Stereoselective Epoxidation Methods of O- and N- containing Heterocycles and Related Models. Attila Kiss

Átírás

1 Stereoselective Epoxidation Methods of - and - containing Heterocycles and elated Models Ph.D. Theses Attila Kiss Supervisor: Prof. Dr. Tamás Patonay Debreceni Egyetem Természettudományi Kar Debrecen, l

2 Aki tanul, de nem gondolkodik, elveszett ember. Aki gondolkodik, de nem tanul, nagy veszélyben van. Konfuciusz

3 Theses 1. Antecedents and Aims xidation is one of the largest part of the preparative organic chemistry underlined by the huge number of related literature. This type of reaction is widely used both in basic research and in the industry and deploys very diverse methods. In my thesis it some oxidation methods connected to our field of interest and the study on the scopes and limits of these procedures have been presented. owadays the preparation and assay of enantiopure compounds grows up apace because the stereo isomers of same constitution show highly varied and different biological properties. In my work I wanted to use and develop such methods which with could produce optically pure or enantiomerically enriched compounds exploiting a kind of selectivity. The benzo-condensed nitrogen- and oxygen containing heterocycles and their biologic effects are well known in the literature. Some of them are naturally occurring derivative or their (semi)synthetic analogs show biologic impact. Several arbitrarily selected analogs are shown by Scheme 1. During my work the selective oxidation of five- and six-membered benzo(hetera)cyclanones containing one ore more double bonds was the main object. The opening of epoxide ring results in different substituted species, in some cases we examined this reactions in details. ur aim was to develop diastereo- and/or enantioselective epoxidation method to reach chiral, non-racemic epoxides and to synthetize α-substituted ketones by means of them. Page 1

4 Theses H H CH 3 H 1 H H H sylibin (liver protecting) H 2 1 = 2 =H: sulfuretin 1 =H; 2 =H: maritimetin 1 =H; 2 =CH 3 : leptosidin 1 =H; 2 =H: auresidin (phytochemicals, plant dyestuff) H H 3 C H Calanolid-A, B (anti HIV) =CH 3 : japonin =H: edulin (alkaloids) H 3 C CH 3 H H =CH 3 : hormathamnion (anti leukemia) =H: 6-dezmetoxihormathamnion (cytotoxic) (numerous 3-styryl derivatives possess anti HV effect) graveolin (alkaloid) H H H H H Ac H H H H H utin (Vitamine P) H H Kapurimycin A3 (antitumor antibiotic) C H steochin, Ipriflavon (osteoporosis inhibitor) Lemakalim (K-channel activator) Scheme 1 Page 2

5 2. Applied Methods Theses The micro-, semimicro and macro methods of modern organic preparative chemistry were applied during our synthetic work. eactions were monitored by thin layer chromatography; the isolation and purification of the crude products were carried out by crystallization or by column chromatography. Elemental analyses, melting point determination, optical rotation measurements, one- or multidimensional M, I spectroscopy and mass spectrometry were applied to identify and characterize the prepared compounds. The determination of the e.e. values and the absolute configurations were performed by on-line LC-CD method. 3. ew esults During our work regio-, diastereo- and enantioselective oxidizing methods were developed which resulted in enantiomerically enriched oxygen heterocyclic compounds. We examined two main types of compounds. The one is the family of α,βunsaturated ketones. Chromone (68), aurone (45b) and 3-styrylchromones (Eand Z-63) belong to this family. Enolesters constitute the other class of compounds whereabout different benzo(hetera)cyclanones (81a-d, 90a-h and 101a,b) were studied under oxidative conditions. ur most important results in the field of the three main types of compounds (exo- and endocyclic α,βunsaturated ketones, 3-styrylchromones and enol acetates of benzo(hetera)cyclanones) are as follows xidation of Chromone We have established that in the oxidation of chromone (68) by dimethyldioxirane the substrate reacts with electrophilic oxidant sluggishly and a low conversion was found even if it was used in high excess. This phenomenon was interpreted in terms of the electron deficient property of Page 3

