Divergent Synthesis of 4-epi-Fagomine, 3,4-Dihydroxypipecolic Acid, and a Dihydroxyindolizidine and Their Î²-Galactosidase Inhibitory and Immunomodulatory Activities
Kumar | K. S. Ajish | Rathee | J. S. | Subramanian | M. | Chattopadhyay | S.
A divergent asymmetric synthesis of the titled iminosugars has been formulated starting from a chiral homoallyl alcohol as the versatile intermediate. The homoallyl alcohol was prepared by a highly diastereoselective Barbier reaction on a d-glucose-derived aldehyde. The protection of its hydroxyl function followed by reductive ozonolysis of the olefin and a subsequent one-pot three-step protocol involving a Staudinger reaction, reductive amination, and benzyloxy carbonyl protection yielded an important bicyclic furanopiperidine derivative. This was converted to the target compounds by following standard reactions. Among the synthesized compounds, 4-epi-fagomine (2b) was the best Î²-galactosidase inhibitor, and it also prevented LPS-mediated activation of Raw 264.7 macrophage cells. Its congener, 3,4-dihydroxypipecolic acid (4b) also showed similar trends in its cytokine- and enzyme-inhibitory properties at a low concentration (10 Î¼M) but was proinflammatory at higher concentrations. The bicyclic compound dihydroxyindolizidine (21) reduced the proinflammatory cytokine (IL-1Î² and TNF-Î±) levels in the LPS-activated Raw 264.7 cells without showing any enzyme-inhibition activity.Show more [+] Less [-]