Synthesis of the Azepinobisindole Alkaloid Iheyamine A Enabled by a Cross-Mannich Reaction

The total synthesis of the azepinobisindole alkaloid iheyamine A is described. The successful strategy hinged on an intermolecular cross-Mannich reaction between 5-methoxy-3-acetoxyindole and a protected tryptamine to access an unsymmetrical 2,2'-bisindole, which was subsequently converted into iheyamine A via a deep blue 3-indolone intermediate. VT H-1 NMR infers that iheyamine A exists as a mixture of tautomers that undergo intermediate chernical exchange on the NMR time scale. The intermolecular cross-Mannich reaction described herein is a viable alternative to metal-catalyzed cross-coupling strategies commonly employed to access 2,2'-bisindoles.