6 Theses oxidable double bond. We have demonstrated the chromone (68) does not react with the enantioselective oxidizing system dimethyldioxirane (DMD)/Jacobsen catalyst developed earlier by our research group since the enantiopure oxidant decomposes by other reaction paths because of the low reactivity of the substrate (Scheme 2). These statements were proved by titrimetry and UV/VIS spectroscopic measurements. 13a acetone, T rac Scheme 2 13a acetone, T S,S-27 * * 3.2. Preparation and xidation of Aurone, Investigation of ing-opening of btained Epoxide The rac-46b epoxide was prepared by the oxidation of aurone (45b) DMD under racemic conditions. However, the enantioselective variant of epoxidation was unsuccessful, epoxidation did not occur and the unchanged starting material was recovered in this case. Again, the reason of this failure was the high reactivity of Mn(V)oxo complex formed from the catalyst and the low reactivity of the substrate as mentioned in details in Section 3.1. The rac-46b epoxide could also be prepared by using the Weitz-Scheffer method with quaternary ammonium-hydroxide (Triton-B) as a base, but a side reaction with the formation of remarkable amount of 3-hydroxy-flavone (70) has also taken place (Scheme 3). H 2 2, Triton-B H dioxane, 42-48% 45b Triton-B: PhCH 2 (CH 3 ) 3 + H - H rac-46b + 65 Scheme 3 Page 4

7 Theses A mechanism of the formation of 70 was proposed. ur experiments revealed the advantage of the DMD oxidation in the synthesis of racemic aurone epoxides due to the better yields, the lack of side reactions and the easier work-up. We have demonstrated that in the presence of enantiopure phase transfer catalysts obtained from cinchona-alkaloids in alkaline hydroperoxide (Wynberg oxidation) chiral, non-racemic 46b epoxide could be prepared and the method was adequately tuneable. These results clearly show the oxidation system which works well with high enantioselectivity in the chalkone series has lower efficiency when oxidise the more rigid α,β-unsaturated ketone with α-branching. rac-46b H -H reflux 36-88% H α β H 66a-d H A =H, Me, ipr, Ac α*,βs*/α*,β*=44:56-71:29 Scheme 4 During the solvolysis of racemic rac-46b epoxide 72a,b,d α-hydroxy-βsubstituted 3-coumaranones known in the literature and a new α-isopropoxy compound (72c) have been prepared (Scheme 4). The absolute configuration of the epoxide, the elution order and the characteristic CD transitions belonging to the single enantiomers were determined by chiral chromatographic studies on the 45b, rac-46b compounds. The absolute configuration of enantiomer favoured by the catalyst in the enantioselective reactions was determined. During the development of the chromatographic method the conjugated addition of alcohol used as solvent to the α,β-enone system was pointed out. This reversible solvent addition has also been observed under other chromatographic conditions, too. The presentation of these latter experiments does not belong to the field of my thesis. Page 5

8 3.3. Preparation and xidation of 3-Styrylchromones Theses The second group of the investigated compounds was 3-styrylchromone (E-, Z-63a) and its substituted derivatives (E-, Z-63a-f). We developed a process for the preparation of E-63 styryl compounds starting from 3- formylchromones (62) and phenylmalonic acid by a modified Knoevenagel synthesis under solvent-free conditions on silica carrier under microwave assisted irradiation. In this case two double bonds with different electron density were examined. The regioselectivity of DMD in the case of compounds containing more double bonds with different electron density is known from literature and it was also verified by our experiments. The oxidation always takes place on the double bond of higher electron density. In the case of our model system the regioselectivity of both of the oxidant DMD and hydrogenperoxide/sodium hydroxide was nearly 100%. Epoxidation of the styryl double bond (Schemes 5, 6) was exclusively taken place by the electrophilic DMD whereas in the Weitz-Scheffer oxidation only the double bond of chromone ring was epoxidized (Scheme 7) by the hydroperoxide anion. The epoxidation was fast in each case and gave the epoxides in good yields. These epoxides are new compounds according to literature. E-63 13a acetone, T = H, Me, Me, Cl, Br trans rac-77 Yield (%) a H 88 b 6-Cl 61 c 7-Cl 74 d 6-Me 55 e 6-Br 65 f 6-Me 71 Scheme 5 trans rac-77 Page 6

