The synthesis of ω-thienylalkane acids from ω-chloroalkane acids

Summary We have worked out a preparative method for the synthesis of -thienylalkane acids by acylation of thiophene with -chloroalkane acid chlorides followed by conversion of the resulting -chloroalkyl(2-thienyl)ketones into the corresponding acids by reaction with sodium malonic ester or potassium cyanide, and reduction of the resulting products with their simultaneous hydrolysis.Here and later we mean -(2-thienyl)alkne acids.We take this opportunity to thank R. Kh. Freidlina, A. A. Beér, and M. A. Besprozvannii for giving us enough -chloroalkane acids.     

Direct synthesis of α-thio aromatic acids from aromatic amino acids

Modified amino acids are useful synthetic components in both chemistry and biology. Here we describe a simple, scalable two-step procedure to generate α-thio aromatic acids from aromatic amino acids with yields of up to 96%. Diazotization and α-lactone mediated bromination efficiently form the α-bromo acid with retention of configuration. Thiol substitution with mild reagents such as sodium hydrosulfide or sodium trithiocarbonate provides the inverted, free α-thio acid. The mildly acidic soft nucleophile can then be utilized in many synthetic applications.     

Water-soluble xanthobilirubinic acids?

Abstract  Xanthobilirubinic acid, a model dipyrrinone for one-half of the bilirubin molecule in photochemical and metabolism studies, is more polar than bilirubin and insoluble in water and in chloroform. Replacing the β-alkyl substituents on the lactam ring of xanthobilirubinic acid with methyl-capped ethylene glycol, diethylene glycol, and triethylene glycol (PEG) groups steadily increased the water solubility of the pigment so that the last is completely soluble in both water and chloroform. Synthesized by base-catalyzed condensation of the corresponding methyl-capped 3,4-diPEG-pyrrolin-2-one with 3,5-dimethyl-4(2-ethoxycarbonylethyl)-2-formyl-1H-pyrrole, these new PEGylated analogs of xanthobilirubinic acid are yellow-colored dipyrrinones that form intermolecular hydrogen-bonded dimers in chloroform solution but are monomeric in methanol and water, as revealed by ¹H NMR spectroscopy and vapor pressure osmometry. Methyl xanthobilirubinate has served as a synthetic precursor to bilirubinoids; its amphiphilic PEGylated analogs suggest a route to water-soluble bilirubinoids and biliverdinoids. Graphical abstract        

Enamines of 3-acyltetramic acids from β-enamino amides and amino acids

A novel approach for the synthesis of enamine derivatives of N-protected 3-acyltetramic acids is described. The synthetic procedure relies on α-C-acylation of β-enamino amides with N-protected α-amino acids and subsequent cyclisation of the obtained intermediates in refluxing TFA. The tetramic derivatives are obtained with very good enantiopurity (e.r. ≥95:5). Ring-enlarged analogues (piperidine-2,4-diones) can also be obtained from β-amino acids.     

Glycoconjugates of amino acids. Preparation throughN-alkylation of amino acids withN-chloroacetyl-β-glycopyranosylamines

Monoalkylation of amino acids of different structural types withN-chloroacetyl-glycosylamines was shown to be applicable for the preparation of glycoconjugates containing β-d-galactose,N-acetyl-β-d-glucosamine, β-d-mannose, and lactose residues. The glycoconjugates were synthesized from amino acids with secondary (sarcosine,l-proline) or primary (l-2- and 4-aminobutyric acids,l-tryptophan) amino groups as well as from various amino dicarboxylic acids (N-methyl-dl-aspartic,dl-aspartic,l-glutamic, anddl-2-aminoadipic acids). The derivatives obtained may be of interest for glycotargeting of physiologically active compounds of this series. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1377–1380, July, 1999.     

Facile synthesis of α-hydroxy carboxylic acids from the corresponding α-amino acids

An effective and improved procedure is developed for the synthesis of α-hydroxy carboxylic acids by treatment of the corresponding protonated α-amino acid with tert-butyl nitrite in 1,4-dioxane–water. The amino moiety must be protonated and located α to a carboxylic acid function in order to undergo initial diazotization and successive hydroxylation, since neither β-amino acids nor acid derivatives such as esters and amides undergo hydroxylations. The method is successfully applied for the synthesis of 18 proteinogenic amino acids.     

Heteropoly acids of the Keggin type with N-substituted β-amminoethylphosphonic acids as coordinate center

Organophosphorus-heteropolytungstic acids of 1 : 12 of P/W ratio, with N-substituted 2-amminoethylphosphonic acids R2R'N+CH2CH2PO3H- (R = R' = H; R = Me, R' = H; R = R' = Me; R = H, R' = Me2CH; R = H , R' = CH3(CH2)2CH2) as coordinate centers were prepared, and characterized by means of elemental analysis, IR, UV spectroscopy, TG and DSC thermal analysis. The results indicate that these organophosphorous-HPAs possess Keggin type structure, and their stoichiometric formulation is R2R'N+CH2CH2PO3H - ·W12O36 ·nH2O. The organic side chain with the ammino-group R2R'N+CH2CH2- and the phosphono-group-PO3H- participate altogether in the formation of the primary structure of the heteropoly anion. In other words, the entirety of each compound R2R'N+CH2CH2PO3H- is as the core or coordinate center of the heteropoly anions. The number of crystal water in the HPA was affected obviously by the N-substituents of the organo-phosphonic acids.     

