New developments in the synthesis of pyrrolizidinone-based dipeptide isosteres

1,3-Dipolar cycloaddition of acrylamide with the cyclic nitrone derived from proline tert-butyl ester has been employed in the synthesis of bicyclic Gly-(s-cis)Pro isosteres suitably protected for the Fmoc-based solid phase peptide synthesis. (R)-1-Phenylethylamine was introduced as chiral auxiliary to resolve racemic intermediates and obtain enantiopure compounds. Using methacrylamide as dipolarophile, the analogous Ala-Pro mimetics have been prepared in racemic form, whereas the same strategy applied to methyl itaconate failed to give the corresponding Asp-Pro mimetic.     

Synthesis and Structure Investigations of Potential Sedative and Anticonvulsant Hydroxy- and Acetoxy-N-(3-oxobutyl)-pyrido[2,3-d]pyridazinonesa

Summary.  Novel N-(3-oxobutyl)-hydroxy- and acetoxypyrido[2,3-d]pyridazinones were synthesized and tested in vivo for their sedative and anticonvulsant activity. The Michael-type reaction of quinolinic acid hydrazide and methyl vinyl ketone afforded a mixture of two isomers, 5-hydroxy-N ⁷-(3-oxobutyl)-pyrido[2,3-d]pyridazin-8(7H)-one and 8-hydroxy-N ⁶-(3-oxobutyl)-pyrido[2,3,-d]pyridazin-5-(6H)-one, in a ratio of 2:1 which were separated by crystallization. Subsequent acetylation of both isomers yielded the corresponding 5- and 8-acetoxy compounds. The structures of the compounds were proven and completely assigned on the basis of ¹H, ¹³C, ¹⁵N NMR, and 1D NOE difference spectra as well as 2D C,H-correlation experiments. Preliminary pharmacological tests showed low acute toxicity with a LD ₅₀ > 1000 mg/kg in the mouse and sedative activity for the title compounds. 5-Acetoxy-N ⁷- (3-oxobutyl)-pyrido[2,3-d]pyridazin-8(7H)-one displayed a borderline anticonvulsant activity in the metrazole test model. Corresponding author. E-mail: edith.goessnitzer@uni-graz.at Received March 20, 2002; accepted April 3, 2002     

Novel Host Compounds, 1,1′-Binaphthyl-2,2′-Dihydroxy-5,5′- and 6,6′-Dicarboxylic Acid, which Trap Guest Molecules Tightly in their Inclusion Crystals

The host compounds 1,1’-binaphthyl-2,2′-dihydroxy-5,5′-dicarboxylic acid (1) and 1,1′-binaphthyl-2,2′-dihydroxy-6,6′-dicarboxylic acid (2) have been synthesized, and their inclusion properties have been studied. Inclusion complexes formed by 1 and 2 with volatile guests such as acetone and methanol release the guests only at much higher temperatures than their boiling points. The crystal structures of the inclusion complexes have been determined from single crystal X-ray diffraction data and show different host lattices.     

The interactions of (=O→Si)-(benzoyloxymethyl)trifluoro-and -(benzoyloxymethyl) methyldifluorosilanes with a solvent

The IR spectra of solutions of (=OSi)-(benzoyloxymethyl)trifluorosilane (1),-(benzoyloxymethyl)methyldifluorosilane (2), and butyl benzoate (3) are examined in the region of thev(C=O) stretching vibrations in 24 solvents. The ability of compounds1—3 to undergo specific intermolecular interactions is evaluated from the dependence ofv(C=O) on the Kamlet-Taft (^*,, ) parameters, which was obtained for the carbonyl groups involved in the intramolecular coordinate (=OSi) bond and for free carbonyl groups. The corresponding values of the coefficients in the Kamlet-Taft equations are indicative of a weak ability of pentacoordinate silicon compounds1 and2 to undergo acid-base interactions.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 689–692, April, 1995.     

Thermal decomposition of rare earth element enanthates

The conditions of formation of Y, La and lanthanide (from Ce(III) to Lu) enanthates were worked out, their composition and their solubilities in water at 291 K were determined, and the conditions of their thermal decomposition were studied. They were prepared as crystalline solids with general formula Ln(C₇H₁₃O₂)₃·nH₂O, wheren=2–10. On heating, they decompose in two or three steps. They first lose some water molecules and then decompose to the oxides directly (salts of Y and heavy lanthanides) or via the intermediate formation of Ln₂O₂CO₃ (salts of La, Pr, Nd, Sm and Eu). Only yttrium enanthate dihydrate loses 2 water molecules on heating to form an anhydrous complex, which decomposes directly to Y₂O₃. The temperatures of dehydration are similar for all complexes (323–343 K), while the temperatures of oxide formation vary irregularly from 823 K for CeO₂ to 1078 K for La₂O₃.     

