Total Synthesis of the Branched Human Milk Oligosaccharide Lacto-N-neohexaose

The chemical synthesis of the rare branched human milk oligosaccharide lacto-N-neohexaose (LNnH) was accomplished in a total of 19 steps, starting from commercially available disaccharides─lactulose and lactose. The synthesis features regioselective silyl protection using tin chemistry, strategically designed [2+2] and [2+4] glycosylation reactions, and an orthogonal protection/deprotection sequence to ensure efficiency and selectivity. Careful optimization of reaction conditions and donor–acceptor combinations minimized the need for extensive chromatographic purifications, facilitating the isolation of crystalline intermediates in high yields. This streamlined approach provides a scalable and efficient route to LNnH, contributing to the synthetic accessibility of complex human milk oligosaccharides.