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Chirosciences thematics

Research directions

Asymmetric catalysis.
Asymmetric Metal and organocatalysis 
Bioconversion and enzymatic resolution
Dynamic stereochemistry and chirality 
Self-assembled chiral supramolecular systems 

All these field of competence have the chance to have in Marseille, on the same campus, the Chiral Chromatography Centerand several chiroptical methods to analyze enantioenriched or, most commonly, enantiopure compounds. These state-of-the-art methods include Electronic and Vibrational Circular Dichroism, (ECD & VCD), magnetic circular dichroism (MCD) enabled by a 1.6 Tesla permanent magnet, Optical Rotatory Dispersion (ORD) and polarimetry. Additionally single crystal X-ray structures are solved with a high throughput and with the future option to assign the absolute configuration of chiral compounds in the absence of heavy atoms. Additionally, the ChirBase™ database which is a discovery and data mining tool for chiral chromatography separations. This is a unique constellation, not only in Europe, but also worldwide, where several competences are bundled within the unique Chirosciences Team and the associated Spectropole. This enables obtaining rapidly a performant separation of enantiomers and the confident assignment of their absolute configuration, that is in a simplistic view, a specification of their right- or left-handness.

The Chiral Chromatography Center was created by Prof Christian Roussel and besides several screening units, semi-preparative HPLC can be performed on a variety of chiral columns. A screening unit with up to twelve different columns is shown below together with a multiple selection valve. This allows finding optimum conditions of solvents and flux for a certain resolution problem. The group also operates ChirBase™, a database collecting all chiral separations reported in the literature with all the details to allow reproducible resolutions of enantiomers.

Supercritical CO2 screening unit (SFC) with thermostated multiple chiral columns.

Selection valve for a normal phase HPLC screening unit.

Once the optimal conditions have been identified for a certain suitable chiral column, by repeated injections on a semi-preparative scale the Chiral Chromatography Center can separate on a gram scale in one day racemic mixtures.

For instance the chiral bis-Schiff base below has two enantiomers and an optically inactive meso form which on different chiral stationary phases have different elution orders. Chiroptical detectors (polarimetric detection or on-line circular dichroism detector) (link to: allow a safe assignment to each chromatographic peak.

Selected recent publications from the Center of Chiral Chromatography and the Group of Prof. Christian Roussel on Dynamic Stereochemistry:

Assembly of Helicene-Capped N,P,N,P,N-Helicands within CuI Helicates: Impacting Chiroptical Properties by Ligand-Ligand Charge Transfer
V. Vreshch, M. E. Moussa, B. Nohra, M. Srebro, N. Vanthuyne, C. Roussel, J. Autschbach, J. Crassous, C. Lescop, R. Reau
Angew. Chem. Int. Ed. 201352, 1968-1972. DOI: 10.1002/anie.201207251

Novel phenyl(thio)ureas bearing (thio)oxothiazoline group as potential BACE-1 inhibitors: synthesis and biological evaluation
F. Andreoli, A. L. Doukara, M. A. Mehdid, N. Vanthuyne, C. Roussel, J. Dessolin, J. L. Kraus
J. Enzym. Inhib. Med. Ch. 201328, 153-162. DOI: 10.3109/14756366.2011.642375

Self-disproportionation of enantiomers via achiral chromatography: a warning and an extra dimension in optical purifications
V.A. Soloshonok, C. Roussel, O. Kitagawa, A.E. Sorochinsky
Chem. Soc. Rev. 201241, 4180-4188. DOI: 10.1039/c2cs35006h

Resolution and absolute configuration of some alpha-aminoacetals: en route to enantiopure N-protected alpha-aminoaldehydes
 M. Albalat-Serradeil, G. Primazot, D. Wilhelm, J.C. Vallejos, N. Vanthuyne, C. Roussel
Amino Acids 201243, 687-696. DOI: 10.1007/s00726-011-1117-6

Atropisomerism and Axial Chirality in Heteroaromatic Compounds
I. Alkorta, J. Elguero, C. Roussel, N. Vanthuyne, P. Piras
Advances in Heterocyclic Chemistry 2012105, 1-188. DOI: 10.1016/B978-0-12-396530-1.00001-2

Ruthenium-Vinylhelicenes: Remote Metal-Based Enhancement and Redox Switching of the Chiroptical Properties of a Helicene Core
E. Anger, M. Srebro, N. Vanthuyne, L. Toupet, S. Rigaut, C. Roussel, J. Autschbach, J. Crassous, R. Reau
J. Am. Chem. Soc. 2012, 15628-15631. DOI: 10.1021/ja304424t

