Asymmetric Michael Addition Reaction Research Articles

Dipeptidic Proline‐Derived Thiourea Organocatalysts for Asymmetric Michael addition Reactions between Aldehydes and Nitroolefins

AbstractThe enantiodivergent synthesis of syn‐Michael adducts can be easily achieved by switching the terminal proline in dipeptidic proline‐thiourea catalysts. In this study, a dipeptidic proline‐derived thiourea organocatalyst was rationally designed and facilely prepared from dipeptidic proline, a chiral diamine as a linker, and isothiocyanate. This asymmetric bifunctional catalyst for Michael addition between aldehydes and nitroolefins provided chiral 4‐nitro aldehyde adducts with yields of up to 99 %, 92 : 8 syn‐diastereoselectivity, and 97 % enantiomeric excess at room temperature.

Integrating Bifunctional Catalysis into Senior Undergraduate Organic Chemistry: A Laboratory Experiment on the Asymmetric Michael Addition Reaction

Integrating Bifunctional Catalysis into Senior Undergraduate Organic Chemistry: A Laboratory Experiment on the Asymmetric Michael Addition Reaction

Preparation of Indolin-3-one-Containing 1,4-Naphthoquinone Derivatives via Organocatalytic Asymmetric Michael Addition Reaction.

This article explores the asymmetric Michael addition reaction of 2-hydroxy-1,4-naphthoquinone and indole-3-ones catalyzed by cinchona alkaloids. This strategy utilizes 2-hydroxy-1,4-naphthoquinone and easily prepared indole-3-one as substrates, resulting in the synthesis of 23 unprecedented indolin-3-ones bearing a 1,4-naphthoquinone unit at the C2 position of indole under simple and mild reaction conditions, with up to 88% yield, 98% ee, and >20:1 dr.

Tripeptide-Catalyzed Asymmetric Michael Addition Reaction of β-Nitrostyrenes with Cyclohexanone

AbstractA tripeptide catalyst derived from natural l-amino acids was employed in the reaction of β-nitrostyrenes with cyclohexanone, serving as a model for the asymmetric Michael addition reaction. The reaction was conducted in the presence of H-Pro-Tle-Gly-OH and 2-fluoro-4-chlorobenzoic acid as co-catalysts (each at 20 mol%) in DMF-H2O (5:1) at 0 °C for 3 days. This process yielded the desired Michael adducts with excellent efficiency and good stereoselectivity (up to 98% yield, up to 92% ee).

Three-Dimensional Homochiral Covalent Organic Frameworks with Intrinsic Chiral qzd Topology.

Although a variety of chiral porous framework materials have been reported, there are few examples known to combine molecular chirality, helicity, and three-dimensional (3D) intrinsically chiral topology in one structure, which is beneficial for chirality transfer and amplification. Here, we report the synthesis of the first two 3D covalent organic frameworks (COFs) with an intrinsic chiral qzd topology, which exhibit unusual integration of various homochiral and homohelical features. By imine condensation of 4-connected porphyrin tetraamines and 2-connected enantiopure diene dialdehyde, we prepared two isostructural COFs with a noninterpenetrated qzd topology. The specific geometry and conformation flexibility of the V-shaped diene linker control the alignment of square-planar porphyrin units with rotational linkages and facilitate the creation of homochiral extended porous structures that feature a helical arrangement of porphyrins. Post-synthetic metalation of CCOF 23 with Rh(I) affords a heterogeneous catalyst for the asymmetric Michael addition reaction of aryl boronic acids to 2-cyclohexenone, which shows higher enantioselectivities compared to their homogeneous counterparts, presumably due to the confined effect of helical channels. This finding will provide an impetus to explore multichirality materials, offering new insights into the generation and control of helicity, homochirality, and enantioselectivity in the solid state.

Helical polyisocyanide-based macroporous organic catalysts for asymmetric Michael addition with high efficiency and stereoselectivity.

Porous materials have attracted interest due to their high specific surface area and rich functionality. Immobilizing organocatalysts onto porous polymers not only boosts enantioselectivity but also improves the reaction rates. In this work, a series of porous polymers C-poly-3ms with rigid polyisocyanide-carrying secondary amine pendants as building blocks were successfully prepared. And the pore size and optical activity of C-poly-3ms can be controlled by the length of the polyisocyanide blocks due to their rigid and helical backbone. C-poly-3150 demonstrated a preferred left-handed helix with a θ 364 value of -8.21 × 103. The pore size and S BET of C-poly-3150 were 17.52 nm and 7.98 m2 g-1, respectively. The porous C-poly-3150 catalyzes the asymmetric Michael addition reaction efficiently and generates the target products in satisfactory yield and excellent enantioselectivity. For 6ab, an enantiomeric excess (ee) and a diastereomeric ratio (dr) up to 99% and 99/1 could be achieved, respectively. The recovered catalyst can be recycled at least 6 times in the asymmetric Michael addition reaction while maintaining activity and stereoselectivity.

