Hai-Lei Cui

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

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

Tertiary amine-catalyzed chemoselective and asymmetric [3 + 2] annulation of Morita-Baylis-Hillman carbonates of isatins with propargyl sulfones.

A chemo- and enantioselective [3 + 2] annulation of Morita-Baylis-Hillman carbonates of isatins with propargyl sulfones was catalyzed by a β-ICD O-MOM ether 1c, affording spirocyclic 2-oxindoles bearing an unusual cyclopentadiene motif in outstanding ee values (up to >99%). More electrophiles, such as N-phenylmaleimide, have been also utilized to deliver complex spirocyclic 2-oxindoles with good results.

Direct Asymmetric Allylic Alkylation of Butenolides with Morita−Baylis−Hillman Carbonates

The direct asymmetric allylic alkylation of beta,gamma-butenolides with MBH carbonates to access gamma,gamma-disubstituted butenolides containing adjacent quaternary and tertiary chiral centers has been presented in excellent stereoselectivities (86-96% ee, dr >95:5) and moderate to good yield (50-83%). Their synthetic utility has been well demonstrated by the facile construction of bicyclic lactones bearing 4-5 stereogenic centers.

Organocatalytic asymmetric Friedel–Crafts alkylation/cascade reactions of naphthols and nitroolefins

The asymmetric Michael-type Friedel-Crafts reaction of naphthols and nitroolefins promoted by bifunctional thiourea-tertiary amine organocatalysts (up to 95% ee) was investigated; on simply extending the reaction time further cascade reactions could occur to generate enantiopure dimeric tricyclic 1,2-dihydronaphtho[2,1-b]furanyl-2-hydroxylamine derivatives.

Organocatalytic and electrophilic approach to oxindoles with C3-quaternary stereocenters.

A Lewis base-catalyzed asymmetric allylic alkylation of Morita-Baylis-Hillman carbonates derived from isatins has been investigated, which provides an electrophilic pathway to access oxindoles bearing C3-quaternary stereocenters. Excellent diastereoselectivity and high enantioselectivity have been obtained in the vinylogous functionalization of α,α-dicyanoolefin nucleophiles, giving multifunctional products with vicinal quaternary and tertiary chiral carbon centers.

Organocatalytic Direct Vinylogous Michael Addition of α,β‐Unsaturated γ‐Butyrolactam to α,β‐Unsaturated Aldehydes and an Illustration to Scaffold Diversity Synthesis

The development of efficient synthetic protocols to access small-molecule libraries that contain structurally and stereochemically diverse scaffolds is highly desirable because of the increasing demand for collections of probe and drug candidates. Therefore, the design of asymmetric reactions from readily available starting materials, which can deliver enantioenriched and multifunctional products and allow subsequent skeletal variation constructions, is extremely attractive. Not surprisingly, the vinylogous reactions of a,b-unsaturated systems, which can supply an additional and versatile olefinic functionality in the products, trigger increasing attention in modern synthetic organic chemistry, and intensive studies have been concentrated on the applications of g-butenolides and their O-silyl derivatives. Over the past years we have developed a number of asymmetric direct vinylogous-type reactions, which provide facile access to useful chiral materials with structural diversity and complexity. Later we were fascinated by the utilization of the aza analogues of g-butenolides, a,b-unsaturated g-butyrolactams, not only because they have been much less explored, but also the associated aza heterocycles might have more potential in the subsequent synthetic transformations and related biological investigation. In particular, we envisaged that the unprecedented stereoselective direct vinylogous Michael addition of a,b-unsaturated g-butyrolac ACHTUNGTRENNUNGtams[5a,b] to a,b-unsaturated aldehydes, under the well-established iminium activation of secondary amine 1 a, would afford chiral adducts that have fruitful and orthogonal sets of functional groups in an atom-economic fashion, which would be ideal for the following couple and pair reactions for scaffold diversity synthesis (Scheme 1).

Lewis base assisted Brønsted base catalysis: direct regioselective asymmetric vinylogous alkylation of allylic sulfones.

A Lewis base assisted Brønsted base catalysis (LBABB) strategy is applied for direct asymmetric vinylogous alkylation of allylic sulfones with Morita-Baylis-Hillman (MBH) carbonates, in which a strong Brønsted base, tert-butoxy anion, generated in situ from a tertiary amine catalyst and MBH carbonate, is crucial in activating unstabilized nucleophiles. The γ-regioselective alkylation products were obtained with good to excellent enantiomeric excess values when catalyzed by a modified cinchona alkaloid.