The Golden Age of Transfer Hydrogenation

Isatins As Privileged Molecules in Design and Synthesis of Spiro-Fused Cyclic Frameworks

140 years ago Adolf von Baeyer proposed the structure of a heteroaromatic compound which revolutionized organic and medical chemistry: indole. After more than a century, indole itself and the complexity of naturally occurring indole derivatives continue to inspire and influence developments in synthetic chemistry. In particular, the ubiquitous presence of indole rings in pharmaceuticals, agrochemicals, and functional materials are testament to the ever increasing interest in the design of mild and efficient synthetic routes to functionalized indole derivatives. This Review emphasizes the achievements in the selective catalytic functionalization of indoles (C-C bond-forming processes) over the last four years.

Catalytic Functionalization of Indoles in a New Dimension

After an initial period of validating asymmetric organocatalysis by using a wide range of important model reactions that constitute the essential tools of organic synthesis, the time has now been reached when organocatalysis can be used to address specific issues and solve pending problems of stereochemical relevance. This Review deals with selected studies reported in 2006 and the first half of 2007, and is intended to highlight four main aspects that may be taken as testimony of the present status and prospective of organocatalysis: a) chemical efficiency; b) discovery of new substrate combinations to give new asymmetric syntheses; c) development of new catalysts for specific purposes by using mechanistic findings; and d) applications of organocatalytic reactions in the asymmetric total synthesis of target natural products and known compounds of biological and pharmaceutical relevance.

Asymmetric Organocatalysis: From Infancy to Adolescence

The 3,3′-disubstituted oxindole structural motif is a prominent feature in many alkaloid natural products, which include all kinds of tetrasubstituted carbon stereocenters, spirocyclic or not, all-carbon or heteroatom-containing. The catalytic asymmetric synthesis of the tetrasubstituted carbon stereocenter at the C-3 position of the oxindole framework integrates new synthetic methods and chiral catalysts, reflects the latest achievements in asymmetric catalysis, and facilitates the synthesis of sufficient quantities of related compounds as potential medicinal agents and biological probes. This review summarizes the recent progress in this area, and applications in the total synthesis of related bioactive compounds.

Catalytic Asymmetric Synthesis of Oxindoles Bearing a Tetrasubstituted Stereocenter at the C‐3 Position

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.200790125

Highly Asymmetric Michael Addition to α,β‐Unsaturated Ketones Catalyzed by 9‐Amino‐9‐deoxyepiquinine

Enantioselective 1,3-Dipolar Cycloaddition of Cyclic Enones Catalyzed by Multifunctional Primary Amines: Beneficial Effects of Hydrogen Bonding†

The indole framework represents a key structural motif in a large number of biologically active natural products and pharmaceutical compounds. Consequently, modifications on the indole structure, including the development of enantioselective variants, have triggered increasing interests. Because of the inherent nucleophilic characteristics of indole compounds, their reactions preferentially take place at the C3-position of the ring system. As a result, the majority of enantioselective reactions of indoles focus on the C3-selective addition of electron-rich indoles to electrophilic imines, epoxides, carbonyl compounds, a,b-unsaturated carbonyl compounds, and nitroalkenes etc., thus leading to the formation of diversely structured enantioenriched C3-functionalized indole derivatives. Recently, the enantioselective synthesis of C2-substituted indoles has also been realized through the asymmetric alkylation of 4,7-dihydroindoles and subsequent oxidation. In sharp contrast to the progress in enantioselective alkylation at the C3or C2-positions, the asymmetric Nalkylation of indoles has been underdeveloped: probably because of the privileged C3-chemoselectivity of indole compounds. The limited examples include the palladiumcatalyzed N-allylic alkylation of 3-substituted indoles developed by Trost et al. and the enantioselective intramolecular aza-Michael addition of tethered indole-2-carboxylates under chiral phase-transfer catalysis developed by Bandini et al. Indeed, N-alkylated indoles have been applied as useful intermediates for the synthesis of polyheterocycles and occur widely among natural products and biologically active pharmaceuticals (Scheme 1). For example, mitomycin C exhibits potent antitumour activity and is used clinically in the treatment of certain cancers. Yuremamine, which was recently isolated from the stem bark of Mimosa hostilis, shows hallucinogenic and psychoactive effects. Pyrrolo[3,2,1-ij]quinoline derivatives are active antihistamines and inhibitors of leukotriene, and they offer the possibility of a novel multimediator approach to the treatment of allergic diseases. Therefore, it would be extremely desirable to develop effective protocols to access optically pure N-alkylated indoles. Recently, the allylic alkylation of Morita-Baylis–Hillman (MBH) adducts catalyzed by a metal-free organic Lewis base has emerged as an attractive strategy to prepare multifunctional compounds. Our research group has also reported that modified cinchona alkaloids are outstanding catalysts for the asymmetric allylic alkylation of a,a-dicyanoolefins with MBH carbonates. We anticipated that, as outlined in Scheme 2, the deprotonation of the acidic NH group of the

Chemoselective Asymmetric N‐Allylic Alkylation of Indoles with Morita–Baylis–Hillman Carbonates

Asymmetric quadruple aminocatalytic domino reactions to fused carbocycles incorporating a spirooxindole motif.

Regulating both the chemo- and diastereoselectivity, divergently, of a reaction is highly attractive but extremely challenging. Presented herein is a catalyst-controlled switch in the chemo- and diastereodivergent annulation reactions of Morita-Baylis-Hillman carbonates, derived from isatins and 2-alkylidene-1H-indene-1,3(2H)-diones, in exclusive α-regioselectivity. α-Isocupreine efficiently catalyzed [2+1] reactions to access cyclopropane derivatives, and the diastereodivergent [3+2] annulations were accomplished by employing either a chiral phosphine or a DMAP-type molecule. All reactions exhibited excellent chemoselectivities, and good to remarkable stereoselectivities were furnished, thus leading to a collection of compounds with skeletal and stereogenic diversity. Moreover, DFT computational calculations elucidated the catalyst-based switch in mechanism.

Ying-Chun Chen

Papers

Highly Asymmetric Michael Addition to α,β‐Unsaturated Ketones Catalyzed by 9‐Amino‐9‐deoxyepiquinine

Enantioselective 1,3-Dipolar Cycloaddition of Cyclic Enones Catalyzed by Multifunctional Primary Amines: Beneficial Effects of Hydrogen Bonding†

Chemoselective Asymmetric N‐Allylic Alkylation of Indoles with Morita–Baylis–Hillman Carbonates

Asymmetric quadruple aminocatalytic domino reactions to fused carbocycles incorporating a spirooxindole motif.

Catalyst-Controlled Switch in Chemo- and Diastereoselectivities: Annulations of Morita-Baylis-Hillman Carbonates from Isatins.