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Publications / Résumés

Les deux thématiques de recherche développées au laboratoire :

  • Isolement de Produits Naturels bioactifs et Bioinspiration.
  • Synthèse et Chimie Médicinale.


Unaromatized Tetrahydrobenzimidazole Synthesis from p-Benzoquinone and N-Arylamidines and their Cytotoxic Potential.

M. Q. Tran, T. B. Nguyen, W. R. Sawadogo, L. Ermolenko, S. Song, P. Retailleau, M. Diederich, A. Al-Mourabit, Eur. J. Org. Chem. 2018, 5878–5884.

A diverse set of unaromatized and densely functionalized tetrahydrobenzimidazole adducts was obtained in good yields by simple mixing p-benzoquinone 1 with N-arylamidines 2 under mild conditions. The main features of these adducts include a hemi N,O-acetal function, and an imidazoline regioselectively and stereoselectively fused with a conjugated cyclohexenone ring. These compounds were evaluated for their cytotoxic potential against hematopoietic cancer cell lines including Jurkat, Raji, K562 and U937 compared to peripheral blood mononuclear cells (PBMCs) from healthy donors. Some of them including 3a, 3k and 3l were found to exhibit significant selective cytotoxicity against cancer cells with IC50 values between 3 and 10 µM at 48 hours.

Bioactive Bromotyrosine-Derived Alkaloids from the Polynesian Sponge Suberea ianthelliformis.

A. El-Demerdash, C. Moriou, J. Toullec, M. Besson, S ; Soulet, N. Schmitt, S. Petek, D. Lecchini, C. Debitus, A ? Al-Mourabit, Marine Drugs, 2018, 16 (5), 146.

DOI : 10.3390/md16050146

Herein, we describe the isolation and spectroscopic identification of eight new tetrabrominated tyrosine alkaloids 2–9 from the Polynesian sponge Suberea ianthelliformis, along with known major compound psammaplysene D (1), N,N-dimethyldibromotyramine, 5-hydroxy xanthenuric acid, and xanthenuric acid. Cytotoxicity and acetylcholinesterase inhibition activities were evaluated for some of the isolated metabolites. They exhibited moderate antiproliferative activity against KB cancer cell lines, but psammaplysene D (1) displayed substantial cytotoxicity as well as acetylcholinesterase inhibition with IC50 values of 0.7 μM and 1.3 μM, respectively.

Toward the Synthesis of Sceptrin and Benzosceptrin : Solvent Effect in Stereo- and Regio- Selective [2 + 2] Photodimerization and Easy Access to the Fully Substituted Benzobutane.

T. B. Nguyen, L. A. Nguyen, M. Corbin, P. Retailleau, L. Ermolenko, A. Al-Mourabit, Eur. J. Org. Chem. 2018, 5861–5868.

DOI : 10.1002/ejoc.201800458

By simply switching solvents, two sets of conditions for the total regio‐ and stereoselective photodimerization of (E)‐3‐(imidazo[1,2‐a]pyrimidin‐2‐yl)acrylic acid [(E)‐7a] have been found. In acetonitrile in the presence of benzophenone as photosensitizer or in cyclohexane, the head‐to‐head cis‐trans‐cis isomer 8a was the only observable cycloadduct. In DMSO, the head‐to‐head trans‐trans‐trans isomer 10a was obtained as the unique cycloadduct. The diester 9a, derived from 8a, was cyclized to the challenging, fully substituted diimidazobenzobutane system 13 present in benzosceptrins.

(2S*,5S*,6Z)-2,5-Epoxydocosan-6-en-21-ynoic Acid, New Fatty Acid from the Marine Sponge Haliclona fascigera.

P.-E. Campos, E. Pichon, B. Illien, P. Clerc, C. Moriou, N. de Voogd, C. Hellio, R. Trépos, M. Frederich, A. Al-Mourabit, A. Gauvin-Bialeck, Nat. Prod. Chem. Res. 2018, 6, 5.

DOI : 10.4172/2329-6836.1000336

Marine sponges are recognized as a rich source of new marine natural products. In this study, chemical investigation of the CH2Cl2 -MeOH (1:1) extract from the marine sponge Haliclona fascigera collected in Mayotte was carried out and highlighted a new unusual acetylenic and tetrahydrofuranic fatty acid, (2S*,5S*,6Z)-2,5- epoxydocosan-6-en-21-ynoic acid (1). Its planar structure was elucidated by HRESIMS data, IR, 1D and 2D NMR spectra. The relative configuration of compound 1 was deduced from density functional theory (DFT) computational calculations fitted using the recently published DP4+ probability.

Batzella, Crambe and Monanchora : Highly Creative Marine Sponge Genera Yielding Compounds with Potential Applications for Cancer and Other Therapeutic Areas.

