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An asymmetric domino Friedel–Crafts/lactonization sequence between phenols and trifluoropyruvate has been accomplished for the first enantioselective synthesis of ( S )-BHFF, a positive allosteric modulator (PAM) of GABA B receptor. The developed protocol leads to 3-OH-benzofuranone derivatives bearing a quaternary stereogenic center, and gives a valuable access to bioactive compounds with promising pharmaceutical applications.

International audience; An asymmetric domino Friedel–Crafts/lactonization sequence between phenols and trifluoropyruvatehas been accomplished for the first enantioselective synthesis of (S)-BHFF, a positive allosteric modulator(PAM) of GABAB receptor. The developed protocol leads to 3-OH-benzofuranone derivatives bearing aquaternary stereogenic center, and gives a valuable access to bioactive compounds with promising pharmaceuticalapplications

A valuable Lewis-acid-catalysed domino reaction involving a Friedel–Crafts alkylation of variously substituted phenols followed by a direct lactonization has been successfully developed (22 examples, yields up to 98 %). This protocol tolerates not only opposite electron demand substituents on the starting materials, but also drastic modifications of the alkylating agents, and gives direct access to the corresponding 3-hydroxy-benzofuran-2-ones, which could easily undergo further chemical transformation. The relevance of our method was further confirmed by the straightforward synthesis of rac-BHFF, the recently discovered and extremely promising positive allosteric modulator of the GABAB receptor.

A large series of hydroxytyrosyl esters of C2-C18 fatty acids with increasing lipophilicity was prepared by a new highly efficient method based on acylation of methylorthoformate-protected hydroxytyrosol. All products were tested for the relative antioxidant effect using ABTS assays in ethanolic medium and DCF assays in L6 cells. No linear correlation between lipophilicity and antioxidant effect was found. ABTS assays showed a growing antioxidant capacity, with respect to hydroxytyrosol, only for medium-sized ester chains (C4-C10), and a nearly constant capacity for the higher homologues. This has been rationalized by molecular dynamics experiments in terms of partial shielding of the catecholic hydroxyls by long chained esters. A similar and dose-dependent pattern was observed in DCF assays in L6 cells, but a sharp antioxidant activity drop resulted for long chain esters, probably due to membrane entrapment.

The reactions of (2-trimethylsilanylmethyl) alpha,beta-unsaturated carboxylic ethyl esters with NsONHCO(2)Et and CaO produce, after treatment with AcOH, alpha-methylene N-(ethoxycarbonyl) beta-amino carboxylic esters through ring opening and elimination of the trimethylsilyl group from the intermediate aziridine. By ozonization and subsequent reductive cleavage these products give the corresponding N-(ethoxycarbonyl) beta-amino alpha-hydroxy esters.

The lithium salts of 4-methoxy-derivatives of pyrimidinic bases undergo chemoselective N1-methylation or ethylation when treated with the appropriate alkylsulphate in dry dioxane. Under the same conditions, 4-unprotected pyrimidinic bases afford mixtures of N1-, O2- and N1,N3-alkylation products. This is explained in terms of HSAB principle.

An interpretation is given of a number of observations on the chemiotropic behavior ofBactrocera oleae in connection with olive maceration water and the fly's return to the olive groves after the first summer rains. To this end, the headspace of both maceration water and leaf leaching water, simulating rainfall, were examined. In both cases, the presence of ammonia, which is generally known to attract fruit flies (Diptera, Tephritidae), was detected and, for the first time, in addition to other compounds that are inert for the fly, the presence of styrene was also detected. This aromatic hydrocarbon was found to be a strong attractant. It is shown that both ammonia and styrene are products of the metabolism of microbial flora present on the olive and leaf surface.

""A large panel of novel catecholic antioxidants and their fatty acid or methyl carbonate esters has been synthesized in satisfactory to good yields through a 2-iodoxybenzoic acid (IBX)-mediated aromatic hydroxylation as the key step. The new catechols are structural analogues of naturally occurring hydroxytyrosol (3,4-DHE). To evaluate structure\\\/activity relationships, the antioxidant properties of all catecholic compounds were evaluated in vitro by ABTS assay and on whole cells by DCF fluorometric assay and compared with that of the corresponding already known hydroxytyrosyl derivatives. Results outline that all of the new catechols show antioxidant capacity in vitro higher than that of the corresponding hydroxytyrosyl derivatives. Less evident positive effects have been detected in whole cells experiments. Cytotoxicity experiments, using MTT assay, on a representative set of compounds evidenced no influence in cell survival. ""

The title reaction affords enantioenriched spiro compounds (II) and (III) with two contiguous stereocenters.

