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We have investigated the formation of various metal enolates of 1-O-silylated erythrulose 3,4-acetonides. We were able to prepare boron enolates using Brown's dicyclohexylboron chloride/tertiary amine system. When these enolates were allowed to react with a range of achiral aldehydes, highly stereoselective aldol additions took place with formation of the syn/syn stereoisomer. This has been attributed to the exclusive formation of a Z boron enolate, which is in a sharp contrast with the usual behaviour of the aforementioned reagent.

A potentially bio-mimetic Diels–Alder cyclization to construct the bicyclo[2.2.2] ring system common to the paraherquamides, marcfortines, sclerotamides, brevianamides, VM55599, and asperparaline is reported. Epi-deoxybrevianamide E (22) is converted into the corresponding lactim ether (23) and then oxidized with DDQ to provide an azadiene (24) which is tautomerized in the presence of base to azadiene 25 which, spontaneously cyclizes to give a 2:1 mixture of cycloadducts 26 and 27. These cycloadducts are each in turn, converted into d , l -C-19-epi-brevianamide A (20) and d , l -brevianamide B (6). The stereochemical implications of the [4+2] cycloaddition is discussed in the context of a working hypothesis on the biosynthesis of this family, particularly VM55599.

The reaction of the 3,4-O-isopropylidene- l -(S)-erythrulose with hydroxylamine, followed by treatment of the resulting mixture of (E)- and (Z)-oximes with acetone and an acid catalyst, afforded two crystalline chiral compounds. Through X-ray diffraction analysis, these products were identified as a double acetonide derived from the (E)-oxime and a cyclic nitrone derived from the (Z)-oxime. The additions of organolithium and organomagnesium reagents to the CN bond of the nitrone were found to be diastereoselective. The addition products are useful intermediates for the preparation of α,α-disubstituted α-aminoacids and other nitrogen-containing compounds in enantiopure form.

The aerial parts of Euphorbia terracina yielded 11 new jatrophane derivatives as well as a further diterpene displaying the novel 1(15 → 14) abeo -jatrophane framework.

The aerial parts of Artemisia inculta collected in three different locations in Egypt have been chemically investigated. As a result, a new eudesmanolide and a new tetranorsesquiterpene lactone have been isolated, together with several known compounds. The chemical data available suggest the existence of distinct chemotypes for this species, but do not support its identity with other North African members of the genus.

The latex of Euphorbia canariensis yielded, in addition to five known ingenol esters, the ingenane derivatives ingenol 3-angelate 5,20-diacetate and 5-deoxyingenol 3-angelate 20-acetate, and the lathyrane derivatives 2,3-diepiingol 7,12-diacetate 8-benzoate, 2,3-diepiingol 7,12-diacetate 8-isobutyrate and 2-epiingol 3,7,12-triacetate 8-benzoate. The structures were established with the aid of spectroscopic methods, mainly NMR, and molecular mechanics calculations. They were also supported by the results of some chemical transformations.

The aerial parts of Artemisia lucentica yielded, in addition to several known compounds, a bicyclic monoterpene ketone, two germacranolides, an eudesmanolide, a 10- epi neudesmanolide, a 2-norelemanolide and three bisabolene derivatives. The stereochemistry of a germacranolide, described as 2α-hydroxyartemorin in a previous investigation of the species, has now been corrected and the compound has been renamed lucentolide.

We have analysed the effects of 7,12-O-diacetyl-8-O-benzoil-2,3-diepiingol (DBI), an ingol derivative isolated from E. canariensis, on isometric tension developed by isolated rabbit basilar and carotid arteries. Concentration-response curves to DBI (10−8 - 3 × 10−5 m) were obtained cumulatively in both arteries at resting tension and active tone (KC1, 50 mm). At resting tension, DBI induced a concentration-dependent contraction, which was not inhibited in Ca2+-free medium. H7 (1-(5-isoquinoline sulphonyl)-2-methylpiperazine dichloride) (10−4 m) inhibited the DBI-induced contraction both in basilar and in carotid arteries. Calmidazolium (10−4 m) inhibited the maximum contraction of the carotid artery to DBI, and completely abolished the response in the basilar artery. In pre-contracted basilar arteries DBI induced a concentration-dependent relaxation that was not modified by incubation with NG-nitro-l-arginine (l-NOARG; 10−5 m) or indomethacin (10−5 m). In the carotid artery with active tone DBI induced further contractions, which were not significantly modified by l-NOARG (10−5 m) and were potentiated by indomethacin (10−5 m). These results suggest that DBI contracts rabbit basilar and carotid arteries by a mechanism that is independent of extracellular Ca2+ and involves the participation both of protein kinase C and of calmodulin. DBI relaxes basilar but not carotid arteries by a mechanism independent of the liberation of nitric oxide and prostacyclin. In the carotid artery prostacyclin but not nitric oxide partially counteracts the contractile action of DBI.

