Enantioselective Organocatalytic Conjugate Addition Research Articles

ChemInform Abstract: A Strategy Enabling Enantioselective Direct Conjugate Addition of Inert Aryl Methane Nucleophiles to Enals with a Chiral Amine Catalyst under Mild Conditions.

AbstractAn organocatalytic enantioselective conjugate addition of aryl methyl nucleophiles to a wide range of α,β‐unsaturated aldehydes is developed.

ChemInform Abstract: Organocatalytic Asymmetric Michael Addition of 4‐Hydroxycoumarin to β,γ‐Unsaturated α‐Keto Esters.

The coumarin core is present as a characteristic structural motif in a large number of natural products and biologically active molecules. 1 Particularly, many of these naturally occurring 4-hydroxycoumarin and their synthetic analogues are important precursors for the synthesis of natural products and pharmaceuticals. 2 Enantioselective organocatalytic conjugate addition of 4-hydroxycoumarin to α,β-unsaturated ketones is a straightforward method to access warfarin which is an effective anticoagulants. 3 Although a number of reactions of α,β-unsaturated ketones as Michael acceptors have been reported, 3,4 the corresponding β,γ-unsaturated αketo esters have received relatively little attention as Michael acceptors. Recently, several groups have reported the asymmetric Michael addition of 4-hydroxycoumarin to β,γ-unsaturated α-keto esters catalyzed by Cu(II)-bisoxazoline, N,N'-dioxide-Ni(II) complexes, thiourea catalysts. 5 Although several efficient methods have been achieved by these systems, an effective method for the synthesis of warfarin analogues is still a challenge. In the framework of our research program for the development of synthetic methods for the enantioselective construction of stereogenic carbon centers, 6 we recently reported asymmetric Michael addition reaction of active methylenes and methines using chiral catalysts. 7 Herein, we wish to describe the enantioselective asymmetric conjugate addition of 4-hydroxycoumarin to β,γ-unsaturated α-keto esters promoted by binaphthyl-modified thiourea organocatalyst. We initially investigated a reaction system with 4-hydroxycoumarin (1) with (E)-ethyl 2-oxo-4-phenylbut-3-enoate (2a) in the presence of 10 mol % bifunctional organocatalysts (Fig. 1) at room temperature. As shown in Table 1, Takemoto’s catalyst I and quinine-derived thiourea catalyst II effectively promoted the reaction with moderate enantioselectivities (entry 1-2). While both of binaphthyl-modified (thio)urea catalysts III-IV and squaramide organocatalysts V-VI bearing both central and axial chiralities gave high enantioselectivities (entries 3-6). The best result has been obtained with binaphthyl-modified thiourea catalyst III. We studied the effect of the ester group of (E)-4-phenylbut-3-en2-one 2 using catalyst III in CH2Cl2 (entries 3 and 7). When employing synthetically attractive, methyl ester of (E)-2oxo-4-phenylbut-3-enoate (2b), the corresponding Michael adduct 3b was obtained with high enantioselectivity of 93% ee (entry 7). Among the solvents probed, the best results

Organocatalytic enantioselective conjugate addition–cyclization domino reactions of o-N-protected aminophenyl α,β-unsaturated aldehydes

A highly enantioselective synthesis of biologically useful tetrahydroquinolines has been developed through the asymmetric organocatalytic conjugate addition–cyclization reaction of malonates with o-N-protected aminophenyl α,β-unsaturated aldehydes using a diphenylprolinol TMS ether as an organocatalyst followed by reductive deoxygenation. This novel protocol allows for the formation of 4-substituted chiral tetrahydroquinolines, which are not easily accessible using other methodologies, in good yields with high enantioselectivities (up to >99% ee).

