Recent Advances in the Catalytic Asymmetric Friedel–Crafts Reactions of Indoles

Abstract

Functionalized chiral indole derivatives are privileged and versatile organic frameworks encountered in numerous pharmaceutically active agents and biologically active natural products. The catalytic asymmetric Friedel–Crafts reaction of indoles, catalyzed by chiral metal complexes or chiral organocatalysts, is one of the most powerful and atom-economical approaches to access optically active indole derivatives. Consequently, a wide range of electrophilic partners including α,β-unsaturated ketones, esters, amides, imines, β,γ-unsaturated α-keto- and α-ketiminoesters, ketimines, nitroalkenes, and many others have been successfully employed to achieve a plethora of functionalized chiral indole moieties. In particular, strategies for C–H functionalization in the phenyl of indoles require incorporation of a directing or blocking group in the phenyl or azole ring of indole. The discovery of chiral catalysts which can control enantiodiscrimination has gained a great deal of attention in recent years. This review will provide an updated account on the application of the asymmetric Friedel–Crafts reaction of indoles in the synthesis of diverse chiral indole derivatives, covering the timeframe from 2011 to today.

Advances in Catalytic Asymmetric Construction of Quaternary Stereogenic Centers by Conjugate Addition to β,β‐Disubstituted Nitroalkenes

“…Notably, the heterocyclic isoxazole moiety is commonly found in numerous natural products and biologically important synthetic compounds. [68] Recently, Kudo and colleagues also reported the successful asymmetric Michael addition of acetylacetone (76) to sterically congested α-phenyl-β-nitroacrylate (63), catalyzed by a resin-supported Nterminal guanidinylated peptide Cat-10 (Scheme 21). [28] The reaction proceeded at a catalyst loading of 10 mol% and afforded the desired Michael adduct (77 a) with an all-carbon quaternary stereocenter in 86% yield and 94% ee.…”

Chiral organophosphates as ligands in asymmetric metal catalysis

“…10 To clearly set the scope for this Minireview, we will mention all examples (to the best of our knowledge) that are not included in Rueping's review. Thus, to give a full picture of recent developments we have included some examples that were mentioned in reviews on related topics, such as enantioselective Friedel–Crafts reactions, 11 Mannich reactions, 12 radical reactions, 13 C–H functionalization reactions 14 and multicomponent reactions, 15 or in reviews about enantioselective catalysis with complexes of rhodium, 16 silver, 17 gold 18 or lanthanides. 19 In order to focus on phosphates as chiral ligands, we have excluded examples of tandem catalysis, in which a phosphoric acid and a metal-catalyst act in independent catalytic cycles.…”

Asymmetric Catalytic Friedel–Crafts Reactions of Unactivated Arenes

“…Furthermore, the scope of the Friedel–Crafts reaction is limited by the arene’s nucleophilicity, which is particularly apparent in the construction of benzylic stereocenters. In the past decades, asymmetric catalytic Friedel–Crafts reactions have been investigated extensively. − Careful analysis of these methods, however, reveals that the full variety of aromatic molecules is not represented equally throughout the field of asymmetric catalytic Friedel–Crafts reactions: while reactive heterocyclic arenes, especially indoles , or pyrroles are well investigated, less nucleophilic arenes such as naphthols or phenols find less application and even more inert only hydrocarbon arenes have, to the best of our knowledge, not yet been transformed in an asymmetric fashion (Figure A). Overcoming this formidable challenge would enable a shortcut to enantioenriched building blocks and has the potential to streamline chemical processes by improving step-, time-, and atom-efficiencies …”