Oxetane as a part of modern medicinal chemistry toolbox: the case of 3,3-disubstituted building blocks

Despite numerous potential advantages of oxetanes, their restricted synthetic accessibility and propensity to ring-opening hampers their wide application in drug design. In this work, we disclose our 10-year experience in oxetane chemistry and provide a comprehensive analysis of the oxetane core tolerance towards the reaction conditions of the typical toolbox of organic and medicinal chemists. The scope includes oxidation, reduction, alkylation, acylation, nucleophilic substitution, C–C/C=C/C≡C bond formation, hydrolysis and protecting groups cleavage, and also demonstrates the stability of the oxetane's moiety towards acidic and basic conditions. Over 30 transformations were applied to generate the oxetane chemical stability profile and prepare novel 3,3-disubstituted oxetanes as accessible small building blocks (over 100 examples). The work's additional aim included optimizing the synthetic protocols with the possibility of scaling on up to 1 kg in a single run, also addressing the potential instability of the oxetane ring. These results benefit the development of oxetanes as a part of the toolbox of modern medicinal chemistry, as well as their incorporation into drug development programs.