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Palladium-catalyzed synthesis of 2H-pyrano[2,3-g]isoquinolinones have been described from easily accessible precursor 6-cyanoumbelliferone triflate via sequential of Sonogashira coupling an...

Aim and Objective: We studied the synthesis of new groups of functionalized isobenzofurans and isoindolines by selective gold catalyzed cycloisomerization of some new optically active furandialkynes derived from the natural furanolabdanoid lambertianic acid. Functionalized isobenzofurans and isoindolines are considered as privileged structures that are currently experiencing a renewed interest in medicinal chemistry. Materials and Methods: Using the AuCl3-catalyzed cycloisomerization of furanolabdanoid dialkynes we synthesized several new groups of biologically interested isobenzofurans and isoindolines with labdanoid substitution. The structure of all new compounds was proven by elemental and spectral analysis: IR, mass-, and NMR data. Results: The synthesis of 15,16-dialkynyl substituted furanolabdanoids was carried out. Au(III)-Catalyzed cycloisomerization of those compounds proceeded highly selectively with the formation of optically active 4- substituted 7-hydroxy-3(6)-propargylaminomethylisobenzofurans or 7-hydroxy-3(6)-propargyloxymethylisoindolines. The cycloisomerization of the 15-(prop-2-yn-1-yloxymethyl)-16-((N-p-toluenesulfonyl)-prop- 2-yn-1-ylaminomethyl)labdatriene proceeded in part on the 15 position and involved the previously unknown intramolecular transfer of N-(p-toluenesulfonyl)propargylaminomethyl substituent to the oxygen in the stage of formation of an aromatic ring. A feasible reaction mechanism for this transformation is presented. It was revealed that the conversion of labdanoid furan-15-ynes to 1,3-dihydroisobenzofurans depends on the nature of the substituent in the 16 position of the furanolabdanoid. Conclusions: The present study sheds light on the Au(III)-catalyzed cycloisomerization of new group of highly functionalized furandialkynes. Also, new groups of alkynyloxymethyl or alkynylaminomethyl substituted optically active isobenzofurans and isoindolines were obtained and fully characterized.

(17R)-17,18-Dipropargyloxylabda-13,15-diene was synthesized and underwent Cu-catalyzed cycloaddition with 1,10-diazodecane or 1,2-bis(2-azidoethoxy)ethane to produce macroheterocycles of the furanolabdanoid decalin fragment. The macroheterocyclic labdanoids showed significant cytotoxicity in MEL-8, MT-4, and U-937 human tumor cell models.

Twenty-one phenolic compounds (1–21) including dihydrocinnamic acid, isoflavonoids, flavonoids, coumestans, pterocarpans, chalcones, isoflavan and isoflaven, were isolated from the roots of Glycyrrhiza pallidiflora Maxim. Phloretinic acid (1), chrysin (6), 9-methoxycoumestan (8), isoglycyrol (9), 6″-O-acetylanonin (19) and 6″-O-acetylwistin (21) were isolated from G. pallidiflora for the first time. Isoflavonoid acetylglycosides 19, 21 might be artefacts that could be produced during the EtOAc fractionation process of whole extract. Compounds 2–4, 10, 11, 19 and 21 were evaluated for their cytotoxic activity with respect to model cancer cell lines (CEM-13, MT-4, U-937) using the conventional MTT assays. Isoflavonoid calycosin (4) showed the best potency against human T-cell leukaemia cells MT-4 (CTD50, 2.9 μM). Pterocarpans medicarpin (10) and homopterocarpin (11) exhibit anticancer activity in micromolar range with selectivity on the human monocyte cells U-937. The isoflavan (3R)-vestitol (16) was highly selective on the lymphoblastoid leukaemia cells CEM-13 and was more active than the drug doxorubicin

Several 15,16-epoxy-8,13,14-labdatriene derivatives modified at the C-16 position with a 1,2,4-oxadiazole ring with various substituent in the 5-th position, were obtained via multistep synthesis from 16-formyl derivatives of natural diterpenoid lambertianic acid. The cytotoxicity of furanolabdanoid-based 1,2,4-oxadiazoles was evaluated against human cancer cells (CEM-13, MT-4, U-937, MCF-7, MDA-MB-231, MEL-8) using the conventional MTT assays. All the tested diterpenoid-oxadiazole hybrids displayed better cytotoxic activity then lambertianic acid. The activity and selectivity to the cell line increased even further in the compounds containing a chloromethyl substituent in the 5-th position of the 1,2,4-oxadiazole ring. Two of the synthesized compounds exhibited high cytotoxic activity against lymphoblastoid cell line CEM-13 (GI50 0.08-0.34 μM), which was higher that than of the comparative drug Doxorubicin. The antitumor mechanism may be related to apoptosis induction in U-937, MCF-7, and CEM-13 cells.

