Laboratoire de Glycochimie, des Antimicrobiens
et des Agroressources UMR 7378 CNRS


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  • Tutelle du CNRS
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Sylvain LACLEF

Ingénieur de recherche (IGR)

Mail :

Tel : 03 22 82 75 69

Fax : 03 22 82 75 60

Axe de recherche : Chimie pour le Développement Durable

Description des travaux de recherche

  • Nos travaux portent sur la valorisation des substrats issus de la biomasse. Nous intéressons plus particulièrement à la valorisation des glycosides cyanogènes qui sont trouvés en grande quantité dans les graines de lin ainsi que dans les noyaux d’abricots.

  • Un autre axe est la mise au point de nouvelles méthodes de modifications de glucides en mettant en jeu des procédés plus respectueux de l’environnement, notamment  par voie micro-onde et mécanochimie en évitant l’utilisation de groupements protecteurs. Nous nous intéressons plus spécifiquement dans ce cadre, à la synthèse de C-glycosides.

  • Mots clés : N.C.

    Sélection de publications

    Amide Synthesis by Transamidation of Primary Carboxamides
    Kolympadi Marković, M.; Marković, D.; Laclef, S.
    The amide functionality is one of the most important and widely used groups in nature and in medicinal and industrial chemistry. Because of its importance and as the actual synthetic methods suffer from major drawbacks, such as the use of a stoichiometric amount of an activating agent, epimerization and low atom economy, the development of new and efficient amide bond forming reactions is needed. A number of greener and more effective strategies have been studied and developed. The transamidation of primary amides is particularly attractive in terms of atom economy and as ammonia is the single byproduct. This review summarizes the advancements in metal-catalyzed and organocatalyzed transamidation methods. Lewis and Brønsted acid transamidation catalysts are reviewed as a separate group. The activation of primary amides by promoter, as well as catalyst- and promoter-free protocols, are also described. The proposed mechanisms and key intermediates of the depicted transamidation reactions are shown.

    New biobased-zwitterionic ionic liquids: efficiency and biocompatibility for the development of sustainable biorefinery processes
    Huet, G.; Araya-Farias, M.; Alayoubi, R.; Laclef, S.; Bouvier, B.; Gosselin, I.; Cézard, C.; Roulard, R.; Courty, M.; Hadad, C.; Husson, E.; Sarazin, C.; Nguyen Van Nhien, A.
    Green Chem. 2020, 22, 2935-2946.
    A new family of biobased-zwitterionic ionic liquids (ZILs) have been synthesized starting from the renewable resource l-histidine natural amino acid and varying the lengths of the alkyl chains. These ZIL derivatives were firstly studied for their biocompatibility with different microorganisms including bacteria, molds and yeast. The obtained MIC values indicated that all the microorganisms were 5 to 25 times more tolerant to ZIL derivatives than the robust 1-ethyl-3-methylimidazolium acetate [C2mim][OAc] used as a reference. Modeling studies also revealed that the presence of the cation and the anion on the same skeleton together with the length of the N-alkyl chain would govern the biocompatibility of these neoteric solvents. Among the different synthesized ZILs, the N,N′-diethyl derivative has been demonstrated to be a suitable eco-alternative to the classically used [C2mim][OAc] for efficient pretreatment of harwood sawdust leading to a significant improvement of enzymatic saccharification. In addition, with up to a 5% w/v concentration in the culture medium, ZILs did not induce deleterious effects on fermentative yeast growth nor ethanol production.

    Marine Natural Products with High Anticancer Activities
    Dario, M.; Karlo, W.; Nela, M.; Sylvain, L.; Maris, T.; Maria, K.; Gabriela, A.; Dean, M.
    Curr. Med. Chem. 2020, 27, 1-63.
    This review covers recent literature from 2012-2019 concerning 170 marine natural products and their semisynthetic analogues with strong anticancer biological activities. Reports that shed light on cellular and molecular mechanisms and biological functions of these compounds, thus advancing the understanding in cancer biology are also included. Biosynthetic studies and total syntheses, which have provided access to derivatives and have contributed to the proper structure or stereochemistry elucidation or revision are mentioned. The natural compounds isolated from marine organisms are divided into nine groups, namely: alkaloids, sterols and steroids, glycosides, terpenes and terpenoids, macrolides, polypeptides, quinones, phenols and polyphenols, and miscellaneous products. An emphasis is placed on several drugs originating from marine natural products that have already been marketed or are currently in clinical trials.

