Diversity-Oriented Catalytic Asymmetric Dearomatization of Indoles with o-Quinone Diimides.

Herein, the first diversity-oriented catalytic asymmetric dearomatization of indoles with o-quinone diimides (o-QDIs) is reported. The catalytic asymmetric dearomatization (CADA) of indoles is one of the research focuses in terms of the structural and biological importance of dearomatized indole derivatives. Although great achievements have been made in target-oriented CADA reactions, diversity-oriented CADA reactions are regarded as more challenging and remain elusive due to the lack of synthons featuring multiple reaction sites and the difficulty in precise control of chemo-, regio-, and enantio-selectivity. In this work, o-QDIs are employed as a versatile building block, enabling the chemo-divergent dearomative arylation and [4 + 2] cycloaddition reactions of indoles. Under the catalysis of chiral phosphoric acid and mild conditions, various indolenines, furoindolines/pyrroloindolines, and six-membered-ring fused indolines are collectively prepared in good yields with excellent enantioselectivities. This diversity-oriented synthesis protocol enriches the o-quinone chemistry and offers new opportunities for CADA reactions.

Catalytic asymmetric dearomatization of phenols via divergent intermolecular (3 + 2) and alkylation reactions.

The catalytic asymmetric dearomatization (CADA) reaction has proved to be a powerful protocol for rapid assembly of valuable three-dimensional cyclic compounds from readily available planar aromatics. In contrast to the well-studied indoles and naphthols, phenols have been considered challenging substrates for intermolecular CADA reactions due to the combination of strong aromaticity and potential regioselectivity issue over the multiple nucleophilic sites (O, C2 as well as C4). Reported herein are the chiral phosphoric acid-catalyzed divergent intermolecular CADA reactions of common phenols with azoalkenes, which deliver the tetrahydroindolone and cyclohexadienone products bearing an all-carbon quaternary stereogenic center in good yields with excellent ee values. Notably, simply adjusting the reaction temperature leads to the chemo-divergent intermolecular (3 + 2) and alkylation dearomatization reactions. Moreover, the stereo-divergent synthesis of four possible stereoisomers in a kind has been achieved via changing the sequence of catalyst enantiomers.

Dinuclear Zinc-Catalyzed Asymmetric Desymmetrization of Cyclopentendiones: Access to Functional Cyclopentanediones Bearing an All-carbon Quaternary Stereocenter.

The success in the identification of the two enantioisomeric surfaces of electrophiles by dinuclear zinc catalysts is disclosed. This protocol realizes a dinuclear zinc-cocatalyzed desymmetrization of cyclopentendiones using α-hydroxy aryl ketones as nucleophiles through Michael addition reaction. Under mild conditions, a series of functional cyclopentanediones bearing multiple stereogenic centers including an all-carbon quaternary stereocenter, were obtained in moderate to good yields with excellent stereoselectivities.

Zn-ProPhenol catalyzed asymmetric inverse-electron-demand Diels-Alder reaction.

The first Zn-ProPhenol catalyzed asymmetric inverse-electron-demand Diels-Alder reaction has been accomplished. This protocol was carried out by a dual-activation mode under mild conditions, allowing the preparation of various biologically important dihydropyrans in good yields with excellent stereoselectivities.

Catalytic asymmetric de novo construction of 4-pyrrolin-2-ones via intermolecular formal [3+2] cycloaddition of azoalkenes with azlactones.

The chiral phosphoric acid-catalyzed asymmetric intermolecular formal [3+2] cycloaddition of azoalkenes with azlactones has been established. This convergent protocol leads to a facile and enantioselective de novo construction of a wide range of fully substituted 4-pyrrolin-2-ones bearing a fully substituted carbon atom in good yields and with excellent enantioselectivities (26 examples, 72-95% yields and 87-99% ee).

Zinc-Catalyzed Asymmetric Cascade Michael/Acyl Transfer Reaction between α-Hydroxy Aryl Ketones and Enynones.

We described herein a neoteric enantioselective cascade Michael/acyl transfer reaction of enynones and α-hydroxy aryl ketones catalyzed by dinuclear zinc cooperative catalysis. A series of structurally diverse chiral 1,5-dicarbonyl compounds were synthesized in good yields with excellent stereoselectivities. This strategy features broad substrate scope, high atom economy, as well as enynones as efficient electrophilic acyl transfer reagents in asymmetric cascade reactions for the first time.

Zinc-Catalyzed Enantioselective [3 + 3] Annulation for Synthesis of Chiral Spiro[indoline-3,4'-thiopyrano[2,3-b]indole] Derivatives.

With a dinuclear zinc-ProPhenol complex as a catalyst, an efficient and novel [3 + 3] annulation of indoline-2-thiones and isatylidene malononitriles has been successfully developed via the Brønsted base and Lewis acid cooperative activation model. This practical methodology gives access to a broad range of chiral spiro[indoline-3,4'-thiopyrano[2,3-b]indole] derivatives in good yields with excellent levels of enantioselectivities (up to 88% yield and 99% ee).

