1‐Azaspiroheptane 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...

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Published inAngewandte Chemie Vol. 135; no. 51
Main Authors Kirichok, Alexander A, Tkachuk, Hennadii, Kozyriev, Yevhenii, Shablykin, Oleh, Datsenko, Oleksandr, Granat, Dmitry, Yegorova, Tetyana, Bas, Yuliya P, Semirenko, Vitalii, Pishel, Iryna, Kubyshkin, Vladimir, Lesyk, Dmytro, Oleksii Klymenko‐Ulianov, Mykhailiuk, Pavel K
Format Journal Article
LanguageEnglish
Published Weinheim Wiley Subscription Services, Inc 01.12.2023
Subjects
Alkenes
Amides
Bupivacaine
Chemistry
Cycloaddition
Heptanes
Isocyanates
Piperidine
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Summary: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.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.202311583