Synthesis of the pan-TEAD Inhibitor GDC-8025 via a Flow Chan–Evans–Lam Coupling and Enantioselective Biocatalytic α‑Ketoester Reduction

The first-generation synthesis of <b>GDC-8025</b> relied on a Sharpless asymmetric dihydroxylation of <b>7</b> to install the chiral diol moiety (<b>8</b>). This chemistry was not suitable for large scale manufacturing due to the instability of the requisite 4-vinylpyridine intermediate (<b>7</b>) and occupational toxicity concerns of osmium tetroxide.

To address these challenges, a second-generation route utilizing a biocatalytic enantioselective reduction of an α-ketoester substrate (<b>18</b>) was developed. Together with optimization of a Chan–Evans–Lam coupling in flow, a tandem ester/nitrile reduction, and a chemoselective acrylamidation, implementation of this new route facilitated the robust multikilogram synthesis of <b>GDC-8025</b> in 8 chemical steps.