Asymmetric Michael Addition Reaction Research Articles

Asymmetric Michael addition reactions of pyrrolones with chalcones catalyzed by vicinal primary-diamine salts

The asymmetric Michael addition reaction of pyrrolones with chalcones catalyzed by vicinal primary-diamine salts has been developed in good yields and high enantioselectivities.

Asymmetric Michael addition in an aqueous environment with the assistance of optically active hyperbranched polymers

A novel optically active hyperbranched polymer can serve as the chiral scaffolds to promote asymmetric Michael addition reaction in an aqueous environment with a high product yield and enantioselectivity.

Synthesis of pyrrolidine-3-carboxylic acid derivatives via asymmetric Michael addition reactions of carboxylate-substituted enones.

To concisely synthesize highly enantiomerically enriched 5-alkyl-substituted pyrrolidine-3-carboxylic acids, organocatalytic enantioselective Michael addition reactions of 4-alkyl-substituted 4-oxo-2-enoates with nitroalkanes have been developed. Using the developed reaction method, 5-methylpyrrolidine-3-carboxylic acid with 97% ee was obtained in two steps.

ChemInform Abstract: Organocatalytic Asymmetric Michael Addition of 3‐Pyrrolyloxindoles to β‐Phthalimidonitroethene for the Synthesis of 3,3′‐Disubstituted Oxindoles Bearing Contiguous 3,α,β‐Triamino Functionality.

An organocatalytic asymmetric Michael addition reaction of 3-pyrrolyloxindoles to β-phthalimidonitroethene has been developed with a bifunctional thiourea–tertiary amine as the catalyst. A range of 3,3′-disubstituted oxindoles bearing contiguous 3,α,β-triamino functionality could be obtained in high yields with good diastereoselectivities and high enantioselectivities (up to 99% yield, 99:1 dr, and 98% ee). The higher reactivity of β-phthalimidonitroethene compared to the reactivity of ordinary nitroalkenes in the reaction with 3-pyrrolyloxindoles was demonstrated by contrast experiments.

Biomimetic asymmetric Michael addition reactions in water catalyzed by amino-containing β-cyclodextrin derivatives

Nine β-cyclodextrin derivatives containing an amino group were synthesized via nucleophilic substitution from mono(6-O-p-tolylsulfonyl)-β-cyclodextrin and used in asymmetric biomimetic Michael addition reactions in water at room temperature. The mechanism responsible for the moderate activity and enantioselectivity of the β-cyclodextrin derivatives was explored using nuclear magnetic resonance spectroscopy, namely 2D 1H rotating-frame overhauser effect spectroscopy (ROESY), ultraviolet absorption spectroscopy, and quantum chemical calculations, which provide a useful technique for investigating the formation of inclusion complexes. The effects of the pH of the reaction medium, the β-cyclodextrin derivative dosage, the structure of the modifying amino group, and various substrates on the yield and enantioselectivity were investigated. The results indicated that these factors had an important effect on the enantiomeric excess (ee) in the reaction system. Experiments using a competitor for inclusion complex formation showed that a hydrophobic cavity is necessary for enantioselective Michael addition. A comparison of the reactions using 4-nitro-β-nitrostyrene and 2-nitro-β-nitrostyrene showed that steric hindrance improved the enantioselectivity. This was verified by the optimized geometries obtained from quantum chemical calculations. An ee of 71% was obtained in the asymmetric Michael addition of cyclohexanone and 2-nitro-β-nitrostyrene, using (S)-2-aminomethylpyrrolidine-modified β-CD as the catalyst, in an aqueous buffer solution, i.e., CH3COONa-HCl (pH 7.5).

