Studies On The Synthesis Of Macrocyclic Phenol Glycosides And Phenolic Glycosylation

Phenolic glycosides occur widely in nature; many of them have important bioactivities. Because phenols are poorly nucleophilic and vulnerable toward electrophilic species, glycosylation of phenols is a difficult task. In this thesis, we focused on the glycosylation of phenols and synthesis of macrocyclic phenol glycodides.1. Total synthesis of macrocyclic phenolic glycosides Clemoarmanoside A and Clemahexapetoside AClemoarmanoside A and Clemahexapetoside A, two novel cyclic dimers containing the unusual D-allopyranose as one of the sugar units, were isolated from Clematis hexapetala in 2006. Using benzyl ether as permanent protecting group and trityl and allyl groups as temporary protecting groups, three 4-(glycosyloxy)benzoate building blocks (i.e., 3-17, 3-43, and 3-44) were synthesized from D-glucose. Via a reaction sequence of intermolecular and intramolecular esterification, hydrogenolysis and protecting group manipulations, clemoarmanoside A and clemahexapetoside A were synthesized for the first time. The 1H and 13C NMR data of the natural compound Clemahexapetoside A were in apparent discrepancy with those of the synthetic compound 3-54. Nevertheless, X-ray diffraction analysis of clemahexapetoside A confirmed that the structure of the synthetic sample was correct.2. Synthesis of clemoarmanoside analogues with enlarged cavities and their recognition abilities.The synthetic approach to clemoarmanoside A was successfully adapted to the synthesis of larger cyclic congeners (i.e., 3-64, 3-68, and 3-71) from D-glucose and 4-hydroxybenzoic acid methyl ester. Association constants, determined by fluorescence titration, suggested that ANS associated more strongly within the cavities of the cyclic trimer thanα-CD.3. Mechanistic studies on the phenolic glycosylationThe glycosylation of phenols with peracetyl glucopyranosyl trichloroacetimidate have been studied carefully. It was found that the percentage of theα-anomers increased with the decrease of the pKa value and hindrance of the phenols when TMSOTf was used as the promoter. In contrast, completeβselectivity were obtained with BF₃·Et₂O as the promoter regardless of the pKa value and the streric hindrance of the phenols. Further experiments showed that the configuration of the 2, 3-OAc of the donors also have great effect on the stereoselectivity of the glycosylation reactions.To further investigate the reaction mechanism, glycosyl orthoester was confirmed as one intermediate in the phenolic glycosylation. Low-temperature NMR experiments were conducted. The glycosyl triflates were identified as the major intermediates in the phenolic glycosylation when TMSOTf was used as the promoter.