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

Abstract

Despite numerous potential advantages of oxetanes, their restricted synthetic accessibility and propensity to ring-opening hamper their wide application in drug design. In this work, we disclose our experimental achievements and 10 years of experience in oxetane chemistry and provide a comprehensive study on the oxetane core tolerance towards the reaction conditions of the typical toolbox of organic and medicinal chemists, which is based on our original, unpublished developments. The scope of examined reactions includes oxidation, reduction, alkylation, acylation, nucleophilic substitution, C–C/CC/CC bond formation, hydrolysis, and protecting groups cleavage, and demonstrates the stability of the oxetane's moiety towards acidic and basic conditions. Over 40 transformations were applied to generate the oxetane chemical stability profile, which could direct the design of other synthetic approaches for the synthesis and incorporation of oxetanes in the future. The additional aim of the work included the optimization of the synthetic protocols with the possibility of scaling up to 1 kg in a single run. Newly designed synthetic protocols in our hands allowed for the preparation of novel 3,3-disubstituted oxetanes as small building blocks (over 100 examples, almost 90% of which were not reported previously in the literature). 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.