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45568-AC1
Synthesis of Complex Indoles and Related Natural Products
The present project involves the synthesis and exploitation of fused heterocycles as vehicles for the synthesis of biologically important indoles, carbazoles, carbolines, and other natural products. One key step in these syntheses is a cycloaddition to the appropriate fused heterocyclic indole or pyrrole. For example, as a route to the trikentrin and herbindole group of biologically active natural products, we have carried out an intramolecular Diels-Alder cycloaddition of the fused heterocycle furo[3,4-b]pyrrole to afford a tricyclic indole embodying the structure of these natural indoles. Nitroindoles continue to be of interest to us and we have developed two different one-pot reductive acylations of 3-nitroindoles leading to the N-acylated aminoindoles, protected versions of the relatively unstable aminoindoles. One method utilizes indium and the other employs catalytic hydrogenation. Applications of this reductive acylation chemistry to 2- and 3-nitropyrroles has afforded access to the naturally occurring polyhalogenated 2,2'- and 1,2'-bipyrroles, including those metabolites such as “Q1” that are found in myriad marine organisms, seabirds, and marine mammals. We have found that 2-iodo-3-nitroindoles undergo an efficient nucleophilic amination with amines to give the corresponding 2-amino-3-nitroindoles, which offer a potential route to the virtually unknown 2,3-diaminoindoles via our reductive acylation methodology. We have identified a new route to pyrrolo[3,4-b]indoles via a 1,3-dipolar cycloaddition reaction between 2- and 3-nitroindoles and azomethine ylides. Subsequent tin-mediated denitrosation and manganese dioxide oxidation furnishes the pyrrolo[3,4-b]indoles. In our study of the fused heterocycles pyrrolo[3,4-b]indoles and pyrrolo[2,3-b]indoles, we have uncovered a novel ipso acylation–detosylation reaction upon reaction with acid chlorides and aluminum chloride leading to the corresponding acylated heterocycles. As an extension of our syntheses of fused heterocycles using lithiation methods, we have pursued the synthesis of novel 3,3'-diiodo-2,2'-biindoles, oxazolylindoles, bis(3-indolylacetylene), bisindolylmaleimides, and indolocarbazoles. In collaboration with Professor Jerry Jasinski at Keene State University, we have performed X-ray crystallography studies on several of our novel indoles prepared during the project period. Attempts thus far to synthesize and isolate an example of the elusive indole-2,3-quinodimethane have been unsuccessful.