Asymmetric Michael Addition Reaction via Rhodium Catalyst Fragmentation

Asymmetric Michael Addition Reaction via Rhodium Catalyst Fragmentation

Natural Sugars Derived Chiral Ionic Liquids for Asymmetric Michael Addition Reaction

AbstractHerein, we report the application of a new class of D‐xylose derived chiral ionic liquids (CILs) as chiral catalysts for the enantioselective Michael addition reaction between chalcone and diethylmalonate. These CILs were successfully employed for the same reaction and Michael adducts were obtained in very good yields with moderate enantioselectivity.

Organocatalytic Asymmetric Michael Addition of 3-Pyrrolyloxindoles to β-Phthalimidonitroethene for the Synthesis of 3,3'-Disubstituted Oxindoles Bearing Contiguous 3,α,β-Triamino Functionality.

An organocatalytic asymmetric Michael addition reaction of 3-pyrrolyloxindoles to β-phthalimidonitroethene has been developed with a bifunctional thiourea-tertiary amine as the catalyst. A range of 3,3'-disubstituted oxindoles bearing contiguous 3,α,β-triamino functionality could be obtained in high yields with good diastereoselectivities and high enantioselectivities (up to 99% yield, 99:1 dr, and 98% ee). The higher reactivity of β-phthalimidonitroethene compared to the reactivity of ordinary nitroalkenes in the reaction with 3-pyrrolyloxindoles was demonstrated by contrast experiments.

G-quadruplex DNA-based asymmetric catalysis of michael addition: Effects of sonication, ligands, and co-solvents.

There is an escalating interest of using double stranded DNA molecules as a chiral scaffold to construct metal-biomacromolecule hybrid catalysts for asymmetric synthesis. Several recent studies also evaluated the use of G-quadruplex DNA-based catalysts for asymmetric Diels-Alder and Friedel-Crafts reactions. However, there is still a lack of understanding of how different oligonucleotides, salts (such as NaCl and KCl), metal ligands and co-solvents affect the catalytic performance of quadruplex DNA-based hybrid catalysts. In this study, we aim to systematically evaluate these key factors in asymmetric Michael addition reactions, and to examine the conformational and molecular changes of DNA by circular dichroism (CD) spectroscopy and gel electrophoresis. We achieved up to 95% yield and 50% enantiomeric excess (ee) when the reaction of 2-acylimidazole 1a and dimethylmalonate was catalyzed by 5'-G3 (TTAG3 )3 -3' (G4DNA1) in 20 mM MOPS (pH 6.5) containing 50 mM KCl and 40 µM [Cu(dmbipy)(NO3 )2 ], and G4DNA1 was pre-sonicated in ice bath for 10 min prior to the reaction. G-quadruplex-based hybrid catalysts provide a new tool for asymmetric catalysis, but future mechanistic studies should be sought to further improve the catalytic efficiency. The current work presents a systematic study of asymmetric Michael addition catalyzed by G-quadruplex catalysts constructed via non-covalent complexing, and an intriguing finding of the effect of pre-sonication on catalytic efficiency. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:891-898, 2016.

A Recyclable Organocatalyst for Asymmetric Michael Addition

In this study, a new organocatalyst derived from proline was developed and shown to be an efficient catalyst for asymmetric Michael addition reactions of ketones and aldehydes to nitroolefins with high diastereo- and enantioselectivities. (syn;anti up to 99:1, ee. up to 98 %.). Furthermore, the catalyst is easily recovered and could be reused six times without significant loss of its ability to affect the outcome of the asymmetric reactions. In addition, computational studies at the B3LYP/6-311G(d,p)//6-311 + G(2dp,f) level was conducted on a model reaction, and confirmed the following hypotheses: first, the hydrogen bonding between carboxyl group and nitro group plays an important role in catalysis, and second, the energy barrier for re-face attack in reactions of ketones to form 2S, 3R products is lower than that for the si-face attack leading to 2S, 3R products. Structural modification of a previously reported organocatalyst (lead compound in figure) was used to design an efficient and recyclable organocatalyst for asymmetric Michael addition. The introduced carboxyl group not only enhances the enantioselectivity but also brings convenience to the recovery of the catalyst.

