Studies on the Synthesis of Trisaccharide Analogues of the Antibiotic Moenomycin A

Abstract

A new approach for the synthesis of moenomycin trisaccharide analogues is reported in which three monosaccharide building blocks are used and allows the introduction of different substituents at the 6‐position of unit E (Scheme 2). Furthermore, a new procedure for the introduction and manipulation of unit F is described (Scheme 3).

Recent trends in the synthesis of O-glycosides of 2-amino-2-deoxysugars

“…Over the years, these and other classes of 2-NHTroc glycosyl donors have been used in glycoside and oligosaccharide synthesis: as trichloroacetimidates, 165,238,258,277, for the synthesis of pyruvated saccharide fragments, 280,304 Lipid A derivatives, 165,281,288,290,294,297,298,305,306 glycopeptides, 277,284,285 lactosaminyl donors, 282,307 Re-type lipopolysaccharides, 289 sialyl Lewis X glycolipids, 291,301 gangliosides, 292 peptidoglycan partial structures, 258,308 thiooligosaccharide analogues 286 of Nod factors, carbohydrate antigens, 295,302 sialyl-trimeric-Lewis X, 300 hyaluronan trisaccharides, 309 meonomycin A analogues, 310 and ceramidated GLA-60 293 derivatives; as fluorides, 282,311,312 for the synthesis of lactosaminyl donors, glycosylamines, 312 and tumor-associated antigen 311 Globo-H; as chlorides; 313 as thioglycosides, 283,286,[314][315][316][317][318][319][320][321][322]…”

Prospects for novel inhibitors of peptidoglycan transglycosylases

“…Moenomycin has amphiphilic properties due to the hydrophilic nature of the A to F carbohydrate units, the phosphate group of the phosphorglycerate linker and the folded hydrophobic domain formed by the lipid chain. Structure-activity relationships have been carried out on the moenomycin A molecule through selective degradation of its structure and the synthesis of di- and trisaccharide analogues, resulting in an understanding of the minimal pharmacophore [9,60,61] . The degradation of moenomycin to chemical entities that retain the carbohydrate units C, E and F, can be performed with retention of transglycosylase inhibition and antibacterial activity [62,63] .…”

Studies on the Synthesis of Di‐ and Trisaccharide Analogues of Moenomycin A. Modifications in Unit E and in the Lipid Part

“…In view of the above results, we based our further synthetic efforts on to the C ± E ± F trisaccharide precursor 6a of moenomycin analogues, the synthesis of which was discussed in the preceding communication [1]. As described, removal of the Nphthaloyl (PhthN) protecting group in the aminosugar moieties in later stages of the trisaccharide synthesis turned out to be incompatible with the urethane function at C(3) of unit F. Thus, in a new attempt, we replaced the N-phthaloyl groups in an early phase of the synthesis by N-(2,2,2-trichloroethoxy)carbonyl (TrocN) groups, which we expected to be easily convertible to N-Ac groups under mild conditions [9a] (see also [9b]).…”

“…22) indicated the presence of only the a-d-anomer. Treatment of 6c with Cl 3 CCN and Cs 2 CO 3 furnished the disaccharide donor 6d (88%) which was coupled with the ring-F acceptor building block 7, which is more reactive than previously employed ring-F acceptor units [1]. When the reaction was performed in ClCH 2 CH 2 Cl solution with Me 3 SiOTf as promotor, trisaccharide 8a was obtained in 55% yield.…”

“…In the case of 17a, we succeeded to separate the P-stereoisomers. Removal of the trichloroethyl-1,1-dimethyl protecting group from 17a under the Imai conditions [30] gave a mixture of two compounds (87%) from which the desired compound 18a was isolated and characterized by 1 H-NMR and MS; the second compound, most likely, again arose from the loss of an acetyl group. For the next step, the mixture was used without separation.…”