using rearing experiments carried out on two naturally co-occurring host plants with differing CG profiles. Our results show significant differences in both the amount of synthesized and sequestered compounds between butterflies reared in captivity and those collected in the field. We also found a significant effect of species and an effect of sex in some, but not all, species. We show that chemical defences in H. numata continue to increase throughout their life, likely because of continued biosynthesis, and we suggest that variation in the amount of synthesized CGs in this species does not appear to stem from larval host plants, although this warrants further study. Interestingly, we detected a significant effect of brood lines, consistent with heritability influencing CG concentrations in H. numata. Altogether, our results point to multiple factors resulting in chemical defence variation in Heliconiini butterflies and highlight the overlooked effect of synthesis capabilities, which may be genetically determined to some extent.

Programmed Multiple C-H Bond Functionalization of the Privileged 4-hydroxyquinoline Template.

The introduction of substituents on bare heterocyclic scaffolds can selectively be achieved by directed C-H functionalization. However, such methods have only occasionally been used, in an iterative manner, to decorate various positions of a medicinal scaffold to build chemical libraries. We herein report the multiple, site selective, metal-catalyzed C-H functionalization of a "programmed" 4-hydroxyquinoline. This medicinally privileged template indeed possesses multiple reactive sites for diversity-oriented functionalization, of which four were targeted. The C-2 and C-8 decorations were directed by an N-oxide, before taking benefit of an O-carbamoyl protection at C-4 to perform a Fries rearrangement and install a carboxamide at C-3. This also released the carbonyl group of 4-quinolones, the ultimate directing group to functionalize position 5. Our study highlights the power of multiple C-H functionalization to generate diversity in a biologically relevant library, after showing its strong antimalarial potential.

Diversity-oriented synthesis of 17-spirosteroids.

A diversity-oriented synthesis (DOS) approach has been used to functionalize 17-ethynyl-17-hydroxysteroids through a one-pot procedure involving a ring-closing enyne metathesis (RCEYM) and a Diels-Alder reaction on the resulting diene, under microwave irradiations. Taking advantage of the propargyl alcohol moiety present on commercially available steroids, this classical strategy was applied to mestranol and lynestrenol, giving a collection of new complex 17-spirosteroids.

Complex Polypropionates from a South China Sea Photosynthetic Mollusk: Isolation and Biomimetic Synthesis Highlighting Novel Rearrangements.

Placobranchus ocellatus is well known to produce diverse and complex γ-pyrone polypropionates. In this study, the chemical investigation of P. ocellatus from the South China Sea led to the discovery and identification of ocellatusones A-D, a series of racemic non-γ-pyrone polyketides with novel skeletons, characterized by a bicyclo[3.2.1]octane (1, 2), a bicyclo[3.3.1]nonane (3) or a mesitylene-substituted dimethylfuran-3(2H)-one core (4). Extensive spectroscopic analysis, quantum chemical computation, chemical synthesis, and/or X-ray diffraction analysis were used to determine the structure and absolute configuration of the new compounds, including each enantiomer of racemic compounds 1-4 after chiral HPLC resolution. An array of new and diversity-generating rearrangements is proposed to explain the biosynthesis of these unusual compounds based on careful structural analysis and comparison with six known co-occurring γ-pyrones (5-10). Furthermore, the successful biomimetic semisynthesis of ocellatusone A (1) confirmed the proposed rearrangement through an unprecedented acid induced cascade reaction.

Variation of chemical compounds in wild Heliconiini reveals ecological factors involved in the evolution of chemical defenses in mimetic butterflies.

Evolutionary convergence of color pattern in mimetic species is tightly linked with the evolution of chemical defenses. Yet, the evolutionary forces involved in natural variations of chemical defenses in aposematic species are still understudied. Herein, we focus on the evolution of chemical defenses in the butterfly tribe Heliconiini. These neotropical butterflies contain large concentrations of cyanogenic glucosides, cyanide-releasing compounds acting as predator deterrent. These compounds are either de novo synthesized or sequestered from their Passiflora host plant, so that their concentrations may depend on host plant specialization and host plant availability. We sampled 375 wild Heliconiini butterflies across Central and South America, covering 43% species of this clade, and quantify individual variations in the different CGs using liquid chromatography coupled with tandem mass spectrometry. We detected new compounds and important variations in chemical defenses both within and among species. Based on the most recent and well-studied phylogeny of Heliconiini, we show that ecological factors such as mimetic interactions and host plant specialization have a significant association with chemical profiles, but these effects are largely explained by phylogenetic relationships. Our results therefore suggest that shared ancestries largely contribute to chemical defense variation, pointing out at the interaction between historical and ecological factors in the evolution of Müllerian mimicry.

Time resolved transient circular dichroism spectroscopy using synchrotron natural polarization.

Ultraviolet (UV) synchrotron radiation circular dichroism (SRCD) spectroscopy has made an important contribution to the determination and understanding of the structure of bio-molecules. In this paper, we report an innovative approach that we term time-resolved SRCD (tr-SRCD), which overcomes the limitations of current broadband UV SRCD setups. This technique allows accessing ultrafast time scales (down to nanoseconds), previously measurable only by other methods, such as infrared (IR), nuclear magnetic resonance (NMR), fluorescence and absorbance spectroscopies, and small angle X-ray scattering (SAXS). The tr-SRCD setup takes advantage of the natural polarization of the synchrotron radiation emitted by a bending magnet to record broadband UV CD faster than any current SRCD setup, improving the acquisition speed from 10 mHz to 130 Hz and the accessible temporal resolution by several orders of magnitude. We illustrate the new approach by following the isomer concentration changes of an azopeptide after a photoisomerization. This breakthrough in SRCD spectroscopy opens up a wide range of potential applications to the detailed characterization of biological processes, such as protein folding and protein-ligand binding.

Marine sponges of the genus Stelletta as promising drug sources: chemical and biological aspects.

Marine sponges of the genus Stelletta are well known as rich sources of diverse and complex biologically relevant natural products, including alkaloids, terpenoids, peptides, lipids, and steroids. Some of these metabolites, with novel structures and promising biological activities, have attracted a lot of attention from chemists seeking to perform their total synthesis in parallel to intensive biological studies towards new drug leads. In this review, we summarized the distribution of the chemically investigated Stelletta sponges, the isolation, synthesis and biological activities of their secondary metabolites, covering the literature from 1982 to early 2018.

One-Pot Synthesis of Metastable 2,5-Dihydrooxepines through Retro-Claisen Rearrangements: Method and Applications.

A one-pot methodology to synthesize metastable bicyclic 2,5-dihydrooxepines from cyclic 1,3-diketones and 1,4-dibromo-2-butenes through the retro-Claisen rearrangement of syn-2-vinylcyclopropyl diketone intermediates is reported. DFT calculations were performed to understand the reaction selectivity and mechanisms towards [1,3]- or [3,3]-sigmatropic rearrangements, highlighting the crucial influence of the temperature. The reaction was successfully applied to a short protecting group-free total synthesis of radulanin A, a natural 2,5-dihydrobenzoxepine. Moreover, the strong herbicidal potential of this natural product is demonstrated for the first time.