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

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 S1 and S2 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 (TS1', ΔG^‡ = 26.8 kcal/mol, Scheme 5 and TS5b, ΔG^‡ = 14.9 kcal/mol, Scheme 8). Given the synthetic tunability and the reported anticancer activity of S2 (via CDK2 inhibition), we introduce application inspirations, utilizing prodrug strategy, to load a biotargeting molecule on S2 and employ the newly discovered reaction in the bioactivation mechanism. Furthermore, the S1 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 TS1'-like rate-limiting step, within the designed glutathione-induced prodrug bioactivation mechanism (Scheme 9).