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‐azaspiro3.3heptane 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‐azabicyclo1.1.0butanes—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‐azaspiro3.3heptane 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.
Natho et al. (Tue,) studied this question.