Chiral Bifunctional Research Articles

Enantioselective Seleno‐Michael Addition Reactions Catalyzed by a Chiral Bifunctional N‐Heterocyclic Carbene with Noncovalent Activation

AbstractThe Michael reaction is a conjugate addition and is one of the most powerful methods with which to prepare functional molecules with a β‐stereogenic center. Despite its success in the formation of various asymmetric carbon–carbon and carbon–heteroatom bonds, enantioselective seleno‐Michael addition remains essentially unexplored. We report here a highly enantioselective Michael addition reaction of alkyl selenols to enones. This method conveniently introduces a Se atom to an electron‐deficient double bond asymmetrically. A chiral bifunctional N‐heterocyclic carbene (NHC)/thiourea catalyst was developed as a key ingredient that delivers chiral β‐seleno ketones with remarkable selectivity. This new catalyst and its mode of action support broad applications in the catalytic activation of nucleophilic reactions.

Enantioselective Seleno‐Michael Addition Reactions Catalyzed by a Chiral Bifunctional N‐Heterocyclic Carbene with Noncovalent Activation

The Michael reaction is a conjugate addition and is one of the most powerful methods with which to prepare functional molecules with a β-stereogenic center. Despite its success in the formation of various asymmetric carbon-carbon and carbon-heteroatom bonds, enantioselective seleno-Michael addition remains essentially unexplored. We report here a highly enantioselective Michael addition reaction of alkyl selenols to enones. This method conveniently introduces a Se atom to an electron-deficient double bond asymmetrically. A chiral bifunctional N-heterocyclic carbene (NHC)/thiourea catalyst was developed as a key ingredient that delivers chiral β-seleno ketones with remarkable selectivity. This new catalyst and its mode of action support broad applications in the catalytic activation of nucleophilic reactions.

Chiral N-Heterocyclic Carbene Bifunctional Organocatalyst for Aza-Michael Addition Reactions

Chiral N-Heterocyclic Carbene Bifunctional Organocatalyst for Aza-Michael Addition Reactions

Catalyst-Controlled Regio- and Stereoselective Bromolactonization with Chiral Bifunctional Sulfides

Highly regioselective 5-exo bromolactonizations of stilbene-type carboxylic acids bearing electron-withdrawing substituents are achieved for the first time via the use of chiral bifunctional sulfide catalysts possessing a urea moiety. The chiral phthalide products are obtained in moderate to good enantioselectivities as the result of 5-exo cyclizations.

Front Cover: Recyclable Chiral Bifunctional Thioureas Derived from [60]Fullerene and Their Use as Highly Efficient Organocatalysts for the Asymmetric Nitro‐Michael Reaction (Eur. J. Org. Chem. 19/2017)

Front Cover: Recyclable Chiral Bifunctional Thioureas Derived from [60]Fullerene and Their Use as Highly Efficient Organocatalysts for the Asymmetric Nitro‐Michael Reaction (Eur. J. Org. Chem. 19/2017)

Recent Advances in Dynamic Kinetic Resolution by Chiral Bifunctional (Thio)urea- and Squaramide-Based Organocatalysts.

The organocatalysis-based dynamic kinetic resolution (DKR) process has proved to be a powerful strategy for the construction of chiral compounds. In this feature review, we summarized recent progress on the DKR process, which was promoted by chiral bifunctional (thio)urea and squaramide catalysis via hydrogen-bonding interactions between substrates and catalysts. A wide range of asymmetric reactions involving DKR, such as asymmetric alcoholysis of azlactones, asymmetric Michael–Michael cascade reaction, and enantioselective selenocyclization, are reviewed and demonstrate the efficiency of this strategy. The (thio)urea and squaramide catalysts with dual activation would be efficient for more unmet challenges in dynamic kinetic resolution.

ChemInform Abstract: Enantioselective Allylic Substitution of Morita—Baylis—Hillman Adducts Catalyzed by Chiral Bifunctional Ferrocenylphosphines.

