Enantioselective Cascade Research Articles

Enantioselective Cascade Catalysis for the Construction of Tetrahydroquinolines.

Secondary amines are widely used as robust catalysts for the enantioselective functionalization of aldehydes, yet they are rarely employed as Lewis bases or hydrogen-bonding catalysts for alkene activation. In this study, we present a decarboxylative [4 + 2] cycloaddition of vinyl benzoxazinanones with nitroolefins to construct tetrahydroquinolines through cascade catalysis. A single chiral morpholine catalyst sequentially functions as both a Lewis base and a hydrogen-bonding catalyst. These activation modes effectively drive the cascade process and control the stereochemistry.

Enantioselective Cascade Reactions of Aminocatalytic Dienamines and Trienamines Initiated by a Cycloaddition Reaction.

Cycloadditions are widely accepted as a group of reactions that rapidly generate molecular complexity. Being highly atom economic and often predictable, these reactions can generate up to four stereogenic centers and two C-C (or C-X) bonds in one reaction step. During the last two decades, asymmetric aminocatalysis has shown to be a successful strategy for controlling stereoselectivity and enabling reactivity of cycloaddition reactions. By increasing the conjugation of the carbonyl species employed, dienamines and trienamines can be catalytically formed. Not only can these facilitate the cycloaddition, often accompanied by high levels of stereocontrol, but they also leave a residual enamine or carbonyl (by hydrolysis) in the cycloadduct. This residual functionality can engage in further intramolecular reactions generating complex cyclic systems in a one-pot cascade manner. In this regard, asymmetric aminocatalysis can add another layer of complexity to the already complex nature of cycloadditions. In this review, we will present the general concept of such reactivity patterns of dienamines and trienamines, and hereafter showcase examples in the literature. We aspire that the chemical community can use these concepts to design new enantioselective aminocatalytic cascade reactions to access enantioenriched, complex compounds, and perhaps use these in complex molecule synthesis.

One‐Step Synthesis of Chiral 9,10‐Dihydrophenanthrenes via Ligand‐Enabled Enantioselective Cascade β,γ‐Diarylation of Acids

AbstractPd(II)‐catalyzed enantioselective C−H activation has emerged as a versatile platform for constructing point, axial, and planar chirality. Herein, we present an unexpected discovery of a Pd‐catalyzed enantioselective cascade β,γ‐methylene C(sp3)−H diarylation of free carboxylic acids using bidentate chiral mono‐protected amino thioether ligands (MPAThio), enabling one‐step synthesis of a complex chiral 9,10‐dihydrophenanthrene scaffolds with high enantioselectivity. In this process, two methylene C(sp3)−H bonds and three C(sp2)−H bonds were activated, leading to the formation of four C−C bonds and three chiral centers in one pot. A plausible catalytic pathway starts with enantioselective β,γ‐dehydrogenation to form chiral β,γ‐cyclohexene. Intriguingly, this olefin serves as a norbornene‐type reagent (presumably assisted by the carboxyl directing effect), relaying two successive Catellani arylation reactions and a C−H arylation reaction to furnish chiral 9,10‐dihydrophenanthrenes along with meta‐selective homocoupling products of iodoarene.

One-Step Synthesis of Chiral 9,10-Dihydrophenanthrenes via Ligand-Enabled Enantioselective Cascade β,γ-Diarylation of Acids.

Pd(II)-catalyzed enantioselective C-H activation has emerged as a versatile platform for constructing point, axial, and planar chirality. Herein, we present an unexpected discovery of a Pd-catalyzed enantioselective cascade β,γ-methylene C(sp3)-H diarylation of free carboxylic acids using bidentate chiral mono-protected amino thioether ligands (MPAThio), enabling one-step synthesis of a complex chiral 9,10-dihydrophenanthrene scaffolds with high enantioselectivity. In this process, two methylene C(sp3)-H bonds and three C(sp2)-H bonds were activated, leading to the formation of four C-C bonds and three chiral centers in one pot. A plausible catalytic pathway starts with enantioselective β,γ-dehydrogenation to form chiral β,γ-cyclohexene. Intriguingly, this olefin serves as a norbornene-type reagent (presumably assisted by the carboxyl directing effect), relaying two successive Catellani arylation reactions and a C-H arylation reaction to furnish chiral 9,10-dihydrophenanthrenes along with meta-selective homocoupling products of iodoarene.

Enantioselective Synthesis of Spiro[cyclopentane-1,3'-oxindole] Scaffolds with Five Consecutive Stereocenters.

A highly diastereo- and enantioselective cascade annulation reaction of Morita-Baylis-Hillman (MBH) maleimides of isatins with ortho-hydroxychalcones was achieved by a chiral N,N'-dioxide/Mg(II) complex Lewis acid catalyst. This strategy provides a concise and efficient route to densely functionalized spiro[cyclopentane-1,3'-oxindole] compounds with five consecutive stereocenters. The reaction itself features mild conditions, good functional group compatibility, and broad substrate scope (62 examples, up to 99% yield, up to >20:1 dr, 97% ee). In addition, an obvious ligand acceleration effect and chiral amplification effect were observed. DFT calculations were performed to elucidate the stereoselectivity observed. The gram-scale synthesis and the inhibitory effect of two products on the viability of A549 cells demonstrate the potential utility of the current method.