"""""""A novel asymmetric nucleophilic epoxidation for R-ylideneoxindole esters has been successfully devised, resulting in enantioenriched spiro compounds with two new contiguous stereocenters. The employed (S)-R,R-diphenylprolinol functions as a bifunctional catalyst, creating a complex H-bond network in conjunction with a substrate and an oxidant"""""""

The M1 strain, able to grow on β-myrcene as the sole carbon and energy source, was isolated by an enrichment culture and identified as a Pseudomonas sp. One β-myrcene-negative mutant, called N22, obtained by transposon mutagenesis, accumulated ( E )-2-methyl-6-methylen-2,7-octadien-1-ol (or myrcen-8-ol) as a unique β-myrcene biotransformation product. This compound was identified by gas chromatography-mass spectrometry. We cloned and sequenced the DNA regions flanking the transposon and used these fragments to identify the M1 genomic library clones containing the wild-type copy of the interrupted gene. One of the selected cosmids, containing a 22-kb genomic insert, was able to complement the N22 mutant for growth on β-myrcene. A 5,370-bp-long sequence spanning the region interrupted by the transposon in the mutant was determined. We identified four open reading frames, named myrA , myrB , myrC , and myrD , which can potentially code for an aldehyde dehydrogenase, an alcohol dehydrogenase, an acyl-coenzyme A (CoA) synthetase, and an enoyl-CoA hydratase, respectively. myrA , myrB , and myrC are likely organized in an operon, since they are separated by only 19 and 36 nucleotides (nt), respectively, and no promoter-like sequences have been found in these regions. The myrD gene starts 224 nt upstream of myrA and is divergently transcribed. The myrB sequence was found to be completely identical to the one flanking the transposon in the mutant. Therefore, we could ascertain that the transposon had been inserted inside the myrB gene, in complete agreement with the accumulation of ( E )-2-methyl-6-methylen-2,7-octadien-1-ol by the mutant. Based on sequence and biotransformation data, we propose a pathway for β-myrcene catabolism in Pseudomonas sp. strain M1.

Substituted cis -1-formyl (or acetyl) bicyclo[3.3.0]octanes are stereospecifically obtained in high yield by a base-catalyzed rearrangement of readily accessible substituted 1-chloro-9-hydrony (or acetoxy) bicyclo[3.3.1] nonanes.

The title compound is the only product in the intramolecular aldol condensation of dione 3 , obtained in turn from the bicyclo[3.3.1]nonanic hydroxyketal 5 . This behaviour is at variance with force field calculations.

Coprostane steroids are selectively oxyfunctionalized at C 5 by dimethyldioxirane and methyltrifluoromethyldioxirane to give useful intermediates for bioactive compounds.

The reactions of (2-trimethylsilanylmethyl) α,β-unsaturated carboxylic ethyl esters with NsONHCO 2 Et and CaO produce, after treatment with AcOH, α-methylene N -(ethoxycarbonyl) β-amino carboxylic esters through ring opening and elimination of the trimethylsilyl group from the intermediate aziridine. By ozonization and subsequent reductive cleavage these products give the corresponding N -(ethoxycarbonyl) β-amino α-hydroxy esters.

Substituted cis -1-formyl (or acetyl) bicyclo[3.3.0]octanes are stereospecifically obtained in high yield by a base-catalyzed rearrangement of readily accessible substituted 1-chloro-9-hydrony (or acetoxy) bicyclo[3.3.1] nonanes.

New potentially bioactive α-spiroaziridino-γ- and -δ-lactams have been prepared by treatment of α-methylene-γ- and -δ-lactams with ethyl N-{[(4-nitrophenyl)sulfonyl]oxy}carbamate (NsONHCO2Et) in the presence of CaO. These compounds, through reductive aziridine ring opening, can be intermediates for the synthesis of α- and β-aminolactams, which are useful as conformational constraints in peptides. The above procedure has been successfully extended to one α-methyleneoxindole to obtain a new spirooxindole derivative, a potential precursor of natural alkaloids. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Oxiranyl ring opening of trans-stilbene oxide gave rise to anti- or syn-2-bromo-1,2-diphenylethanols, using either MgBr(2).Et(2)O or MgBr(2).Et(2)O, NaBr, and KBr with Amberlyst 15, respectively. Starting from optically pure (R,R)-trans-stilbene oxide, (1R,2R)- and (1R,2S)-2-amino-1,2-diphenylethanols were obtained in high yield and ee.

A valuable Lewis-acid-catalysed domino reaction involving a Friedel–Crafts alkylation of variously substituted phenols followed by a direct lactonization has been successfully developed (22 examples, yields up to 98 %). This protocol tolerates not only opposite electron demand substituents on the starting materials, but also drastic modifications of the alkylating agents, and gives direct access to the corresponding 3-hydroxy-benzofuran-2-ones, which could easily undergo further chemical transformation. The relevance of our method was further confirmed by the straightforward synthesis of rac-BHFF, the recently discovered and extremely promising positive allosteric modulator of the GABAB receptor.

The title compound is the only product in the intramolecular aldol condensation of dione 3 , obtained in turn from the bicyclo[3.3.1]nonanic hydroxyketal 5 . This behaviour is at variance with force field calculations.

Chiral epoxide (+) 2 has been synthesized in very good yield and high enantiomeric excess via a modified Solladie procedure starting from commercially available orotic acid. Chiral HPLC chromatographic analysis and 300 MHz 1H-NMR with the addition of chiral shift reagent Eu(hfc)3 of compound (+) 2 are also reported.