A. El-Demerdash, A. G. Atanasov, A. Bishayee, M. Abdel-Mogib, J. Hooper, A. Al-Mourabit, Nutrients, 2018, 10 (1), 33.


Pyrroloquinoline and guanidine-derived alkaloids present distinct groups of marine secondary metabolites with structural diversity that displayed potentialities in biological research. A considerable number of these molecular architectures had been recorded from marine sponges belonging to different marine genera, including Batzella, Crambe, Monanchora, Clathria, Ptilocaulis and New Caledonian starfishes Fromia monilis and Celerina heffernani. In this review, we aim to comprehensively cover the chemodiversity and the bioactivities landmarks centered around the chemical constituents exclusively isolated from theses three marine genera including Batzella, Crambe and Monanchora over the period 1981-2017, paying a special attention to the polycyclic guanidinic compounds and their proposed biomimetic landmarks. It is concluded that these marine sponge genera represent a rich source of novel compounds with potential applications for cancer and other therapeutic areas.


Unguiculins A-C : Cytotoxic bis- Guanidine Alkaloids from the French Polynesian Sponge, Monanchora n. sp.

A. El-Demerdash, C. Moriou, M.-T. Martin, S. Petek, C. Debitus, A. Al-Mourabit, Nat. Prod. Res. 2017, 1-6.

DOI : 10.1080/14786419.2017.1385011

Three acyclic bis-guanidine alkaloids, unguiculins B-C were isolated from a French Polynesian sponge Monanchora n. sp. in addition to the known compound unguiculin A. Their structures were established by spectroscopic data interpretation and comparison with the literature. Unguiculins A-C displayed antiproliferative and cytotoxic efficacy against several human cancer cells with IC50 values in the micromolar range.

Amphimedonoic acid and psammaplysene E, novel brominated alkaloids from Amphimedon sp.

P.-E. Campos, J.-L. Wolfender, E. F. Queiroz, L. Marcourt , A. Al-Mourabit, N. De Voogd, B. Illien, A. Gauvin-Bialecki, Tetrahedron Letters, 2017, 58, 3901-3904.

DOI : org/10.1016/j.tetlet.2017.08.072

Chemical study of tthe sponge Amphimedon sp. collected in Madagascar led to two new brominated alkaloids, amphimedonoic acid and psammaplysene E, along with the known 3,5-dibromo-4-methoxybenzoic acid. Their structures were elucidated by 1D and 2D NMR spectra and HRESIMS data. This first report of bromotyrosine-derivated metabolites from an Amphimedon sponges belonging to Haplosclerida order. Bromotirosine alkaloïds are rather found in Verongida order. These compounds did not show in vitro cytotoxicity against human epidermoid carcinoma KB cells (IC50 > 10 µg/mL).

Orbicularisine : a New Spiro-indolo-thiazine Skeleton Isolated from Gills of the Tropical Bivalve Codakia orbicularis.

F. Goudou, P. Petit, C. Moriou, O. Gros, A. Al-Mourabit, J. Nat. Prod. 2017, 80, 1693–1696.

DOI : 10.1021/acs.jnatprod.7b00149

A novel spiro-indolofuranone fused to a thiazine skeleton, orbicularisine (1), was isolated from gills of the mollusk Codakia orbicularis. The isolation, structure elucidation using spectroscopic evidence including mass and NMR spectroscopy are described. The final structure of 1 was supported key HMBC correlation.

Unguiculin A and Ptilomycalins E–H, Antimalarial Guanidine Alkaloids from the Marine Sponge Monanchora unguiculata

P.-E. Campos, J.-L. Wolfender, E. Queiroz, L. Marcourt, A. Al-Mourabit, M. Frederich, A. Bordignon, N. de Voogd, B. Illien, A. Gauvin-Bialecki, J. Nat. Prod. 2017, 80,1404–1410.

DOI : 10.1021/acs.jnatprod.6b01079

Chemical study of the sponge Monanchora unguiculata collected in Madagascar highlighted five new compounds, one acyclic guanidine alkaloid, unguiculin A and four pentacyclic alkaloids, ptilomycalins E−H. All compounds were evaluated for their cytotoxicity against KB cells and their antiplasmodial activity. The new ptilomycalin E and the mixture of the new ptilomycalins G (4) and H (5) showed promising cytotoxicity against KB cells with IC50 of 0.85 and 0.92 μM, respectively. Ptilomycalin F and fromiamycalin exhibited promising activity against Plasmodium falciparum with IC50 values of 0.23 and 0.24 μM, respectively.

Metabolomics approach to chemical diversity of the Mediterranean marine sponge Agelas oroides.

P. Sauleau, C. Moriou, A. Al-Mourabit, Nat. Prod. Res. 2017, 31, 1625-1632.

DOI : 10.1080/14786419.2017.1285298

The Mediterranean marine sponge Agelas oroides is known to contain a large quantity of oroidin, a deterrent, antifouling and antibiofilm pyrrole-2-aminoimidazole. In contrast with other tropical specimens and with regard to the known work, the chemical composition of the Mediterranean Agelas oroides was found relatively poor in other related metabolites. Its LC-MS based metabolomics study has however, revealed this sponge contains in fact a great diversity of known pyrrole-imidazole alkaloids in minute amounts. Here, we describe identification of 13 known oroidin class alkaloids along with one new monobromoagelaspongin. Five betaines were also identified from the aqueous fraction. One of those compounds (−)-equinobetaine B was found to be an enantiomer of the known natural product (+)-equinobetaine B. he mechanism switching the chemical step involved in the biosynthesis of the antipodal (+)-equinobetaine B/(–)-equinobetaine B and the biological impact of such switching is an interesting question.


