Design And Synthesis Of Erythromycin Derivatives And C-glycosyl Flavones

This thesis consists of two following parts: design and synthesis of erythromycin derivatives and C-glycosyl flavones.Part 1: design and synthesis of erythromycin derivatives.Abusing of antibiotics has led to a worldwide increase in bacterial resistance.It is of great practical significance to find novel anti-resistant bacterial macrolides through the structural modification of the third generation of erythromycin.In order to find compounds with higher activity,we focused on the modification of the structure of erythromycin,based on the bacterial resistance mechanisms and structure-activity relationship(SAR)of the third generation of erythromycin.The synthesized modified C-3 novel alkylides are a series of 3-O-descladinosyl-3-O-(3-aryl-2-propargyl)-6-O-methyl erythromycin A 9-O-methyloxime-11,12-cyclic carbonates.Also,in order to reveal the structure-activity relationship of ketolides,a series of 2-fluoro-3-O-descladinosyl-3-keto-6-O-methyl erythromycin A 9-O-(3-aryl-2-propargyl)oxime-11,12-cyclic carbonates were synthesized.Novel ketolides with high antibacterial activity were found.Via in vitro activity test,the series of alkylides 10 possessed better antibacterial activity against constitutive S.aureus than clarithromycin and telithromycin,especially compounds 10 c and 10 e which share common substructure phenyl group.It may lay the foundation for the future research.Compound 22 a,the best candidate of ketolides,possessed better activity against mef-encoded S.pneumoniae and inducible-erm S.pyogenes than clarithromycin,and its antibacterial activity against susceptible M.catarrhalis was even more potent than telithromycin.Moreover,it was also active against H.influenzae.Part 2: design and synthesis of C-glycosyl flavones.C-glycosyl flavones have a variety of bioactivities and exhibit excellent advantages on resistance to acid and enzyme degradation and molecular recognition,which makes them as important lead compounds.But most of them were separated through natural products.In this work,chemical methods were used for total synthesis of natural C-glycosyl flavones.A glycosidation method to synthesis acetophenone C-glycoside derivatives has been found through studying the glycosylation between phenols and O-(2,3,4,6-tetra-O-benzyl-?-D-glucopyranosyl)trichloroacetimidate.The reaction of tetra-O-benzyl-?-D-glucopyranosyl trichloroacetimidate,as glycosyl donor,with phenols,as accepter,was initiated by catalytic amounts of trimethylsilyl trifluoromathanesulfonate(TMSOTf)at-30?,resulting in key intermediate 4,6-dimethoxy-3-C-(2,3,4,6-tetra-O-benzyl-?-D-glucopyranosyl)-2-hydroxyacetophenone.