Assoc. Prof. Elena Stanoeva

Group (Module): Chemistry and stereochemistry of heterocylic compounds

Coordinator: Dr. Rositca Nikolova

 

Team Members: Assoc. Prof. Dr. Elena Stanoeva, Head Assist. Prof. Dr. Milen Bogdanov, Head Assist. Prof. Dr. Nikola Burdzhiev, Head Assist. Prof. Dr. Meglena Kandinska & co-workers:

 

1 Theme: Synthesis, stereochemistry and transformations of heterocyclic compounds with potential biological activity. Ionic liquids.

Introduction

Tetrahydroisoquinolinones, piperidinones and pyrrolidinones are important core structures of alkaloids and pharmaceuticals. Introduction of lactam rings into a peptide chain leads to its conformational constraint via induction of b-turn, which results in enhancement of the affinity and binding selectivity of the peptide to a given receptor [1-4]. This makes lactams perspective pharmaceuticals. Bioactivity of lactams depends largely on the substituents of the heteroring. Numerous synthetic approaches to these heterocyclics have been elaborated. A concise route to polysubstituted lactams is based on the reaction of mono- and bicyclic CH acid anhydrides with imines. This synthetic strategy is straightforward using cheap and easily accessible starting materials with high yields of the target structures. [5]. Since the lactams thus obtained contain carboxylic groups, the latters have been transformed into other derivatives exhibiting diverse biological activity: anticonvulsant [6], transcription factor inhibitors [7], non-steroid aromatase inhibitors [8] etc.

 

References (Introduction)

1. Freidinger, R.M.; Veber, D.F.; Perlow, D.S.; Brooks, J.R. Bioactive conformation of luteinizing – hormone – releasing hormone – evidence from a conformationally constraint analog. Science 1980, 210, 656.

2. Freidinger, R.M.; Perlow, D.S.; Veber, D.F. Protected lactam-bridged dipeptides for use as conformational constraints in peptides. J. Org. Chem. 1982, 47, 104.

3. Freidinger, R.M. Synthesis of G. A. M. M. – lactam-constraint tryptophyl-lysine derivatives. J. Org. Chem. 1985, 50, 3631.

4. Robl, J.; Cimarusti, M. P.; Simpkins, L. M. et al. Peptidomimetic synthesis – a novel, highly stereoselective road of two substituted Freidinger lactams. J. Am. Chem. Soc. 1994, 116, 2348.

5. Gonzales-Lopez, M.; Shaw, J. Cyclic anhydrides in formal cycloadditions and multicomponent reactions. Chem. Rev. 2009, 109, 164.

6. Gitto, R.; Francica, E.; De Sarro, G.; Scicchitano, F.; Chimirri, A. Solution-phase parallel synthesis of novel 1,2,3,4-tetrahydroisoquinolin-1-ones as anticonvulsant agents. Chem. Pharm. Bull. 2008, 56, 181.

7. Ng, P. Y.; Tang, Y.; Knosp, W.; Stadler, H.; Shaw, J. Synthesis of diverse lactam carboxamides leading to the discovery of a new transcription-factor inhibitor. Angew. Chem. Int. Ed. 2007, 46, 5352.

7. Tabcheh, M.; Baroudi, M.; Elomar, F.; Elzant A.; Elkhatib, M., Roland, V. New imidazole compounds derived from pyrrolidonic and piperidonic acids as non-steroid aromatase inhibitors. Asian J. Chem. 2006, 18, 2006.

Results Description

1. Synthesis of mono- and bicyclic lactams.

Reaction of homophthalic anhydride with imines was investigated using imines of various heterocyclic aldehydes. In this way carboxylic acids of trans and cis tetrahydroisoquinolinones containing at position 3 pyridyl and furyl sunbstituents were obtained. [1] In analogy to homophthalic anhydride the monocyclic anhydrides – glutaric and succinic have been investigated in reactions with benzylidenebenzylamine [2,3] to give trans-1-benzyl-6-oxopiperidine-3-carboxylic acids and trrans-1-benzyl-5-oxopyrrolidine-3- carboxylic acids corresp. It was established that homophthalic anhydride is much more reactive towards imines then monocyclic anhydrides, which is important for the reaction conditions. NMR spectroscopy was used to establish the relative configuration and the preferred conformation in solution of the heterocycles obtained. In some cases, polysubstituted tetrahydroisoquinolines were analyzed by means of X-ray analysis, which gave information about the ring shape and spatial substituents position. Several types of carboxylic group transformations have been investigated. The aim of the transformations was the introduction of an either a peptide bond, or another heterocycle in the side chain to the tetrahydroisoquinolinone, piperidinone and pyrrolidinone ring resp.[4]. The selected substituents are known for their pharmacophoric properties. In this way several series of the aforementioned heterocycles have been obtained and bioactivity of some derivatives was investigated. The preliminary results have shown that tetrahydroisoquinolinone and piperidinone containing aminoacid residues in the side chain exhibit ACE inhibitory activity. Piperidinones incorporating either tryptophan or piperazine moiety exhibit antihistamine activity.