The reaction of isoalantolactone, a sesquiterpene α-methylidene-γ-lactone, with bromo(iodo)pyridines under the Heck reaction conditions gave 3-(pyridylmethylidene)-8а-methyldecahydronaphtho[2,3-b]furan-2(3Н)-ones and 3-(pyridylmethyl)-8а-methyloctahydronaphtho[2,3-b]-furan-2(4Н)-ones, products of double bond migration. The yield and product ratio depended on the reaction conditions and the nature of halopyridine. The effectiveness of Pd(OAc)2–caffeine catalytic system was demonstrated in this reaction.

Derivatives of natural diterpenoid methyl lambertianate containing propargyloxy substituents in 16,17-positions were obtained. CuAAC reaction of methyl 17-propargyloxy-16-[(prop-2-yn-1-yloxy)methyl]labdadienoate with various diazides in the presence of Cu(II)/sodium ascorbate in methylene chloride/water reaction medium gave chiral macrocyclic compounds connected on the 16 and 17-positions by 1,2,3-triazole rings with methylene, ethyloxyethyl or ethylethoxyethyl units. The obtained macrocyclic structures showed high selectivity and affinity for Hg2+ ion by the 1,2,3-triazole rings.

A selective synthesis of 7‐ or 14‐nitrogen containing tricyclic diterpenoids was completed according to a strategy in which the key step was the catalyzed direct allylic amination of methyl 14α‐hydroxy‐15,16‐dihydroisopimarate with a wide variety of nitrogenated nucleophiles. It was revealed that the selectivity of the reaction depends on the nature of nucleophile. The catalyzed reaction of the mentioned diterpenoid allylic alcohol with 3‐nitroaniline, 3‐(trifluoromethyl)aniline, and 4‐(trifluoromethyl)aniline yield the subsequent 7α‐, 7β‐ and 14αnitrogen‐containing diterpenoids. The reaction with 2‐nitroaniline, 4‐nitro‐2‐chloroaniline, 4‐methoxy‐2‐nitroaniline, phenylsulfamide, or tert‐butyl carbamate proceeds with the formation of 7α‐nitrogen‐substituted diterpenoids as the main products.

A series of 2-(4-R-triazolyl)substituted 3-oxo-2,3-dihydrofurocoumarins have been synthesized by a regioselective cycloaddition of 2-azidooreoselone 1 or 2-azido-9-[(4-methylpiperazin-1-yl)methyl]oreoselone 2 with various alkynes in the presence of Cu(II)/ascorbate in water/methylene chloride reaction medium. The structure of 2-azidooreoselone was established by X-ray structure analysis. The cytotoxicity of 2-substituted dihydrofurocoumarins was determined against three cancer cell lines (CEM-13, MT-4, U-937) using the conventional MTT assays. Among the tested molecules, most of the analogs displayed better cytotoxic activity then the parent natural furocoumarin peucedanin 3. The activity and selectivity to the cell line increased even further in the series of 2-(4-{2,3-dihydrobenzo[b][1,4]dioxine}triazolyl)-3-oxo-2,3-dihydrofurocoumarins and 2-(4-aryltriazolyl)-3-oxo-2,3-dihydrofurocoumarins having the (4-methylpiperazin-1-ylmethyl) substituent in the 9-th position. The most active compound 20 contain the 4-hydroxy-3-methoxybenzamidomethyl substituent in the 4-th position at the triazole ring of 2-(triazol-1-yl)dihydrofurocoumarins. The obtained 2-triazolyl substituted dihydrofurocoumarins were studied as inhibitors of phosphodiesterase (PDE-4B) using docking experiments. As a result of virtual screening 3 compounds are selected based on minimum binding energy. The interactions of the most active compound and amino acid residues in the binding site were studied.