Organocatalytic Asymmetric Michael Addition of 4-Hydroxycoumarin to β,γ-Unsaturated α-Keto Esters

The coumarin core is present as a characteristic structural motif in a large number of natural products and biologically active molecules. 1 Particularly, many of these naturally occurring 4-hydroxycoumarin and their synthetic analogues are important precursors for the synthesis of natural products and pharmaceuticals. 2 Enantioselective organocatalytic conjugate addition of 4-hydroxycoumarin to α,β-unsaturated ketones is a straightforward method to access warfarin which is an effective anticoagulants. 3 Although a number of reactions of α,β-unsaturated ketones as Michael acceptors have been reported, 3,4 the corresponding β,γ-unsaturated αketo esters have received relatively little attention as Michael acceptors. Recently, several groups have reported the asymmetric Michael addition of 4-hydroxycoumarin to β,γ-unsaturated α-keto esters catalyzed by Cu(II)-bisoxazoline, N,N'-dioxide-Ni(II) complexes, thiourea catalysts. 5 Although several efficient methods have been achieved by these systems, an effective method for the synthesis of warfarin analogues is still a challenge. In the framework of our research program for the development of synthetic methods for the enantioselective construction of stereogenic carbon centers, 6 we recently reported asymmetric Michael addition reaction of active methylenes and methines using chiral catalysts. 7 Herein, we wish to describe the enantioselective asymmetric conjugate addition of 4-hydroxycoumarin to β,γ-unsaturated α-keto esters promoted by binaphthyl-modified thiourea organocatalyst. We initially investigated a reaction system with 4-hydroxycoumarin (1) with (E)-ethyl 2-oxo-4-phenylbut-3-enoate (2a) in the presence of 10 mol % bifunctional organocatalysts (Fig. 1) at room temperature. As shown in Table 1, Takemoto’s catalyst I and quinine-derived thiourea catalyst II effectively promoted the reaction with moderate enantioselectivities (entry 1-2). While both of binaphthyl-modified (thio)urea catalysts III-IV and squaramide organocatalysts V-VI bearing both central and axial chiralities gave high enantioselectivities (entries 3-6). The best result has been obtained with binaphthyl-modified thiourea catalyst III. We studied the effect of the ester group of (E)-4-phenylbut-3-en2-one 2 using catalyst III in CH2Cl2 (entries 3 and 7). When employing synthetically attractive, methyl ester of (E)-2oxo-4-phenylbut-3-enoate (2b), the corresponding Michael adduct 3b was obtained with high enantioselectivity of 93% ee (entry 7). Among the solvents probed, the best results

A Strategy Enabling Enantioselective Direct Conjugate Addition of Inert Aryl Methane Nucleophiles to Enals with a Chiral Amine Catalyst under Mild Conditions

Nitro-charged activation: An organocatalytic enantioselective conjugate addition of aryl methyl nucleophiles to enals has been developed to produce ubiquitous chiral benzylic building blocks (see scheme; TES=triethylsilyl). Taking advantage of the strongly electron-withdrawing nature of nitro groups, which can be conveniently transformed into other functionalities, this functionality was incorporated into aromatic systems as a temporary activating group.

Chiral Squaramide Catalyzed Asymmetric Conjugate Additions of 3-Substituted Oxindoles to Vinylphosphonates

An efficient organocatalytic enantioselective conjugate addition of 3-substituted oxindoles to activated vinylphosphonates has been described. This reaction allows the facile synthesis of a new family of organophosphorus derivatives bearing an oxindole motif in high chemical yields with good to excellent stereoselectivities.

ChemInform Abstract: Asymmetric Synthesis of Ring‐Fused Tetrahydroquinolines Using Organocatalytic Enantioselective Conjugate Addition and Cross‐Dehydrogenative Coupling.

AbstractEnantioenriched ring‐fused tetrahydroquinolines (IV) are synthesized via enantioselective conjugate addition of malonates (II) to 2‐N‐tetrahydroisoquinolinyl‐substituted cinnamaldehyde (I), followed by intramolecular cross‐dehydrogenative coupling.

Organocatalytic enantioselective conjugate addition of 2-nitrocyclohexanone to acrylaldehyde: a concise two-step synthesis of chiral building block 1-azaspiro[4.5]decan-6-one

A gram-scale organocatalytic enantioselective Michael addition of α-nitrocyclohexanone to acrolein has been developed, and it was successfully applied to a concise two-step synthesis of (1S)-azaspiro[4.5]decan-6-one, a useful chiral building block for the synthesis of a variety of natural alkaloids.