Chemistry for eco-inspired living

B. Banaigs, A. Al-Mourabit, G. Clavé, C. Grison, Chemical Ecology, Anne-Geneviève Bagnères, Martine Hossaert-McKey, August 2016, Wiley-ISTE

ISBN : 978-1-84821-924-3

Cytotoxic Guanidine Alkaloids from a French Polynesian Monanchora n. sp. Sponge

A. El-Demerdash, C. Moriou, M.-T. Martin, A. de Souza Rodrigues-Stien, S. Petek, M. Demoy-Schneider, K. Hall, J. N. A. Hooper, C. Debitus, A. Al-Mourabit, J. Nat. Prod. 2016, 79 (8), 1929-1937.

DOI : 10.1021/acs.jnatprod.6b00168

Four bicyclic and three pentacyclic guanidine alkaloids were isolated from a French Polynesian Monanchora n. sp. sponge, along with the known alkaloids monalidine A, and the known crambescidins.The relative and absolute configurations of the alkaloids were established by analysis of 1H NMR and NOESY spectra, and by circular dichroism analysis. The new norcrambescidic acid corresponds to interesting biosynthetic variation within the pentacyclic core. All compounds exhibited antiproliferative and cytotoxic efficacy against KB, HCT116, HL60, MRC5 and B16F10 cancer cells, with IC50 values ranging from 4 nM to 10 μM.

Remarkably High Homoselective [2+2] Photodimerization of trans-Cinnamic Acids in Multicomponent Systems.

T. B. Nguyen, A. Al-Mourabit, Photochem. Photobiol. Sci. 2016, 15(9), 1115-1119.

DOI : 10.1039/C6PP00201C

[2+2] Homoadducts were exclusively obtained with total regio- and stereo- selectivities when a suspension of several solid photoactive trans-cinnamic acids in cyclohexane were stirred and irradiated with a 365 nm UV lamp. The following compounds were found not to cross-react when tested as a suspension.

Molecular Iodine-Catalyzed Aerobic α,β-Diamination of Cyclohexanones with 2-Aminopyrimidine and 2-Aminopyridines.

T. B. Nguyen, L. Ermolenko, P. Retailleau, A. Al-Mourabit, Org. Lett. 2016, 18, 2177.

DOI : 10.1021/acs.orglett.6b00823

Molecular iodine is shown to be an excellent catalyst for aerobic oxidative α,β-diamination of cyclohexanones with 2-aminopyrimidine/2-aminopyridines. This α,β-C–H functionalization is remarkable for its simplicity in both substrates and conditions, involving one and a half oxygen molecules and releasing three water molecules as the only byproduct. In addition, the functionalized products including protected 2-aminoimidazoles introduced without aromatization can serve as useful building blocks for natural product synthesis benzosceptrin and medicinal chemistry.

Formic Acid as a Sustainable and Complementary Reductant : Approach to Fused Benzimidazoles by Molecular Iodine-Catalyzed Reductive Redox Cyclization of o-Nitro-t-Anilines.

T. B. Nguyen, L. Ermolenko, A. Al-Mourabit, Green Chem. 2016, 18, 2966.

DOI : 10.1039/C6GC00902F

Molecular iodine was found to be an excellent catalyst for reductive redox cyclization of o-nitro-t-anilines 1 into fused tricyclic or 1,2-disubtituted benzimidazoles 2. A range of functions such as halides (F, Cl, Br), methoxy, ester, trifluoromethyl, cyano, pyridine and even nitro groups were tolerated using formic acid as a clean, safe, user-friendly and complementary reductant. When iodine was used in stoichiometric amount (50 mol %), the methodology allowed direct synthesis of benzimidazole hydroiodides 2.HI in high yields by simple precipitation from reaction mixture.

Redox condensation of o-Halonitrobenzene with 1,2,3,4-Tetrahydroisoquinoline : Involvement of an Unexpected Auto-catalyzed Redox Cascade.

T. B. Nguyen, L. Ermolenko, A. Al-Mourabit, Chem. Commun. 2016, 52, 4914.

DOI : 10.1039/C6CC01436D

A practical synthesis of fused benzimidazoles 5 has been developed by simply heating o-halonitrobenzenes 1 with tetrahydroisoquinolines 2. In this transformation, 2 played multiple roles : building block, base and double hydride donor in a cascade of uncatalyzed aromatic substitution, reduction of the nitro group, oxidation of the α-methylene group and condensation.


Cytotoxic, antiproliferative and pro-apoptotic effects of 5-hydroxy-6,7,3’,4’,5’ pentamethoxyflavone isolated from Lantana ukambensis.

W. R. Sawadogo, C. Cerella, A. Al-Mourabit, C. Moriou, M.-H. Teiten, G. I. Pierre, M. Dicato, M. Diederich, Nutrients, 2015, 7, 10388.

