Total Synthesis And Anticoronary Activity Evaluation Of Homoeriodictyol-7-O-?-D-apiosyl-(1?2)-?-D-glycoside

Viscum coloratum(Kom.)Nakai(V.coloratum)is a semi-parasitic plant which grows on branches or stems of deciduous trees.It is known as Hujisheng in Chinese.V.coloratum,which is an important medicinal herb that has been used widely in traditional Chinese medicine for treatment of various diseases,including coronary heart disease with angina pectoris,cancer,hepatitis and hemorrhage.Studies have shown that the Homoeriodictyol-7-O-?-D-apiose-(1?2)-?-D-glycoside is responsible for the anti-angina pectoris activity.The promising anti-angina pectoris activity and limited availability from natural sources makes Homoeriodictyol-7-O-?-D-apiose(1?2)-?-D-glycoside a suitable target for which to develop synthetic strategies.The total synthesis of Homoeriodictyol-7-O-?-D-apiose(1?2)-?-D-glycoside has not been reported so far,which possesses a ?-D-apiofuranosyl-(1?2)-?-Dglucopyranose sugar chain,apiofuranose-containing glycosides,the synthetic route requires delicate protective manipulation of the hydroxyl groups on the aglycone and sugars because of regioselective construction of two glycosidic linkages.The total synthesis of this natural product is of great importance for investigating the structure-activity relationships(SARs)of viscumneosides,which will in turn promote further understanding of the molecular mechanism of its bioactivities and clinical effects.The main research contents and results are as follows:1.The first total synthesis of Homoeriodictyol-7-O-?-D-apiose(1?2)-?-D-glycoside has been achieved with 6.29% overall yield(calcd with phloroglucinol).2.2-(4-(Benzyloxy)-3-methoxyphenyl)-5,7-dihydroxychroman-4-one 8 was synthesized via 5 steps from phloroglucinol.3.Glycosyl bromides 13 was synthesed via 4 steps from Diacetone-D-Glucose.4'-Benzyloxy-homoeriodictyol-7-O-3-benzyloxy-4,5-benzylidene-?-D-glycoside 16 is the key intermediate for the synthesis of the target compound 1,which can be built up by glycosylation of glycosyl bromides 13 and the partially protected homoeriodictyol 7.4.Apiofuranosyl donor 23 was synthesized via six steps from Diacetone-D-Mannitol,the 5-benzoyl could avoid the D configuration from transformation.5.Reaction of 16 with trichloroacetimidate donor 23 in the presence of TMSOTf(trimethylsilyl trifluoromethanesulfonate)in anhydrous dichloromethane at-20? provided the homoeriodictyol disaccharide derivative 24 in 86% isolated yield.6.Removal of the protecting groups from 24 using sodium methoxide,acidic resin beads,and 10% Pd/C successively afforded the deprotected product 1 in high yield.The total synthesis of a promising anti-angina pectoris component of the viscumneosides was reported here for the first time.The longest linear sequence(from 2 to 1)in the synthetic route required thirteen steps and afforded an overall yield of 6.3%.The study addressed issues associated with the inherent chemical reactivity of apiose.Trichloroacetimidate was employed as the apiofuranosyl donor to construct the key building block of Homoeriodictyol-7-O-?-D-apiosyl-(1?2)-?-D-glycoside.It is anticipated that the developed strategy will pave the way for the synthesis of other natural and novel viscumneosides to allow biological investigation as additional promising anti-angina pectoris agents.