The corresponding hydrazones and thiosemicarbazones were synthesized via the reaction of pinostrobin hydrazone with carbonyl compounds (aromatic aldehydes, acetone) or alkyl(aryl)isothiocyanates, respectively. The new pinostrobin derivatives showed significant cytotoxicity (MTT-assay) against MT-4, CEM-13, and U-937 human tumor cell models.

The reaction of flavanone pinostrobin with dibromoalkanes in acetone in the presence of potassium carbonate followed the path of retro-Michael addition – О-alkylation and resulted in the formation of the respective 2-(bromoalkoxy)chalcones. Treatment of the latter with sodium azide gave the respective azides, which were highly active in the Сu-catalyzed 1,3-dipolar cycloaddition reaction. The reaction of these azides with 6-substituted 7-ethynylcoumarins gave coumarin-chalcone hybrids containing a 1,2,3-triazole linker.

An aza-Michael reaction of isoalantolactone with 5-bromo- or 5-iodo-substituted uracils gave (11R)-13-[5-bromo(iodo)-2,4-dioxotetrahydropyrimidin-1-yl]eudesma-4(15)-en-8β,12-olides, which were highly active in Pd-catalyzed cross-coupling reaction with terminal alkynes. Copper-catalyzed Mannich reaction of (11R)-13-(5-ethynyl-2,4-dioxotetrahydropyrimidin-1-yl)eudesma-4(15)-en-8β,12-olide with secondary amines and formaldehyde was used for the synthesis of (11R)-13-[5-(diethyl-amino)propynyl]-, (11R)-13-[5-(pyrrolidinyl-1-yl)propynyl]-, (11R)-13-[5-(4-oxopiperidin-1-yl)-propynyl]-, (11R)-13-[5-(4-methylpiperazin-1-yl)propynyl]-, and (11R)-13-(5-{[2-(pyridin-3-yl)piperidin-1-yl]propynyl}-2,4-dioxotetrahydropyrimidin-1-yl)eudesmanolides. The treatment of 13-[5(propargyl-amino)tetrahydropyrimidin-1-yl]eudesmanolides with silver nitrate led to the corresponding (11R)-13-(2-oxofuro[2,3-d]pyrimidin-3(2H)-yl)eudesmanolides. The structures of two compounds were proved by X-ray structural analysis.

New isopimaric acid derivatives containing amines and methyl esters of α-, β-, and ω-amino acids were prepared. Conditions were found for cyclic isomerisation of isopimaric acid propargylamide into 2-(dodecahydrophenanthren-1-yl)-5-methyloxazole or 2-(dodecahydrophenanthren-1-yl)-5-methylene-4,5-dihydrooxazole. The latter was selectively modified by adding the methyl ester of (2-methylamino)butanoic acid at the oxazole C-5 position.

Cross-coupling of methyl 2-acetylamino-5-bromobenzoate and 5′-bromolappaconitine with aryl-, furyl-, pyridyl-, and 5-acetylthiophen-2-ylboronic acids or 1-(2-fluoroquinolin-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane gave the corresponding 5-aryl(hetaryl)-substituted anthranilic acid derivatives. The use of the two-phase toluene-water system as reaction medium and addition of tetrabutylammonium bromide allows the cross-coupling to be accomplished under mild conditions. The catalytic system Pd(dba)2-AsPh3 was found to be efficient in the cross-coupling of methyl 2-acetylamino-5-bromobenzoate with furyl- and pyridylboronic acids, whereas the system Pd(OAc)2-(o-Tol)3P ensured good results in the reactions of 5′-bromolappaconitine with hetarylboronic acids. Facile esterification at the C8-OH and C9-OH groups of the aconitane skeleton was observed in the reactions of 5′-bromolappaconitine and 5′-phenyllappaconitine with phenylboronic acid. 5′-Bromo-8,9-O-(phenylboranediyl)lappaconitine under the Suzuki reaction conditions underwent hydrolysis of the boronic ester moiety with formation of the cross-coupling product of 5′-bromolappaconitine with phenylboronic acid.

