Loránd Kiss

Synthesis of Carbocyclic and Heterocyclic β-Aminocarboxylic Acids

In consequence of their biological e ff ects, conformationally constrained carbocyclic β -amino acids have generated great interest among synthetic and medicinal chemists in the past 2 decades, and they have become a hot topic in organic and bioorganic chemistry. These compounds are found in natural products and antibiotics. They are also considered important precursors for pharmacologically interesting β -lactams and other bioactive compounds. Certain carbocyclic β -amino acids, e.g., cispentacin , icofungipen , and BAY Y9379 , possess noteworthy antifungal or antibacterial activities, while tilidin , a phenyl-substituted cyclohexene amino ester, is an analgetic.

Alkyne-azide cycloadditions with copper powder in a high-pressure continuous-flow reactor: High-temperature conditions versus the role of additives

A safe and efficient flow-chemistry-based procedure is presented for 1,3-dipolar cycloaddition reactions between organic azides and acetylenes. This simple and inexpensive technique eliminates the need for costly special apparatus and utilizes Cu powder as a plausible Cu(I) source. To maximize the reaction rates, high-pressure/high-temperature conditions are utilized; alternatively, the harsh reaction conditions can be moderated at room temperature by the joint application of basic and acidic additives. A comparison of the performance of these two approaches in a series of model reactions has resulted in the formation of useful 1,4-disubstituted 1,2,3-triazoles in excellent yields. The risks that are associated with the handling of azides are lowered, thanks to the benefits of flow processing, and gram-scale production has been safely implemented. The synthetic capability of this continuous-flow technique is demonstrated by the efficient syntheses of some highly functionalized derivatives of the antifungal cispentacin.

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.

Applicability of sucrose laurate as surfactant in solid dispersions prepared by melt technology.

This study focused on an investigation of the applicability of sucrose laurate as surfactant in solid dispersions. Although this surfactant has a US Drug Master File, it has not been used so far in internal pharmaceutical products. High drug-loaded solid dispersion systems consisting of gemfibrozil as a model drug and PEG 6000 as a carrier, with or without sucrose laurate (D1216), were prepared by the melting method. Cytotoxicity studies on Caco-2 monolayer cells were also performed, in order to gain information on the applicability of D1216 in oral formulations. The results showed that the presence of the surface-active agent did not affect the solid-state characteristics of the model drug significantly. A markedly improved dissolution of gemfibrozil from the ternary solid dispersion systems was observed as compared with the binary solid dispersion systems. The optimum concentration range of the D1216 in the formulations was determined to be 5-10%. The effective final concentrations of D1216 in the dissolution experiments proved to be non-toxic towards CaCo-2 cells. The results suggest the potential use of D1216 in innovative internal pharmaceutical formulations.

Asymmetric synthesis of α,β-diamino acid derivatives with an aziridine-, azetidine- and γ-lactone-skeleton via Mannich-type additions across α-chloro- N-sulfinylimines†

The efficient asymmetric synthesis of new chiral γ-chloro-α,β-diamino acid derivatives via highly diastereoselective Mannich-type reactions of N-(diphenylmethylene) glycine esters across a chiral α-chloro-N-p-toluenesulfinylimine was developed. The influence of the base, LDA or LiHMDS, used for the formation of the glycine enolates, was of great importance for the anti-/syn-diastereoselectivity of the Mannich-type reaction. The γ-chloro-α,β-diamino acid derivatives proved to be excellent building blocks for ring closure towards optically pure anti- and syn-β,γ-aziridino-α-amino esters, and subsequent ring transformation into trans-3-aminoazetidine-2-carboxylic acid derivatives and α,β-diamino-γ-butyrolactones.

Functional linkage of Na+-Ca2+-exchanger to sarco/endoplasmic reticulum Ca2+ pump in coronary artery: comparison of smooth muscle and endothelial cells.

