Exploring Synthetic Routes to 6-Functionalized 4-Azaspiro[2.3]hexanes

Azaspirohexanes are promising derivatives for the synthesis of piperidine bioisosteres in medicinal chemistry. Previous work in this area has focused on developing 5-azaspiro[2.3]hexane analogues, but the synthesis of 4-azaspiro[2.3]hexanes has been largely unexplored. To synthesize functionalized 4-azaspiro[2.3]hexane analogues we explored the use of several substituted azetidines as key intermediates. We found that ring closure of an acyclic amine performed the best for the synthesis of 3,3-dimethoxy-2-ester azetidine, providing good yields without the need for hazardous materials or precious metal catalysts. From these key intermediate azetidine enamines, we synthesized two 6-functionalized 4-azaspiro[2.3]hexanes. Additionally, we explored the synthesis for various 6-functionalized 4-azaspiro[2.3]hexanes, which have potential as useful synthetic motifs in both medicinal chemistry and chemical biology.