Mechanistic Investigation of Enediyne-Connected Amino Ester Rearrangement. Theoretical Rationale for the Exclusive Preference for 1,6-or 1,5-Hydrogen Atom Transfer Depending on the Substrate. A Potential Route to Chiral Naphthoazepines 
D. Campolo, A. Gaudel-Siri, S. Mondal, D. Siri, E. Besson, N. Vanthuyne, M. Nechab, M. P. Bertrand
J. Org. Chem. 2012, 2773-2783. DOI: 10.1021/jo202580y

XRD and VCD: a marriage of love or convenience? Honeymoon around a cyclic urea derivative
D. Gherase, J.V. Naubron, C. Roussel, M. Giorgi
Acta Crystallogr. C 201268, O247-O252. DOI: 10.1107/S010827011202358X

Chiral enantiopure bis(thio)ureas derived from TADDOL and their carboxylate complexation capacity
D. Gherase, C. Roussel
Cent. Eur. J. Chem. 201210, 1066-1072. DOI: 10.2478/s11532-012-0011-8 

Asymmetric 4-Aryl-1,4-dihydropyridines Potentiate Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
M. Giampieri, N. Vanthuyne, E. Nieddu, M.T. Mazzei, M. Anzaldi, N. Pedemonte, L.J.V. Galietta, C. Roussel, M. Mazzei
ChemMedChem20127, 1799-1807. DOI: 10.1002/cmdc.201200311

Resolution of protected silaproline for a gram scale preparation
C. Martin, N. Vanthuyne, H. Miramon, J. Martinez, F. Cavelier
Amino Acids 201243, 649-655. DOI: 10.1007/s00726-011-1112-y

Synthesis and reactivity of a cyclopentadienyl-indenyl ligand ring-coupled by a chiral bridge derived from ethyl (S)-(-) lactate 
R. Laï , J.-C. Daran, D. Nuel, M. Sanz, N. Summerton, N. Vanthuyne, A. Zaragori-Benedetti  
Dalton Transactions201342, 7980-7990. DOI: 10.1039/c3dt33019b

A focus on the asymmetric synthesis of a novel threo-beta-benzyl-beta-hydroxy aspartate analogue
S. Mekki, S. Bellahouel, N. Vanthuyne, M. Rolland, A. Derdour, J. Martinez, M. Vignes, V. Rolland
Tetrahedron Asymmetry201223, 94-99. DOI: 10.1016/j.tetasy.2012.01.004
Copper Carbenoid, Reactant and Catalyst for One-Pot Diazo Ester Coupling Cascade Rearrangement of Enediynes: Formation of Two Contiguous Tetrasubstituted Stereocenters
S. Mondal, M. Nechab, D. Campolo, N. Vanthuyne, M. P. Bertrand
Adv. Synth. Catal. 2012354, 1987-2000. DOI: 10.1002/adsc.201200045

One-pot Crabbe homologation-radical cascade cyclisation with memory of chirality
S. Mondal, M. Nechab, N. Vanthuyne, M.P. Bertrand
Chem. Comm. 201248, 2549-2551. DOI: 10.1039/C2cc17830c

Synthesis of Enantiopure Tertiary Skipped Diynes via One-Pot Desymmetrizing TMS-Cleavage
M. Nechab, N. Vanthuyne
Org. Lett201214, 3974-3977. DOI: 10.1021/Ol3017462

N-Octanoyldimethylglycine Trifluoroethyl Ester, an Acyl Donor Leading to Highly Enantioselective Protease-Catalysed Kinetic Resolution of Amines
S. Queyroy, N. Vanthuyne, S. Gastaldi, M.P. Bertrand, G. Gil
Adv. Synth. Catal2012354, 1759-1764. DOI: 10.1002/adsc.201100993

Enantiomers of dimethyl [(2E)-1,3-diphenylprop-2-en-1-yl]propanedioate resulting from allylic alkylation reaction: Elution order on major high-performance liquid chromatography chiral columns
M. Ramillien, N. Vanthuyne, M. Jean, D. Gherase, M. Giorgi, J.V. Naubron, P. Piras, C. Roussel
J. Chromatogr. A, 20121269, 82-93. DOI: 10.1016/j.chroma.2012.09.025

Rhenium complexes bearing phosphole-pyridine chelates: simple molecules with large chiroptical properties
E. Takacs, A. Escande, N. Vanthuyne, C. Roussel, C. Lescop, E. Guinard, C. Latouche, A. Boucekkine, J. Crassous, R. Reau, M. Hissler
Chem. Comm. 201248, 6705-6707. DOI: 10.1039/C2cc32542j 

