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

## TL;DR

This paper explains how C-4 acyl groups control the stereochemistry of galactoside synthesis, offering insights for creating more selective glycosylation methods.

## Contribution

The study reveals that C-4 acyl groups sterically block α-glycosyl triflate pathways, enabling stereoselective α-galactoside formation.

## Key findings

- C-4 acyl groups shield the β-face of galactosyl donors, disfavoring α-glycosyl triflate pathways.
- β-glycosyl triflates are detected and likely glycosylate via an SN2-like displacement mechanism.
- The Curtin–Hammett scenario explains the stereodirecting effect of C-4 acyl groups in galactosylation.

## 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 SN2‐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.

Tipping the balance of the reaction coordinate by changing a single protecting group. We demonstrate that α‐ and β‐galactosyl triflates are formed during galactosylation reactions and likely glycosylate according to a Curtin–Hammett scenario. C‐4 acyl groups exert their stereodirecting effect by sterically blocking displacement of α‐galactosyl triflates thus providing α‐galactosides via the displacement of β‐galactosyl triflates.