Py-2NO ligand enabled Ni(ii)-catalyzed asymmetric Michael addition reaction of indoles with β,γ-unsaturated α-keto esters

This work diversified the Py-2NO ligand library recently developed by our group and further expanded the application of chiral Py-2NO ligands in asymmetric catalysis.

Catalytic asymmetric synthesis of guaiazulene analogues

The asymmetric Michael addition reaction of guaiazulene to α,β-unsaturated 2-acyl imidazoles was developed with a chiral-at-metal Rh(iii) complex as the catalyst for the first time.

Enantioselective Total Synthesis of (-)-Cephalotanin B.

Cephalotaxus diterpenoids are attractive natural products with intriguing molecular frameworks and promising biological features. As a structurally unusual member, (-)-cephalotanin B possesses an extraordinarily congested heptacyclic skeleton, three lactone units, and nine consecutive stereocenters. Herein, we report an enantioselective total synthesis of (-)-cephalotanin B based on crucial transformations including a divergent asymmetric Michael addition reaction, a novel Pauson-Khand/deacyloxylation process discovered in the development of the second-generation of stereoselective Pauson-Khand reaction protocol, and the developed epoxide-opening/elimination/dual lactonization cascade to achieve the challenging propeller shaped A-B-C ring system.

Enantioselective Total Synthesis of (−)‐Cephalotanin B

AbstractCephalotaxus diterpenoids are attractive natural products with intriguing molecular frameworks and promising biological features. As a structurally unusual member, (−)‐cephalotanin B possesses an extraordinarily congested heptacyclic skeleton, three lactone units, and nine consecutive stereocenters. Herein, we report an enantioselective total synthesis of (−)‐cephalotanin B based on a divergent asymmetric Michael addition reaction, a novel Pauson–Khand/deacyloxylation process discovered in the development of a second‐generation stereoselective Pauson–Khand reaction protocol, and an epoxide‐opening/elimination/dual‐lactonization cascade to construct the challenging propeller‐shaped A–B–C ring system as key transformations.

Development of L-Proline-Based Chiral Ionic Liquids for Asymmetric Michael Reaction

Different Chiral Ionic Liquids (CIL) based on L-proline have been developed. Simple and efficient synthetic methodologies are used, allowing preparation in good yields for twelve novel CILs using L-proline as a cation or anion combined with suitable counter-ions. A detailed physical and chemical characterization of the CILs was performed to evaluate the influence of counter-ions on the final properties. The most promissory CILs were tested as efficient chiral catalysts in IL media for asymmetric Michael addition reactions of ketones and aldehydes to nitro-olefins. Similar or even better conversions and enantioselectivities (ee up to 95%) compared to the original L-proline were achieved. Additionally, a good product extraction performance using supercritical CO2 processes was obtained.

Anl-proline-modified chiral porous hyper-crosslinkedl-phenylalanine dipeptide—increased reaction rate and selectivity in asymmetric catalysis

Two heterogeneous catalysts were synthesized from aromatic amino acids. Asymmetric Michael addition reaction and Mannich reaction were catalyzed, and the product shows a high ee value.

Acyl transfer-enabled catalytic asymmetric Michael addition of α-hydroxy-1-indanones to nitroolefins

We report herein an enantioselective acyl transfer protocol via electrophile activation. The reaction cascade sequence encompasses dinuclear zinc-catalyzed asymmetric Michael addition, intramolecular cyclization, and retro-Claisen reaction, which leads to a step- and atom-economic approach to a variety of protected cyclic tertiary α-hydroxyketones in good yields with excellent enantioselectivities (24 examples, 56%-82% yield, 1.5-13 dr and 79%-96% ee). Besides, the large-scale synthesis and further transformation of the products demonstrate the effectiveness of this method for organic synthesis.

Organocatalytic asymmetric Michael addition reaction of aldehydes with 2-furanones: experimental, applications and DFT studies

Organocatalytic asymmetric Michael additions of aldehydes to 2-furanones are successfully conducted and have been applied to the synthesis of vorapaxar's analogues.

Sulfonated chiral covalent organic frameworks-mediated asymmetric Michael addition of acetone to β-nitroolefins

Organo-catalysts for the Michael addition reaction of nitrostyrene with acetone are essential to improve the efficiency and enantioselectivity, and their recycling also faces great challenges. Herein, a sulfonated chiral covalent organic framework (SDA-CCOF) was successfully constructed by post modification of the pre-prepared sulfonated COF with chiral 1, 2-diaminocyclohexane via N-sulfonylation. The catalytic performance was evaluated by the asymmetric Michael addition reaction of β-nitrostyrene with acetone. Under the optimized conditions, 81% conversion of β-nitrostyrene and 90% enantioselectivity were achieved. The generality of the catalyst was examined for diverse substrates with 84–96% enantioselectivity. Moreover, a possible catalytic mechanism of the Michael reaction by SDA-CCOF was speculated based on the characterization results and previous reports. This novel catalyst may provide inspirations for the development of CCOF and the loading of organo-catalysts.

