Synthesis of Polyhydroxylated Dihydro-Oxazines, Their Reactivity Studies, and Applications in the Construction of 1,2-Oxazinane Iminosugar Library with Bioactivities

Four polyhydroxylated dihydro-oxazines have been synthesized as competitive products of well-known nitrones from corresponding carbohydrates through efficient and practical procedures involving a five–to–seven–steps sequence in moderate overall yields (15%–35%). The key S N 2 N - or O -attack ring-cyclization steps to afford the desired dihydro-oxazines were found to be significantly influenced by fluoride concentration, alkalinity, and water content in the reaction system. Reactivities of d - and l -ribose-derived polyhydroxylated dihydro-oxazines were then fully screened under reduction and nucleophilic organometallic addition conditions, revealing them as excellent synthons in affording versatile products including C-1 modified N, O -ketal, 1,2-oxazinanes, and related nitrile derivatives under different conditions. Subsequently, a compound library containing 34 polyhydroxylated 1,2-oxazinanes was established and subjected to thorough glycosidase inhibition and an anticancer study. While most of them showed no inhibition of the tested glycosidases, part of these compounds demonstrated moderate or weak inhibitory activities against the MOLT-4 cell line, providing implications for subsequent screening of related iminosugar derivatives with potential anticancer activities.