Exploring the Isomeric Precursors of Olive Oil Major Secoiridoids: An Insight into Olive Leaves and Drupes by Liquid-Chromatography and Fourier-Transform Tandem Mass Spectrometry

Secoiridoids play a key role in determining health benefits related to a regular consumption of extra-virgin olive oil (EVOO), in which they are generated from precursors of the same class naturally occurring in drupes and leaves of the olive (Olea europaea L.) plant. Here, reversed-phase liquid chromatography coupled to electrospray ionization and Fourier-transform single/tandem mass spectrometry (RPLC-ESI-FTMS and MS/MS) was employed for a structural elucidation of those precursors. The presence of three isoforms in both matrices was assessed for oleuropein ([M-H]− ion with m/z 539.1770) and was emphasized, for the first time, also for ligstroside (m/z 523.1821) and for the demethylated counterparts of the two compounds (m/z 525.1614 and 509.1665, respectively). However, only the prevailing isoform included an exocyclic double bond between carbon atoms C8 and C9, typical of oleuropein and ligstroside; the remaining, less abundant, isoforms included a C=C bond between C8 and C10. The same structural difference was also observed between secoiridoids named elenolic acid glucoside and secoxyloganin (m/z 403.1246). This study strengthens the hypothesis that secoiridoids including a C8=C10 bond, recently recognized as relevant species in EVOO extracts, arise mainly from specific enzymatic/chemical transformations occurring on major oleuropein/ligstroside-like precursors during EVOO production, rather than from precursors having that structural feature.

Genome mining of cryptic tetronate natural products from a PKS-NRPS encoding gene cluster in Trichoderma harzianum t-22

The gene cluster of trihazones was identified from Trichoderma harzianum t-22 and heterologously activated in Aspergillus nidualns. The α-KG dependent dioxygenase ThnC was confirmed to catalyze exocyclic double bond formation.

One-step route to tricyclic fused 1,2,3,4-tetrahydroisoquinoline systems via the Castagnoli–Cushman protocol

The Castagnoli–Cushman reaction of 3,4-dihydroisoquinolines with glutaric anhydride, its oxygen and sulfur analogues was investigated as a one-step approach to the benzo[a]quinolizidine system and its heterocyclic analogs. An extension towards the pyrrolo[2,1-a]isoquinoline system was achieved with the use of succinic anhydride. The results are evidence of an unexplored method for the access of the aforementioned tricyclic annelated systems incorporating a bridgehead nitrogen atom. The structures and relative configurations of the new compounds were established by means of 1D and 2D NMR techniques. The reactions between 1-methyldihydroisoquinoline and glutaric, diglycolic and succinic anhydrides yielded unexpected isoquinoline derivatives containing an exocyclic double bond. The compounds prepared bear the potential to become building blocks for future synthetic bioactive molecules.

HETEROCYCLIZATION OF 3-PROPARGYLSULFANYL-5 PHENYL-1,2,4-TRIAZINE: TANDEM REACTIONS WITH BROMINE LEADING TO NEW DERIVATIVES OF 7 PHENYL[1,3]THIAZOLO[3,2-B][1,2,4]TRIAZINIUM

Derivatives of 1,2,4-triazine-3-thione exhibit biological activity in a wide range. They have optoelectronic properties and can be used as synthons in synthesis of various pyridines by the Diels-Alder reaction. 1,2,4-Triazines are of the greatest interest, for organic synthesis in particular. In the present study we have established that the interaction of 3-propargylsulfanyl-5-phenyl-1,2,4-triazine, obtained by alkylation of 5-phenyl-2,3-dihydro-1,2,4-triazine-3-thione with 3-bromopropyne in acetone in the presence of triethylamine, with halogens leads to annelation of thiazole cycle. At that, [1,3]thiazolo[3,2-b][1,2,4]triazinium systems contain either endo- or exocyclic double bond in their structure, depending on the halogen type. By way of example, iodine acting on propargyl sulfide forms a dark precipitate of (3Z)-3-iodomethylene-7-phenyl-2,3-dihydro-[1,3]thiazolo[3,2-b][1,2,4]triazinium triiodide, the structure of which has been confirmed by 1H and 13C NMR spectroscopy, including two-dimensional 2D 1H-13C HSQC, HMBC and 1H-1H NOESY experiments. Treatment of the obtained triiodide by sodium iodide in acetone leads to synthesis of the corresponding monoiodide, which precipitates from the reaction mixture as a dark red precipitate. Reaction with bromine, as distinct from heterocyclization under iodine action, comprises an unusual cascade reaction including the stages of electrophile heterocyclization, bromine addition, and hydrogen bromide elimination, which leads to formation of 3-dibromomethyl-7-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazinium bromide. It should be pointed out that the identifying feature of 3-propargylsulfanyl-5-phenyl-1,2,4-triazine heterocyclization under iodine and bromine action is the signal bias of the aromatic proton in a triazine ring towards weak field in the 1H NMR spectrum of the reaction products. This is presumably associated with formation of the positively charged nitrogen atom.

