Stereochemical effect on biological activities of new series of piperidin-4-one derivatives

New series of (2S,3R,4S,6R)-3-methyl-4-alkyl-2,6-diarylpiperidin-4-ol were synthesised by the reduction of cis-3-alkyl-2,6-diarylpiperidin-4-one using Grignard reagent. The structural assignments and conformational studies of the synthesised compounds were established based on the IR, ¹H NMR, ¹³C NMR, NOESY and mass spectral studies. Their stereochemical effect on antibacterial, antifungal and anthelmintic activities was studied.     

Regio- and stereochemistry of the photo-ring contraction of 4-pyrones

Irradiation of 2-ethyl-3-methyl-4-pyrone 3 in aqueous solution led to the formation of trans-4-ethyl-5-methy-4,5-dihydroxycyclopent-2-enone 4 and trans-2-methyl-3-ethyl-4,5-dihydroxycyclopent-2-enone 5 . In the latter case ¹H nmr analysis confirmed the trans-configuration at C₄ and C₅ . These results are consistent with trapping of a photochemically generated oxabicyclohexenyl zwitterion by nucleophilic attack of both sides of the oxyally system along a path anti to the epoxide ring.     

A simple synthesis of the pentacyclic lamellarin skeleton from 3-nitro-2-(trifluoromethyl)-2H-chromenes and 1-methyl(benzyl)-3,4-dihydroisoquinolines

The basic structural framework of lamellarin alkaloids, 8,9-dihydro-6H-chromeno[4′,3′:4,5]pyrrolo[2,1-a]isoquinoline derivatives, has been obtained in good yields via Grob synthesis between 3-nitro-2-(trifluoromethyl)-2H-chromenes and 1-methyl-3,4-dihydroisoquinolines in refluxing isobutanol. In the case of 1-benzyl-3,4-dihydroisoquinolines, a dynamic NMR effect was observed in the ¹H and ¹⁹F NMR spectra of the products as a result of restricted rotation about the single bond linking the benzene ring and the heterocyclic system. When the reaction was carried out with 3-nitro-2-(trichloromethyl)-2H-chromenes in toluene at room temperature, only Michael adducts, as a mixture of two diastereomers, were isolated.     

Oxidation and isomerism of thietane-containing heterocycles

Oxidation of 6-methyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione, 5(6)-nitro-1-(thiethan-3-yl)-benzimidazole, 2-methyl-4-nitro-1-(thiethan-3-yl)- and 5-bromo-2-methyl-4-nitro-1-(thiethan-3-yl)imidazoles was examined. Corresponding 1-oxothietan-3-yl- and 1,1-dioxothietan-3-yl derivatives were synthesized for the first time. Some factors affecting the quality of the final products and optimal conditions of the oxidation of thietanyl derivatives of pyrimidine-2,4(1H,3H)-dione, nitrobenzimidazole, and nitroimidazole were found. According to 1H NMR spectroscopy data, the obtained sulfoxides are mixtures of cis/trans isomers, the diastereomers ratio determined by the substituent at position 3 of thietane ring.     

Reaction of ethyl 4-aryl-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates with N-methylmorpholinium 3-cyano-1,4-dihydro- and 3-cyano-1,4,5,6-tetrahydropyridine-2-thiolates

Alkylation of N-methylmorpholinium 4-Ar¹-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates using ethyl 4-Ar-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (10 % KOH, DMF) gives mixtures of diastereomers of ethyl 4-Ar-6-[(4-Ar¹-3-cyano-1,4,5,6-tetrahydropyridin-2-ylthio)methyl]-1-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates in overall 30-58 % yield. Under these conditions the N-methylmorpholinium 4-Ar1-5-(N-Ar²-carbamoyl)-3-cyano-6-methyl-1,4-dihydropyridine-2-thiolates undergo aromatization of the dihydropyridine ring to give ethyl 4-Ar-6-[4-Ar¹-5-(N-Ar²-carbamoyl)-3-cyano-6-methylpyridin-2-ylthio)methyl]-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (37-51 %). In the absence of KOH, only the substituted pyridine-2(1 H)-thione is formed as a product of oxidation of the dihydropyridine ring in the starting substrate. Some of the alkylation products obtained possess weak or moderate antibacterial activity towards the specific strains of Escherichia coli and Bacillus subtilis but are inactive towards Candida albicans and Staphylococcus aureus.     