DOI : 10.3390/nu7125537

Lantana ukambensis (Vatke) Verdc. is an African food and medicinal plant. This plant was extensively used in African folk medicinal traditions to treat chronic wounds but also as anti-leishmanial or cytotoxic remedies, especially in Burkina Faso, Tanzania, Kenya, or Ethiopia. This study investigates the in vitro bioactivity of polymethoxyflavones extracted from a L. ukambensis as anti-proliferative and pro-apoptotic agents. We isolated two polymethoxyflavones, 5,6,7,3ʹ,4ʹ,5ʹ-hexamethoxyflavone and 5-hydroxy-6,7,3ʹ,4ʹ,5ʹ-pentamethoxyflavone. Compound 5-hydroxy-6,7,3ʹ,4ʹ,5ʹ-pentamethoxyflavone was selectively cytotoxic against monocytic lymphoma (U937), acute T cell leukemia (Jurkat), and chronic myelogenous leukemia (K562) cell lines, but not against peripheral blood mononuclear cells (PBMCs) from healthy donors, at all tested concentrations. Moreover, this compound exhibited significant anti-proliferative and pro-apoptotic effects against U937 acute myelogenous leukemia cells. This study highlights the anti-proliferative and pro-apoptotic effects of 5-hydroxy-6,7,3ʹ,4ʹ,5ʹ-pentamethoxyflavone (2) and provides a scientific basis of traditional use of L. ukambensis.

Apoptotic effect of compound 2 at 10 µg/mL and UNBS1450 at 0.01 µg/mL, 24 h on U937 cells. U937 cells treated with (2) at 10 µg/mL, dimethyl sulfoxide (DMSO) (negative control)

Netamines O-S, Five New Tricyclic Guanidine Alkaloids from the Madagascar Sponge Biemna laboutei and their Antimalarial Activity.

E. Gros, M.-T. Martin, J. Sorres, C. Moriou, J. Vacelet, M. Frederich, M. Aknin, Y. Kashman, A. Gauvin-Bialecki, A. Al-Mourabit, Chem. Biodivers. 2015, 12, 1725.

DOI : 10.1002/cbdv.201400350.

In our continuing program to isolate new compounds from the Madagascar sponge Biemna laboutei, five new tricyclic guanidine alkaloids, netamines O-S (1-5) have been identified together with the known netamine E (6) and mirabilin J (7). Netamines O, P and Q isolated in sufficient quantities were tested for their cytotoxicity against KB cells and their activity against the malaria parasite Plasmodium falciparum. Netamines O and Q were found to be moderately cytotoxic. Netamines O, P and Q exhibited antiplasmodial activity with an IC50 value 16.99 ± 0.25, 36.23 ± 3.44 and 8.37 ± 1.35 µM respectively.

Quorum Sensing Inhibitors from French Polynesian Marine Sponges.

T. Mai, F. Tintillier, A. Lucasson, C. Moriou, E. Bonno, S. Petek, K. Magré, A. Al-Mourabit, D. Saulnier, C. Debitus, Lett. Appl. Microbiol. 2015, 61, 311. Featured as editor’s choice, Letters of Applied Microbiology, issue 4, 2015

DOI : 10.1111/lam.12461

Sponges’s self defence mechanisms involving dialog molecules thus represent a pertinent research track for potent anti-infective and anti-biofilm activities such as quorum sensing inhibitors (QSI). Sponge Leucetta chagosensis led to the isolation of three new alkaloids, isonaamine D, di-isonaamidine A and leucettamine D. Isonaamidine A and isonaamine D were identified as the QSI of Vibrio harveyi on CAI-1, AI-2 and HAI QS pathways. These results outline the importance of these secondary metabolites for their producing organisms themselves in their natural environment, as well as the potential of the marine resource for aquaculture needs.

Marine Natural Occurring 2,5-Diketopiperazines : Isolation, Synthesis and Optical Properties.

R. Laville, T. B. Nguyen, C. Moriou, S. Petek, C. Debitus, A. Al-Mourabit, Hetetocycles, 2015, 90, 1351.

DOI : 10.3987/COM-14-S(K)87

Seven 2,5-diketopiperazines (DKPs) were isolated from the Fijian marine sponge Acanthella cavernosa. NMR and circular dichroism (CD) comparison with synthetic L-L DKPs allowed us to determine unambiguously the L-L absolute configuration of the natural DKPs. This work initiated the setting up of an optical properties database of natural DKPs, including specific rotation and CD.

Elements as Direct Feedstocks for Organic Synthesis : Fe/I2/O2 for Diamination of 2-Cyclohexenones with 2-Aminopyrimidine and 2-Aminopyridines.

T. B. Nguyen, M. Corbin, P. Retailleau, L. Ermolenko, A. Al-Mourabit, Org. Lett. 2015, 17 ,4956.

DOI : 10.1021/acs.orglett.5b02340

Elements as feedstocks for organic synthesis, the trio of metallic iron, molecular iodine, and dioxygen, were found to be an excellent tool for oxidative regioselective diamination of conjugated enones with 2-aminopyrimidine (a guanidine surrogate) and 2-aminopyridines leading to Natural unaromatized fragment of benzosceptrin in moderate to good yields.

