Abstract
A practical synthesis of ring‐modified calystegine analogues with a 6‐oxa‐nor‐tropane structure has been developed. The methodology relies on the ability of the masked carbonyl group of hexose precursors to act as the electrophilic target for the nitrogen atom of pseudoamide (urea or thiourea) groups located at the C‐5 position through the open‐chain aldehyde form. The resulting piperidine species undergoes spontaneous intramolecular glycosylation reaction involving 6‐OH provided that the resulting bicyclic aminoacetal fulfils the anomeric effect. The hydroxylation profile of the imino sugar glycomimetics thus obtained can be modified by judicious choice of the monosaccharide template. The validity of the strategy has been demonstrated by the preparation of N‐thiocarbamoyl and N‐carbamoyl derivatives of 1‐deoxy‐6‐oxa‐(+)‐calystegine B~2~, (−)‐B~4~, (+)‐B~3~, and (−)‐B~2~ from L‐ido, L‐gulo, L‐altro, and D‐ido precursors. The requested thioureas and ureas were obtained from 5‐amino‐ or 5‐azido‐5‐deoxyhexofuranose derivatives by a coupling reaction with isothiocyanates or a tandem Staudinger−aza‐Wittig‐type reaction with triphenylphosphane and an isothiocyanate followed by addition of water to the resulting carbodiimide, respectively. Attempts to prepare analogues with the unnatural 3‐epi‐(+)‐calystegine B~2~ hydroxylation profile from L‐talofuranose (thio)ureas by this methodology led, however, to equilibrium mixtures of the furanose anomers, with only traces of the nor‐tropane form. Evaluation of the inhibitory activity of the whole series of calystegine analogues against several glycosidases indicated that the main structural requirements for strong and specific inhibition of bovine liver β‐glucosidase/β‐galactosidase are the all‐equatorial orientation of the triol system at the piperidine ring, the presence of a lipophilic substituent at the nitrogen atom and the location of the intramolecular aminoacetal oxygen atom at the 6‐position of the nor‐tropane core. On the basis of these data, a structural analogy of 6‐oxa‐(+)‐calystegine B~2~ derivatives with the natural calystegine C~1~ has been established and a 1‐azasugar inhibition mode is proposed. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)