Thiol Reactivity of N-Aryl α-Methylene-γ-lactams: Influence of the Guaianolide Structure

Abstract

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.

Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update

“…α,β-Unsaturated ketones have recently been incorporated into peptidomimetic compounds by a modified Ugi multi-component reaction, as shown for (E)-4-oxo-4-arylbut-2enoate-containing inhibitors designed to target the catalytic selenocysteine of thioredoxin reductase 1 (TrxR1). 109,110 A recent example of the exploration of natural productderived α,β-unsaturated lactams was published by the groups of Liu and Brummond, 111,102 who generated N-aryl-substituted α-methylene-γ-lactam analogs of guaianolide sesquiterpene lactones (exemplified by compound 25, Figure 9A). Thiol reactivity studies under biomimetic conditions showed that trans-annulated lactams exhibited faster reaction kinetics (t 1/2 ) compared to cis-lactams, which was rationalized computationally by a strain-driven acceleration.…”

“…A recent example of the exploration of natural product-derived α,β-unsaturated lactams was published by the groups of Liu and Brummond, , who generated N -aryl-substituted α-methylene-γ-lactam analogs of guaianolide sesqui­terpene lactones (exemplified by compound 25 , Figure A). Thiol reactivity studies under biomimetic conditions showed that trans -annulated lactams exhibited faster reaction kinetics ( t 1/2 ) compared to cis -lactams, which was rationalized computationally by a strain-driven acceleration.…”

Controllable conformation and reactivity of bicyclic α-methylene cyclopentanones and their NF-κB pathway inhibitory activity

“…Compared with the electronic effects, however, the steric effects tuning the reactivity have not been investigated comprehensively. 10 Such steric effects were only accidentally found in some natural products and their derivatives containing sterically unique electrophiles. 11,12 In this context, we were curious to know whether the steric effect of electrophiles tunes both reactivity and biological activity.…”