2-Naphthylmethyl Protecting Group Strategy for Streamlined Synthesis of a Fondaparinux Analogue.

Fondaparinux synthesis remains challenging because of demanding stereochemical control, protecting group manipulation, and purification of highly functionalized intermediates. We report a 2-naphthylmethyl (Nap) protecting group strategy for an azide-functionalized fondaparinux analogue. Direct C-2 Nap installation, combined with C-6 2-(diphenylphosphinoyl)acetyl (DPPA)-assisted β-glucosylation, streamlined assembly, while Nap-mediated phase behavior enabled 17 of 20 intermediates to be isolated without chromatography. The final analogue showed anti-FXa activity comparable to commercial fondaparinux.