Synthesis and investigation of L-fuco- and D-glucurono-azafagomine

Abstract

The new azasugars (3S,4R,5S)-4,5-dihydroxy-3-methylhexahydropyridazine (3, azafucofagomine) and (3S,4R,5R)-4,5-dihydroxyhexahydropyridazine-3-carboxylic acid (4, azaglucuronofagomine) were synthesised. Azafucofagomine (3) was made from D-ribose in ten steps in a synthesis that involved partial 2,3-protection, deoxygenation of the 5-OH, reductive amination with tert-butyl carbazate, mesylation, cyclisation and deprotection. Compound 4 was made from L-xylose in 12 steps in a related way starting with 2,3,5-protection, reductive amination with tert-butyl carbazate, mesylation and cyclisation. The key step in this synthesis is selective debenzylation of a primary benzyl ether with acetyl bromide to produce a partially benzylated hexahydropyridazine that was oxidised to the acid and deprotected. The 3-, 4- and 6-deoxy analogues of azafagomine [1, (3R,4R,5R)-4,5-dihydroxy-3-hydroxymethylhexahydropyridazine] were also made. Compounds 3 and 4 were shown to be potent α-fucosidase and β-glucuronidase inhibitors, respectively.