Lycopladine H, a novel alkaloid with fused-tetracyclic skeleton from Lycopodium complanatum

A novel Lycopodium alkaloid, lycopladine H (1), with a fused-tetracyclic ring system consisting of an azocane ring connected to a [2,2,2]-bicyclooctane ring and a 3-piperidone ring, was isolated from the club moss Lycopodium complanatum. The structure and relative stereochemistry of 1 were elucidated on the basis of spectroscopic data.     

Synthesis of new benzo[b]thieno fused ring systems via transition metal-mediated cyclisations

The compact synthesis of a new ring fused benzo[b]thieno derivative with an embedded nine-membered ring system via ring closing metathesis methodology is described. The preparation of the novel 11H-benzo[b]thieno[2,3-c]pyrrolo[2,3-a]indol-11-one via palladium-mediated oxidative cyclisation of benzo[b]thien-2-oyl indole derivatives is also reported.     

Synthesis and rotational barriers of atropisomers of 1,2-bis[5-(11H-benzo[b]fluorenyl)]benzenes and related compounds

Several 1,2-bis[5-(11H-benzo[b]fluorenyl)]benzenes and related compounds were synthesized via a cascade reaction sequence of the corresponding benzannulated enyne-allene precursors. The X-ray structures showed that the two benzo[b]fluorenyl moieties attached via the C5 carbons to the adjacent carbon atoms of the central benzene ring are oriented essentially perpendicular to the central benzene ring. The rates of rotation around the carbon-carbon single bonds attaching the benzo[b]fluorenyl moieties to the central benzene ring are relatively slow, allowing several anti and syn atropisomers to be separated at ambient temperature.     

A novel synthesis of aryl tethered imidazo[4,5-b]pyrazin-2-ones through in situ ring construction and contraction

An innovative synthesis of aryl tethered 1,3-dimethylimidazo[4,5-b]pyrazin-2-ones 4 and 6 has been delineated through base catalyzed ring transformation of 6-aryl-4-(piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1 and methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carboxylates 5 with 7-acetyl-1,3-dimethyllumazine 2 with subsequent ring contraction of the fused pyrimidine to an imidazole ring. An additional product, methyl [6-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-4-thiophen-2-ylpyran-2-ylidene]acetate 8b, was also isolated from the reaction of 5 and 2, as a minor constituent.     

Calyciphylline G, a novel alkaloid with an unprecedented fused-hexacyclic skeleton from Daphniphyllum calycinum

Calyciphylline G (1), a novel Daphniphyllum alkaloid with an unprecedented fused-hexacyclic skeleton containing a 5-azatricyclo[6.2.1.0^1,5]undecane ring, has been isolated from the stem of Daphniphyllum calycinum (Daphniphyllaceae), and the structure and relative stereochemistry were elucidated on the basis of spectroscopic data.     

Regioselective synthesis of novel polyfunctionally substituted pyrazolo[1,5-a]pyrimidines under solvent-free conditions

A series of 2-(pyrazolo[1,5-a]pyrimidin-5-yl)benzoic acids 5 has been prepared by a novel protocol that uses the fusion method between 5-amino-1H-pyrazoles 4 and 3-(3-oxo-2-benzofuran-1(3H)-ylidene)pentane-2,4-dione 3. The use of this novel protocol renders good to excellent yields along with short reaction times. In addition, this solvent-free cyclocondensation proceeds in a regiospecific fashion by intramolecular ring opening of the furane ring in a Michael-type reaction.     

3,4-seco-Diterpenoids from Trigonostemon flavidus

Phytochemical investigation on the stems of Trigonostemon flavidus resulted in the isolation of five new 3,4-seco-diterpenoids, trigoflavidones A-E (1-5), structurally related to the main co-occurring known 3,4-seco-sonderianic acid (6) and 3,4-seco-sonderianol (7). Compound 4 possesses new 3,4-seco rearranged ent-pimarane skeletal type, characteristic of a vinyl group at C-8, while 5 features a unique five-membered ring (C₁) fused with a cyclopropane ring (C₂). The structures of the new compounds were established by a combination of spectroscopic data and computational methods. Compounds 1-7 were tested for their cytotoxicities on HL-60, SMMC-7721, A-549, MCF-7, and SW480 human tumor cell lines.     

