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

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.