Enantiospecific Synthesis of 1-Azafagomine

✍ Scribed by Bettina V. Ernholt; Ib B. Thomsen; Anders Lohse; Igor W. Plesner; Kenneth B. Jensen; Rita G. Hazell; Xifu Liang; Astrid Jakobsen; Mikael Bols

• Publisher: John Wiley and Sons
• Year: 2000
• Tongue: English
• Weight: 192 KB
• Volume: 6
• Category: Article
• ISSN: 0947-6539
• DOI: 10.1002/(sici)1521-3765(20000117)6:2<278::aid-chem278>3.0.co;2-6

✦ Synopsis

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 2,3,5tribenzylfuranose, 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 (À)-1-azafagomine ((À)-1). Enzymatic and other routes to optically pure 1-azafagomine were also studied. Compound (À)-1 is a potent competitive glycosidase inhibitor, while ()-1 has no biological activity. The inhibition of almond b-glucosidase by (À)-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 Â 10 4 m À1 s À1 and 0.011 s À1 , respectively, yielding K i 0.33 mm.