TMG-chitotriomycin: Total Synthesis, Structure Revision, And Structure-Activity Relationship Studies

2-Amino-2-deoxy-D-glucopyranose (D-glucosamine) is an integral component of numerous biologically important prokaryotic and eukaryotic carbohydrates, including chitin, nodulation factor and heparin. Nevertheless, introduction of the glucosamine residue into oligosaccharides has been a long-standing problem in preparative carbohydrate chemistry. We found that glycosylation of a variety of alcohols with 2-N-dimethylphosphoryl-2-deoxy-a-D-glucopyranosyl trichloroacetimidate as a glycosyl donor provided the corresponding coupled products in high yields and goodβ-selectivity. And in the presence of acyl chlorides and DMAP in pyridine, the N-dimethylphosphoryl-protection could be readily transformed into the corresponding N-acyl derivatives, this method provided an effective approach to the synthesis of glucosamine-containing oligosaccharides with alternate N-acyl substitutions.TMG-chitotriomycin was disclosed by Kanzaki and co-workers from the culture filtrate of Streptomyces anulatus NBRC13369 in 2008, which exhibited potent and selective inhibition against theβ-N-acetylglucosaminidase (GlcNAcase) of insects and fungi and would be ideal lead compound for understanding the molecular mechanisms of GlcNAcase and the development of new antifungal agents. The proposed structrure of TMG-chitotriomycin was also intriguing in that this tetrasaccharide possesses a unique N,N,N-trimethyl-D-glucosamine (TMG) residueα-(1→4)-linked at the nonreducing end of a chitotriose; moreover, the presence of the trimethylammonium could astonishingly result in epimerization at the remote C2 of the reducing-end GlcNAc unit. In this dissertation, We developed a convergent [2+2] approach to complete the first total synthesis of the proposed structure of TMG-chitotriomycin efficiently, where the sterically demandingα-(1→4)-andβ-(1→4)-glycosidic linkages were assembled smoothly by our newly developed glycosylation protocol with glycosyl ortho-hexynylbenzoates as donors and Au(I) as the catalyst. However, the synthetic compound was apparently not identical to the natural TMG-chitotriomycin isolated by Kanzaki and co-workers, as determined by a comparison of their 1H NMR spectra. Thus we revised the structure of natural TMG-chitotriomycin. We suspected that the TMG might beβ-linked to the chitotriose in the natural product instead ofα-linked as in the previous assignment. In the event, the revised structure of TMG-chitotriomycin was validated unambiguously via the total synthesis. Then, a series of anologues of the natural product were also synthesized, which elucidated the structure-activity relationship of TMG-chitotriomycin on the selective inhibition of GlcNAcases and might be developed into efficient inhibitors for the studies of antifungal drugs.In addition, we found that the Au(I)-catalyzed glycosylation of acid alcohols with glycosyl ortho-hexynylbenzoates in the presence of BF3·OEt2 and DBU provided the corresponding ester glycosides chemoselectively in high yield; while with DTBP as an additive instead, orthoester formation with the alcohol was effected selectively. This finding provided an effective approach to the chemoselective glycosylation of carboxylic acid in the synthesis of triterpene saponins.