New P,Nsp3 ligands for palladium-catalyzed asymmetric allylic substitutions.

New P,Nsp3 bidentate ligands containing two chiral carbon centers were developed and applied to palladium-catalyzed asymmetric allylic substitution reactions. Good generalities with various nucleophiles, including carbon, nitrogen and oxygen containing nucleophiles, were achieved with up to 96% ee and 98% yield. This reaction provides an efficient method for the asymmetric formation of C-C, C-N and C-O bonds.

Development of spirocyclic phosphoramidite-based hybrid diphosphorus ligands for enantioselective iridium-catalyzed hydrogenation of imines.

Unsymmetrical hybrid chiral diphosphorus ligands bearing a spirocyclic phosphoramidite scaffold have been developed and successfully applied in the iridium-catalyzed asymmetric hydrogenation of imines. With this newly developed chiral iridium catalytic system, a wide range of imines including sterically hindered ones could be hydrogenated to give the corresponding optically active amines in high yields (up to >99%) and with excellent enantioselectivities (up to >99% ee). The utility of this hydrogenation has been demonstrated by the preparation of the chiral fungicide (S)-benalaxyl.

Decarboxylation-promoted Pd-catalyzed asymmetric propargylic [3 + 2] annulation for the enantioselective construction of a quaternary stereocenter in 2,3-dihydrofurans.

The enantioselective construction of a quaternary stereocenter in 2,3-dihydrofuran frameworks has been realized via the palladium-catalyzed asymmetric [3 + 2] cycloaddition of tertiary propargylic carbonates with ß-ketoesters enabled by a chiral ferrocene/benzimidazole-based bidentate P,N-ligand. The reaction was significantly promoted by loss of CO2 to irreversibly form π-propargylpalladium or allenylpalladium intermediates. This protocol features a good tolerance of functional groups in both tertiary propargylic carbonates and ß-ketoesters, thereby delivering a variety of highly functionalized chiral 2,3-dihydrofurans bearing a quaternary stereocenter at the 2-position and an exocyclic double bond at the 3-position in good chemical yields and high enantioselectivities (up to 98% ee).

Cu-Catalyzed asymmetric Friedel-Crafts propargylic alkylation of phenol derivatives.

A copper-catalyzed asymmetric Friedel-Crafts propargylic alkylation of electron-rich phenol derivatives with a variety of propargylic esters has been described. With Cu(OTf)2 decorated with a chiral tridentate ketimine P,N,N-ligand as the catalyst, asymmetric Friedel-Crafts propargylic alkylation of 3,5-dialkoxyphenol derivatives proceeded smoothly in high yields and with good to excellent enantioselectivities. The present study suggested that the presence of an electron-rich substituent on the meta-position of phenol is essential for the promotion of Friedel-Crafts propargylic alkylation, and the substrate bearing two electron-rich groups on both the 3,5-positions of phenol tends to give a satisfactory performance.

Desilylation-Activated Propargylic Transformation: Enantioselective Copper-Catalyzed [3+2] Cycloaddition of Propargylic Esters with ß-Naphthol or Phenol Derivatives.

A copper-catalyzed asymmetric [3+2] cycloaddition of 3-trimethylsilylpropargylic esters with either ß-naphthols or electron-rich phenols has been realized and proceeds by a desilylation-activated process. Under the catalysis of Cu(OAc)2⋅H2O in combination with a structurally optimized ketimine P,N,N-ligand, a wide range of optically active 1,2-dihydronaphtho[2,1-b]furans or 2,3-dihydrobenzofurans were obtained in good yields and with high enantioselectivities (up to 96 % ee). This represents the first desilylation-activated catalytic asymmetric propargylic transformation.

Enantioselective synthesis of highly functionalized dihydrofurans through copper-catalyzed asymmetric formal [3+2] cycloaddition of ß-ketoesters with propargylic esters.

An enantioselective synthesis of highly functionalized dihydrofurans through a copper-catalyzed asymmetric [3+2] cycloaddition of ß-ketoesters with propargylic esters has been developed. With a combination of Cu(OTf)2 and a chiral tridentate P,N,N ligand as the catalyst, a variety of 2,3-dihydrofurans bearing an exocyclic double bond at the 2 position were obtained in good chemical yields and with good to high enantioselectivities. The exocyclic double bond can be hydrogenated in a highly diastereoselective fashion to give unusual cis-2,3-dihydrofuran derivatives, thus further enhancing the scope of this transformation.

Enantioselective copper-catalyzed decarboxylative propargylic alkylation of propargyl ß-ketoesters with a chiral ketimine P,N,N-ligand.

