The Influence of the Electron Density in Acyl Protecting Groups on the Selectivity of Galactose Formation

The stereoselective formation of 1,2-cis-glycosidic
bonds is a major bottleneck in the synthesis of carbohydrates. We
here investigate how the electron density in acyl protecting groups
influences the stereoselectivity by fine-tuning the efficiency of
remote participation. Electron-rich C4-pivaloylated galactose building
blocks show an unprecedented α-selectivity. The trifluoroacetylated
counterpart with electron-withdrawing groups, on the other hand, exhibits
a lower selectivity. Cryogenic infrared spectroscopy in helium nanodroplets
and density functional theory calculations revealed the existence
of dioxolenium-type intermediates for this reaction, which suggests
that remote participation of the pivaloyl protecting group is the
origin of the high α-selectivity of the pivaloylated building
blocks. According to these findings, an α-selective galactose
building block for glycosynthesis is developed based on rational considerations
and is subsequently employed in automated glycan assembly exhibiting
complete stereoselectivity. Based on the obtained selectivities in
the glycosylation reactions and the results from infrared spectroscopy
and density functional theory, we suggest a mechanism by which these
reactions could proceed.