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 (2 S ,4 R )‐ 4 and (2 R ,4 S )‐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 (2 S ,4 R )‐ 20a and (2 R ,4 S )‐4‐acetoxy‐ N ‐[(2 S ,3 S )‐1,2,3‐trihydroxybutyl]pipecolate ( 20b ) were obtained by displacement of (–)‐(2 S ,2 S )‐2‐ O ‐benzyl‐3,4‐ O ‐isopropylidene‐1‐deoxy‐1‐iodothreitol ( 19 ) by 4 and 5 . Compounds 20a , b were converted into (2 S ,4 R ,2′ S ,2′ S )‐ 21a and(2 R ,4 S ,2′ S ,3′ S )‐4‐hydroxy‐2‐hydromethyl‐ N ‐(2‐benzyloxy‐3,4‐isopropylidenedioxy)piperidine ( 21b ) and finally into unprotected pentols 22a , b . Nonprotected (2 S ,2′ S ,3′ S )‐ 11a and (2 S ,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, (2 S ,3 S )‐2,3‐diacetoxy‐4‐[(2 R ,4 S )‐4‐acetoxy‐2‐(methoxycarbonyl)piperidin‐1‐yl]‐4‐oxobutanoic acid ( 13b ) is an inhibitor (IC 50 = 157 μ M ) of α‐ L ‐fucosidase from bovine kidney.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)