Total Synthesis of the Marine Macrolide Amphidinolide F

International audienceA new and efficient convergent approach toward the synthesis of amphidinolide F is described through the assembly of three fragments. The two trans-tetrahydrofurans were built by a diastereoselective C-glycosylation with titanium enolate of bulky N-acetyloxazolidinethiones. The side chain was inserted by a Liebeskind–Srogl cross-coupling reaction. A sulfone condensation/desulfonylation sequence, a Stille cross-coupling, and a macrolactonization were applied to connect the fragments

Synthesis of 3,5-Disubstituted 1,2-Dioxolanes through the Use of Acetoxy Peroxyacetals

International audienceThe synthesis of acetoxy-endoperoxyacetal derivatives allowed the formation of functionalized 3,5-disubstituted-1,2-dioxolanes through the formation of reactive peroxycarbenium species under Lewis acid mediation. The introduction of a neutral nucleophile such as allylsilanes, silanes, or silyl enol ethers was accomplished with moderate to good yields. The two studied Lewis acids, TiCl4 and SnCl4, gave contrasted results. The higher diastereoselectivity towards the trans diastereomer in experiments with TiCl4 as Lewis acid was explained by a faster degradation of the cis isomer product, conducting generally to lower yields. A rationalization of this result was supported by calculation

Lauflumide (NLS-4) Is a New Potent Wake-Promoting Compound

Psychostimulants are used for the treatment of excessive daytime sleepiness in a wide range of sleep disorders as well as in attention deficit hyperactivity disorder or cognitive impairment in neuropsychiatric disorders. Here, we tested in mice the wake-promoting properties of NLS-4 and its effects on the following sleep as compared with those of modafinil and vehicle. C57BL/6J mice were intraperitoneally injected with vehicle, NLS-4 (64 mg/kg), or modafinil (150 mg/kg) at light onset. EEG and EMG were recorded continuously for 24 h after injections and vigilance states as well as EEG power densities were analyzed. NLS-4 at 64 mg/kg induced significantly longer wakefulness duration than modafinil at 150 mg/kg. Although no significant sleep rebound was observed after sleep onset for both treatments as compared with their vehicles, modafinil-treated mice showed significantly more NREM sleep when compared to NLS-4. Spectral analysis of the NREM EEG after NLS-4 treatment indicated an increased power density in delta activity (0.75–3.5 Hz) and a decreased power in theta frequency range (6.25–7.25 Hz), while there was no differences after modafinil treatment. Also, time course analysis of the delta activity showed a significant increase only during the first 2 time intervals of sleep after NLS-4 treatment, while delta power was increased during the first 9 time intervals after modafinil. Our results indicate that NLS-4 is a highly potent wake-promoting drug with no sign of hypersomnia rebound. As opposed to modafinil, recovery sleep after NLS-4 treatment is characterized by less NREM amount and delta activity, suggesting a lower need for recovery despite longer drug-induced wakefulness

Loups, chiens et sociétés du Paléolithique supérieur

Le processus de domestication du loup vraisemblablement initié au cours du Paléolithique supérieur, pose aujourd’hui encore de nombreuses questions en termes notamment d’ancienneté du phénomène et de sa diffusion au sein des différents groupes de chasseurs-cueilleurs se succédant au cours de cette période. Pour tenter d’apporter de nouveaux éléments de discussion, de nouvelles analyses pluridisciplinaires ont récemment été entreprises sur la Grotte Maldidier, l’Abri Pataud, l’Abri du Morin, l’Abri Mège, Rochereil, la Grotte-Abri du Moulin à Troubat et le Pont d’Ambon. Ce travail, à visée diachronique, permet de lancer une discussion concernant le statut sauvage ou domestique des grands Canidés dans ces contextes et plus généralement dans les séries du Paléolithique supérieur du Sud-Ouest de la France. Pour cette analyse, nous avons notamment croisé biométrie et archéozoologie. Les données biométriques obtenues à partir des restes de Canidés participent à la diagnose taxinomique. Les études archéozoologique et taphonomique de l’ensemble des vestiges fauniques associés à ces restes permettent quant à elle de documenter la prédation humaine et animale. L’ensemble de ces données nous permet donc de contextualiser la mise en place de cette innovation zootechnique majeure qu’est la domestication ; et plus globalement, de questionner l’évolution des relations Hommes-Canidés à travers les différents techno-complexes du Paléolithique supérieur

