Research Topics



Heterocyclic and medicinal chemistry

The laboratory of organic synthesis in Leuven has a long tradition in synthetic heterocyclic chemistry. Different nitrogen-containing building blocks such as pyrroles, pyrazoles, 1,2,3-thiadiazoles, 1,2,3-triazoles, pyrimidines, pyrazin(on)es, (fused) indoles and carbazoles have been investigated extensively, including their use in supramolecular or dendrimer chemistry (see below).

In connection with this, many of these heterocyclic compounds have been tested for their biological properties or are especially synthesized to be screened for their activity in collaboration with our colleagues from pharmacy. In collaboration with the Rega institute, we are looking at different aspects of the synthesis and structure-activities of antiviral (e.g. HIV, HCV) drugs. A few simple structures and their properties are listed below.



In recent years, we have also started on a semisynthetic research program in which isolated natural products are modified, for instance the diterpene steviol or the antimalarial sesquiterpene artemisinin, to modify or enhance the pharmacological properties.



References

  1. M. A. Abramov, W. Dehaen, B. D'hooge, M. L. Petrov, S. Smeets, S. Toppet, M. Voets, "Nucleophilic intramolecular cyclization reactions of alkynechalcogenates", Tetrahedron 2000, 56, 3933-3940.

  2. M. A. Abramov, W. Dehaen, "A novel approach to sulfide derivatives of furocoumarin natural products", Synthesis 2000, 1529-1531.

  3. A. Hameurlaine, M. Abramov, W. Dehaen, "Formation of new heterocycles by intramolecular cyclization of alkynethiolates with nitrogen nucleophiles", Tetrahedron Lett. 2002, 43, 1015-1017.

  4. A. Geronikaki, E. Babaev, J. Dearden, W. Dehaen, D. Filimonov, I. Galaeva, V. Krajneva, A. Lagunin, F. Macaev, G. Molodavkin, V. Porikov, S. Pogrebnoi, V. Saloutin, A. Stepanchikova, E. Stingaci, N. Thack, L. Vlad, T. Voronina, "Design, synthesis, computational and biological evaluation of new anxiolytics", Bioorg. Med. Chem. 2004, 6559-6568.

  5. E. V. Sadchikova, V. A. Bakulev, W. Dehaen, K. Van Hecke, K. Robeyns, L. Van Meervelt, V. S. Mokrushin, A. Padwa, "Synthesis of novel azolo[1,2,3,5]-thiatriazines", Synlett 2004, 2037-2039.

  6. B. Metten, M. Kostermans, G. Van Baelen, M. Smet, W. Dehaen, "Synthesis of 5-aryl-2-oxopyrrole derivatives as synthons for highly substituted pyrroles", Tetrahedron 2006, 62, 6018-6028.

  7. T. Van Neck, S. Van Mierloo, W. Dehaen, "Functionalisation of artemisinin and its ring-contracted derivatives", Molecules 2007, 12, 395-405.

  8. V. S. Berseneva, V. A. Bakulev, W. Dehaen, S. Toppet, M. Borovkova, "Reactions of malonthioamides and malonamidines with methyl acetylpyruvate as a one step method to prepare 4-thio and 4-aminopyrrolo[3,4-c]pyridines", Tetrahedron 2007, 63, 4491-4496.

  9. N. P. Belskaia, T. G. Deryabina, A. V. Koksharov, M. I. Kodess, W. Dehaen, A. T. Lebedev, V. A. Bakulev, "Novel fused 1,2,4-triazines by intramolecular cyclisation of 1,2-diaza-1,3-butadienes bearing allyl(propargyl)sulfanyl and cyclic tert-amino groups", Tetrahedron Lett. 2007, 48, 9128-9131.


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Dendrimers and hyperbranched polymers

Dendrimers were prepared starting from heterocyclic building blocks (1,3,4-oxadiazoles, 1,3,5-triazines, pyrimidines, 1,2,4-triazoles) using a convergent strategy based on the nucleophilic aromatic substitution reaction. Within this class of heterocyclic dendrimers, the pyrimidines represent the optimum reactivity and stability. Other efficient "double stage convergent" strategies of dendritic ethers and ether ketones have been reported.



A successful synthesis of hyperbranched polymers with 100 % degree of branching based on the superacid-catalysed condensation of isatin or acenaphthenedione based monomers was reported by us. The resulting materials can be used further in highly efficient functionalisation experiments, influencing the properties.