Discovery of novel reactions and the preferential formation of only one enantiomer is another research topic related to the development of enantioselective syntheses. Such high yielding reactions, if performed catalytically, can have important applications for obtaining active pharmaceutical ingredients, pesticides, herbicides, odorants, etc. In the focus have been chiral phosphorus compounds such as phosphine oxides that can bind various metal atoms. Several contributions to transition metal catalysis in homogeneous media have been recently made. An example where enantiomers were resolved on a gram scale is shown below

D. Gatineau, L. Giordano, G. Buono, J. Am. Chem. Soc. 2011,133, 10728-10731.
L. Giordano, J. Leclaire, G. Buono, D. Gatineau, D. Hérault, D. Moraleda, D. Nuel, C. Roussel, N. Vanthuyne EP13305019.5

Other recent selected publications
Palladium-Mediated [2+1] Cycloaddition of Norbornene Derivatives with Ynamides
H. Clavier, A. Lepronier, N. Bengobesse-Minsta, D. Gatineau, H. Pelissier, L. Giordano, A. Tenaglia, G. Buono 
Adv. Synth. Catal. 2013355, 404-408. DOI: 10.1002/adsc.201200903 

Analysis of the discriminative inhibition of mammalian digestive lipases by 3-phenyl substituted 1,3,4-oxadiazol-2(3H)-ones
V. Point, K. V. P. P. Kumar, S. Marc, V. Delorme, G. Parsiegla, S. Amara, F. Carrière, G. Buono, F. Fotiadu, S. Canan, J. Leclaire, J. F. Cavalier
Eur. J. Med. Chem201258, 452-463. DOI: 10.1016/j.ejmech.2012.10.040 

An ultraviolet spectrophotometric assay for the screening of sn-2-specific lipases using 1,3-O-dioleoyl-2-O-alpha-eleostearoyl-sn-glycerol as substrate
L. D. Mendoza, J.-A. Rodriguez, J. Leclaire, G. Buono, F. Fotiadu, F. Carrière, A. Abousalham,
J. Lipid Res. 201253, 185-194. DOI: 10.1194/jlr.D019489

Recent Developments in Enantioselective Metal-Catalyzed Domino Reactions
H. Clavier, H. Pellissier
Adv. Synth. Catal2012354, 3347-3403. DOI: 10.1002/adsc.201200254 

Palladium-mediated phosphine-oriented chemoselective bis allylic alkylation leading to spirocarbocycles 
H. Clavier, L. Giordano, A. Tenaglia
Angew. Chem. Int. Ed. 201251, 8648-8651. DOI: 10.1002/anie.201204629 
Comparison of two soft chemistry routes for the synthesis of mesoporous carbon/-β-SiC nanocomposites.
X. Deschanels, D. Hérault, G. Arrachart, C. Rey, A. Grandjean, G. Toquer, R. Podor, T. Zemb, G. Cerveau, R. Corriu,
Journal of Materials Science201348, 4097–4108. DOI:10.1007/s10853-013-7222-z

Synthesis and characterization of (±)-13-hydroxy-3,11-diaza steroids 
M. Ibrahim-Ouali, E. Romero, Steroids 201277, 157-167. DOI: 10.1016/j.steroids.2011.11.003 

Ring-closing metathesis towards functionalized pentacyclic steroids
M. Ibrahim-Ouali, H. Bouleghlem, N.-E. Aouf, Tetrahedron Lett.201253, 1859-1862. DOI: 10.1016/j.tetlet.2012.02.005

Stereoselective synthesis of pentacyclic steroids functionalized at C-11 
M. Ibrahim-Ouali, E. Romero, K. Hamze, Steroids 201277, 1092-1100. DOI: 10.1016/ j.steroids.2012.04.004

Synthesis of various secosteroidal macrocycles by RCM 
M. Ibrahim-Ouali, E. Romero, Steroids 2013, in press. DOI: 10.1016/j.steroids.2013.03.004