Concise Access to 2-Aroylbenzothiazoles by Redox Condensation Reaction between o-Halonitrobenzenes, Acetophenones, and Elemental Sulfur.

T. B. Nguyen, K. Pasturaud, L. Ermolenko, A. Al-Mourabit, Org. Lett. 2015, 17 , 2562.

DOI : 10.1021/acs.orglett.5b01182

A wide range of 2-aroylbenzothiazoles 3 including some pharmacologically relevant derivatives can be obtained in high yields by simply heating o-halonitrobenzenes 1, acetophenones 2, elemental sulfur, and N-methylmorpholine.

Debromokeramadine from the marine sponge Agelas cf. mauritiana : isolation and short regioselective and flexible synthesis.

C. Schroif-Grégoire, J. Appenzeller, C. Debitus, A. Zaparucha, A. Al-Mourabit, Tetrahedron, 2015, 71, 3609.

DOI : 10.1016/j.tet.2014.12.081

Atom economy, regio and stereoselective synthesis of the newly isolated debromokeramadine (2a) from the sponge Agelas cf. mauritiana : the debromokeramadine (2a), that we isolated from the Pacific sponge Agelas cf. mauritiana and its known brominated analog, keramadine (1) were synthesized using our regioselective oxidative addition of a guanidine derivative on N-acylpyrrole dihydropyridines technilogy. This flexible approach was applied to the preparation of three debromo-analogs 2b-2d by varying the substitution of the guanidine bis-nucleophile. The reaction is a great progress for the regio and stereoselective synthesis of keramadine (2a) analogs and interesting library of pyrrole-2-aminoimidazole allowing biological activity studies.

Atom economy, regio and stereoselective synthesis of the newly isolated debromokeramadine (2a) from the sponge Agelas cf. mauritiana

Sodium Sulfide : A Sustainable Solution for Unbalanced Redox Condensation Reaction between o-Nitroanilines and Alcohols Catalyzed by an Iron–Sulfur System.

T. B. Nguyen, L. Ermolenko, A. Al-Mourabit, Synthesis, 2015, 47, 1741.

DOI : 10.1055/s-0034-1380134

Unbalanced redox condensation reaction between o-nitroanilines and alcohols, leading to benzimidazole and quinoxaline heterocycles can be efficiently promoted and catalyzed by sodium sulfide (40 mol%) in combination with iron(III) chloride hexahydrate (1 mol%). Beside the role as a precursor for the iron–sulfur (Fe/S) catalyst formation, hydrated sodium sulfide was shown to be an excellent noncompetitive, multi-electron reducing agent.


Netamines H-N, Tricyclic Guanidine Alkaloids from the Marine Sponge Biemna laboutei and their Antimalarial Activity.

E. Gros, A. Al-Mourabit, M-T. Martin, J. Sorres, J. Vacelet, M. Frederich, M. Aknin, Y. Kashman, A. Gauvin-Bialecki, J. Nat. Prod. 2014, 77, 818.

DOI : 10.1021/np4009283

Chemical examination of the CH2Cl2/MeOH (1:1) extract of the Madagascar sponge Biemna laboutei resulted in the isolation of seven new tricyclic guanidine alkaloids, netamines H-N (1-7) along with the known netamine G, mirabilin A, C and F. Their structures were elucidated by interpretation of 1D and 2D NMR spectra and HRESIMS data. All compounds were evaluated for their cytotoxicity against KB cells and their antiplasmodial activity. Netamine M (6) was found to be cytotoxic, with IC50 value in the micromolar range and netamine K (4) exhibited activity against Plasmodium falciparum with an IC50 value of 0.6 µg/mL.

Reaction of Quinones and Guanidine Derivatives : Simple Access to bis-2-Aminobenzimidazole Moiety of Benzosceptrin and Other Benzazole Motifs.

M. Q. Tran, L. Ermolenko, P. Retailleau, T. B. Nguyen, A. Al-Mourabit, Org. Lett. 2014, 16, 920

DOI : 10.1021/ol403672p

A new strategy for the synthesis of 2-aminobenzimidazol-6-ols via a reaction of quinones with guanidine derivatives is reported. Sequential application of this methodology provided a simple access to the first benzosceptrin analogue bearing a bis-2-aminoimidazole moiety. A concomitant addition of two guanidines to the naphtho[1′,2′:4,5]imidazo[1,2-a]pyrimidine-5,6-dione, which includes the redox neutral debenzylation and guanidine-assisted cleavage of the 2-aminopyrimidine part resulted in the synthesis of the free challenging contiguous bis-2-aminoimidazole moiety of benzosceprins in one step.

Concise synthesis of Didebromohamacanthin A and Deme-thylaplysinopsine : Addition of Ethylenediamine and Guani-dine Derivatives to the Pyrrole - Amino Acid Diketopipera-zines in Oxidative Conditions.

