Fructose-1,6-Bisphosphate Aldolase-Mediated Synthesis of Aminocyclitols (Analogues of Valiolamine) and their Evaluation as Glycosidase Inhibitors

• Published in: ChemCatChem Vol. 1; no. 4; pp. 463 - 471
• Main Authors: El Blidi, Lahssen, Assaf, Zeinab, Camps Bres, Flora, Veschambre, Henri, Théry, Vincent, Bolte, Jean, Lemaire, Marielle
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 07-12-2009; WILEY‐VCH Verlag
• Subjects: cyclitols; enantioselectivity; enzymes; glycosylation; inhibitors
• ISSN: 1867-3880; 1867-3899
• DOI: 10.1002/cctc.200900151

A highly stereoselective method for the preparation of nitro‐ and aminocyclitols, using fructose‐1,6‐bisphosphate aldolase, which catalyzes the aldol reaction of dihydroxyacetone phosphate (DHAP) on hydroxynitrobutanals, is reported. The key part of the synthesis is based on a one‐pot /two‐enzyme process whereby three reactions take place; rabbit muscle aldolase (RAMA) catalyzed aldolization, phytase‐catalyzed phosphate hydrolysis, and intramolecular spontaneous nitroaldolization. Two families of nitrocyclitols were obtained depending on the carbon configuration in the β position to the nitro group. Reduction of the latter afforded the aminocyclitols. Evaluation of the inhibition properties of the amines towards five commercially available glycosidases has shown selectivity for β‐glucosidase and β‐galactosidase.
The synthesis of nitrocyclitols is performed in a one‐pot process with two enzymes (RAMA and phytase) and three reactions in which two carbon–carbon bonds are formed with high stereoselectivity. Four stereocenters are created and an enantiomerically pure compound is isolated for each aldehyde tested. The inhibition properties of the corresponding amines show selectivity for β‐Glc and β‐Gal.