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

Abstract GDC-8025 is a potent pan-TEAD inhibitor that features a functionalized 1H-pyrazolo[3,4-b]pyridine core and a reactive acrylamide warhead. The first-generation synthesis of GDC-8025 relied on a Sharpless asymmetric dihydroxylation of 7 to install the chiral diol moiety (8). This chemistry was not suitable for large scale manufacturing due to the instability of the requisite 4-vinylpyridine intermediate (7) 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 (18) 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 GDC-8025 in 8 chemical steps.