Three Togolese aromatic plants' essential oils diurnal variations and their insecticidal activities against the dengue vector Aedesaegypti.

The present reported work deals with the ability of Togolese plants' essential oils (EOs) to act as repellents for Aedes aegypti mosquitoes in order to use them as personal protective requirements or actions against mosquito bites and therefore to drastically reduce the risk of contracting dengue or yellow fever. EOs studied here were extracted from dry leaves of Ageratum conyzoides L., Eucalyptus citriodora Hook, and Lantana camara Linn, three plants that were collected at different daytimes (7 a.m., 1 p.m., and 7 p.m.) at various locations in Togo. Using a Clevenger-type device, EOs were obtained by the hydrodistillation method (Clevenger, 1928). The physical parameters of the EOs such as density, refractive index, rotatory power, and organoleptic properties were determined. Then, the characterization of EOs using gas chromatography equipped with a flame ionization detector (GC/FID) and gas chromatography coupled to mass spectrometry (GC/MS) was conducted. Chemical analyses showed the presence of several main compounds from EO samples of the three plants. The major compounds were characterized and identified as: (i) precocene I (67.7, 70.6, and 66.9%) and ß-caryophyllene (17.4, 12.1, and 16.5%) for the EO of A. conyzoïdes; (ii) citronellal (63.3, 67.2, and 75.4%) and citronellol (24.5, 21.4, and 14.3%) for E. citriodora and (iii) ß-caryophyllene (15.3, 11.7, and 12.4%), sabinene (28.4, 35, and 33.3%) and eucalyptol (11.5, 14.1, and 15.6%) for L. camara at 7 a.m., 1 p.m., and 7 p.m., respectively. The yield and the chemical composition of the oils vary according to harvesting time and sunlight. The insecticidal activity of EOs was evaluated following the CDC bottle method on Aedes aegypti females. All the EOs tested on the female adults of Aedes aegypti showed significant insecticidal activity. The EO of A. conyzoïdes at 1 p.m. and 7 p.m. resulted in 100% mortality after 8 min of exposure time at the lowest concentration (0.0025%). At the same concentration for the EO of E. citriodora, the mortality rates were 83%, 38.8%, and 30.80% at 7 a.m., 1 p.m., and 7 p.m., respectively for an exposure time of 8 min. The EO extracted from the leaves of L. camara harvested at 7 a.m. was effective after an exposure time of 15 min for a concentration of 0.02%. For the same concentration, the mortality rates of the EO of L. camara harvested at 1 p.m. and 7 p.m., after 8 min were 62.9% and 52%, respectively. From these interesting results reported for the first time in Togo, EOs from leaves of three Togolese plants harvested at different times of the day appear to be a valuable alternative for mosquito vector control in Togo or abroad countries in which dengue and yellow fever constitute a terrible scourge.

Dichotomic Dearomatizations of Benzene vs Pyridine Rings of Sulfonyloxypyridine via (3 + 2) Cycloaddition.

Electron-poor arenesulfonyloxypyridines are selectively dearomatized whether on the pyridine or on the phenyl group through 1,3-dipolar cycloaddition (1,3-DC) involving non-stabilized azomethine ylides (AMY). Electronic effects of substituents on the aromatic rings allow to induce the regioselectivity of the transformation. Novel pyrrolidinic polycyclic heterocycles are thereby produced under mild acidic conditions at room temperature.

Novel Oleanolic Acid-Phtalimidines Tethered 1,2,3 Triazole Hybrids as Promising Antibacterial Agents: Design, Synthesis, In Vitro Experiments and In Silico Docking Studies.

As part of the valorization of agricultural waste into bioactive compounds, a series of structurally novel oleanolic acid ((3ß-hydroxyolean-12-en-28-oic acid, OA-1)-phtalimidines (isoindolinones) conjugates 18a-u bearing 1,2,3-triazole moieties were designed and synthesized by treating an azide 4 previously prepared from OA-1 isolated from olive pomace (Olea europaea L.) with a wide range of propargylated phtalimidines using the Cu(I)-catalyzed click chemistry approach. OA-1 and its newly prepared analogues, 18a-u, were screened in vitro for their antibacterial activity against two Gram-positive bacteria, Staphylococcus aureus and Listeria monocytogenes, and two Gram-negative bacteria, Salmonella thyphimurium and Pseudomonas aeruginosa. Attractive results were obtained, notably against L. monocytogenes. Compounds 18d, 18g, and 18h exhibited the highest antibacterial activity when compared with OA-1 and other compounds in the series against tested pathogenic bacterial strains. A molecular docking study was performed to explore the binding mode of the most active derivatives into the active site of the ABC substrate-binding protein Lmo0181 from L. monocytogenes. Results showed the importance of both hydrogen bonding and hydrophobic interactions with the target protein and are in favor of the experimental data.

