Exploring synthetic routes to 6-functionalized 4-azaspiro[2.3]hexanes

Abstract

Azaspirohexanes are promising scaffolds 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 6-functionalized 4-azaspiro[2.3]hexanes remains largely unexplored. To synthesize 6-functionalized 4-azaspiro[2.3]hexane analogues, we explored the use of several substituted azetidines (fluoro-, dimethoxy- and methoxybenzyl-substituted) as key intermediates. We found that intramolecular ring closure of an acyclic amine was optimal 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 azetidine enamine intermediates, we synthesized two 6-functionalized 4-azaspiro[2.3]hexanes: 6-OBn-4-azaspiro[2.3]hexane and 6-dimethoxy-4-azaspiro[2.3]hexane. Additionally, we explored the synthesis of various 6-functionalized 4-azaspiro[2.3]hexanes, which have potential as useful motifs in both medicinal chemistry and chemical biology.