An efficient and versatile synthesis of GlcNAcstatins-potent and selective O-GlcNAcase inhibitors built on the tetrahydroimidazo[1,2-a]pyridine scaffold.

ABSTRACT: We report a novel approach to the synthesis of GlcNAcstatins-members of an emerging family of potent and selective inhibitors of peptidyl O-GlcNAc hydrolase build upon tetrahydroimidazo[1,2-a]pyridine scaffold. Making use of a streamlined synthetic sequence featuring de novo synthesis of imidazoles from glyoxal, ammonia and aldehydes, a properly functionalised linear GlcNAcstatin precursor has been efficiently prepared starting from methyl 3,4-O-(2',3'-dimethoxybutane-2',3'-diyl)-?-d-mannopyranoside. Subsequent ring closure of the linear precursor in an intramolecular S(N)2 process furnished the key fused d-mannose-imidazole GlcNAcstatin precursor in excellent yield. Finally, a sequence of transformations of this key intermediate granted expeditious access to a variety of the target compounds bearing a C(2)-phenethyl group and a range of N(8) acyl substituents. The versatility of the new approach stems from an appropriate choice of a set of acid labile permanent protecting groups on the monosaccharide starting material. Application was demonstrated by the synthesis of GlcNAcstatins containing polyunsaturated and thiol-containing amido substituents.

SUBMITTER: Borodkin VS 

PROVIDER: S-EPMC2956484 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature