C-3-ALKYLATED AND C-4-ALKYLATED POLYHYDROXYPYRROLIDINES - ENANTIOSPECIFIC SYNTHESES AND GLYCOSIDASE INHIBITORY ACTIVITY

Short, efficient, and stereoselective syntheses of enantiomerically pu re C-3- and C-4-alkylated analogues of (2R,3S,4R)-3,4-dihydroxy-2-(hyd roxymethyl) a potent alpha-galactosidase inhibitor, from 4-hydroxy-L-p roline are presented. Grignard addition or enolate alkylation of a lfl uoren-9-yl)-4-oxo-3-[(methoxymethyl)oxy]proline and epoxidation or hyd roboration of a 4-methylene-3-[(methoxymethyl)oxy]proline proceeded wi th complete stereoselection and in excellent yields. The inhibitory ac tivities of the synthesized pyrrolidines were measured and showed that the fit of A. niger alpha-galactosidase and the jack bean alpha-manno sidase around C-3 of the pyrrolidine ring (alpha face) must be very ti ght, while the fit around C-4 (alpha face) is much looser. Positioning a methylene group between the hydroxyl at C-4 and the pyrrolidine rin g completely abolishes the inhibitory activity (see analogue 5).