Glucosamine and Glucosamine-6-phosphate Derivatives: Catalytic Cofactor Analogs for the glmS Ribozyme

摘要

Two analogues of glucosamine-6-phosphate (GlcN6P, >1) and five of glucosamine (GlcN, >2) were prepared for evaluation as catalytic cofactor of the glmS ribozyme, a bacterial gene-regulatory RNA that controls cell wall biosynthesis. Glucosamine and allosamine with 3-azido substitutions were prepared by SN2 reactions of the respective 1,2,4,6-protected sugars; final acidic hydrolysis afforded the fully deprotected compounds as their TFA salts. A 6-phospho-2-aminoglucolactam (>31) was prepared from glucosamine in a 13-step synthesis, which included a late-stage POCl3-phosphorylation. A simple and widely applicable 2-step procedure with the triethylsilyl (TES) protecting group was developed to selectively expose the 6-OH group in N-protected glucosamine analogs, which provided another route to chemical phosphorylation. Mitsunobu chemistry afforded 6-cyano (>35) and 6-azido (>36) analogues of GlcN-(Cbz) and the selectivity for the 6-position was confirmed by NMR (COSY, HMBC, HMQC) experiments. Compound >36 was converted to the fully deprotected 6-azido-GlcN (>37) and 2,6-diaminoglucose (>38) analogs. A 2-hydroxylamino glucose (>42) analogue was prepared via an oxaziridine (>41). Enzymatic phosphorylation of >42 and chemical phosphorylation of its 6-OH precursor (>43) were possible, but >42 and the 6-phospho product (>44) were unstable under neutral or basic conditions. Chemical phosphorylation of the previously described 2-guanidinyl-glucose (>46) afforded its 6-phospho analogue (>49) after final deprotection.