AbstractAir‐stable chiral ferrocenylphosphines are synthesized and utilized in the asymmetric allylic substitution of Morita—Baylis—Hillman adducts with phthalimide under mild reaction conditions.

ChemInform Abstract: Enantioselective Michael Addition of Nitroalkanes to Nitroalkenes Catalyzed by Chiral Bifunctional Quinine‐Based Squaramides.

AbstractThe reaction between (E)‐β‐nitrostyrenes and 1‐nitropropane proceeds with moderate to very high yields, high dia‐ and very high enantioselectivities.

Enantioselective Allylic Substitution of Morita–Baylis–Hillman Adducts Catalyzed by Chiral Bifunctional Ferrocenylphosphines

AbstractA series of air‐stable chiral ferrocenylphosphines (LB1–LB4) were prepared and used in the asymmetric allylic substitution of Morita–Baylis–Hillman (MBH) adducts with phthalimide under mild reaction conditions; the (R,SFc)‐ferrocenylphosphine LB4 afforded the desired amination products 3 in moderate yields with excellent enantioselectivities. The absolute configuration of 3o was confirmed by X‐ray analysis.

ChemInform Abstract: Diastereo‐ and Enantioselective Direct Vinylogous Michael Addition of γ‐Substituted Butenolides to 2‐Enoylpyridines Catalyzed by Chiral Bifunctional Amine‐Squaramides.

AbstractThe reaction tolerates aryl, but no alkyl substituted butenolides and aryl, hetaryl, alkyl, and carboxyl‐substituted 2‐enoylpyridines.

Enantioselective Michael Addition of Nitroalkanes to Nitroalkenes Catalyzed by Chiral Bifunctional Quinine‐Based Squaramides

AbstractA family of chiral bifunctional acid‐/base‐type quinine/squaramide organocatalysts is shown to be highly active promoters of the conjugate addition of 1‐nitropropane to various trans‐β‐nitroalkenes. The cooperation of the quinine and the sterically encumbered squaramide moieties catalyzed the Michael addition reactions at 0 °C by using a catalyst loading of only 2 mol % to afford the 1,3‐dinitro Michael adducts with excellent enantioselectivity and diastereoselectivity (up to 95 % ee and syn/anti isomers up to 96:4).

ChemInform Abstract: Chiral Bifunctional Guanidine‐Catalyzed Enantioselective Aza‐Henry Reaction of Isatin‐Derived Ketimines.

An efficient asymmetric aza-Henry reaction of isatin-derived ketimines has been achieved by using a chiral guanidine–amide organocatalyst. A series of 3-substituted 3-amino-2-oxindoles was obtained with excellent results (up to 99% yield, 94% ee). Other functionalized derivatives were also conveniently transformed. This metal-free system was convenient, practical, and insensitive to air and moisture. On the basis of the crystal structure of the catalyst and NMR spectra analysis, a bifunctional catalytic model was suggested to explain the origin of the asymmetric process.

ChemInform Abstract: Enantioselective Desymmetrization of meso‐Aziridines with Aromatic Thiols Catalyzed by Chiral Bifunctional Quaternary Phosphonium Salts Derived from α‐Amino Acids.

Desymmetrization of meso-aziridines with aromatic thiols was realized by using α-amino acids-derived chiral quaternary phosphonium salts catalysts to provide chiral β-amino sulfides with high yields (up to 99%) and in moderate enantioselectivities (up to 70%).

ChemInform Abstract: Chiral Bifunctional Squaramide Catalyzed Asymmetric Michael Addition of Ethyl α‐Nitroacetate to β,γ‐Unsaturated α‐Ketoesters.

Abstract We have developed an efficient bifunctional squaramide catalyst for the asymmetric Michael addition of ethyl α-nitroacetate to β,γ-unsaturated α-ketoesters. This organocatalytic asymmetric reaction provides convenient and valuable access to highly functionalized 2-nitro-5-oxo-3-arylhexanedioates in excellent yields with uniformly high levels of enantioselectivity (up to >99% ee) albeit with no diastereoselectivity. The resulting products could be conveniently transformed into 5-nitro-2-oxo-4-arylpentanoic acids without loss of enantiomeric excess via basic hydrolysis and the subsequent decarboxylation. This represents an example of in-direct, but efficient asymmetric conjugate addition of pyruvic acid to nitroolefins.