ChemInform Abstract: Cinchona Alkaloid‐Based Chiral Catalysts Act as Highly Efficient Multifunctional Organocatalysts for the Asymmetric Conjugate Addition of Malonates to Nitroolefins.

AbstractCatalyst (I) and its O‐allylated derivative (not shown) are tested in asymmetric Michael addition reactions.

Enantioselective synthesis of chiral α,β-unsaturated γ-substituted butyrolactams by organocatalyzed direct asymmetric vinylogous Michael addition of α,β-unsaturated γ-butyrolactam to 2-enoylpyridines.

An organocatalyzed direct asymmetric vinylogous Michael addition reaction of α,β-unsaturated γ-butyrolactam to 2-enoylpyridines has been developed with a chiral bifunctional amine-squaramide as the catalyst. This approach provides easy access to a series of optically active α,β-unsaturated γ-substituted butyrolactams in high yields (up to 99%) with excellent diastereoselectivities (up to >99 : 1) and enantioselectivities (up to >99% ee).

Organocatalyzed asymmetric Michael addition by an efficient bifunctional carbohydrate-thiourea hybrid with mechanistic DFT analysis.

A series of thiourea based bifunctional organocatalysts having d-glucose as a core scaffold were synthesized and examined as catalysts for the asymmetric Michael addition reaction of aryl/alkyl trans-β-nitrostyrenes over cyclohexanone and other Michael donors having active methylene. Excellent enantioselectivities (<95%), diastereoselectivities (<99%), and yields (<99%) were attained under solvent free conditions using 10 mol% of 1d0. The obtained results were explained through DFT calculations using the B3LYP/6-311G(d,p)//B3LYP/6-31G(d) basic set. The QM/MM calculations revealed the role of cyclohexanone as a solvent as well as reactant in the rate determining step imparting 31.91 kcal mol-1 of energy towards the product formation.

ChemInform Abstract: Asymmetric Michael Addition Reaction of α‐Aryl‐Substituted Lactams Catalyzed by Chiral Quaternary Ammonium Salts Derived from Cinchona Alkaloids: A New Short Synthesis of (+)‐Mesembrine.

AbstractThe utility of this method is demonstrated in the synthesis of (+)‐mesembrine (VI).

Organocatalytic asymmetric Michael addition of α-alkylidene succinimides to nitrostyrenes.

A bifunctional squaramide-catalyzed asymmetric Michael addition reaction of α-alkylidene succinimides with nitrostyrenes and a nitrodiene has been developed. This organocatalytic asymmetric reaction provides easy access to functionalized succinimides with two contiguous stereocenters with a broad substrate scope. The desired succinimide derivatives were obtained in good to excellent yields (up to 98%) with high to excellent diastereoselectivities (up to >99 : 1 dr) and excellent enantioselectivities (up to 99% ee). This protocol provides a straightforward entry to functionalized chiral succinimide derivatives from simple starting materials.

In search of diamine analogs of the α,α-diphenyl prolinol privileged chiral organocatalyst. Synthesis of diamine derivatives of α,α-diphenyl-(S)-prolinol and their application as organocatalysts in the asymmetric Michael and Mannich reactions

This paper describes improved reaction conditions for the substitution of the hydroxyl group in (S)-diphenyl(pyrrolidin-2-yl)methanol by the azide group, which was then reduced to the diamine derivative. We examined two protecting groups (N-Bn and N-Boc) on the pyrrolidine nitrogen in order to functionalize the primary amino group into various amide, alkylated amine, sulfonamide, thiourea and triazole derivatives. Notably, carefully controlled conditions were required to generate the desired derivatives from the sterically hindered benzhydrylamine moiety. Unexpectedly, upon removal of the N-protecting group in derivatives containing electrophilic polar double bonds (CS, CO) cyclization took place, affording products such as amidines. The target compounds were evaluated as bifunctional organocatalysts in the asymmetric Michael and Mannich addition reactions. (S)-2-(Azidodiphenylmethyl)pyrrolidine (S)-7 was identified as the most efficient organocatalyst among the various diamine derivatives of α,α-diphenyl-(S)-prolinol prepared in this work.

