Rise of Ketone α-Hydrolysis: Revisiting S_NAcyl, E1cB Mechanisms and Carbon-Based Leaving Groups in One Reaction for Drug-Targeting Applications

Nucleophilic substitution of carbon-leaving groups (CLGs) and base-catalyzed alcohol dehydration reactions are rare in the organic chemistry literature. Herein, we introduce an unprecedented example of a novel reaction that challenges the poor leaving group abilities of both CLGs and hydroxide ions via a concerted transition state, demonstrating E1cB_anion step-2/S_NAcyl step-1 reaction mechanism interference, displayed by <b>S1</b> and <b>S2</b> scaffolds in an alkaline medium (Schemes 5,8). The work offers swift access to C-C bond hydrolysis in the form of ketone α-hydrolytic cleavage under environmentally convenient conditions. Three reaction products were characterized by single-crystal X-ray crystallography, which supported their computed most stable ring conformer structures. Experimental and DFT evidence evoke fast reaction rates (<b>TS1'</b>, Δ<i>G</i>^‡ = 26.8 kcal/mol, Scheme 5 and <b>TS5b</b>, Δ<i>G</i>^‡ = 14.9 kcal/mol, Scheme 8). Given the synthetic tunability and the reported anticancer activity of <b>S2</b> (via CDK2 inhibition), we introduce application inspirations, utilizing prodrug strategy, to load a biotargeting molecule on <b>S2</b> and employ the newly discovered reaction in the bioactivation mechanism. Furthermore, the <b>S1</b> scaffold offers two covalent derivatization sites that would allow for the sequential biorelease of a C2-linked biotargeting molecule and then a C4-linked drug, in a <b>TS1'</b>-like rate-limiting step, within the designed glutathione-induced prodrug bioactivation mechanism (Scheme 9).