The stereoselective synthesis of cis- and trans-fused pyrrolidine containing bicyclic azepine and oxepine derivatives using aza-Cope rearrangement-Mannich cyclization as a key step

Abstract

The development of novel methods and strategies for the formation of fused five-, six-, and seven-membered ring structures is of utmost importance in organic syntheses. The present study describes the investigation of a [3,3]-sigmatropic rearrangement to construct new cis- and trans-fused heterocyclic compounds, such as decahydropyrrolo[2,3-c]azepines, octahydro-1H-oxepino[4,5-b]pyrroles, and decahydropyrrolo[2,3-d]azepines, using the aza-Cope–Mannich reaction. An investigation of the [3,3]-sigmatropic rearrangement of 3-amino-4-vinyltetrahydro-2H-pyran-4-ol, 3-amino-4-vinylpiperidin-4-ol, and 4-amino-3-vinylpiperidin-3-ol derivatives revealed that the process proceeded with a high yield and diastereoselectivity. The stereoselectivity of the annulation process can be rationalised by examining the low-energy conformations of the trans-amino alcohol starting materials. These results demonstrate the efficiency and the potential of the aza-Cope–Mannich reaction in the creation of cis- and trans-fused pyrrolidine containing bicyclic azepine and oxepine derivatives (5,7-bicyclic ring systems). The absolute configuration of the corresponding 5,7-bicyclic ketones was also established, which has rarely been achieved. The target scaffolds were achieved in 6–7 steps from commercially available starting materials and could be obtained in racemic form on a multigram scale.