Send Orders for Reprints to [email protected] 2639 Current Organic Chemistry, 2016, 20, 2639-2646 RESEARCH ARTICLE ISSN: 1385-2728 eISSN: 1875-5348 Impact Factor: Anomalous Products in the Halogenation Reactions of Vinca Alkaloids 1.949 BENTHAM SCIENCE András Keglevich,1 László Hegeds,2 Lilla Péter,1 Judit Gyenese,1 Csaba Szántay, Jr.,3 Zsófia Dubrovay,3+ Miklós Dékány,3 Áron Szigetvári,3 Ana Martins,4++ József Molnár,4 Attila Hunyadi,5 Péter Keglevich1* and László Hazai1* 1Department of Organic Chemistry and Technology, University of Technology and Economics, Budapest, Hungary, H-1111 Budapest, Gellért tér 4. Hungary; 2MTA–BME Organic Chemical Technology Research Group, Hungarian Academy of Sciences, Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budafoki út 8, H-1111 Budapest, Hungary; 3Spectroscopic Research Division, Gedeon Richter Plc., H-1475 Budapest 10, P. O. Box 27, Hungary; 4Department of Medical Microbiology and Immunobiology, University of Szeged, 6720 Szeged, Dóm tér 10., Hungary; 5Institute of Pharmacognosy, University of Szeged, H-6720 Szeged, Eötvös u. 6., Hungary Abstract: Halogenation reactions of vindoline and 14,15-dihydrovindoline and its hydro- chloric salt were investigated and the anomalous reductions were discussed. Performing the hydrogenation in the presence of chlorine-containing solvent, e.g. dichloromethane, hydrogenolysation reaction of chlorine also took place. In this case unexpected chlorin- ated product could be observed. Performing the hydrogenation reaction only in the pres- ence of methanol, the expected reduced derivative was obtained. Upon bromination of vindoline with excess NBS, oxidation products with ring contraction and developing an oxygen bridge were isolated. The fluorination reactions of vinblastine using Selectfluor® and xenon difluoride as the fluorination reagents were unsuccessful because of the de- composition of the starting material. Reactions of vindoline with Selectfluor® a mixture of products were obtained. Using xenon difluoride as fluorination agent resulted in a pure quinoidal product containing the fluorine atom in the bridgehead carbon atom of the indole ring. The fluorination of catharan- A R T I C L E H I S T O R Y thine gave an anomalous indolenine type product. Received: February 22, 2016 Revised: May 24, 2016 Accepted: June 15, 2016 Dedicated to the memory of Professor Csaba Szántay who passed away on January 17, 2016. DOI: 10.2174/1385272820666160617080202 Keywords: Vindoline, catharanthine, halogenation, Selectfluor®, xenon difluoride, quinoidal products. 1. INTRODUCTION plant in China, but it was likely an artefact because hydrochloric acid was used in the extraction [4]. The chemical space of organohalogen natural compounds com- prises of halogenated alkaloids in about 25% [1]. Brominated and The Vinca alkaloids vindoline (1) and catharanthine (2) are the chlorinated nitrogen heterocycles such as pyrrols, indoles, car- components of the famous antimitotic agents vinblastine (3) and bolines etc. can mostly be found in the marine environment [1]. In vincristine (4) which are present in the Madagascar periwinkle Ca- these compounds iodine or fluorine substituents rarely occur. Sev- tharanthus roseus (Scheme 1). Halogenation of vindoline (1) in eral halogenated alkaloids, mainly those with a bromo substitutent position 10 was carried out with N-chloro- and N-iodosuccinimide, isolated from marine intervebrates, exhibit cytotoxic protein kinase respectively [5]. The reaction with N-bromosuccinimide led to the inhibitory and antimicrobial activity [2]. From a hairy root culture corresponding 10-bromovindoline [6, 7]. Recently, derivatives of of Catharanthus roseus which contained exogenously added chlo- vinblastine (3) and vincristine (4), including iodo- and chloro sub- rinated or brominated tryptamine, halogenated indole alkaloids, e.g. stituted dimer alkaloids, were reviewed [8]. Halogenation of ca- chlorinated tabersonine could be obtained [3]. A similar chloro tharanthine gave indolenine-type derivatives halogenated in bridge- derivative was isolated from Alstonia yunnanensis, a medicinal head position 7 [9]. Catharanthine bearing two fluorine atoms in the methylene group of the ethyl substituent in position 19 was synthe- sized; however, its coupling with vindoline did not result in the *Address correspondence to these authors at the Department of Organic Chemistry expected fluorinated vinblastine [10]. 