A piperidine proxy

Abstract

The molecular motif 1-azaspiro[3.3]heptane may look peculiar, with its two four-membered rings that share a single carbon. But the structure can behave like a mimic of piperidine, a popular heterocycle in many drugs. Until now, however, this molecular motif has been tough to make. Chemists led by Pavel K. Mykhailiuk at the Kyiv, Ukraine–based pharmaceutical chemical firm Enamine report a synthesis of monosubstituted 1-azaspiro[3.3]heptanes. The route expands the molecular toolbox for medicinal chemists looking to add diverse motifs to their molecules. 2-Azaspiro[3.3]heptanes have been popular piperidine mimics, or bioisosteres, since they were first proposed for this purpose in 2010. The motif has appeared in at least 100 research manuscripts, 500 patents, and 7,000 new compounds. But the isomeric 1-azaspiro[3.3]heptane has been rare because there was no modular route to make this motif with just one substituent. Mykhailiuk and colleagues decided to take up this challenge because of perceived demand from