Chemoselective Ring-Opening Polymerization of Bio-Renewable α-Methylene-γ-Butyrolactone via an Organophosphazene/urea Binary Synergistic Catalytic System Toward a Sustainable Polyester

Despite the great potential of bio-renewable a-methylene-<a></a><a></a><a>g-butyrolactone</a> (MBL) to produce functional recyclable polyester, the ring-opening polymerization (ROP) of MBL remains as a challenge due to the competing polymerization of the highly reactive exocyclic double bond and the low strained five membered ring. In this contribution, we present the first organocatalytic chemoselective ROP of MBL to exclusively produce recyclable unsaturated polyester by utilizing a phosphazene base/urea binary catalyst. We show that delicate chemoselectivity can be realized by controlling the temperature and using selected urea catalysts. Experimental and theoretical calculations provide mechanistic insights and indicate that the kinetically controlled ROP pathway is favored by using urea with stronger acidity at low temperatures.

Chemoselective Ring-Opening Polymerization of Bio-Renewable α-Methylene-γ-Butyrolactone via an Organophosphazene/urea Binary Synergistic Catalytic System Toward a Sustainable Polyester

Despite the great potential of bio-renewable a-methylene-<a></a><a></a><a>g-butyrolactone</a> (MBL) to produce functional recyclable polyester, the ring-opening polymerization (ROP) of MBL remains as a challenge due to the competing polymerization of the highly reactive exocyclic double bond and the low strained five membered ring. In this contribution, we present the first organocatalytic chemoselective ROP of MBL to exclusively produce recyclable unsaturated polyester by utilizing a phosphazene base/urea binary catalyst. We show that delicate chemoselectivity can be realized by controlling the temperature and using selected urea catalysts. Experimental and theoretical calculations provide mechanistic insights and indicate that the kinetically controlled ROP pathway is favored by using urea with stronger acidity at low temperatures.

Stereoselective Synthesis of Carbon-Sulfur-Bridged Glycomimetics by Photoinitiated Thiol-Ene Coupling Reactions

Oligosaccharides and glycoconjugates are abundant in all living organisms, taking part in a multitude of biological processes. The application of natural O-glycosides in biological studies and drug development is limited by their sensitivity to enzymatic hydrolysis. This issue made it necessary to design hydrolytically stable carbohydrate mimetics, where sulfur, carbon, or longer interglycosidic connections comprising two or three atoms replace the glycosidic oxygen. However, the formation of the interglycosidic linkages between the sugar residues in high diastereoslectivity poses a major challenge. Here, we report on stereoselective synthesis of carbon-sulfur-bridged disaccharide mimetics by the free radical addition of carbohydrate thiols onto the exo-cyclic double bond of unsaturated sugars. A systematic study on UV-light initiated radical mediated hydrothiolation reactions of enoses bearing an exocyclic double bond at C1, C2, C3, C4, C5, and C6 positions of the pyranosyl ring with various sugar thiols was performed. The effect of temperature and structural variations of the alkenes and thiols on the efficacy and stereoselectivity of the reactions was systematically studied and optimized. The reactions proceeded with high efficacy and, in most cases, with complete diastereoselectivity producing a broad array of disaccharide mimetics coupling through an equatorially oriented methylensulfide bridge.