An increase in cytosolic Ca2+ concentration in coronary artery smooth muscle causes a contraction but in endothelium it causes relaxation. Na+‐Ca2+‐exchanger (NCX) may play a role in Ca2+ dynamics in both the cell types. Here, the NCX‐mediated 45Ca2+ uptake was compared in Na+‐loaded pig coronary artery smooth muscle and endothelial cells. In both the cell types, this uptake was inhibited by KB‐R7943, SEA 0400 and by monensin, but not by cariporide. Prior loading of the cells with the Ca2+ chelator BAPTA increased the NCX‐mediated 45Ca2+ uptake in smooth muscle but not in endothelial cells. In the presence or absence of BAPTA loading, the Na+‐mediated 45Ca2+ uptake was greater in endothelial than in smooth muscle cells. In smooth muscle cells without BAPTA loading, thapsigargin diminished the NCX‐mediated 45Ca2+ entry. This effect was not observed in endothelial cells or in either cell type after BAPTA loading. The results in the smooth muscle cells are consistent with a limited diffusional space model in which the NCX‐mediated 45Ca2+ uptake was enhanced by chelation of cytosolic Ca2+ or by its sequestration by the sarco/endoplasmic reticulum Ca2+ pump (SERCA). They suggest a functional linkage between NCX and SERCA in the smooth muscle but not in the endothelial cells. The concept of a linkage between NCX and SERCA in smooth muscle was also confirmed by similar distribution of NCX and SERCA2 proteins when detergent‐treated microsomes were fractionated by flotation on sucrose density gradients. Thus, the coronary artery smooth muscle and endothelial cells differ not only in the relative activities of NCX but also in its functional linkage to SERCA.

Efficient continuous-flow synthesis of novel 1,2,3-triazole-substituted β-aminocyclohexanecarboxylic acid derivatives with gram-scale production

Summary The preparation of novel multi-substituted 1,2,3-triazole-modified β-aminocyclohexanecarboxylic acid derivatives in a simple and efficient continuous-flow procedure is reported. The 1,3-dipolar cycloaddition reactions were performed with copper powder as a readily accessible Cu(I) source. Initially, high reaction rates were achieved under high-pressure/high-temperature conditions. Subsequently, the reaction temperature was lowered to room temperature by the joint use of both basic and acidic additives to improve the safety of the synthesis, as azides were to be handled as unstable reactants. Scale-up experiments were also performed, which led to the achievement of gram-scale production in a safe and straightforward way. The obtained 1,2,3-triazole-substituted β-aminocyclohexanecarboxylates can be regarded as interesting precursors for drugs with possible biological effects.

A novel and selective fluoride opening of aziridines by XtalFluor-E. synthesis of fluorinated diamino acid derivatives

The selective introduction of fluorine onto the skeleton of an aminocyclopentane or cyclohexane carboxylate has been developed through a novel and efficient fluoride opening of an activated aziridine ring with XtalFluor-E. The reaction proceeded through a stereoselective aziridination of the olefinic bond of a bicyclic lactam and regioselective aziridine ring opening with difluorosulfiliminium tetrafluoroborate with the neighboring group assistance of the sulfonamide moiety to yield fluorinated diamino acid derivatives. The method based on the selective aziridine opening by fluoride has been generalized to afford access to mono- or bicyclic fluorinated substances.

Regio- and diastereoselective fluorination of alicyclic β-amino acids

A regio- and stereoselective approach to fluorinated β-aminocyclohexene or cyclohexane esters has been developed, starting from a bicyclic β-lactam (1). The procedure involves six or seven steps, based on regio- and stereoselective iodolactonization, lactone opening and hydroxy-fluorine exchange. The method has been extended to the synthesis of fluorinated amino ester enantiomers.

A New Access Route to Functionalized Cispentacins from Norbornene β-Amino Acids

An efficient and simple new stereocontrolled access route to novel disubstituted cispentacin derivatives with multiple stereogenic centers from norbornene β-lactam has been developed. The synthesis involves olefinic bond functionalization by dihydroxylation followed by oxidative ring cleavage and transformation of the dialdehyde intermediate through a Wittig reaction.