Deactivating Influence of 3-O-Glycosyl Substituent on Anomeric Reactivity of Thiomannoside Observed in Oligomannoside Synthesis.
It has been long recognized that, in chemical glycosylation, the anomeric reactivity of glycosyl donor can be influenced greatly by protecting groups. As opposed to the effects of protecting groups, we report herein a finding on how O-glycosyl substituent can affect the reactivity of oligosaccharyl donor, which in turn should have impact on convergent assembly of oligosaccharide. During our synthetic efforts toward Pichia holstii oligomannoside, a type of α-1,3-linked dimannosyl thioglycosides was found to exhibit unexpected low reactivity toward the activation of NIS/TMSOTf. This observation prompted us to perform a series of comparative reactivity studies, which attributed the donor deactivation to the presence of 3-O-glycosyl substituent, by comparison with O-acetyl group and O-glycosidic linkages at C-4/C-6 positions. To rationalize the unusual phenomenon, we hypothesize that O-glycosyl moiety at C-3 could destabilize the oxocarbenium ion intermediate by additionally increasing the O2-C2-C3-O3 torsional strain, which was further supported by DFT calculation of the hypothetical4H3-like oxocarbeniums. The observed deactivating influence provides a basis for estimation of donor reactivity and logical selection of synthetic strategy in oligosaccharide synthesis. Following this finding, we opted to use an iterative strategy for the synthesis of targeted pentamannoside 1 by using monomeric thiomannosides that ensured sufficient reactivity.
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , 3663 North Zhongshan Road, Shanghai 200062, China.
Jun
J
Zhou
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , 3663 North Zhongshan Road, Shanghai 200062, China.
Siying
S
Lv
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , 3663 North Zhongshan Road, Shanghai 200062, China.
Dan
D
Zhang
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , 3663 North Zhongshan Road, Shanghai 200062, China.
Fei
0000-0001-9458-9175
F
Xia
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , 3663 North Zhongshan Road, Shanghai 200062, China.
Wenhao
0000-0002-1461-3671
W
Hu