Asymmetric Organocatalytic Cycloadditions 
H. Pellissier, Tetrahedron,2012, 68, 2197-2232. DOI: 10.1016/j.tet.201110103 
Recent Developments in Asymmetric Organocatalytic Domino Reactions 
H. Pellissier, Advanced Synthesis and Catalysis,2012, 354, 237-294. DOI: 10.1002/adsc.201100714
Catalytic Kinetic Resolution 
H. Pellissier, Book Chapter in “The Separation of Enantiomers” Editors: M. Todd, J. Eames, Wiley, soumis.
Organocatalytic Intermolecular Formation of 3,4 and 5-Membered Cycles 
H. Pellissier, Book Chapter in “Comprehensive Enantioselective Organocatalysis” Editor: P. Dalko, Wiley, soumis.
Recent Developments in the [5+2] Cycloaddition 
Hervé Clavier and Hélène Pellissier, Book Chapter in “Methods and Applications of Cycloaddition Reactions in Organic Syntheses” Editor: N. Nishiwaki, Wiley, soumis.
Stereocontrolled Domino Reactions 
Hélène Pellissier, Chem. Rev. 2013113, 442-524. DOI: 10.1021/cr300271k 
Organocatalysis in Domino Reactions 
H. Pellissier, Book Chapter in "Domino Reactions - Concepts for Efficient Organic Synthesis" Editor: L. F. Tietze, soumis.
Asymmetric Domino Reactions 
H. Pellissier, Book, Royal Society of Chemistry, ISBN: 978-1-84973-710-4.

Supramolecular interactions involving chiral molecules are studied in the group of Silviu Balaban who is also heading the Team Chirosciences since January 2012. Especially phenomena of homo- and/or hetero-chiral assembly and aggregation are intriguing and not easily explained or quantified. This can lead to symmetry breaking and spontaneous apparition of only one enantiomorphic supramolecular species. This phenomenon is related to the homochirality on Earth for aminoacids (L) and the related (D) sugars and their covalent assembly into chiral proteins and nucleic acids, respectively, all which have only one handness. Translation of chirality from the molecular level to the supramolecular level is a particular active field of research to which our team has recently made some contributions. A long standing problem related to a very simple water soluble porphyrin which self-assembles into chiral tubes has been solved by electron cryo-microscopy:

Electron Cryo-microscopy of meso-Tetrakis-(4-sulphonatophenyl)porphyrin Dihydrochloride Tubes Reveals a Helical Organisation Explaining the Origin of their Chirality 
J. M. Short, J. A. Berriman, C. Kübel, Z. El-Hachemi, J.-V. Naubron, T. S. Balaban
ChemPhysChem, in press.

Other selected publications:

Nanoscopic Imaging of meso-Tetraalkylporphyrins Prepared in High Yields Enabled by Montmorrilonite K10 and 3 Å Molecular Sieves
R. Plamont, Y. Kikkawa, M. Takahashi, M. Kanesato, M. Giorgi, A. Chan Kam Shun, C. Roussel, T. S. Balaban
Chem. Eur. J.201319, 11293-11300(Front Cover Illustration).

An Atropisomer as a Chiral Probe to Study the Supramolecular Organization in Chromophoric Porphyrin Self-Assemblies 
C. Chappaz-Gillot, G. Canard, F. Andreoli, N. Vanthuyne, M. Giorgi, J.-V. Naubron, V. Monnier, R. Rosas, C. Roussel, T. S. Balaban
Eur. J. Org. Chem. 2012, 6526-6536. DOI: 10.1002/ejoc.201200985

Syntheses and Characterization of Undecaaryl Copper Corroles and of a First Undeacaaryl Corrole Free Base 
Di Gao, G. Canard, M. Giorgi, T. S. Balaban
Eur. J. Inorg. Chem. 2012, 5915-5920. DOI: 10.1002/ejic.201201158

Water Coordinated Zinc Dioxo-Chlorin and Porphyrin Self-assemblies as Chlorosomal Mimics: Variability of the Supramolecular Interactions 
A. Jesorka, A. R. Holzwarth, A. Eichhöfer, C. Malla Reddy, Y. Kinoshita, H. Tamiaki, M. Katterle, J.-V. Naubron, T. S. Balaban
Photochem. Photobiol. Sci. 201211, 1069-1080. DOI: 10.1039/C2PP25016k

Anisotropic Organization and Microscopic Manipulation of Self-assembling Synthetic Porphyrin Microrods that Mimic Chlorosomes: Bacterial Light-Harvesting Systems
C. Chappaz-Gillot, P. L. Marek, B. J. Blaive, G. Canard, J. Bürck, G. Garab, H. Hahn, T. Jávorfi, L. Kelemen, R. Krupke, D. Mössinger, P. Ormos, C. Malla Reddy, C. Roussel, G. Steinbach, M. Szabó, A. S. Ulrich, N. Vanthuyne, A. Vijayaraghavan, A. Zupcanova, T. S. Balaban
J. Am. Chem. Soc. 2012134, 944-954. DOI: 10.1021/ja203838p

