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The hydroazulene core of the bioactive sesquiterpenoid (-)-dehydrocostus lactone was generated by domino enediyne metathesis. A triple hydroboration/oxidation of the resultant conjugated triene installed three out of four stereogenic centers of the target in a single step. The enantiopure acyclic metathesis substrate was readily available by an asymmetric anti aldol reaction. Masking of the γ-lactone as an acetal allowed for an efficient completion of the synthesis through late-stage double carbonyl olefination.

(−)-Isoguaiene was prepared from (S)-citronellal in only 9–10 steps with good overall yields. Either a trienyne or a dienediyne metathesis and highly diastereoselective organocatalytic Michael additions of aldehydes derived from (S)-citronellal served as the key transformations.

1-Arylazo-substituted 2-naphthylamines, which are easily obtainable by the coupling of arene diazonium salts with 2-aminonaphthalene-sulfonic acid, can be transformed by reaction with reactive carboxylic acid derivatives or nitrosation reagents into novel 2-aryl-substituted naphtho[2,1-e][1,2,4]triazinium and naphtho[2,1-e][1,2,3,4]tetrazinium salts, respectively.

A concise and highly enantioselective synthesis of structurally diverse isoflavans from a single chromone is described. The key transformation is a single-step conversion of racemic isoflavanones into virtually enantiopure isoflavans by domino asymmetric transfer hydrogenation/deoxygenation with dynamic kinetic resolution.

Desymmetrization of a p-quinone monoacetal by organocatalytic sulfa-Michael addition provided rapid access to a C-ring building block for a formal synthesis of (-)-codeine. By means of a diastereoselective 1,2-addition for A/C-ring union, an intramolecular nitrone cycloaddition for construction of the phenanthrene core, and a sulfoxide elimination, an enantiopure key intermediate of the authors' previous synthesis of racemic codeine was available in 12 steps from isovanillin.

The first total synthesis of the title diterpene was accomplished starting from the Wieland-Miescher ketone. A diastereoselective sulfa-Michael addition enabled the generation of the delicate β,γ-unsaturated ketone moiety, while the tetracyclic kempane skeleton was readily constructed through domino metathesis.

Some novel chromene and pyrano[2,3-c]pyrazole derivatives could be achieved successfully by reacting cyclic β-diketones with 2-acetylfuran/2-acetylthiophene and malononitrile in a one-pot synthesis. Active methylene pyrazolones reacted with 2-(1-furan-2-yl-ethylidene)-malononitrile and 2-(1-thiophen-2-yl-ethylidene)-malononitrile derivatives to afford the desired pyrano[2,3-c]pyrazole derivatives. Structures of all new compounds were established based on analytical and spectral data as well as X-ray crystallography. A plausible mechanism for the reaction is suggested. The solvents and catalyst used are environmentally benign, and no hazardous solvents or heavy metals were involved.

A concise and highly enantioselective synthesis of the natural flavans kazinol U and (2S)-7,3'-dihydroxy-4'-methoxyflavan is reported for the first time. The key transformation is a single-step conversion of a racemic flavanone to a flavan by means of an asymmetric transfer hydrogenation/deoxygenation cascade with kinetic resolution.

Pyrazoles, thiazoles and fused thiazoles have been reported to possess many biological activities. 3-Methyl-5-oxo-4-(2-arylhydrazono)-4,5-dihydro-1H-pyrazole-1-carbothioamides3a,b(obtained from the reaction of ethyl 3-oxo-2-(2-arylhydrazono)butanoates1a,bwith thiosemicarbazide) could be transformed into a variety of thiazolyl-pyrazole derivatives6a–h,10a–c,15a–c,17,19and21via their reaction with a diversity hydrazonoyl chlorides as well as bromoacetyl derivatives. Moreover, the computational studies were carried out for all new compounds. The results indicated that five compounds showed promising binding affinities(10a: − 3.4 kcal/mol,6d: − 3.0 kcal/mol,15a: − 2.2 kcal/mol,3a: − 1.6 kcal/mol, and21: − 1.3 kcal/mol) against the active site of the epidermal growth factor receptor kinase (EGFR). The cytotoxicity of the potent products3a,6d,10a,15a, and21was examined against human liver carcinoma cell line (HepG-2) and revealed activities close to Doxorubicin standard drug. There was an understanding between the benefits of restricting affinities and the data obtained from the practical anticancer screening of the tested compounds.

