Isolation and characterization of atropisomers of seven-membered-ring benzolactams

The atropisomeric properties of seven-membered-ring benzolactams (7a-c and 8a) [1,5-benzodiazepin-2-one (a), 1,5-benzothiazepin-4-one (b), and 1-benzazepin-2-one (c)] were examined. The atropisomers were isolated as the diastereomers with an (S)-phenethylamide moiety, which were characterized by X-ray crystallography, and the barriers to their interconversion were clarified.     

Versatile synthesis of functionalised dibenzothiophenes via Suzuki coupling and microwave-assisted ring closure

Amino-substituted biphenyls were obtained by Suzuki cross-coupling of 2,6-dibromoaniline with a phenylboronic acid (substituted with Me, NO(2), OH, OMe or Cl) preferably assisted by microwave irradiation. Conversion of the amino group into a thiol preceded a base-induced intramolecular substitution, also facilitated by microwave heating, to generate the second C-S bond of the target dibenzothiophene. The 1-, 2-, 3- or 4-substituted 6-halodibenzothiophenes obtained were subjected to a palladium-mediated coupling with 2-morpholin-4-yl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-chromen-4-one to give the respective 6-, 7-, 8- or 9-substituted dibenzothiophen-4-ylchromenones. These compounds were evaluated as inhibitors of DNA-dependent protein kinase (DNA-PK) and compared to the parent 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholin-4-yl-4H-chromen-4-one. Notably, derivatives bearing hydroxy or methoxy substituents at C-8 or C-9 retained activity, whereas substitution at C-7 lowered activity. Substitution with chloro at C-6 was not detrimental to activity, but a chloro group at C-7 or C-8 reduced potency. The data indicate permissive elaboration of hydroxyl at C-8 or C-9, enabling the possibility of improved pharmaceutical properties, whilst retaining potency against DNA-PK.     

5C + 1S] annulation: a facile and efficient synthetic route toward functionalized 2,3-dihydrothiopyran-4-ones

[reaction: see text] A facile and efficient synthetic route toward highly substituted 2,3-dihydrothiopyran-4-ones 2 has been developed via a formal [5C + 1S] annulation of readily available alpha-alkenoyl ketene-(S,S)-acetals 1 with sodium sulfide nonahydrated salt (Na2S x 9H2O) and utilized in the synthesis of 2-(4-chlorophenyl)-6-(morpholin-4-yl)-4H-thiopyran-4-one 5l, an inhibitor of DNA-dependent protein kinase (DNA-PK).     

Judicious application of allyl protecting groups for the synthesis of 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl triflate, a key precursor of DNA-dependent protein kinase inhibitors

[Structure: see text] 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl 2,2,2-trifluoromethanesulfonate is a key intermediate for the synthesis of the DNA-dependent protein kinase (DNA-PK) inhibitor 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one (NU7441). Two improved methods for the synthesis of this triflate have been developed: (A) in 35% overall yield, through modification of the published route, and (B) in 15% overall yield, by a new route employing a Baker-Venkataraman rearrangement to enable generation of the chromenone scaffold. Both syntheses depend on the judicious use of allyl protecting groups.     

Non-catalytic approach to the synthesis of partially reduced 'S' shaped dioxathia- and oxadithiahelicenes through base induced inter- and intramolecular C-C bond formation

An efficient and convenient route for the construction of helical 'S' shaped dioxathia- and oxadithiahelicenes with oxygen and sulfur atoms located in the middle of the outer helix has been developed through base induced inter- and intramolecular C-C bond formation from the reaction of 4-sec-amino-2-oxo-2,5-dihydrothiochromeno[4,3-b]pyran-3-carbonitriles with 3,4-dihydro-2H-benzo[b]oxepin-5(2H)-ones, 3,4-dihydrobenzo[b]thiepin-5(2H)-one and thiochroman-4-ones separately. Quantum chemical calculations have also been carried out to explore the geometries and electronic structures of newly synthesized compounds to envisage the pathway for interconversion of both atropisomers. The determination of helicity parameters and configurational stability demonstrate that the energy barrier is strongly dependent on the nature of hetero-atoms present.     

