Optimizing the Synthesis Strategy of the Chlorinated Chain Characteristic to the Enacyloxin Series Using Models.

In this paper are presented the results of the preliminary studies conducted on two model substrates that allowed the testing of various strategies and set the proper conditions that thereafter culminated in the synthesis of the C1-C23 chain of enacyloxin-IIa and its congeners. Innovative strategic options were explored on each model allowing the stereochemical control of the following two elements: (a) the 2E, 4E, 6E, 8E, and 10Z chlorinated undecapentaenoic chain, thanks to Z-selective Kaneda's alkyne allylchlorination and an E-selective Pd/Cu allene-alkyne coupling and (b) the unusual syn-anti -OH/-Cl/-OCONH2 C17-C19 triad, thanks to a highly diastereoselective Mukaiyama aldol reaction.

A combined toxicokinetic and metabolic approach to investigate deschloro-N-ethylketamine exposure in a multidrug user.

The use of new psychoactive substances derived from ketamine is rarely reported in France. A chronic GHB, 3-MMC, and methoxetamine consumer presented a loss of consciousness in a chemsex context and was referred to the intensive care unit with a rapid and favorable outcome. To investigate the chemicals responsible for the intoxication, a comprehensive analysis was conducted on the ten plasma samples collected over a 29.5-hour period, urine obtained upon admission, a 2-cm hair strand sample, and a seized crystal. These analyses were performed using liquid chromatography hyphenated to high resolution tandem mass spectrometry operating in targeted and untargeted modes. Additionally, analyses using gas chromatography coupled to mass spectrometry and nuclear magnetic resonance were conducted to probe the composition of the seized crystal. The molecular network-based approach was employed for data processing in non-targeted analyses. It allowed to confirm a multidrug exposure encompassing GHB, methyl-(aminopropyl)benzofuran (MAPB), (aminopropyl)benzofuran (APB), methylmethcathinone, chloromethcathinone, and a new psychoactive substance belonging to the arylcyclohexylamine family namely deschloro-N-ethyl-ketamine (O-PCE). Molecular network analysis facilitated the annotation of 27 O-PCE metabolites, including phase II compounds not previously reported. Plasma kinetics of O-PCE allowed the estimation of the elimination half-life of ∼5 hours. Kinetics of O-PCE metabolites was additionally characterized, possibly useful as surrogate biomarkers of consumption. We also observed marked alterations in lipid metabolism related to poly consumption of drugs. In conclusion, this case report provides a comprehensive analysis of exposure to O-PCE in a multidrug user including kinetic and metabolism data in human.

Advancements in Enacyloxins Total Synthesis: Access to the Chlorinated Polyunsaturated Chain Peculiar to this Promising Family of Antibiotics.

The first synthesis of the protected chain specific to the enacyloxin antibiotic family is reported. The noticeable features are (a) the construction of the chlorinated undecapentaenoic moiety implementing the sequence Tsuji's alkyne syn allyl-chlorination, E-selective Pd/Cu-catalyzed allene-alkyne coupling, Horner-Wadsworth-Emmons olefination, dehydration; (b) control of the C18 chlorinated stereogenic center by organo-catalyzed aldehyde α-chlorination; and (c) the assemblage of this aldehyde with the C1-C16 ketone using a highly diastereoselective Mukaiyama aldol.

Identification of new Omega-3 very long chain poly-unsaturated fatty acids in meibomian gland secretions.

Three new very long chain polyunsaturated fatty acids (VLC PUFA) belonging to the omega-3 family have been identified in meibum samples collected by Schirmer strips. These VLC PUFA, namely FA (32:3), FA (34:3) and FA (36:3), were detected in O-acyl-ω-hydroxy fatty acids using a molecular network approach, and as free fatty acids. Identification was supported by retention time prediction model, exact mass determination and isotopic patterns. Double bond location was determined using cross metathesis reaction associated to tandem mass spectrometry. In meibum, synthesis of these VLC PUFA is likely to be mediated by elongation of very long chain fatty acids 4 enzyme. The biological role of these newly VLC PUFA and their occurrence in other tissues and biological fluids remains to be elucidated.

