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

As one of the most potent and selective protein phosphatase inhibitors, fostriecin shows a broad range of anticancer activities. In light of this property, a phase I clinical trial was conducted on fostriecin 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 17-34 steps. Herein, we develop a modular chemoenzymatic approach that provides fostriecin and its analogs in a collective manner in 9 steps (longest linear sequence) from readily available (R)-1,2,4-butanetriol. 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 rational enzyme engineering and small molecule additives for activity improvement. 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 investigations into the biological activities and medicinal chemistry of the natural product family.