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1‐Azafagomine: A Hydroxyhexahydropyridazine That Potently Inhibits Enzymatic Glycoside Cleavage
Author(s) -
Bols Mikael,
Hazell Rita G.,
Thomsen Ib B.
Publication year - 1997
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.19970030616
Subject(s) - chemistry , yield (engineering) , hydrolysis , stereochemistry , hydroxymethyl , geraniol , organic chemistry , medicinal chemistry , chromatography , materials science , essential oil , metallurgy
(3,4‐ trans ‐4,5‐ trans )‐4,5‐dihydroxy‐3‐hydroxymethylhexahydropyrida‐zine ( 16 ) was synthesized in four steps from 2,4‐pentadienol ( 22 ) and 4‐phenyl‐triazolin‐3,5‐dione ( 18 ) in an overall yield of 32%. In the first step a Diels‐Alder reaction between 18 and 22 gave (π)‐2‐hydroxymethyl‐8‐phenyl‐1,6,8‐triazabicyclo[4.3.0]non‐3‐ene‐7,9‐dione ( 23c ) in 88% yield. Epoxidation of 23c with trifluoromethyl(methyl)dioxirane, generated in situ, gave the trans epoxide 24c in 62% yield. Hydrolysis of the epoxide with perchloric acid gave stereoselectively (2,3‐ trans ‐3,4‐ trans )‐3,4‐dihydroxy‐2‐hydroxy‐methyl‐8‐phenyl‐1,6,8‐triazabicyclo[4.3.0]‐nonane‐7,9‐dione ( 26 ) in 73% yield. In the fourth and final step, hydrazinolysis of 26 gave 16 in 84% yield. Pyridazine 16 was found to be a potent inhibitor of α‐and β‐glucosidase, isomaltase and glyco‐gen phosphorylase, while galactosidases and α‐mannosidase were not inhibited. The inhibition of β‐glucosidase is independent of pH, and was found to be due to unprotonated 16 .