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

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-1 H -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-2 H -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. 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.