Observations arising from a Beckmann rearrangement-Mannich cyclization approach to the azepinobisindole alkaloid iheyamine A

Abstract

An overview of an iterative Beckmann rearrangement-Mannich cyclization approach to the azepinobisindole alkaloid iheyamine A is described. In a preliminary model study, the (E)-oxime 10 underwent Beckmann rearrangement to give the bisindolylacetamide 4 followed by an intramolecular Mannich cyclization affording 2-(indolin-2-yl)indole 5 containing the heterocyclic framework of the iheyamine alkaloids. However, the 2-(indolin-2-yl)indole 5 could not be converted into the azepinobisindole core of iheyamine A. When the same Beckmann-Mannich approach was applied toward the natural product itself, a result was obtained that contrasted the model study. The (E)-oxime 3 did not undergo Beckmann rearrangement, but instead an intramolecular Mannich cyclization whereby the electron rich C4 site attacked the intermediate iminum ion, generating the 4-(indolin-2-yl)indole 25 bearing the heterocyclic framework of the slime mould pigment arcyriacyanin A. Although this route did not result in the synthesis of iheyamine A being accomplished, some interesting observations related to the venerable Beckmann rearrangement and Mannich cyclization reactions are described.