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Trehalose-based probes are useful tools that allow the detection of the mycomembrane of mycobacteria through the metabolic labeling approach. Trehalose analogues conjugated to fluorescent probes can be used, and other probes are functionalized with a bioorthogonal chemical reporter for a two-step labeling approach. The synthesis of such trehalose-based probes mainly relies on the desymmetrization of natural trehalose using a large number of regioselective protection-deprotection steps to differentiate the eight hydroxyl groups. Herein, in order to avoid these time-consuming steps, we reinvestigated our previously reported tandem protocol mediated by FeCl

International audience; The synthesis of glycopyranosyl nucleosides modified in the sugar moiety is less frequently explored, notably because of a lack of a reliable method to glycosylate pyrimidine bases. Herein we report a solution in the context of the synthesis of peptidonucleosides. They were obtained after glycosylation of different pyrimidine nucleobases with glucopyranosyl donors carrying an azide group at the C4 position. A methodological study involving different anomeric leaving groups (acetate, phenylsulfoxide and ortho-hexynylbenzoate) showed that a sulfoxide donor in combination with trimethylsilyl triflate as the promoter led to the best yields.

International audience; We report a total synthesis of tiacumicin B, a natural macrolide whose remarkable antibiotic properties are used to treat severe intestinal infections. The strategy is in part based on our experience of the synthesis of the tiacumicin B aglycone, and on the decisive use of sulfoxides as anomeric leaving-groups in H-bond-mediated Aglycone Delivery (HAD). This new HAD variant permitted highly b-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 reliable Suzuki-Miyaura cross-coupling used for the aglycone synthesis. Ring-size selective macrolactonization provided a compound engaged directly in the noviolysation step with a virtually total b-selectivity. The final efficient removal of all the protective groups (PGs) provided synthetic tiacumicin B.

The selective preparation of α-glycosides of GlcNAc has been accomplished using a direct copper(II) triflate-catalyzed glycosylation between the α-D-glucosamine pentaacetate, readily available from chitin, and a range of alcohol acceptors. The α-selectivity resulted from a post-glycosylation anomerization.

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.

Regioselective differentiation of the hydroxy groups of mono- and oligosaccharide substrates is necessary to form building blocks that can be used for synthetic transformations. In this paper, we show that iron(III) chloride hexahydrate catalyses the tandem protection of mono- and disaccharides to give, in a one-pot procedure, selectively protected carbohydrate building blocks. This tandem protocol was successfully applied to a trisaccharide. The procedure is easy to carry out; for optimal results, each carbohydrate substrate required a fine tuning of the one-pot reaction conditions.

We report a total synthesis of tiacumicin B, one of the most structurally complex natural antibiotic macrolides. Endowed with remarkable biological properties, it is used to treat very severe intestinal infections. The strategy is in part based on our experience of the synthesis of the tiacumicin B aglycone, and on the decisive implementation of an H-bond-mediated Aglycone Delivery (HAD) using sulfoxides as anomeric leaving-groups. This new HAD variant permitted highly beta-selective rhamnosylation and noviosylation. To increase the convergence, the rhamnosylated C1-C3 fragment thus obtained was anchored to the C4-C19 aglycone fragment by adapting the reliable Suzuki-Miyaura cross-coupling conditions used for the aglycone synthesis. The ring-size selective macrolactonization provided a compound engaged directly in the noviolysation step with a virtually total beta-selectivity. The final and efficient removal of all the protective groups (PGs) provided synthetic tiacumicin B.

Mycolic acids are fundamental cell wall components, found in the outer membrane barrier (mycomembrane) of Mycobacterium related genera, that have shown antigenic, murine innate immunity inducting and inflammatory activity triggering action. The mycolic acid derivatives, such as the lipid extractable trehalose monomycolates (TMM) and dimycolates (TDM), have been extensively investigated by several biochemical and biological methods and, more recently, we have performed the first neutron scattering measurements on these molecules in order to characterize their dynamical behavior as well as their rigidity properties. In the present paper, we show the first systematic FT-IR study on TMM, TDM and glucose monomycolate (GMM). It includes the analysis of individual lipids but also mixtures of TMM/TDM (ratio of 1:1) or TMM/GMM (ratio of 1:2). The present work is aimed to the first characterization of the vibrational behavior of mycolates and their mixtures enabling us to elucidate the molecular mechanisms responsible for the capability of mycolic acids to affect the flexibility and permeability properties of the mycomembrane. As a whole, the present FT-IR findings provide information that have relevant biological implications, allowing to demonstrate that the membrane fluidity is not only linked to the chain length, but also to the specific conformational behavior adopted by mycolates, which in the mixtures is strongly affected by their mutual interactions. In addition, the capability of trehalose to drive the mycolate conformational behavior and then the chain order and packing is emphasized; due to the TDM relevant evidences shown by our data, this trehalose effect could be related to the TDM toxicity and inflammation action.