L. Ermolenko, H. Zhaoyu, C. Lejeune, C. Vergne, C. Ratinaud, T. B. Nguyen, A. Al-Mourabit, Org. Lett. 2014, 16, 872–875.

DOI : 10.1021/ol4036177

Oxidative nucleophilic addition of ethylenediamine and guanidine derivatives to pyrrole - amino acid diketopiperazines was shown to provide substituted 5,6-dihydro-2(1H)-piperazinones, quinoxalinones and 2-aminoimidazolones. On the basis of this methodology, a concise approach to natural products didebromohamacanthin B and demethylaplysinopsine has been demonstrated.

Elemental Sulfur Disproportionation in Redox Condensation Reaction between o-Halonitrobenzenes and Benzylamines.

T. B. Nguyen, L. Ermolenko, P. Retailleau, A. Al-Mourabit, Angew. Chem. Int. Ed. 2014, 53, 13808.

DOI 10.1002/anie.201408397

The disproportionation of elemental sulfur at moderate temperatures is investigated in the redox condensation involving o-halonitrobenzenes 1 and benzylamines 2. As a redox moderator, elemental sulfur plays the dual role of both electron donor and acceptor, generating its lowest and highest oxidation states : S(-2) (sulfide equivalent) in benzothiazole 3 and S(+6) (sulfate equivalent) in sulfamate 4, and filling the electron gap of the global redox condensation process. Along with this process, a cascade of reactions of reduction of the nitro group of 1, oxidation of the aminomethyl group of 2, metal-free aromatic halogen substitution, and condensation finally led to 2-arylbenzothiazoles 3.

Three-component Reaction between Isocyanides, Aliphatic Amines and Elemental Sulfur en route to Thioureas under Mild Conditions with Complete Atom Economy.

T. B. Nguyen, L. Ermolenko, P. Retailleau, A. Al-Mourabit, Synthesis, 2014, 46, 3172.

DOI : 10.1055/s-0034-1379327

The reaction of isocyanides with aliphatic amines in the presence of elemental sulfur was found to proceed efficiently at, or near, room temperature to produce thioureas in excellent yields and with complete atom economy.

Fe/S-catalyzed decarboxylative redox condensation of arylacetic acids with nitro arenes.

T. B. Nguyen, L. Ermolenko, M. Corbin, A. Al-Mourabit, Org. Chem. Front. 2014, 1, 1157.

DOI : 10.1039/C4QO00221K

Fe/S clusters generated in situ from simple iron salts and sulfur S8 were found to be highly efficient to catalyze the decarboxylative redox condensation of arylacetic acids with nitroarenes in the presence of N-methylpiperidine as a basic additive. A wide range of aza-heterocycles was obtained in an atom-, step-, and redox-economical manner with water and carbon dioxide as the only by-products.


Unprecedented Biomimetic Homodimerization of the Oroidin and Clathrodin Marine Metabolites in the Presence of HMPA or Phosphonate Salt Tweezers.

C. Lejeune, H. Tian, J. Appenzeller, L. Ermolenko, M.-T. Martin, A. Al-Mourabit, J. Nat. Prod. 2013, 76, 903.

DOI : 10.1021/np400048r

The first biomimetic homodimerization of oroidin and clathrodin was effected in the presence HMPA and diphosphonate salts, strong guanidinium and amide chelating agents. The intermolecular associations probably interfere with the entropically and kinetically favored intramolecular cyclizations. Use of oroidin.½HCl salt or clathrodin.½HCl was indicative in the presence of the ambident nucleophilic and electrophilic tautomers of the 2-aminoimidazolic oroidin and clathrodin precursors. Surprisingly, the homodimerization of oroidin led to the nagelamide D skeleton, while the homodimerization of clathrodin gave the benzene para-symmetrical structure 19. The common process was rationalized from tautomeric precursors I and III.

Hydrogen bond organocatalysis of benzotriazole in transamidation of carboxamides with amines.

T. B. Nguyen, L. Ermolenko, M. E. Tran Huu Dau, A. Al-Mourabit, Heterocycles, 2013, 403.

DOI : 10.3987/COM-13-S(S)41

We have identified benzotriazole as an efficient organocatalyst for transamidation reaction. This catalyst can be applied efficiently in the preparation of diversely substituted amides bearing different functional groups under mild conditions. The presence of two contiguous nitrogen atoms in the catalyst is of crucial importance.

Nitro-Methyl Redox Coupling : Efficient Approach to 2-Hetarylbenzothiazoles from 2-Halonitroarene, Methylhetarene, and Elemental Sulfur.

T. B. Nguyen, L. Ermolenko, A. Al-Mourabit, Org. Lett. 2013, 15, 4218.

DOI : 10.1021/ol401944a

A simple, straightforward, and atom economic approach to 2-hetarylbenzothiazoles starting from 2-halonitroarene, methylhetarene, and elemental sulfur under mild conditions is described. The method is highlighted by the direct redox nitro-methyl reaction for carbon–nitrogen bond formation without an added oxidizing or reducing agent.

Green and Selective Autoxidation of Benzylamines : Application to the Synthesis of Some Nitrogen Heterocycles.

