Márta Palkó

Syntheses of Hydroxylated Cyclic β-Amino Acid Derivatives

This review is intended to give a short summary of the developments in the field of natural and synthetic alicyclic and heterocyclic hydroxylated β-amino acids and to focus on the main strategies that have been reported for their synthesis. Given the medicinal and biological significance of the hydroxylated β-amino acids, an increasing volume of research is currently being directed toward regio-, stereo- and enantioselective access to this class of compounds.

Structural and temperature effects on enantiomer separations of bicyclo[2.2.2]octane-based 3-amino-2-carboxylic acids on cinchona alkaloid-based zwitterionic chiral stationary phases

Procedures for the direct high-performance liquid chromatographic enantiomer separation of four bicyclo[2.2.2]octane-based 3-amino-2-carboxylic acids were developed in polar-ionic mode on zwitterionic chiral stationary phases (CSPs) based on cinchonane alkaloide quinine, quinidine and chiral sulfonic acid motifs. The effects of the mobile phase composition including the type of acid and base additives, the structures of the analytes and temperature were investigated. Experiments were performed at constant mobile phase compositions in the temperature range 10-50°C in order to study the effects of temperature, and thermodynamic parameters were calculated from plots of ln k or ln α vs. 1/T. Some mechanistic aspects of the chiral recognition process are discussed with respect to the structures of the analytes. It was found that the enantiomeric separations were in most cases enthalpically driven, but entropically driven separation was also observed. The sequence of elution of the enantiomers on the pseudo-enantiomerically behaving CSPs was determined in all cases.

Synthesis of all four enantiomers of 1-aminoindane-2-carboxylic acid, a new cispentacin benzologue

Abstract Racemic cis- and trans -1-aminoindane-2-carboxylic acids ( 3 and 5 ) were prepared from indene by chlorosulphonyl isocyanate addition followed by ring opening and isomerisation. The intermediate racemic hydroxymethylated β-lactam 6 was resolved through the lipase-catalysed asymmetric acylation of the primary hydroxy group at the ( R )-stereogenic centre. High enantioselectivities ( E >200) were observed when the enzymatic reactions were performed with lipase AK or lipase PS as catalyst and vinyl acetate or vinyl butyrate as acyl donor. The hydrolysis and isomerisation resulted in all four enantiomers ( 9 , 11 , 13 and 14 ) of 1-aminoindane-2-carboxylic acid, a new benzologue of cispentacin.

Enantiomeric Separation of Bicyclo[2.2.2]octane‐Based 2‐Amino‐3‐Carboxylic Acids on Macrocyclic Glycopeptide Chiral Stationary Phases

Direct high-performance liquid chromatographic (HPLC) separation of four bicyclo[2.2.2]octane based 2-amino-3-carboxylic acid enantiomers were developed on chiral stationary phases (CSPs) containing different macrocyclic glycopeptide antibiotic selectors. The analyses were performed under reversed-phase, polar organic and polar ionic mode on macrocyclic-glycopeptide-based Chirobiotic T, T2, TAG, and R columns. The effects of the mobile phase composition including the acid and base modifier, the structure of the analytes, and the temperature on the separations were investigated. Experiments were achieved at constant mobile phase compositions on different stationary phases in the temperature range 5-40°C. Thermodynamic parameters were calculated from plots of ln k or ln α versus 1/T. It was recognized that the enantioseparations in reversed-phase and polar organic mode were enthalpically driven, but under polar-ionic conditions entropically driven enantioseparation was observed as well. Baseline separation and determination of elution sequence were achieved in all cases.

Synthesis and Transformations of di-endo-3-Aminobicyclo- (2.2.2)oct-5-ene-2-carboxylic Acid Derivatives

all-endo-3-amino-5-hydroxybicyclo[2.2.2]octane-2-carboxylic acid (13) and all-endo-5-amino-6-(hydroxymethyl)bicyclo[2.2.2]octan-2-ol (10) were prepared via dihydro-1,3-oxazine or γ-lactone intermediates by the stereoselective functionalization of an N-protected derivative of endo-3-aminobicyclo[2.2.2]oct-5-ene-2-carboxylic acid (2). Ring closure of β-amino ester 4 resulted in tricyclic pyrimidinones 15 and 16. The structures, stereochemistry and relative configurations of the synthesized compounds were determined by IR and NMR.

Continuous-flow retro-Diels-Alder reaction: An efficient method for the preparation of pyrimidinone derivatives

The syntheses of various pyrimidinones as potentially bioactive products by means of the highly controlled continuous-flow retro-Diels–Alder reaction of condensed pyrimidinone derivatives are presented. Noteworthy, the use of this approach allowed us to rapidly screen a selection of conditions and quickly confirm the viability of preparing the desired pyrimidinones in short reaction times. Yields typically higher than those published earlier using conventional batch or microwave processes were achieved.

Synthesis of Pyrrolo[1,2-a]pyrimidine Enantiomers via Domino Ring-Closure followed by Retro Diels-Alder Protocol

From 2-aminonorbornene hydroxamic acids, a simple and efficient method for the preparation of pyrrolo[1,2-a]pyrimidine enantiomers is reported. The synthesis is based on domino ring-closure followed by microwave-induced retro Diels-Alder (RDA) protocols, where the chirality of the desired products is transferred from norbornene derivatives. The stereochemistry of the synthesized compounds was proven by X-ray crystallography. The absolute configuration of the product is determined by the configuration of the starting amino hydroxamic acid.

Synthesis and receptor binding of new thieno[2,3-d]-pyrimidines as selective ligands of 5-HT3 receptors

With the aim to develop new potent and selective ligands of 5‐HT3‐type serotonin receptors and to acquire more information on their structure‐affinity relationships, new thieno[2,3‐d]pyrimidine derivatives 32–39 were synthesized and their binding to 5‐HT3 versus 5‐HT4 receptors was studied. Some of these new compounds exhibit good affinity for cortical 5‐HT3 receptors, but not for 5‐HT4 receptors. Among these derivatives, 6‐ethyl‐4‐(4‐methyl‐1‐piperazinyl)‐2‐(methylthio)thieno[2,3‐d]pyrimidine 32 is the most potent ligand (Ki = 67 nM); it behaves as a competitive antagonist of the 5‐HT3 receptor function in the guinea pig colon. Its binding interactions with 5‐HT3A receptors were analysed by using receptor modelling and comparative docking.

Synthesis of imidazo[1′,5′: 1,2]pyrido [3,4-b]indole derivatives

Summary. The reactions of 1,2,3,4-tetrahydro-β-carboline-1-carboxylic acid and its ethyl ester with alkyl and aryl isothiocyanates under mild conditions resulted in the corresponding thiohydantoin-fused tetrahydro-β-carbolines. Treatment of the ethyl ester with isocyanates furnished ethyl 2-alkyl- or arylcarbamoyl-1,2,3,4-tetrahydro-β-carboline-1-carboxylates which were transformed to hydantoin-fused tetrahydro-β-carbolines. The structures of the thiohydantoin compounds, involving two conformers and the presence of keto-enol tautomerism, were determined by NMR spectroscopy.