    Secondary Metabolites from Gorgonian Corals of the Genus Eunicella: Structural Characterizations, Biological Activities, and Synthetic Approaches
    Matulja, D.; Kolympadi Markovic, M.; Ambrožić, G.; Laclef, S.; Pavelić, S. K.; Marković, D.
    Molecules 2019, 25, 129.
    Gorgonian corals, which belong to the genus Eunicella, are known as natural sources of diverse compounds with unique structural characteristics and interesting bioactivities both in vitro and in vivo. This review is focused primarily on the secondary metabolites isolated from various Eunicella species. The chemical structures of 64 compounds were divided into three main groups and comprehensively presented: a) terpenoids, b) sterols, and c) alkaloids and nucleosides. The observed biological activities of depicted metabolites with an impact on cytotoxic, anti-inflammatory, and antimicrobial activities were reviewed. The most promising biological activities of certain metabolites point to potential candidates for further development in pharmaceutical, cosmetic, and other industries, and are highlighted. Total synthesis or the synthetic approaches towards the desired skeletons or natural products are also summarized.

    Solvent- and catalyst-free transamidations of unprotected glycosyl carboxamides
    Bensalah, F. O.; Bil, A.; Wittine, K.; Bellahouel, S.; Lesur, D.; Markovic, D.; Laclef, S.
    Org. Biomol. Chem. 2019.
    The transamidation reactions of unprotected mono- and disaccharidic carboxamides with various primary and secondary arylic, heterocyclic or aliphatic amines are described. This new method is green and atom efficient and gives good to high yields. Notably, the conditions do not require either a solvent or a catalyst and give ammonia as a single by-product. The described coupling reaction is compatible with a variety of functional groups and was used in the synthesis of various glycosidic derivatives and biologically relevant glycolipids. A plausible reaction mechanism involving an intermolecular H-bond activation of the starting carboxamides is proposed.

    Straightforward extraction and selective bioconversion of high purity chitin from Bombyx eri larva: Toward an integrated insect biorefinery
    Huet, G.; Hadad, C.; Husson, E.; Laclef, S.; Lambertyn, V.; Araya Farias, M.; Jamali, A.; Courty, M.; Alayoubi, R.; Gosselin, I.; Sarazin, C.; Van Nhien, A. N.
    Carbohydr. Polym. 2020, 228, 115382.
    Chitins of different purity grades (45%, 89.7% and 93.3%) were efficiently extracted from Bombyx eri larva and fully physico-chemically characterized. Compared to commercially available and extracted α-chitin from shrimp shell, the collected data showed that insect chitins had similar characteristics in terms of crystallographic structures (α-chitin), thermal stability and degree of acetylation (>87%). The major differences lay in the crystallinity indexes (66% vs 75% for shrimp chitin) and in the morphological structures. Furthermore, low ash contents were determined for the insect chitins (1.90% vs 21.73% for shrimp chitin), making this chitin extraction and purification easier, which is highly valuable for an industrial application. Indeed, after only one step (deproteinization), the obtained chitin from Bombyx eri showed higher purity grade than the one extracted from shrimp shells under the same conditions. Insect chitins were then subjected to room temperature ionic liquid (RTIL) pretreatment prior to enzymatic degradation and presented a higher enzymatic digestibility compared to commercial one whatever their purity grade and would be thus a more relevant source for the selective production of N-acetyl-D-glucosamine (899.2 mg/g of chitin-2 steps vs 760 mg/g of chitin com). Moreover, for the first time, the fermentescibility of chitin hydrolysates was demonstrated with Scheffersomyces stipitis used as ethanologenic microorganism.