The first enantioselective copper-catalyzed decarboxylative propargylic alkylation has been developed. Treatment of propargyl ß-ketoesters with a catalyst, prepared in situ from [Cu(CH3 CN)4 BF4 ] and a newly developed chiral tridentate ketimine P,N,N-ligand under mild reaction conditions, generates ß-ethynyl ketones in good yields and with high enantioselectivities without requiring the pregeneration of ketone enolates. This new process provides facile access to a range of chiral ß-ethynyl ketones in a highly enantioenriched form.

Copper-Catalyzed Difunctionalization of Propargylic Carbonates through Tandem Nucleophilic Substitution/Boroprotonation.

Highly functionalized organic molecules are in high demand, but their preparation is challenging. Copper-catalyzed transformation of alkynyl- and allenyl-containing substrates has emerged as a powerful tool to achieve this objective. Herein, an efficient copper-catalyzed difunctionalization of propargylic carbonates through tandem nucleophilic substitution/boroprotonation has been developed, affording the formation of thiol-, selenium-, and boron-functionalized alkenes with high yield and stereoselectivity. Two distinct catalytic mechanisms involving a single reaction without any requirement of catalyst change were successfully demonstrated.

Highly diastereo- and enantioselective Cu-catalyzed [3 + 3] cycloaddition of propargyl esters with cyclic enamines toward chiral bicyclo[n.3.1] frameworks.

A new Cu-catalyzed asymmetric [3 + 3] cycloaddition of propargyl esters with cyclic enamines is reported. With a combination of Cu(OAc)(2)·H(2)O and a chiral tridentate ferrocenyl-P,N,N ligand as the catalyst, perfect endo selectivities (endo/exo > 98/2) and excellent enantioselectivities (up to 98% ee) for endo cycloadducts were achieved under mild conditions. This method provides a simple and efficient approach for the synthesis of optically active bicyclo[n.3.1] frameworks.

Intramolecular Copper-Catalyzed Asymmetric Propargylic [4 + 2]- Cycloaddition toward Optically Active Tetrahydroisoindolo[2,1-a]quinoxalines.

An intramolecular Cu-catalyzed asymmetric propargylic [4 + 2] cycloaddition of bis-N-nucleophile-functionalized propargylic esters has been realized in the support of a chiral tridentate N-ligand, (S,S)-Pybox-diOAc, leading to chiral tetrahydroisoindolo[2,1-a]quinoxalines in high yields and with good to excellent enantioselectivities. The reaction features high efficiency, simplicity, and broad substrate scope, thus providing a powerful and concise strategy for stereoselective access to optically active polycyclic heterocycle frameworks that are otherwise difficult to synthesize.

Highly Enantioselective Iridium-Catalyzed Hydrogenation of o-Amidophenyl Ketones Enabled by 1,2-Diphenylethylenediamine-Derived P,N,N-Ligands with Tertiary Amine Terminus.

A readily available and highly modular class of chiral P,N,N-ligands based on a structurally flexible nonchiral phosphine-amine framework with an optically active 1,2-diphenylethylenediamine unit bearing a tertiary amine terminus as the chiral source have been developed and successfully applied in the Ir-catalyzed asymmetric hydrogenation of o-amidophenyl ketones. These tridentate P,N,N-ligands exhibited excellent activity, enantioselectivity, and substrate tolerance, thus furnishing various optically active o-amidobenzhydrols in up to 99% yields and with >99% ee. The utility of this protocol has been proven by synthetically diverse product transformation and highly enantioselective production of a rice plant growth regulator, (S)-inabenfide.

Palladium-catalysed construction of butafulvenes.

Butafulvene is a constitutional isomer of benzene, comprising a cyclobutene skeleton bearing two exocyclic conjugated methylene units. As a result of the intrinsic high strain energy and anti-aromaticity, the preparation of butafulvene compounds has been a fundamental issue for the development of butafulvene chemistry. Here an efficient palladium-catalysed coupling protocol involving propargylic compounds has been developed, providing a solid and versatile strategy for the rapid assembly of symmetric butafulvene derivatives. Based on mechanistic studies, two complementary mechanisms, both involving palladium catalysis, have been confirmed. With the mechanism unveiled, the synthesis of non-symmetric butafulvenes has also been achieved. Advantages of this strategy include tolerance to a wide range of propargylic molecules, mild reaction conditions, simple catalytic systems and easy scalability. The synthetic potential of the products as platform molecules for cyclobutene derivatives has also been demonstrated.

Bicyclic Bridgehead Phosphoramidite-Based Hybrid Diphosphorus Ligands: Design, Synthesis, and Application in Catalytic Asymmetric Hydrogenation.

A strategy for chiral ligand design has been developed that allows for incorporation of an achiral bicyclic bridgehead phosphoramidite to generate a class of hybrid diphosphorus ligands for high activity and asymmetric control. Using this concept, a series of chiral phosphine-phosphoramidite ligands bearing the sole chirality at the ligand backbone have been prepared and successfully employed in the Rh-catalyzed asymmetric hydrogenation of 2-vinylanilides for the synthesis of optically active anilines bearing an ortho-tertiary benzylic stereocenter.

