Daniel P. Dempe, Chong-Lei Ji, Peng Liu, and Kay M. Brummond
The Journal of Organic Chemistry, 2020
The α-methylene-γ-lactam offers promise as a complementary warhead for the development of targeted covalent inhibitors. However, an understanding of the factors governing its electrophilic reactivity is needed to promote the development of lead compounds utilizing this motif. Herein we synthesize a series of N-aryl-substituted α-methylene-γ-lactams installed within the framework of a bioactive guaianolide analog. To determine the effects of the guaianolide structure on the electrophilic reactivity, these compounds were reacted with glutathione under biomimetic conditions, and the rate constants were measured. A linear free-energy relationship was observed with the Hammett parameter of the N-aryl group within the cis- or trans-annulated isomeric series of compounds. However, the trans-annulated compounds exhibited a ca. 10-fold increase in reactivity relative to both the cis-annulated compounds and the corresponding N-arylated 3-methylene-2-pyrrolidinones. Density functional theory calculations revealed that the reactivity of the trans-annulated stereoisomers is promoted by the partial release of the ring strain of the fused seven-membered ring in the thio-Michael addition transition state.