Investigation of the reactions of fluorine containing 3-hydrazino-5H-1, 2, 4-triazino[5, 6-b]indoles with ethyl acetoacetate. Synthesis of some novel tetracyclic ring systems

Novel tetracyclic ring systems viz. 3-methyl-1-oxo-12H-1, 2, 4-triazepino[3′,4′:3, 4][1, 2, 4]triazino[5, 6-b]indole ( 4a ) and 3-methyl-5-oxo-12H-1, 2, 4-triazepino[4′,3′:2, 3][1, 2, 4]triazino[5, 6-b]indole ( 5a ), having angular and linear structures respectively, were synthesized by the cyclization of 3-oxobutanoic acid [5H-1, 2, 4-triazino-[5, 6-b]indole-3-yl]hydrazone ( 3a ). However, cyclization of 3b (R = CH_a, R¹ = R² = H) afforded the angular product 4b exclusively. Moreover, cyclization of 3c (R = R³ = H, R¹ = F) yielded 7-fluoro-1-0xo-10H-1, 3-imidazo[2′,3′:3, 4][1, 2, 4]triazino[5, 6-b]indole ( 6c ) and 7-fluoro-3-oxo-10H-1, 3-imidazo[3′,2′:2, 3][1, 2, 4]triazino-[5, 6-b]indole ( 7c ) instead of the expected triazepinone derivatives. Compound 3d (R = R¹ = H, R² = CF₃) also gave an imidazole derivative but only one angular product was obtained. In all these reactions, formation of the angular product involving cyclization at N-4 is favoured. Characterization of these products have been done by elemental analyses, ir, pmr, ¹⁹F nmr and mass spectral studies.     

Hydrogenation and conformational analysis of (1<Emphasis Type="Italic">R</Emphasis>,2<Emphasis Type="Italic">R</Emphasis>,6<Emphasis Type="Italic">S</Emphasis>)-3-methyl-6-(1-methylethenyl)cyclohex-3-ene-1,2-diol

Hydrogenation of (1R,2R,6S)-3-methyl-6-(1-methylethenyl)cyclohex-3-ene-1,2-diol was studied. Nickel chloride-sodium tetrahydridoborate system turned out to selectively reduce the double bond in the isopropenyl group. The results of conformational analysis of (1R,2R,6S)-3-methyl-6-(1-methylethenyl)cyclohex-3-ene-1,2-diol and its partly and completely hydrogenated derivatives were in a good agreement with the NMR data.     

New chiral spiro[2.5]octanones as products of methylenation of (3<Emphasis Type="Italic">R</Emphasis>, 6<Emphasis Type="Italic">R</Emphasis>)-2-arylidene-6-isopropyl-3-methylcyclohexanones with dimethylsulfoxonium methylide. Synthesis,stereochemistry, and behavior in liquid-crystalline systems