Direct multiple glycosylations of thioaryl and propargyl mannopyranosides with peracetylated β-d-glucosamine have been carried out using catalytic iron(III) triflate as a promoter in the presence of 2,4,6-tri-tert-butylpyrimidine under microwave irradiation. This has led to the one-step formation of various oligosaccharides with mannose at the branching point. Subsequent direct introduction of a linker through copper-catalyzed azide–alkyne cycloaddition with the propargyl branched glycan and final deprotection gave rapid access to N-glycan mimetics.

In this study, we report the first synthesis of an alkyne-based trehalose monomycolate probe containing a β-hydroxylated fatty acid and an α-branched chain similar to those of the natural mycolic acid. We demonstrate its utility for the labeling of the mycomembrane of Corynebacteria as well as for the study of mycoloyltransferases.

International audience; An environmentally improved synthesis of the N-differentiated chitotetrasaccharide CO-IV-(NH2), a key intermediate for the preparation of lipochitooligosaccharides and the TMG-chitotriomycin, is reported based on a chromatography-free ionic-liquid tagging approach. The method involves the glycosylation of ionic-liquid-tagged acceptors with thioglucosamine donors leading to the stereoselective formation of -(14)-linked glucosamine-containing oligomers.

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.

International audience; The activation of aryl glycosyl sulfone donors has been achieved using scandium(III) triflate and has led to the selective preparation of alpha-mannosides resulting from a post-glycosylation anomerization.

International audience; The longer, the better: Increasing the lengths of the 1,3-methyl-branched fatty acyl chain units in mycobacterial diacylated sulfoglycolipid (Acyl2 SGL) analogues led to dramatic improvements in their antigenic properties and gave products more potent than the natural antigen Acyl2 SGLs.

A new synthesis of the fungal lipo-chitooligosaccharide Myc-IV (C16:0, S), which was recently reported to be a major symbiotic signalling molecule in arbuscular mycorrhiza, is described. Key steps include the oxidative cleavage of a 4,6-O-benzylidene acetal to prepare a disaccharidic glycosyl acceptor, and stereoselective glycosylations with 2-methyl-5-tert-butylphenyl thioglycosyl donors.

International audience

International audience; The fragmentation mechanisms of prototypical disaccharides have been studied herein by coupling tandem mass spectrometry (MS) with collisional chemical dynamics simulations. These calculations were performed by explicitly considering the collisions between the protonated sugar and the neutral target gas, which led to an ensemble of trajectories for each system, from which it was possible to obtain reaction products and mechanisms without pre‐imposing them. The β‐aminoethyl and aminopropyl derivatives of cellobiose, maltose, and gentiobiose were studied to observe differences in both the stereochemistry and the location of the glycosidic linkage. Chemical dynamics simulations of MS/MS and MS/MS/MS were used to suggest some primary and secondary fragmentation mechanisms for some experimentally observed product ions. These simulations provided some new insights into the fundamentals of the unimolecular dissociation of protonated sugars under collisional induced dissociation conditions.

International audience; Lipo-chitotetrasaccharide analogues where one central GlcNAc residue was replaced by a triazole unit have been synthesized from a derivative obtained by chitin depolymerization and a functionalized N-acetyl-glucosamine via the copper-catalyzed azide-alkyne cycloaddition. Their evaluation in a binding assay using LYR3, a putative lipo-chitooligosaccharide receptor in Medicago truncatula, shows a complete loss of binding.