Atropisomers of 1-(acyl or aroyl)-2-naphthylindolines. Isolation,X-ray crystal structure and conformational analysis

A series of pairs of stable diastereomeric atropisomers caused by restricted rotation around the Csp3-Csp2 bond of [2-(2-hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-(3- or 4-substituted phenyl)-methanone or [2-(2-hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-1-alkanone were isolated. The conformational analyses of the atropisomers were performed based on the X-ray crystallographic and (1)H-NMR spectral data. It became clear that rotation about the C2-naphthyl bond is restricted at room temperature, whereas the >NCO-Ar bond rotates freely.     

Synthesis and separation of the atropisomers of 2-(5-benzo[b]fluorenyl)-2′-hydroxy-1,1′-binaphthyl and related compounds

Several syn and anti atropisomers of 2-(5-benzo[b]fluorenyl)-2′-hydroxy-1,1′-binaphthyl and related compounds were synthesized from 1,1′-binaphthyl-2,2′-diol (BINOL). It was possible to separate the syn and anti atropisomers by silica gel column chromatography. The syn atropisomers are potential hetero-bidentate ligands for complex formation with metals. By starting from enantiomerically pure (R)-(+)-BINOL and (S)-(−)-BINOL, four optically active syn atropisomers and two anti atropisomers with high enantiomeric purity were obtained. The structures of two syn atropisomers and one anti atropisomer were established by X-ray structure analyses.     

Enantiospecific Syntheses of Congested Atropisomers through Chiral Bis(aryne) Synthetic Equivalents

The synthetic equivalents of the enantiopure binaphthyl bis(aryne) atropisomers derived from BINOL (1,1′-bi-2,2′-naphtol) featuring a stereogenic axis vicinal to the two reactive triple bonds can be generated for the first time in solution in an enantiospecific manner. Using a two-step sequence based on the bidirectional [4+2] cycloaddition of furan derivatives followed by an aromatizative deoxygenation reaction, several 9,9’-bianthracenyl-based atropisomers could be prepared enantiospecifically in high enantiomeric purity. Alternatively, bidirectional reactions with anthracene, 2-bromostyrene, and perylene as the arynophiles afforded very congested bis(benzotriptycene), bis(tetraphene) and bis(anthra[1,2,3,4-ghi]perylene) nanocarbon atropisomers in equally high enantiomeric purity. In complement, cross reactions with two different arynophiles revealed possible. The unusual atropisomer prototypes described in this study open the way to enantiopure nanographene atropisomers designed for functions.     

Synthesis, structure and complexation of the fluorinated 1,3-enaminoketones containing at the nitrogen atom substituents with a terminal C≡C bond

The reaction of fluorinated lithium 1,3-diketonates with propargylamine hydrochloride and 1,1,1-trifluorpentane-2,4-dione or 1,1,1-trifluoro-4-methoxypent-3-en-2-one with propargylamine and 3-aminophenylacetylene were performed to obtain fluorinated 1,3-enaminones containing at a nitrogen atom substituents with terminal C≡C bonds: (Z)-1,1,1-trifluoro-4-(2-propynylamino)-3-pentene-2-one, (Z)-1,1,2,2-tetrafluoro-5-(2-propynylamino)-4-hexen-3-one, and 4-(3-ethynylphenylamino)-1,1,1-trifluoropentyl-3-en-2-one. Reactions of 4-(3-ethynyl-phenylamino)-1,1,1-trifluoro-pentyl-3-en-2-one with Cu(II) acetate or nanosized powder of copper or its oxides led to the respective chelate complex. The structure of (Z)-1,1,2,2-tetrafluoro-5-(2-propynylamino)-4-hexen-3-one and a copper complex of 4-(3-etinilphenylamino)-1,1,1-trifluoropenta-3-en-2-one was determined by XRD.     

Crystallographic analysis of a pair of isolable atropisomers of 2-aryl substituted indoline derivatives

The crystal and molecular structures of isomeric compounds of 1-(4′-chlorobenzoyl)-2-(2″-hydroxynaphthyl)-3,3-Dimethylindoline have been determined by single crystal X-ray analyses as a pair of diastereomeric atropisomers due to restricted rotation about a Csp³-Csp² bond.     

Synthese von 3-Oxacholestanen

Successive treatment of 5α-cholestan-3-one ( 1 ) with O₂ under basic conditions and then NaBH₄ led to 5α-3-oxa-cholestan-2-one ( 5 ). Analogous reactions with 5β-cholestan-3-one ( 6 ) yielded 5α-4-oxa-cholestan-3-one ( 7 ) and 5 ξ-3-oxa-cholestan-4-one ( 8 ). 4-Cholesten-2-one ( 10 ), which was prepared starting from 4-cholesten-3-one, was isomerized by methanolic KOH to give a mixture of 5α-cholest-3-en-2-one ( 11 ) and 5β-cholest-3-en-2-one ( 12 ). 5β-Cholestane-2,3-dione ( 17 ) was synthesized from 4β-bromo-5β-cholestan-3-one ( 13 ). Ozonolysis of the dione 17 and subsequent NaBH₄ reduction of the oxidation product gave both 5β-2-oxa-cholestan-3-one ( 18 ) and 5β-3-oxa-cholestan-2-one ( 19 ).     

Synthese von Alkylphenolen und -pyrocatecholen aus Plectranthus albidus (Labiatae)

Synthesis of Alkylphenols and -catechols from Plectranthus albidus (Labiatae) In the preceding paper, we described the isolation and structure elucidation of a series of even-numbered phenol- or pyrocatechol-derived 1-arylalkane-5-ones. To establish the assigned structures unambiguously and to have larger quantities available for physiological testing, the following compounds were prepared: in the alkylphenol series, 1-(4′-hydroxyphenyl)tetradecan-5-one ( 2a ), 1-(4′-hydroxyphenyl)hexadecan-5-one ( 2b ), and 1-(4′-hydroxyphenyl)octadecan-5-one ( 2c ); in the alkylcatechol series, 1-(3′,4′-dihydroxyphenyl)decan-5-one ( 3a ; not isolated as a natural compound), 1-(3′,4′-dihydroxyphenyl)dodecan-5-one ( 3b ), 1-(3′,4′-dihydroxyphenyl)tetradecan-5-one ( 3c ), 1-(3′,4′-dihydroxyphenyl)hexadecan-5-one ( 3d ), 1-(3′,4′-dihydroxyphenyl)octadecan-5-one ( 3e ), and 1-(3′,4′-dihydroxyphenyl)icosan-5-one ( 3f ); in the alkenylphenol series, (Z)-1-(4′-hydroxyphenyl)octadec-13-en-5-one ( 4a ) and (E)-1-(4′-hydroxyphenyl)octadec-13-en-5-one ( 4b ); in the alkenylcatechol series, (E,E)-1-(3′,4′-dihydroxyphenyl)deca-1,3-dien-5-one ( 1 ) and (Z)-1-(3′,4′-dihydroxyphenyl)octadec-13-en-5-one ( 5 ). All compounds proved to be identical with the previously assigned structures. Compound 1 was synthesized by regioselective aldol condensation of heptan-2-one with (E)-1-(3′,4′-dimethoxyphenyl)prop-2-enal ( 6d ; Scheme 1), the phenols 2a–c and the catechols 3a–f by addition of the corresponding alkyl Grignard reagent to 5-(4′-methoxyphenyl)- or 5-(3′,4′-dimethoxyphenyl)pentanal ( 17c and 18c , resp.; Scheme 4), and the olefins 4a, 4b and 5 from 17c or 18c via the 9-O-silyl-protected 13-(4′-methoxyphenyl)- or 13-(3′,4′-dimethoxyphenyl)tridecanals ( 26 and 27 , resp.) and Wittig olefination as the key steps (Scheme 5).     

