Synthesis of N ‐Acetylglucosamine‐Derived Nagstatin Analogues and Their Evaluation as Glycosidase Inhibitors

Abstract The gluco ‐configured analogue 15 of nagstatin ( 1 ) and the methyl ester 14 were synthesized via condensation of the thionolactams 17 or 18 with the β ‐amino ester 19 . The silyl ethers 20 and 21 resulting from 17 were desilylated to 22 and 23 ; these alcohols were directly obtained by condensing 18 and 19 . The attempted substitution of the C(8)OH group of 22 by azide under Mitsunobu conditions led unexpectedly to the deoxygenated α ‐azido esters 24 . The desired azide 25 was obtained by treating the manno ‐configured alcohol 23 with diphenyl phosphorazidate. The azide was transformed to the debenzylated acetamido ester 14 that was hydrolyzed to the nagstatin analogue 15 . The imidazole‐2‐acetates 14 and 15 are nanomolar inhibitors of the N ‐acetyl‐ β ‐glucosaminidases from Jack beans and from bovine kidney, submicromolar to micromolar inhibitors of the β ‐glucosidase from Caldocellum saccharolyticum , and rather weak inhibitors of the snail β ‐mannosidase. In all cases, the ester was a stronger inhibitor than the corresponding acid. As expected from their gluco ‐configuration, both imidazopyridines 14 and 15 are stronger inhibitors of the β ‐ N ‐acetylglucosaminidase from bovine kidney than nagstatin.