Organic Process Research & Development· 2026Q1
Synthesis of the pan-TEAD Inhibitor GDC-8025 via a Flow Chan–Evans–Lam Coupling and Enantioselective Biocatalytic α-Ketoester Reduction
- 1citations
- Q1SCImago
- 2026year
Short summary
A new, robust multikilogram synthesis of the pan-TEAD inhibitor GDC-8025 was achieved in 8 steps, replacing an unstable intermediate and toxic reagents with a flow Chan–Evans–Lam coupling and an enantioselective biocatalytic α-ketoester reduction.
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Key points
- Developed a new 8-step synthesis for the pan-TEAD inhibitor GDC-8025.
- Replaced unstable 4-vinylpyridine intermediate and toxic osmium tetroxide from the first-generation route.
- Utilized a flow Chan–Evans–Lam coupling and enantioselective biocatalytic α-ketoester reduction.
- Enabled robust multikilogram synthesis of GDC-8025.
AI-generated from the title and abstract; the full text is not read.
Abstract
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.
The authors' abstract, as published at the source. Organic Process Research & Development, 2026 · DOI ↗
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Field: Cell Biology
Cell BiologyBiochemistry, Genetics and Molecular Biology