A stereoselective synthesis of the calicheamicin core trisaccharide

Calicheamicin {dollar}gammasp1{dollar} is an extremely potent antitumor antibiotic which cleaves DNA site specifically. The oligosaccharide portion of calicheamicin has been suggested to contribute to DNA binding. This thesis focuses on the development of an efficient synthetic route to the calicheamicin oligosaccharide. As a model for the real calicheamicin oligosaccharide, the core trisaccharide found in both calicheamicin and esperamicin was stereoselectively constructed. The key steps of the synthesis are the following. (1) Construction of the {dollar}alpha{dollar}-glycosidic linkage between the A ring and the E ring. The E ring sulfoxide (made from L-serine) was coupled with the tributyltin ether of 3,4-O-isopropylidene-{dollar}beta{dollar}-methyl-D-fucoside in the presence of triflic anhydride in ether to give the {dollar}alpha{dollar}-linked A-E disaccharide in 70% yield with excellent stereoselectivity ({dollar}alpha{dollar}:{dollar}beta{dollar} ratio 12:1). (2) Construction of the {dollar}beta{dollar}-glycosidic linkage between the B ring and hydroxylamine. By a neighboring group participation from the axial p-methoxybenzoate (at C-3), the {dollar}beta{dollar}-O-glycosylated N-hydroxyurethane was synthesized in 39% yield ({dollar}alpha{dollar}:{dollar}beta{dollar} ratio 1:12) when the B ring sulfoxide reacted with the tributyltin ether of N-hydroxyurethane in the presence of triflic anhydride in {dollar}rm CHsb2Clsb2{dollar}. (3) Construction of the hydroxylamine linkage between the B ring and the A ring. A general method for the stereoselective construction of hydroxylamine linkages in oligosaccharides has been developed. O-Glycosylation of N-hydroxyurethane was followed by deprotonation of the amide proton with NaH in ether-HMPA; and an S{dollar}sb{lcub}rm N{rcub}{dollar}2 displacement of the urethane anion on a triflate gave cleanly the coupled product. The protecting carboethoxy group on nitrogen was removed under mild basic condition to yield the desired hydroxylamine linked oligosaccharide. This method was successfully applied to the construction of the calicheamicin core trisaccharide.