We report a new approach to preparing iminosugars - 4-substituted 1-benzylpiperidin-3,5-diols by reaction of 1-benzyl-4,5-epoxypiperidine-3-ols in the presence of lithium perchlorate. This regio- and stereoselective synthesis proceeds via successive nucleophilic cleavage of 1-benzyl-4,5-epoxypiperidin-3-ols by benzylamine, thiophenol and diallylamine. Initial 1-benzyl-4,5-epoxypiperidin-3-ols were obtained by oxidation of trifluoroacetates of 1-benzyl-1,2,3,6-tetrahydropyridin-3-ols. [GRAPHICS] .

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-l-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. (C) 2017 Elsevier Ltd. All rights reserved.

We have developed a simple and effective method for the activation of palladium phosphine complexes in the Suzuki reaction (TON up to 9800, TOF up to 58800 h -1 ) by selecting an aqueous reaction medium instead of organic solvents. This method was elaborated for a high yield synthesis of heteroaromatic biaryls with furyl and thienyl groups.

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.

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 ⩾10kJ/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.

Enantiomerically pure trans-(3R,4R)-4-aminopiperidin-3-ols, which are convenient precursors for making natural and synthetic aminohydroxylated piperidine alkaloid analogs, were efficiently synthesized through the reaction of enantiomerically pure (3R,4S)-3,4-epoxypiperidine with amines in the presence of LiClO4 in CH3CN at room temperature. The absolute stereochemistry of the resultant amino alcohols was determined by the stereochemical correlation method and single-crystal X-ray analysis.