Strain‐Release Driven Spirocyclization of Azabicyclo[1.1.0]butyl Ketones

Due to their intrinsic rigidity, three-dimensionality and structural novelty, spirocyclic molecules have become increasingly sought-after moieties in drug discovery. Herein, we report a strain-release driven synthesis of azetidine-containing spirocycles by harnessing the inherent ring strain of the azabicyclo[1.1.0]butane (ABB) fragment. Novel ABB-ketone precursors bearing silyl-protected alcohols were synthesized in a single step and shown to engage in electrophile-induced spirocyclization-desilylation reactions. Primary, secondary and tertiary silyl ethers were effectively transformed into a library of new spiro-azetidines, with a range of substituents and ring sizes. In addition, the products are generated with synthetically useful ketone and protected-amine functional groups, which provides the potential for further elaboration and for this chemistry to be utilized in the rapid assembly of medicinally relevant compounds.