Synthesis and glycosidase inhibitory activities of pyrrolidines and piperidines with N-(polyhydroxyalkyl) side chains

Amidification of L-proline (3) with (+)-(R,R)-6 and (-)-(S,S)tartaric anhydride diacetate (7) gave N-substituted L-proline derivatives 8a,b, respectively. Acids 8a,b were transformed into diesters 9a,b with MeOH/HCl. Similar reactions with methyl (2S,4R)-4 and (2R,4S)-4-acetoxypipecolate (5) led to bicyclic lactams 14a,b and 15a. Compounds 8a,b were converted into N-(trihydroxybutyl)pyrrolidine derivatives 8c,d, 10a,b and 11a,b. Methyl (2S,4R)-20a and (2R,4S)-4-acetoxyN-[(2S,3S)-1,2,3-trihydroxybutyl]pipecolate (20b) were obtained by displacement of (-)-(2S,2S)-2-O-benzyl-3,4-O-isopropylidene-1-deoxy-1-iodothreitol (19) by 4 and 5. Compounds 20a,b were converted into (2S,4R,2'S,2'S)-21a and (2R,4S,2'S,3'S)-4-hydroxy-2-hydromethyl-N-(2-benzyloxy-3,4-isopropylidenedioxy)piperidine (21b) and finally into unprotected pentols 22a,b. Nonprotected (2S,2'S,3'S)-11a and (2S,2'R,3'R)-N-(1,2,3-trihydroxybutyl)prolinol (11b), as well as 22a,b, did not inhibit any of the 13 glycosidases assayed. However, a triacetoxy derivative, (2S,3S)-2,3-diacetoxy-4[(2R,4S)-4-acetoxy-2-(methoxycarbonyl)piperidin-1-yl]-4- oxobutanoic acid (13b) is an inhibitor (IC50 = 157 mu M) of alpha-L-fucosidase from bovine kidney.