T. B. Nguyen, L. Ermolenko, A. Al-Mourabit, Green Chem. 2013, 2713.

DOI : 10.1039/C3GC41186A

A green and remarkably simple synthesis of nitrogen heterocycles from benzylamines and anilines o-substituted by a cyclizable group has been developed based on selective uncatalyzed autoxidation of benzylamines.

Iron sulfide catalyzed redox/condensation cascade reaction between 2-amino/hydroxy nitrobenzenes and activated methyl groups : a straightforward atom economical approach to 2-hetaryl-benzimidazoles and -benzoxazoles.

T. B. Nguyen, L. Ermolenko, A. Al-Mourabit, J. Am. Chem. Soc. 2013, 135, 118.

DOI : 10.1021/ja311780a

Iron sulfide generated in situ from elemental sulfur and iron was found to be highly efficient in catalyzing a redox/condensation cascade reaction between 2-amino/hydroxy nitrobenzenes and activated methyl groups. This method represents a straightforward and highly atom economical approach to 2-hetaryl-benzimidazoles and -benzoxazoles.


Donnazoles A and B from Axinella donnani sponge : very close derivatives from the postulated intermediate ’pre-axinellamine’.

J. Munoz, C. Moriou, J. F. Gallard,P. D. Mmarie, A. Al-Mourabit, Tet. Lett. 2012, 53, 5828.

DOI : 10.1016/j.tetlet.2012.07.110

Two novel dimeric pyrrole-aminoimidazole (PAI) alkaloids (-) donnazoles A–B (1–2) were isolated from the marine sponge Axinella donnani collected off the Mauritius Island. Their structures were elucidated mainly by 2D NMR. Both compounds bear the crucial substituted cyclopentane of ‘pre-axinellamine’, the hypothetical common intermediate of all dimeric PAIs. Additionally, the essential trans-6,7 ring junction of palau’amine’s congeners is already established in 1 and 2. The absolute configurations of 1 and 2 were deduced via NOE correlations in combination with the comparison of their circular dichroism data with the one of (-) sceptrin. The absolute configuration of (-)-donnazoles A (1) and B (2) is coherent with the absolute configuration of the known dimeric members of PAI alkaloids.

Pipestelides A-C : cyclodepsipeptides from the pacific marine sponge Pipestela candelabra.

J. Sorres, M.-T. Martin, S. Petek, H. Levaique, T. Cresteil, S. Ramos, O. Thoison, C. Debitus, A. Al-Mourabit, J. Nat. Prod. 2012, 75, 759.

DOI : 10.1021/np200714m

Pipestelides A–C (2–4) are three new NRPS–PKS hybrid macrolides containing uncommon moieties, isolated from the Pacific marine sponge Pipestela candelabra. Their structures were elucidated on the basis of spectroscopic data. These cyclodepsipeptides appear to be biosynthetically related to jaspamide (aka jasplakinolide) (1) by chemical modification of the building blocks of the polyketide or peptide chains. Pipestelides A–C (2–4) contain a bromotyrosine [3-amino-3-(bromo-4-hydroxyphenyl)propanoic acid] unit, a polypropionate with a Z double bond, and a 2-hydroxyquinolinone, respectively. Revised chemical shift assignments are provided for the co-isolated known jasplakinolide Ca (5). In addition, compounds 2 and 3 exhibited cytotoxic activities in the micromolar range.

N-Chlorosuccinimide/sodium hydroxide-mediated synthesis of benzimidazoles from amidines under mild conditions.

T. B. Nguyen, L. Ermolenko, A. Al-Mourabit, Heterocycles, 2012, 86, 555.

DOI : 10.3987/COM-12-S(N)53

A convenient room-temperature one-pot procedure for the preparation of benzimidazoles derivatives from N-arylamidines has been developed. The reaction of N-aryl-N’-chloro amidines, generated by the treatment of N-aryl amidines with N-chlorosuccinimide, in presence of sodium hydroxide provides benzimidazoles in good to excellent yields. Nitrogen anion generated in situ from succinimide (by-product of the chlorination step using NCS) and hydroxide anion was found to be highly effective as Brønsted base to promote the cyclization into benzimidazole of N-aryl-N’-chloroamidine.

Benzazoles from aliphatic amines and o-amino/mercaptan/hydroxyanilines : elemental sulfur as a highly efficient and traceless oxidizing agent.

T. B. Nguyen, L. Ermolenko, W. A. Dean, A. Al-Mourabit, Org. Lett. 2012, 14, 5948.

DOI : 10.1021/ol302856w

A novel remarkably simple solvent-free and catalyst-free synthesis of benzazoles from alkylamines and o-hydroxy/amino/mercaptan anilines using elemental sulfur as traceless oxidizing agent has been developed.

Efficient and selective multicomponent oxidative coupling of two different aliphatic primary amines into thioamides by elemental sulfur.

T. B. Nguyen, L. Ermolenko, A. Al-Mourabit, Org. Lett. 2012, 14, 4274.

DOI : 10.1021/ol3020368

A novel remarkably simple solvent-free and catalyst-free synthesis of benzazoles from alkylamines and o-hydroxy/amino/mercaptan anilines using elemental sulfur as traceless oxidizing agent has been developed.