Methylenation of (3R,6R)-2-(4-X-benzylidene)-6-isopropyl-3-methylcyclohexanones (X = F, Cl, Ph) with dimethylsulfoxonium methylide occurs stereoselectively to give 1(S)-(4-X-phenyl)-5(R)-isopropyl-8(R)-methyl-3(R)-spiro[2.5]octanones, whose stereochemistry was established by ¹H NMR spectroscopy. The configuration of the chiral centers in the cyclohexanone fragment and its preferred conformation (methyl is axial and isopropyl is equatorial) in the products do not change with respect to the starting enones. The mutual trans-arrangement of the carbonyl and aryl groups at the newly formed three-membered ring was established; the aryl group also occupies the trans-position with respect to the axial methyl group of the cyclohexanone fragment. Using methylenation of the compound with X = Ph as an example, a mixture of by-products resulting from oxidative hydroxylation at the α-position relative to the carbonyl group was isolated. The resulting chiral spiro[2.5]octanones induce a helical supramolecular ordering in the nematic mesophase of 4-pentyl-4′-cyanobiphenyl and exhibit a twisting power only somewhat (by 20–30%) lower than the starting enones. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2331–2341, October, 2005.     

Chiral cyclohexene block from <Emphasis Type="Italic">R</Emphasis>-(−)-carvone

The oxidation with SeO₂ of a methyl group linked to an sp²-hybridized carbon in the product of the intramolecular iodoetherification of cis-carveol afforded (1R,5R,7S)-7-iodomethyl-7-methyl-6-oxabicyclo[3.2.1]-oct-3-en-4-carbaldehyde and [(1R,5R,7S)-7-iodomethyl-7-methyl-6-oxabicyclo[3.2.1]oct-3-en-4-yl]methanol that were oxidized to methyl (1R,5R,7S)-7-iodomethyl-7-methyl-6-oxabicyclo[3.2.1]oct-3-en-4-carboxylate. The latter by the Zn-promoted opening of the γ-oxide ring was converted into the target chiral block, methyl (4R,6R)-6-hydroxy-4-(prop-1-en-2-yl)cyclohex-1-encarboxylate.     

1H and 13C NMR chemical shift assignments and conformational analysis for the two diastereomers of the vitamin K epoxide reductase inhibitor brodifacoum

Proton and ¹³C NMR chemical shifts and ¹H? ¹H scalar couplings for the two diastereomers of the potent vitamin K epoxide reductase (VKOR) inhibitor brodifacoum have been determined at 293 K from acetone solutions containing both diastereomers. To facilitate difficult assignments, homo‐ and heteronuclear correlation spectra were acquired at 750 and 900 MHz over 268–303 K temperature range. Conformations of both diastereomers inferred from the scalar couplings and 1‐D NOE measurements reveal that one diastereomer (SS/RR) adopts a strained geometry in the cyclohexene ring system of the tetralin group. The NMR spectra also show evidence of line broadening due to conformational exchange at room temperature for the SR/RS diastereomer. These assignments and conformational analyses may be useful in studies of biomolecular interactions of brodifacoum with target proteins such as VKOR and in source determination of brodifacoum. Copyright © 2009 John Wiley & Sons, Ltd.     

Conformational analysis of 2-methyl-5-nitro-1,3,2-dioxaborinane

Quantum-chemical methods HF/6-31G(d), HF/6-31+G(d), MP2/6-31G(d)//HF/6-31G(d), and MP2/6-31+G(d)//HF/6-31+G(d) were used to investigate the conformational isomerization of 2-methyl-5-nitro-1,3,2-dioxaborinane. It has been shown that a potential energy surface of this compound includes two minima: an axial form of semi-chair and equatorial sofa together with a transition state belonging to the conformation of 2,5-twist-form. A comparison between experimental NMR ¹H and theoretical vicinal coupling constants was used to determine the quantitative conformational composition of cyclic boric acid ester and a value of ΔG ⁰ for nitro group at the ring carbon atom C⁵ in CCl₄ and C₆D₅NO₂ solutions.     

One-pot synthesis of conformationally restricted spirooxindoles

Diastereomeric three-, five- and six-membered spirocycloalkyloxindoles were successfully synthesized in a rapid and convenient manner from readily accessible starting materials in moderate to high yields using 1-methyl-3-acetonitriloxindole after a one-pot base-mediated double-alkylation strategy. It was found that the diastereoselection is dependent on the reaction conditions and the spirocycloalkyl ring size, with the 3R^∗,8R^∗ diastereomers being thermodynamically favored under the basic reaction conditions for three- and five-membered rings, and the 3R^∗,8S^∗ diastereomer in the case of six-membered rings, as predicted by DFT calculations. The relative stereochemistry was supported by 2D NMR spectra and X-ray crystal structural analysis. The conformational rigidity of the spirocycloalkyloxindoles in solution was established based on NMR experimental and theoretical DFT approaches.     

