Synthesis of 5-azacastanospermine, a conformationally restricted azafagomine analogue.
The 5-aza-6-deoxy analogue of castanospermine (+/-)-5a and its 1-epimer (+/-)-5b was synthesized. The synthesis started from the known compound 5-benzyloxy-7-hydroxyhepta-1,3-diene, which was protected and subjected to Diels-Alder reaction with 4-phenyl-1,2,4-triazoline-3,5-dione to give two epimeric adducts. One of these was transformed through epoxidation, acetolysis, a series of side-chain transformations that converted it into a terminally protected aldehyde, deprotection, and hydrogenolysis/reductive amination into 5a. By a similar set of reactions the other adduct epimer was converted into 5b. The castanospermine analogue 5a was a weaker inhibitor of almond beta-glucosidase and rice alpha-glucosidase than castanospermine (2) or 1-azafagomine (4), but was considerably more potent than its epimer 5b. This suggests that these enzymes have a strong preference for binding substrates or azasugars with the 6-OH in an axial conformation.
Søndergaard
K
K
Department of Chemistry, University of Aarhus, Denmark. mb@kemi.aau.dk
Liang
X
X
Bols
M
M
D001372:Aza Compounds / Q000737:chemistry*; D001555:Benzene Derivatives / Q000737:chemistry; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D006834:Hydrazines / Q000737:chemistry*; D007212:Indolizines / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D009005:Monosaccharides / Q000138:chemical synthesis*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry; D054836:Indolizidines
D001372:Aza Compounds; D001555:Benzene Derivatives; D004791:Enzyme Inhibitors; D006026:Glycoside Hydrolases; D006834:Hydrazines; D007212:Indolizines; D009005:Monosaccharides; D014230:Triazoles; C414749:1-azafagomine; C430645:5-azacastanospermine; C430646:5-benzyloxy-7-hydroxyhepta-1,3-diene; C053540:4-phenyl-1,2,4-triazoline-3,5-dione; C037806:castanospermine; D054836:Indolizidines