A Novel Class of “Super‐Strained” Spiro Heterocycles: Gateway to 1‐Azaspiro[3.3]heptane Derivatives, and Biological Validation

Strained spiro heterocycles have gained popularity in medicinal chemistry due to their potential to act as conformationally rigid non-classical three-dimensional bioisosteres. Recently, 1-azaspiro[3.3]heptane has been validated as a piperidine bioisostere, although synthetic methods available for functionalized or heteroatom-containing derivatives are scarce. We address this shortcoming by accessing spirocyclic 1-azabicyclo[1.1.0]butanes-a novel class of "super-strained" spirocycles-through a Johnson-Corey-Chaykovsky reaction between cyclobutane-, oxetane-, and azetidine-substituted sulfonium salts, and azirines. We demonstrate that such spirocycles are suitable precursors for highly functionalized 1-azaspiro[3.3]heptane derivatives. In addition, such super-strained spirocycles have been validated in vitro as potential sigma-1 receptor agonists, a target identified through an artificial intelligence-supported target fishing approach.