Laboratory of Natural Products Chemistry, FCHPT

Faculty of Chemical and Food Technology

Department/Institute: Department of Organic Chemistry
Contact person:         prof. Ing. Tibor Gracza, DrSc.
Contact:                    +421 2 5249 5410
e-mail:                      tibor.gracza@stuba.sk
web page:                 http://www.chtf.stuba.sk/koch/gracza.php


Description:

The Laboratory of natural products chemistry deals with the synthesis of selected natural products of biomedical significance and the  development of synthetic methodology for the construction of complex, biologically intriguing molecules. Total synthesis technology platforms, deploying new methodology in the area of palladium(II)-catalysed cyclisations of unsaturated polyols and aminoalcohols in particular.

 

Projects:

APVV-0203-10, 2010-2014

Design, synthesis and antiproliferative activity of tetrahydrofurans related to (+)-varitriol

Design, synthesis and antiproliferative activity of tetrahydrofurans related to natural (+)-varitriol. Notably cytotoxic varitriol towards selected human cell lines serves as lead structure for synthesis and rational design of new substances with high activity and selectivity toward cancer cells. Development of new synthetic methodology for synthesis of tetrahydrofuran compounds with defined configuration at all stereogenic centres and its application in the syntheses of analogues, hmologues and vinylogues of varitriol. Study of structure-activity relationship (SAR, QSAR). Investigation of molecular targets and mechanism of action for molecular design.

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Vega 1/0115/10, 2009-2011

Stereoselective palladium catalysed cyclisations and cross-coupling reactions in natural product synthesis

Development of new synthetic methodology for synthesis of oxa- and azaheterocyclic compounds with defined configuration at all stereogenic centers. The application of the methodologies in the syntheses of natural products and biologically interesting compounds.

Study of chemo-, diastereo- and substrate selectivity of palladium(II)-catalysed cyclisation of unsaturated polyols. Exploration of the reaction by trapping of intermediary sigma-alkyl Pd(II)-complex in the domino reaction with subsequent C-C, C-O, C-N cross-coupling reactions. The application of the domino reactions for construction of dioxa[2.2.1]bicyclic skeletons, polyhydroxylated tetrahydrofurans, tetrahydropyrans, pyrrolidines and piperidines with defined stereochemistry. Synthetic strategies will be applied in the total syntheses of natural C-15 acetogenins, goniothalesdiols, varitriol and deoxyanhydroaminoalditols. Synthesis of modified isoxazolidinyl nucleosides using Pd-catalysed cross-coupling reactions.

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LPP-0071-09, 2009-2013

Stereoselective Pd(II)-catalysed bicyclisation in the natural product synthesis

Development of new synthetic methodology for construction of the dioxa[2.2.1]bicyclic skeleton,  polyhydroxyl substituted tetrahydrofuran derivatives with 2,3-trans arrangement of substituents. Their application in the syntheses of natural products and biologically  interesting compounds.

Optimisation of the total synthesis of (+)-varitriol, natural tetrahydrofuran possesing high cytotoxic aktivity toward selected  human tumor cell lines. The synthesis of the l-xylo-4-O-benzylhex-5-en-2,3,4-triol using chiral pool approach from d-glucose and dimethyl l-tartrate. Study of chemo-, diastereo- and substrate selectivity of palladium(II)-catalysed bicyclisation of unsaturated diols. Pd(II)-catalysed bicyclisation of diols  with E- and Z-symetrically disubstituted C=C double bond. The application of the stereocontrolled Pd-catalysed bicyclisations in the syntheses of compounds isolated  from marine organisms. Synthetic study towards natural C-15 acetogenins.

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SK-FR-0005-07, 2008-2008

Domino reactions in the ionic liquids and their application in the natural product synthesis

Development of new strategies for stereoselective funcionalization of C=C double bond of alkenes with introduction of O- and/or N-functions.  Study of new Pd(II)-catalyzed oxy-/aminocarbonylations and cross-coupling domino reactions in enviroment frendly ionic liquids. Application of Pd-domino reactions in the total syntheses of natural compounds and biologically interesting compounds.

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Selected publications:

1. Gracza T., Jäger V. Synlett. 1992, 191-193. "Pd(II)-Catalyzed Oxycarbonylation of Unsaturated Polyols. Synthesis of (-)-Goniofufurone and Assignment of Absolute Configuration to the Natural (+)-Enantiomer, a Cytotoxic Styryllactone".
2. Gracza T., Jäger V. Synthesis 1994, 1359-1368. "Synthesis of Natural and Unnatural Enantiomers of Goniofufurone and Its 7-Epimers from D-Glucose. Application of Pd(II)-Catalyzed Oxycarbonylation of Unsaturated Polyols"
3. Hümmer W., Dubois E., Gracza T., Jäger V., Synthesis 1997, 634-642. "Halocyclization and Palladium(II)-Catalyzed Amidocarbonylation of Unsaturated Aminopolyols, Synthesis of 1,4-Iminoglycitols as Potential Glycosidase Inhibitors".
4. Dixon D. J., Ley S. V., Gracza T., Szolcsanyi P., J. Chem. Soc., Perkin Trans 1, 1999, 8, 839-843. “Total synthesis of the polyenolyltetramic acid mycotoxin erythroskyrine”.
5. Szolcsanyi P., Gracza T., Koman M., Pronayova N., Liptaj T. Chem.Commun. 2000, 471-472. „Total synthesis of new C-6 homologues of 1-deoxynojirimycin and 1-deoxy-L-idonojirimycin“.
6. Szolcsanyi P., Gracza T., Koman M., Pronayova N., Liptaj T. Tetrahedron Asymmetry. 2000, 2579-2597. „Pd(II)-Catalysed aminocarbonylation as a key step in the total synthesis of C-6 homologues of 1-deoxynojirimycin and 1-deoxy-L-idonojirimycin“.
7.  Babjak M., Kapitán P., Gracza T. Tetrahedron Lett. 2002, 43, 6983-6985.„The first total synthesis of goniothalesdiol“.
8. Babjak M., Kapitán P., Gracza T. Tetrahedron 2005, 61, 2471-2479. „Synthesis of (+)-goniothalesdiol and (+)-7-epi-goniothalesdiol”.
9. Szolcsányi P., Gracza T. Chem. Commun. 2005, 3948-3950. “Novel Pd(II)-catalysed N,O-bicyclisation as an efficient route to the 6-oxa-2-azabicyclo[3.2.1]octane skeleton”.
10. Szolcsányi P., Gracza T. Tetrahedron 2006, 62, 8498-8502. „PdCl₂/CuCl₂-catalysed chlorocyclisation of sugar-derived aminoalkenitols in the synthesis of new iminohexitols“.
11. Kapitán P., Gracza T. Tetrahedron: Asymmetry 2008, 19, 38-44. „Stereocontrolled oxycarbonylation of 4-benzyloxy-hepta-1,6-diene-3,5-diols promoted by chiral palladium(II) complexes“.
12. Szolcsányi P., Gracza T., Špánik I. Tetrahedron Lett. 2008, 49, 1357-1360. „Short racemic syntheses of calvine and epicalvine“.
13. Palík M., Karlubíková O., Lásiková A., Kožíšek J., Gracza T. Eur. J. Org. Chem. 2009, 709-715. „Total synthesis of (+)-varitriol“.
14. Koóš P., Špánik I., Gracza T. Tetrahedron: Asymmetry 2009, 20, 2720-2723. „Asymmetric intramolecular Pd(II)-catalysed amidocarbonylation of unsaturated amino alcohols“.
15. Palík, M.; Karlubíková, O.; Lackovičová, D.; Lásiková, A.; Gracza, T. Tetrahedron 2010, 66, 5244-5252. “Formal synthesis of (+)-varitriol. Application of Pd(II)-Cu(II)-catalysed bicyclisation of unsaturated polyols”.
16. Karlubíková, O.; Palík, M.; Lásiková, A.; Gracza, T. Synthesis 2010, 3449-3452. “An efficient total synthesis of (+)-varitriol from d-ribonolactone “.
17. Karlubíková, O; Babjak, M; Gracza, T. Tetrahedron 2011, 67, 4980-4987. “Tetrahydropyran synthesis by palladium(II)-catalysed hydroxycarbonylation of hexenols: synthesis of (±)-diospongin A and (+)-civet cat compound”.
18. Doháňošová, J; Lásiková, A.; Toffano, M.; Gracza, T.; Vo-Thanh, G. New J. Chem. 2012, 36, 1744-1750. DOI: 10.1039/C2NJ40170C “Kinetic resolution of pent-4-ene-1,3-diol by Pd(II)-catalysed oxycarbonylation in ionic liquids”.
19. Lásiková, A.; Doháňošová, J; Hlavínová, L.; Toffano, M.; Vo-Thanh, G.; Kožíšek, J.; Gracza, T. Tetrahedron: Asymmetry 2012, 23, 818-827. “Domino reaction: Pd(II)-catalyzed cyclization of unsaturated polyols and cross-coupling“.
20. Markovič, M.; Ďuranová, M.; Koóš, P.; Szolcsányi, P.; Gracza, T. Tetrahedron 2013, 69, 4185-4189. “Synthesis of bis-tetrahydrofuran subunit of (-)-neopallavicinin”.
21. Gracza, T. Intramolecular Oxycarbonylation in Stereoselective Synthesis in Stereoselective Synthesis of Drugs & Natural Products, Edited by Vasyl Andrushko and Natalia Andrushko, ISBN-10: 978-1118032179, ISBN-13: 978-1118032176, Copyright © 2000 Wiley[Imprint], Inc. 2013, Chapter 15, pp 421-440.

 

Photos:

Analytical laboratory, LC-MS chromatograf

Synthetical laboratory, preparatory MPLC chromatograf

Synthetic laboratórium, polarimeter

Automatic destilation equipment