Stereolabile and configurationally stable atropisomers of hindered aryl carbinols

Carbinols of the Ar-C(OH)R(2) type, Ar being o-isopropylphenyl, exist as stereolabile syn-clinal (sc) and anti-periplanar (ap) atropisomers when R = Me, Et, i-Pr. In the latter compound, the major atropisomer also comprises two enantiomeric forms that interchange with a barrier of 6.4 kcal mol(-1). X-ray diffraction, NOE experiments, and ab initio calculations indicate that the sc-atropisomer is the more stable form when R = Me, i-Pr, t-Bu but is the less stable one when R = Et. NMR spectra at variable temperature allowed the determination of the barriers for the interconversion of the sc- into the ap-atropisomers (DeltaG++ = 7.6, 8.8, and 13.5 kcal mol(-1) for Me, Et, i-Pr, respectively). When R is a tert-butyl group, the two atropisomers are configurationally stable: the ap-atropisomer is obtained as the kinetic controlled compound, which can be transformed into the thermodynamically more stable sc-atropisomer with a free energy of activation of 29.3 kcal mol(-1). Both atropisomers exhibit restricted rotation of the tert-butyl moiety, the corresponding DeltaG++ values being 9.4 and 8.8 kcal mol(-1) for the sc- and ap-atropisomer, respectively.     

Isolierung und Struktur von langkettigen Alkylphenolen und -pyrocatecholen aus Plectranthus albidus (Labiatae)

Isolation and Structure of Long-Chain Alkylphenols and -catechols from Plectranthus albidus (Labiatae) From the title plant, a series of even-numbered long-chain, phenol- or pyrocatechol-derived 1-arylalkan-5-ones was isolated by classical chromatography and preparative reversed phase HPLC. By chemical and spectroscopic methods, including coupled chromatographic techniques (GC/MS/FT-IR, HPLC/MS), their structures were established to be 1-(4′-hydroxyphenyl)tetradecan-5-one ( 2a ), 1-(4′-hydroxyphenyl)hexadecan-5-one ( 2b ), 1-(4′-hydroxyphenyl)octadecan-5-one ( 2c ), and (Z)-1-(4′-hydroxyphenyl)octadec-13-en-5-one ( 2d ); (E,E)-1-(3′,4′-dihydroxyphenyl)deca-1,3-dien-5-one ( 1a ), 1-(3′,4′-dihydroxyphenyl)dodecan-5-one ( 3a ), 1-(3′,4′-dihydroxyphenyl)-tetradecan-5-one ( 3b ), 1-(3′,4′-dihydroxyphenyl)hexadecan-5-one ( 3c ), 1-(3′,4′-dihydroxyphenyl)octadecan-5-one ( 3d ), 1-(3′,4′-dihydroxyphenyl)icosan-5-one ( 3e ), and (Z)-1-(3′,4′-dihydroxyphenyl)octadec-13-en-5-one ( 3f ). In vitro, the compounds show significant antioxidant activity, the inhibitory concentration of the most potent one, 1a , being slightly lower than for 2-(tert-butyl)-4-methoxyphenol (BHA) and 2,6-di(tert-butyl)-4-methylphenol (BHT) in the Fe²⁺-catalysed autooxidation of linoleic acid, whereas the acitivities of phenols 2a–d are in the same order of magnitude as α-tocopherol.     

Synthesis and pharmacological evaluation of some 3-(4-methoxyphenyl)-2-substitutedamino-quinazolin-4(3H)-ones as analgesic and anti-inflammatory agents

A variety of novel 3-(4-methoxyphenyl)-2-substitutedamino-quinazolin-4(3H)-ones were synthesized by reacting the amino group of 2-hydrazino-3-(4-methoxyphenyl)-quinazolin-4(3H)-one with a variety of alkyl and aryl ketones. The starting material 2-hydrazino-3-(4-methoxyphenyl)-quinazolin-4(3H)-one was synthesized from 4-methoxyaniline. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic index activities. While the test compounds exhibited significant activity, compounds 2-(1-methylpropylidene)-hydrazino-3-(4-methoxyphenyl)-quinazolin-4(3H)-one (A1), 2-(1-ethylpropylidene)-hydrazino-3-(4-methoxyphenyl)-quinazolin-4(3H)-one (A2) and 2-(1-methylbutylidene)-hydrazino-3-(4-methoxyphenyl)-quinazolin-4(3H)-one (A3) showed moderately more potent analgesic activity and the compound 2-(1-methylbutylidene)-hydrazino-3-(4-methoxyphenyl)-quinazolin-4(3H)-one (A3) showed moderately more potent anti-inflammatory activity when compared to the reference standard diclofenac sodium. Interestingly the test compounds showed only mild ulcerogenic potential when compared to aspirin.     