Recent Advances in the Total Synthesis of Aspidosperma and Kopsia Alkaloids Using Tetracyclic Pyridocarbazoles as Versatile Building Blocks

AbstractOver the past decades, aspidosperma and kopsia alkaloids have attracted significant interest by the organic synthetic community owing to their intricate fused‐ring structures and broad biological activities. Consequently, numerous strategically distinct total syntheses have been accomplished, among which tetracyclic pyridocarbazoles have seen widespread adoption as versatile building blocks. In this review, we elaborate and discuss the synthesis of such tetracyclic pyridocarbazoles according to the different approaches for the establishment of the all‐carbon quaternary center at C5. This includes (1) classic synthetic reactions (cycloaddition, Michael addition, nucleophilic substitution, and Claisen rearrangement), (2) palladium‐catalyzed asymmetric decarboxylative allylation reactions, and (3) thiourea‐catalyzed asymmetric Michael addition reactions. Furthermore, we also describe the late‐stage key transformations in the realm of the total syntheses of aspidosperma and kopsia alkaloids.magnified image

Primary amine–thiourea grafted graphene–based heterogeneous chiral catalysts for highly enantioselective Michael additions

Heterogeneous asymmetric catalysis based on earth-abundant carbon materials put together the advantages for the ease of separation, simple regeneration, and high stability of solid catalysts as well as acts as low-cost, environmentally friendly metal-free alternative to the metal-based catalysts. Two new bifunctional carbocatalysts [(S,S) and (R,R) GO-PATU] were prepared by anchoring enantiomerically pure organosilanes bearing primary amine and thiourea groups to the graphene oxide (GO) skeleton covalently via silane coupling reaction. The surface modification of GO was analyzed by a combination of Fourier-transform infrared spectroscopy (FT-IR), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and transmission electron spectroscopy (TEM) techniques. The catalytic performances of graphene-based materials were investigated in the asymmetric Michael addition reactions of α,α-disubstituted-aldehydes to nitrostyrenes and N-substituted-maleimides. The effects of solvents and Brønsted basic or acidic additives were evaluated using both catalysts and good yields (up to 85%) and stereoselectivities (up to 95% ee) were obtained in dichloromethane at room temperature in the presence of l- and d-camphorsulfonic acid. Besides, recycling and reusing studies of the catalysts were successfully performed.

C5’‐Nitrated Cinchona Catalysts for Asymmetric Michael Addition Reaction

AbstractC5’‐Nitro‐dihydroquinine (Q1), prepared from dihydroquinine (HQ), exhibited high catalytic activity in an asymmetric Michael reaction. The nitro group at the C5’ position of Q1 was vertically fixed to the quinoline ring, as confirmed by X‐ray crystallography. Q1 exerted a high level of asymmetric induction, superior to that of the non‐nitrated HQ catalyst.

Chiral 1,3-aminosquaramides derived from cis-2-benzamidocyclohexanecarboxylic acid as organocatalysts for asymmetric Michael addition reactions

Herein, chiral 1,3-aminosquaramides derived from cis-2-benzamidocyclohexanecarboxylic acid, which is a chiral β-amino acid derivative, were synthesized and applied as bifunctional organocatalysts for asymmetric Michael addition reaction of 1,3-dicarbonyl compounds to β-nitrostyrenes. The catalyst structure and reaction conditions, such as solvent and temperature, were examined, and then, the optimized organocatalyst was successfully applied to the reaction of 1,3-diketones and 1,3-ketoesters with an enantioselectivity of up to 96%. Plausible transition state was proposed based on the results reported in previous reports and DFT calculations.

Enantioselective Organocatalytic Michael Addition Reactions Catalyzed by Proline/Prolinol/Supported Proline based Organocatalysts: An Overview

AbstractEver since the discovery of enantioselective organocatalytic Michael addition reactions, it has emerged as a significant path for synthesizing a variety of stereochemical products under mild conditions, also a prominent C−X (X=C, O, N, S) bond formation reaction in organic chemistry. Over time, substantial progress has been accomplished in diversity‐ and target‐ oriented asymmetric Michael addition reactions. This review provides a brief overview of the results, scope, and limitations of several influential strategies involving enantio‐selective Michael addition reactions promoted by mono‐functional proline/prolinol/supported‐proline‐based chiral organocatalysts. Furthermore, we also sincerely believe that the various synthetic strategies documented in this review will pave a pathway to improve the status of Michael addition reactions for synthesizing various drug molecules involving complex intermediates.