Diastereoselective Synthesis, Glycosidase Inhibition, and Docking Study of C-7-Fluorinated Casuarine and Australine Derivatives

C-7-fluorinated derivatives of two important polyhydroxylated pyrrolizidines, casuarine and australine, weresynthesized with organocatalytic stereoselective alpha-fluorination of aldehydes as the key step. The strategy is extensively applicable to some synthetically challenging fluorinated iminosugars and carbohydrates. The docking studies indicated that the potentinhibitions of trehalase and amyloglucosidase by thefluorinatedpolyhydroxylated pyrrolizidines are due to the interaction modesdominated byfluorine atoms in these iminosugars with the aminoacids'residues of the corresponding enzymes. Steady interactionswere established between the C-7fluoride and a hydrophobicpocket in amylo glucosidase by untypical anion-pi interactions. These unexpected docking modes and related structure-activity relationship studies emphasize the value of fluorination in the design of polyhydroxylated pyrrolizidine glycosidase inhibitors.