A series of new analogs of combretastatin A-4 (CA-4, 1) with the A or B-ring replaced by a 3-oxo-2,3-dihydrofurocoumarin or a furocoumarin residue have been designed and synthesized by employing a cross-coupling approach. All the compounds were evaluated for their cytotoxic activity with respect to model cancer cell lines (CEM-13, MT-4, U-937) using conventional MTT assays. Structure-activity relationship analysis reveals that compounds 2, 3, 6–8 in which the (Z)-styryl substituent was connected to the 2-position of the 3-oxo-2,3-dihydrofurocoumarin core, demonstrated increased potency compared to 3-(Z)-styrylfurocoumarins 4, 5, 9–11. The methoxy-, hydroxyl- and formyl- substitution on the aromatic ring of the (Z)-styryl moiety seems to play an important role in this class of compounds. Compounds 2 and 3 showed the best potency against the CEM-13 cell lines, with CTD50 values ranging from 4.9 to 5.1 μM. In comparison with CA-4, all synthesized compounds presented moderate cytotoxic activity to the T-cellular human leucosis cells MT-4 and lymphoblastoid leukemia cells CEM-13, but most of them were active in the human monocyte cell lines U-937.

19-(2,6-Dimethylpyrid-4-yl)-20,29,30-trinorlupanes in addition to triterpenoid derivatives condensed in ring A of the pyran-4-one ring were synthesized for the first time from betulin, betulin diacetate, and methyl esters of 3-acetylbetulinic and betulonic acids.

2,6-Di-tert-butyl-4-(2-hydroxyethyl)phenol undergoes oxidative self-coupling by the action of K3Fe(CN)6 in alkaline medium at room temperature to give 7,9-di-tert-butyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-hydroxymethyl-2-oxaspiro[4.5]deca-6,9-dien-8-one. The composition of the reaction products has been determined, and the mechanism of their formation is discussed.

1H and 13C NMR studies and quantum chemical calculations show the interaction between 2,11-dithia-5,6,8,9-tetramethyl[32](1,4)cyclophane and nitrosonium cation to result in the formation of π- and n-complexes. According to DFT/B3LYP/6-31G(2d,p) calculations, formation of nitrosonium complexes is a strongly exothermic process both in gas phase and in SO2. Affinity of single-charged complexes to NO+ is usually larger than that of double-charged and triple-charged complexes, affinity of all the charged complexes to nitrosonium cation in SO2 being larger than that in gas phase. The π-complex with nitrosonium cation coordinated to the methylated aromatic ring is the most stable with structural characteristics being close to those obtained by X-ray diffraction for nitrosonium π-complexes of hexamethylbenzene and other arenes. The N―O bond lengths in all the complexes are quite close to each other and larger than that in NO+ cation. The S―N bond length increases upon transition from single-charged to double-charged and polycharged complexes. Copyright © 2014 John Wiley & Sons, Ltd.

Methods were proposed for preparing 15,16-dihydroisopimaric acid and its methyl ester. Oxidation of methyl dihydroisopimarate through the action of 3-chloroperbenzoic acid occurred with formation of 7,8-epoxy-derivatives and 7α-hydroxydihydrosandaracopimarate. The latter in addition to 7-oxotetrahydroisopimarate were formed through the action of t-butylhydroperoxide in the presence of MoCl5. Oxidation of dihydroisopimaric acid or the ester by selenium dioxide in dioxane gave the corresponding 14α-hydroxy-derivatives. Pyridinium chlorochromate transformed 14α-hydroxydihydroisopimarate into a mixture of methyl esters of 7α-hydroxy-8,14-epoxyisopimaric, 7-oxo-8,14-epoxyisopimaric, 7-oxo-14-hydroxyisopimaric, and 7α-hydroxysandaracopimaric acids. Oximation of methyl 7-oxotetrahydroisopimarate by hydroxylamine hydrochloride in MeOH in the presence of NaOAc gave a mixture of the corresponding (Z)- and (E)-oximes. Beckmann rearrangement of the 7-(E)-oxime of methyl tetrahydroisopimarate through the action of thionylchloride led to tetradecahydrodibenzo[b,d]azepine.