Asymmetric Michael Addition Reaction of α-Aryl-Substituted Lactams Catalyzed by Chiral Quaternary Ammonium Salts Derived from Cinchona Alkaloids: A New Short Synthesis of (+)-Mesembrine

The enantioselective Michael addition reaction of α-aryl-substituted lactams with electron-deficient olefins was efficiently catalyzed using chiral quaternary ammonium salts derived from cinchona alkaloids. This method was highly useful for the construction of an all-carbon-substituted quaternary carbon stereogenic center at the α-position of lactams in good to high yields and with good enantiomeric excess and could be applied to the short synthesis of (+)-mesembrine.

ChemInform Abstract: Asymmetric Michael Addition Reactions of Nitroalkanes to 2‐Furanones Catalyzed by Bifunctional Thiourea Catalysts.

AbstractHighly functionalized γ‐lactones with two or three consecutive stereogenic carbons are synthesized with diastereoselectivities up to &lt;20:1 dr and enantioselectivities up to &lt;99% e.e.

Optically active helical polymers with pendent thiourea groups: Chiral organocatalyst for asymmetric michael addition reaction

ABSTRACTThis article reports a novel category of helical substituted polyacetylenes bearing pendant thiourea groups and showing remarkable asymmetric catalysis ability. Thiourea‐based monomer and another chiral monomer underwent copolymerization, affording copolymers with considerable optical activity. The copolymers were used as chiral organocatalyst to homogeneously catalyze the asymmetric Michael addition of diethyl malonate to trans‐β‐nitrostyrene. During catalysis, a synergetic effect occurred between the pendant thiourea moieties and the helical structures in the polymer backbones. The enantioselectivity of the reaction was governed by the thiourea moieties. Meanwhile, the concaves along the helices provided specific domains where the substrates and catalytic groups were packed together, leading to a remarkable enhancement of product yield and enantioselectivity. Product with high yield (85%) and satisfactory ee (up to 72%) can be obtained. The present helical polymers open up new opportunities for developing macromolecules as mimetic enzymes catalyzing asymmetric reactions. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 1816–1823

Asymmetric Base‐Free Michael Addition at Room Temperature with Nickel‐Based Bifunctional Amido‐Functionalized N‐Heterocyclic Carbene Catalysts

AbstractA series of nickel‐based chiral bifunctional catalysts (1d–3d) with N‐heterocyclic carbene (NHC) ligands derived from (1R)‐(–)‐menthol, (1S)‐(–)pinene, and (1R)‐(+)‐camphor have been successfully designed for asymmetric Michael addition reactions under base‐free conditions. The NHC complexes, namely, [1‐R‐3‐{N‐(phenylacetamido)}imidazol‐2‐ylidene]2Ni [R = (1S)‐menthyl (1d), (1S)‐pinane (2d), and (1R)‐isobornyl (3d)], bearing chiral ancillaries on the amido‐functionalized side arms of the NHC ligands, performed the bifunctional catalysis of the asymmetric base‐free Michael addition reaction of the α‐methyl cyano ester substrates ethyl 2‐cyanopropanoate (4), isopropyl 2‐cyanopropanoate (5), and tert‐butyl 2‐cyanopropanoate (6) with the activated olefinic substrates methyl vinyl ketone (7) and acrylonitrile (8) in 63–98 % yields with enantiomeric excess (ee) values of 2–75 % at room temperature in 8 h. More interestingly, only the longest of the three catalysts, the menthol derivative 1d, showed significant chiral induction of up to 75 % ee; this has been attributed to the reduction of the steric influence owing to the relatively distant dispositions of the chiral ancillaries from the catalytically active metal center that arise as a consequence of the cis geometries of 1d–3d.