References

  1. M. Smet, E. Schacht, W. Dehaen, "Synthesis, characterization and modification of hyperbranched polyaryleneoxindoles with a degree of branching of 100%", Angew. Chem. 2002, 4729-4732.

  2. M. A. Abramov, R. Shukla, D. B. Amabilino, W. Dehaen, "A new strategy for synthesis of poly (ether ketone) dendrons", J. Org. Chem. 2002, 67, 1004-1007.

  3. W. Maes, D. Amabilino, W. Dehaen, "Synthesis of novel dendrimers containing pyrimidine units", Tetrahedron 2003, 59, 3937-3943.

  4. N. D. McClenaghan, R. Passalacqua, F. Loiseau, S. Campagna, B. Verheyde, A. Hameurlaine, W. Dehaen, "Ruthenium (II) dendrimers containing carbazole-based chromophores as branches", J. Am. Chem. Soc. 2003, 125, 5356-5365.

  5. F. Loiseau, S. Campagna, A. Hameurlaine, W. Dehaen, "Dendrimers constructed from porphyrin cores and carbazole chromophores as peripheral units. Absorption spectra, luminescence properties, and oxidation behaviour", J. Am. Chem. Soc. 2005, 127, 11352-11363.

  6. M. Smet, Y. Fu, X. Zhang, E. H. Schacht, W. Dehaen, "A Convenient A2 + B3 approach to hyperbranched poly(arylene oxindole)s", Macromol. Rapid Commun. 2005, 26, 1458-1463.

  7. S. A. Chavan, W. Maes, L. E. M. Gevers, J. Wahlen, I. F. J. Vankelecom, P. A. Jacobs, W. Dehaen, D. E. Devos, "Porphyrin-functionalized dendrimers: synthesis and application as recycable photocatalysts in a nanofiltration membrane reactor", Chem. Eur. J. 2005, 6754-6762.

  8. H. Xu, J. Gao, Y. Wang, M. Smet, W. Dehaen, X. Zhang, "Hyperbranched polyselenide as glutathione peroxidase mimics", Chem. Commun. 2006, 796-798.

  9. W. Maes, J. Vanderhaegen, S. Smeets, C. V. Asokan, L. M. Van Renterghem, F. E. Du Prez, M. Smet, W. Dehaen, "Synthesis of multi(metallo)porphyrin dendrimers through nucleophilic aromatic substitution on meso-pyrimidinyl substituted porphyrins", J. Org. Chem. 2006, 71, 2987-2994.

  10. W. Maes, W. Dehaen, "Dendrimers containing N-, O-heterocycles" in Modern Approaches to the Synthesis of O- and N-Heterocycles, Vol. 2 (Eds. T. S. Kaufman, L. S., Larghi), Research Signpost, 2007, 309-332.

  11. Y. Fu, C. Van Oosterwijck, A. Vandendriessche, A. Kowalcyuk-Bleja, X. Zhang, A. Dworak, W. Dehaen, M. Smet, "Hyperbranched poly(arylene oxindoles) with a degree of branching of 100 % for the construction of nanocontainers by orthogonal modification", Macromolecules 2008, 41, 2388-2393.


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Porphyrins, corroles and other pyrrole-based macrocycles

We have prepared different porphyrins substituted with heterocyclic rings, such as 1,2,3-thiadiazoles. The latter could be cleaved in basic medium to afford meso-ethynylporphyrin derivatives. Most of the work dealt (and still deals) with meso-pyrimidinyl substituted porphyrins, that are easily functionalized on the pyrimidine rings, e.g. by nucleophilic aromatic substitution and Pd-catalyzed cross-coupling reactions. This feature has also been used to prepare porphyrin dendrimers.

During these studies, it was observed that corroles, contracted porphyrin analogues lacking one meso-carbon atom, are accessible in good yields by variation of the (amount of) acid during the condensation reaction of the pyrrole and aldehyde building blocks. Further variation gives access to expanded macrocycles such as hexaphyrins. Again, easy functionalisation is possible in all cases where pyrimidine is present at the meso-positions.

The properties of the porphyrins and corroles are investigated together with other research groups. Work has been reported on a) selective oxidation catalysis b) supramolecular binding of phenols and c) photophysical behavior.




