370-31-0Relevant academic research and scientific papers
Systematic Study of the Glutathione Reactivity of N-Phenylacrylamides: 2. Effects of Acrylamide Substitution
Birkholz, Adam,Kopecky, David J.,Volak, Laurie P.,Bartberger, Michael D.,Chen, Yuping,Tegley, Christopher M.,Arvedson, Tara,McCarter, John D.,Fotsch, Christopher,Cee, Victor J.
, p. 11602 - 11614 (2020/12/04)
A comprehensive understanding of structure-reactivity relationships is critical to the design and optimization of cysteine-targeted covalent inhibitors. Herein, we report glutathione (GSH) reaction rates for N-phenyl acrylamides with varied substitutions at the α- and β-positions of the acrylamide moiety. We find that the GSH reaction rates can generally be understood in terms of the electron donating or withdrawing ability of the substituent. When installed at the β-position, aminomethyl substituents with amine pKa's > 7 accelerate, while those with pKa's 7 slow the rate of GSH addition at pH 7.4, relative to a hydrogen substituent. Although a computational model was able to only approximately capture experimental reactivity trends, our calculations do not support a frequently invoked mechanism of concerted amine/thiol proton transfer and C-S bond formation and instead suggest that protonated aminomethyl functions as an electron-withdrawing group to reduce the barrier for thiolate addition to the acrylamide.
Rhodium-Catalyzed Enantioselective Defluorinative α-Arylation of Secondary Amides
Jang, Young Jin,Rose, Daniel,Mirabi, Bijan,Lautens, Mark
supporting information, p. 16147 - 16151 (2018/11/23)
We exploited the reactivity of an electronically biased Michael acceptor to perform a defluorinative α-arylation reaction using a chiral diene(L*)-rhodium catalyst. Through this methodology, we are able to obtain various secondary amides, containing a tertiary α-stereocenter and a β,γ-unsaturated gem-difluoro olefin, with excellent enantioselectivities. This methodology addresses the limitations of the previously described α-arylation methods to construct stereo-labile tertiary α-stereocenters. Further investigation of the reaction via in situ 19F NMR monitoring suggests that the formation of the product leads to the inhibition of the active rhodium catalyst.
