Synthesis of and tautomerism in 3-acyltetramic acids

The synthesis of 3-acyltetramic acids, the substructure of bioactive natural products, via O-acylation of tetramic acids with carboxylic acids followed by acyl migration, has been investigated. This acylation sequence is mediated by N,N'-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) and is very sensitive to the nature of the nitrogen substituent (R(1)), the nature of the carboxylic acid (R(2)CO(2)H), and the amount of DMAP. Acylation of N-acyl tetramic acids with an alkyl carboxylic acid using 1.3 equiv of DMAP (with 1.1 equiv of DCC) unexpectedly gave the 3-acyltetramic acid directly as a result of acyl migration induced by excess amounts of DMAP. On the other hand, N-unsubstituted, N-alkyl, and N-acyl tetramic acids with alkyl and aromatic carboxylic acids gave the O-acyl tetramic acids by using only 0.1 equiv of DMAP (with 1.1 equiv of DCC); these could be further rearranged to the acyl product by treatment with excess DMAP. The tautomeric equilibrium of these 3-acyltetramic acids in solution was found to strongly depend on the nitrogen substituent group (R(1)) rather than the 3-acyl group.     

Selective nucleophilic chemistry in the synthesis of 5-carbamoyl-3-sulfanylmethylisoxazole-4-carboxylic acids

The solution-phase syntheses of 5-carbamoyl-3-sulfanylmethylisoxazole-4-carboxylic acids were accomplished from dimethyl 3-chloromethylisoxazole-4,5-dicarboxylate by selective nucleophilic chemistry. For example, treatment of this trifunctionalized core with 3-bromobenzylamine and subsequent X-ray analysis identified the sole product as methyl 5-(3-bromobenzylcarbamoyl)-3-chloromethylisoxazole-4-carboxylate. Subjecting this amide/ester to thiophenol in the presence of 1 N NaOH completed the two-step transformation of this versatile starting material to the targeted 5-carbamoyl-3-sulfanylmethylisoxazole-4-carboxylic acid. Employing various amines and thiophenols, this chemistry was applied in the generation of a 90-compound library of druglike isoxazoles.     

Solid-phase synthesis of "mixed" peptidomimetics using Fmoc-protected aza-beta3-amino acids and alpha-amino acids

[structure: see text] A solid-phase fluorenylmethyloxycarbonyl (Fmoc)-based synthesis strategy is described for "mixed" aza-beta3-peptides as well as a convenient general approach for their required building blocks, the aza-beta3-amino acid residues (aza-beta3-aa). These monomers allow the synthesis of relatively large quantities of pure mixed aza-beta3-peptides. The required Fmoc-substituted aza-beta3-amino acids are accessible by convenient synthesis, and a number of monomers including those containing side chains with functional groups have been synthesized. The method was applied toward the solid-phase synthesis of aza-beta3-peptide mimetics of a biologically active histone H4 sequence.     

N-methyl-N-nosyl-beta(3)-amino acids

N-Methyl-beta(3)-amino acids are important building blocks in the synthesis of biologically active molecules. A very simple and efficient approach to transform natural alpha-amino acids into their corresponding N-methyl-beta(3)-amino acids is here presented. In the method, the key intermediates N-methyl-N-nosyl-alpha-aminoacyldiazomethanes are prepared in only one step, by a simple treatment of the corresponding N-nosyl-alpha-aminoacyl chlorides with diazomethane. The synthetic route takes advantage from the use of the nosyl group. This N-masking moiety activates the NH function, and the N-methylation can directly occur during the acylation step of diazomethane, rendering useless a second step that instead is shown to be necessary in all the classical procedures already reported for the preparation of N-methyl-beta(3)-amino acids. The Wolff rearrangement of N-methyl-N-nosyl-alpha-aminoacyldiazomethanes provides the corresponding N-methyl-N-nosyl-beta(3)-amino acids with total retention of the chiral configuration of the starting alpha-amino acids. No epimerization of the chiral carbon atom is observed also when N-methyl-N-nosyl-beta(3)-amino acids are transformed into chlorides and coupled with alpha-amino acid methyl esters to achieve model scaffolds for biologically important modified peptides.     