Synthesis and tautomerism of 2-(3,5-diaryl-1H-pyrazol-4-yl)-1-methyl-1H-benzimidazoles

The cyclocondensation of 1-methyl-2-phenacyl-1H-benzimidazole with aroylhydrazines yields 2-(3,5-diaryl-1H-pyrazol-4-yl)-1-methyl-1H-benzimidazoles. The ¹H NMR spectra indicate that these products display tautomerism. The more stable tautomers have structures containing electron-donor aryl substituents at C-5 and electron-withdrawing aryl substituents at C-3 of the pyrazole ring.     

Synthesis and some properties of 6-di(tri)fluoromethyl-and 5-di(tri)fluoroacetyl-3-methyl-1-phenylpyrano[2,3-<Emphasis Type="Italic">c</Emphasis>]pyrazol-4(1<Emphasis Type="Italic">H</Emphasis>)-ones

Condensation of 4-acetyl-5-hydroxy-3-methyl-1-phenylpyrazole with R^FCO₂Et (R^F = CF₂H, CF₃) in the presence of LiH affords 4-di(tri)fluoroacetoacetyl-5-hydroxy-3-methyl-1-phenylpyrazoles from which 6-di(tri)fluoromethyl-and 5-di(tri)fluoroacetyl-3-methyl-1-phenylpyrano[2,3-c]pyrazol-4(1H)-ones were synthesized. The reactions of pyrano-pyrazoles with hydrazine hydrate, ethyl mercaptoacetate, or aromatic amines proceed at the C(6) atom with pyrone ring opening and formation of aminoenones, pyrazoles, or thiophenes with the 5-hydroxy-3-methyl-1-phenyl-4-pyrazolyl fragment. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2750–2754, December, 2005.     

Rearrangement products of some 1R,4R-2-arylidene-p-menthan-3-ones in acidic media, their structures, and conformational analysis

1R,4R-2-(4-Phenylbenzylidene)-p-menthan-3-one in acidic media undergoes rearrangement with migration of the exocyclic double bond to the cyclohexane ring to form three 2-(4-phenylbenzyl) derivatives ofp-menthen-3-ones. The reaction products differ in the location of the endocyclic double bond (Δ¹ or Δ⁴) and in the configuration of the new chiral C(2) center in the resultingp-menth-4-en-3-ones. The configurations of the 1R,2R- and 1R,2S-2-(4-phenylbenzyl)-p-menth-4-en-3-ones were established based on analysis of their¹H NMR spectra in combination with calculations by molecular mechanics. The molecular conformations of these compounds as well as of some racemic 2-benzyl-p-menth-1-en-3-one derivatives were studied.     

Reaction of Methylmalonyl Dichloride with Unsaturated Carboxamides

Methylmalonyl dichloride reacts with (2E)-3-phenylacrylamides and (2E)-3-(2-furyl)acrylamide to give the corresponding E-isomeric 2-substituted 4-hydroxy-5-methyl-6H-1,3-oxazin-6-ones. The reaction of methylmalonyl dichloride with acrylamide afforded N-(3-chloropropionyl)-2-methylmalonamic acid. The structure of the products was confirmed by the ¹H and ¹³C NMR, IR, and UV spectra.     

