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.     

Membrane transport of dicarboxylic and α-hydroxy carboxylic acids induced by α-amino phosphonates

New -amino phosphonates containing different alkyl and aryl substituents at the -carbon atom were synthesized in high yields by the Kabachnik—Fields and Pudovik reactions. These compounds were studied as carriers of several -hydroxy carboxylic and dicarboxylic acids through liquid impregnated membranes. These -amino phosphonates studied are capable of molecular recognition of oxalic acid among structurally similar -hydroxy carboxylic and dicarboxylic acids. The efficiency and selectivity of mass transfer of oxalic acid increase with an increase in the lipophilicity of the -amino phosphonate.     

Novel chiral solvating agents derived from natural amino acid: enantiodiscrimination for chiral α-arylalkylamines

Two benzo[de]isoquinoline 1,3-dione amino acids 1 and 2 were readily prepared, and their enantiodiscriminating ability were investigated by ¹H NMR spectroscopy. It was found that 1 exhibited an excellent chiral recognition ability toward chiral α-phenylethylamine and some of its derivatives, leading to clear baseline separation of the multiplet of the probe groups in two enantiomers. The stoichiometric ratio and association constants of some host-guest complexes were determined. The interactions between the hosts and guest 3 were further studied by intermolecular NOE experiment and ESI-MS.     

Roof shape amines: synthesis and application as NMR chiral solvating agents for discrimination of α-functionalized acids

A series of new chiral roof shape amines have been prepared from anthracene involving simple chemical steps and enzymatic resolution of isomers. The amines were screened as chiral solvating agents for the discrimination of enantiomers of several α-functionalized acids by the ¹H NMR analysis. The system can also be used to accurately measure enantiomeric excess of mandelic acid by ¹H NMR analysis. The roof shape CSAs were capable of detecting the shift in the signals for the standard four nuclei of ¹H, ¹³C, ¹⁹F and ³¹P of various optically active acids.     

Electrophilic asymmetric syntheses of α-hydroxy carboxylic acids

Asymmetric electrophilic synthesis of α-hydroxy carboxylic acids from chiral amide derivatives of tert-butyl- and trialkylsilyl- protected glycolic and lactic acids are described which lead to chiral α-hydroxy carboxylic acids in 60–95% diastereomic excess.     

Enantioselective synthesis of α-amino acids in chiral reverse micelles

Through alkylation of ethyl 2-phthalimidoacetate in chiral reverse micelles formed from chiral surfactants, followed by hydrazinolysis and hydrolysis of the resulting products, optically active α-amino acids were synthesized. The highest enantioselectivity was 59.5%. Meanwhile, we have found that the asymmetric induction depends on the reaction temperature, the alkyl chain length of surfactant and the strucure of the surfactants.     

Asymmetric synthesis of quaternary α-amino acids using d-ribonolactone acetonide as chiral auxiliary

We describe a new simple methodology to prepare enantiopure α,α-dialkylglycines based on the use of commercially available d-ribonolactone as a chiral auxiliary. Enantiopure α-methyl and α-butyl series are prepared through diastereoselective alkylation and subsequent Schmidt rearrangement of α,α-dialkylacetoacetates of d-ribonolactone acetonide. Absolute configuration was assigned through preparation of enantiopure 4,4-disubstituted 3-methyl-2-pyrazolin-5-ones.     

A simple approach for the synthesis of new pyrimidinyl α-amino acids

A simple synthetic method for the preparation of optically active pyrimidinyl α-amino acids is presented. A nucleophilic ipso-substitution reaction between 2-(benzylsulfonyl)-4-isopropoxypyrimidines and a nucleophilic side chain of several protected natural α-amino acids is investigated to obtain new pyrimidin-2-yl α-amino acids. A detailed optimisation study of this reaction is discussed. Moreover, the selective O-alkylation of 2-(benzylsulfanyl)-4(3H)pyrimidinones with a hydroxylic side chain of some natural α-amino acids under Mitsunobu conditions is studied as a method to prepare new pyrimidin-4-yl α-aminoesters.     

Stereoselective alkylation of C2-symmetric chiral N-phthaloylglycinamides in the preparation of enantiopure α-amino acids

The novel, chiral glycinamides (S,S)-3 and (S,S)-4 were prepared in good yields from C₂-symmetric chiral amines (S,S)-1 and (S,S)-2, respectively. Enolate formation and addition to methyl iodide and benzyl bromide proceeded in good yield and high diastereoselectivity, especially in the presence of LiCl or DMPU. Removal of the phthaloyl protecting group with hydrazine, followed by hydrolysis with 6N HCl, converted the benzylated product (S,S,S)-7 to enantiopure (S)-phenylalanine.     

