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

Abstract

ABSTRACT 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 N 2‐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.