Iriomoteolide-13a,a cytotoxic 22-membered macrolide from a marine dinoflagellate Amphidinium species

Iriomoteolide-13a (1) has been isolated from a benthic dinoflagellate Amphidinium sp. (strain KCA09053) as a new 22-membered macrolide containing one hexahydrofuro[3,2-b]furan ring, one tetrahydropyran ring, two tetrahydrofuran rings, three one-carbon branches, and three hydroxyl groups including two hemiketals. The structure of 1 was assigned on the basis of a detailed 2D NMR analysis. Compound 1 exhibited cytotoxic activity against human cervix adenocarcinoma HeLa cells (IC₅₀: 0.5 μg/mL).     

Reactivity of cyclopropanic δ-oxo-α,β-unsaturated esters towards SmI2: 3-exo-trig cyclisation versus cyclopropane ring opening

trans-(2′,2′-Diphenyl-bicyclopropyl-2-yl)-4,4-dimethyl-5-oxo-pent-2-enoic acid methyl ester 9, undergoes 3-exo-trig cyclisation in the presence of SmI₂ without competitive ring opening of Newcomb's bicyclopropylic probe next to the carbonyl group. From this result, it may be concluded that the absence of ring opening observed earlier in the case of 5-cyclopropyl-4,4-dimethyl-5-oxo-pent-2-enoate 7 is not due to the potentially reversible character of this process. Meanwhile, as deduced from kinetic considerations based on data of the literature, the absence of ring opening does not necessarily mean that formation of ketyl radicals is not involved in the 3-exo-trig cyclisations of δ-oxo-α,β-unsaturated esters.Compounds 7 and 9 cyclise with total syn selectivity, leading ultimately to lactones. This syn selectivity contrasts with that of other alkylic δ-oxo-α,β-unsaturated esters.     

Experimental and theoretical study of the structure of N,N-dimethyl-4-nitroaniline derivatives as model compounds for non-linear optical organic materials

Molecular and crystal structure of a series of derivatives of N,N-dimethyl-4-nitroaniline has been studied by both X-ray diffraction method and high-level ab initio calculations. According to these data, the dimethylamino groups were found to have a trigonal-pyramidal configuration and are considerably turned with respect to the ring plane in all molecules having a substituent in the ortho-position; on the contrary, this group is planar in the meta-substituted molecules. Topological analysis of the electron density function for all molecules studied within the framework of Bader's ‘atoms in molecules’ (AIM) theory revealed that introduction of a substituent into the ortho- or meta-position of the ring results in increasing of the contribution of the resonance forms different from the quinoid one. Contribution of the latter form is predominant for the structure of N,N-dimethyl-4-nitroaniline (1). Topological analysis of the electron density distribution was used to explain a decreasing of the molecular hyperpolarisabilites of the ortho- and meta-substituted compounds as compared with those for 1.     

Investigation of oxacycle formation by base-promoted endo-mode ring-closing reaction of allenes

The base-promoted endo-mode ring closure of electron-withdrawing group-substituted allenes provided the following interesting results: (1) the endo-mode ring-closing reaction of 1-(benzyloxycarbonyl)-1-(ω-hydroxyalkyl)allenes smoothly proceeded during the formation of five-, seven-, and eight-membered rings; (2) base treatment of benzyloxycarbonylallene and sulfonylallene, having a 2-hydroxyethyl group at the C-1 position, in the presence of an aldehyde led to the ring closure and condensation with the aldehyde in one-pot; and (3) endo-mode ring closure of the sulfonylallenes by internal attack of the carboxylate anion afforded the six-membered lactone.     