10’-Fluorovinblastine and and Technology, University of Technology and Economics, Budapest, Hungary, H-1111 Budapest, Gellért tér 4. Hungary; E-mails: [email protected], 10’-fluorovincristine with excellent antitumor activity were pre- [email protected] pared by Boger et al [11, 12]. In this case the fluoro atom was in- + Present address: XiMo Hungary Ltd., 1031 Budapest, Záhony u. 7., Hungary ++ Present address: Synthetic Systems Biology Unit, Institute of Biochemistry, Biologi- troduced in position 10 of catharanthine via 10-amino substituent cal Research Centre, 6726 Szeged, Temesvári krt. 62., Hungary following the coupling reaction with vindoline. Current Organic Chemistry 1875-5348/16 $58.00+.00 © 2016 Bentham Science Publishers 2640 Current Organic Chemistry, 2016, Vol. 20, No. 24 Keglevich et al. 5 N 3 4 14 6 5 3 9 21 15 9 6 4 H 20 8 7 10 18 10 N 8 7 17 14 15 11 2 17 19 1 16 11 1 H CO 13 N OCOCH 13 N 2 16 21 20 3 12 3 H H OH 12 COOCH H 3 19 18 CH3 COOCH3 2 1 21' 4' 5' OH 18' N 20' 9' 6' 15' 19' 8' 10' 7' 3' 14' 5 11' 1' 16' 17' N 3 14 13' N 2' 4 12' H 9 6 21 15 20 3; R= CH3 H3COOC 18 10 8 7 4; R=CHO 17 11 19 1 2 16 13 H3CO 12 N OCOCH3 H OH R COOCH3 Scheme 1. Cl H N 14 N 14 N 14 15 15 15 10 10 H Pd/C aq. NaHCO 10 2, 3 EtOH, CH Cl 2 2 H3CO N OCOCH3 H3CO N OCOCH3 H CO N OCOCH H OH H OH 3 3 CH COOCH CH H OH 3 3 3 COOCH3 CH3 COOCH3 5 6 1 NBS, CH2Cl2 NBS, CH2Cl2 90% N 14 N 14 N 14 15 10 15 15 Cl 10 Br Br 10 H3CO N OCOCH3 H3CO N OCOCH3 H3CO N OCOCH3 H OH 12 H OH H OH CH3 COOCH3 Br CH3 COOCH3 CH3 COOCH3 7 8 9 Scheme 2. 2. RESULTS AND DISSCUSSION Performing the hydrogenation in methanolic solution under pressure, only 14,15-dihydrovindoline base (6) formed [14]. The 2.1. Chemistry HCl was generated by the hydrogenolization of dichloromethane As a continuation of our work aimed at synthesizing Vinca al- resulting in the salt (5), which was supported with several samples kaloid derivatives with an antitumor activity [13], 14,15- in connection with hydrodehalogenation of halogenated hydrocar- dihydrovindoline (6) [14], saturated in positions 14 and 15, was bons using Pd catalyst [15-17]. In the course of NBS bromination prepared. Catalytic hydrogenation of vindoline (1) was achieved in of the base (6) the expected 10-bromo-14,15-dihydrovindoline (9) a mixture of ethanol-dichloromethane in the presence of Pd/C cata- [13] was obtained in 90% yield. In the bromination reaction of the lyst at room temperature under atmospheric pressure. The weight of hydrochloric salt of 14,15-dihydrovindoline (5), however, three the used catalyst had to be the same as of the substrate, otherwise products were isolated which could not be separated: 10-chloro- the reduction failed and was very slow, especially in larger quanti- 14,15-dihydrovindoline (7), 10,12-dibromo-14,15-dihydrovindoline ties (e.g. 5-10 g). In this case the product proved to be the 14,15- (8), and 10-bromo-14,15-dihydrovindoline (9) [13], as the major dihydrovindoline hydrochloric salt (5) and the base (6) was isolated product. Identification of the positions of halogen atoms in com- after washing with sodium hydrogen carbonate (Scheme 2). pounds 7 and 8 are discussed in Experimental. Chlorination can be Anomalous Products in the Halogenation Reactions Current Organic Chemistry, 2016, Vol. 20, No. 24 2641 N 14 N D 15 Br A OH NBS OH H CO N OCOCH CHCl H CO N OCOCH 3 H 3 3 3 H 3 CH3 COOCH3 Br CH3 COOCH3 1 10 CHCl3 NBS H 22 23 H 14 O O N O N O DD22' 23' Br Br A O + A O H3CO N OCOCH3 H3CO N OCOCH3 H H CH3 COOCH3 CH3 COOCH3 11 12 Scheme 3. N N F 10 XeF2 K2CO3 8 CH2Cl2 H3CO N OCOCH3 -40oC O N OCOCH3 H OH H OH CH3 COOCH3 10% CH3 COOCH3 1 13 SelectF CH3CN N N F F 10 F 10 + 13 + 8 H3CO N OCOCH3 O N OCOCH3 H OH H OH CH3 COOCH3 CH3 COOCH3 14 15 Scheme 4. explained by NBS oxidation of the chloride ion to chlorine. This an aldehyde function formed and gave with ethyl alcohol (stabiliz- type of oxidation of halogen ions by N-haloimides to free halogen is ing the chloroform) the acetal 11, and the carboxylic acid (evolving mentioned by Filler [18]. Moreover, NBS mediated oxidation is from the aldehyde) resulted in the ethyl ester 12. Vindoline (and extensively known in the literature [18-21]. vinblastine) derivatives with a 5-membered D-ring were synthe- Nevertheless, directly introducing two bromo atoms into 14,15- sized by Boger and co-workers [24]. Nevertheless, NBS induced dihydrovindoline was unsuccessful [22]. In the course of bromina- ring contraction in the presence of alcohol is presented by Karimi tion reactions a complete transformation could not be observed et al. [25]. Similarly, in our case without alcohol no reaction could either in the reaction of 14,15-dihydrovindoline (6), or in the case be observed, moreover the two compounds (11, 12) could not be of 10-bromo-14,15-dihydrovindoline (9) [13]; only inseparable separated and thus could not be characterized in pure form, because complex mixtures were obtained.