References

  1. S. Smeets, C. V. Asokan, F. Motmans, W. Dehaen, "Synthesis and functionalization of double picket fence porphyrins starting from 4,6-disubstituted pyrimidine-5-carbaldehydes", J. Org. Chem. 2000, 65, 5882-5885.

  2. C. V. Asokan, S. Smeets, W. Dehaen, "Sterically encumbered triarylcorroles from aryldipyrromethanes and aromatic aldehydes", Tetrahedron Lett. 2001, 42, 4483-4485.

  3. W. Maes, W. Dehaen, "Sterically encumbered porphyrins by Suzuki reactions of a 5,15-bis(4,6-dichloropyrimidin-5-yl) Derivative", Synlett 2003, 79-82.

  4. E. Dolusic, S. Smeets, S. Toppet, B. Tinant, L. Van Meervelt, W. Dehaen, "Porphotetramethenes (Calix[4]pyrroletetraquinomethides) From Oxidative N-Alkylation of Porphyrin Tetraphenols", Tetrahedron 2003, 59, 395-400.

  5. W. Maes, J. Vanderhaeghen, W. Dehaen, "Meso-dichloropyrimidinyl substituted expanded porphyrins" Chem. Commun. 2005, 2612-2614.

  6. W. Maes, J. Vanderhaegen, S. Smeets, C. V. Asokan, L. M. Van Renterghem, F. E. Du Prez, M. Smet, W. Dehaen, "Synthesis of multi(metallo)porphyrin dendrimers through nucleophilic aromatic substitution on meso-pyrimidinyl substituted porphyrins", J. Org. Chem. 2006, 71, 2987-2994.

  7. W. Maes, T. H. Ngo, J. Vanderhaeghen, W. Dehaen, "Meso-pyrimidinyl- substituted A2B-corroles", Org. Lett. 2007, 9, 3165-3168.


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Highly fluorescent materials

The synthesis and functionalisation of different highly fluorescent building blocks such as rubicene, dipyrrolopyrrole (DPP), and BODIPY has been investigated, and these units have been incorporated into dendrimers and rod-like oligomers, or otherwise used in supramolecular chemistry as a sensor element.




References

  1. J. Hofkens, W. Verheijen, R. Shukla, W. Dehaen, F. C. De Schryver, "Detection of a single dendrimer macromolecule with a fluorescent dihydropyrrolopyrroledione (DPP) core embedded in a thin polystyrene polymer film", Macromolecules 1998, 31, 4493-4497.

  2. S. De Backer, Y. Prinzie, W. Verheijen, M. Smet, K. Desmedt, W. Dehaen, F. C. De Schryver, " Solvent dependance of the hydrodynamical volume of dendrimers with a rubicene core", J. Phys. Chem. A. 1998, 102, 5451-5455.

  3. M. Smet, R. Shukla, L. Fülöp, W. Dehaen, "A general synthesis of disubstituted rubicenes", Eur. J. Org. Chem. 1998, 1, 2769-2773.

  4. M. Smet, J. Van Dijk, W. Dehaen, "An improved synthesis of substituted rubicenes providing access to heterocyclic rubicene analogues", Synlett 1999, 495-497.

  5. M. Smet, B. Metten, W. Dehaen, "Construction of rod-like diketopyrrolopyrrole oligomers with well defined length", Tetrahedron Lett. 2001, 42, 6527-6530.

  6. W. Verheijen, J. Hofkens, B. Metten, J. Vercammen, R. Shukla, M. Smet, W. Dehaen, Y. Engelborghs, F.C. De Schryver, "The photophysical properties of dendrimers containing 1.4-dioxo-3.6-diphenyl-pyrrolo[3.4-c]pyrrole (DPP) as a core", Macromol. Chem. Phys. 2005, 206, 25-32.

  7. N. Basaric, W. Qin, M. Baruah, B. Metten, M. Smet, W. Dehaen, N. Boens, "Synthesis and fluorimetric characterisation of novel BODIPY based on-off indicators with low affinity for calcium", Org. Biomol. Chem. 2005, 2755-2761.

  8. B. Song, Z. Wang, S. Chen, X. Zhang, Y. Fu, M. Smet, W. Dehaen, "The introduction of a - stacking moiety for enhancing the stability of micellar structure: formation and dynamics of disc-like micelles", Angew. Chem. Int. Ed. 2005, 44, 4731-4735.