    Solid-phase synthesis of molecularly imprinted polymer nanolabels: Affinity tools for cellular bioimaging of glycans
    Medina Rangel, P. X.; Laclef, S.; Xu, J.; Panagiotopoulou, M.; Kovensky, J.; Tse Sum Bui, B.; Haupt, K.
    Scientific Reports 2019, 9, 3923.
    Hyaluronic acid (HA) is a glycosaminoglycan that plays many roles in health and disease and is a key biomarker of certain cancers. Therefore, its detection at an early stage, by histochemical methods, is of importance. However, intracellular HA can be masked by other HA-binding macromolecules, rendering its visualization somehow problematic. We show that fluorescent molecularly imprinted polymer nanogels (MIP-NPs), can localize and detect intracellular HA. MIP-NPs were synthesized by solid-phase synthesis on glass beads (GBs). GBs were functionalized with terminal alkyne groups on which an azide derivative of the template molecule glucuronic acid was immobilized via click chemistry. Immobilization via the anomeric carbon left the template’s carboxyl moiety free to enable strong stoichiometric electrostatic interactions with a benzamidine-based functional monomer, to confer selective recognition to the MIP-NPs. Due to the two-point orientation of the template, the resulting MIP-NPs were endowed with improved binding site homogeneity and specificity, reminiscent of monoclonal antibodies. These synthetic antibodies were then applied for probing and staining HA, of which glucuronic acid is a substructure (epitope), on human epidermal cells. Their excellent sensitivity, small size and water compatibility, enabled the MIP-NPs to visualize HA, as evidenced by confocal fluorescence micrographs.

    The effect of room temperature ionic liquids on the selective biocatalytic hydrolysis of chitin via sequential or simultaneous strategies
    Husson, E.; Hadad, C.; Huet, G.; Laclef, S.; Lesur, D.; Lambertyn, V.; Jamali, A.; Gottis, S.; Sarazin, C.; Nguyen Van Nhien, A.
    Green Chem. 2017, 19, 4122-4131.
    An efficient conversion of chitin, the second most abundant renewable polymer on the Earth, into N-acetylglucosamine and N,N[prime or minute]-diacetylchitobiose, using room temperature ionic liquids (RTILs) and commercially available chitinases is described for the first time. The sequential strategy consists of the use of RTILs to pretreat chitin under mild conditions as a first step before enzymatic hydrolysis. [C2mim][OAc] (1-ethyl-3-methyl imidazolium) pretreatment provides an efficient production of N-acetylglucosamine (185.0 +/- 4.0 mg per g chitin) or N,N[prime or minute]-diacetylchitobiose (667.60 +/- 20.71 mg per g chitin) catalyzed by chitinase from Trichoderma viride or Streptomyces griseus, respectively. A thorough investigation of the structural changes of chitin induced by RTIL pretreatment suggested an increase in enzymes' accessibility to the chitin substrate. Alternatively, a one-pot enzymatic hydrolysis of chitin in [C2mim][OAc]-aqueous medium constitutes a promising simultaneous route to selectively generate N-acetylglucosamine or N,N[prime or minute]-diacetylchitobiose by decreasing the required [C2mim][OAc] amount and the number of steps. Finally, the combination of the two chitinases from T. viride and S. griseus was shown to be very relevant to considerably increase the production of N-acetylglucosamine up to 760.0 +/- 0.1 mg per g chitin.

    Synthesis and Applications of Silyl 2-Methylprop-2-ene-1-sulfinates in Preparative Silylation and GC-Derivatization Reactions of Polyols and Carbohydrates
    Markovic, D.; Tchawou, W. A.; Novosjolova, I.; Laclef, S.; Stepanovs, D.; Turks, M.; Vogel, P.
    Chemistry 2016, 22, 4196-205.
    Trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and triisopropylsilyl 2-methylprop-2-ene-1-sulfinates were prepared through (CuOTf)2C6H6-catalyzed sila-ene reactions of the corresponding methallylsilanes with SO2 at 50 degrees C. Sterically hindered, epimerizable, and base-sensitive alcohols gave the corresponding silyl ethers in high yields and purities at room temperature and under neutral conditions. As the byproducts of the silylation reaction (SO2 +isobutylene) are volatile, the workup was simplified to solvent evaporation. The developed method can be employed for the chemo- and regioselective semiprotection of polyols and glycosides and for the silylation of unstable aldols. The high reactivity of the developed reagents is shown by the synthesis of sterically hindered per-O-tert-butyldimethylsilyl-alpha-D-glucopyranose, the X-ray crystallographic analysis of which is the first for a per-O-silylated hexopyranose. The per-O-silylation of polyols, hydroxy carboxylic acids, and carbohydrates with trimethylsilyl 2-methylprop-2-ene-1-sulfinate was coupled with the GC analysis of nonvolatile polyhydroxy compounds both qualitatively and quantitatively.