Palladium-catalyzed cross-coupling of isoalantolactone with 1,3-disubstituted or 1-substituted 5-bromo(iodo)uracils afforded mainly (13E)-13-(2,4-dioxotetrahydropyrimidin-5-yl)eudesma-4(15),11(13)-dien-8β,12-olides whose yields depended on the composition of the catalytic system, base, and additive. The structure of (13E)-13-[3-(2-cyanoethyl)-2,4-dioxotetrahydropyrimidin-5-yl]eudesma-4(15),11(13)-dien-8β,12-olide was proved by X-ray analysis.

13-Aryl-substituted derivatives of the germacranolide argolide were synthesized by a Heck reaction with arylhalides. The structure of (E)-13-(4-methoxyphenyl)-3-oxogermacra-1(10),11(13)-dien-6α,12-olide was proved by an x-ray crystal structure analysis. Analgesic activity was found in the acetic-acid writhing test for the 13-arylgermacranolides.

Reactions of methyl phlomisoate with methyl acrylate, phenyl acrylate, methyl vinyl ketone, phenyl vinyl ketone, or N-substituted acrylamides catalyzed by Pd(OAc)2 in the presence of Cu(OAc)2, p-benzoquinone in the mixture of propionic acid and acetonitrile proceed regio- and stereoselectively with the formation of (E)-16-vinyl labdatrienoates. The oxidative coupling under these conditions of the methyl phlomisoate with styrene results in a mixture of 15,16-distyryl-, 16-styryl-, and 16-(1-phenylvinyl)-derivatives of furanolabdanoid.

New derivatives of betulin, betulinic acid methyl ester, and their acetate analogs containing 1,2,3-triazole fragments in the C-30 position were synthesized. It was shown using the Ames test that 30-azidolup-20(29)-enes and 3β,28-diacetoxy-30-(4-R-1,2,3-triazol-1-yl)lup-20(29)-enes did not exhibit mutagenic properties.

16-(1-R-1,2,3-Triazol-4-ylethyl)-, 16-(1-R-1,2,3-triazol-4-ylmethoxymethyl)-, and 16-{2-(1-R-1,2,3-triazol-4-yl)-1-[(1-R-1,2,3-triazol-4-ylmethoxy)ethyl]}-substituted derivatives of methyl lambertianate were synthesized by 1,3-cycloaddition of labdanoid alkynes with azides. The compounds obtained possess considerable cytotoxicity toward the human tumor cell lines CEM-13, MT-4, and U-937. The most active compound, methyl 16-(2-{2-[(1-benzyl-1H-1,2,3-triazol-4-yl)acetyl]furan-3-yl}ethyl)lambertianate, was found to inhibit the viability of the tumor cells by 50% (CCID50) in the concentration of 7–12 μmol L−1.

Bromooreoselone reacted with sodium azide to give 2-azidooreoselone, which was highly reactive in a catalytic Huisgen reaction with various terminal alkynes. These reactions yielded 4-substituted 2-(triazol-1-yl)furocoumarins. The reaction of oreoselone azide with dimethyl acetylene-1,2-di-carboxylate gave 2-[(4,5-dimethoxycarbonyl)triazolyl]oreoselone and reaction with 7-ethynyl-6-methoxycarbonylcoumarin gave 1,4-dicoumarin-substituted 1,2,3-triazole.

Substituted salicylaldehydes reacted with ethyl diazoacetate to give ethyl 1-benzofuran-3-carboxylates containing various substituents in the aromatic ring. The Diels-Alder reaction of these compounds with Danishefsky’s diene was regioselective, and it provided an effective method for the construction of the heterocyclic skeleton of hexahydrodibenzo[b,d]furan-7-one or tetrahydrodibenzo[b,d]furan-7-one. The adducts were found to undergo rearrangement to substituted 4′-hydroxybiphenyl-2-yl methyl carbonates during column chromatography on silica gel.

N-Aryloxyalkylanabasine derivatives were prepared via the reaction of anabasine hydrochloride with various aryloxyhaloalkanes in the presence of potash in DMF. The reaction occurred with retention of the chiral center C-(2) of the piperidine group. Side products of bis(aryloxy)ethanes were characterized.

