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An Alternative Route to the Anticancer Agent: 2‑Fluorofucose from Readily Available L‑(−)Rhamnose and Mechanistic Insights into a Zinc/Ammonium Iodide-Mediated Elimination Reaction

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journal contribution
posted on 05.08.2022, 21:20 authored by Roozbeh Yousefi, Bradley J. Paul-Gorsline, Omid Soltani, Kumar D. Ashtekar
2-Fluorofucose (6) is a fucosylation inhibitor administered orally to patients with advanced solid tumors. 6 exhibits antitumor activity, putatively via multiple mechanisms. Herein, we report a robust formal synthetic route for obtaining 6 (SGD-2083) from L-(−)­rhamnose as a starting material. This provides an alternative expedient route toward its commercial-scale production for a First in Human (FIH) campaign. In this work, we have optimized a linear synthesis constituting a sequential, strategic protection, oxidation, reduction, and bromination. Importantly, we biased the reactivity of an organozinc intermediate toward an ionic pathway by inclusion of salt additives. Computational insights and mechanistic studies highlighting the role of relative configuration and the reactivity of these protected sugars are the key toward the success of this efficient and scalable route. The efficiency of this eight-step linear synthesis was demonstrated on multigram scale, furnishing key intermediate 4 in 32% overall yield.