9 Theses Z a acetone, T = H, Me; 1 =H, Cl, 2 cis rac-77 cis rac-77 1 Yield (%) a H H 88 d 6-Me H 74 g 6-Me 4-Cl 61 h H i H 4-Et 55 Scheme 6 1 E-63 H 2 2, H - 1,4-dioxane T = H, Me, Me, Cl, Br E-76 E-76 Yield (%) a H 63 b 6-Cl 51 c 7-Cl 61 d 6-Me 27 e 6-Br 58 f 6-Me 34 Scheme 7 In the enantioselective reactions the Wynberg oxidation worked well, in the case of PTC-2 catalyst the achieved e.e. s was promising (46% e.e.) for preparing 76 epoxides. The enantioselectivity of the epoxidation can be increased by further optimization. We pointed out that from its alkaline dioxane-water solution epoxide crystallises as a racemate which means the enantiomeric excess can be improved by crystallisation (Scheme 8). The regioselectivity of the reaction disappeared by using DMD/Jacobsen s system, each of the possible three products (76, 77, 78) could be detected in the reaction mixture. Therefore, this enantioselective oxidizing system is not suitable for preparing chiral, non-racemic 77. Page 7

10 Theses E-63a H 2 2, H - 1,4-dioxane T PTC-2-6 * * 76a H H 1 Hlg PTC Me 1 4-Br-Ph H 1-naphthyl Me 1-naphthyl Hlg - 2 H 4-2 -Ph Br 3 H 4-Br-Ph Br Br Cl Cl PTC Precipitate Mother liquor Weighted Yield (%) e.e.(%) Yield (%) e.e.(%) e.e.(%) a , , , , a (Y 1 X ee 1 + Y 2 X ee 2 )/ (Y 1 + Y 2 ) Scheme 8 The chiral chromatographic separation of rac-77a and E-76a revealed if the formation of epoxide ring occured on the chromone moiety (E-76a) the diastereomer complex formed on the stationary phase was less stable than in the case of rac-77a enantiomeric pair since the retention times of the latter higher. The chiral recognition of the column showed the same tendency which can be explained by the fact that the space around the stereogenic centres of the rac-77a is less crowded Preparation and xidation of Enolacetates Enolacetates of indanone (81a) and tetralone (81b), as well as that of the oxygen analogues chromanone (81c) and flavanone (81d), were prepared by the application of literature methods and their oxidations by DMD were studied. We demonstrated the formed epoxides with one exception were unstable and transformed into the corresponding α-hydroxy- (67) and α- acetoxy ketone (66) under the condition of epoxidation. Page 8

11 Theses X 79 Ac 80 H + / 66,67 79,81,82 a b c d X bond CH 2 H H H Ph 81 X Ac 13a acetone, T S,Sor,-27 X * * H 67 Ac 82 X * * * X * * Ac Ph Scheme 9 We managed to prepare and isolate 1-acetoxy-1,2-epoxytetraline (82b) from 81b enolacetate by the modification of reaction conditions and its chemical properties were studied. We established the formation of the 67b alcohol and 66b acetate from the epoxide by the ring-opening occurs in different reaction paths. In the case of the flavanone (79d) both 3-hydroxyflavanone (67d) and 3-acetoxyflavanone (66d) were obtained by complete trans diastereoselectivity and the configuration of C-3 atom remained unchanged. A mechanism to explain the phenomenon was proposed. Enantioselective oxidation of model enolacetates with DMD/Jacobsen s catalyst has also been investigated. The low enantioselectivity of epoxidation could be remarkably by using different nitrogen-containing axial ligands and the corresponding α-oxyfunctionalized benzo(hetera)cyclanones could be prepared with 50-60% enantiomer excesses. The absolute configuration of the formed alcohols and acetates were determined and it was found that both product had S configuration using,-(-)-jacobsen s catalyst whereas alcohol and acetates could be obtained in the presence of the opposite enantiomeric catalyst. These results provided further evidence that the C α - bond of the epoxide ring did not break during the ring-opening of epoxide ring leading to α-hydroxy- and α-acetoxy-ketones, therefore, the original configuration of this center is retained. The absolute configuration of the Page 9

