Asymmetric Synthesis And α-glucosidase Inhibitory Activity Of Chiral Aegeline

Aegeline, a natural occurring N-cinnamoyl arylethanolamine extracted from thethe dry leaves of Aegle marmelos, has been shown to exhibit hypoglycemic activity.One possible mechanism for the this activity is to reduce sugar intake and postprandialblood glucose by inhibitingα-glucosidase in upper small-intestine. There is a chiralcenter in the molecular structure of aegeline and several asymmetric synthesis of（R）-aegeline have been reported in view of the fact that （R）-isomers are active isomersfor aryl ethanolamine-type β-adrenergic receptor agonists. However, there is no reporton the relationship between the steric configuration of Aegeline and its biologicalactivity. To partly address this issue, the following work has been carried out.（1） Two cinchona alkaloid-derivatives,1,4-bis（9-O-quininyl）phthalazine [（QN）₂PHAL] and1,4-bis（9-O-quinidinyl）phthalazine [（QD）₂PHAL], were synthesizedaccording to a reported procedure and used as chiral ligands in the osmium-catalyzedasymmetric dihydroxylation of4-methoxystyrene to give （S）-and （R）-1-（4-methoxyphenyl）ethanediol respectively.（S）-/（R）-aegeline was prepared from（S）-/（R）-1-（4-methoxyphenyl）ethanediol by selective tosylation, azide substitution,Pd/C-catalyzed hydrogenation, and finally N-cinnamoylation. Racemic Aegeline wasobtained by the same approach with triethylamine as the catalyst in place of.（QN）₂PHAL or （QD）₂PHAL.（2） Two new N, N-ligands,1,2:4,5-Di-O-isopropylidene-3-（pyridine-2-methylene）amino-3-deoxy-β-D-fructopyranose （Fru-Py-amine） and1,2:4,5-Di-O-isopropylidene-3-（pyridine-2-methylene）imino-3-deoxy-β-D-fructopyranose（Fru-Py-imine）, were synthesized from D-fructose. Asymmetric Henry reaction ofbenzaldehyde with nitromethane with in situ complex of the N, N-ligands with CuCl₂,CuBr or Cu（OAc）₂as the catalysts gave （R）-1-phenyl-2-nitroethanol in various eevalues and Fru-Py-amine-Cu（OAc）₂showed the best eantioselectivity （67.2%ee）.Fru-Py-amine-Cu（OAc）₂was further used in the asymmetric Henry reaction of4-methoxybenzaldehyde with nitromethane affording （R）-1-（4-methoxy-phenyl）-2-nitroethanol in70.3%ee, which was transformed into （R）-aegeline （69.3%ee） viareduction using NiCl₂/NaBH₄and N-N-cinnamoylation using E-cinnamic acidN-hydroxysuccinimide ester.（3） Theα-glucosidase inhibitory activities of （R）-aegeline,（S）-aegeline and recemic aegeline were determined by a reported procedure with4-nitrophenyl–D-glucopy-ranoside （PNPG） as the substrate. The IC50values of the inhibitors werecalculated according to the absorbance of4-nitrophenol released from PNPG at402nm.The IC50value of （R）-aegeline,（S）-aegeline and recemic aegeline was2.62×10^-3mol/L，1.50×10^-3mol/L，1.57×10^-3mol/L respectively, which showed no significantdependence on the steric configuration of aegeline. In vivo study is necessary forclarification of the relationship between the hypoglycemic activities and and the stericconfigurations of aegeline.