The aerial parts of Euphorbia terracina yielded five new bishomoditerpene lactones, named terracinolides C-G, which display the novel C 22 17-ethyljatrophane framework.

An ab initio study of the transition structures for the intramolecular Diels−Alder cycloaddition of the aza diene 6 to give brevianamides A, 1, and B, 2, has been carried out with analytical gradients at ab initio 3-21G and 6-31G* basis sets within Hartree−Fock procedures. The correlation effects have been estimated by using the perturbational approach at MP2 and MP3 levels. The geometry, electronic structure, and transition vector component are qualitatively model independent in this study. An analysis of the geometries and energies of the corresponding transition structures provides an explanation for the fact that brevianamide A, 1, is biosynthesized in larger quantities than brevianamide B, 2, while their respective epimers at C7 are not formed.

The addition of organolithium reagents to the CN bond of several erythrulose-derived chiral (E)- and (Z)-ketoxime ethers has been shown to be highly diastereoselective for the (E)-isomers. A chelated transition state has been proposed to explain this result. The addition products were converted into the two α,α-disubstituted α-aminoacids (R)-2-(−)-methylserine and (R)-(+)-2-phenylserine.

10.1016/j.tet.2013.02.062 A stereoselective synthesis of a C1¿C18 segment of the structure of the cytotoxic macrolides amphidinolides G and H is reported. The target compound was retrosynthetically disconnected into three fragments. In the synthetic sense, connection of the fragments was made by means of a Stille coupling and a Julia¿Kocienski olefination. Precursors from the chiral pool were used as the starting materials.

We here report the synthesis and biological evaluation of several combretastatin A-4 derivatives alkylated at the phenol hydroxyl group. Some of these derivatives contain an (E)-arylalkene fragment reminiscent of that present in some natural stilbenes like resveratrol. The cytotoxicities towards one human healthy kidney embryonic and two tumoral cell lines were determined. In addition, the ability of these compounds to inhibit the production of the vascular endothelial growth factor (VEGF) was measured. Finally, the expression of genes controlling the production of telomerase was measured. Some of the compounds were found to have an activity comparable or higher than that of combretastatin A-4 in at least one of the aforementioned biological properties. The compounds with the (E)-arylalkene fragment were in general terms more active than the simple O-alkyl derivatives. However, no clear structure/activity correlations were perceived when comparing the observed compound activities across the three biological properties. This points out the existence of marked differences between the mechanisms responsible for their cytotoxicity.

D- and l-Erythrulose derivatives 2–6 bearing protective O-silyl and O-benzyl groups in various positions were synthesized in enantiopure form from l-ascorbic acid, D-isoascorbic acid, and D-glucose.

The aerial parts of Artemisia chamaemelifolia ssp. chamaemelifolia yielded, in addition to known compounds, four acids with the silphiperfolane framework, a presilphiperfolane derivative, a bicyclic sesquiterpene formed therefrom by oxidative cleavage, a diacetylated monoterpene diol, a cadinane derivative, three acyclic sesquiterpenes and two tetrahydrofurane lignans.

A stereoselective synthesis of the C1-C12 fragment of the naturally occurring, cytotoxic macrolide FD-891, is described. The initial chirality was created via an asymmetric Evans aldol reaction. Two other asymmetric reactions, a Sharpless epoxidation and an aldehyde Brown allylation were further key steps of the synthesis.

A stereoselective synthesis of the C14–C26 fragment of the naturally occurring, cytotoxic macrolide FD-891, is described. Asymmetric Evans aldol reactions and aldehyde Brown allylations are key steps of the synthesis.

Acid-catalyzed cyclization of the natural germacranolide gallicin (8) yielded, among other products, the 1,4-epoxyeudes-manolide 9, which has a trans-fused decaline system. Under the same conditions the closely related germacranolide shonachalin A (8α-hydroxygallicin) (3) cyclized to the eudesmanolide 4 with a cis fused decaline system. The structures of these cyclization products were secured by means of chemical correlations and X-ray diffraction analyses.

