Syntheses of indoles and natural indole alkaloids from 2-nitrostyrene derivatives

A short and flexible synthesis of 2,3-disubstituted indoles employing a Barluenga-type palladium-catalyzed cross-coupling of p-tosylhydrazones with 2-nitroarylhalides followed by a palladium-catalyzed, carbon monoxide-mediated reductive cyclization was developed. Significantly better overall yields were obtained performing the two-step reaction sequence in a one-pot reaction. Secondly, in order to facilitate biological studies of ergotryptamine, a recently isolated ergot alkaloid, it was selected as a target for synthesis. In an attempt to synthesize ergotryptamine, a palladium catalyzed Kosugi-Migita-Stille cross coupling, a Mizoroki-Heck reaction, and a carbon monoxide-mediated palladium-catalyzed reductive cyclization were utilized as the key steps. Using a similar synthetic approach, synthesis of another indole norpsilocin, a component of magic mushroom, was accomplished in two additional steps. Additionally, a selection of β-acyl-β-alkyl substituted 2-nitrostyrenes were subjected to a palladium-catalyzed, carbon monoxide-mediated reductive cyclization. 2-Substituted 3-acylindoles with rearranged carbon skeleton were observed in all cases. In addition to indoles, small amounts of the corresponding quinolone-N-oxide and/or quinoline were isolated as side products in a number of cases. The cyclization precursors, β-acyl-β-alkyl substituted 2-nitrostyrenes, were synthesized via either a Wittig reaction or an aldol condensation. Finally, a short synthetic sequence leading to two marine diastereomeric azepino indole alkaloids hyrtioreticulins C and D was completed. A reductive amination via a trans-imination, a regioselective intramolecular Mizoroki-Heck reaction, and a palladium-catalyzed reductive cyclization were the major steps in the synthetic sequence