Asymmetric Michael Addition Research Articles

Copper/Ruthenium Relay Catalysis for Stereodivergent Access to δ‐Hydroxy α‐Amino Acids and Small Peptides

AbstractAn atom‐ and step‐economical and redox‐neutral cascade reaction enabled by asymmetric bimetallic relay catalysis by merging a ruthenium‐catalyzed asymmetric borrowing‐hydrogen reaction with copper‐catalyzed asymmetric Michael addition has been realized. A variety of highly functionalized 2‐amino‐5‐hydroxyvaleric acid esters or peptides bearing 1,4‐non‐adjacent stereogenic centers have been prepared in high yields with excellent enantio‐ and diastereoselectivity. Judicious selection and rational modification of the Ru catalysts with careful tuning of the reaction conditions played a pivotal role in stereoselectivity control as well as attenuating undesired α‐epimerization, thus enabling a full complement of all four stereoisomers that were otherwise inaccessible in previous work. Concise asymmetric stereodivergent synthesis of the key intermediates for biologically important chiral molecules further showcases the synthetic utility of this methodology.

Copper/Ruthenium Relay Catalysis for Stereodivergent Access to δ-Hydroxy α-Amino Acids and Small Peptides.

An atom- and step-economical and redox-neutral cascade reaction enabled by asymmetric bimetallic relay catalysis by merging a ruthenium-catalyzed asymmetric borrowing-hydrogen reaction with copper-catalyzed asymmetric Michael addition has been realized. A variety of highly functionalized 2-amino-5-hydroxyvaleric acid esters or peptides bearing 1,4-non-adjacent stereogenic centers have been prepared in high yields with excellent enantio- and diastereoselectivity. Judicious selection and rational modification of the Ru catalysts with careful tuning of the reaction conditions played a pivotal role in stereoselectivity control as well as attenuating undesired α-epimerization, thus enabling a full complement of all four stereoisomers that were otherwise inaccessible in previous work. Concise asymmetric stereodivergent synthesis of the key intermediates for biologically important chiral molecules further showcases the synthetic utility of this methodology.

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.

Catalytic asymmetric conjugate addition of coumarins to unsaturated ketones catalyzed by a chiral-at-metal Rh(III) complex.

The first catalytic asymmetric vinylogous Michael addition of coumarins to unsaturated ketones catalyzed by chiral rhodium catalysts has been established. This strategy allowed the synthesis of a variety of highly enantioenriched compounds containing coumarin skeletons in 41-99% yields and 84-99% ee. The developed reaction enriches the chemistry of catalytic asymmetric vinylogous Michael additions of 3-cyano-4-methylcoumarins. Furthermore, the protocol showed obvious advantages in reaction enantioselectivity. When the chiral rhodium catalyst was reduced to 0.06 mol%, a Gram-level reaction was still achieved to provide the desired products with 99% ee.

A de novo synthesis of the bisindole alkaloid geissolosimine: collective synthesis of geissoschizoline, akuammicine, (16S)-deshydroxymethylstemmadenine and Aspidospermatan alkaloids

Collective synthesis of geissolosimine, geissoschizoline, akuammicine, (16S)-deshydroxymethylstemmadenine and Aspidospermatan alkaloids was achieved based on a catalytic asymmetric double Michael addition.

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.

Asymmetric Michael addition catalysed by copper-amyloid complexes.

We developed self-assembled peptides containing a partial amyloid β protein sequence and a metal-coordination site. The amyloid fibril-copper complexes exhibited excellent reactivity and moderate enantioselectivity in Michael addition reactions with 2-azachalcone and dimethylmalonate. The catalytic amyloids were characterized using various measurements to confirm their amyloid-like nanofibre structures.

Organocatalytic Asymmetric Vinylogous Michael Addition of Electron-Deficient Aryl Alkane Nucleophiles to Enals.

We report herein a protocol for an organocatalyzed asymmetric vinylogous Michael addition of aryl alkane nucleophiles with enals under base- and additive-free conditions. A series of allylic building blocks were obtained in 60%-93% yield and 88-99% ee with 20 mol % diphenylprolinol silyl ether as catalyst. This protocol has advantages such as excellent chemoselectivity and regioselectivity, good tolerance of functionalities, and simple reaction conditions.

