Quantum Chemical Characterization of Rotamerism in Thio-Michael Additions for Targeted Covalent Inhibitors

Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy and is a severe condition with no treatment currently available. Recently, small-molecule ligands have been developed that have some selectivity for and covalently inhibit cyclin dependent kinase 12 (CDK12). CDK12 is involved in the transcription of elongated RNA sections that results in the DM1 condition. The covalent bond is achieved after nucleophilic addition to a Michael acceptor warhead. Previous studies of the conformational preferences of thio-Michael additions have focused on characterizing the reaction profile based on the distance between the sulfur and β-carbon atoms. Rotamerism, however, has not been investigated extensively and can have a large impact on reaction rates and adduct yields. Here, we use high-level quantum chemistry calculations, up to coupled cluster with single, double, and perturbative triple excitations [CCSD(T)], to characterize the gas-phase nucleophilic addition of an archetypal nucleophile, methanethiolate, to various nitrogen-containing Michael acceptors which are representative of the small-molecule CDK12 inhibitors. By investigating the structural, energetic, and electronic properties of the enolate intermediates, we show that synclinal additions are energetically favored over antiperiplanar additions due to the greater magnitude of attractive non-covalent interactions permitted by the conformation. The calculated transition states associated with the addition process indicate that synclinal addition proceeds via lower energetic barriers than antiperiplanar addition and is the preferred reaction pathway. The mechanistic insights from this study will inform the design of new derivatives with faster reaction rates and higher yields of the adducts required for CDK12 inhibition and treatment of DM1.