Stereoselective Reduction of 5-C-bromo-D-glucuronyl β-fluoride with the Mediation of Tributyltin Hydride - A DFT Investigation

L-iduronic acid (L-ido) and its derivatives, critical components of glycosaminoglycans involved in various biological processes are challenging to extract from natural sources. C-5 epimeric D-glucuronic acid (D-gluco) derivatives are commonly used to synthesise the corresponding L-ido derivatives. Previous experimental results showed that the L-ido/D-gluco isomeric ratio of products from tributyltin hydride-mediated radical epimerization depends on the anomeric substituent, with exclusive L-ido production when the substituent is β-F. To elucidate the reaction mechanism, five possible transition states were identified through the conformational search, and DFT calculations were performed on the respective reaction barriers to predict the isomer ratio. Benchmarking with seven exchange-correlation functionals yielded L-ido:D-gluco ratios ranging from 1:0.03 to 1:0.06, close to the experimental value of 1:0, confirming the strong stereoselectivity for L-ido. This selectivity is driven by 1,3-axial interaction, anomeric effect, and conformational preferences of the pyranose ring.