•A convenient synthesis of trans-3-amino-1-benzylpiperidin-4-ols is proposed.•Regiospecific aminolysis of 1-benzyl-3,4-epoxypiperidine is done by the DIBAL amides.•The products are potential intermediates towards analogues of pseudodistomin D.The report presents a first example of a regio- and stereospecific Lewis acid-catalyzed aminolysis of 1-benzyl-3,4-epoxypiperidine leading to trans-3-amino-1-benzylpiperidin-4-ols, in contrast with other Lewis acid-catalyzed reactions leading to trans-4-amino-1-benzylpiperidin-3-ols. The reaction is performed at room temperature using the reagents prepared by interaction of a hard Lewis acid – diisobutylaluminum hydride (DIBAL-H) with primary and secondary amines. The obtained products are potential intermediates on the way to stereochemical analogues of the antitumor piperidine alkaloid pseudodistomin D.Download high-res image (58KB)Download full-size image

Amphiphilic trans-3,4-bis(acyloxy)-1-benzylpiperidines able to perform a pH-triggered conformational flip (flipids) have been suggested as components of a new type of pH-sensitive liposomes (fliposomes). According to 1H NMR, their acid-induced conformational flip occurs in methanol-d4 when the apparent pD decreases from 6 to 3. The protonation-generated intramolecular hydrogen bond and electrostatic interactions make the conformer with axial acyloxy-groups predominant, which drastically increases the separation of hydrocarbon chains. The power of this trigger was estimated as ⩾10 kJ/mol. This flip perturbs the liposome membrane causing rapid release of the liposome cargo specifically in response to lowered pH. The pH-sensitive fliposomes containing one of these flipids, POPC and PEG-ceramide, and loaded with ANTS/DPX performed a content release within a few seconds at pH <5 demonstrating a potential of the piperidine derivatives as pH-switches for the design of liposomes for drug/gene delivery.

Derivatives of trans-3-hydroxy-4-aminopiperidine are suggested as potential pH-sensitive conformational switches able to perform two consecutive flips (or flip–flop) when basicity/acidity of solution changes. Such a double switch of conformation was detected by 1H NMR for a model compound—trans-3-hydroxy-4-morpholinopiperidine. A combination of hydrogen bonding and electrostatic/dipole–dipole interactions was suggested for rationalization. Computational studies provided additional insight into the complex intra- and intermolecular forces that determine the relative stabilities of conformers. In similar structures an incorporated trans-3-hydroxy-4-aminopiperidine moiety can serve as a conformational pH-trigger when equipped with substituents designed to perform certain geometry-dependent functions, for example, as cation chelators or as lipid tails.

An acid-induced conformational flip of trans-3,4-diacetoxy-1-benzylpiperidine has been determined by 1H NMR. It occurs while the apparent pH (pD) of the d4-methanol solution decreases from 6 to 3. Due to an intramolecular hydrogen bond, the conformer with axial position of both acetoxy groups becomes strongly predominant. The separation of the acetoxy groups increases drastically. Thus, in similar structures an incorporated trans-3,4-disubstituted piperidine moiety can serve as a conformational pH-trigger when equipped with substituents designed to perform certain geometry-dependent functions, for example, as cation chelators or as lipid tails. The power of this trigger was estimated as ∼10 kJ/mol.

This review summarizes methods for the conformational control of cyclohexane derivatives and for the control of conformation-dependent molecular properties by external stimuli affecting the intra- and intermolecular interactions of substituents. These stimuli include complexation, change of medium acidity, change of the substituents’ size and structure, as well as formation and breaking of labile bonds. Successful application of the compounds equipped with such conformational switches as the acid-sensitive components of liposomes for targeted drug delivery, selective ion carriers in membrane transport, and fluorescent sensors for cations and acids opens a way for broad development in this area toward controllable compounds and intelligent materials.

Glycosidases are very important enzymes involved in a variety of biochemical processes with a special importance to biotechnology, food industry, and pharmacology. Novel structurally simple inhibitors derived from cyclohexane-1,2-dicarboxylic acids were synthesized and tested against several fungal glycosidases from Aspergillus oryzae and Penicilliumcanescens. The presence of at least two carboxylic groups and one hydroxy group was essential for efficient inhibition. Significant selective inhibition was observed for α- and β-glucosidases, the magnitude of which depended on the configuration of substituents; inhibition increased for β-glucosidase by lengthening the alkoxy group of the inhibitor.Glycosidases are very important enzymes involved in a variety of biochemical processes with a special importance to biotechnology, food industry, and pharmacology. Novel structurally simple inhibitors derived from cyclohexane-1,2-dicarboxylic acids were synthesized and tested toward several fungal glycosidases from Aspergillus oryzae and Penicilliumcanescens. The presence of at least two carboxylic groups and one hydroxy group was essential for efficient inhibition. Significant selective inhibition was observed for α- and β-glucosidases, which magnitude depended on configuration of substituents and increased for β-glucosidase with lengthening of the inhibitor’s alkoxy group.

Protonation-induced conformational change of lipid tails is reported as a novel strategy to render pH-sensitive lipid amphiphiles and lipidcolloids.

Protonation-induced conformational change of lipid tails is reported as a novel strategy to render pH-sensitive lipid amphiphiles and lipidcolloids.