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Updated: Jul 1, 2026

Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles
Published on: August 22, 2018
A Novel Class of "Super-Strained" Spiro Heterocycles: Gateway to 1-Azaspiro[3.3]heptane Derivatives, and Biological
Philipp Natho1, Annarita Vicenti1, Marco Colella1
1Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Bari, Italy.
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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.
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