15-Hydroxygermacranolides as Sources of Structural Diversity: Synthesis of Sesquiterpene Lactones by Cyclization and Rearrangement Reactions. Experimental and DFT Study.

A study on the electrophile-induced rearrangement of two 15-hydroxygermacranolides, salonitenolide and artemisiifolin, was carried out. These compounds underwent electrophilic intramolecular cyclizations or acid-mediated rearrangements to give sesquiterpene lactones with different skeletons such as eudesmanolides, guaianolides, amorphanolides, or other germacranolides. The cyclization that gives guaianolides can be considered a biomimetic route to this type of sesquiterpene lactones. The use of acetone as a solvent changes the reactivity of the two starting germacranolides to the acid catalysts, with a 4,15-diol acetonide being the main product obtained. The δ-amorphenolide obtained by intramolecular cyclization of this acetonide is a valuable intermediate for accessing the antimalarials artemisinin and its derivatives. Mechanistic proposals for the transformations are raised, and to provide support them, quantum chemical calculations [DFT B3LYP/6-31+G(d,p) level] were undertaken.

Acyloxylation of 1,4-Dioxanes and 1,4-Dithianes Catalyzed by a Copper-Iron Mixed Oxide.

The use of a copper-iron mixed oxide as a heterogeneous catalyst for the efficient synthesis of α-acyloxy-1,4-dioxanes and 1,4-dithianes employing t-butyl peroxyesters is reported. The preparation and characterization of the catalyst are described. The effect of the heteroatoms and a plausible mechanism are discussed. The method is operationally simple and involves low-cost starting materials affording products in good to excellent yields.

Acyloxylation of cyclic enones: synthesis of densely oxygenated guaianolides.

The α'-acyloxylation of cyclic enones with linear carboxylic acids is described. The reaction is promoted by KMnO4 in the presence of a carboxylic acid and its corresponding carboxylic anhydride. The optimization of the reaction has been carried out using the statistical methodology known as design of experiments. The optimized reaction conditions have been evaluated in terms of substrate scope and compatibility with different functional groups. The methodology has been applied to the synthesis of densely oxygenated guaianes and guaianolides.

A phenylpropanoid, a slovenolide, two sulphur-containing germacranes and Ca2+-ATPase inhibitors from Thapsia villosa.

A phenylpropanoid 1, a slovenolide 2, and two germacranes bearing a methylthiopropenoate moiety, 3 and 4, along with twenty known metabolites have been isolated from the roots of Thapsia villosa var. villosa L. The structures of two known phenylpropanoids 5 and 6 have been corrected. Compounds 7 and 8 showed activity as potential inhibitors of the sarco- and endoplasmic Ca(2+)-dependent ATPases (SERCA) pump. Compounds 9, 10 and 11 increased significantly the cytoplasmic free calcium concentration ([Ca(2+)](c)) in human platelets in a concentration-dependent manner.

A pyran-2-one and four meroterpenoids from Thapsia transtagana and their implication in the biosynthesis of transtaganolides.

Four meroterpenoids (3a, 3b, 4 and 5), a prenylated pyran-2-one (2) along with the known compounds 7-O-geranylscopoletin (1), and thapsitranstagin (6) have been isolated from the roots of Thapsia transtagana. The presence of 1 and 2 supports the biogenetic hypothesis that transtaganolides, a group of bioactive metabolites, are meroterpenoids which come from an O-prenylated coumarin via successive pericyclic reactions.

Toward the synthesis of thapsigargin: enantioselective synthesis of 7,11-dihydroxyguaianolides.

[reaction: see text] The enantioselective synthesis of a 7,11-dihydroxyguaianolide bearing the stereochemistry present in thapsigargin, a potent and selective inhibitor of the Ca(2+) SERCA-ATPase pumps, is described. Starting from (+)-dihydrocarvone, the synthesis presents two key steps. The first one involves the photochemical rearrangement of a gamma,delta-unsaturated ketone eudesmane into the corresponding guaiane. The second step consists of the regioselective oxidation of an unprotected tetrahydroxylated ketone to provide a dihydroxylactone with the required stereochemistry.

Phenylpropanoids from Thapsia transtagana.

Five phenylpropanoids have been isolated from the roots of Thapsia transtagana. Their structures have been elucidated by spectroscopic means.

TiCl4/Et3N-Mediated Condensation of Acetate and Formate Esters: Direct Access to ß-Alkoxy- and ß-Aryloxyacrylates.

A methodology to build (E)-ß-alkoxy- and (E)-ß-aryloxyacrylate moieties from acetate and formate esters promoted by the TiCl4/Et3N system is presented. The reaction is compatible with a broad range of structural skeletons and elapses through an unusual condensation pathway. Taking into account the obtained results, we propose a plausible mechanism involving a bimetallic titanium intermediate for this type of transformation.

Transtaganolides A-D: novel metabolites from Thapsia transtagana.

Four novel and unusual C-19 compounds from Thapsia transtagana, named transtaganolides A-D, have been isolated. Their structures were established by physical methods, including X-ray analysis of transtaganolides A and B. This is the first time that a 7-methoxy-4,5-dihydro-3H-oxepin-2-one ring has been found in a natural product. [structure: see text]

Allylic oxidation of alkenes catalyzed by a copper-aluminum mixed oxide.

A strategy for the allylic oxidation of cyclic alkenes with a copper-aluminum mixed oxide as catalyst is presented. The reaction involves the treatment of an alkene with a carboxylic acid employing tert-butyl hydroperoxide as the oxidant. In all cases, the corresponding allylic esters are obtained. When L-proline is employed, the allylic alcohol or ketone is obtained. The oxidation of cyclohexene and valencene has been optimized by design of experiments (DoE) statistical methodology.

Recent advances in the synthesis of sesquiterpenolides from Umbelliferae.

A review of our latest developments in the synthesis of sesquiterpenolides isolated from plants of the Umbelliferae family is presented.

Sesquiterpenes from Thapsia nitida var. meridionalis and Thapsia nitida var. nitida.

Nine new eudesmanolides (1-9), two new guaianolides (12 and 13), and a new germacrane (10), along with a previously reported guaianolide (11), have been isolated from the roots of Thapsia nitida var. meridionalis. Thapsia nitida var. nitida also afforded compound 13 along with a new guaianolide (14). The structure of 13 was confirmed by X-ray crystallographic analysis. Compounds 1, 2, and 11-14 have been tested as potential inhibitors of the sarco- and endoplasmic Ca2+-dependent ATPases (SERCA) pump. None of them showed significant activities.