Autotandem Catalysis: Inexpensive and Green Access to Functionalized Ketones by Intermolecular Iron-Catalyzed Amidoalkynylation/Hydration Cascade Reaction via N-Acyliminium Ion Chemistry.

Iron-based catalysts were applied in cascade-type reactions for the synthesis of different carbonyl compounds. The reactions proceeded by a new iron-catalyzed cascade of alkynylation/hydration by using both the σ- and π-Lewis acid properties of iron salts. The alkynylation reactions of several endo and exocyclic acetoxylactams were achieved with three different catalysts including FeCl3 ⋅ 6H2 O, FeCl3 , and Fe(OTf)3 showing the efficiency of σ-Lewis acidity of iron (III) salts in catalyzing the alkynylation reaction. We also demonstrated that the reaction sequence could be shortened by the direct use of hydroxylactams, leading to an environmentally friendly protocol, avoiding the need to perform unnecessary lengthy steps. A combination of the hard/soft iron Lewis acid properties was then used to implement an unprecedented tandem intermolecular alkynylation/intramolecular hydration sequence allowing expedient access to a new carbonyl structures from trivial materials.

Phenyliodine(III) Diacetate/I2 -Mediated Domino Approach for Pyrrolo[1,4]Thiazines and 1,4-Thiazines by a One-Pot Morin Rearrangement of N,S-Acetals.

An efficient domino transformation using a phenyliodine(III) diacetate (PIDA)/I2 combination towards Morin 1,4-thiazine compounds has been developed starting from N,S-acetals. The latter leads to "one-step" regioselective methylene insertion without the need for traditional sulfoxide intermediates in good yields. The reaction involves easily accessible N,S-acetals obtained from cost-effective basic ketones and cysteamine as starting materials. This process ultimately leads to 1,4-thiazines related to natural product and fused derivatives necessary for further QSAR study.

Access to 3-spiroindolizines containing an isoindole ring through intra-molecular arylation of spiro-N-acyliminium species: a new family of potent farnesyltransferase inhibitors.

Based on N-acyliminium species, two efficient and rapid approaches to diversify spirocyclic systems connected by two different carbon centers to the isoindole ring have been developed. The imide reduction and the tandem oxidative cleavage of olefin/formyl-amide equilibration were at first selected as the key steps for these strategies. Ultimately the intramolecular α-amidoalkylation reaction was achieved through the arylation of α-acetoxy lactams or α-hydroxy lactams using, respectively, a Lewis acid or a Brønsted acid depending on the nature of N-acyliminium precursors. The latter led, in addition to the spiro-6-membered aza-heterocycles, to the formation of scarce spiro-5-membered analogues which show promising inhibitory activities on human farnesyltransferase in the nanomolar range demonstrating improved IC50 values of up to 1.5 nM.

Design and semisynthesis of new herbicide as 1,2,3-triazole derivatives of the natural maslinic acid.

Interesting biological activities (anti-inflammatory, anticancer, antiviral, antioxidant, antidiabetic…) have been reported for maslinic acid (MA) and MA-based compounds. In continuation of our previous work on MA, herbicide potential of Tunisian plant extracts and 1,4-triazolyl derivatives of MA, we now wish to report semisynthesis of new MA-based triazole hybrid compounds with herbicide potential. These compounds were synthesized through Cu-catalyzed azide-alkyne cycloaddition (CuAAC) under microwave irradiation conditions between propargylated MA and a series of phthalimide azides. Here, the first partner of CuAAC reaction (propargylated MA) resulted from propargylation of C-28 carboxylic acid group of isolated MA from the well-known Mediterranean plant Olea europaea L. (Oleaceae). So far, phthalimide azide derivatives were achieved by trapping of N-acyliminium ion, in-situ generated under catalytic condition of Bi(OTf)3, by aromatic nucleophiles. The cycloaddition reaction afforded regiospecifically 1,4-disubstituted triazoles in good yields. The latter hybrid compounds were shown to exhibit a high inhibition potential of seed germination. This constitutes the first step in development of potent herbicides since one of the final semisynthesized structures can serve as a promising lead candidate for further studies.

