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A series of derivatives of the natural sesquiterpene lactones alantolactone (1) and isoalantolactone (2) was prepared. The α-methylene-γ-lactone moiety was retained in the structures of these for further modifications using reactions that affected exclusively the nonconjugated double bonds of the decalin ring.The great potential biological and pharmacological activities of natural sesquiterpene lactones are responsible for the interest in developing this area of chemistry [1,2]. The most promising direction is the chemical modification of compounds isolated from natural sources in order to prepare substances with new properties. Certain natural sesquiterpene lactones have been used as effective medicinal preparations (for example, the antitumor preparation Arglabin [3]).The goal of the present work was to prepare a series of derivatives based on the natural sesquiterpene lactones alantolactone (1) and isoalantolactone (2) in the structures of which the α-methylene-γ-lactone moiety was retained for further modifications. This was achieved using reactions that affected exclusively the nonconjugated double bonds of the decalin ring.A mixture of lactones 1 and 2 (~1:1 ratio) was isolated from roots of Inula helenium L. (Asteraceae) by a method consisting of extraction of the ground raw material with CHCl 3 and subsequent chromatography over a column of SiO 2 . Fractions containing this mixture were evaporated and crystallized (2-3 times) from aqueous CH 3 OH (70%) to afford about 25% (of the total content of the extract) of pure 2. The isomers were further separated over a column of SiO 2 impregnated with AgNO 3 (5%) with gradient elution by benzene in light petroleum ether. The compounds isolated by chromatography over the column impregnated with Ag contained an impurity of Ag (2-5% according to elemental analysis) that was removed by passing their benzene solution over a layer of neutral Al 2 O 3 (activity I). The resulting compounds were identical to those in the literature [4].It is well known that olefins can undergo acidic isomerization to form intermediates and transition-state carbonium ions in which prototropic and skeletal rearrangements are observed. Therefore, we investigated the reactions of the alantolactone derivatives with acids.Alantolactone (1) is stable to acids (under drastic conditions the reaction mixture polymerizes) according to the literature [5] and our data.Shifts of the exocyclic double bond in the decalin ring of 2 that occur in the presence of acids have been reported [6]. This formed a mixture of the thermodynamically more favorable isomeric trisubstituted olefins that contain an endocyclic double bond between C-4 and C-5 (3) or C-3 and C-4. The ratio of products depends on the acid used (2:1 for methanesulfonic acid in trifluoroethanol [5] and 1:3 in formic acid [7]). We found the conditions for selective isomerization of 2 into 3. The PMR spectrum of 3 contained a singlet for the methyl on the double bond (1.60 ppm) instead of signals for the exomethylene protons on C-15. The 13 C NMR...

Starting with the α,β‐unsaturated ketones (I), the title compounds (V) are prepared via the carbinols (III) and characterized as the adducts (VII) with maleic anhydride (VI).

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Previously unknown amino-derivatives of the natural sesquiterpene lactone α-santonin were synthesized. The activity of the products against several human tumor-cell lines was studied.Natural sesquiterpene lactones exhibit various types of biological activity including antitumor activity [1]. A study of structure-activity relationships has found that high cytotoxicity correlates with the presence of an exocyclic double bond in the lactone ring [2]. Furthermore, the presence of an activated double bond allows modification (by a Michael reaction), introduction of new pharmacophores, and production of water-soluble and transportable forms [3].Compounds containing in a lactone ring not a methylene group but a methyl are found among the large variety of natural sesquiterpene γ-lactones isolated from plants of the family Asteraceae. For example, austricin (1) [4] was isolated from Artemisia leucodes Schrenk, A. austriaca Jacg.; arborescin (2) [5], from A. arborescens L.; and balchanolide (3) [6], from Achillea millefolium L. and A. balchanorum H. Krasch, etc.These and other sesquiterpene lactones with a methyl in the lactone ring are found in plants in large quantities and can be considered promising synthons for modification in order to introduce a new reactive center such as an activated exocyclic double bond that reacts readily with nuclophiles. These transformations could produce new derivatives of natural sesquiterpene lactones containing pharmacophores and their water-soluble or transportable forms.Our goal was to use α-santonin (4), which is isolated from certain Artemisia species (Asteracea), as an example to demonstrate the ability to introduce an active methylene into the lactone ring, to use the resulting lactone as a synthon for synthesis of previously unknown amino-derivatives of lactones, and to study their cytotoxic activity.Chemical and biochemical transformations of α-santonin and its pharmacological properties have been studied already for over 100 years. It has been used previously as an antiparasite preparation [7]. Other types of activity have recently been found for it, for example, antipyretic, anti-inflammatory, and fungicidal [8,9]. Santonin presents several reactive centers and is a convenient starting material for further chemical modification. Various transformations involving the dienone ring have been reported [10][11][12][13]. Methods for opening the lactone ring using various reagents are known [1,14,15].

Reactions of α difluoro azides with olefins result in oxidative fluoroamination or amination of the C=C bond.

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