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

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

Catalysis with chiral secondary amines (asymmetric aminocatalysis) has become a well-established and powerful synthetic tool for the chemo- and enantioselective functionalization of carbonyl compounds. In the last eight years alone, this field has grown at such an extraordinary pace that it is now recognized as an independent area of synthetic chemistry, where the goal is the preparation of any chiral molecule in an efficient, rapid, and stereoselective manner. This has been made possible by the impressive level of scientific competition and high quality research generated in this area. This Review describes this "Asymmetric Aminocatalysis Gold Rush" and charts the milestones in its development. As in all areas of science, progress depends on human effort.

Asymmetric aminocatalysis--gold rush in organic chemistry.

Catalytic C-C bond-forming multi-component cascade or domino reactions: pushing the boundaries of complexity in asymmetric organocatalysis.

Catalytic Enantioselective Formation of C−C Bonds by Addition to Imines and Hydrazones: A Ten-Year Update

An efficient tandem reaction for the asymmetric synthesis of six-membered spirocyclic oxindoles has been successfully developed through a formal [2+2+2] annulation strategy. The amine-catalysed stereoselective Michael addition of aliphatic aldehydes to electron-deficient olefinic oxindole motifs gave chiral C3 components, which were further combined with diverse electrophiles (activated olefins or imines) to afford spirocyclic oxindoles with versatile molecular complexity (up to six contiguous stereogenic centres, high diastereo- and enantioselectivities).

Organocatalytic Tandem Reaction to Construct Six-Membered Spirocyclic Oxindoles with Multiple Chiral Centres through a Formal [2+2+2] Annulation

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

Aminocatalysis, the activation of carbonyl compounds by enamines, iminium ions, or the SOMO-activation strategy, has become a fundamental approach in asymmetric synthesis. Moreover, the catalytic modes of amines are still under expansion. Recently, Jørgensen and co-workers developed dienamine catalysis by inverting the inherent reactivity of a,bunsaturated aldehydes, which acted as nucleophiles for direct enantioselective g amination with diethyl azodicarboxylate. However, the synthetic potential of dienamine catalysis seems to be underestimated, and very limited progress has been made to date in spite of the extensive studies on asymmetric aminocatalysis over the past decade. The development of efficient methodologies that enable simpler, cheaper, and more concise approaches to the generation of structural complexity with exquisite levels of stereocontrol remains a preeminent goal in modern organic chemistry. Recently, we presented a highly enantioselective inverse-electron-demand aza-Diels–Alder reaction of N-sulfonyl 1-aza-1,3-butadienes and aliphatic aldehydes to form optically pure piperidines through enamine activation. We were fascinated by the possible and conceptually unprecedented application of dienamine catalysis in an inverseelectron-demand aza-Diels–Alder reaction of a,b-unsaturated aldehydes with electron-deficient N-sulfonyl 1-aza-1,3butadienes to construct chiral piperidine derivatives bearing several functional groups in a straightforward manner (Scheme 1). We wondered whether the chemo-, regio-, and stereoselectivity of this complicated reaction could be controlled simultaneously in an elegant manner. We initially investigated the reaction of N-tosyl-1-aza-1,3butadiene (2a) and hexen-2-al (3a) in a mixture of THF and H2O at room temperature under the catalysis of the chiral secondary amine 1 a (10 mol%) and benzoic acid (10 mol %). The reaction proceeded smoothly with exclusive a regioselectivity. The chiral hemiaminal 4a (an E/Z mixture) was isolated as the sole product. The oxidation of 4a with pyridinium chlorochromate (PCC) gave a separable mixture of lactam 5a and its Z isomer 6a. Excellent enantioselectivity was observed for the formation of the E isomer 5a (Table 1, entry 1). Similar results were obtained when the Scheme 1. Proposed inverse-electron-demand aza-Diels–Alder reaction of a dienamine intermediate generated in situ as an electron-rich olefin. Ts = 4-toluenesulfonyl.

Organocatalytic Regio- and Stereoselective Inverse-Electron-Demand Aza-Diels-Alder Reaction of α,β-Unsaturated Aldehydes andN-Tosyl-1-aza-1,3-butadienes

Kun Jiang

Papers

Organocatalytic Tandem Reaction to Construct Six-Membered Spirocyclic Oxindoles with Multiple Chiral Centres through a Formal [2+2+2] Annulation

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

Organocatalytic Regio- and Stereoselective Inverse-Electron-Demand Aza-Diels-Alder Reaction of α,β-Unsaturated Aldehydes andN-Tosyl-1-aza-1,3-butadienes

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

Organocatalytic stereoselective mannich reaction of 3-substituted oxindoles.