Salts of 1,2,3-benzodithiazolium (1), 2,1,3-benzothiaselenazolium (3), and 1,2,3-benzodiselenazolium (4) (Herz cations), namely, [1][BF4], [1][SbCl6], [3][BF4], [3][GaCl4], [3][SbCl6], and [4][GaCl4], were prepared from the corresponding chlorides and NaBF4, GaCl3, or SbCl5. It was found that [1][SbCl6] and [3][SbCl6] spontaneously transform in MeCN solution to [1](3)[SbCl6](2)[0] and [3](3)[SbCl6](2)[Cl], respectively. [1][BF4], [1](3)[SbCl6](2)[Cl], [3][BF4], [3](3)[SbCl6](2)[Cl], and [4]-[GaCl4] were structurally characterized by X-ray diffraction (XRD). In solution, these [BF4](-) and [GaCl4](-) salts as well as [1][GaCl4], [2][GaCl4], [3][GaCl4], [3][Cl], and [4][Cl] were characterized by multinuclear nuclear magnetic resonance (NMR). The corresponding Hen radicals 1(center dot)-4(center dot) were obtained in toluene and DCM solutions by the reduction of the appropriate salts with Ph3Sb and characterized by EPR. Cations 1-4 and radicals 1(center dot)-4(center dot) were investigated computationally at the density functional theory (DFT) and second-order Moller-Plesset (MP2) levels of theory. The B1B95/cc-pVTZ method was found to satisfactorily reproduce the experimental geometries of 1-4; an increase in the basis set size to cc-pVQZ results in only minor changes. For both 1-4 and 1(center dot)-4(center dot), the Hirshfeld charges and bond orders, as well as the Hirshfeld spin densities for the radicals, were calculated using the B IB95/cc-pVQZ method. It was found for both the cations and the radicals that replacing S atoms with Se atoms leads to considerable changes in the atomic charges, bond lengths, and bond orders only at the involved and the neighboring sites. According to the calculations, 60% of the positive charge in the cations and 80% of the spin density in the radicals is localized on the heterocycles, with the spin density distributions being very similar for all radicals 1(center dot)-4(center dot). For the cations 1-4, the NICS values (B3LYP/cc-pVTZ for B1B95/cc-pVTZ geometries) lie in the narrow range from -5.5 ppm to -6.6 ppm for the carbocycles, and from -14.4 ppm to -15.5 ppm for heterocycles, clearly indicating the aromaticity of the cations. Calculations on radical dimers [1(center dot)](2)-[4(center dot)](2) revealed, with only one exception, positive dimerization energies, i.e., the dimers are inherently unstable in the gas phase.

Interaction of betulonic acid chloride with 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl, 3-amino-2,2,5,5-tetramethylpyrrolidine-1-oxyl, and 3-aminomethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl yielded the corresponding triterpene amides. The synthesized derivatives of betulonic acid were shown to exhibit a cytotoxic activity on models of the CEM-13, U-937, and MT-4 tumor cells. The concentration of the most active N-[3-oxo-28-norlup-20(29)-en-17-carbamoyl-(2,2,6,6-tetramethylpiperidine-4-yl)-1-oxyl that inhibited survival of the tumor cells by 50% (CCID50) proved to be 5.7–33.1 μM.

Plants of the genus Peucedanum attract the attention of researchers as sources of coumarins. We isolated previously from P. terebinthaceum Fischer et Turcz. of Mongolia flora the pyranocoumarin (+)-pteryxin [1]. Plants of the species Ferulopsis hystrix Bunge (P. hystrix) were characterized as sources of angular furocoumarins [2]. The species P. baicalense (Redow.) Koch is broadly distributed over Mongolia [3]. Peucedanin, imperatorin, isoimperatorin, fellopterin, deltoin, bergapten, and 8-hydroxy-5-methoxypsoralen were previously isolated from its roots [3]. We studied compounds extracted from P. baicalense collected in Baruunburen, Selenge Province, Mongolia, during budding-flowering. The concentrated EtOH extract of subterranean organs was diluted with H2O. Coumarins were extracted sequentially by hexane (1.15% yield), Et2O (0.33%), and EtOAc (2.28%). An analysis of PMR spectra of the fractions showed that the principal components of the hexane extract were diacetylene compounds, coumarins (~30%), and sterols (~12%). Extracted compounds were separated by column chromatography over silica gel. Chromatography of the hexane extract (2.4 g) isolated sequentially the diacetylene alcohol falcarinol (1) and pure linear furocoumarins isoimperatorin (2) (0.032% of raw material weight), fellopterin (3) (0.038%), and 8-(1,1-dimethylallyloxy)bergapten (4) (0.044%).