Boric acid : a highly efficient catalyst for transamidation of carboxamides with amines.

T. B. Nguyen, J. Sorres, M. Q. Tran, L. Ermolenko, A. Al-Mourabit, Org. Lett. 2012, 14, 3202.

DOI : 10.1021/ol301308c

A novel method of transamidation of carboxamides with amines using catalytic amounts of readily available boric acid under solvent-free conditions has been developed. The scope of the methodology has been demonstrated with (i) primary, secondary, and tertiary amides and phthalimide and (ii) aliphatic, aromatic, cyclic, acyclic, primary, and secondary amines.


New insight into marine alkaloid metabolic pathways : revisiting oroidin biosynthesis.

GG. Genta-Jouve, N. Cachet, S. Holderith, F. Oberhansli, J. L. Teyssie, R. Jeffree, A. Al-Mourabit, O. P. Thomas, ChemBioChem. 2011, 12, 2298.

DOI : 10.1002/cbic.201100449

Sponge natural product biosynthesis : A highly sensitive in vivo protocol based on 14C radiolabeled precursors and beta-imager autoradiography allowed the unraveling of the origin of the pyrrole 2-aminoimidazole-containing key biosynthetic intermediate oroidin. Proline and lysine are now proposed as the early precursors of the pyrrole and the 2-aminoimidazole moieties of oroidin respectively.

Structure elucidation of the new citharoxazole from the mediterranean deep-sea sponge Latrunculia (Biannulata) citharistae.

G. Genta-Jouve, N. Francezon, A. Puissant, P. Auberger, J. Vacelet, A. Fontana, A. Al-Mourabit, O. P. Thomas, Magn. Reson. Chem. 2011, 49, 533.

DOI : 10.1002/mrc.2772

Citharoxazole (1), a new batzelline derivative featuring a benzoxazole moiety, was isolated from the Mediterranean deep-sea sponge Latrunculia (Biannulata) citharistae (Vacelet, 1969) together with the known batzelline C (2). This is the first chemical study of a Mediterranean Latrunculia species and the benzoxazole moiety is unprecedented for this family of marine natural products. The structure was mainly elucidated by the interpretation of NMR spectra and especially HMBC correlations.

Biosynthesis, asymmetric synthesis, and pharmacology, including cellular targets, of the pyrrole-2-aminoimidazole marine alkaloids.

A. Al-Mourabit, , M. A. Zancanella, S. Tilvi, D. Romo, Nat. Prod. Rep. 2011, 28, 1229.

DOI : 10.1039/C0NP00013B

The pyrrole-2-aminoimidazole (P-2-AI) alkaloids are a growing family of marine alkaloids, now numbering well over 150 members, with high topographical and biological information content. Their intriguing structural complexity, rich and compact stereochemical content, high N to C ratio (1 : 2), and increasingly studied biological activities are attracting a growing number of researchers from numerous disciplines world-wide. This review surveys advances in this area with a focus on the structural diversity, biosynthetic hypotheses with increasing, but still rare, verifying experimental studies, asymmetric syntheses, and biological studies, including cellular target receptor isolation studies, of this stimulating and exciting alkaloid family.

Dihydrohymenialdisines, new pyrrole-2-aminoimidazole alkaloids from the marine sponge Cymbastela cantharella.

P. Sauleau, P. Retailleau, S. Nogues, I. Carletti, L. Marcourt, R. Raux, A. Al-Mourabit, C. Debitus, Tet. Lett. 2011, 52, 2676.

DOI : 10.1016/j.tetlet.2011.03.073

In our investigation of bioactive marine natural products, we revisited an ethanolic extract of the New Caledonian sponge Cymbastela cantharella. Four new natural compounds (3–6) were isolated and their structural determinations as dihydrohymenialdisine derivatives were achieved by spectral data analysis and chemical conversion. These products did not show any activity in the Polo Like kinase bioassay, demonstrating thus the importance of the unique structure of hymenialdisine, known as an improved kinase inhibitor.

Biomimetic Synthesis of Marine Pyrrole-2-Aminoimidazole and Guanidinium Alkaloids

E. Poupon and B.Nay (book chapter). J. Appenzeller and A. Al-Mourabit, 2011

DOI : 10.1002/9783527634606.ch7

Pyrrole-assisted and easy oxidation of cyclic α,-amino acid- derived diketopiperazines under mild conditions.

H. Tian, L. Ermolenko, M. Gabant, C. Vergne, C. Moriou, P. Retailleau, A. Al-Mourabit, Adv. Synth. Catal. 2011, 353, 1525.

DOI : 10.1002/adsc.201100112

A new procedure for the aerobic oxidation of α-amino acids acylated by pyrrole-carboxylic acid with triplet dioxygen is introduced. The reaction is general for a variety of pyrrole-amino acid derivatives and represents a very practical and controllable method for the selective preparation of α-hydroperoxy- or α-hydroxy-α-amino acid diketopiperazines with molecular dioxygen. Furthermore, the non-catalyzed direct oxidation of amino acid derivatives at the α-position with molecular dioxygen represents a fundamental question.