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.