Kinetic investigation of the OH radical and Cl atom initiated degradation of unsaturated ketones at atmospheric pressure and 298 K

Rate coefficients for the reactions of hydroxyl radicals and chlorine atoms with 4-hexen-3-one, 5-hexen-2-one, and 3-penten-2-one have been determined at 298 ± 2 K and atmospheric pressure of air. Rate coefficients for the compounds were determined using a relative kinetic technique with different reference compounds. The experiments were performed in a large photoreactor (480 L) using in situ FTIR spectroscopy to monitor the decay of reactants. From the different measurements the following rate coefficients (in units of cm(3) molecule(-1) s(-1)) have been determined: k(1)(OH + 4-hexen-3-one) = (9.04 ± 2.12) × 10(-11), k(2)(OH + 5-hexen-2-one) = (5.18 ± 1.27) × 10(-11), k(3)(OH + 3-penten-2-one) = (7.22 ± 1.74) × 10(-11), k(4)(Cl + 4-hexen-3-one) = (3.00 ± 0.58) × 10(-10), k(5)(Cl + 5-hexen-2-one) = (3.15 ± 0.50) × 10(-10) and k(6)(Cl + 3-penten-2-one) = (2.53 ± 0.54) × 10(-10). The reactivity of the double bond in alkenes and unsaturated ketones at 298 K toward addition of OH radicals and Cl atoms are compared and discussed. In addition, a correlation between the reactivity of the unsaturated ketones toward OH radicals and the HOMO of the compounds is presented. On the basis of the kinetic measurements, the tropospheric lifetimes of 4-hexen-3-one, 5-hexen-2-one, and 3-penten-2-one with respect to their reaction with hydroxyl radicals are estimated to be between 2 and 3 h.     

Two new homoisoflavonoids from Caesalpinia pulcherrima

Two new homoisoflavonoids, (E)-7-methoxy-3-(4'-methoxybenzylidene)chroman-4-one (1) and (E)-7-hydroxy-3-(3',4',5'-trimethoxybenzylidene)chroman-4-one (5), along with three known homoisoflavonoids (Z)-7-hydroxy-3-(4'-methoxybenzylidene)chroman-4-one (isobon ducellin) (2), (E)-7-hydroxy-3-(4'-methoxybenzylidene)chroman-4-one (bonducellin) (3) and (E)-7-hydroxy-3-(2',4'-dimethoxybenzylidene)chroman-4-one (4) were isolated from the whole plant of Caesalpinia pulcherrima. The structures of these new compounds were elucidated by electron impact mass spectrometry (EI-MS) and 1D and 2D-NMR spectral studies. Antimicrobial activity of the new compounds was evaluated.     

Static and dynamic stereochemistry of the conformational atropisomers of tetra(o-tolyl)benzene

[graph: see text] Whereas only one atropisomer of 1,2,4,5-tetra(o-tolyl)benzene was observed by X-ray diffraction in the solid, five conformational atropisomers were detected by low-temperature NMR in solution. Their structures were assigned by a combination of NOE experiments, solvent effect, and ab initio calculations. Variable temperature dynamic NMR and bidimensional EXSY experiments allowed the barrier for the interconversion of these atropisomers to be determined (deltaG(double dagger) = 15.3 kcal mol(-1)).     

Conformational studies by dynamic NMR. 100. Enantiomerization process of stereolabile atropisomers in pyridine-substituted adamantane derivatives

The barriers for interconverting the conformational enantiomers (stereolabile atropisomers) of pyridine-substituted adamantane derivatives have been determined by dynamic 13C NMR spectroscopy. The trend of these values parallels that anticipated by MM calculations. In at least one case, the computed structure was found to agree with that obtained by single-crystal X-ray diffraction. In addition, it has been possible to achieve a physical separation of a pair of these stereolabile atropisomers at -60 degrees C by means of the enantioselective cryogenic HPLC technique.     

苯乙烯基取代的缩杂环(艹卓)酮类化合物的合成

本文研究了3-(3,4,5-三甲氧基)肉桂酰基(艹卓)酚酮和3-(3,4-亚甲二氧基)肉桂酰基(艹卓)酚酮与盐酸缩杂环(艹卓)酮类化合物,并用光谱分析和元素分析证明了它们的结构。