Elucidating the Stereodirecting Effect of C-4 Acyl Groups on Galactosyl Donors

The stereoselective synthesis of 1,2-cis glycosidic bonds is a significant challenge in carbohydrate chemistry. 1,2-Cis galactosides can be obtained by using C-4 acyl protection groups as a stereodirecting group, yet the underlying mechanism that steers selective galactosylation has remained elusive. Herein, we investigate the stereodirecting effect of C-4 acyl groups in galactosides using glycosylation reactions, exchange NMR spectroscopy and DFT-calculations. We found no experimental evidence for C-4 dioxepanium ion formation through C-4 acyl neighboring group participation. Instead, β-glycosyl triflates were detected using exchange NMR which could afford α-galactosides via S_N2-like displacement. Computational studies of the product-forming transition state geometries reveal that the C-4 benzoate group shields the β-face of the galactosyl donor, thereby disfavoring reactions that proceed via the α-glycosyl triflate pathway. These findings can explain the stereodirecting effect of C-4 acyl groups on galactosyl donors, and provides fundamental insights for the development of stereoselective glycosylation methods in the future.