Peucedanin reacted with methylideneiminium salt generated in situ from N,N,N′,N′-tetramethylmethanediamine and acetyl chloride to give 2-(dimethylaminomethyl)oreoselone. Reactions of peucedanin with aminomethylating agents generated in situ from formaldehyde and dimethylamine, N-methylpiperazine, or N-Boc-piperazine in boiling methanol smoothly afforded the corresponding 9-aminomethyl derivatives whose hydrolysis produced 9-aminomethyl-substituted oreoselones. 2,3,9-Trisubstituted linearly fused furocoumarins were synthesized by reactions of 9-substituted oreoselone trifluoromethanesulfonates with arylboronic acids.

Derivatives of lappaconitine containing styryl, hetarylvinyl, 3-oxobutenyl, and acetyl substituents on the aromatic ring were synthesized using a Heck reaction of 5′-iodolappaconitine and various olefines.

The reaction of a linearly fused furocoumarin, oreoselone, with p-toluenesulfonyl chloride gave 2-tosyloreoselone which showed a high reactivity in palladium-catalyzed cross-coupling reactions with formation of a new carbon-carbon bond. 2-Tosyloreoselone reacted with terminal alkynes in the presence of Pd(PPh3)2Cl2 to give the corresponding 2-alkynylfuro[3,2-g]chromen-3-ones. 2-Aryl(hetaryl)alkynyloreoselones were obtained in high yield directly by palladium-catalyzed reaction of oreoselone with tosyl chloride and aryl(hetaryl)acetylenes. The reaction of 2-tosyloreoselone with aryl(hetaryl)boronic acids in the presence of palladium complexes with uni- and bidentate ligands, tetrabutylammonium bromide, and a base afforded 2-aryl(hetaryl)-substituted oreoselones. 2-Vinyloreoselone was synthesized from 2-tosyloreoselone and potassium trifluoro(vinyl)borate.

Several 15,16-epoxy-8,13,14-labdatriene derivatives modified at the C-16 position with a 1,2,4-oxadiazole ring with various substituent in the 5-th position, were obtained via multistep synthesis from 16-formyl derivatives of natural diterpenoid lambertianic acid. The cytotoxicity of furanolabdanoid-based 1,2,4-oxadiazoles was evaluated against human cancer cells (CEM-13, MT-4, U-937, MCF-7, MDA-MB-231, MEL-8) using the conventional MTT assays. All the tested diterpenoid-oxadiazole hybrids displayed better cytotoxic activity then lambertianic acid. The activity and selectivity to the cell line increased even further in the compounds containing a chloromethyl substituent in the 5-th position of the 1,2,4-oxadiazole ring. Two of the synthesized compounds exhibited high cytotoxic activity against lymphoblastoid cell line CEM-13 (GI50 0.08-0.34 μM), which was higher that than of the comparative drug Doxorubicin. The antitumor mechanism may be related to apoptosis induction in U-937, MCF-7, and CEM-13 cells.

New polyfluorinated Ar Se Se Ar, Ar Se Cl (Ar = 4-RC 6 F 4 -1-yl, 5-HC 5 F 3 N-3-yl), non-symmetric Ar Se Ar′ (Ar = 4-RC 6 F 4 -1-yl, Ar′ = 4-NC 5 F 4 -1-yl) and non-symmetric, i.e. chiral, Ar Se( O) Ar′ (Ar = Ar = 4-RC 6 F 4 -1-yl, Ar′ = 4-NC 5 F 4 -1-yl) derivatives, as well as (4-NC 5 F 4 -1-yl)SeNa, were prepared and characterized by single-crystal X-ray diffraction and multinuclear NMR ( 1 H, 13 C, 14 N, 19 F, 77 Se).