Some observations concerning the lactonization of 3-aroylpropionic acids

The ease of lactonization of the γ-keto acids ArCOCH₂CH₂COOH is shown to depend on the nature of the aryl group: the presence of electron-releasing substituents on the aryl group results in a more rapid reaction as compared to the presence of electron-withdrawing substituents. The case of this cyclodehydration reaction is also shown to depend on the reagent used: acetic anhydride-sulfuric acid is a more drastic reagent than acetic anhydride alone. Acetyl chloride, a reagent of intermediate reactivity in this reaction, is shown to yield easily the corresponding 5-arylfuran-2(3H)-ones in satisfactory yields.     

Reactions of 2-acetylindole-3-carboxylic acids

Information is given on the synthesis and establishment of the structures of previously unreported 2-acetyl-3-bromoindoles formed by the action of bromine on 2-acetylindole-3-carboxylic acids. The reduction of the latter with sodium tetrahydroborate leads to the formation of 2-(1-hydroxyethyl)indole-3-carboxylic acids.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1211–1213, September, 1984.     

Condensation of 3-methylbenzoxazolinone with α,β-unsaturated acids

The reaction between 3-methylbenzoxazolinone and some unsaturated acids in PPA leads to mixtures of compounds, depending on the acid: 6-crotonyl- (or cinnamoyl)-3-methylbenzoxazolinones, 2,3-dihydro-2,5-(or 2,7)dioxo-3-methylcyclopenta[f]benzoxazoles and 6-(3-oxo-indanyl)-3-methylbenzoxazolinones. The structure of the products was established by ¹³C and ¹H nmr spectroscopy and (or) by independent synthesis. Possible mechanisms of the reaction are discussed; when competition is possible as in the last step of the cyclization, the benzene ring shows a higher reactivity than the aromatic nucleus of the benzoxazolinone; the contrary is observed when the benzene ring is p-chloro-substituted.     

Reaction of 3-carene with perfluoroalkanoic acids

The addition of perfluoroalkanoic acids to 3-carene involves opening of the cyclopropane ring at the peripheral bonds with formation of a mixture of isomeric p-menth-1-en-8-yl and m-menth-1-en-8-yl perfluoroalkanoates. The reaction rate decreases as the length of the perfluoroalkyl radical of the acid increases. Trichloroacetic acid reacted with 3-carene at a lower rate than does trifluoroacetic acid, but the products are analogous p-menth-1-en-8-yl and m-menth-1-en-8-yl trichloroacetates.     

Palladium-catalyzed cross-coupling of 3-iodobut-3-enoic acid with organometallic reagents. Synthesis Of 3-substituted but-3-enoic acids

3-Substituted but-3-enoic acids were obtained in good yields under mild experimental conditions by palladium-catalyzed cross-coupling of 3-iodobut-3-enoic acid with organozinc or organotin compounds using PdCl(2)(MeCN)(2) as catalyst and DMF as solvent.     

ortho-metalation of unprotected 3-bromo and 3-chlorobenzoic acids with hindered lithium dialkylamides

Upon treatment of 3-chloro/bromobenzoic acids with hindered lithium dialkylamides (LDA or LTMP) at -50 degrees C, lithium 3-chloro/bromo-2-lithiobenzoates are generated. These dianions can be trapped as such to afford after electrophilic quenching a variety of simple 2-substituted-3-chloro/bromobenzoic acids. The 3-bromo-2-lithiobenzoate is less stable than the corresponding 3-chloro derivative and partly eliminates lithium bromide, thus setting free lithium 2,3- and 3,4-dehydrobenzoates that can be intercepted in situ with the hindered base.     

