Towards the Synthesis of 3,3‐Difluoro Deaminated Sialic Acid (C3DFKDN)

2‐Keto‐3‐deoxy‐d‐glycero‐d‐galacto‐nononic acid (KDN) is a nine‐carbon monosaccharide of the sialic acid family. As a deaminated analogue of N‐acetylneuraminic acid (Neu5Ac), KDN features a hydroxyl group at C5 instead of an amine. Although present at low levels in mammalian tissues, KDN is abundant in certain tumor cells and pathogens, making it and its processing enzymes attractive targets for understanding biological functions and developing potential therapeutics. Fluorinated carbohydrate derivatives are widely used to probe and modulate carbohydrate‐active enzymes (CAZymes). Here, we report the first total synthesis of 3,3‐difluoro KDN (C3DFKDN), a novel fluorinated sialic acid derivative and a key intermediate for designing covalent inhibitors and activity‐based probes targeting KDN‐processing enzymes. Introduction of a C3‐difluoro group prevents elimination side reactions common with monofluorinated sialic acid analogues. Two synthetic strategies were explored: (1) coupling a pyranose precursor with a difluorinated alkyne bromide followed by oxidation, and (2) incorporation of a difluoroacetate building block via a Reformatsky‐type reaction. The latter approach proved more effective, affording protected C3DFKDN in an overall yield of 3.7% over 12 steps from methyl α‐d‐mannopyranoside. This work establishes methodology for the synthesis of C3‐difluorinated sialic acids and provides a foundation for developing fluorinated probes and inhibitors of KDN‐related enzymatic pathways.