The iodination of N′-substituted (2,5-dioxopyrrolidino)[3,4-h]-6,14-endo-ethenotetrahydrothebaines with N-iodosuccinimide in trifluoroacetic acid afforded depending on the excess of the reagent either 1-iodo- or 1,2-diiodoendo-ethenotetrahydrothebaines. The Sonogashira reaction of 1-iodo-6,14-endo-ethenotetrahydrothebaines with trimethylsilylacetylene led to the formation of N′-substituted 1-(trimethylsilylethynyl)-(2,5-dioxopyrrolidino)-[3,4-h]-6,14-endo-ethenotetrahydrothebaines whose desilylation cleanly furnished the corresponding 1-ethynylendo-ethenotetrahydrothebaines. The Mannich reaction of the acetylene derivatives of tetrahydrothebaine with amines and formaldehyde catalyzed by compounds of Cu(I) provided 1-[3-(morpholin-4-yl)propynyl]-, 1-[3-(4-methylpiperazin-1-yl)propynyl]-, and 1-[3-(4-tert-butoxycarbonylpiperazin-1-yl)propynyl]-(2,5-dioxopyrrolidino)[3,4-h]-6,14-endo-ethenotetrahydrothebaines.

The Heck reaction of the eudesman-type methylidenelactones (alantolactone, alloalantolactone, and 4,15-epoxyisoalantolactone) with haloarenes afforded the corresponding (E)-13-aryleudesma-4(15),11(13)-dien-8β,12-olides and 11-arylmethyl-13-noreudesma-4(15),7(11)-dien-8α,12-olides. The yields and the ratios of the arylation products depended on the reaction conditions and the structure of lactone. Certain side processes were found to take place.

16-Propargylaminomethyl substituted and 16-propargyloxymethyl substituted furanolabdanoids were synthesized, which under the action of AuCl3 in acetonitrile underwent cycloisomerization forming 7-hydroxyisoindolines or 7-hydroxydihydroisobenzofurans substituted by a terpenoid fragment.

By Suzuki cross-coupling reaction of peurutenicin triflate with arylboric, furanylboric, pyridinylboric, and indolylboric acids the corresponding 7-aryl(hetaryl)coumarins were synthesized. The high activity of hetaryl-substituted boric acids in the Suzuki reaction was observed. Heck reaction of 7-O-trifluoromethylsulfonylpeur utenicin with terminal olefins (styrene, vinylpyridines, vinylpyrazine, vinyltriazole) was used to prepare (E)-7-[aryl(hetaryl)vinyl]coumarins. The dependence of reaction products yield on the nature of the catalytic system was found.

It was shown that plants of the genus Ferulopsis are valuable sources of coumarins. Nine angular 8-substituted and 8,9-disubstituted 8,9-dihydrofurocoumarins were isolated. The cytotoxicity of these compounds was studied on models of human CEM-13, MT-4, and U-937 tumor cells. X-ray structure data were obtained for peucenidin.

Chloro-containing compounds, the ratio of which depended on the reaction time, were formed via reaction of isoalantolactone and CHCl3 through the action of a phase-transfer catalyst. 4,15-(2,2-Dichlorocycloprop1-yl)isoalantolactone exhibited high activity and selectivity in the Heck reaction with arylhalides. Data for the cytotoxicity of the synthesized chloro-derivatives of isoalantolactone in CEM-13, MT-4, and U-937 cell tumor models were obtained. The doses of the most active compounds inhibiting the viability of tumor cells by 50 % (CCID50) were 3.2–11.1 1 M.

Allylic oxidation of phlomisoic acid and its methyl ester by selenium dioxide occurred stereoselectively to form 7α-hydroxy derivatives of labdanoids, which were oxidized by active manganese dioxide to 7-ketofuranolabdanoids. Oximation of the last by hydroxylamine hydrochloride in MeOH in the presence of NaOAc gave pure (E)-ketooximes. Beckmann rearrangement of 7-ketooximes of phlomisoic acid and its methyl ester occurred with formation of the corresponding octahydro-1 H-benzoazepines.

13-Aryl-substituted tourneforin derivatives were synthesized via the Heck reaction with aryliodides. The structure of (E)-13-(3,4-dimethoxybenzyl)-eudesma-4(5),11(13)-dien-6α,12-olide was confirmed by an XSA. A study of the cytotoxicity of the synthesized derivatives for CEM-13, MT-4, and U-937 tumor models showed promise for the modification.