Publication Inra prise en compte dans l'analyse bibliométrique des publications scientifiques mondiales sur les Fruits, les Légumes et la Pomme de terre. Période 2000-2012. http://prodinra.inra.fr/record/256699; International audience; Initially known for their role in the rhizosphere in stimulating the seed germination of parasitic weeds such as the Striga and Orobanche species, and later as host recognition signals for arbuscular mycorrhizal fungi, strigolactones (SLs) were recently rediscovered as a new class of plant hormones involved in the control of shoot branching in plants. Herein, we report the synthesis of new SL analogs and, to our knowledge, the first study of SL structure-activity relationships for their hormonal activity in garden pea (Pisum sativum). Comparisons with their action for the germination of broomrape (Phelipanche ramosa) are also presented. The pea rms1 SL-deficient mutant was used in a SL bioassay based on axillary bud length after direct SL application on the bud. This assay was compared with an assay where SLs were fed via the roots using hydroponics and with a molecular assay in which transcript levels of BRANCHED1, the pea homolog of the maize TEOSINTE BRANCHED1 gene were quantified in axillary buds only 6 h after application of SLs. We have demonstrated that the presence of a Michael acceptor and a methylbutenolide or dimethylbutenolide motif in the same molecule is essential. It was established that the more active analog 23 with a dimethylbutenolide as the D-ring could be used to control the plant architecture without strongly favoring the germination of P. ramosa seeds. Bold numerals refer to numbers of compounds.

Nod factors are lipochitoligosaccharides originally produced by the soil bacteria Rhizobia that are involved in the symbiotic process with leguminous plants. Some synthetic analogs of the Nod factors present a strong biological activity, and the conformational behavior of these molecules is of interest for structure/function studies. Nod factor analogs containing an insertion of a phenyl group in the acyl chain at the oligosaccharidic non-reducing end were previously synthesized (Grenouillat N, Vauzeilles B, Bono J-J, Samain E, Beau J-M. 2004. Simple synthesis of nodulation-factor analogues exhibiting high affinity towards a specific binding protein. Angew Chem Int Ed Engl. 43:4644). Conformational studies of natural compounds and synthetic analogs have been performed combining molecular dynamics simulations in explicit water and NMR. Data revealed that the glycosidic head group can adopt only restricted conformations, whereas chemical modifications of the lipid chains, highly flexible in a water environment, influence the global shape of the molecules. Collected structural data could be used in the future to rationalize and understand their biological activity and affinity toward a putative receptor.

A library of paclitaxel (taxol) mimics was obtained by a straightforward strategy involving rational design and an efficient synthesis of a simplified taxane core substitute, together with a click-chemistry combinatorial search for phenylisoserine side-chain surrogates.

International audience; A regio- and stereocontrolled solution for a selective modification at the C-2 or C-4 position of N-acetylneuraminic acid involves the use of allylic substitution catalyzed by palladium. As illustrated in the scheme, regioselective malonylation is under the strict influence of the ligands associated with the allylpalladium complex.

The conformational behavior of two C-glycosyl analogues of the sialyl-Tn antigen has been determined by a combination of NMR methods and molecular mechanics calculations. Both compounds show a major solution conformation that is drastically different from the major one of the natural compound.

The three-component Petasis borono-Mannich reaction starting with easily accessible N-protected α-amino aldehydes produces efficiently and diastereoselectively 1,2-trans-diamines with an enantiomeric excess of up to 98%.

Dynamic Combinatorial Chemistry: Direct detection of imines in water and their adaptive re-equilibration in the presence of a target are possible by simple HPLC analysis. The equilibrating mixture is fixed by a fast drop in the pH during the analytical step. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

A sequence combining Petasis and Diels—Alder reactions gives access to hexahydroisoindole scaffolds in a one-step procedure.

The three-component Petasis borono-Mannich reaction starting with easily accessible N-protected α-amino aldehydes produces efficiently and diastereoselectively 1,2-trans-diamines with an enantiomeric excess of up to 98%.