Deepening of lipidome annotation by associating cross-metathesis reaction with mass spectrometry: application to an in vitro model of corneal toxicity.

The in-depth knowledge of lipid biological functions needs a comprehensive structural annotation including a method to locate fatty acid unsaturations, which remains a thorny problem. For this purpose, we have associated Grubbs' cross-metathesis reaction and liquid chromatography hyphenated to tandem mass spectrometry to locate double bond positions in lipid species. The pretreatment of lipid-containing samples by Grubbs' catalyst and an appropriate alkene generates substituted lipids through cross-metathesis reaction under mild, chemoselective, and reproducible conditions. A systematic LC-MS/MS analysis of the reaction mixture allows locating unambiguously the double bonds in fatty acid side chains of phospholipids, glycerolipids, and sphingolipids. This method has been successfully applied at a nanomole scale to commercial standard mixtures consisting of 10 lipid subclasses as well as in lipid extracts of human corneal epithelial (HCE) cell line allowing to pinpoint double bond of more than 90 species. This method has also been useful to investigate the lipid homeostasis alteration in an in vitro model of corneal toxicity, i.e., HCE cells incubated with benzalkonium chloride. The association of cross-metathesis and tandem mass spectrometry appears suitable to locate double bond positions in lipids involved in relevant biological processes.

Total Synthesis of Tiacumicin†B: Study of the Challenging ß-Selective Glycosylations*.

We give a full account of the total synthesis of tiacumicin B (Tcn-B), a natural glycosylated macrolide with remarkable antibiotic properties. Our strategy is based on our experience with the synthesis of the tiacumicin B aglycone and on unique 1,2-cis-glycosylation steps. We used sulfoxide anomeric leaving-groups in combination with a remote 3-O-picoloyl group on the donors that allowed highly ß-selective rhamnosylation and noviosylation that rely on H-bond-mediated aglycone delivery. The rhamnosylated C1-C3 fragment was anchored to the C4-C19 aglycone fragment by a Suzuki-Miyaura cross-coupling. Ring-size-selective Shiina macrolactonization provided a semiglycosylated aglycone that was engaged directly in the noviolysation step with a virtually total ß-selectivity. Finally, a novel deprotection method was devised for the removal of a 2-naphthylmethyl ether on a phenol, and efficient removal of all the protecting groups provided synthetic tiacumicin B.

In Vitro Chemopreventive Potential of Phlorotannins-Rich Extract from Brown Algae by Inhibition of Benzo[a]pyrene-Induced P2X7 Activation and Toxic Effects.

Phlorotannins are polyphenols occurring exclusively in some species of brown algae, known for numerous biological activities, e.g., antioxidant, antiproliferative, antidiabetic, and antiallergic properties. Their effects on the response of human lung cells to benzo[a]pyrene (B[a]P) has not been characterized. Our objective was to in vitro evaluate the effects of a phlorotannin-rich extract obtained from the brown algae Ascophyllum nodosum and Fucus vesiculosus on B[a]P cytotoxic effects. The A549 cell line was incubated with B[a]P for 48 and 72 h in the presence or absence of the brown algae extract. Cytochrome P450 activity, activation of P2X7 receptor, F-actin disorganization, and loss of E-cadherin expression were assessed using microplate cytometry and fluorescence microscopy. Relative to control, incubation with the brown algae extract was associated with lower B[a]P-induced CYP1 activity, lower P2X7 receptor activation, and lower reactive oxygen species production. The brown algae extract inhibited the alterations of F-actin arrangement and the downregulation of E-cadherin expression. We identified a phlorotannins-rich extract that could be deeper investigated as a cancer chemopreventive agent to block B[a]P-mediated carcinogenesis.

