Synthesis of mycothiol, 1D-1-O-(2-[N-acetyl-l-cysteinyl]amino-2-deoxy-α-d-glucopyranosyl)-myo-inositol, principal low molecular mass thiol in the actinomycetes

• Published in: Bioorganic & medicinal chemistry Vol. 10; no. 4; pp. 875 - 881
• Main Authors: Jardine, M.Anwar, Spies, Hendrik S.C, Nkambule, Comfort M, Gammon, David W, Steenkamp, Daniel J
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.04.2002; Elsevier Science
• Subjects: Actinomycetales - chemistry; Carbohydrates with 4, 5, 6, ... C atoms, dissacharides and oligosaccharides; Carbohydrates. Nucleosides and nucleotides; Chemistry; Cysteine; Disaccharides - biosynthesis; Disaccharides - chemical synthesis; Disaccharides - metabolism; Exact sciences and technology; Glycopeptides; Inositol; Molecular Weight; Mycobacterium smegmatis - enzymology; Nuclear Magnetic Resonance, Biomolecular; Organic chemistry; Preparations and properties; Pyrazoles - chemical synthesis; Pyrazoles - metabolism; Sulfhydryl Compounds - chemical synthesis; Sulfhydryl Compounds - metabolism; Biosynthesis precursor; Cyclitol; Enantioselectivity; Chemical synthesis; Aminoglycoside; Disaccharide
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(01)00383-2

Members of the actinomycetes produce 1D-1-O-(2-[N-acetyl-l-cysteinyl]amino-2-deoxy-α-d-glucopyranosyl)-myo-inositol or mycothiol 1 as principal low molecular mass thiol. Chemical synthesis of a biosynthetic precursor of mycothiol, the pseudodisaccharide 1D-1-O-(2-amino-2-deoxy-α-d-glucopyranosyl)-myo-inositol 13 was achieved by the following steps: (1) Enantioselective synthesis gave the glycosyl acceptors (−)-2,3,4,5,6-penta-O-acetyl-d-myo-inositol D-7 and the corresponding l-isomer L-7. (2) Condensation of D-7 and L-7 with the glycosyl donor 3,4,6-tri-O-acetyl-2-deoxy-2-(2,4-dinitrophenylamino)-α-d-glucopyranosylbromide afforded the corresponding α and β anomeric products, which could be resolved by silica gel chromatography. (3) Deprotection of these by hydrolysis using an anion exchange resin gave 1D- and 1L-1-O-(2-amino-2-deoxy-α-d-glucopyranosyl)-myo-inositol 13 and 15 and the corresponding β-coupled anomers 14 and 16. Only 13, and to a much lesser extent 15, were used by enzymes present in an ammonium sulphate fraction of a cellfree extract of Mycobacterium smegmatis for the enzymatic synthesis of mycothiol. In the absence of acetyl-SCoA, the immediate biosynthetic precursor of 1, desacetylmycothiol, was the major product. Graphic