12 Theses epoxide prepared by enantioselective oxidation pathway was interpreted according to a steric approach control, which means the Mn(V) oxo complex attacks with a parallel or slightly skewed side-on approach according to the Katsuki trajectory. ur experiments revealed that in the case of flavanone enolacetate (81d) the doubly activated C 2 -H bond was preferentially attacked by the reactive oxidizing species generated from the DMD/Jacobsen s catalyst system to afford flavone as a major product in a C-H insertion reaction followed by dehydration beside the expected acetoxy-epoxide. Therefore, the synthetic value of enantioselective α-oxyfunctionalisation in the flavanone series is little Preparation and xidation eactions of itrogensubstituted Enolacetates By changing the oxygen heteroatom to an acetyl-protected nitrogen we have studied the DMD oxidation of various 90, aryl/alkyl-substituted-1- acetyl-1,2-dihydroquinolines. During the oxidation experiments substrates 90 were prepared by acetylation of 88 tetrahydroquinolin-4-ones shown by Scheme 10. H 2 87 H 3 P 4 /AcH or MW 27-91% H 88 B Ac 2 /aac/ Ac 2 / 10-52% A Ac 90 Ac Ac 2 /aac 15-67% Ac 89 =H, 2-Me, 4-Me, 4-Me, 4-Me 2,4-C, 4-2, 4-Cl Scheme 10 We have demonstrated that the related epoxides could be prepared in good yields and we found that they are stable products in all cases (Scheme 11). Page 10

13 Theses Their 2,3-cis relative configuration was determined by E methods. It was also demonstrated that the epoxide intermediates could give cis-3-hydroxy (92) derivatives under acidic hydrolytic conditions, while they could produce cis-3- acetoxy-1-acetyl-2-substituted-1,2,3,4-tetrahydro-4-quinolones (93) by thermal reaction in excellent yields (Scheme 12). Ac 90 Ac (2 equiv.) acetone <1min Ac Ac 91 90, 91 a b d f i H Me Cl 2 Br Yield % Scheme 11 Ac H 92 Ac Ac H 2 /H + 1day Ph 2 / 3 hours Ac 91 91, 92, 93 a B d f i H Me Cl 2 Br Yield % (92) Yield % (93) Ac 93 Scheme 12 In these cases the ring-opening processes take place in completely diastereoselective ways, again. The observed 2,3-cis preference is opposite to that of the flavanone derivatives. This phenomenon can be explained in terms of the relative configuration of 91 epoxide intermediate and the fact that the C 3 - bond does not participate in the cleavage. The possible reason of the different diastereomeric preference in the formation of epoxide species is the steric hindrance of the -acetyl group. We have developed a CSP-HPLC method for the separation of the enantiomers of 1-acetyl-2-phenyl-3-hydroxy- 1,2,3,4-tetrahydro-4-quinolone (92a) and the related acetate and assigned the absolute configuration of alcohol enantiomers. Page 11

14 Theses DMD equiv. epoxide conv (C) enolacetate e.e. epoxide e.e. S DMD (equiv.) 0,5 1 1,5 2 Conversion of epoxide (%) e.e.% of enolacetate e.e.% of epoxide s * 4,40 2,30 2,38 2,34 * s = ln(1-c)(1-ee)/ln(1-c)(1+ee), whereabouts c is the conversion, ee is the enantiomeric excess of unchanged starting material Scheme 13 We have also investigated the oxidations of 90a enolacetate with DMD/Jacobsen s catalyst/axial ligand system and it was established that - in accordance with the previously determined complete or almost complete diastereoselectivity - a kinetic resolution takes place during the epoxidation. We have also determined the values of stereoselectivity factor (s) (Scheme 13). In this way we found a possibility to prepare enantiomerically enriched enolacetates and their epoxides, respectively, and on the basis of these latter compounds, to the enantiomerically pure/enriched cis-3-hydroxy- and acetoxy-2-alkyl/aryl-1,2,3,4-tetrahidro-4-quinolones. We have established that iodosobenzene/ Jacobsen s catalyst/axial ligand system oxidises the substrate similarly with kinetic resolution but the selectivity is smaller than that we observed by using DMD as oxygen source. Page 12

