Zsolt Szakonyi

Synthesis of bi- and tricyclic β-lactam libraries in aqueous medium

Water as a solvent is not only inexpensive and environmentally benign, but may allow good reactivity. The present work focuses on the application of a modified Ugi reaction, i.e. the Ugi four-centre three-component reaction (U-4C-3CR), in aqueous medium to construct β-lactam libraries. All the attempted reactions could be successfully performed in water. The reaction conditions under which the precipitation process was effective were investigated; no further work-up or purification was necessary. In several cases when less water-soluble β-amino acids were used, the precipitated products were isolated easily by simple filtration. In other cases, evaporation of the solvent was appropriate for isolation; when the product was crystalline, recrystallization was necessary to obtain the pure final compounds. In water, the yields were higher as compared with the reactions in organic solvents. When bicyclic β-amino acids and the bulky tert-butyl isocyanide were used as starting materials, noteworthy increases in diastereoselectivity were observed.

Synthesis and transformations of enantiomeric 1,2-disubstituted monoterpene derivatives

Abstract Regio- and stereospecific addition of chlorosulfonyl isocyanate to (+)- and (−)-α-pinene 1 resulted in enantiomerically pure β-lactams 2 , which were converted to enantiomeric β-amino esters 3 and 1,3-amino alcohols 4 and 6 with ee >99%. The resulting 1,3-difunctional compounds 3 , 4 and 6 were transformed to fused saturated 1,3-heterocycles such as tetrahydro-1,3-oxazines 7 and 9 , 2,4-pyrimidinedione 11 and 2-thioxopyrimidin-4-one 13 enantiomers.

Monoterpene-based chiral β-amino acid derivatives prepared from natural sources: Syntheses and applications

Natural monoterpenes have proved to be good starting materials for the synthesis of β-amino acid derivatives. In the past decade, a number of well-known synthetic procedures have been applied for the preparation of monoterpene-based β-amino acid derivatives, e.g. from β-lactams via the 1,2-dipolar cycloaddition of chlorosulfonyl isocyanate to commercial or readily available monoterpenes [e.g. (+)- and (−)-α- or δ-pinene, (+)-3- and 2-carene, (+)- and (−)-apopinene], the conjugate addition of amides to monoterpene-based α,β-unsaturated esters or the transformations of (−)-cis-pinonoic acid prepared by the oxidative cleavage of (+)- and (−)-verbenone. β-Amino acid derivatives are excellent building blocks for versatile transformations, e.g. multicomponent reactions resulting in β-lactams, syntheses of 1,3-heterocycles and diaminopyrimidine derivatives or the formation of peptides containing an H12 helix. 1,3-Amino alcohol derivatives prepared from β-amino esters have been applied as chiral catalysts in enantioselective transformations. Several of these compounds are of noteworthy pharmacological importance, such as tyrosine kinase Axl inhibitor diaminopyrimidine-coupled β-aminocarboxamides, MDR inhibitor thiourea derivatives of β-amino esters or 2-imino-1,3-oxazines, which exhibit marked growth inhibitory activity on multiple cancer cell lines. The present review summarizes recent developments relating to the syntheses, applications and pharmaceutical importance of monoterpene-based β-amino acids and their derivatives.

High-performance liquid chromatographic enantioseparation of monoterpene-based 2-amino carboxylic acids on macrocyclic glycopeptide-based phases.

The enantiomers of five monoterpene-based 2-amino carboxylic acids were directly separated on chiral stationary phases containing macrocyclic glycopeptide antibiotics such as teicoplanin (Astec Chirobiotic T and T2) and teicoplanin aglycone (Chirobiotic TAG) as chiral selectors. The effects of pH, the mobile phase composition, the structure of the analyte and temperature on the separations were investigated. Experiments were performed at constant mobile phase compositions in the temperature range 10-40°C to study the effects of temperature and thermodynamic parameters on separations. Apparent thermodynamic parameters and T(iso) values were calculated from plots of ln k or ln α versus 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 enantioseparations were in most cases enthalpy driven. The sequence of elution of the enantiomers was determined in all cases.

Effect of mobile phase composition on the liquid chromatographic enantioseparation of bulky monoterpene-based β-amino acids by applying chiral stationary phases based on Cinchona alkaloid

Stereoselective HPLC separations of five sterically constrained monoterpene-based 2-aminocarboxylic acid enantiomers were carried out by using the newly developed zwitterionic chiral stationary phases Chiralpak ZWIX(+)™ and ZWIX(-)™ based on Cinchona alkaloid. In order to optimize the retention and enantioselectivity parameters, the ratio of the different organic solvents in the mobile phase and the nature of the acid and base additives (counter- and co-ions) were systematically varied. The effects of structure variants of the analytes on the resolution were investigated. The elution sequence was determined in all cases and observed to be opposite on ZWIX(+)™ and ZWIX(-)™.