A reasonably stereospecific multistep conversion of Boc-protected α-amino acids to Phth-protected β-amino acids

A method for the synthesis of β³-amino acids starting from α-amino acids is described. This conversion can be effected by an eight-step procedure which involves the transformation of the carboxylic group into an alkyne followed by a selenium-mediated conversion of the carbon-carbon triple bond to a Se-phenyl selenocarboxylate intermediate. The reactive Se-phenyl selenocarboxylate intermediates can be trapped with water, alcohols or the amine of an amino acid derivative to give β³-amino acids, β³-amino esters or mixed peptides, respectively. The whole transformations of the carboxylic group into an alkyne and of the alkyne group into β³-amino acids may not require purification of the intermediate products but a work-up and isolation procedure of crude materials.     

Carbocyclic α-amino acids: asymmetric synthesis of all four 1-amino-2-hydroxycyclohexanecarboxylic acids

Starting from racemic 2-methoxycyclohexanone and (S)- or (R)-1-phenylethylamine, respectively, the four stereoisomers of 1-amino-2-hydroxycyclohexanecarboxylic acid are obtained via an asymmetric Strecker synthesis with ee values ranging from 87 to 98%. Their stereochemistry is established by NMR methods and by X-ray analyses. Hydrogenolysis of a benzylic C–N bond by conc. sulphuric acid as well as cleavage of a methoxy ether by conc. HCl are two intriguing reactions which are observed within the five-step procedure described herein.     

Ternary mixed-ligand complexes of copper(II) with α-aminoalkylphosphonic acids and amino acids

Formation of ternary mixed-ligand complexes of copper (II) with 16 -amino acids and -aminophosphonic acids (APA) with a 111 ratio of initial concentrations has been studied by potentiometric titration at 25C and 0.1 M KC1 in aqueous solution. The complexes Cu_pA_nB_sH_q are formed in solution, where A and B are the deprotonated ligands. The stability of the mixed-ligand complexes (log ) increases and the equilibrium is displaced more towards their formation (log K) as the hydrophobic nature of the ligands increases.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 3, pp. 570–575, March, 1991.     

Chirality measures of α-amino acids

To measure molecular chirality, the molecule is treated as a finite set of points in the Euclidean R(3) space supplemented by k properties, p(1)((i)), p(2)((i)), ..., p(k)((i)) assigned to the ith atom, which constitute a point in the Property P(k) space. Chirality measures are described as the distance between a molecule and its mirror image minimized over all its arbitrary orientation-preserving isometries in the R(3) × P(k) Cartesian product space. Following this formalism, different chirality measures can be estimated by taking into consideration different sets of atomic properties. Here, for α-amino acid zwitterionic structures taken from the Cambridge Structural Database and for all 1684 neutral conformers of 19 biogenic α-amino acid molecules, except glycine and cystine, found at the B3LYP/6-31G** level, chirality measures have been calculated by a CHIMEA program written in this project. It is demonstrated that there is a significant correlation between the measures determined for the α-amino acid zwitterions in crystals and the neutral forms in the gas phase. Performance of the studied chirality measures with changes of the basis set and computation method was also checked. An exemplary quantitative structure–activity relationship (QSAR) application of the chirality measures was presented by an introductory model for the benchmark Cramer data set of steroidal ligands of the sex-hormone binding globulin.     

Synthesis of quaternary α-aminophosphonic acids

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Enantioselective synthesis of β-hydroxy carboxylic acids: direct conversion of β-oxocarboxylic acids to enantiomerically enriched β-hydroxy carboxylic acids via neighboring group control

β-Oxocarboxylic acids can be reduced to the corresponding β-hydroxy carboxylic acids employing DIP-Cl^™ as a reducing agent. The β-carboxylic substituent exerts a remarkable neighboring group effect on the reduction. The reaction presumably proceeds in an intramolecular fashion through a `rigid' bicyclic transition state assembly, which produces enantioselectivities approaching 99%.     

Carbocyclic α-amino acids: asymmetric Strecker synthesis of a series of 2-alkylated 1-aminocyclopentanecarboxylic acids

A series of 12 carbocyclic α-amino acids has been prepared from four different racemic 2-alkylated cyclopentanones and (R)-1-phenylethylamine as the chiral auxiliary by means of an asymmetric Strecker synthesis. The stereoselectivity was influenced by solvent, temperature and size of the substituent at the 2-position of the cyclopentanones. For the methyl and ethyl substituted amino acids all four possible stereoisomers could be obtained, whereas for the isopropyl and tertiary butyl compounds an unexpected side reaction prohibited the isolation of the cis configured amino acids. The 1,3-induction mechanism observed for the kinetically controlled α-amino nitrile formation in the 2-methyl and 2-ethyl series was overlayed by a 1,2-induction in the respective 2-isopropyl and 2-tertiary butyl series.     

Preparation of α,α-difluoroalkanesulfonic acids

Chlorodifluoromethanesulfonic acid (1) was prepared using a new procedure starting from perchloromercaptan, which is readily obtained from chlorination of CS₂. Modified Swarts reaction transformed N,N-diethyl trichloromethanesulfenamide into N,N-diethyl chlorodifluoromethanesulfenamide, and the latter species was further oxidized and hydrolyzed into chlorodifluoromethanesulfonic acid. The preparations of other two new α,α-difluoroalkanesulfonic acids, phenyl difluoromethanesulfonic acid (2) and 2-phenyl-1,1,2,2,-tetrafluoroethanesulfonic acid (3), are also disclosed. The acids 2 and 3 are stable in the forms of sodium (lithium) salts or in aqueous solutions; however, the pure forms of 2 and 3 can readily undergo defluorinations. 1-3 and their salts have potential applications as superacid catalysts and lithium battery electrolytes.