Diastereoselective access to densely-functionalized azaspirobicyclic scaffolds from bicyclobutanes
Kushal Dhake1, Muskan Sharma1, Faith Alberts1
1Department of Chemistry, University of Victoria, 3800 Finnerty Rd., Victoria, BC, V8P 5C2, Canada. dcleitch@uvic.ca.
Abstract:
Azaspiro[3.3]heptanes are known as conformationally stable bioisosteres of piperidines in drug discovery. However, the limited number of synthetic routes to access diverse derivatives of these scaffolds poses a major challenge to their use in medicinal chemistry. We report a one-step addition/spirocyclization process between N-alkyl imines and bicyclobutanes that forms 2-azaspiro[3.3]hept-5-en-1-ones. These densely-functionalized scaffolds serve as access points to several azaspirocyclic structures. In addition to N-functionalization through reduction, deprotection, and acylation, we demonstrate skeletal rearrangements to spirocyclic [2.3] and [3.4] systems from the parent molecule.
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