Synthesis,spectroscopic and configurational study,and ab initio calculations of new diazaphospholanes

New 2-substituted diazaphospholane-2-oxides (I-III, V-VIII) and diazaphosphorinane-2-oxide (IV) were synthesised and characterised by ¹H, ¹³C, and ³¹P NMR, IR spectroscopy, and elemental analysis. The presence of chiral diamino groups in compounds II and V–VIII gives rise to various diastereomers so that the ³¹P{¹H} NMR spectra demonstrated three and two peaks with different ratios, respectively. Also, the ¹H and ¹³C{¹H} NMR spectra of compounds II and V–VIII revealed three and two sets of signals for the related conformers (diastereomers). Interestingly, the ³¹P NMR spectrum of V in D₂O indicated a great upfield shift (Δδ = 19.0) for ³¹P relative to the value obtained in DMSO-d₆ (solvent effect). The two signals in V split further to three signals in the presence of β-cyclodextrin. Moreover, conformational analysis of diazaphospholane V was studied by ab initio calculations at the HF and B3LYP levels of theory using the Gaussian 98 program. Results indicated that among four suggested diastereomers (C1–C4) of V, C1 and C3 containing methyl group in the equatorial position are the most stable forms.     

13C NMR spectra of 2,3-dihydro-1H-benzo[b]azepines: Differentiation of diastereomers

The ¹³C NMR spectra of 23 2,3-dihydro-1H-benzo[b]azepines, including nine pairs of diastereomers separated by chromatography, [(2R*, 3R^*) and (2R^*), 3S^*)] are hereby assigned and discussed. The relative configurations of the diastereomers were assigned by two methods. The first, based on the chemical shifts of the asymmetric carbons C-2 and C-3 (with regression analysis), shows that the values for (R^*, R^*) are approximately 1 ppm lower than those for (R^*, S^*) diastereomers. The second method uses the chemical shifts, δ₃, of the R₃(CH₃) substituents. When these δ₃ values are compared by means of the δ₃-δ_m difference (δ_m is the mean value obtained from compounds where R₂=H), the difference is always negative for (R^*, R^*) and positive for (R^*, S^*). This is attributed to a γ-gauche effect between R₂ and R₃ in the case of (R^*, R^*) diastereomers (R₂ and R₃ are cis). The results corroborate those already obtained by ¹H NMR [J(23)(R^*, R^*)<J(23)(R^*, S^*)] and are a confirmation of the results of a radiocrystallographic examination carried out on two nitrogen acetylated diastereomers.     

Furylcyclohexenones. 3. Synthesis and properties of 6-acetyl-3(5)-furylcyclohex-2-enones. Molecular and crystal structure of 6-acetyl-3-(2-furyl)-5-phenylcyclohex-2-enone

6-Acetyl-3(5)-furylcyclohex-2-enones were prepared by condensation of furan-containing chalcones with acetylacetone. Acetylcyclohex-2-enones were subjected to C-methylation. Studies by IR and ¹H NMR spectroscopy demonstrated that the resulting compounds occur predominantly in the enol form both in solutions and in the crystalline state. The molecular structure of 6-acetyl-3-(2-furyl)-5-phenylcyclohex-2-enone was established by X-ray diffraction analysis.     

1H n.m.r. spectra of some bicyclic compounds: I—relative configurations of the diastereomeric endo-α-methyl-5-norbornene-2-methanols,the corresponding saturated analogues,and their cyclization ether products

The configurational and conformational relationship at C-2 and C-α in the two racemic diastereomeric endo-α-methyl-5-norbornene-2-methanols and the corresponding saturated endo-α-methyl-2-norbornanemethanols were determined by first-order analysis of the ¹H n.m.r. spectra of these compounds and of their cyclization ether products, i.e. 3-methyl-2-oxatricyclo[4.2.1.0^4,8]nonanes and 5-methyl-4-oxatricyclo[4.3.0.0^3,8]nonanes. In addition, the conformational preference of the hydroxyl group in the unsaturated and saturated alcohols was confirmed by the lanthanide induced shift technique, using Eu(fod)₃ as shift reagent, combined with a computer program involving various conformations of the –CHOHMe group.