1‐Azaspiro[3.3]heptane as a Bioisostere of Piperidine**
Alexander A. Kirichok, Hennadii Tkachuk, Yevhenii Kozyriev, Oleh Shablykin, Oleksandr Datsenko, Dmitry Granat, Tetyana Yegorova, Yuliya P. Bas, Vitalii Semirenko, Iryna Pishel, Vladimir Kubyshkin, Dmytro Lesyk, Oleksii Klymenko‐Ulianov, Pavel K. Mykhailiuk
Abstract
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, ClO 2 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.