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oai:figshare.com:article/34023762 2026-09-29T12:33:29Z category_4 category_146 category_14 category_19 category_24 category_873 category_45 category_61 category_62 category_132 portal_63 item_type_6 month_year_09_2026

Synthesis of the pan-TEAD Inhibitor GDC-8025 via a Flow Chan–Evans–Lam Coupling and Enantioselective Biocatalytic α‑Ketoester Reduction Nicholas A. White (4994780) Matthew M. Pompeo (23935680) Kyle Clagg (1695886) Jeff Shen (1520119) Di Xu (1443394) Carmela Molinaro (1685800) Lauren E. Sirois (2068171) Francis Gosselin (1442914) Biochemistry Space Science Molecular Biology Pharmacology Evolutionary Biology Chemical Sciences not elsewhere classified Sociology Developmental Biology Marine Biology Infectious Diseases sharpless asymmetric dihydroxylation reactive acrylamide warhead occupational toxicity concerns new route facilitated >] pyridine core 8 chemical steps generation route utilizing biocatalytic enantioselective reduction robust multikilogram synthesis 7 </ b 8025 </ b tead inhibitor gdc tead inhibitor 8025 via h </ b </ nitrile reduction generation synthesis tandem ester requisite 4 osmium tetroxide functionalized 1 chemoselective acrylamidation >- pyrazolo 4 -< <b>GDC-8025</b> is a potent pan-TEAD inhibitor that features a functionalized 1<i>H</i>-pyrazolo[3,4-<i>b</i>]pyridine core and a reactive acrylamide warhead. 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. 2026-09-29T00:00:00Z Text Journal contribution 10.1021/acs.oprd.6c00216.s001 https://figshare.com/articles/journal_contribution/Synthesis_of_the_pan-TEAD_Inhibitor_GDC-8025_via_a_Flow_Chan_Evans_Lam_Coupling_and_Enantioselective_Biocatalytic_Ketoester_Reduction/34023762 CC BY-NC 4.0