β‐Silylacrylate as a Multipurpose Reagent in Organic Synthesis

AbstractAcrylates are well known electrophilic alkenes having multitude of applications in organic synthesis. They are very good acceptors in Michael addition reactions and are good enophile/dienophile/dipolarophile partners in cycloaddition reactions. Replacing the β‐alkyl/aryl groups in acrylates by a silicon group would be interesting. In addition to the conventional reactions displayed by acrylates, β‐silylacrylates (β‐SAs) can show reactivity specifically related to the silicon group. Many conventional organic reactions such as hydrodimerization, organocatalytic asymmetric Michael additions, inter‐ and intra‐molecular Diels–Alder reactions, and asymmetric 1,3‐dipolar cycloadditions have been used to generate the complex chemical entities from β‐SAs. Some of the reaction outcomes were vastly influenced by the silicon substituent. This review describes the practical synthesis β‐SAs and their use as starting point in complex molecule generation including total synthesis of some natural products/bioactive molecules.

Synthesis of D-Fructose-Based Bifunctional Primary Amine-Thiourea Organocatalysts and Their Applications in Asymmetric Reactions

The preparation of a new class of six bifunctional thiourea organocatalysts having a D-fructose scaffold and a primary amino group was demonstrated. In the present study, the novel organocatalysts exhibited excellent enantio- and moderate diastereoselectivities in the asymmetric Michael addition of aliphatic ketones and 1,3-diketone to substituted nitroolefins at room temperature. In addition, the direct asymmetric aldol reaction between cyclic aliphatic ketone and aromatic aldehydes was also studied in the presence of the saccharide-thiourea organocatalysts giving excellent yield with moderate enantioselectivity.

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.

Lithium Binaphtholate-Catalyzed Asymmetric Michael Reaction of Acrylamides.

Chiral lithium binaphtholates prepared from the corresponding binaphthols and lithium tert-butoxide effectively catalyze the asymmetric Michael additions of ketones to poorly reactive acrylamides. The lithium binaphtholate catalyst mediates ketone deprotonation and enantioselective carbon-carbon bond formation to the acrylamide to deliver the Michael adduct in good yield and enantioselectivity. A small excess of lithium tert-butoxide relative to the binaphthol successfully enolizes the ketone in the initial stage of the reaction to promote the Michael reaction. Computational analysis of the transition state suggested that the 3- and 3'-phenyl groups of the binaphtholate catalyst regulate the orientation of the lithium enolate and the subsequent approach of the acrylamide, leading to superior enantioselectivity.

Crystallization-Enabled Stereoconvergent Michael Additions of β-Keto Esters to Nitroolefins.

Asymmetric Michael additions are powerful tools to meet the growing need for stereochemically complex products. While 1,3-dicarbonyls are common nucleophiles, the successful use of configurationally unstable β-keto esters in diastereoselective variants remains understudied. In this Letter, crystalline β-keto esters were leveraged in a two-phase, one-pot merger of an asymmetric Michael addition with a crystallization-induced diastereomer transformation. Tuning the crystallinity of β-keto ester adducts enabled stereoconvergence of the products, which were isolated by filtration.

Enantioselective synthesis of Benzofurans bearing adjacent quaternary and tertiary carbon stereocenters by Organocatalytic asymmetric Michael addition of 3-methylbenzofuran −2(3H)-ones to azadienes

An enantioselective Michael addition of 3-methylbenzofuran-2(3H)-ones to azadienes catalyzed by an L-tert- leucine derived squaramide catalyst was developed, by which a variety of benzofuranones bearing adjacent quaternary and tertiary carbon centers were obtained in high yields (up to 98%) with moderate to excellent diastereoselectivities (up to 97:3) and enantioselectivities (up to 97%).

