化学
Negishi偶联反应
组合化学
吡啶
共价键
产量(工程)
克拉斯
立体化学
有机化学
催化作用
生物化学
材料科学
冶金
突变
基因
作者
Jie Xu,Samantha Grosslight,Kyle A. Mack,Sierra C Nguyen,Kyle Clagg,Ngiap‐Kie Lim,Jacob C. Timmerman,Jeff Shen,Nicholas A. White,Lauren E. Sirois,Chong Han,Haiming Zhang,Matthew S. Sigman,Francis Gosselin
摘要
An efficient asymmetric synthesis of a potent KRAS G12C covalent inhibitor, GDC-6036 (1), is reported. The synthesis features a highly atroposelective Negishi coupling to construct the key C-C bond between two highly functionalized pyridine and quinazoline moieties by employing a Pd/Walphos catalytic system. Statistical modeling by comparing computational descriptors of a range of Walphos chiral bisphosphine ligands to a training set of experimental results was used to inform the selection of the best ligand, W057-2, which afforded the desired Negishi coupling product (Ra)-3 in excellent selectivity. A subsequent telescoped reaction sequence of alkoxylation, global deprotection, and acrylamide formation, followed by a final adipate salt formation, furnished GDC-6036 (1) in 40% overall yield from starting materials pyridine 5 and quinazoline 6.
科研通智能强力驱动
Strongly Powered by AbleSci AI