Diastereoselective access to densely-functionalized azaspirobicyclic scaffolds from bicyclobutanes.

Azaspiro[3.3]heptanes are known as conformationally stable bioisosteres of piperidines in drug discovery. However, the limited number of synthetic routes to access diverse derivatives of these scaffolds poses a major challenge to their use in medicinal chemistry. We report a one-step addition/spirocyclization process between N-alkyl imines and bicyclobutanes that forms 2-azaspiro[3.3]hept-5-en-1-ones. These densely-functionalized scaffolds serve as access points to several azaspirocyclic structures. In addition to N-functionalization through reduction, deprotection, and acylation, we demonstrate skeletal rearrangements to spirocyclic [2.3] and [3.4] systems from the parent molecule.