Lipo-chitin oligosaccharides (Nod and Myc LCOs) are molecules involved in symbiotic phenomena in the plant kingdom. They play a major role in the process of atmospheric nitrogen fixation and mineral soil nutrients uptake both in legumes and in non-legumes, and are active at extremely low concentrations down to the nano- and even picomolar range. These compounds contain various substitutions along the oligosaccharide backbone of the molecule including an essential fatty acid on the non-reducing unit and are considered as environmentally-friendly fertilizers. Currently, chemical synthesis cannot produce precursors of Nod and Myc LCOs at a large scale and an in vitro chemoenzymatic pathway is presented here as a new and efficient method for preparing quantities of these high-value oligosaccharides. VC1280 (Vibrio cholerae) is a chitin deacetylase (CD) capable of regioselectively cleaving an acetate from the non-reducing penultimate N-acetyl-D-glucosaminyl (GlcNAc) unit of chitin oligosaccharides (COs). This provides a free amino group which can be further N-acylated with a fatty-acid chain to give analogues of LCOs. Alternatively, the non-reducing GlcNAc unit can be removed by β-N-acetylglucosaminidase treatment, followed by N-acylation to give natural LCOs. VC1280 CD was produced in the periplasm of E. coli. Under the conditions used, 120 mg of the pure enzyme was recovered from 1 L of culture medium. For the first time, in vitro production of a library of natural LCOs as well as their analogues has been carried out at a preparative scale from biosourced chitin oligosaccharides constituting an approach of major interest for sustainable agriculture.

The umpolung of glycals with samarium diiodide offers a simple route to novel carbohydrate-derived nucleophilic reagents in a single step using a readily available reductant. The corresponding allyl samarium reagent that arises from the hexose series reacts with ketones at the C3 position with high stereoselectivity; carbon–carbon bond formation takes place only anti to the substituent at the C4 position of the dihydropyran ring. For the sialic acid series, the completely regio- and stereoselective coupling process of the samarium reagent occurs at the anomeric carbon atom and provides a new approach to the α-C-glycosides of N-acetyl neuraminic acid.

International audience; One-step assembly of hexahydroisoindole scaffolds by a sequence that combines the Petasis (borono-Mannich) and Diels-Alder reactions is described. The unique selectivity observed experimentally was confirmed by quantum calculations. The current method is applicable to a broad range of substrates, including free sugars, and holds significant potential to efficiently and stereoselectively build new heterocyclic structures. This easy and fast entry to functionalized polycyclic compounds can be pursued by further transformations, for example, additional ring closure by a cross-metathesis/Michael addition domino sequence.

International audience; The direct and chemoselective N-transacylation of peracetylated chitooligosaccharides (COSs), readily obtained from chitin, to give per-N-trifluoroacetyl derivatives offers an attractive route to size-defined COSs and derived glycoconjugates. It involves the use of various acceptor building blocks and trifluoromethyl oxazoline dimer donors prepared with efficiency and highly reactive in 1,2-trans glycosylation reactions. This method was applied to the preparation of the important symbiotic glycolipids which are highly active on plants and to the TMG-chitotriomycin, a potent and specific inhibitor of insect, fungal, and bacterial N-acetylglucosaminidases.

The method is developed to prepare the building blocks for the construction of oligosaccharides.

N-Acetyl glucosamine and chitooligosaccharides are selectively converted into β-glycosides without protection of the other hydroxyl groups by alkylation of the anomeric alkoxides in N,N-dimethylformamide containing lithium bromide. Addition of the lithium salt notably improves the stereoselectivity of the glycosylation of the monomer and the efficiency of the process with higher oligomers.

The mannosyl pyridylsulfone 1 undergoes a remarkably efficient coupling reaction with the 2-deoxy-C2-formyl glycoside 2 in the presence of samarium diiodide to provide the corresponding C-disaccharide in high yield. This represents the first step in the synthesis of C-mannobioside, a synthesis which closely resembles approaches employed in O-glycosylation.

A method for the synthesis of spiro-δ-lactonic α-C-sialosides by samarium diiodide mediated cyclization reactions of glycosyl 2-pyridylsulfides or acetates with appropriate carbonyl side chains has been developed.

The umpolung of glycals with samarium diiodide offers a simple route to novel carbohydrate-derived nucleophilic reagents in a single step using a readily available reductant. The corresponding allyl samarium reagent that arises from the hexose series reacts with ketones at the C3 position with high stereoselectivity; carbon–carbon bond formation takes place only anti to the substituent at the C4 position of the dihydropyran ring. For the sialic acid series, the completely regio- and stereoselective coupling process of the samarium reagent occurs at the anomeric carbon atom and provides a new approach to the α-C-glycosides of N-acetyl neuraminic acid.

International audience; Combining triflic acid-catalyzed acetalation, benzylation, reductive ring opening of benzylidene acetal and glycosylation in one-pot transformations leads to a wide range of d-glucosamine building blocks for assembling oligomers.