Asymmetric Michael Reaction Research Articles

New Entries in Organocatalysts from an Alkaloid Library; Development of Aminal Catalysis for a Michael Reaction Based on Calycanthine.

Natural products have historically been actively evaluated for their biological activity in the development of pharmaceuticals, while their evaluation as asymmetric catalysts has rarely been explored. In this study, we evaluated the catalytic activity of the natural product library. Three naturally occurring alkaloids, gardnerine, spiradine A, and calycanthine, were found to catalyze an asymmetric Michael reaction using oxindole and nitrostyrene. We further studied (+)-calycanthine, which is characterized by its aminal structure. Concise synthetic and extraction protocols were developed to provide both enantiomers of calycanthine. Further derivatization of this alkaloid led to improved enantioselectivity in a model reaction. Computational studies suggested that the aminal moiety of the catalyst activated nucleophiles and electrophiles through multiple hydrogen bonding interactions, including nonclassical hydrogen bonds between carboxylic acid and the aminal C-H.

Catalytic Performance of Chiral Tetraaza-Bridged Calix[4]arene[2]triazine Derivatives for Enantioselective Michael Reactions.

Novel chiral tetraaza-bridged calix[4]arene[2]triazine-based organocatalysts were synthesized and used for catalytic asymmetric Michael reaction of acetylacetone to various aromatic nitrostyrenes. Chiral subunits (R)- and (S)-1,2,3,4-tetrahydro-1-naphthylamine were attached to the tetraaza-bridged calix[4]arene[2]triazine platform in both enantiomeric forms. The R configuration of the major enantiomer of the Michael product was obtained when 3a was used as catalyst, and the S configuration was obtained when 3b was used as catalyst. This indicated that the configuration of the Michael product was controlled by the chiral calixarene moiety. The Michael adducts were obtained in excellent yields (91%) and enantioselectivities (98%).

Construction of central and axial chirality via Pd(II)/Bim-catalyzed asymmetric dearomative Michael reaction of polycyclic tropones.

A highly enantioselective Pd/Bim-catalyzed dearomative Michael reaction applying polycyclic tropones as non-benzenoid aromatic Michael acceptors and arylboronic acids as aryl pronucleophiles has been developed. The bridged biaryls bearing central and axial chirality, including pentacyclic cyclohepta[b]indoles and 6,7-dihydrodibenzo[a,c][7]annulen-5-ones, are generally generated in good to high yields and excellent enantioselectivities and can be readily transformed into useful derivatives.

Unified chemical synthesis of cephalotaxus diterpenoids: A biosynthetic reversed strategy

In this work, we present the details of the first unified chemical synthesis of cephalotaxus diterpenoids with three distinct carbon skeleton structures. Drawing on our previous synthesis of cephalotane-type C18 dinorditerpenoid and inspired by the proposed biosynthetic synthesis pathway, we formulated a biosynthetic reversed chemical synthetic strategy. This strategy facilitated the conversion of C18 dinorditerpenoid into troponoid-type C19 norditerpenoid and intact cephalotane-type C20 diterpenoid through pivotal one-carbon introduction and ring expansion reactions. In the synthesis of troponoid-type C19 norditerpenoid, we utilized TMSCHN2 as one-carbon unit and meticulously examined the selective regulatory effect of halogen substituents in ring expansion and rearrangement reactions. This endeavor culminated in the successful synthesis of natural product molecules within this subclass, notably including cephinoid H and fortalpinoid C, marking the first chemical total synthesis in this line of research. In the investigation of intact cephalotane-type C20 diterpenoid synthesis, while adhering to the overall synthesis strategy, we initially pursued a ring expansion before carbon introduction approach, which proved unsuccessful. Subsequently, we explored a synthetic route of introducing carbon first and then expanding the ring, leading to a successful outcome and resulting in the first chemical total synthesis of the representative molecule cephanolide E within this subclass. Various challenges such as establishing crucial quaternary carbon stereocenters, selecting appropriate one-carbon units, and controlling ring expansion reactions were effectively addressed throughout this process. Moreover, enantioselective synthesis of natural products within this family was achieved through the development of asymmetric Michael reactions.

A Squaramide-Based Organocatalyst as a Novel Versatile Chiral Solvating Agent for Carboxylic Acids.