Stereoselective total synthesis of the (Z)-isomer of a novel phytotoxic nonenolide from Phomopsis sp. HCCB03520 and its C-6 epimer

The (Z)-isomer of a phytotoxic nonenolide, (6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9-lactone isolated from Phomopsis sp. HCCB03520 and its C-6 epimer have been synthesized through a common route starting from butyraldehyde. The synthesis involves enantioselective Maruoka allylation, Sharpless asymmetric epoxidation and intramolecular ring closing metathesis as the important steps.     

An efficient non-catalytic, regioselective approach to the synthesis of angularly fused polycyclic systems

A novel approach to the synthesis of partially reduced different ring sizes of PAH analogs with sec.amino and nitrile functionalities is delineated through base-induced ring transformation of 4-sec.amino-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles by a carbanion, generated in situ from cyclopentanone, cyclohexanone, cycloheptanone, and cyclooctanone separately in good yields. An increase in the size of cycloalkanone ring beyond cyclooctanone restricts the ring transformation under analogous reaction conditions possibly due to bulky conformation of higher homologs. The synthetic method provides an efficient general route for the construction of angularly fused partially reduced polycyclic aromatic hydrocarbons: 5-sec.amino-2,3,6,7-tetrahydro-1H-cyclopenta[c]phenanthrene-4-carbonitriles, 6-sec.amino-2,3,4,7,8-pentahydro-1H-benzo[c]phenanthrene-5-carbonitriles, 7-sec.amino-2,3,4,5,8,9-hexahydro-1H-cyclohepta[c]phenanthrene-6-carbonitriles, and 8-sec.amino-2,3,4,5,6,9,10-heptahydro-1H-cycloocta[c]phenanthrene-7-carbonitriles.     

Design and synthesis of novel benzopyrazolodiazepinones via intra-molecular alkylation of α-alkylcarbonyl radicals mediated by dilauroylperoxide

Using a tin-free strategy, novel 4H-benzo[f]pyrazolo[1,5-a][1,3]diazepin-5(6H)-ones were synthesized in acceptable yields via intra-molecular alkylation over a benzene ring, of α-alkylcarbonyl radicals generated from ethyl pyrazolylbenzylaminoxanthates, using dilauroyl peroxide (DLP) as the radical initiator.     

Synthesis of 3,4-dihydrobenzo[g]isoquinoline-1(2H)-ones and 3,4-dihydroisoquinoline-1(2H)-ones skeleton via intramolecular electrophilic cyclization

An original alternative approach to isoquinolines based on the installation of a benzene nucleus on a performed heterocyclic ring. Synthesis of 3,4-dihydrobenzo[g]isoquinoline-1(2H)-ones and 3,4-dihydroisoquinoline-1(2H)-ones via intramolecular electrophilic cyclization of 3,4-disubstituted lactams is reported.     

Regioselective construction of six-membered fused heterocyclic rings via Pd/C-mediated C-C coupling followed by iodocyclization strategy: a new entry to 2H-1,2-benzothiazine-1,1-dioxides

We describe a practical and elegant method of constructing a thiazine ring fused with benzene under mild reaction conditions. A variety of 4-iodo-2H-benzo[e][1,2]thiazine-1,1-dioxides were prepared with high regioselectivity via a two-step process involving Pd/C-mediated C-C coupling of o-halobenzenesulfonamides with terminal alkynes, followed by iodocyclization of the resulting o-(1-alkynyl)arenesulfonamide using elemental iodine in acetonitrile. The coupling reaction was carried out using 10% Pd/C-PPh₃-CuI as a catalyst system in the presence of Et₃N. The process worked well for bromides and iodides, and a wide array of terminal alkynes containing alkyl and aryl substituents were employed. The iodocyclization step tolerated a variety of functional groups such as hydroxy, chloro, cyano, and methoxy, producing the six-membered heterocyclic ring selectively. The resulting 4-iodo-2H-benzo[e][1,2]thiazine-1,1-dioxides participated in Sonogashira, Heck, and Suzuki reactions producing a wide range of functionally substituted benzothiazines in good yields.     