Organocatalytic enantioselective conjugate addition of nitromethane to alkylidenemalonates: asymmetric synthesis of pyrrolidine-3-carboxylic acid derivatives

A highly enantioselective nitromethane addition to alkylidene malonates catalyzed by cinchona-alkaloid derived thiourea based organocatalyst has been developed that offers a new route to the synthesis of substituted pyrrolidine-3-carboxylic acid derivatives and 3-arylpyrrolidines/pyrrolidones.

Organocatalytic Asymmetric Conjugate Addition of 3-Alkyl-Substituted Oxindoles to Vinyl Ketones

phosphate. 5 Although there have been reports for the catalytic enantioselective conjugate addition reaction of 3-aryl-substituted oxindoles to vinyl ketones, 5 a few examples for the catalytic enantioselective conjugate addition reaction of 3alkyl-substituted oxindoles to cyclic enones were reported using chiral primary or secondary amine catalysts. 6 Therefore, the development of alternative catalysts for the catalytic enantioselective conjugate addition reaction of 3-alkyl-substituted oxindoles to vinyl ketones would be highly desirable. As part of the research program toward the development of synthetic methods for the catalytic carbon-carbon bond formations, 7 we recently reported the organocatalytic conjugate addition reaction to α,β-unsaturated carbonyl compounds 8 and the other Michael acceptors. 9 In this communications, we wish to describe the enantioselective conjugate addition reaction of prochiral 3-alkyl-substituted oxindoles with vinyl ketones catalyzed by binaphthyl-modified bifunctional organocatalysts bearing both central and axial chiral elements. In an attempt to validate the feasibility of the organocatalytic enantioselective conjugate addition reaction of 3substituted oxindoles, we first investigated the reaction system with 3-benzyl oxindole 1a with methyl vinyl ketone (2a) in the presence of 10 mol % of catalyst in toluene at room temperature. We examined the impact of the structure of catalysts I-IV on enantioselectivities (Table 1, entries 1-4). Quinine-derived thiourea catalyst I was ineffective (Table 1, entriry 1). While binaphthyl-modified chiral bifunctional organocatalysts II-III bearing both central and axial chiral

ChemInform Abstract: Recent Advances in Asymmetric Organocatalytic Conjugate Addition of Arenes and Hetero‐arenes

AbstractReview: 82 refs.

Asymmetric synthesis of ring-fused tetrahydroquinolines using organocatalytic enantioselective conjugate addition and cross-dehydrogenative coupling

Enantioenriched ring-fused tetrahydroquinolines were synthesized by a facile and straightforward process involving the organocatalytic enantioselective conjugate addition reaction of malonates with o-N-tetrahydroisoquinolinyl-substituted cinnamaldehyde, followed by intramolecular cross-dehydrogenative coupling. Diphenylprolinol TMS ether was used as an organocatalyst in the asymmetric catalytic conjugate addition reaction and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) was used as an oxidant in the cross-dehydrogenative coupling (CDC) reaction. The desired ring-fused tetrahydroquinolines were obtained in moderate yields and with high enantioselectivities (up to 97% ee).

Enantioselective Organocatalytic Conjugate Addition of Nitroalkanes to Electrophilic 2-Iminochromenes

We disclose a new efficient enantioselective organocatalytic conjugate addition method for the preparation of 2-amino-4H-chromenes in high to excellent yields (75–95%) and with high to excellent enantioselectivities (86–97% ee). It is noteworthy that the 2-iminochromene was first disclosed as an active electrophile.

Enantioselective Conjugate Addition of 4-Hydroxycoumarin to Enones Catalyzed by Binaphthyl-Modified Primary Amine Organocatalyst