Coprostane steroids are selectively oxyfunctionalized at C 5 by dimethyldioxirane and methyltrifluoromethyldioxirane to give useful intermediates for bioactive compounds.

An unusual condensation of pyrimidinones (2), (3), and (12) in the presence of lithiated furan derivatives or LiHMDS leads to the formation of 7, 8 and 13. In the case of the self condensation of 3, a novel acyloin reaction is invoked to explain the formation of product (8) where the substrate acts as the catalyst in the reaction.

6-Alkyl- and 5,6-dialkyl-2-methoxy-4(3H)-pyrimidinones are transformed into the 2-alkyl(and 2-aryl)amino-derivatives, in good yield, by reaction with the corresponding amines. Treatment with SOCl2 -DMF gives 6-alkyl- and 5,6-dialkyl-2-methoxy-4-chloro pyrimidines.

Treatment of endo-2 or exo-2-hydroxy-1-substituted ketals 1a–d with p-toluensulfonic acid in dry benzene results in a reversible C9 bridge cleavage and affords equilibrium mixtures where 2-substituted-6-(1,3-dioxolan-2-yl)cyclooctanones 6a–d are present as main products. Yields in 6a–d are present as the steric hindrance of the substituents at C1 in the substrate increases as well. Deuterium exchange experiments are in favour of an intramolecular 1,3-hydride shift from C2 to C9.

The total synthesis of (±) pinguisone 1, the sterically crowded unusual [5-6] fused-ring sesquiterpene, was accomplished by synthetic elaboration of the 3β,3aβ,7,7aβ-tetramethylbicyclo [4.3.0] non-6-en-1-one 2a prepared by acid catalyzed rearrangement of the easily accessible 1,4β,5,9-tetramethylbicyclo [3.3.1] nonan-9-hydroxy-2-one 3 . This rearrangement constitutes an example of the scarcely observed 1,2 shift of a carbonyl group toward an electron deficient centre.

A new useful synthetic route, to A-nortestosterone via Δ 3(5) A-norsteroids is described.

Phenylselenenyl chloride addition to the 3-exomethylene-1-cepham 1 gave mainly the seleno derivative 2 at room temperature while the dichloro derivative 3 was obtained in refluxing 1,2-dichloroethane. Compounds 2 and 3 transformed into the Δ2 and Δ3 chloromethyl isomer respectively.

All the main fragmentation pathways undergone by trans-4- and trans-2-p-substituted phenylcyclohexanols have been studied, and the ionic abundances have been correlated with the σ constants. This analysis shows that electron withdrawing substituents, increasing the fraction of molecular ions having sufficient energy to decompose, favour all fragmentations. However, along with this ‘non-specific’ substituent effect, there is a ‘specific’ effect, in the opposite sense, increasing the formation of the [M—59]+ and [M—85]+ ions with increasing electron releasing power of the substituents. The loss of water, although it is almost exclusively a 1,4 elimination in the case of trans phenyl cyclohexanols, is not specifically influenced by the substituents.

The methyl 3-methylene-7-phthalimidocepham-4-carnoxylate 3, the corresponding (R)-oxide 2 and the 1,1-dioxide 1 add bromine affording stereoisomeric mixtures of dibromoderivatives. These results are at variance with previous reports regarding 3-exomethylene sulfides and sulfoxides. The stereochemistry of the dibromoderivatives was unambiguously determined via X ray crystallography of 5a, following 1H-NMR correlations. The single dibromo derivatives as well as the isomeric mixtures, can be dehydrobrominated to afford 3-bromomethyl cephem derivatives (7,8,9) in very good yields.

Substituted 2-dichloromethyl-2H-pyrroles, when treated with strong bases under appropriate conditions, undergo ring enlargement giving substituted 3-chloropyridines. The data collected on different substrates and reagents indicate the carbenoid nature of intermediate.

The total synthesis of (±) pinguisone 1, the sterically crowded unusual [5-6] fused-ring sesquiterpene, was accomplished by synthetic elaboration of the 3β,3aβ,7,7aβ-tetramethylbicyclo [4.3.0] non-6-en-1-one 2a prepared by acid catalyzed rearrangement of the easily accessible 1,4β,5,9-tetramethylbicyclo [3.3.1] nonan-9-hydroxy-2-one 3 . This rearrangement constitutes an example of the scarcely observed 1,2 shift of a carbonyl group toward an electron deficient centre.

Dehydrations of the anti -ketol 5 and its isomer 10 have been studied. In both cases the 1-hydrindenones 6 and 7 have been almost quantitatively obtained (1:1 ratio) through skeletal rearrangement of the kinetically favoured 9-methylene bicyclononane 9 . This strongly supports the hypothesis of a stepwise rearrangement driven by the relative stabilities of the involved carbonium ions.

Reduction de quelques N-aryl et N-alkyl cetimines en les amines secondaires correspondantes