C-(β-d-Glucopyranosyl)formamidrazones,formic acid hydrazides and their transformations into 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles: a synthetic and computational study

Synthesis of O-perbenzoylated 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles, precursors of potent inhibitors of glycogen phosphorylase, was studied by ring closures of N¹-acyl-carboxamidrazone type intermediates. Reactions of C-(β-d-glucopyranosyl)formimidate or C-(β-d-glucopyranosyl)formamidine with acid hydrazides as well as acylation of C-(β-d-glucopyranosyl)formamidrazone by acid chlorides unexpectedly gave the corresponding 1,3,4-oxadiazoles instead of 1,2,4-triazoles. The desired triazoles were obtained in reactions of C-(β-d-glucopyranosyl)formamidine or C-(β-d-glucopyranosyl)formyl chloride with arenecarboxamidrazones, and also in acylations of N¹-tosyl-C-(β-d-glucopyranosyl)formamidrazone with acid chlorides. Theoretical calculations (B3LYP and M06-2X DFT with the standard 6-31G(d,p) basis set) on simple model compounds with methyl and phenyl substituents to understand the bifurcation of the ring closure of N¹-acyl-carboxamidrazones indicated that in general the reaction led to 1,2,4-triazoles. However, the probability of the 1,3,4-oxadiazole forming pathway was shown to be significantly higher with N¹-benzoyl-acetamidrazones, which were closest analogues of the intermediates resulting in C-glucosyl-1,3,4-oxadiazoles. It was thereby demonstrated that the substitution pattern of the N¹-acyl-carboxamidrazones played a fundamental role in determining the direction of the ring closing reaction.     

6-endo Versus 5-exo radical cyclization: streamlined syntheses of carbahexopyranoses and derivatives by 6-endo-trig radical cyclization

Three factors that can direct 6-endo radical cyclization over 5-exo ring closure: substitution at C-5, vinyl radical cyclization and ring strain, have been considered in the context of the preparation of carbapyranoses from carbohydrate derivatives. As a result, alkyl radicals in substrates containing a strain inducing 2,3-O-isopropylidene ring, and vinyl radical in non-strained compounds undergo a completely regioselective 6-endo-trig ring closure leading to carbasugar derivatives.     

Cesium fluoride and tetra-n-butylammonium fluoride mediated 1,4-N-->O shift of disubstituted phenyl ring of a bicalutamide derivative

A novel 1,4-N→O migration of a disubstituted phenyl ring was observed during N-methylation of a bicalutamide derivative, (2S)-2-(tert-butyldimethylsilanyloxy)-N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenoxy)-2-methylpropionamide, in the presence of CsF-Celite/acetonitrile and desilylation of (2S)-2-(tert-butyldimethylsilanyloxy)-N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenoxy)-2,N-dimethylpropionamide in tetra-n-butylammonium fluoride/THF. Both NMR and X-ray analysis confirmed the structure of the 1,4-N→O disubstituted phenyl ring migrated product.     

Substituent control in the diastereoselectivity of dipolar cycloadditions of nitrones and their Zn(II) complexes with N-arylmaleimides

The π-π stacking interactions between maleimide's and nitrone's aromatic rings during the 1,3-dipolar cycloaddition were assumed to control the exo-endo selectivity of the reaction. The exo-endo ratios change during the reactions until they reach a constant value, which depends on the substituent. Electron-withdrawing groups favour the exo adduct while electron-donating groups favour the endo adduct. The nitrone ZnBr₂ complexes react much more slowly than the free nitrone and the cycloaddition is exo selective in all cases independent of the substituents on the maleimide's aromatic ring. Thermal retrocycloaddition of the cycloadducts produce the corresponding nitrones. The ring opening in the presence of secondary amines did not induce imine formation. endo Adducts were shown for the first time to be the stable paramagnetic compounds.