Enantioselective Photochemical Rearrangements of Spirooxindole Epoxides Catalyzed by a Chiral Bifunctional Xanthone

The title compounds were shown to undergo an enantioselective photochemical rearrangement to 3-acylindolin-2-ones (16–33 % ee). A xanthone, which is tethered via an anellated oxazole to a chiral 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-2-one scaffold, efficiently catalyzed this reaction at λ 366 nm, presumably by triplet sensitization. The observed enantioselectivity can be explained by hydrogen bonding of the oxindole substrate and the putative 1,3-diradical intermediate to the lactam part of the catalyst. Although one substrate enantiomer is processed with minor preference over the other, it was shown that the reaction is not stereospecific. Rather, the main reason for the observed selectivity is the enantioselective migration step.

Continuous-Flow Stereoselective Synthesis in Microreactors: Nucleophilic Additions to Nitrostyrenes Organocatalyzed by a Chiral Bifunctional Catalyst

Metal-free stereoselective additions of activated nucleophiles to β-nitrostyrenes were investigated under continuous-flow conditions in microreactors, in the presence of a chiral bifunctional catalyst. Optimization of the experimental setup gave excellent enantioselectivities (up to 85% e.e.) and higher productivities if compared to the flask syntheses. The potential of this flow chemistry approach was demonstrated by the successful synthesis of an advanced intermediate for the preparation of the GABAB receptor agonist Baclofen.

ChemInform Abstract: Chiral Bifunctional Squaramide Catalyzed Asymmetric Tandem Michael‐Cyclization Reaction: Efficient Synthesis of Optically Active 2‐Amino‐4H‐chromene‐3‐carbonitrile Derivatives.

AbstractAn enantioselective cascade Michael addition/cyclization of ortho‐hydroxy‐nitrostyrenes (I) with malononitrile is developed using a chiral bifunctional squaramide derivative as catalyst.

Rencent Advances in Asymmetric Michael Addition Catalyzed by Chiral Bifunctional Thioureas

Asymmetric organocatalysis has been a frontier in the field of asymmetric catalysis. The comparable advantages, including mild reaction conditions, environment benign, and so on, render the organocatalytic reaction to possess some fea- tures of green chemistry. Chiral amino-thiourea organocatalyst, especially chiral bifunctional thiourea, has been shown excel- lent catalytic performance in a variety of asymmetric reactions. This review provides an overview of applications of chiral bifunctional thiourea in asymmetry Michael addition reaction, and the prospect and development are depicted finally.

ChemInform Abstract: Asymmetric Michael/Cyclization Tandem Reaction of 4‐Hydroxycoumarin with β‐Nitroalkenes Catalyzed by Chiral Bifunctional Thioureas.

The first asymmetric Michael/cyclization tandem reaction of 4-hydroxycoumarin with nitroolefins catalyzed by chiral bifunctional thioureas was reported and 2,3-dihydrofuro[3,2-c]-coumarin adducts have been obtained in moderate yields (53–75%) and good enantioselectivities (64–90% ee).

Enantioselective Friedel–Crafts Alkylation of N‐Methylindoles with Nitroalkenes Catalyzed by Chiral Bifunctional Abietic‐Acid‐Derived Thiourea‐ZnII Complexes

AbstractThe catalytic asymmetric Friedel–Crafts alkylation of N‐methylindoles with nitroalkenes catalyzed by bifunctional abietic‐acid‐derived thiourea‐ZnII complexes was investigated. Various types of the nitroalkylated indoles were synthesized under mild conditions and obtained with excellent yields (up to 99 %) and good enantioselectivities (up to 86 % ee). These chiral thiourea catalysts are easily available from the commercial abietic acid.