Cytotoxic and Anti-Inflammatory Effects of Ent-Kaurane Derivatives Isolated from the Alpine Plant Sideritis hyssopifolia.

This paper reports the isolation and structural characterization of four new ent-kaurane derivatives from the Lamiaceae plant Sideritis hyssopifolia. Planar structures and relative configurations were determined using both mass spectrometry and nuclear magnetic resonance (1D and 2D). Absolute configurations were determined by comparing experimental and theoretical electronic circular dichroism spectra. The cytotoxic and microbial activities of all new compounds were tested. Compounds that were non-cytotoxic were further evaluated for anti-inflammatory activity.

Total Synthesis of Tiacumicin†B: Implementing Hydrogen Bond Directed Acceptor Delivery for Highly Selective ß-Glycosylations.

A total synthesis of tiacumicin B, a natural macrolide whose remarkable antibiotic properties are used to treat severe intestinal infections, is reported. The strategy is in part based on the prior synthesis of the tiacumicin B aglycone, and on the decisive use of sulfoxides as anomeric leaving groups in hydrogen-bond-mediated aglycone delivery (HAD). This new HAD variant permitted highly ß-selective rhamnosylation and noviosylation. To increase convergence, the rhamnosylated C1-C3 fragment thus obtained was anchored to the C4-C19 aglycone fragment by adapting the Suzuki-Miyaura cross-coupling used for the aglycone synthesis. Ring-size-selective macrolactonization provided a compound engaged directly in the noviolysation step with virtually total ß selectivity. The final efficient removal of all the protecting groups provided synthetic tiacumicin B.

Stereoselective Access to ( E)-1,3-Enynes through Pd/Cu-Catalyzed Alkyne Hydrocarbation of Allenes.

PdII and CuI cooperate in catalyzing the alkynes hydrocarbation of allenes (AHA) giving ( E)-1,3-enynes with high yields, atom economy, and high regio-/stereoselectivities. We devised new efficient conditions and expanded the substrate scope. Experimental and computational studies support a nonorthodox PdII/PdIV catalytic cycle involving an oxidative addition triggered by a stereodeterminant H+ transfer. This reaction is leveraged in a new strategy of stereoselective synthesis of 1,3-dienes.

MS/MS-Guided Isolation of Clarinoside, a New Anti-Inflammatory Pentalogin Derivative.

Re-investigation of the chemical composition of the annual plant Mitracarpus scaber Zucc. led to the identification of clarinoside, a new pentalogin derivative containing a rare quinovose moiety, and the known compound harounoside. While the planar structure was fully determined using tandem mass spectrometry (MS) and quantum mechanics (QM) calculations, the tridimensional structure was unravelled after isolation and NMR analysis. The absolute configuration was assigned by comparison of experimental and theoretical synchrotron radiation circular dichroism spectra. Both compounds were tested for anti-inflammatory activity, and compound 1 showed the ability to inhibit the production of interleukin-8 (Il-8) with an IC 50 value of 9.17 µ M.

Stereochemical Study of Puna'auic Acid, an Allenic Fatty Acid from the Eastern Indo-Pacific Cyanobacterium Pseudanabaena sp.

The isolation and structure elucidation of puna'auic acid, an allenic fatty acid isolated from a marine cyanobacterium, is described. All configurations were first assessed through molecular modeling of NMR and ECD spectra and then confirmed through a straightforward enantioselective total synthesis of puna'auic acid featuring a key reductive opening of a propargylic epoxide.

Palladium Nanoparticle-Catalyzed Stereoretentive Cross-Coupling of Alkenyl Sulfides with Grignard Reagents.

Reaction conditions allowing a stereoretentive cross-coupling of alkenyl sulfides with Grignard reagents using ligand-free Pd catalysis are discussed here. The presence of an adequately positioned OH function is a key feature that allows a Mg-promoted Lewis acid activation of the mercaptide leaving group. This easy to implement procedure actually relies on an in situ generation of stable Pd nanoparticles by simply mixing Pd2(dba)3, the Grignard reagent, and the vinyl sulfide cross-coupling partner in THF. The efficiency of this procedure has been demonstrated in a natural product total synthesis context.

