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An efficient and versatile synthesis of GlcNAcstatins—potent and selective O-GlcNAcase inhibitors built on the tetrahydroimidazo[1,2-a]pyridine scaffold
- Source :
- Tetrahedron
- Publication Year :
- 2010
- Publisher :
- Elsevier BV, 2010.
-
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)-α-d-mannopyranoside. Subsequent ring closure of the linear precursor in an intramolecular SN2 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.<br />Graphical abstract
- Subjects :
- chemistry.chemical_classification
0303 health sciences
Ketone
Intramolecular reaction
010405 organic chemistry
Stereochemistry
medicine.drug_class
Organic Chemistry
Carboxamide
01 natural sciences
Biochemistry
Chemical synthesis
Article
3. Good health
0104 chemical sciences
03 medical and health sciences
chemistry.chemical_compound
chemistry
Aldose
Drug Discovery
Pyridine
medicine
Glyoxal
Protecting group
030304 developmental biology
Subjects
Details
- ISSN :
- 00404020
- Volume :
- 66
- Database :
- OpenAIRE
- Journal :
- Tetrahedron
- Accession number :
- edsair.doi.dedup.....474c8ac5f3bb1aa7d51aba2b6db0ca78