The total synthesis of the title compounds in optically active form from geraniol as the starting material is described. The physical and spectral properties of the synthetic amide are identical with those of the natural compound acacialactam, this fact confirming that the structure proposed for the latter compound is not correct. The configuration of the single stereogenic carbon atom in the natural amide is shown to be S .

We here report the synthesis of several stilbene derivatives. They show a measurable inhibitory effect on angiogenesis, some of them to a higher degree than resveratrol. Test methods included cell proliferation and tube formation assays using bovine aorta endothelial cells. In addition, it has been confirmed through the reverse transcriptase/polymerase chain reaction experiment that these stilbene derivatives downregulate the expression of the gene related to the production of the angiogenesis factor VEGF in cancer cells.

The aerial parts of five Cheirolophus species yielded three new guaianolides, a new lignan and three new aromatic esters, together with other known compounds of the same type.

The aerial parts of Artemisia reptans yielded a new thiophene acetylene, four new guaianolides, a new acyclic sesquiterpene related to davanone and several known compounds.

The aerial parts of two Andryala species yielded several guaianolides and guaianolide glycosides, three of them being new. The aerial parts of Urospermum dalechampii yielded several known germacranolides and the new dihydroflavonol 3- O -methyltaxifolin.

The aerial parts of Artemisia hugueti and A. ifranensis yielded several known compounds and 15 new ones, among these were 13 eudesmanolides, a 1,10-secoeudesmanolide, and a dialcohol with a menthane framework. The stereochemistry of a previously described epimer of the eudesmanolide artemin has been corrected.

The first total synthesis of the naturally occurring nonenolide, microcarpalide, is described. The key step in the synthesis was the ring-closing metathesis of a dienic ester prepared in turn by coupling an acid and an alcohol stereoselectively synthesized from (S,S)-tartaric acid and (R)-glycidol, respectively. [structure: see text]

Stereoselective syntheses of five naturally occurring, pharmacologically active medium and large ring lactones are described. Key synthetic methods used were, depending on the cases, olefin metatheses, asymmetric allylations and C-glycosidations.

The first syntheses of the polyhydroxylated alkaloids (iminosugars) broussonetines D and M glycosidase inhibitors of the pyrrolidine class, have been performed in a convergent, stereocontrolled way from D-serine as the chiral starting material. A cross metathesis step was one key feature of the synthesis. The versatility of the synthetic concept chosen permits the access to many members of this compound family, both natural ones and analogues thereof

Three new xanthanolides have been isolated from Xanthium spinosum and X. strumarium subsp. italicum , together with other known compounds. The absolute configurations of xanthanol, isoxanthanol and their C-4 epimers have been established.

The aerial parts of Artemisia turcomanica and A. deserti yielded two new germacranolides, a new guaianolide, and several known mono- and sesquiterpenes.

The aerial parts of Artemisia sieberi yielded three new oplopanone derivatives, three new monoterpene glycosides, a new germacrane alcohol and a monoterpene acid related to nerolidol.

The diastereoselectivity of the addition of several organometallic reagents to the carbonyl group of the title compounds has been investigated. Some organomagnesium reagents display high diastereoselectivities (90–99%) and the major products are those predicted by the α-chelation model.

The aerial parts of Imula crithmoides yielded a known bisnorlabdane and six thymol derivatives, five of which were new. Two of these are the first chlorinated thymol derivatives reported in natural sources.

The aerial parts of three species of the genus Cousinia have been investigated. All three species yielded sesquiterpene lactones, mainly guaianolides. In addition, one of the species yielded oxygenated bisabolene derivatives.

Boron aldol additions of 1- O -silylated 3,4-di- O -benzyl- and 3,4-di- O -benzoyl- l -erythrulose and achiral aldehydes using dicyclohexylboron chloride have been investigated. The dibenzyl derivative gave syn/syn stereoisomers with high stereoselectivity, whereas the dibenzoyl derivative gave syn/anti stereoisomers. It is believed that, while the dibenzoyl erythrulose gives rise to the E enolate in the presence of dicyclohexylboron chloride, as usually observed with this reagent, only the Z enolate is formed in the case of the dibenzyl derivative.

We have investigated a number of nucleophilic additions of allylating reagents to several α,α′,β-trioxygenated ketones ( O -protected erythrulose derivatives). Reagents based on lithium, magnesium, copper and titanium gave low to medium stereoselectivities and did not display any recognizable trend in the sense of stereoselection. In contrast, reactions involving silicon and tin derivatives were highly stereoselective and gave rise to essentially a single diastereoisomer, the structure of which depended on the type of protecting group. Thus, α,β-di- O -benzylated derivatives experienced almost exclusive addition to the carbonyl Si side, whereas α,β- O , O -alkylidene derivatives (dioxolane acetals) yielded the opposite diastereoisomers as a result of addition to the Re side. These results suggest the intermediacy of α-chelates in the additions of silicon and tin reagents to the di- O -benzylated derivatives. In contrast, the opposite stereoisomers, formed in the reactions of dioxolanes, are believed to be formed through Felkin–Anh transition states, pointing again to the reluctance of acetal oxygens to participate in chelated intermediates.

The stereoselective synthesis of the naturally occurring lactones osmundalactone (−)-1 and muricatacin (−)-2 is described. The key steps in each synthesis are the stereoselective addition of a Grignard reagent to a suitably protected α-hydroxy aldehyde and a ring-closing metathesis. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Total, stereoselective syntheses of the naturally occurring, cytotoxic macrolides aspergillide A and B are described. Olefin metatheses and asymmetric allylations were key steps in the synthetic sequences. Cytotoxicity assays against several tumor cell lines have been performed for the two aspergillides and some of the intermediates or side products of the synthetic sequence. One of these intermediates has been found markedly active against the human leukemia cancer cell line HL-60, with an IC(50) value comparable with that of the clinical drug fludarabine.

A stereoselective synthesis of the cytotoxic 14-membered macrolide aspergillide A has been performed. The preparation of a cis-2,6-disubstituted tetrahydropyran ring via stereoselective reduction of an intermediate cyclic hemiacetal was one key feature of the synthesis. The macrocyclic lactone ring was created by means of a ring-closing metathesis (RCM), whereby the new C=C bond displayed exclusively the undesired Z configuration. Conversion to the required E configuration was achieved via photochemical isomerization.

The diastereoselectivity of the addition of several organometallic reagents to the carbonyl group of protected D - and L -erythrulose derivatives has been investigated. Tertiary alcohols are stereoselectively formed, the diastereomeric ratio being markedly dependent on the reagent type, solvent and temperature.

The aerial parts of Centaurea calcitrapa yielded cnicin, cnicin 4′-acetate, melitensin, a related elemanolide, the two new germacranolides 11α,13- and 11β,13-dihydrosalonitenolide, and the lignans arctigenin, pinoresinol and 7′( S )-hydroxyarctigenin. The latter compound is described for the first time as a natural product. The aerial parts of Centaurea pabotii yielded 11,13-dihydrodeacylcynaropicrin, aguerin A and a new guaianolide related to cynaropicrin.

Reaction of 1,1,1-trifluoropropanone (trifluoroacetone) ( 1a ) with 30% hydrogen peroxide in the presence of conc. sulfuric acid afforded in good yield 3,6-bis(trifluoromethyl)-3,6-dimethyl-1,2,4,5-tetroxane or trifluoroacetone diperoxide ( 2a ). Peroxide 2a is quantitatively converted into trifluoroacetone ( 1a ) and dioxygen by a catalytic amount of tetrabutylammonium iodide through a reductive electron transfer chain reaction carried out by the superoxide ion. Trifluoroacetone diperoxide ( 2a ) is capable of O-atom transfer to alkenes and sulfides.

The 13C NMR spectral data of 18 eudesmane derivatives, mainly acids and esters of natural and synthetic origin, are reported, and the γ-effect of the epoxide ring in two diastereoisomeric epoxy esters is discussed.

A reinvestigation of the aerial parts of Pulicaria dysenterica has allowed the isolation of six new caryophyllene derivatives and 12 known ones. 13 C NMR data of all these derivatives are reported.

The first total stereodirected synthesis of the monoterpenes (−)-mintlactone and (+)-isomintlactone from the same chiral starting product is described. A stereoselective, radical-mediated ring closure was the key step in both syntheses.

A very short and stereoselective synthesis of the non-natural enantiomer of malyngolide from l -erythrulose is described. Key features of the synthesis are the Felkin–Anh diastereoselective allylation of a polyoxygenated ketone and the allylation/metathesis/allylic oxidation protocol recently described by our group.

A short, stereoselective synthesis of the naturally occurring pyrrolidine radicamine B is reported. Garner′s (R)-aldehyde, prepared from d-serine, was the chiral starting material. The pyrrolidine ring was stereoselectively created in a very efficient way through a five-step, one-pot transformation. In addition, an intermediate of this synthesis was transformed into an intermediate of a previously published synthesis of the potent α-glucosidase inhibitor nectrisine.