Continuous-Flow Synthesis of Carbohydrate Building Blocks: d-Glucuronate Monosaccharide

Continuous-flow synthesis provides an opportunity to improve reproducibility and scalability in carbohydrate chemistry. Advanced monosaccharide building blocks are essential tools in glycoscience for assembling complex glycans. Here, we report a predominantly continuous-flow synthesis of a d-glucuronic acid building block through a series of optimized and modular transformations, including O-p-methoxyphenyl (PMP) glycosylation, Zemplén deacylation, 4,6-O-benzylidene protection/deprotection, 2-O-benzoylation, and C6 oxidation/methylation. The resulting building block is directly applicable to the synthesis of glycosaminoglycans. Notably, β-selective glycosylation was achieved at elevated temperatures, eliminating the need for cooling, and a biphasic TEMPO/BAIB [2,2,6,6-tetramethylpiperidine-1-oxyl/bis(acetoxyiodo)benzene] oxidation protocol enables selective conversion of the C6 primary alcohol to the uronic acid. The total residence time (t_r) for all seven continuous-flow steps is 91.2 min. Overall, compared to traditional batch processes, the continuous-flow route delivered the final product with significantly enhanced productivity and space-time yield (STY), highlighting the utility of flow chemistry in streamlining glycan synthesis. Incorporation of automation using our open-source Python-based software, MechWolf, further ensures reproducibility of the reported methods.