15 4. Publications Theses 4.1. Papers underlying the Theses 1. Kiss-Szikszai, A.; Jekő, J.; Lévai, A.; Patonay, T.: Stereoselective α- xyfunctionalization of Benzo(hetera)cyclanones by Dimethyldioxirane. 3 rd Electronic Conference on Synthetic rganic Chemistry (ECSC-3), n-line: CD-M: ISB Patonay, T.; Jekő, J.; Kiss-Szikszai, A.; Lévai, A.: Synthesis of acemic and Enantiomerically Enriched α-xifunctionalized Benzocyclanones and Chromanones by Dimethyldioxirane and Dimethyldioxirane/Mn(III) salen System. Monatsh. Chem/Chem. Monthly 2004, 135, Patonay, T.; Kiss-Szikszai, A.; Cavaleiro, J.A.S.; Silva, A.M.S.: Microwave-assisted Synthesis, and egio- and Stereoselective Epoxidation of 3-Styrylchromones. Eur. J. rg. Chem. submitted 4. Patonay, T.; agy, G.; Kiss-Szikszai, A.: Synthesis and Stereoselective Epoxidation of 2-Substituted 4-Acetoxy-1,2-dihidroquinolines: a ew Entry to the 3-xifunctionalized-2-substituted 1,2,3,4- tetrahidroquinolin-4-ones. J. rg. Chem. under preparation 4.2. ther Papers 1. Kiss-Szikszai, A.; Patonay, T.; Jekő, J.: Synthesis of 2-(Substitutedphenyl)-5-(aminomethyl)- and (thiomethyl)-1,3,4-oxadiazoles. xidation of Thiomethyloxadiazole Derivatives by Dimethyldioxirane. AKIVC 2001, 3, Page 13

16 Theses 2. Micskei, K.; Gyarmati, J.; Kiss-Szikszai, A.; Hajdu, Cs.: Carbon-carbon Bond Formation in eutral Aqueous Medium: Modification of the ozaki-hiyama eaction. Tetrahedron Lett. 2001, 42, Ferrari, J.; Terreaux, C.; Kurtán, T.; Kiss-Szikszai, A.; Antus, S.; Msonthi, J.D.; Hostettmann, K.: Isolation and n-line LC/CD Analysis of 3,8 -Linked Biflavonoids from Gnidia involucrata. Helv. Chim. Acta 2003, 86, Hallgas, B.; Patonay, T.; Kiss-Szikszai, A.; Dobos, Zs.; Hollósy, F.; Erdős, D.; Őrfi, L.; Kéri, Gy.; Idei, M.: Comparison of Measured and Calculated Lipophilicity of Substituted Aurones and elated Compounds J. Chrom. B 2004, 801, Micskei, K.; Hajdu, Cs.; Wessjohann, L.A.; Mercs, L.; Kiss-Szikszai, A.; Patonay, T.: Enantioselective eduction of Prochiral Ketones by Chromium(II) Amino Acid Complexes. Tetrahedron: Asymmetry 2004, 15, Kónya, K.; Kiss-Szikszai, A.; Antus, S.: Enantiomeric Separation of acemic eolignans. J. Chrom. Sci. 2004, 42, Kónya, K.; Kurtán, T.; Kiss-Szikszai, A.; Juhász, L.; Antus, S.: A General Method for the Configurational Assignment of erythro eolignans. AKIVC 2004, 13, Page 14