A squaramide-based organocatalyst for asymmetric Michael reactions has been tested as a chiral solvating agent (CSA) for 26 carboxylic acids and camphorsulfonic acid, encompassing amino acid derivatives, mandelic acid, as well as some of its analogs, propionic acids like profens (ketoprofen and ibuprofen), butanoic acids and others. In many cases remarkably high enantiodifferentiations at 1H, 13C and 19F nuclei were observed. The interaction likely involves a proton transfer from the acidic substrates to the tertiary amine sites of the organocatalyst, thus allowing for pre-solubilization of the organocatalyst (when a chloroform solution of the substrate is employed) or the simultaneous solubilization of both the catalyst and the substrate. DOSY experiments were employed to evaluate whether the catalyst-substrate ionic adduct was a tight one or not. ROESY experiments were employed to investigate the role of the squaramide unit in the adduct formation. A mechanism of interaction was proposed in accordance with the literature data.

Proline-derived carboxylic acid as a bifunctional organocatalyst for highly efficient asymmetric Michael addition of aldehydes to nitroalkenes

A novel bifunctional proline amide–carboxylic acid catalyst was used for the highly stereoselective Michael reaction of various aldehydes with different nitroalkenes. This catalyst was easily prepared using commonly available anhydrides and proline linked with a diamine spacer. The asymmetric catalytic Michael reactions afforded high yields (up to 98 %), diastereoselectivities (syn/anti ratio: up to 86:14), and enantioselectivity (up to 99 % ee) when 5 mol% of the catalyst is used with N-methylmorpholine as a base in a dichloromethane solvent at room temperature.

Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues.

Herein, we present a unified chemical synthesis of three subgroups of cephalotaxus diterpenoids. Key to the success lies in adopting a synthetic strategy that is inspired by biosynthesis but is opposite in nature. By employing selective one-carbon introduction and ring expansion operations, we have successfully converted cephalotane-type C18 dinorditerpenoids (using cephanolide B as a starting material) into troponoid-type C19 norditerpenoids and intact cephalotane-type C20 diterpenoids. This synthetic approach has enabled us to synthesize cephinoid H, 13-oxo-cephinoid H, 7-oxo-cephinoid H, fortalpinoid C, 7-epi-fortalpinoid C, cephanolide E, and 13-epi-cephanolide E. Furthermore, through the development of an intermolecular asymmetric Michael reaction between β-oxo esters and β-substituted enones, we have achieved the enantioselective synthesis of advanced intermediates within our synthetic sequence, thus formally realizing the asymmetric total synthesis of the cephalotaxus diterpenoids family.

Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues

AbstractHerein, we present a unified chemical synthesis of three subgroups of cephalotaxus diterpenoids. Key to the success lies in adopting a synthetic strategy that is inspired by biosynthesis but is opposite in nature. By employing selective one‐carbon introduction and ring expansion operations, we have successfully converted cephalotane‐type C18 dinorditerpenoids (using cephanolide B as a starting material) into troponoid‐type C19 norditerpenoids and intact cephalotane‐type C20 diterpenoids. This synthetic approach has enabled us to synthesize cephinoid H, 13‐oxo‐cephinoid H, 7‐oxo‐cephinoid H, fortalpinoid C, 7‐epi‐fortalpinoid C, cephanolide E, and 13‐epi‐cephanolide E. Furthermore, through the development of an intermolecular asymmetric Michael reaction between β‐oxo esters and β‐substituted enones, we have achieved the enantioselective synthesis of advanced intermediates within our synthetic sequence, thus formally realizing the asymmetric total synthesis of the cephalotaxus diterpenoids family.

Catalytic asymmetric Michael and Nef-type sequential reaction of nitroolefin with azlactone to construct oxazole-fused succinimide.

A series of oxazole-fused succinimides bearing vicinal quaternary carbon centers were synthesized. This process takes place between nitroolefins and azlactones in the presence of a bifunctional chiral guanidine-sulfonamide organocatalyst, followed by a Nef-type transformation under the treatment of DMAP/Ac2O. Several control experiments were conducted to propose the mechanism.

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).

Experimental and Computational Investigation of Facial Selectivity Switching in Nickel-Diamine-Acetate-Catalyzed Michael Reactions.

Chiral Ni complexes have revolutionized both asymmetric acid-base and redox catalysis. However, the coordination isomerism of Ni complexes and their open-shell property still often hinder the elucidation of the origin of their observed stereoselectivity. Here, we report our experimental and computational investigations to clarify the mechanism of β-nitrostyrene facial selectivity switching in Ni(II)-diamine-(OAc)2-catalyzed asymmetric Michael reactions. In the reaction with a dimethyl malonate, the Evans transition state (TS), in which the enolate binds in the same plane with the diamine ligand, is identified as the lowest-energy TS to promote C-C bond formation from the Si face in β-nitrostyrene. In contrast, a detailed survey of the multiple potential pathways in the reaction with α-keto esters points to a clear preference for our proposed C-C bond-forming TS, in which the enolate coordinates to the Ni(II) center in apical-equatorial positions relative to the diamine ligand, thereby promoting Re face addition in β-nitrostyrene. The N-H group plays a key orientational role in minimizing steric repulsion.