Controlled racemization and asymmetric transformation of α-substituted carboxylic acids in the melt

The racemization and asymmetric transformation of a series of α-substituted carboxylic acids, viz. mandelic acid, hydratropic acid, ibuprofen and naproxen, were studied. Several racemization methods for mandelic acid were studied and it was found that base-catalyzed racemization in aprotic polar solvents was the most efficient method. Moreover, a fast and mild base-catalyzed racemization reaction in the melt was developed. DBN turned out to be a very efficient racemizing base for the substrates studied. Combination of the base-catalyzed racemization in the melt with known resolution processes resulted in crystallization-induced asymmetric transformations. Treating racemic ibuprofen or hydratropic acid with 1.5–2.5 equivalents of enantiopure α-methylbenzylamine and a catalytic amount of DBN resulted in the isolation of enantiomerically enriched ibuprofen or hydratropic acid with ees of up to 75% and almost quantitative yields.     

New polymer-supported chiral phase-transfer catalysts in the asymmetric synthesis of α-amino acids: the role of a spacer

Polymer-supported cinchona alkaloid salts with different spacers were used as phase-transfer catalysts in the asymmetric C-alkylation of N-diphenyl methylene glycine tert-butyl ester. Various catalysts and alkylation conditions were studied, the best result being 81% e.e. with cinchoninium iodide bound to polystyrene with a four-carbon spacer.     

Catalytic hydrolysis of α-amino esters in the presence of chiral palladacycles

The rate of hydrolysis of esters derived from optically active α-amino acids, catalyzed by chiral cyclopalladated benzylamines, depends on the configuration of chiral centers in the substrate and catalyst. The catalytic hydrolysis of sulfur-containing amino esters follows an intramolecular mechanism, and the difference in the reaction rates for the stereoisomers increases in going from ortho-palladated primary benzylamines (k _S/k _R = 1.1) to tertiary amines (k _S/k _R = 1.5); the strongest catalytic effect is observed for an ester and a complex with the same absolute configuration of the chiral centers. The efficiency of intermolecular catalysis is greater for a complex and ester with opposite absolute configurations of the chiral centers, and the rate constants of catalytic hydrolysis for two pairs of stereoisomers coincide within experimental error. The maximal difference in the reaction rates is observed for cyclopalladated secondary benzylamines; it reaches 2.3 for the phenylalanine ester.     

Enantioselective α-alkylation of unsaturated carboxylic acids using a chiral lithium amide

The regio- and stereochemistry of the alkylation of dienediolates from unsaturated carboxylic acids with benzylic halides, which often results in mixtures of isomers, can be controlled by means of changes in the lithium amide, allowing the α-regioisomer to be obtained as the major diastereoisomer. In addition, when chiral amines are used, moderate enantiomeric excesses can be attained.     

The preparation and alkylation of a butanedione-derived chiral glycine equivalent and its use for the synthesis of α-amino acids and α,α-disubstituted amino acids

A benzyloxycarbonyl protected glycine equivalent 2 has been prepared in enantiopure form and has been used in the synthesis of both α-substituted amino acids and α,α-disubstituted amino acids. The process involved deprotonation to form the corresponding enolates which underwent stereoselective alkylation with various electrophiles and upon hydrolysis gave the corresponding amino acid derivatives as enantiomerically pure products.     

Cleavage of hindered α-methylbenzylamides,intermediates in the resolution of carboxylic acids

α-Methylbenzylamides, useful intermediates in the resolution of carboxylic acids, are cleaved with a two step procedure; enolizable amides are not racemized.     

Synthesis of difluorinated pseudopeptides using chiral α,α-difluoro-β-amino acids in the Ugi reaction

2,2-Difluoro-3-(2-hydroxy-1 R-phenylethylamino)-3 S-phenylpropionic acid 3, obtained by a Reformatsky-type reaction of ethyl bromodifluoroacetate with (4R)-2,4-diphenyloxazolidine, was used as a classical carboxylic acid in the Ugi reaction to prepare various difluorinated pseudopeptides 5a-n. Compounds 5 were then deprotected by hydrogenolysis to furnish difluorinated pseudopeptides 6.