17 4.3. Poop Sheets Theses 1. Dinya, Z.; Suszter, G.; Kiss-Szikszai, A.; Papp, G.; Bak, I.: Környezetszennyező szerves vegyületek analitikája. Kossuth Egyetemi Kiadó, Presentations at Scientific Meetings 1. Patonay, T.; Jekő, J.; Kiss-Szikszai, A.; Lévai, A.: Gyűrűs α-hidroxiketonok sztereoszelektív szintézise. MTA Flavonoidkémiai és DAB Gyógyszerkémiai és Vegyipari Munkabizottság tudományos előadó ülésee, , Debrecen 2. Kiss-Szikszai, A.: Gyűrűs α-hidroxi-ketonok enantioszelektív előállítása. XXIV. rszágos Tudományos Diákköri Konferencia, , Veszprém 3. Kiss-Szikszai, A.; Patonay, T.; Lévai, A.: Benzo(hetera)ciklanonok enantioszelektív α-hidroxilezése. MTA Heterociklusos Munkabizottság tudományos előadó ülésee, , Balatonszemes 4. Patonay, T.; Jekő, J.; Kiss-Szikszai, A.; Lévai, A.: Stereoselective α- Hydroxylation of Benzo(hetera)cyclanones by Dimethyldioxirane. 17 th International Congress of Heterocyclic Chemistry, August 1-6, 1999, Vienna, Austria Page 15

18 Theses 5. Kiss-Szikszai, A.; Juhász-Tóth, É.; Patonay, T.; Dinya Z.: α-azidoketonok, 3-azido-kromanonok és flavanonok tömegspektroszkópiás vizsgálata. MTA Flavonoidkémiai Munkabizottság tudományos előadó ülése, , Budakalász 6. Kiss-Szikszai, A.; Juhász-Tóth, É.; Dinya, Z.; Patonay, T.: Mass Spectrometric Studies of α-azido Ketones. 19 th Informal Meeting on Mass Spectrometry, April 29 -May 3, 2001, oszvaj, Hungary 7. Kövér, A.; Kiss-Szikszai, A.; Hajdu, Cs.; Micskei, K.: Természetes aminosavak, mint kiralitásforrások alkalmazása szén-szén kötés enantioszelektív kialakítására. MKE XXXVI. Komplexkémiai Kollokvium, , Pécs 8. Patonay, T.; Adam, W.; Gyuricza, L.; Kiss-Szikszai, A.; Lévai, A.; agy, G.: Dioxirane xidation of Heterocycles Containing an Endocyclic α,β- Enone Unit. Stereoselective Transformations of Heterocyclic Compounds (CST D12 Symposium), ctober 9, 2001, Würzburg, Germany 9. Kónya, K.; Kiss-Szikszai, A.; Varga, Zs.; Antus, S.: Antioxidáns hatású típusú neolignánok rezolválása. MTA Flavonoidkémiai Munkabizottság tudományos előadó ülése, , Budapest 10. Kiss-Szikszai, A.; Patonay, T.; Lévai, A.: Gyűrűs α,β-telítetlen ketonok epoxidálása és átalakításaik. MTA Heterociklusos Munkabizottság tudományos előadó ülése, , Balatonszemes Page 16