Study of the Construction of the Tiacumicin B Aglycone.

Our study of the synthesis of the aglycone of tiacumicin B is discussed here. We imagined two possible strategies featuring a main retrosynthetic disconnection between C13 and C14. The first strategy was based on Suzuki-Miyaura cross-coupling of 1,1-dichloro-1-alkenes, but the failure of this pathway led us to use a Pd/Cu-dual-catalyzed cross-coupling of alkynes with allenes that had never been implemented before in a total synthesis context. We used density functional theory calculations to guide our strategic choices concerning a [2.3]-Wittig rearrangement step and the final ring-size selective Yamaguchi macrolactonization. This led to two syntheses of the aglycone of tiacumicin B, with one of last generation delivering ultimately an adequately protected and glycosylation-ready aglycone.

Synthesis of a Tiacumicin B Protected Aglycone.

Tiacumicin B is an antibiotic endowed with the remarkable ability to interact with a new biological target, giving it an inestimable potential in the context of the ever-growing and worrisome appearance of resistances of bacteria and mycobacteria to antibiotics. The synthesis of an aglycone of tiacumicin B ready for glycosylation is reported. The key steps of this approach are a [2,3]-Wittig rearrangement, a Pd/Cu-catalyzed allene-alkyne cross-coupling, a E-selective cross-metathesis, and a final ring-size selective macrolactonization.

Counteranion-directed catalysis in the Tsuji-Trost reaction: stereocontrolled access to 2,5-disubstituted 3-hydroxy-tetrahydrofurans.

Hydrogen bonds can play a prominent role in organometallic catalysis, as shown for the title reaction, in which a counteranion directs the cyclization through the formation of hydrogen bonds that likely involve a proton of the π-allyl/palladium species itself. The reaction allows access to four out of the eight stereoisomers of 2,5-disubstitued 3-hydroxy-tetrahydrofurans and thus fragments of complex natural products.

Study of the total synthesis of (-)-exiguolide.

In this article, we disclose the various routes and strategies we had to explore before finally achieving the total synthesis of (-)-exiguolide ((-)-1). Two first types of approaches were set, both relying on the Trost's domino ene-yne coupling/oxa-Michael reaction that we choose for its ability to control the geometry of the methylacrylate-bearing tetrahydropyrane ring B. In our first approach, we expected to assemble the two main fragments (C14-C21 and C1-C13) by creating the C13-C14 bond through a palladium(0)-catalyzed cross-coupling, but this step failed, unfortunately. In the second approach, which was more linear, we created the C16-C17 bond through condensation of a lithium acetylide on a Weinreb amide, and we assembled the C1-C5 and C6-C21 subunits through Trost's domino ene-yne coupling/oxa-Michael reaction. These two approaches served us to design an ameliorated third strategy, which finally led to the total synthesis of (-)-exiguolide.

Synthesis of the landomycinone skeleton.

The synthesis of the highly functionalized tetracyclic skeleton of landomycinone (2), the aglycon of landomycins, was performed using two pivotal steps relying on metal-catalyzed reactions. They are (1) a [2 + 2 + 2] cycloaddition of alkynes promoted by Wilkinson's catalyst to build rings B and C concomitantly and (2) a ring-closing metathesis followed by aromatization to build ring D.

Pd(0)-Catalyzed carbonylation of 1,1-dichloro-1-alkenes, a new selective access to Z-α-chloroacrylates.

A novel and fully chemo- and stereoselective three component strategy leading to Z-α-chloroacrylates by a Pd(0)-catalyzed reaction of CO (1 atm) with 1,1-dichloro-1-alkenes and various alcohols is disclosed. This catalytic approach compares favourably with the Wittig type strategies as α-chloroacrylates of pure Z configuration are obtained in high yield.