From Ring-Expansion to Ring-Contraction: Synthesis of γ-Lactones from Cyclobutanols and Relative Stability of Five- and Six-Membered Endoperoxides toward Organic Bases

International audienceCyclobutanols undergo ring expansion with molecular oxygen in the presence of Co(acac)2 to afford 1,2-dioxane-hemiperoxyketals. In the course of acylation, we observed that endoperoxides rearranged into γ-lactone in the presence of triethylamine. Thus, a generalization of this ring contraction through a Kornblum–DeLaMare rearrangement is here reported. Application of this transformation to monosubstituted 1,2-dioxane derivatives also led to 1,4-ketoaldehydes, in proportions depending on the nature of the substituent. These same conditions applied to five-membered dioxolane analogues led to fragmentation instead, through a retro-aldol type process. This study emphasizes the difference of stability of 1,2-dioxane and 1,2-dioxolane against organic bases, 1,2-dioxolanes having proved to be particularly reactive whereas 1,2-dioxanes showed a relative tolerance under these conditions

Amphidinolides F and C2: An Odyssey in Total Synthesis

International audienceAmphidinolides F, C, C2, and C3 are marine natural products isolated from dinoflagellates amphidinium species. They share the same macrolactone core, the difference between them residing at the side chain level. A predominant feature of these amphidinolides is the presence of two trans-THF rings inside the macrolactone core, titanium mediated C-glycosylation being applicable to build these motives. Thus, the original strategy for their total synthesis was based on the assembly of three main fragments corresponding to C 1-C 9 , C 10-C 19 , and C 20-C 29 or C 20-C 34 disconnections. Whereas synthesis of all fragments was successful, the C-glycosylation reaction between C 19 and C 20 turned out to be an issue. Therefore, a second route was designed. The new disconnection between C 17 and C 18 was based on a sulfone addition and a desulfonylation sequence. Our convergent strategy allowed the total synthesis of amphidinolide F and enabled a new unifying route towards the synthesis of amphidinolides C, C2, and C3 using a late-stage divergent approach. Although unsatisfying yields at some critical steps, our work culminated into the first total synthesis of amphidinolide C2

Oxidative Ring Expansion of Cyclobutanols: Access to Functionalized 1,2-Dioxanes

Cyclobutanols undergo an oxidative ring expansion into 1,2-dioxanols by using Co(acac)2 and triplet oxygen (3O2) as radical promoters. The formation of an alkoxy radical drives to the regioselective break of the strained ring with stabilization of a new radical on the most substituted side. The radical traps then oxygen to form 1,2-dioxanols. The reaction is particularly effective on secondary cyclobutanols but can work also on tertiary alcohols. Further acetylation generates peroxycarbenium species under catalytic Lewis acid conditions, which react with neutral nucleophiles. Many original 1,2-dioxanes, which would be difficult to prepare by another method, were then obtained with a preferred 3,6-cis-configuration. This method provides an interesting access to the total synthesis of many natural endoperoxides

Scope and Limitations of Exploiting the Ability of the Chemosensitizer NV716 to Enhance the Activity of Tetracycline Derivatives against Pseudomonas aeruginosa

The spread of antibiotic resistance is an urgent threat to global health that requires new therapeutic approaches. Treatments for pathogenic Gram-negative bacteria are particularly challenging to identify due to the robust OM permeability barrier in these organisms. One strategy is to use antibiotic adjuvants, a class of drugs that have no significant antibacterial activity on their own but can act synergistically with certain antibiotics. Previous studies described the discovery and development of polyaminoisoprenyl molecules as antibiotic adjuvants with an OM effect. In particular, the compound NV716 has been shown to sensitize Pseudomonas aeruginosa to tetracycline antibiotics such as doxycycline. Here, we sought to explore the disruption of OM to sensitize P. aeruginosa to otherwise inactive antimicrobials using a series of tetracycline derivatives in the presence of NV716. We found that OM disruption expands the hydrophobicity threshold consistent with antibacterial activity to include hydrophobic molecules, thereby altering permeation rules in Gram-negative bacteria

Anti-protozoal and anti-fungal evaluation of 3,5-disubstituted 1,2-dioxolanes

International audienc