Synthesis of a C‐2 Functionalized <scp>l</scp> ‐Iduronic Acid Derivative as a Candidate Pharmacological Chaperone for MPS II (Hunter Syndrome)

A C-2 functionalized l-IdoA derivative was designed as a potential pharmacological chaperone for MPS II, and several routes to its synthesis were investigated. Successful synthesis proceeded via an oxidation/Horner-Wadsworth-Emmons sequence, overcoming significant challenges with competing elimination reactions to give alkene derivatives in good overall yields. Catalytic hydrogenation of the double bonds proceeded stereoselectively in high yield to give the desired L-ido-configured products, confirmed by x-ray crystallographic analysis. These were subsequently elaborated to the target dicarboxylate prodrug 1 in good overall yield. Molecular docking studies suggest the parent compound engages with the active site and makes several H-bonding interactions with key active site residues. Target prodrug 1 and known chaperone D2S0 were evaluated against two MPS II cell lines, but neither compound was able to reduce HS substrate levels at the doses tested.