Sustainable Organocatalyzed Enantioselective Catalytic Michael Additions in Betaine-Derived Deep Eutectic Solvents

AbstractThe organocatalyst cinchonidine-squaramide was immobilized within three different deep eutectic solvents (DESs): betaine:d-sorbitol:water, betaine: d-xylitol:water, and betaine:d-mannitol:water and evaluated in a well-known asymmetric Michael addition. These reactions provided excellent yields (up to 99%) and enantioselectivities (up to 98%) using only 1 mol% of organocatalyst. It was also possible to achieve 9 cycles in reactions with DES (betaine:d-sorbitol:water), proving the high recyclability of this system. In the reactions realized with only 0.5 mol% of organocatalyst, it was possible to achieve 5 cycles, and the products were obtained with high yields (up to 95%) and excellent enantioselectivities (up to 94%), using DES (betaine:d-sorbitol:water).

MeSesamol, a bio-based and versatile polar aprotic solvent for organic synthesis and depolymerization

Applications of polar aprotic solvents are inevitable in the chemical industry, but few nonhazardous alternatives are available. Herein, we propose methyl sesamol (MeSesamol) as a promising new bio-based alternative for polar aprotic solvents and demonstrate its versatile applications. MeSesamol was derived from natural resources using environmentally friendly and facile procedures, such as methylation using dimethyl carbonate. MeSesamol has a distinctive smell and demonstrates excellent properties as a green solvent candidate: high boiling and open-cup flash points, immiscibility with water but miscibility with common organic solvents, high stability and resistance to several acids and bases. MeSesamol was an effective solvent in nine C–C coupling reactions, including the Suzuki and Sonogashira reactions and asymmetric Michael addition. MeSesamol lies close to dichloromethane (DCM) in Hansen space and achieves a similar or higher yield and enantiomeric excess (up to 97% and 99%, respectively) in the asymmetric Michael reactions compared to DCM. MeSesamol proved to be an excellent recyclable solvent in the depolymerizations of bisphenol-A polycarbonate (BPA–PC) and polyethylene terephthalate (PET). MeSesamol was recycled in five reaction cycles with excellent efficiency (92%–100%) and outstanding cumulative monomer yields (92% bisphenol-A from BPA–PC and 92% terephthalic acid from PET). To properly compare the depolymerization reactions, we propose two green metrics, namely, the corrected energy-economy factor (εcorr) and the corrected environmental energy impact (ξcorr).

Heterogeneous fiber-based asymmetric quinine catalyst for highly enantioselective Michael addition and tandem cyclization to 4H-pyrans

As a new type of catalyst support, polyacrylonitrile fiber (PANF) has diverse advantages in physical and chemical properties. Quinine and its derivatives have been widely used as asymmetric organocatalysts recently. By combining the advantages of PANF and quinine, a novel fiber-based asymmetric catalyst (PANQNF) was successfully prepared through thiol-ene click reaction and characterized by FTIR, XRD, EA, SEM, TGA and mechanical strength analysis. The PANQNF exhibited excellent catalytic performance for asymmetric Michael addition of malononitrile to chalcone with ee up to > 99%. Further research revealed that the (S)-2-amino-4H-pyran derivatives were also successfully prepared using PANQNF as a catalyst in asymmetric tandem Michael addition-nucleophilic annulation of α-phenylchalcone and malononitrile, and the ee of the tandem reaction can also reach greater than 99%. In addition, as an immobilized catalyst, PANQNF showed relatively wide temperature tolerance and good recycling performance. Overall, the fiber catalyst has the advantages of easy preparation, high activity, high enantioselectivity, wide reaction temperature range, simple separation and good recyclability, which exhibits great potential for industrial application.

Desymmetrization of Prochiral N-Pyrazolyl Maleimides via Organocatalyzed Asymmetric Michael Addition with Pyrazolones: Construction of Tri-N-Heterocyclic Scaffolds Bearing Both Central and Axial Chirality.

The desymmetrization of N-pyrazolyl maleimides was realized through an asymmetric Michael addition by using pyrazolones under mild conditions, leading to the formation of a tri-N-heterocyclic pyrazole-succinimide-pyrazolone assembly in high yields with excellent enantioselectivities (up to 99% yield, up to 99% ee). The use of a quinine-derived thiourea catalyst was essential for achieving stereocontrol of the vicinal quaternary-tertiary stereocenters together with the C-N chiral axis. Salient features of this protocol included a broad substrate scope, atom economy, mild conditions and simple operation. Moreover, a gram-scale experiment and derivatization of the product further illustrated the practicability and potential application value of this methodology.