1-Azaspiro[3.3]heptane as a Bioisostere of Piperidine

  • Angew Chem Int Ed Engl. 2023 Dec 18;62(51):e202311583. doi: 10.1002/anie.202311583.
Alexander A Kirichok  1  2 ,  Hennadii Tkachuk  1 ,  Yevhenii Kozyriev  1  3 ,  Oleh Shablykin  1  4 ,  Oleksandr Datsenko  1 ,  Dmitry Granat  1 ,  Tetyana Yegorova  2 ,  Yuliya P Bas  2 ,  Vitalii Semirenko  1 ,  Iryna Pishel  1 ,  Vladimir Kubyshkin  1 ,  Dmytro Lesyk  5 ,  Oleksii Klymenko-Ulianov  5 ,  Pavel K Mykhailiuk  1  2
Affiliations
  • 1. Enamine Ltd, Winston Churchill Str. 78, 02094, Kyiv, Ukraine.
  • 2. Taras Shevchenko National University of Kyiv, Faculty of Chemistry, Volodymyrska 60, 01601, Kyiv, Ukraine.
  • 3. Oles Honchar Dnipro National University, Faculty of Chemistry, 72 Gagarina Ave., 49010, Dnipro, Ukraine.
  • 4. V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Akademika Kukharya 1, 02094, Kyiv, Ukraine.
  • 5. Bienta, Winston Churchill Str. 78, 02094, Kyiv, Ukraine.
PMID: 37819253 DOI: 10.1002/anie.202311583
Abstract

1-Azaspiro[3.3]heptanes were synthesized, characterized, and validated biologically as bioisosteres of piperidine. The key synthesis step was thermal [2+2] cycloaddition between endocyclic alkenes and the Graf isocyanate, ClO2 S-NCO, to give spirocyclic β-lactams. Reduction of the β-lactam ring with alane produced 1-azaspiro[3.3]heptanes. Incorporation of this core into the anesthetic drug bupivacaine instead of the piperidine fragment resulted in a new patent-free analogue with high activity.

Keywords
1-Azaspiro[3.3]Heptane; Bioisosteres; Drug Design; Medicinal Chemistry; Piperidine.
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