Structure-Based Kinetic Control in a Domino Process: A Powerful Tool Toward Molecular Diversity in Chromone Series.

Two successive original routes leading to two novel families of polyheterocycles starting from the versatile chromone-based Michael acceptors platform are reported herein. The major aspect of this work is the selective access to these frameworks by changing the course of the domino process involved in their formation. First, enaminochromanones were selectively accessed under uncommon kinetic control. In this study, we showed that the tuning of the selectivity toward the kinetic product could be achieved by key structural modifications of the different reaction partners involved in the domino process. Once selectivity was efficiently controlled, enaminochromanones were ultimately transformed into a more complex family of polyheterocycles containing the pyrrolo-oxazinone framework. Here, the modulation of the domino sequence toward these particularly scarce structures was enabled by a pivotal switch in reactivity induced by aryl-λ3-iodanes.

Phytochemical and biological studies of Atriplex inflata f. Muell.: isolation of secondary bioactive metabolites.

OBJECTIVES: This work describes the phytochemical and biological investigation of the Tunisian Atriplex inflata F. Muell (Chenopodiaceae). METHODS: Their chemical structures were elucidated on the basis of extensive spectroscopic methods, including 1D NMR and 2D NMR, ESI-HRMS and comparison with available literature data. The isolates were evaluated for their antioxidant activity by the DPPH• , ABTS+• , Fe3+ and catalase assays and also for their antibacterial and anticholinesterase activity. KEY FINDINGS: The chemical study of Atriplex inflata F. Muell led to the isolation of two fatty acids (9E)-methyl-8,11,12-trihydroxyoctadec-9-enoate 1 and (9E)-8,11,12-trihydroxyoctadecenoic acid 2 together with (Z)-litchiol B 3 and 20-hydroxyecdysone 4. Three of which are reported here for the first time in Atriplex genus. Based on the biosynthesis of hydroxylated arachidonic acid and derivatives, a plausible biogenesis pathway of the two fatty acids (1 and 2) was proposed. (Z)-litchiol B (3) was found to be the most active against Staphylococcus aureus. According to the literature, this is the first time that compounds 1, 2 and 3 were tested for their eventual biological activity. CONCLUSIONS: In the results of the present work, we have proposed the biogenesis pathway of unsaturated fatty acid and described the structure-activity relationship.

Development of SECheM Concept for Isolation and Chemical Modification of Gossypol Directly from Cienfuegosia digitata.

INTRODUCTION: Gossypol is an axially chiral natural polyphenol classically extracted from the Malavaceae family. Nevertheless, its extraction and isolation from a plant can be quite complicated and extremely time-consuming since gossypol is known to be sensitive to degradation under solvents, high temperature and light action. Moreover, its purification over column chromatography is a challenging problem due to its ability to oxidise and the existence of various tautomer forms. OBJECTIVE: To develop an efficient "one-step" strategy for simultaneous extraction and semi-synthesis by short-circuiting critical gossypol isolation and purification steps. METHODOLOGY: Gossypol was first isolated from Cienfuegosia digitata roots, characterised (by 1D and 2D NMR) and quantified (by UV spectrophotometry). Thus, aniline was selected to test the "one-step" in situ trapping of freshly extracted gossypol leading to a Schiff base analogue. After screening solvents and extraction times on this model reaction, the "SECheM" (simultaneous extraction and chemical modification) concept was successfully extended to other amines, underlining the efficiency and the robustness of the strategy. RESULTS: After having shown that gossypol occurred as a major compound in C. digitata roots, different experimental procedures using Soxhlet extraction in the presence of aniline pointed out the best conditions for the SECheM concept (7 h of reaction and extraction time in ether as solvent). Ultimately, the concept has been generalised to 17 other amines. CONCLUSION: This is a report of the first semi-synthesis that allows: (1) "in situ" preparation of more stable gossypol Schiff base derivatives directly from ground plant material and (2) circumvention of gossypol extraction and purification problems. Copyright © 2017 John Wiley & Sons, Ltd.

Metal-Free Cascade Approach toward Polysubstituted Indolizines from Chromone-Based Michael Acceptors.

An efficient cascade transformation toward indolizine-based molecules has been developed. This process leads to the rapid construction of two C-N bonds and one C-C bond without the need of any metal catalysis. The approach involves easily accessible chromone-based Michael acceptors and propargylamine derivatives as starting materials. This cascade constitutes a novel and very competitive alternative to the well reported strategies using pyridine or pyrrole derivatives for accessing the indolizine ring with substituents at uncommon C-positions.

