The "epimerisation" of UDP-GlcNAc to ManNAc, the first step in the biosynthesis of sialic acids, is catalyzed by UDP-GlcNAc 2-epimerase. In this paper we report the synthesis of transition state based inhibitors of this enzyme. To mimic the assumed first transition state of this reaction (TS 1), we designed and synthesized the novel UDP-exo-glycal derivatives 1-4. We also report herein the synthesis of 5 and 6, the first C-glycosidic derivatives of 2-acetamidoglucal, and the synthesis of the ketosides 7 and 8, which were designed as bis-substrate analogue and bis- product analogue, respectively, to mimic the second step of the reaction via the assumed second transition state TS 2.

No abstract

Reaction of α‐lithiated methyl glyoxylate diethyl mercaptal (3) with 2,3,5‐tri‐O‐benzyl‐D‐arabinose (2) stereoselectively afforded the D‐gluco‐2‐heptulosonate derivative 4. Mercaptal cleavage led to the corresponding pyranose 5a which could be directly transformed into unprotected D‐gluco‐2‐heptulosonic acid (1a), one of the target molecules. Deoxygenation of 5a at C‐3 could also be readily accomplished as its 3‐hydroxy group is unprotected. Thus, the second target molecule, 1b, was obtained in just a few steps.

0-Benzyl protected gluconolactone 1 reacts readily with 2-lithio derivatives of quinaldine, 2-methylquinoxaline, 2-methylbenzimidazole and N-protected derivatives, and 1-benzyloxymethyl-2-methylimidazole at low temperatures to afford as monoaddition products the corresponding ~-g~uco-2-heptuloses 2-5. The benzyl protective groups can be readily removed by hydrogenolysis as shown for the transformation of 4a into 8. Acylation reactions with 4a exhibited an interesting interplay between 0-and N-acylation which is dependent on the nature of the acylating agent and on the reaction conditions. Reductive removal of the anomeric hydroxy group in 4a-c and 5 was readily performed via elimination products 18a-c and 23; their hydrogenation with Pd/C gave directly the 0,N-deprotected C-P-D-ghcopyranosylmethyl derivatives 21 and 25, respectively.