Synthetic studies of fluorinated analogues of 1-azafagomine: Remarkable nucleophilic substitution of fluorine by hydrazine

Abstract

(±)-5-fluoro-4-hydroxy-3-hydroxymethylhexahydropyridazine ( 7 ) and some other azafagomine analogues were synthesis ed with the aim of comparing their glycosidase inhibition to that of (±)-4,5-dihydroxy-3-hydroxymethylhexahydropyridazine (1-azafagomine). Both in the synthesis of 7 and in the attempted synthesis of 4,5-dihydroxy-3-fluoromethylhexahydropyridazine, a remarkable degree of nucleophilic substitution of fluorine by hydrazine was observed in the final deprotection step involving hydrazinolysis. Fluorine analogue 7 was a considerably weaker glycosidase inhibitor than 1 , suggesting that the 3-OH of 1 play a role in its binding by acting as a hydrogen bond donator. Both secondary and primary alkyl fluoride was found to be substituted, in some cases quantitatively, with hydrazine.