    Glycochemical Applications of Diels-Alder Reaction
    Laclef, S.; Toumieux, S.; Kovensky, J.
    Curr. Org. Chem. 2016, 20, 2379-2392.
    Carbohydrates and their analogs are key molecules with a wide range of biological activities. These bioactive compounds are usually synthesized through derivatization of naturally occurring carbohydrates. Nevertheless, this strategy suffers from a limited range of naturally available monosaccharide building blocks and the necessity of laborious steps of protection and deprotection. Consequently new methods began to emerge and Diels-Alder reaction appeared to be a method of choice for their de novo production. The synthesis of carbohydrates and their analogs by means of cycloaddition reactions will be reviewed here. Moreover the potentiality of the use of monosaccharides to induce chirality in Diels-Alder reaction will be presented. Efficient methods for the synthesis of di- and tri-saccharides using the developments shown previously will be also introduced.

    Ligand-free Pd-catalyzed and copper-assisted C-H arylation of quinazolin-4-ones with aryl iodides under microwave heating
    Laclef, S.; Harari, M.; Godeau, J.; Schmitz-Afonso, I.; Bischoff, L.; Hoarau, C.; Levacher, V.; Fruit, C.; Besson, T.
    Org. Lett. 2015, 17, 1700-3.
    A microwave-assisted method for the palladium-catalyzed direct arylation of quinazolin-4-one has been developed under copper-assistance. This method is applicable to a wide range of aryl iodides and substituted (2H)-quinazolin-4-ones. This protocol provides a simple and efficient way to synthesize biologically relevant 2-arylquinazolin-4-one backbones.

    Cu/Pd-Catalyzed C-2-H Arylation of Quinazolin-4(3H)-ones with (Hetero)aryl Halides
    Godeau, J.; Harari, M.; Laclef, S.; Deau, E.; Fruit, C.; Besson, T.
    Eur. J. Org. Chem. 2015, 2015, 7705-7717.
    The regiospecific C-2-H arylation of N-3-substituted quinazolin-4(3H)-ones with a wide range of aryl or (hetero)aryl halides under microwave irradn. was studied. A ligand-dependent palladium/copper bicatalytic system was developed and allowed direct cross-coupling with a variety of (hetero)aryl halides. This useful and scalable procedure promotes the construction of C(sp2)-C(sp2) bonds from arenes or (hetero)arenes and aryl or (hetero)aryl bromides and chlorides in a time-efficient strategy. The extension of the reaction to various N-3-substituted quinazolin-4(3H)-ones with iodobenzene as well as the scope and limitations of the method were also investigated.

    Scalable asymmetric synthesis of a key fragment of Bcl-2/Bcl-xL inhibitors
    Laclef, S.; Taillier, C.; Penloup, C.; Viger, A.; Brière, J.-F.; Hardouin, C.; Levacher, V.
    RSC Adv. 2014, 4, 39817-39821.
    The asym. synthesis of a 1,3-diamine building block for the elaboration of Bcl-2 and Bcl-xL protein inhibitors is described through two key steps: (1) a highly diastereoselective aza-Reformatsky reaction, and (2) a chemoselective amination under Mitsunobu conditions. This synthetic sequence was also demonstrated to be successfully amenable to a large-scale synthesis.

    Mechanistic studies of highly regioselective decarboxylative-prenyl migration reactions of prenyloxycarbonyl-diketo-dioxinones
    Anderson, K.; Laclef, S.; Barrett, A. G. M.
    Tetrahedron 2014, 70, 5569-5579.
    Mechanistic studies of tandem regioselective decarboxylation, prenyl transfer, and aromatization reactions of prenyl dioxinone diketo-carboxylates to provide 3-prenyl-resorcylate derivs. are described. Studies of the effects of concn. and the base employed as well as the results of cross-over expts. were all found to be consistent with the reaction proceeding largely via an intermol. reaction pathway.