The Michael addition reaction is widely recognized as one of the most general methods for formation of C-C bonds in organic synthesis, and the development of enantioselective catalytic conjugate addition reaction has been subject of intensive research. In addition to the great success catalyzed by metal complexes, the powerful and environmentally friendly organocatalyst-mediated asymmetric conjugate addition reaction has been explored intensively in recent years. Enantioselective organocatalytic conjugate addition reaction of β-ketoesters to α,β-unsaturated carbonyl compounds represents a direct and most appealing approach to chiral 1,5-dicarbonyl compounds that are versatile intermediates in organic synthesis. Particularly, the addition of 4-hydroxycoumarin to α,β-unsaturated ketones is a straightforward method to access warfarin which is an effective anticoagulants. Further investigation showed that (S)-warfarin had higher anticoagulant activity than the R enantiomer. As a result, achieving the optically pure R or S enantiomer of warfarin would be of great importance. Among the established strategies for the synthesis of chiral warfarin, chiral auxiliary strategy, hydrogenation, and hetero-Diels-Alder reaction have been intensively studied. Recently, several groups reported an enantioselective conjugate addition reaction of 4-hydroxycoumarin to enones, catalyzed by chiral secondary amines, primary amines, and bifunctional primaryamine thioureas. Although several efficient methods have been achieved by these systems, an effective method for the synthesis of warfarin is still a challenge. As part of the research program related to the development of synthetic methods for the enantioselective construction of stereogenic carbon centers, we recently reported asymmetric conjugate addition reaction of active methylenes and methines. Herein, we wish to describe the enantioselective asymmetric conjugate addition of 4-hydroxycoumarin to α,β-unsaturated ketones promoted by binaphthyl-modified primary amine organocatalyst. Validation of the feasibility of the proposed Michael addition process started by evaluating a model reaction between 4-hydroxycoumarin (1) with (E)-4-phenylbut-3-en-2-one (2a) in the presence of 20 mol % bifunctional catalysts (Fig. 1) and 40 mol % of TFA as additive at room temperature. As shown in Table 1, 9-amino-9-deoxyepicinchonidine (I) effectively promoted the reaction with high enantioselectivity (entry 1). While chiral primary amine organocatalysts (IIIV) bearing both central and axial chiral elements gave moderate to high enantioselectivity (entries 2-4). The best result has been obtained with binaphthyl-modified 1,2diphenylethylenediamine catalyst (III). We examined our

ChemInform Abstract: Organocatalytic Enantioselective Conjugate Addition of Ketones to Isatylidine Malononitriles.

AbstractThe compounds (III) can also be obtained in a more atom‐economical three‐component process through a domino Knoevenagel/ Michael sequence [cf.

Organocatalytic enantioselective conjugate addition of ketones to isatylidine malononitriles

An enantioselective Michael addition of ketones to alkylidenemalononitriles catalyzed by chiral primary amine I with (R)-5c as a co-catalyst in good yields (>90%) and with good enantioselectivities (85-96% ee) has been developed. The strategy has also been extended to a three-component version through a domino Knoevenagel/Michael sequence with similar or better outcomes.

Recent advances in asymmetric organocatalytic conjugate addition of arenes and hetero-arenes

The asymmetric organocatalytic conjugate addition reaction of various nucleophiles to the unsaturated acceptor provides an important route for the synthesis of valuable chiral entities. Recently, aromatic and hetero-aromatic compounds have been successfully used as nucleophiles in the enantioselective conjugate addition reaction. This review provides an overview on the recent developments made in organocatalytic enantioselective conjugate addition of arenes and hetero-arenes to unsaturated acceptors.

ChemInform Abstract: Organocatalytic Enantioselective Conjugate Additions of Heteroatoms to α,β‐Unsaturated Carbonyl Compounds

AbstractReview: 93 refs.

Organocatalytic Enantioselective Conjugate Addition Reactions. A Powerful Tool for the Stereocontrolled Synthesis of Complex Molecules. By Jose L. Vicario, Dolores Badía, Luisa Carillo and Efraim Reyes.

Organocatalytic Enantioselective Conjugate Addition Reactions. A Powerful Tool for the Stereocontrolled Synthesis of Complex Molecules. By Jose L. Vicario, Dolores Badía, Luisa Carillo and Efraim Reyes.

Organocatalytic Conjugate Additions of Acetylacetone to 3-Ylideneoxindoles: A Direct Access to Highly Enantioenriched Oxindole Derivatives

A highly enantioselective organocatalytic conjugate addition of acetylacetone to 3-ylideneoxindoles is described. This method provides polysubstituted oxindoles in good to excellent enantioselectivities and high isolated yields.