Enantioselective Approaches to 3,4-Annulated Indoles Using Organocatalytic Domino Reactions

Organocatalytic domino reactions of 4-substituted indoles are summarized in this account. Two reactions have been developed, one with enals, activated by secondary amine catalysts via iminium ions, and one with nitroethene, using a phosphoric acid catalyst. Both reactions required solving the challenge posed by the very low nucleophilicity of the indole substrates, which bear an electron-withdrawing Michael acceptor at C4. DFT calculations were used to shed light on the unique reaction pathway followed by the phosphoric acid catalyzed transformation, wherein a bicoordinated nitronic acid intermediate was found to evolve preferentially through an intramolecular nitro-Michael reaction, instead of the common tautomerization pathway. These reactions provide new and efficient entries to 3,4-ring-fused indoles in diastereo- and enantioenriched form. In more detail, the structures obtained feature a 1,3,4,5-tetrahydrobenzo[cd]indole core, which is present in the structural framework of ergot alkaloids. Indeed, the preparation of an intermediate previously used in ergot alkaloid (6,7-secoagroclavine) synthesis was possible from one of the catalytic adducts. 1 Introduction 2 Reactions of 4-Substituted Indoles with alpha,beta-Unsaturated Aldehydes Catalyzed by Secondary Amines 3 Reactions of 4-Substituted Indoles with Nitroethene Catalyzed by Bronsted Acids 4 Conclusion