45568-AC1
Synthesis of Complex Indoles and Related Natural Products
Indoles that are substituted at the 2- or 3-position with electron-withdrawing groups (nitro, phenylsulfonyl) undergo nucleophilic addition, 1,3-dipolar cycloaddition, and Diels-Alder reactions to give a variety of indoles, pyrroloindoles, and carbazoles. New methods for the synthesis of furo[3,4-b]indoles and the novel ring system furo[3,4-b]pyrrole are described for the first time. Diels-Alder reactions of furo[3,4-b]pyrroles afford indoles after dehydration of the primary cycloadducts. Efficient syntheses of both 2- and 3-nitroindoles from indole are reported. As a new route to the biologically active 4-aminocarbazoles, such as the antiostatins, we find that pyrrolo[3,4-b]indoles undergo a high-yielding Diels-Alder cycloaddition with acetylenic dienophiles, followed by acid treatment to give the expected carbazoles. Application to the synthesis of the antiostatins is underway. Similarly, furoindoles undergo a variety of Diels-Alder reactions. For example, benzyne reacts with furoindoles to give the expected cycloadducts, which are efficiently deoxygenated to the corresponding benzo[b]carbazoles. Furoindoles also react with dimethyl acetylenedicarboxylate and N-phenylmaleimide to give the Diels-Alder adducts in essentially quantitative yield, and an intramolecular version of this reaction using furo[3,4-b]pyrroles is successful and is being extended to a synthesis of the biologically active indole-containing trikentrins and herbindoles. We have recently discovered the Mn(III)-promoted free radical addition of active methylene compounds, such as malonates, to 2-nitroindole, which is followed by a spontaneous in situ Nef reaction to provide a novel synthesis of 2-oxoindolin-3-ylidenes, which have found recent utility in the synthesis of the maremycins, spirocyclic 2-oxindoles, new Cdc25 phosphatase inhibitors, and carbolines. In the case of active methine compounds this novel radical addition reaction affords the 2-nitro-3-substiuted indole. In an extension of our work to pyrroles, we find that both 2- and 3-nitropyrroles are reductively acylated under catalytic hydrogenation conditions in the presence of alicyclic and cyclic carboxylic acid anhydrides to afford the corresponding N-acylated aminopyrroles. Moreover, 1,2'- and 1,3'-bipyrroles, which are attractive precursors for the synthesis of bipyrrole-based natural products, are synthesized in one-pot from 2- and 3-nitropyrroles by a sequential nitro group reduction - Paal-Knorr pyrrole synthesis. Recent years have seen the isolation and characterization of several halogenated 1,2'- and 1,3'-bipyrroles, in addition to the previously known halogenated 2,2'-bipyrroles. Notably, "Q1", which is a heptachlorinated 1,2'-bipyrrole that is ubiquitous in the marine biosphere, is the first natural organohalogen compound to bioaccumulate in the food web up to humans (Eskimos) who consume whale blubber. We have now achieved a very simple synthesis of Q1 that will allow this important compound to be used by environmental analytical chemists. These extraordinary naturally occurring halogenated bipyrroles chemically resemble the anthropogenic polychlorinated biphenyls (PCBs) of environmental concern. We have also just finished and submitted our work on a simple and efficient synthesis of 2,2'-bipyrroles, which will be particularly useful for the synthesis of N,N'-disubstituted 2,2'-bipyrroles having different nitrogen substituents. This chemistry was applied to the synthesis of the naturally occurring hexabrominated analogue found in sea birds and derived, we believe, from marine bacteria. In unpublished work we have discovered a simple synthesis of 2,3'-biindolyls using a classical Fischer-Indole synthesis on 3-acylindoles.
