Concise Synthesis of Fostriecin and Analogs through Late-Stage Chemoenzymatic Installation of Their Key Pharmacophores

As one of the most potent and selective protein phosphatase inhibitors, fostriecin shows a broad range of anticancer activity. In light of fostriecin’s antiproliferative properties, a phase I clinical trial was conducted on the natural product, but was soon halted due to issues with compound stability and purity. Numerous efforts in the past two decades have yielded 17 successful syntheses that proceed in 19 to 34 steps. Herein, we develop a modular chemoenzymatic approach that provides fostriecin and its analogs in a collective manner in 9 steps (longest linear sequence). The synthesis features a convergent assembly of three key fragments and a late-stage chemoenzymatic derivatization of an advanced intermediate that (i) installs two of the key pharmacophores and (ii) allows ready diversification of the hydrophobic tail. A key feature in this derivatization is the optimization of an enzymatic C–H oxidation step through the concurrent use of decoy molecule strategy and rational enzyme engineering. Cumulatively, our strategy capitalizes on the exquisite chemoselectivity of enzymatic transformations while ensuring synthetic modularity and versatility for analog generation. This work will facilitate future investigation into the biological activities and medicinal chemistry of the natural product family.