Grinding a mixture of 6-aminopyrimidine-2,4(1H,3H)-dione 1a or 6-amino-2-thioxo-2,3-dihydropyrimidine-4(1H)-one 1 b or ethyl 7-amino-5-oxo-1-aryl-1,5-dihydro[1,2,4]-triazolo[4,3-a]pyrimidine-3-carboxylate derivatives 5a–c with 1,2-diphenylethanone 2 and aromatic aldehydes 3a–j in the presence of aluminate sulfonic acid nanoparticles (ASA NPs) in a one pot solvent-free conditions, afforded the pyrido[2,3-d]pyrimidinone derivatives 4a–o and ethyl 5-oxo-1-aryl-6,7,8-triphenyl-1,5,6,9-tetrahydropyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-3-carboxylate derivatives 6a–c, respectively. High yields, short reaction time, easy workup, inexpensive, and reusability of the catalyst are advantages of this method. All structures were elucidated by spectral and elemental analyses. Structures of 6a–c were further proved by alternative synthesis of 6a.

The synthesis of (+)-orientalol F (1) started with aldehyde 6, which is available from (R)-limonene in two steps. Wittig reaction of 6 with unsaturated ylide 7 to give a tetraene, and subsequent ring-closing metathesis yielded hydroazulene 4, selective epoxidation of which gave epoxy ester 3. After generation of the requisite isopropyl unit and regioselective reductive epoxide opening, the derived dienol 2 was used for the installation of the oxygen bridge through intramolecular oxymercuration followed by oxidative demercuration. The resulting allylic alcohol epimers 15 and 16 were readily converted into the target natural product 1 by oxidation/reduction sequences.

Treatment of 2,4-diphenylbutadiene-1,4-sultone with hydrazine in boiling EtOH gives 1-amino- 2,4-diphenyl-1H-pyrrole. On treatment of 2,4-diphenylbutadiene-1,4 -sultone with phenyl hydrazine in glacial acetic acid, 4,5-dihydro-5-met hyl-1,3,5-triphenyl-1H-pyrazole was isolated. On the other hand, 2,4-diphenylbutadiene-1,4-sulton e reacts with 4 H-1,2,4-triazol-3-amine and 5-amino-3-phenyl-1H-pyrazole to afford the novel heterocyclic compounds 2-(2,2-dioxo-4- phenyl-3,4-dihydro-8H-2λ 6 -(1,2,4)triazolo(5,1- c)(1,2,4)thiadiazin-4-yl)-1-phenylethan-1-one, the structure of which was established by X-ray crystal lography, and 2-(2,2-dioxo-4,7-diphenyl-3,4- dihydro-6H-pyrazolo(5,1-c)(1,2,4)thiadiazin-4-yl)-1-phenylethan-1-one.

Heterocyclic 2-aminoazo compounds, prepared by ortho-coupling of primary heterocyclic amines with (het)arene diazonium salts, can by transformed by reaction with strong acylating reagents or nitrosyl sulfonic acid into new hetarene-condensed 2-(het)aryl-1,2,4-triazinium and 2-(het)aryl-1,2,3,4-tetrazinium salts, respectively. Their structures could be unambiguously elucidated by means of IR, mass, and NMR spectroscopy as well as, in few special examples, by means of X-ray analysis.

A concise total synthesis of the neoclerodane diterpene salvinorin A from 3-furaldehyde is reported using two highly diastereoselective intramolecular Diels-Alder reactions (IMDA) as the key transformations.

Pamamycins are macrodiolides of polyketide origin with antibacterial activities. Their biosynthesis has been proposed to utilize succinate as a building block. However, the mechanism of succinate incorporation into a polyketide was unclear. Here, we report identification of a pamamycin biosynthesis gene cluster by aligning genomes of two pamamycin-producing strains. This unique cluster contains polyketide synthase (PKS) genes encoding seven discrete ketosynthase (KS) enzymes and one acyl-carrier protein (ACP)-encoding gene. A cosmid containing the entire set of genes required for pamamycin biosynthesis was successfully expressed in a heterologous host. Genetic and biochemical studies allowed complete delineation of pamamycin biosynthesis. The pathway proceeds through 3-oxoadipyl-CoA, a key intermediate in the primary metabolism of the degradation of aromatic compounds. 3-Oxoadipyl-CoA could be used as an extender unit in polyketide assembly to facilitate the incorporation of succinate.