 

2. Synthesis of isochromanones and dibenzochromenones.

The reaction between homophthalic anhydride and aromatic aldehydes was performed in highly diastereoselective manner by using 4-dimethylaminopyridine as catalyst for the first time. Series of 3,4-disubstituted 3,4-dihydroisocoumarins have been synthesized and their antimicrobial acticity was investigated. [5,6,7]

The conformational equilibrium of conformationally flexible 3,4-disubstituted 3,4-dihydroisocoumarin was investigated by means of NMR-, X-Ray spectroscopy and ab initio calculations. [8]

A series of new blue fluorescent trans-11-aryl-6-oxo-6H-dibenzo[c,h]chromene-12-carboxylic acids has been successfully synthesized through a new Perkin/Michael addition domino reaction between homophthalic anhydride and aromatic aldehydes. The synthesis is straightforward and give good overall yields taking into account the concomitant formation of four C−C, C−O and C=C bonds. A probable reaction mechanism including three proven intermediates was proposed. [9]

 

3. Synthesis of new ionic liquids. (Ils)

A new method for prediction of fundamental physical properties of ionic liquids is developed. The Residual Volume Approach allows the estimation of density, viscosity and ionic conductivity of unknown Ils, using a simple linear correlation between a given property and a newly defined substituent parameter βX. [10, 11]

In order to examine the influence of the alkyl chain length on some physical properties of guanidinium salts, the synthesis of a homologous series of new haxaalkyl substituted guanidinium ILs, containing chloride, tetrafluoroborate, acesulfamate, saccharinate, and tosylate anions, is reported. Some physical properties, such as solubility in water and organic solvents, refractive index, density and polarity are considered as a function of the length of the n-alkyl substituents and the nature of the anion. [12, 13]

 

References (Results description)

1. Kandinska, M.; Kozekov, I.; Palamareva, M. Synthesis of new trans-2-benzyl-3-(furan-2-yl)-4-substituted-1,2,3,4-tetrahydroisoquinolinone. Molecules 2006, 11, 403.

2. Burdzhiev, N.; Stanoeva, E. Reaction between glutaric anhydride and an imine, and further transformations to new substituted piperidin-2-ones. Tetrahedron 2006, 62, 8318.

3. Burdzhiev, N.; Stanoeva, E. Synthesis of new polysubstituted pyrrolidinones with potential biological activity. Z. Naturforsch. 2008, 63b, 313.

4. Burdzhiev, N.; Stanoeva, E. Synthesis of piperidinones incorporating amino acid moiety as potential SP antagonists. Comptes Rend. Chimie (2010) – in press. doi:10,1016/j.crci.2010.08.005.

5. Bogdanov, M.G.; Palamareva, M. D. cis/trans-Isochromanones. DMAP induced cycloaddition of homophthalic anhydride and aldehydes. Tetrahedron, 2004, 60, 2525.

6. Bogdanov, M. G.; Gocheva, B. T., Dimitrova, D. B.; Palamareva, M. D. New Isochromans. 1. Synthesis and Antimicrobial Activity of 4-Substituted (±)-1H-Spiro[benzo(c)pyran-3(4H),1’-cyclohexane]-1-ones. J. Heterocyclic Chem. 2007, 44, 673.

7. Bogdanov, M. G.; Kandinska, M. I.; Gocheva, B. T.; Dimitrova, D. B.; Palamareva, M. D. Preliminary Evaluation of Antimicrobial Activity of Diastereomeric cis/trans-3-Aryl(Heteroaryl) 3,4-Dihydroisocouamrin-4-Carboxylic Acids. Z. Naturforsch. 2007, 62c, 477.

8. Bogdanov, M. G.; Todorov, I.S.; Manolova, P. G.; Cheshmedzhieva, D. V.; Palamareva, M. D. Configuration and conformational equilibrium of (±)-trans-1-oxo-3-thiophen-2-yl-isochroman-4-carboxylic acid methyl ester.Tetrahedron Lett., 2004, 45, 8383.

9. Bogdanov, M. G.; Mitrev, Y. N.; Tiritiris, I. New Perkin/Michael Addition Domino Reaction Between Homophthalic Anhydride and Aromatic Aldehydes: A Facile Approach to Blue Fluorescent 6-oxo-6H-dibenzo[c,h]chromens. Eur. J. Org. Chem. 2010 - in press, MS-201000879.

10. Bogdanov, M. G.; Kantlehner, W. Simple Prediction of Some Physical Properties of Ionic Liquids: The Residual Volume Approach. Z. Naturforsch. 2009. 64b, 215.

11. Bogdanov, M. G.; Iliev, B.; Kantlehner, W. Residual Volume Approach II. Simple Prediction of Ionic Conductivity of Ionic Liquids. Z. Naturforsch. 2009, 64b, 756.

12. Bogdanov, M. G.; Petkova, D.; Hristeva, S.; Svinyarov,I.; Kantlehner W. New Guanidinium-based Room Temperature Ionic Liquids. Substituent and Anion Effect on Density and Solubility in Water. Z. Naturforsch. 2010, 65b, 37 – 48.

13. Bogdanov, M. G.; Svinyarov, I.; Kunkel, H.; Steinle, C.; Arkhipova, M.; Kantlehner, W.; Maas, G. Empirical Polarity Parameters for Hexaalkylguanidinium-Based Room-Temperature Ionic Liquids. Z. Naturforsch. 2010, 65b, 791 – 797.

 

 

Plans for future development of the synthetic work.

Computer-assisted molecular design and planned synthesis of new heterocyclic compounds aimed at obtaining structures with expected properties will be performed. The study will include functional group modifications and ring transformations of heterocycles belonging to different classes. This will result in the introduction of pharmacophoric substituents for desired biological activity, such as antibacterial, antimicotic, ACE inhibitory, antihistaminic, plant-growth regulating, etc. Investigation of antioxidant activity of the suitably substituted heterocycles. QSAR analysis of biologically active derivatives.

The synthesis of new heterocyclic compounds incorporating aminoacids will be carried out in a collaboration with research groups from the Institute of Organic Chemistry with Centre of Phytochemistry for preparation of new ACE inhibitors; a colaboration with biologists from the Faculty of Biology – University of Sofia for investig