Tetrahydro-beta-carboline-3-carboxylic acids and contaminants of L-tryptophan

Methods for the separation, identification, and quantitative assay of contaminants of L-tryptophan implicated in eosinophilia-myalgia syndrome (EMS) are described. Propylsulfonic acid (PRS), benzenesulfonic acid (SCX), and octyl-derivatized silica (C8) bonded-phase cartridges were used for the separation; LC-MS and GC-MS for identification; and HPLC-UV-fluorescence detection for quantitative analyses of norharman, harman, tetrahydro-beta-carboline-3-carboxylic acid (TCCA), 1-methyltetrahydro-beta-carboline-3-carboxylic acid (MTCA), 1,1'-ethylidenbis(tryptophan) (EBT), and 3-(phenylamino)alanine (PAA). The tissue distribution, excretion, and metabolism of these contaminants of L-tryptophan associated with EMS after acute and chronic dosage regimens are described. Considerable amounts of EBT were observed in the large intestine of rats administered EBT, showing a transfer without decomposition in gastric fluid. In addition, MTCA was detected in the blood and urine as well as the organs of rats treated with EBT, suggesting MTCA as a major metabolite of EBT. PAA accumulated markedly in the brain, among the organs of rats, after both acute and chronic administration of PAA, while MTCA accumulated in the kidneys of rats after chronic dosage of MTCA. Ethanol and/or acetaldehyde-induced formation of MTCA, as well as tryptophan-induced formation of TCCA, occurred endogenously in man and animals.     

Cyclization of o-acylphenylacetic acids to 1-aryl-3-hydroxyisoquinolines

Methyl o-acylphenylacetates react with urea to give 1-aryl-3-hydroxyisoquinolines. 1-Phenyl-2-methyl-3-isoquinolone was obtained by the action of methylamine on methyl o-benzoylphenylacetate. The lactim-lactam tautomerism of 1-aryl-3-hydroxyisoquinolines is discussed on the basis of their UV and IR spectra. The biological activity of some 1-aryl-3-hydroxyisoquinolines with respect to 16 strains of bacteria was studied.     

Contribution of omega-3 fatty acids to the thermodynamics of membrane protein solvation

Recent NMR experiments and molecular dynamics simulations have indicated that rhodopsin is preferentially solvated by omega-3 fatty acids compared to saturated chains. However, to date no physical theory has been advanced to explain this phenomenon. The present work presents a novel thermodynamic explanation for this preferential solvation based on statistical analysis of 26,100 ns all-atom molecular dynamics simulations of rhodopsin in membranes rich in polyunsaturated chains. The results indicate that the preferential solvation by omega-3 chains is entropically driven; all chains experience an entropic penalty when associating with the protein, but the penalty is significantly larger for saturated chains.     

T3P-assisted esterification and amidation of phosphinic acids

A few phosphinic acids, such as phenylphosphinic acids, 1-hydroxy-3-phospholene 1-oxides and 1-hydroxyphospholane oxides are esterified with simple alcohols in the presence of propylphosphonic anhydride (T3P^®). If 1.1 equiv of the T3P^® reagent is used, the esterifications are fast and efficient at 25° C. In the case of more reactive models it was enough to apply 0.66 equiv of T3P^® at 85° C under microwave conditions. The amidation of 1-hydroxy-3-methyl-3-phospholene oxide could also be accomplished under similar conditions.     

Enzymatic desymmetrization of 3-alkyl- and 3-arylglutaronitriles, a simple and convenient approach to optically active 4-amino-3-phenylbutanoic acids

The enantioselective hydrolysis of 3-alkyl- and 3-arylglutaronitriles catalyzed by Rhodococcus sp. AJ270 cells, afforded the corresponding (S)-3-substituted 4-cyanobutanoic acids with low to moderate enantiomeric purities. Additives such as acetone were found to significantly enhance the enantioselectivity of the desymmetrization, giving enantiomeric excesses of up to 95%. The synthetic potential of the homochiral product was also demonstrated by the preparation of optically active (R)- and (S)-4-amino-3-phenylbutanoic acids.     