  9. M. Baruah, W. Qin, R.A.L. Vallée, D. Beljonne, T. Rohand, W. Dehaen, N. Boens, "A highly potassium-selective ratiometric fluorescent indicator based on BODIPY azacrown ether and excitable with visible light", Org. Lett. 2005, 7, 4377-4380.

  10. T. Rohand, M. Baruah, W Qin, N. Boens, W. Dehaen, "Functionalisation of fluorescent BODIPY dyes by nucleophilic substitution", Chem. Commun. 2006, 266-268.

  11. T. Rohand, W.Qin, N. Boens, W. Dehaen "Palladium-Catalyzed Coupling Reactions for the Functionalization of BODIPY Dyes with Fluorescence Spanning the Visible Spectrum", Eur. J. Org. Chem. 2006, 4658-4663.

  12. B. Song, H. Wei, Z. Wang, X. Zhang, M. Smet, W. Dehaen, "Supramolecular nanofibers by self-organisation of bola-amphiphiles through a combination of hydrogen bonding and pi-pi stacking interactions", Adv. Mat. 2007, 19, 416-420.

  13. B. Metten, K. Martinez, T. Joice, W. Qin, M. Smet, N. Boens, W. Dehaen, "Synthetic routes to 3-alkylsulfanyl-6-aryl-diketopyrrolo[3,4-c]pyrroles - a class of efficient, visible light excitable fluorophores", Org. Biomol. Chem. 2007, 5, 2587-2591.

  14. W. Qin, T. Rohand, W. Dehaen, J. N. Clifford, K. Driesen, D. Beljonne, B. Van Averbeke, M. Van der Auweraer, N. Boens, "Borondipyrromethene analogs with phenyl, styryl, and ethynylphenyl substituents: synthesis, photophysics, electrochemistry, and quantum-chemical calculations", J. Phys. Chem (A) 2007, 111, 8588-8597.


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(Indolo)carbazoles and pentacenes with semiconducting properties

Carbazoles and indolocarbazoles have interesting electrical and optical properties (and in fact also interesting biological activities). The indolo[3,2-b]carbazoles have been prepared by us starting from simple building blocks such as indole and substituted aldehydes. Substituted arylated pentacenes were shown by us to have increased solubility and stability towards oxidation.




References

  1. A. Hameurlaine, W. Dehaen, "Synthesis of soluble oligocarbazole derivatives", Tetrahedron Lett. 2003, 44, 957-959.

  2. N. D. McClenaghan, R. Passalacqua, F. Loiseau, S. Campagna, B. Verheyde, A. Hameurlaine, W. Dehaen, "Ruthenium (II) dendrimers containing carbazole-based chromophores as branches", J. Am. Chem. Soc. 2003, 125, 5356-5365.

  3. N. Vets, M. Smet, W. Dehaen, "Reduction versus rearrangement of 6,13-dihydro-6,13-diarylpentacene-6,13-diols affording 6,13- and 13,13'-disubstituted pentacene derivatives, respectively", Synlett 2005, 217-222.

  4. N. Vets, H. Diliën, S. Toppet, W. Dehaen, "Synthesis of 5,7,12,14-tetra-arylpentacenes from pentacene-5,7,12,14-tetrone and characterisation of the tetrol intermediates", Synlett 2006, 1359-1362.

  5. R. Gu, A. Hameurlaine, W. Dehaen, "A facile synthesis of novel 6-monoalkylated 5,11-dihydroindolo[3,2-b]carbazoles", Synlett 2006, 1535-1538.

  6. R. Gu, A. Hameurlaine, W. Dehaen, "Facile one-pot synthesis of 6-monosubstituted and 6,12-disubstituted 5,11-dihydroindolo[3,2-b]carbazoles and preparation of various functionalized derivatives", J. Org.Chem. 2007, 72, 7207-7213.


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Macrocycles and anion recognition

We have isolated an N-confused calix[4]pyrrole that is able to bind anions. The free alpha-position can easily be monofunctionalized with arylazo or formyl functions, allowing the introduction of a chromogenic group.


Based on the dichloropyrimidine building block, heteracalix[4]arenes (oxa/thia) can efficiently be prepared. We have found methods for their functionalisation (on the pyrimidine ring) and are currently using them to prepare anion receptors.