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.

Synthesis of cinchona urea polymers using Yamamoto coupling and their application to asymmetric reaction.

Cinchona urea compounds having 3,5-diiodophenyl moieties were subjected to Yamamoto coupling polymerization to afford the chiral urea polymers. These polymers showed high activities as heterogeneous catalysts in asymmetric Michael reactions comparable with those of the corresponding monomeric catalyst in solution systems. Furthermore, the polymeric catalysts are easily recovered from their reaction mixtures due to their insolubility and can be reused several times without loss of catalytic activity.

Enantioselective Distal Functionalization of 3-Cyano-4-methylcoumarins through Direct Vinylogous Conjugate Addition to Maleimides.

An unprecedented organocatalyzed asymmetric vinylogous Michael reaction between 3-cyano-4-methylcoumarins and maleimides with an excellent enantiomeric ratio (up to 99.5:0.5) and yield (up to 95%) is reported. This remarkable selectivity is attributed to the hydrogen bonding ability of l-tert-leucine-derived amine thiourea catalyst. The versatility, practical applicability, and scalability are demonstrated by the generation of γ-functionalized coumarin derivatives.

Immobilization of Functionalized epi-Cinchonine Organocatalysts on Controlled Porous Glass Beads: Applications in Batch and ­Continuous Flow

AbstractA well-known squaramide-cinchonine organocatalyst was immobilized in a controlled way onto three types of commercial porous glass beads EziG™ (EziG OPAL, EziG Amber, and EziG Coral) and applied in asymmetric Michael reactions. The performance of the immobilized catalysts was evaluated under batch and continuous-flow conditions, showing promising results in both approaches. In batch reactions, 0.8 and 1.6 mol% of the immobilized cinchonine-squaramide provided the products with excellent yields (up to 99%) and enantioselectivities (up to 99% ee). These excellent results were also verified in the case of continuous-flow reactions, where also 0.8 and 1.6 mol% of the catalyst immobilized onto the glass beads afforded the product with extraordinary yields (up to 99%) and very high enantioselectivities (up to 97% ee). The immobilized catalysts could be recycled (up to seven cycles) using both approaches.

Asymmetric Michael Reaction of Malononitrile and α,β-Unsaturated Aldehydes Catalyzed by Diarylprolinol Silyl Ether

AbstractAn asymmetric Michael reaction of malononitrile and α,β-unsaturated aldehydes catalyzed by a diarylprolinol silyl ether was developed. Michael products were obtained in good yields and with excellent enantioselectivities without the formation of overreaction products. As a malononitrile moiety can be transformed into an alkoxy or amino carbonyl moiety by oxidative transformation, α-chiral esters or amides with all-carbon quaternary centers can be synthesized with excellent enantioselectivities.

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 Cyclopropenimine-catalyzed Asymmetric Michael Addition of Bulky Glycine Imine to α,β-Unsaturated Isoxazoles.

A highly efficient asymmetric Michael addition of bulky glycine imine to α,β-unsaturated isoxazoles has been achieved by using 5 mol% of chiral cyclopropenimine as a chiral organo-superbase catalyst under mild conditions. Michael adducts were obtained in excellent yields (up to 97%) and stereoselectivities (up to >99 : 1 dr and 98% ee). A significant solvent effect was found in these chiral organosuperbase catalyzed asymmetric Michael reactions. Gram-scale preparation of Michael adducts and their transformations are realized to provide corresponding products without loss of stereoselectivities. The configurations of Michael adduct was determined by single-crystal X-ray diffraction analysis.

Asymmetric organocatalytic Michael addition of cyclopentane-1,2-dione to alkylidene oxindole.

An asymmetric Michael reaction between cyclopentane-1,2-dione and alkylidene oxindole was studied in the presence of a multifunctional squaramide catalyst. Michael adducts were obtained in high enantioselectivities and in moderate diastereoselectivities.

Catalytic Asymmetric Michael Reaction of Methyl Alkynyl Ketone Catalyzed by Diphenylprolinol Silyl Ether.

The asymmetric Michael reaction of methyl alkynyl ketone and α,β-unsaturated aldehyde catalyzed by diphenylprolinol silyl ether was developed. Although methyl alkynyl ketone is a good Michael acceptor, it also acts as a Michael donor to afford the synthetically important δ-oxo aldehydes with excellent enantioselectivity. The products possessing several functional groups, such as alkyne, ketone, and aldehyde moieties, are useful chiral building blocks for further synthesis. Using this reaction as a key step, a side chain of atorvastatin (Lipitor), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, was synthesized in a two-pot sequence with excellent diastereo- and enantioselectivities.