Background: Thiazoles and pyridines are versatile synthetic scaffolds possessing wide spectrum of biological effects including potential antimicrobial activity. Objective: In the efforts to develop suitable antimicrobia drugs, medicinal chemists have focused on thiazole derivatives. A novel series of 2-thiazolyl pyridines was prepared in a one-pot three-component reaction using 2-bromoacetyl pyridine as a starting precursor. Method: Structure of the synthesized compounds was elucidated by spectral data (FT-IR, 1H NMR, 13C NMR, and mass) and elemental analyses. The prepared compounds were screened for their in vitro antimicrobial activity. Results: The results revealed that compounds 4a,b,e-g and 12 showed promising activity. Molecular docking studies using MOE software were carried out for compounds 4a and 4b which exhibited potent activities indicated by the diameter zones (4a; 3.6, 4.0, 1.2 mm) (4b; 4.2, 3.5, 1.5 mm) and the binding affinities (4a; -5.7731, -5.3576, -4.6844 kcal mol-1) (4b; -5.9356, -2.8250, -5.3628 kcal mol-1) against Candida albicans, Bacillus subtilis and Escherichia coli, respectively. Conclusion: This paper describes a facile and efficient MCR for synthesis of 2-thiazolyl pyridines from reaction of 2-bromoacetyl pyridine with different reagents. There was an agreement between the values of binding affinities and interactions and the data obtained from the practical antimicrobial screening of the tested compounds.

Cyclopentanone reacts with malononitrile catalyzed by piperidine or sodium acetate to afford under any case cyclopentylidenemalononitrile dimer: 5-aminospiro-[2,6,7,7a-tetrahydroindene-7,1′-cyclopentane]-4,6,6-tricarbonitrile (7) as the sole product. Contrary to this behavior, cyclohexanone reacts with malononitrile catalyzed by piperidine to afford the analogous cyclohexylidenemalononitrile dimer: 2-aminospiro-[3,4,5,6,7,4a-hexahydronaphthalene-4,1′-cyclohexane]-1,3,3-tricarbonitrile (11); whereas when the reaction is catalyzed by sodium acetate, it afforded 9,10-diaza-8,11-dioxo-tricyclo-[4.3.3.01,6]-dodecane-7,12-dicarbonitrile (12). The structures of these products were established on the basis of their elemental analysis and spectral data, and plausible mechanism has been postulated to account for their formation. X-ray crystallography was carried out as a further evidence for structures 7 and 12.

A highly regioselective synthetic method based on the domino Diels–Alder/retro-Diels–Alder reaction (DA/RDA) of 1,3-dienic δ-sultones with alkynes provides substituted m -terphenyls by elimination of SO 3 . A variety of δ-sultones and alkynes were examined to determine the scope of the reaction. The de novo synthesized aromatic products were obtained using thermal, microwave, and high-pressure activation.

The title compounds were obtained from the reactions of 3-oxo-3,N-diphenylpropionamide 3 with dimethylformamide dimethylacetal followed by hydrazine to afford the pyrazole 7, condensation with benzaldehyde followed by cyclocondensation with guanidine to afford the pyrimidine derivative 13, condensation with active methylenes followed by azo coupling of the products followed by cyclization to afford the pyridazines 17a, 17b. The pyridazinone 17b was explored for the synthesis of some novel pyridazine-fused heterocyclic compounds 19, 21, 24a, 24b, 24c, and 26. All structures were proved via their elemental analyses and spectral data.