On the Way to Biomimetic Dye Aggregate Solar Cells
P. L. Marek, H. Hahn, T. S. Balaban
Energy Environ. Sci20114, 2366-2378; (Perspective Article). DOI: 10.1039/c1ee01053k

Self-assemblies of Novel Magnesium Porphyrins Mimicking Natural Chlorosomal Bacteriochlorophylls 
J. Szmytkowski, J. Conradt, H. Kuhn, C. Malla Reddy, M. C. Balaban, T. S. Balaban, H. Kalt 
J. Phys. Chem. C2011115, 8832-8839. DOI: 10.1021/jp112244m

Two-Dimensional Structures of Anthracene Derivatives: In Situ Photodimerization and Host-Guest Chemistry

Y. Kikkawa, H. Kihara, M. Takahashi, M. Kanesato, T. S. Balaban, J.-M. Lehn
J. Phys. Chem. B2010114, 16718-16722. DOI: 10.1021/jp108069a

Novel Pyridinium Dyes That Enable Investigations of Peptoids at the Single-Molecule Level
B. Rudat, E. Birtalan, I. Thomé, D. K. Kölmel, V. L. Horhoiu, M. D. Wissert, U. Lemmer, H.-J. Eisler, T. S. Balaban, S. Bräse
J. Phys. Chem. B, 2010114, 13473-13480. DOI: 10.1021/jp103308s 
Ridge-Tile-like Chiral Topology: Synthesis, Resolution, and Complete Chiroptical Characterization of Enantiomers of Edge-Sharing Binuclear Square Planar Complexes of Ni(II) Bearing Achiral Ligands
V. Soloshonok, T. Ono, H. Ueki, N. Vanthuyne, T. S. Balaban, J. Bürck, H. Fliegl, W. Klopper, J.-V. Naubron, T. T. T. Bui, A. F. Drake, C. Roussel
J. Am. Chem. Soc. 2010132, 10477-10483. DOI: 10.1021/ja103296g 
Photo- and Thermally-enhanced Charge Separation in Supramolecular Viologen-hexacyano-ferrate Complexes 
A. S. Abouelwafa, V. Mereacre, T. S. Balaban, C. E. Anson, A. K. Powell
Cryst. Eng. Comm. 201012, 94-99. DOI: 10.1039/b915642a

Mimics of the Self-assembling Chlorosomal Bacteriochlorophylls: Regio- and Stereoselective Synthesis and Stereoanalysis of Acyl-(1-hydroxyalkyl)porphyrins 
T. S. Balaban, A. D. Bhise, G. Bringmann, J. Bürck, C. Chappaz-Gillot, A. Eichhöfer, D. Fenske, D. C. G. Götz, M. Knauer, T. Mizoguchi, D. Mössinger, H. Rösner, C. Roussel, M. Schraut, H. Tamiaki, N. Vanthuyne
J. Am. Chem. Soc. 2009131, 14480-14492. DOI: 10.1021/ja905628h

Preferential Pathways for Light-trapping Involving b-Ligated Chlorophylls
T. S. Balaban, P. Braun, C. Hättig, A. Hellweg, J. Kern, W. Saenger, A. Zouni 
Biochimica Biophysica ActaBioenergetics20091787, 1254-1265. DOI: 10.1016/j.bbabio.2009.05.010 

Self-assembling Porphyrins and Chlorins as Synthetic Mimics of the Chlorosomal Bacteriochlorophylls
T. S. Balaban 
in Handbook of Porphyrin Science with Applications to Chemistry, Physics, Materials Science, Engineering, Biology and Medicine, K. M. Kadish, K. M. Smith and R. Guilard, Eds., World Scientific: Singapore, 2010, Vol. 1, pp. 221-306. 

The group of Silviu Balaban benefits from the Future and Emerging Technologies (FET) Project PEPDIODE of the FP7 and also from the Région Provence-Alpes-Côte d’Azur with the project Nanomosaïque

In July 2013, the front cover of Chemistry – A European Journal features the old harbor of Marseille with supramolecular assemblies of molecules published in two back-to-back full papers by members of the Chirosciences Team. Marseille Provence is the 2013 Capital of European Culture. Our intention was to show that Chemistry is an integral part of the Marseille culture, just as the local football team Olympique Marseille (OM) or the Mediterranean Institutions, like the newly inaugurated museum MUCEM.