19 Theses 11. Patonay, T.; Adam, W.; Kiss-Szikszai, A.; Lévai, A.: Stereoselective xidations of Benzopyrans, Benzofurans and elated Compounds. Stereoselective Transformations of Heterocyclic Compounds (CST D12 Symposium), , Debrecen 12. Kiss-Szikszai, A.; Patonay, T.; Lévai, A.: Stereoselective Synthesis and ing pening of Cyclic α,β-unsaturated Ketones. 9 th Blue Danube Symosium on Heterocyclic Chemistry, June 16-20, 2002, Tatranská Lomnica, Slovak epublic 13. Kiss-Szikszai, A.: Chemo- and stereoselective eductions by Chromium (II) Complexes: Transformations and Characterisations. XXII Corso Avanzato in Chimica Farmaceutica e Seminario azionale per Dottorandi E. Duranti, July 1 5, 2002, Urbino, Italy 14. Dinya, Z.; Kovács, Zs.; Kiss-Szikszai, A.; Szabó, L.; Antus, S.: A FLAVI 7, gyümölcs eredetű magyar készítmény, analitikai jellemzése. 10. Magyar Gyógynövény Konferencia, , Kecskemét 15. Kónya, K.; Antus, S.; Varga, Zs.; Kiss-Szikszai, A.: eolignánok szintézise, HPLC-s tulajdonságaik és antioxidáns hatásuk vizsgálata. 10. Magyar Gyógynövény Konferencia, , Kecskemét 16. Kiss-Szikszai, A.; agy, G.; Patonay, T.: Gyűrűs 2-szubsztituált 2,3- dihidro-4-kinolonok α-oxifunkcionálása MTA Heterociklusos Munkabizottság tudományos előadó ülése, , Balatonszemes 17. Kurtán, T.; Kiss, L.; Kiss-Szikszai, A.; Antus, S.: Benzene Chromophores in -Heterocycles. 9 th International Conference on Circular Dichroism in Chemistry and Life Sciences, August 31 September 4, 2003, Budapest Page 17

20 Theses 18. Kónya, K.; Kiss-Szikszai, A.; Kurtán, T.; Antus, S.: Enzyme-Catalyzed Kinetic esolution of Hydroxymethyl-1,4-Benzodioxane Derivatives. 9 th International Conference on Circular Dichroism in Chemistry and Life Sciences, August 31 September 4, 2003, Budapest 19. Patonay, T.; Kiss-Szikszai, A.; agy, G.: Enantioselective α- xyfunctionalization of Benzoheteracyclanones. 10 th Blue Danube Symosium on Heterocyclic Chemistry, September 3-6, 2003, Vienna, Austria 20. Kiss-Szikszai, A.; agy, G.; Patonay, T.: Stereoselective Synthesis of α- xyfunctionalized 2,3-Dihydro-4-Quinolones. 13 th European Symposium on rganic Chemistry, September 10-15, 2003, Cavtat-Dubrovnik, Croatia 21. Kiss-Szikszai, A.; agy, G.; Patonay, T.: 3-Szubsztituált 2-fenil-2,3- dihidro-4-kinolonok sztereoszelektív szintézise MTA Flavonoidkémiai Munkabizottság tudományos előadó ülése, , Budapest 22. Kónya, K.; Kiss-Szikszai, A.; Kurtán, T.; Antus, S.: -heterociklusos vegyületek kinetikus rezolválása MTA Flavonoidkémiai Munkabizottság tudományos előadó ülése, , Budapest 23. Kiss-Szikszai, A.; Silva, A.M.S.; Cavaleiro, J.A.S.; Patonay, T.: 3-Stiril kromonok szintézise, regio- és sztereoszelektív epoxidálása MTA Heterociklusos Munkabizottság tudományos előadó ülése, , Balatonszemes Page 18

21 Theses 24. Kiss-Szikszai, A.; agy, G.; Patonay, T.: Stereoselective α- xyfunctionalization of 2,3-Dihydro-4-Quinolinones. 1 st German-Hungarian Workshop, Chemical Diversity of atural Products Synthesis, Characterization and Applications, July 5-6, 2004, Hannover, Germany 25. Kiss-Szikszai, A.; Patonay, T.; Silva, V.L.M.; Pinto, D.C.G.A.; Cavaleiro, J.A.S.; Silva, A.M.S.: Chemo- and Stereoselective Epoxidation of 3-Styrylchromones. XXI st European Colloquium on Heterocyclic Chemistry, September 12-15, 2004, Sopron, Hungary 26. Patonay, T.; Vasas, A.; Kiss-Szikszai, A.; Juhász-Tóth, É.: Alkenilcsoporttal szubsztituált kromonok szintézise MTA Heterociklusos Munkabizottság tudományos előadó ülése, , Balatonszemes Page 19