N-(4-(Pyrazol-4-yl)thiazol-2-yl)-N′-phenylthiourea derivative 2 was synthesized and then treated with variety of hydrazonoyl chlorides under basic condition at reflux to afford the corresponding 2-(4-(pyrazol-4-yl)thiazol-2-ylimino)-1,3,4-thiadiazole derivatives 6, 10a–e and 17a–e. Reaction of 2 with ethyl chloroacetate and with 3-chloro-2,4-pentanedione gave the thiazolidin-4-one 22 and 1,3-thiazole 25 derivatives, respectively. Condensation of thiazolidin-4-one 22 with aldehydes gave their 5-arylidene derivatives 23a–f. Most of the synthesized compounds were tested for anticancer activity against human hepatocelluar carcinoma HepG2, human breast cancer MCF-7 and human lung cancer A549. Their SAR was studied and variously affected by the electronic factor of electron donating and withdrawing groups. Many of the tested compounds showed moderate to high anticancer activity.

(−)-Oxyphyllol was prepared in only 4 steps from an epoxy enone that already served as an intermediate for the total synthesis of the anticancer guaiane (−)-englerin A. A regio- and diastereoselective Co(II)-catalyzed hydration of the olefin and a transannular epoxide opening were used as the key reactions.

(1 S ,2 S )-3-Trifloxy- cis -1,2-dihydrocatechol acetonide, a useful chiral building block, was prepared from d -ribose in good overall yield using a carbonyl allylation and a ring-closing metathesis as the key C–C bond-forming steps. Negishi cross-coupling of this triflate with a serine-derived organozinc iodide proceeded efficiently to afford an α-amino acid derivative as a potential precursor for scabrosin esters (ambewelamides).

A concise route to multigram quantities of the antibacterial diterpene (+)-totarol (1) is reported. (−)-Sclareol (2) was converted to the target compound 1 using either a sixor a seven-step sequence, while only three steps were required to access (+)-totarol (1) starting from (+)-manool (9) or (+)-13-epi-manool (10), respectively. A novel one-pot intramolecular aldol condensation/ α-alkylation protocol served as the key operation for streamlining the syntheses of 1.

The rhodium-catalyzed carbene cyclization-cycloaddition cascade of a tosyl-substituted diazoketone derivative to a polycyclic sultone is described.

1,3-Dienic δ -sultones 4,6-diaryl-[1,2]oxathiine 2,2-dioxides were synthesized via a one-step reaction of arylalkynes with dioxane sulfotrioxide. The reactivity of various alkynes in this reaction was investigated. The resulting sultones were brominated with Br2 or N-bromosuccinimide regioselectively α to sulfur and subsequently coupled with phenylacetylene using Sonogashira conditions.

Using a combined organocatalytic/metal-catalyzed strategy, the enantiopure title hydroazulenes were prepared in only four steps from (S)- and (R)-citronellal, respectively. A catalyst-controlled diastereoselective Michael addition of these aldehydes to methyl vinyl ketone followed by chemoselective dibromoolefination and one-pot Wittig olefination/alkyne formation afforded the key dienynes that underwent regioselective domino metathesis to yield the target natural products.

The phosphine-free Suzuki-Miyaura carbon-carbon cross-coupling reactions of activated and deactivated aryl halides and 2-acetyl-5-bromobenzofuran with various aryl- or heteroaryl-boronic acids were investigated. A benzothiazole-based palladium(II) complex was used as a precatalyst for the reactions under both thermal and microwave conditions in air using water as a solvent.

Vinylsulfonates have proved to be excellent dipolarophiles for carbonyl ylides derived from diazoketones in rhodium-catalyzed intramolecular cycloadditions. Polyfunctional substrates, such as 8 and (+)-15, were readily available from hydroxy esters, e.g. 1 and the cyclopenta-1,3-dione 10, respectively, and the resulting polycyclic sultones were formed under mild reaction conditions in high yields with very good diastereoselectivities. A ruthenium-catalyzed asymmetric transfer hydrogenation was found to desymmetrize the meso-cyclopenta-1,3-dione 12 efficiently.

The pseudo C 2 -symmetrical diketone 22 was efficiently constructed from furan-3,4-dimethanol (7) using a two-directional route featuring a double asymmetric dihydroxylation. Acidic hydrolysis of the cyclopentylidene acetals of 22 triggered a selective cyclization of the resulting hexaol diketone to generate the 2,8-dioxabicyclo[3.2.1]octane core of the zaragozic acids/squalestatins. Chemoselective oxidative cleavage of a superfluous two-carbon appendage and further functional group manipulations yielded the enantiomerically pure triester 30, which offers itself as a general heterobicyclic building block for naturally occurring zaragozic acids/squalestatins and unnatural analogues.