The effect of molecular geometry on the fragmentation of methyl esters of cyclobut-3-ene-1,2-dicarboxylic acids

Elimination of CH₃OH from the molecular ions of the methyl esters of cyclobut-3-ene-1, 2-dicarboxylic acids under electron-impact occurs to a much greater extent in stereoisomers having a trans configuration than in the cis analogues. Deuterium labelling shows that this process takes place via different mechanisms in the stereoisomeric esters. The abundance ratio [M ? CH₃OH]^˙+/[M ? CH₃O]+ is suggested as the most sensitive criterion for the deduction of configuration in this system. Determination of the geometry of the cyclobutene esters by n.m.r. spectroscopy as well as by pyrolysis to corresponding isomeric muconates is also discussed.     

3-O-alkylascorbic acids as free radical quenchers. II. Inhibitory effects on some lipid peroxidation models.

We previously found that 3-O-dodecylcarbomethylascorbic acid (3-RASA,3,HX-0112) exhibited a potent inhibitory effect on biochemical lipid peroxidation and that 3-RASA (3) alleviated myocardial lesions induced by ischemia-reperfusion treatment in rats. In this study we examined the mode of action of 3-RASA (3) on the inhibition of lipid peroxidation. There was no reducing activity by 3-RASA (3) (i.e., no oxide was produced) against ferric ions and superoxide anion radicals. The low reducing activity of 3-RASA (3) against a radical as compared to that of alpha-tocopherol was obtained by using a stable radical. However, 3-RASA (3) had a potent inhibitory effect, almost equal to that of alpha-tocopherol, in the model of lipid peroxidation dependent on enzymatic superoxide generation. 3-RASA (3) very strongly inhibited the chain-reaction of the peroxidation induced by Fe(2+)-linoleic acid hydroxyperoxide. On the basis of these findings, it appears that the anti-lipid-peroxidative effects of 3-RASA (3) are due to the inhibition of the radical chain-reaction, as a chain-breaking antioxidant.     

A spectrochemometric approach to tautomerism and hydrogen-bonding in 3-acyltetronic acids

3-Acyltetronic acids bearing different 3- and 5-substituents have been examined focussing on tautomerism and inter- and intramolecular hydrogen-bonding properties of these β,β′-tricarbonyl compounds in solution as well as in the solid state. Spectroscopic methods like NMR, IR, Raman-spectroscopy as well as X-ray diffractometry and MAS-NMR for the solid state have been applied. In a solution of CDCl₃, the acids exist as cis/trans pair both involving the 3-acyl group in a ratio 60/40. The pair also involving the carbonyl group at C-4 is tautomeric and the most abundant, whereas the other isomer only shows one form with an exo-cyclic double bond. NMR and IR measurements are in agreement. In the solid state, only one of the four possible tautomers is found. DFT-calculations on the B3LYP/6-31G** level helped to verify the assignment of the IR- and NMR-spectra and yielded an estimation of the relative thermodynamic stabilities of the tautomers of several 3-acyltetronic acids. Low temperature NMR experiments gave an insight into the equilibria. Deuterium isotope effects on the ¹³C NMR chemical shifts have been observed for 5,5-dimethyl 3-pivaloyltetronic acid at low temperature in order to examine the fast internal equilibria.     

3-Nitro-2-naphthalenemethanol: a photocleavable protecting group for carboxylic acids

Photocleavable protecting groups are important in synthesis and caging. Among many such groups, 2-nitrobenzyl and related groups have been found useful in many applications. However, most of the known 2-nitrobenzyl-based caging chromophores show either low quantum yield or the photolysis wavelength is not suitable for various applications. In this paper, we report 2-nitro-3-naphthalenemethanol (NNM) as an efficient photocleavable protecting group for molecules containing a carboxylic function. NNM possesses photochemical properties better than the 2-nitrobenzyl chromophores as it is photoactivatable at 380 nm in aqueous medium (CH₃CN/H₂O, 3:2 v/v) showing the desired photochemistry. The carboxylic acids are efficiently photoreleased from NNM-based esters in almost quantitative yield.     

Enantiospecific synthesis of 3-substituted aspartic acids enzymic amination of substituted fumaric acids

The use of the enzyme 3-methylaspartase in the synthesis of L-aspartic acids containing 3-halogeno- or 3-alkyl- substituents, in the (S)-configuration, and also some of the corresponding C-3 deuteriated isotopomers is described.