Enantiospecific synthesis of 1-azafagomine

Chemistry : a European Journal
B V ErnholtM Bols

Abstract

For the first time the two enantiomeric forms of the glycosidase inhibitor 1-azafagomine have been synthesised starting from D- and L-xylose. D-Xylose was converted to the 2,3,5-tribenzylfuranose, which upon reductive amination with tert-butyl carbazate gave the protected 1-hydrazino-1-deoxypentitol in high yield. N-acetylation, mesylation of the 4-OH, removal of the Boc group, cyclisation and deprotection gave (+)-1-azafagomine ((+)-1). By a similar sequence of reactions, L-xylose was converted to (-)-1-azafagomine ((-)-1). Enzymatic and other routes to optically pure 1-azafagomine were also studied. Compound (-)-1 is a potent competitive glycosidase inhibitor, while (+)-1 has no biological activity. The inhibition of almond beta-glucosidase by (-)-1 was found to be slow owing to a slow binding step of inhibitor to enzyme, with no subsequent conformational rearrangement. The rate constants for binding and release were found to be 3.3 x 10(4)M(-1)s(-1) and 0.011 s(-1), respectively, yielding Ki = 0.33 microM.

Citations

Jul 12, 2001·Chemistry : a European Journal·K SøndergaardM Bols
Mar 14, 2007·Chembiochem : a European Journal of Chemical Biology·Oscar Lopez Lopez, Mikael Bols
Jan 13, 2010·Organic & Biomolecular Chemistry·Tracey M Gloster, Gideon J Davies
Mar 9, 2011·Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences·Ricardo García-Mayoral, Javier Jiménez
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jianlin HanVadim A Soloshonok
Feb 7, 2007·Journal of the American Chemical Society·Tracey M GlosterGideon J Davies

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