[1,1′;3′,1′′]Terphenyl-4′,5′-dicarboxylic acid derivatives were prepared from 1,3-dienic δ-sultone 4,6-diphenyl-[1,2]oxathiine 2,2-dioxide via Diels-Alder/retro-Diels-Alder reaction with dimethyl acetylenedicarboxylate under thermal, microwave or high-pressure activation.

As part of a project directed toward the total synthesis of the tetracyclic diterpene 3α-hydroxy-15-rippertene, a constituent of the defense secretion of higher termites, a fast access to two advanced hydroazulene key intermediates has been achieved by starting from (–)-isopulegol. A regio- and diastereoselective formal hydromethallylation and a regioselective ring expansion served as the key steps in the formation of the seven-membered ring. Completion of the bicyclic title compounds was then achieved by cyclopentene annulation through diastereoselective conjugate addition of organocuprates and subsequent intramolecular aldol condensations.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Using a two-directional strategy, a concise synthesis of a pseudo C2-symmetric tetrabenzyl ether of a hexaol diketone was accomplished. Hydrogenolysis of this compound in the presence of acetic acid and subsequent peracetylation triggered a group-selective intramolecular acetalization to give the desired 2,8-dioxabicyclo[3.2.1]octane derivative with correct relative and absolute configurations at all stereogenic centers of the heterobicyclic core.

Starting from the readily available parent flavonoids, the flavanone 6-prenylnaringenin, the isoflavone 6-prenylgenistein (wighteone, erythrinin B) and a protected derivative of the flavonol 6-prenylquercetin (gancaonin P) have been synthesized in short reaction sequences featuring the title processes as key steps.

Vinylsulfonamides with a furan, carbocyclic, semicyclic or acyclic 1,3-diene moiety are synthetized via a domino elimination-amidation reaction of 2-chloroethanesulfonyl chloride. Intramolecular Diels-Alder reaction of these vinylsulfonamides with thermal (toluene, 110 degrees C) or high pressure (dichloromethane, 13 kbar) activation provides efficient access to a range of gamma- and delta-sultams following a 2-3 d long synthetic procedure. Enantiopure sultams are readily obtained from N-1-phenylethyl substituted vinylsulfonamides.

Asymmetric epoxidation of N-enoylsultams (1, 3–15) incorporating a variety of chiral sultams as the chiral induction elements with UHP/TFAA has been studied. Both diastereomeric isomers of epoxides (2, 16–28) were obtained in high yield and moderate to high optical purity.

Using a sultone as the key intermediate, the first enantioselective total synthesis of the antileukemic 1,10-seco-eudesmanolides (–)-eriolanin (1) and (–)-eriolangin (2) was achieved, which also established the hitherto unknown absolute configuration of these sesquiterpene lactones. Starting from 2-bromo-1-(2-furyl)ethanone, 24 steps were required to generate the common basic structure and two additional steps in each case for completion of the natural products. The effect of 1 and 2 on the cell cycle of human leukemia (HL-60) cells was investigated by flow cytometry. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Novel unsaturated sulfonyl isocyanates were prepared using a boron trichloride promoted thermal cleavage of the corresponding sulfonylcarbamates. Due to their moisture sensitivity, the isocyanates were directly converted into sulfonylureas in good yields. An intramolecular cycloaddition of the olefinic sulfonyl isocyanates to give β-lactam-sulfonamide hybrids was not observed experimentally. Investigation of this cycloaddition by DFT-calculations using the 6-31G* and 6-311+G** basis sets showed it to be endergonic.

8-prenylnaringenin (8-PN) and preparations containing 8-prenylnaringenin have been suggested for use in medicinal and cosmetic applications like hormone replacement or bust enhancement. However, the safety of application is still under considerable debate. Recently it has been shown that human liver microsomes are converting 8-prenylnaringenin to 12 metabolites, with (E)-8-(4''-hydroxyisopentenyl)naringenin (8-PN-OH) and (E)-8-(4''-oxoisopentenyl)naringenin (8-PN=O) being among the most abundant. Applying two independent in vitro test systems we demonstrate that these two metabolites of 8-prenylnaringenin are estrogenic in vitro. These results represent an important piece of information towards the discussion of safety of use of preparations containing 8-prenylnaringenin.