REACTION OF PYRIDO[2,1-a]ISOINDOLE WITH З (R)- AND (S)- N-α-METHILBENZYLMALEIMIDE

Selective chemical reactions create new possibilities for controlled synthesis of compounds with pre-designed properties for further use in medical chemistry, material science and other fields. This is especially useful for such synthetic methodology as [4+2] cycloaddition. Current work is dedicated to study of reactions between N-chiral maleinimides with cyclic dienes based on the pyridoisoindol. Pyrido[2,1-a]isoindol turned out to be the most practical object to study the first example of asymmetric variant of the Diels-Alder reaction involving condensed isoindols. Previously, we established that this heterocyclic system, in contrast to other azino- and azoloisoindols, upon undergoing cycloaddition with non-chiral maleinimides gives only rearranged adducts of the first type. This type of compounds have also interesting stereochemistry: in solid state they have twisted double bond (twist angle 7-10°), while in solution they exist as a mixture of athropodiastereomeres due to the asymmetric Carbon atom and hindered rotation around С–С bond between exocyclic double bond and 2-(α-pyridil)phenyl fragment. Initial expectation was that chiral induction would influence the ratio of corresponding athropodiastereomeres. Calculations show that there are four possible athropodiastereomeres due to the chiral center and sterically hindered chiral axis. In case of non-chiral dienophiles, reaction results in two major diastereomeres (for our purposes marked as A and B) with 70:30 ration and two minor isomers (marked С and D respectively), the latter constituting less than 5% of the total amount. Major and minor isomers are in constant complex equilibrium, controlled via slow rotation of around corresponding С-С bond on one hand (which is the reason for athropodiastereomeres between major forms A and B, shown via NMR spectra at different temperatures), and on the other hand – fast equilibrium due to the 1,5-sigmatropic shift (cause for the minor forms C and D). Target reaction was studied under standard conditions for this rearrangement and under the kinetic control in the inert atmosphere at -80°С using TiCl4 as catalyzer. We therefore show that reaction pathway is similar to our previous examples and results in rearranged adducts of the first type. Ratio of athropodiastereomeres (both major and minor forms) is different from previous examples using non-chiral 2-substituted maleimides. Asymmetric induction spontaneously transfers from influencing the Diels-Alder reaction to influencing synchronic sigmatropic rearrangement, which is the final stage in the formation of the rearranged adduct of the first type in condensed isoindol systems.

Synthesis of Spiro-Isoxazolidine Derivatives of Methyl α-Isocostate

Background: In recent decades, natural products are an important source of chemotherapeutics as more than half of the effective cancer drugs can be traced to natural origins. Objective: Moreover, the modification of natural products is one of the most common and fruitful approaches to obtain novel therapeutic agents in medicinal chemistry. Method: Continuing with a research project based on the support of Moroccan plant resources. we report herein the use of α-isocostic acid extracted in enantiomerically pure form from Dittrichia viscosa as a convenient starting material for the synthesis of new eudesmane derivatives. Results: Novel spiro derivatives with a natural scaffold were prepared. Spiro-isoxazolidine derivatives were generated on the exocyclic double bond adjacent to the ester α,β-unsaturated function by 1,3-dipolar cycloaddition of methyl α-isocostate 1 derived from sesquiterpenic isocostic acid, with nitrones 2. Conclusion: This procedure allowed us to generate enantiomerically pure spiro compounds in one diastereoisomer form with a limited number of steps. These compounds were fully characterized by spectroscopic methods.

Guaiane-Type Sesquiterpenoids From Dendranthema morifolium (Ramat.) S. Kitam Flowers Protect H9c2 Cardiomyocyte From LPS-Induced Injury

This study investigated the protective effects of guaiane-type sesquiterpenoids isolated from Dendranthema morifolium (Ramat.) S. Kitam flowers on lipopolysaccharide (LPS)-induced injury in H9c2 cardiomyocyte. Cell viability was determined by thiazolyl blue tetrazolium bromide (MTT). The content of released tumor necrosis factor alpha (TNF- α) and interleukin 6 (IL-6) was evaluated by enzyme-linked immunosorbent assay. The levels of lactate dehydrogenase (LDH) and creatine phosphate kinase (CK) were measured by using commercial available kits. The protein expression levels of pelF2 α, GRP78, Bax, caspase-3, caspase-9, Bcl-2, LC3-II, and p62 were measured by in-cell Western. Flow cytometry was used to detect H9c2 cardiomyocyte apoptosis. Compounds 5, 7, 1, 8, and 2 exhibited the effects of cardioprotection and activity sequence enhancement. The levels of IL-6, TNF- α, LDH, CK, pelF2 α, GRP78, Bax, caspase-3, caspase-9, p62, and H9c2 cardiomyocyte apoptosis were increased in LPS-treated H9c2 cardiomyocyte, while those of Bcl-2 and LC3-II were decreased. These effects could be effectively reversed by compounds 5, 7, 1, 8, and 2. Results demonstrated that the guaiane-type sesquiterpenoids could prevent LPS-induced injury in cardiomyocyte by decreasing endoplasmic reticulum (ER) stress, apoptosis, and autophagy as well as downregulating the inflammatory mediators. In addition, the active groups of guaiane-type sesquiterpenoids might be the angelate at C-8 and the exocyclic double bond at C-11.