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

ABSTRACT 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.