Using ring closing metathesis (RCM) as the key operation, a rapid access to β-lactams fused to a sultam moiety of variable ring size was developed from low cost, commercially available starting materials. An efficient RCM of 4-vinyl-azetidin-2-ones to give 1-aza-bicyclo[4.2.0]oct-4-en-8-ones is also reported.

The potential estrogenic activity of 8-prenylnaringenin has been investigated using several in vitro test systems. 8-Prenylnaringenin is a natural secondary product of the female blossoms of hops. The aim of the present study was to characterize 8-prenylnaringenin for its estrogenic effects in vivo. A three day uterotrophic assay was carried out on ovariectomized young female rats. A single dose of 8-prenylnaringenin (10 mg/day/kg body mass) was administered subcutaneously. 17beta-Estradiol (0.03 mg/day/kg body mass; subcutaneous administration) was used as a positive control. Uterine wet weight, endometrial and vaginal epithelial height were determined by histological methods. Gene expression in uterus and in liver was assessed using realtime RT-PCR. Both estradiol and 8-prenylnaringenin significantly stimulated uterine wet weight accompanied by a proliferative response. The three day treatment resulted in a statistically significant increase of the uterine epithelial height as well as of the vaginal epithelial height, the latter being the more sensitive parameter. In the uterus of ovariectomized animals estrogen receptor-alpha and clusterin gene expression were down regulated following treatment with estradiol, whereas expression of complement C3 was up-regulated. In response to treatment with 8-prenylnaringenin the same gene expression pattern was detectable, but less pronounced. The levels of estrogen receptor-alpha mRNA in rat liver were very low and therefore could not be quantitatively assessed. Like in the uterine tissue, estradiol down regulated clusterin expression. The response to 8-prenylnaringenin was weaker but still significant. Conversely, 8-prenylnaringenin was found to be more potent than estradiol in inducing expression of IGFBP-1. In summary, the multiparametric assessment of the estrogenic activity of 8-prenylnaringenin provides overwhelming evidence that 8-prenylnaringenin has largely to be regarded as a pure estrogen agonist and is therefore a questionable candidate molecule for hormone replacement therapy.

Enantiomerically pure δ- and γ-sultams have been prepared by intramolecular [4+2] cycloaddition of N-1-phenylethyl substituted vinylsulfonamides with purely thermal activation and under high pressure. An optimized procedure for reductive debenzylation of the resultant δ-sultams is also reported.

Novel THF-amino acids were efficiently synthesized from actic acid methyl esters. The conformational restriction imposed by the 2,5-cis disubstituted tetrahydrofuran moiety is apparent from their facile cyclization to give medium-sized lactams.

The enzymatic kinetic resolution of the racemic alcohols 1-(3′-furyl)-3-buten-1-ol (±)-1 and 2-(2′-furyl)propan-1-ol (±)-2 was investigated by screening a range of lipases and esterases for enantioselective transacylation, as well as for enantioselective hydrolysis. For both alcohols, lipase-catalyzed hydrolysis of the derived racemic acetate gave the best results for accessing the desired (S)-enantiomers. In the case of the secondary alcohol (±)-1, ASL turned out to be the optimum enzyme, whereas PPL was found to be superior in the case of the primary alcohol (±)-2. Additionally, an alternative access to (S)-2 via Oppolzer's camphor sultam methodology is described.

Three different conditions for the title reaction are compared: thermal, microwave, and high-pressure activation, with the latter being the cleanest variant to perform this reaction.

Phenylthiourea derivative (III) is used as building block for the synthesis of several title compounds of type (V), (VII), (IX), and (XI).

The oxidative domino cyclization/cycloaddition of enyne aldehydes and ketones (I) as well as related substrates (III) afford tetracyclic ketoethers (II) and heteroaromatic analogues (IV) by using pyridine N-oxides as external oxidants.