Catalytic asymmetric inverse-electron-demand aza-Diels-Alder reaction of 1,3-diazadienes with 3-vinylindoles.

A facile chiral phosphoric-acid catalyzed asymmetric inverse-electron-demand aza-Diels-Alder reaction of 1,3-diazadienes with 3-vinylindoles was established. By using this mild and practical protocol, a broad range of benzothiazolopyrimidines with three contiguous stereogenic centers were prepared in good yields and excellent diastereo- and enantio-selectivities (43 examples, up to 83% yield, >99% ee and all >20 : 1 dr). A plausible concerted reaction pathway enabled by the dual hydrogen-bonding effect was proposed to account for the observed excellent enantioselectivity and specific trans-trans diastereoselectivity.

Catalytic Asymmetric Umpolung Tandem Reactions of Hemiacetals via Dinuclear Zinc Cooperative Catalysis.

The umpolung activity of hemiacetals serving as α-carbon nucleophiles has been reported via dinuclear zinc cooperative catalysis. This umpolung strategy has been applied to catalytic asymmetric tandem reactions of 1-tosylindoline-2,3-diols with ß,γ-unsaturated-α-keto compounds, providing a broad series of structurally diverse tetrahydrofuran spirooxindoles and dihydrofurans, respectively. In addition, products could be transformed to quinazoline and quinoline derivatives.

Dinuclear Zinc Catalyzed Enantioselective Dearomatization [3+2] Annulation of 2-Nitrobenzofurans and 2-Nitrobenzothiophenes.

The application of dinuclear zinc catalysts in a dearomatization reaction has been developed. Catalytic asymmetric dearomatization [3+2] annulations of 2-nitrobenzofurans or 2-nitrobenzothiophenes with CF3 -containing N-unprotected isatin-derived azomethine ylides catalyzed by dinuclear zinc catalysts are realized with excellent diastereomer ratios (dr) of >20 : 1 and enantiomeric excess (ee) of up to 99 %. This protocol provides a practical, straightforward access to structurally diverse pyrrolidinyl spirooxindoles containing a 2,3-fused-dihydrobenzofuran (or dihydrobenzothiphene) moiety, and four contiguous stereocenters. Reactions can be performed on a gram scale. The absolute configuration of products is confirmed by X-ray single crystal structure analysis, and a possible mechanism is proposed.

Dinuclear zinc-catalyzed enantioselective formal [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines with low reactivity aurone derivatives.

Highly enantioselective formal [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines with aurone derivatives of low reactivity using chiral dinuclear zinc catalysts has been developed via a Brønsted base and Lewis acid cooperative activation model. These transformations involving a domino Michael/Mannich reaction sequence led to efficient construction of a range of chiral spiro[benzofuran-pyrrolidine] scaffolds bearing three biologically relevant heterocyclic moieties and two adjacent spiro quaternary stereocenters in high yields (up to 95%) and with good enantioselectivities (up to 99% ee).

Dinuclear zinc-catalyzed asymmetric Friedel-Crafts alkylation/cyclization of 3-aminophenols with α,α-dicyanoolefins.

An enantioselective Friedel-Crafts alkylation/cyclization tandem reaction of 3-aminophenols with α,α-dicyanoolefins has been performed successfully using a chiral dinuclear zinc catalyst, leading to a range of chiral 2-amino-4H-chromenes (up to 98% yield and >99% ee). To the best of our knowledge, this is the first asymmetric example of the dinuclear zinc-catalysed functionalization of aromatic C(sp2)-H bonds.

Direct Asymmetric α-Selective Mannich Reaction of ß,γ-Unsaturated Ketones with Cyclic α-Imino Ester: Divergent Synthesis of Cyclocanaline and Tetrahydro Pyridazinone Derivatives.

The first regio-, diastereo-, and enantioselective direct Mannich reaction of ß,γ,-unsaturated ketones with benzoxazinone cyclic imines was enabled by Lewis acid/Brønsted base cooperative catalysis. The dinuclear zinc complex catalyzed the reaction of a broad range of ß,γ-unsaturated ketones to proceed at the α-site exclusively, leading to corresponding adducts with two consecutive tertiary carbon stereocenters in diastereomeric ratios of up to >20:1 and enantioselectivities generally in the 90-99 % ee range. These products were used as general intermediates in the synthesis of multisubstituted cyclocanalines, tetrahydro pyridazinones, and 4H-furo[2,3-b][1,4]benzoxazine derivatives.

Enantioselective synthesis of indanone spiro-isochromanone derivatives via a dinuclear zinc-catalyzed Michael/transesterification tandem reaction.