Original Mitsunobu-Triggered Sequence Involved in a One-Pot Domino Process toward Tetracyclic Systems Bearing a Bis-N,O-acetal Junction.

Herein is reported an efficient, one-pot domino process through a 1,6-aza-Michael addition-triggered sequence and an original Mitsunobu-type concerted sequence for the synthesis of tetracyclic systems containing a bis-N,O-acetal junction. This methodology led to the construction of four new bonds, the cleavage of three C-O bonds, and the generation of an asymmetric center. Mitsunobu activation afforded final ring closure involving the creation of two bonds, which remains unprecedented among reported Mitsunobu-type sequences. The latter occurred in a regioselective fashion at the challenging C6-position of 2-pyridone intermediates. In the case of adequately substituted enantiopure amino alcohols, up to 95:5 of diastereoisomeric excess was achieved. Computational studies allowed the discrimination of a favored pathway for Mitsunobu sequence and supported the regioselectivity as well as the diastereoselectivity observed for this step.

Use of chiral-pool approach into epi-thieno analogues of the scarce bioactive phenanthroquinolizidine alkaloids.

The stereoselective synthesis of epi-thieno analogues of the phenanthroquinolizidine bioactive alkaloids (-)-Cryptopleurine and (-)-(15R)-Hydroxycryptopleurine was achieved in five steps starting from easily available enantiopure (S)-2-aminoadipic acid used as chiral pool and nitrogen atom source. During these investigations, both π-cationic cyclization of chiral N-thienylmethyl-6-oxopipecolinic acids into pure (S)-keto-lactams and theirs regioselective and diastereoselective reduction, considered as key steps of this sequence, were studied. Of particular interest, the Friedel-Crafts cyclization using (CF3CO)2O/BF3·Et2O show that near the expected keto-lactams, enamides and enamidones containing trifluoromethyl residue were isolated. A mechanism leading to the latter products with high synthetic potential was discussed.

New septanoside and 20-hydroxyecdysone septanoside derivative from Atriplex portulacoides roots with preliminary biological activities.

The phytochemical investigation of a Tunisian plant Atriplex portulacoides (Chenopodiaceae) led to the isolation of two new compounds designated as portulasoid (2) and septanoecdysone (3) along with the known 20-hydroxyecdysone (20HE) (1). Their chemical structures were elucidated on the basis of extensive spectroscopic methods including ES-HRMS, 1D and 2D-NMR. The isolated compounds were finally tested for their antioxidant activity by using DPPH, ABTS(+), Fe(3+) and catalase assays and also for their antibacterial and anticholinesterase activities.

Simple access to highly functional bicyclic γ- and δ-lactams: origins of chirality transfer to contiguous tertiary/quaternary stereocenters assessed by DFT.

This paper describes the synthesis of both polysubstituted oxazolo-pyrrolidinones and -piperidinones by a domino process. The methodology is based on the reaction between hydroxyl halogenoamides and Michael acceptors, which leads efficiently to bicyclic lactams. The process is compatible with unsymmetrical electron-withdrawing groups on the Michael acceptor, which allows the formation of two contiguous and fully controlled tertiary and quaternary stereocenters. In the case of tetrasubstituted Michael acceptors, two adjacent quaternary stereocenters are formed in good yield. Starting from (R)-phenylglycinol derived amides results in the formation of enantioenriched bicyclic lactams in low to good yields and with high levels of stereoselectivity, thus greatly increasing the scope and interest of this strategy. The origins of chirality transfer and diastereoselectivity were studied by DFT calculations and have been attributed to a kinetic control in one of the last two steps of the reaction sequence. This selectivity is dependent upon both the substituents on the Michael acceptor and the sodium cation chelation.

Synthesis of highly functionalized pyrrolidines as tunable templates for the direct access to (±)-coerulescine and the tricyclic core of martinellines.

An aza-Michael induced ring closure (aza-MIRC) tandem reaction of benzyl (2-bromoethyl)carbamate with various Michael acceptors is described. The N-Cbz-ß-gem-disubstituted pyrrolidines thus obtained were proved to be versatile intermediates for the rapid access to both martinelline and spirooxindole backbones. An application of this strategy towards an expedient 4 step total synthesis of (±)-coerulescine is also presented.