Enantioselective Rh-catalyzed hydrogenation of 3-aryl-4-phosphonobutenoates with a P-stereogenic BoPhoz-type ligand.

A series of chiral 3-aryl-4-phosphonobutyric acid esters were synthesized in high enantioselectivities (93-98% ee) via the Rh-catalyzed asymmetric hydrogenation of the corresponding 3-aryl-4-phosphonobutenoates using a P-stereogenic BoPhoz-type phosphine-aminophosphine ligand. The methodology has been successfully applied to the asymmetric synthesis of a potential GABA(B) antagonist, (R)-phaclofen, in high enantioselectivity.

Chiral 1-phenylethylamine-derived phosphine-phosphoramidite ligands for highly enantioselective Rh-catalyzed hydrogenation of beta-(acylamino)acrylates: significant effect of substituents on 3,3'-positions of binaphthyl moiety.

A series of new chiral phosphine-phosphoramidite ligands with a 3,3'-substituted binaphthyl moiety were prepared from 1-phenylethylamine, and successfully applied in the Rh-catalyzed asymmetric hydrogenation of beta-(acylamino)-acrylates. The research disclosed that the substituents on the 3,3'-positions of binaphthyl moiety significantly influenced the enantioselectivity.

Copper-Catalyzed Asymmetric Propargylic Alkylation with Oxindoles: Diastereo- and Enantioselective Construction of Vicinal Tertiary and All-Carbon Quaternary Stereocenters.

A copper-catalyzed asymmetric propargylic alkylation of propargylic acetates with 3-substituted oxindoles for the stereoselective construction of vicinal tertiary and all-carbon quaternary stereocenters in a 3,3-disubstituted oxindole skeleton has been realized. The reaction proceeded smoothly under the catalysis of Cu(MeCN)4PF6 combined with a chiral tridentate ferrocenyl P,N,N ligand, leading to a broad range of optically active 3,3-disubstituted oxindoles in high yields and with excellent diastereo- and enantioselectivities.

Enantioselective Copper-Catalyzed [3 + 3] Cycloaddition of Tertiary Propargylic Esters with 1H-Pyrazol-5(4H)-ones toward Optically Active Spirooxindoles.

A copper-catalyzed enantioselective [3 + 3] cycloaddition of 3-ethynyl-2-oxoindolin-3-yl acetates with 1H-pyrazol-5(4H)-ones for the construction of optically active spirooxindoles bearing a spiro all-carbon quaternary stereocenter has been realized. With a combination of Cu(OTf)2 and chiral tridentate ketimine P,N,N-ligand as the catalyst, the reaction displayed broad substrate scopes, good yields, and high enantioselectivities. This represents the first catalytic asymmetric propargylic cycloaddition with tertiary propargylic esters as the bis-electrophiles for access to chiral spirocyclic frameworks.

Highly enantioselective Rh-catalyzed hydrogenation of beta,gamma-unsaturated phosphonates with chiral ferrocene-based monophosphoramidite ligands.

An enantioselective synthesis of chiral alkylphosphonates bearing a beta-stereogenic center, based on the Rh-catalyzed asymmetric hydrogenation of corresponding beta-substituted beta,gamma-unsaturated phosphonates with a ferrocene-based monophosphoramidite ligand under the mild hydrogenation conditions, was developed, in which an ee value of up to 98% was obtained.

Enantioselective synthesis of chiral alpha-aryl or alpha-alkyl substituted ethylphosphonates via Rh-catalyzed asymmetric hydrogenation with a P-stereogenic BoPhoz-type ligand.

An enantioselective synthesis of optically active 1-aryl or 1-alkyl substituted ethylphosphonates, based on the first Rh-catalyzed asymmetric hydrogenation of corresponding alpha,beta-unsaturated precursors with a P-stereogenic BoPhoz-type ligand under the mild condition, was developed, in which a wide range of 1-aryl or 1-alkyl substituted ethylphosphonates were achieved in up to 98% ee.

Highly Diastereo- and Enantioselective Ir-Catalyzed Hydrogenation of 2,3-Disubstituted Quinolines with Structurally Fine-Tuned Phosphine-Phosphoramidite Ligands.

A highly diastereo- and enantioselective Ir-catalyzed hydrogenation of unfunctionalized 2,3-disubstituted quinolines, especially 3-alkyl-2-arylquinolines, has been realized. The success of this hydrogenation is ascribed to the use of a structurally fine-tuned chiral phosphine-phosphoramidite ligand with a (Sa)-3,3'-dimethyl H8-naphthyl moiety and (Rc)-1-phenylethylamine backbone. The hydrogenation displayed broad functional group tolerance, thus furnishing a wide range of optically active 2,3-disubstituted tetrahydroquinolines in up to 96% ee and with perfect cis-diastereoselectivity.