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

IF 3.3 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2026-10-16 Epub Date: 2026-09-29 DOI:10.1021/acs.oprd.6c00216

Nicholas A. White, Matthew M. Pompeo, Kyle Clagg, Jeff Shen, Di Xu, Carmela Molinaro, Lauren E. Sirois, Francis Gosselin

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引用次数: 0

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.

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流动Chan-Evans-Lam偶联及α-酮酯还原法制备泛tead抑制剂GDC-8025

GDC-8025是一种潜在的pan- tead抑制剂，具有功能化1h -吡唑[3,4-b]吡啶核心和反应性丙烯酰胺战斗部。第一代GDC-8025的合成依赖于7的Sharpless不对称二羟基化来安装手性二醇部分(8)。由于必需的4-乙烯基吡啶中间体不稳定(7)和四氧化锇的职业毒性问题，这种化学方法不适合大规模生产。为了解决这些挑战，开发了第二代途径，利用α-酮酯底物的生物催化对映选择性还原（18）。再加上优化流动中的Chan-Evans-Lam偶联、串联酯/腈还原和化学选择性丙烯酰胺化，这一新路线的实施促进了8个化学步骤中稳定的多公斤合成GDC-8025。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.