1‐Azaspiro[3.3]heptane as a Bioisostere of Piperidine.

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, ClO2S−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. [ABSTRACT FROM AUTHOR]