Biologisch aktive 3,3-Dimethylbicyclo[2.2.2]octane: Synthesen in der Isocamphanreihe, 35. Mitt.

Summary The bicyclo[2.2.1]- and [2.2.2]-systems are part of numerous biological active substances. Continuing our syntheses in the isocamphane series the homologous isocamphanes of mecamylamine (1 a) and of the fungicidal bicyclic compound2 were synthesized. Furthermore the syntheses ofE-homoisosantalene (15) andE,E-homoisosantalol (16) are described.

     

Highly sensitive determination of haloperidol in human serum by capillary gas chromatography using a surface ionization detector

A method has been developed for highly sensitive determination of haloperidol in human serum involving a simple extraction procedure followed by gas chromatographic separation. Target components were separated from the extracting solvents with a Van den Berg type solventless sample injector before introduction Into a DB-1 capillary separation column. A surface ionization detector (SID), which has highly selective sensitivity for Substituted amines, was employed for quantitation using bromperidol as an internal standard. Chloroform proved to be the best extracting solvent, yielding a quantitative detection limit of 5 ng/ml (S/N = 2). Comparison of the response to target compounds obtained by the SID, FTD (flame thermionic detector), and FID (flame ionization detector) showed the SID to be superior.     

Quantification of Valerenic Acid in Valeriana jatamansi and Valeriana officinalis by HPTLC

A simple, rapid, cost-effective and accurate high performance thin layer chromatographic method has been developed for quantification of valerenic acid in Valeriana jatamansi and Valeriana officinalis which is one of the stable compounds of Valeriana officinalis and designated as a key marker compound. Valerenic acid makes substantial contribution to the sedative and spasmolytic activity of the essential oil and extract of Valeriana officinalis. Separation and quantification was achieved by HPTLC using ternary mobile phase of hexane: ethyl acetate: acetic acid (80:20:0.5 v/v) on precoated silica gel 60F₂₅₄ aluminium plates and densitometric determination was carried out after derivatization with anisaldehyde-sulphuric acid reagent at 700 nm, in absorption-reflectance mode. The calibration curves were linear in the range of (500 ng–2.5 μg). This is the first HPTLC report for the identification and quantification of valerenic acid in Valeriana jatamansi and Valeriana officinalis.     

First synthesis of (±)-vertilecanin A

5-[(Hydroxy)(phenyl)methyl]pyridine-2-carboxylic acid ((±)-vertilecanin A) was prepared from nicotinic acid in four steps with an overall yield of 29%. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2389–2390, October     

Thermodynamic study of N-trifluoroacetyl-O-alkyl nipecotic acid ester enantiomers on diluted permethylated beta-cyclodextrin stationary phase

Thermodynamic studies were performed on 12 pairs of N-trifluoroacetyl-O-alkyl nipecotic acid ester enantiomers on diluted permethylated beta-cyclodextrin stationary phase (CP Chirasil-Dex CB). The influence of ester alkyl group structure on interaction with permethylated beta-cyclodextrin (Me-CD) and enantioselectivity was studied. The types of alkyl groups studied included n-alkyl (C1-C5) and groups containing branching at differing locations relative to the chiral center of the molecule. The results show that for a given molecular weight, the n-alkyl esters have stronger interactions with Me-CD than esters containing branched alkyl groups. However, although having weaker interactions with Me-CD, esters containing alpha-branched alkyl groups exhibit higher enantioselectivity than the corresponding n-alkyl or beta-branched isobutyl esters. From the retention data, thermodynamic parameters were estimated using the retention increment method and enthalpy-entropy compensation plots (ln R' versus deltaH) were constructed. The results suggest that ester enantiomers with branching at the alpha-carbon of the ester alkyl group have additional and/or different types of enantioselective interactions with Me-CD than the C1-C5 n-alkyl esters or beta-branched isobutyl ester. In order to obtain a qualitative sense of the interaction with Me-CD, structures of the diastereomeric complexes formed between Me-CD and some of the ester enantiomers were modeled using simulated annealing molecular dynamics.