669083-19-6Relevant academic research and scientific papers
Copper-Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds
Cai, Aijie,Liu, Wei,Wang, Chao,Yan, Wenhao
supporting information, p. 27070 - 27077 (2021/11/18)
The engagement of unactivated alkyl halides in copper-catalyzed cross-coupling reactions has been historically challenging, due to their low reduction potential and the slow oxidative addition of copper(I) catalysts. In this work, we report a novel strategy that leverages the halogen abstraction ability of aryl radicals, thereby engaging a diverse range of alkyl iodides in copper-catalyzed Negishi-type cross-coupling reactions at room temperature. Specifically, aryl radicals generated via copper catalysis efficiently initiate the cleavage of the carbon–iodide bonds of alkyl iodides. The alkyl radicals thus generated enter the copper catalytic cycles to couple with a difluoromethyl zinc reagent, thus furnishing the alkyl difluoromethane products. This unprecedented Negishi-type difluoromethylation approach has been applied to the late-stage modification of densely functionalized pharmaceutical agents and natural products.
Overcoming mutagenicity and ion channel activity: Optimization of selective spleen tyrosine kinase inhibitors
Ellis, J. Michael,Altman, Michael D.,Bass, Alan,Butcher, John W.,Byford, Alan J.,Donofrio, Anthony,Galloway, Sheila,Haidle, Andrew M.,Jewell, James,Kelly, Nancy,Leccese, Erica K.,Lee, Sandra,Maddess, Matthew,Miller, J. Richard,Moy, Lily Y.,Osimboni, Ekundayo,Otte, Ryan D.,Reddy, M. Vijay,Spencer, Kerrie,Sun, Binyuan,Vincent, Stella H.,Ward, Gwendolyn J.,Woo, Grace H. C.,Yang, Chiming,Houshyar, Hani,Northrup, Alan B.
supporting information, p. 1929 - 1939 (2015/04/27)
Development of a series of highly kinome-selective spleen tyrosine kinase (Syk) inhibitors with favorable druglike properties is described. Early leads were discovered through X-ray crystallographic analysis, and a systematic survey of cores within a selected chemical space focused on ligand binding efficiency. Attenuation of hERG ion channel activity inherent within the initial chemotype was guided through modulation of physicochemical properties including log D, PSA, and pKa. PSA proved most effective for prospective compound design. Further profiling of an advanced compound revealed bacterial mutagenicity in the Ames test using TA97a Salmonella strain, and subsequent study demonstrated that this mutagenicity was pervasive throughout the series. Identification of intercalation as a likely mechanism for the mutagenicity-enabled modification of the core scaffold. Implementation of a DNA binding assay as a prescreen and models in DNA allowed resolution of the mutagenicity risk, affording molecules with favorable potency, selectivity, pharmacokinetic, and off-target profiles.
