Synthesis of ferrocenyl chalcones of the abietane series

Abstract

Two isomeric ferrocenyl chalcones having an abietane fragment were synthesized. Accessibility of various ferrocene derivatives, their high chemical stability, and penetrating ability toward membranes make them promising as substrates for conjugation with biomolecules. In recent time, interest in ferrocene derivatives as alternative drugs for chemotherapy of malignant tumors has increased considerably [1]. Some ferrocene derivatives were found to be active against cervix adenocarcinoma HeLa, melanoma Fem-x, and myelogenous leukemia K562 cell lines [2]. In addition, modifications of drugs used in clinical practice with ferrocenyl fragments were reported [3]. Among other ferrocene derivatives, ferrocenylsubstituted chalcones were synthesized [4]. Ferrocenyl derivatives of diterpenes were described in [5], and chalcones containing a dehydroabietic acid residue were reported in [6]. There are no published data on ferrocenyl chalcones linked to diterpene fragments. In the present communication we describe the synthesis of ferrocenyl chalcones of the abietane series and their cytotoxic activity. By condensation of ferrocenecarbaldehyde (I) with methyl (1R,4aS,10aR)-6-acetyl-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenantrene-1carboxylate (II, 12-acetyldehydroabietic acid methyl ester) [7] according to Claisen–Schmidt (KOH in methanol) we obtained chalcone III in 35% yield (Scheme 1). Pure trans isomer III was isolated by column chromatography on silica gel, followed by recrystallization from methanol. Its configuration followed from the large coupling constant (J ≈ 15 Hz) for the vinylic protons. Isomeric chalcone VI was synthesized in 4% yield from acetylferrocene (IV) and methyl (1R,4aS,10aR)6-formyl-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10aoctahydrophenanthrene-1-carboxylate (V, 12-formyldehydroabietic acid methyl ester) [8]. Aldehyde V was prepared in turn by the Sommelet reaction of 12-chloromethyl derivative VII [9] (Scheme 2). The low yield of VI may be rationalized by steric hindrances created by the isopropyl group to nucleoDOI: 10.1134/S1070428012060152