References

  1. S. Depraetere, M. Smet, W. Dehaen, "N-confused calix[4]pyrroles" Angew. Chem. Int. Ed. Eng. 1999, 38, 3359-3361.

  2. S. Depraetere, W. Dehaen, "Electrophilic substitution reactions of dipyrroheptane", Tetrahedron Lett. 2003, 44, 345-347.

  3. C. Orlewska, W. Maes, S. Toppet, W. Dehaen, "5,5-Dialkyldipyrromethane as a precursor for the synthesis of calix[4]phyrins and pseudocorroles using MacDonald [2+2]condensations", Tetrahedron Lett. 2005, 46, 6067-6070.

  4. J. Radecki, W. Dehaen, "Nitrogen containing macrocycles as host molecules for recognition of phenol derivatives existing in neutral forms - mechanism of potentiometric signal generation", Comb. Chem. High Thr. Scr. 2006, 9, 399-406.

  5. G. W. Bates, M. Kostermans, W. Dehaen, P. A. Gale, M. E. Light, "Organic salt inclusion: the first crystal structures of anion complexes of N-confused calix[4]pyrrole", CrystEngCommun, 2006, 8, 444-447.

  6. W. Maes, W. Van Rossom, K. Van Hecke, L. Van Meervelt, W. Dehaen,"Selective synthesis of functionalized thia- and oxacalix[2]arene[2]pyrimidines", Org. Lett., 2006, 8, 4161-4164.

  7. R. Nishiyabu, M. A. Palacios, W. Dehaen, P. Anzenbacher, "Synthesis, structure, anion binding and sensing by calix[4]pyrrole isomers", J. Am. Chem. Soc. 2006, 128, 11496-11504.

  8. W. Van Rossom, W. Maes, L. Kishore, M. Ovaere, L. Van Meervelt, W. Dehaen,"Efficient post-macrocyclisation functionalisations of oxacalix[2]arene[2]pyrimidines", Org. Lett. 2008, 10, 585-588.


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(Hetera)helicenes

Helicenes are chiral conjugated polycyclic materials that are prepared in a multistep procedure. Often photocyclisation has to be used in the synthetic strategy, as in the case of the heterahelicene tetrathia[7]helicene. Currently, we are looking for procedures that avoid the photocyclisation reactions, since the latter suffer from low yields and/or the need for small scale operations.




References

  1. Waghray, D.; Nulens, W.; Dehaen, W. Org. Lett. 2011, 13, 5516.

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Research Collaborations


Coordination of FWO-WOG (Wetenschappelijke Onderzoeksgemeenschap-Scientific Research Community) 2007-2011

"Heterocyclic synthesis in medicinal and supramolecular chemistry"

Partners: several teams inside and outside of Flanders represented by:

Koen Binnemans (KU Leuven)
Wim Dehaen (KU Leuven)
Norbert De Kimpe, Chris Stevens (UGent)
Bert Maes (University of Antwerp)
Dirk Tourwé (VU Brussel)

Andreé Kirsch-De Mesmaeker (U. L. Bruxelles)
Markus Albrecht (RWTH Aachen)
Peter Matyus (Semmelweis University, Budapest)
Mikael Begtrup (Danish Univ. of Pharm. Sci., Copenhagen)
Claude Piguet (Univ. Of Geneva)
Eric Rose (Univ. P. Et M. Curie, Paris)
Alexander F. Pozharskii (Rostov S. U.)
Philip A. Gale (University of Southampton)


Coordination of COST D31 working group (D31/0021/05) 2005-2009

"Novel and Specific Anion Receptors for use in Sensor Technology"

Partners:

Markus Albrecht (RWTH Aachen)
Philip A. Gale (University of Southampton)
Pavel Lhotak (ICT Prague)
Janez Plavec (NMR center Ljubljana)
Jerzy Radecki (Olsztyn)


Participation in IAP-VI

See http://www.biw.kuleuven.be/COK/IAP/ for more information


Several long term bilateral collaborations

Prof Vasiliy A. Bakulev, Urals State Techn. Univ., Ekaterinburg
Prof Jan Biernat, Dr Ewa Wagner-Wysiecka, Gdansk Univ. of Technology
Prof Kata Majerski, Dr. Nikola Basaric, Rudjer Boskovic Institute Zagreb
Prof Xi Zhang, Tsinghua University, Beijing (Website)
Prof. Rakhmadiyeva Sluken, Eusasian National University, Astana, Kazachstan (Website)


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