Synthesis and ring—Chain tautomerism of angularly substituted cycloalkane-fused tetrahydro-1,3-oxazines

Abstract Starting from 1-methyl-1-cyclopentene and -cyclohexene, regioisomeric 1,3-amino alcohols 6a,b and 7a,b were prepared by regio- and stereospecific reactions. When the amino alcohols were condensed with aromatic aldehydes, well-defined products 8–11 were obtained, which exist as three-component tautomeric mixtures in CDCl3 solution. When equation (1) was applied in all four sets 8–11, good linear correlations were obtained. For regioisomeric compounds, introduction of the methyl group in the bridgehead position resulted in reverse effects on the stability.

Synthesis, in vitro activity, and three-dimensional quantitative Structure-activity relationship of novel hydrazine inhibitors of human vascular adhesion protein-1

Vascular adhesion protein-1 (VAP-1) belongs to the semicarbazide-sensitive amine oxidases (SSAOs) that convert amines into aldehydes. SSAOs are distinct from the mammalian monoamine oxidases (MAOs), but their substrate specificities are partly overlapping. VAP-1 has been proposed as a target for anti-inflammatory drug therapy because of its role in leukocyte adhesion to endothelium. Here, we describe the synthesis and in vitro activities of novel series of VAP-1 selective inhibitors. In addition, the molecular dynamics simulations performed for VAP-1 reveal that the movements of Met211, Ser496, and especially Leu469 can enlarge the ligand-binding pocket, allowing larger ligands than those seen in the crystal structures to bind. Combining the data from molecular dynamics simulations, docking, and in vitro measurements, the three-dimensional quantitative structure-activity relationship (3D QSAR) models for VAP-1 (q(2)(LOO): 0.636; r(2): 0.828) and MAOs (q(2)(LOO): 0.749, r(2): 0.840) were built and employed in the development of selective VAP-1 inhibitors.

Synthesis of (1S)-1-amino-2,2-dimethylcyclopropane-1-carboxylic acid via PLE mediated hydrolysis of bis(2,2,2-trifluoroethyl) 2,2-dimethylcyclopropane-1,1-dicarboxylate

Abstract Hydrolysis of bis(2,2,2-trifluoroethyl) 2,2-dimethylcyclopropane-1,1-dicarboxylate with pig liver esterase afforded (1 R )-2,2-dimethyl-1-(2,2,2-trifluoroethoxycarbonyl)-cyclopropane-1-carboxylic acid in high enantiomeric excess. This compound was rearranged to (1 S )-2,2,2-trifluoroethyl-2,2-dimethyl-1-[( N -ethoxycarbonyl)amino]-cyclopropane-1-carboxylate via a Curtius type reaction with DPPA. Final alkaline hydrolysis gave (1 S )-1-amino-2,2-dimethylcyclopropane-1-carboxylic acid.

Synthesis of conformationally constrained tricyclic β-lactam enantiomers through Ugi four-center three-component reactions of a monoterpene-based β-amino acid

Abstract(1R,2R,3S,4R)-2-Amino-6,6-dimethylbicyclo[3.1.1]heptane-3-carboxylic acid 1 was reacted with three aldehydes and two isocyanides in methanol, in water, and under solvent-free conditions to prepare enantiomeric β-lactams via U-4C-3CRs. The yields in methanol were found to be from acceptable to good. High diastereoselectivities of the reactions were observed, and the diastereoisomers were successfully separated in most cases. In water or under solvent-free conditions, the yields were similar to those in methanol when the aldehyde was pivalaldehyde or propionaldehyde. The advantages of water are the facile isolation of the precipitated product and the shorter reaction time.

Solvent‐Enhanced Diastereo‐ and Regioselectivity in the PdII‐Catalyzed Synthesis of Six‐ and Eight‐Membered Heterocycles via cis‐Aminopalladation

The Pd(II)-catalyzed intramolecular oxidative cyclization of tosyl-protected cis- and trans-N-allyl-2-aminocyclohexanecarboxamides was examined, and efficient syntheses of cyclohexane-fused pyrimidin-4-ones and 1,5-diazocin-6-ones were developed. In the course of the research, a marked solvent effect was observed on both the regio- and diastereoselectivity. Additionally, a novel Pd(II)-mediated domino oxidation, oxidative amination reaction was discovered. Our experimental and theoretical findings suggest that the reactions proceed via a cis-aminopalladation mechanism.