Abstract:
This thesis describes the synthetic efforts towards iheyamine A 209, a unique azepino[3,2-b; 4,5-b´]bisindole isolated from the marine ascidian Polycitorella sp., which ultimately culminated in the first total synthesis of this natural product. Initial attempts towards the synthesis of iheyamine A 209 centred on construction of the azepinobisindole scaffold using sequential Beckmann rearrangement-Mannich cyclisation reactions. When the model oxime 221 was used, the desired pentacyclic framework 222 was formed, but subsequent efforts to convert 222 into the azepinobisindole core of iheyamine A 223 were unsuccessful. When this approach was used in pursuit of iheyamine A, oxime 300 did not undergo the Beckmann rearrangement, but instead the 2,4´-bisindole 305 was formed as a result of the electron rich C4-site reacting during the Mannich reaction. Based on spectroscopic data for the natural product and some biomimetic model studies previously reported by Bremner, we subsequently reinvestigated a biomimetic approach to iheyamine A. A Pictet-Spengler-Plancher rearrangement sequence resulted in the synthesis of a series of azepino[2,3-b; 4,5-b´]bisindoles 344 and 365-367, all of which are regioisomers of the natural product formed by C-N migration during the Plancher rearrangement. Attempts to promote the formation of the desired azepino[3,2-b; 4,5-b´]bisindole present in iheyamine A by C-C bond migration were unsuccessful using this biomimetic approach. The total synthesis of iheyamine A was completed by way of a novel intermolecular cross- Mannich reaction between 3-acetoxyindole 503 and tryptamine 479, which was developed to construct the crucial unsymmetrical 2,2´-bisindole 424. A serendipitously discovered oxidation led to indolone 425, which upon one-pot deprotection-cyclisation-oxidation sequence gave iheyamine A 209. Variable temperature experiments were conducted on 209 to determine if iheyamine A existed as the reported tautomer 209. No change in the 1H NMR spectrum of 209 was observed (even at -30 °C), inferring that in solution iheyamine A 209 exists as a mixture of tautomers that undergo rapid chemical exchange on the NMR timescale.