An enantioselective Michael/transesterification tandem reaction of α-hydroxy indanones with ortho-ester chalcones was realized using dinuclear zinc catalysts. A series of enantiomerically pure spiro[indanone-2,3'-isochromane-1-one] derivatives were obtained in good yields with excellent stereoselectivities (up to >20 : 1 dr, up to >99% ee). This protocol could be conducted on a gram scale without affecting its stereoselectivities. In addition, the absolute stereochemistry of the products was determined by X-ray crystallographic analysis of 3ac, and a positive nonlinear effect was observed. Finally, a possible catalytic cycle was proposed to explain the origin of the enantioselectivity.

Brønsted Base and Lewis Acid Cooperatively Catalyzed Asymmetric exo'-Selective [3 + 2] Cycloaddition of Trifluoromethylated Azomethine Ylides and Methyleneindolinones.

A Brønsted base and Lewis acid cooperatively catalyzed 1,3-dipolar cycloaddition is reported through chiral dinuclear zinc catalysts. An asymmetric exo'-selective [3 + 2] cycloaddition of CF3-containing N-unprotected isatin-derived azomethine ylides is realized. In the presence of 10 mol % of catalyst, azomethine ylides react efficiently with methyleneindolinones, giving a series of trifluoromethyl-substituted 2,3-pyrrolidinyl dispirooxindoles with highly enantio- (up to 99% ee) and exo'-selectivity (>20:1 dr). Up to four contiguous stereogenic centers, including two adjacent spiro quaternary stereocenters, are constructed in one step.

Catalytic Asymmetric Synthesis of Tetrahydrofuran Spirooxindoles via a Dinuclear Zinc Catalyst.

An asymmetric Michael/hemiketalization and Fridel-Crafts reaction has been reported through a one-pot reaction. A number of structurally novel tetrahydrofuran spirooxindoles are synthesized in the presence of a 10 mol % dinuclear zinc catalyst with diastereomer ratios (dr) of 3:1-13:1 and an enantiomeric excess (ee) of 75-99%. The reaction can be performed on a gram scale without impacting its efficiency. The absolute configuration of products is confirmed by X-ray single crystal structure analysis, and a possible mechanism is proposed.

Dinuclear Zinc-Catalyzed Asymmetric Tandem Reaction of α-Hydroxy-1-indanone: Access to Spiro[1-indanone-5,2'-γ-butyrolactones].

A highly efficient method for the enantioselective build of spiro[1-indanone-5,2'-γ-butyrolactones] has been developed through the tandem Michael/transesterification reaction of α-hydroxy-1-indanone and α,ß-unsaturated esters. A broad range of spiro(1-indanone-butyrolacones) with contiguous stereocenters have been synthesized with excellent stereoselectivities (up to >20:1 dr, up to >99% ee) under the catalysis of dinuclear zinc complex. Moreover, the reaction can be run on a gram scale without affecting its stereoselectivities. A possible mechanism is proposed.

Dinuclear zinc cooperative catalytic three-component reactions for highly enantioselective synthesis of 3,3'-dihydrofuran spirooxindoles.

A new dinuclear zinc cooperative catalytic enantioselective three-component reaction via a domino Knoevenagel /Michael/cyclization sequence has been developed. A series of chiral 3,3'-dihydrofuran spirooxindoles are obtained in excellent yields (up to 99%) and enantioselectivities (up to 99% ee). In addition, the reaction is carried out smoothly on a gram scale under mild conditions.

Access to Chiral 2,5-Pyrrolidinyl Dispirooxindoles via Dinuclear Zinc-Catalyzed Asymmetric Cascade Reactions.

A series of new nonsymmetric semi-azacrown ether ligands were developed and applied to the asymmetric Michael/cyclic keto-imine formation/Friedel-Crafts alkylation reactions of 3-amino oxindole hydrochlorides and ß,γ-unsaturated α-keto amides. A diversity of 2,5-pyrrolidinyl dispirooxindoles containing two nonadjacent spiro-quaternary stereocenters were obtained in excellent diastereoselectivities and moderate to excellent enantioselectivities (up to 95% ee). A possible catalytic cycle was proposed to explain the origin of the asymmetric induction.

Dinuclear zinc synergistic catalytic asymmetric phospha-Michael/Michael cascade reaction: synthesis of 1,2,3-trisubstituted indanes bearing phosphoryl groups.

A new dinuclear zinc synergistic catalytic asymmetric phospha-Michael/Michael cascade reaction of o-dienones and dialkyl phosphates is reported. This method has been proven to be general and efficient for the formation of a range of chiral 1,2,3-trisubstituted indane compounds containing phosphorus groups in good yields (up to 92%) with excellent stereoselectivities (up to >99% ee and up to >99 : 1 dr). The relative configuration of the product was identified as having a trans,trans substitution pattern via two-dimensional (2D) nuclear Overhauser effect spectroscopy 1H-1H NMR experiments. A possible mechanism was proposed.