Photocatalytic Enantioselective Radical Cascade Multicomponent Minisci Reaction of β-Carbolines Using Diazo Compounds as Radical Precursors.

Here, a photocatalytic asymmetric multicomponent cascade Minisci reaction of β-carbolines with enamides and diazo compounds is reported, enabling an effective enantioselective radical C─H functionalization of β-carbolines with high yields and enantioselectivity (up to 83% yield and 95% ee). This enantioselective multicomponent Minisci protocol exhibits step economy, high chemo-/enantio-selective control, and good functional group tolerance, allowing access to a variety of valuable chiral β-carbolines. Notably, diazo compounds are suitable radical precursors in enantioselective cascade radical reactions. Moreover, the efficiency and practicality of this approach are demonstrated by the asymmetric synthesis of bioactive compounds and natural products.

Bridging the incompatibility gap in dual asymmetric catalysis over a thermoresponsive hydrogel-supported catalyst

The integration of dual asymmetric catalysis is highly beneficial for the synthesis of organic molecules with multiple stereocenters. However, two major issues that need to be addressed are the intrinsic deactivation of dual-species and the extrinsic conflict of reaction conditions. To overcome these concerns, we have utilized the compartmental and thermoresponsive properties of poly(N-isopropylacrylamide) (PNIPAM) to develop a cross-linked PNIPAM-hydrogel-supported bifunctional catalyst. This catalyst is designed with Rh(diene) species situated on the outer surface and Ru(diamine) species positioned within the interior of the hydrogel. The compartmental function of PNIPAM in the middle overcomes intrinsic mutual deactivations between the dual-species. The thermoresponsive nature of PNIPAM allows for precise control of catalytic pathways in resolving external conflicts by controlling the reaction switching between an Rh-catalyzed enantioselective 1,4-addition at 50°C and a Ru-catalyzed asymmetric transfer hydrogenation (ATH) at 25°C. As we envisioned, this sequential 1,4-addition/reduction dual enantioselective cascade reaction achieves a transformation from incompatibility to compatibility, resulting in direct access to γ-substituted cyclic alcohols with dual stereocenters in high yields and enantio/diastereoselectivities. Mechanistic investigation reveals a reversible temperature transition between 50°C and 25°C, ensuring a cascade process comprising a 1,4-addition followed by the ATH process.

Enantioselective synthesis of 2-amino-4H-chromene derivatives with antifungal activities on phytopathogenic fungi

An Ir-catalyzed enantioselective cascade allylation/cyclization reaction of 2-(1-hydroxyallyl)phenols was developed, affording antifungal 2-amino-4H-chromene derivatives with good to excellent enantioselectivities.

Photoinduced Palladium-Catalyzed Enantioselective Cascade Dearomatization

Photoinduced Palladium-Catalyzed Enantioselective Cascade Dearomatization

Iridium-Catalyzed Enantioselective Cascade Allylic Etherification/[2+2] Photocycloaddition

Iridium-Catalyzed Enantioselective Cascade Allylic Etherification/[2+2] Photocycloaddition

Highly active and recyclable immobilized multiple enzymes for one-pot enantioselective cascade reactions: Synthesis of (R)- and (S)-α-amino acids from racemic α-hydroxy acids

Cascade biotransformation of racemic alcohols to enantiopure amines is highly wanted in pharmaceutical manufacturing but requires green and efficient solution. Here we developed the first immobilized enzyme-based approach for this transformation, being cleaner and more productive than whole-cells biocatalysis, and more economic and higher-yielding than using isolated enzymes. As demonstration, the conversion of racemic mandelic acids to high-value (R)- or (S)-phenylglycines was achieved by immobilized enantioselective alcohol oxidase, racemase, catalase, and (S)- or (R)-transaminase. Co-immobilization of the four enzymes on Ni-NTA functionalised carriers gave high enzyme loadings (192–195 mg enzyme/g carrier), loading efficiencies (97–98%), and free enzyme activities (107–113%). Immobilized enzymes transformed racemic mandelic acids to the corresponding four (S)-phenylglycines in 91–99% ee and 82–95% yields or five (R)-phenylglycines in 93–99% ee and 83–94% yields. These catalysts showed good recyclability, retaining 86–98% productivities in the fifth reaction cycles.

Synergistic Pd/Cu-catalyzed regio- and stereoselective cascade Heck cyclization/borylation/cross-coupling

A cooperative Pd/Cu-catalyzed three-component cross-coupling reaction of alkynes, B2Pin2 and alkene-tethered aryl halides is reported. This reaction proceeds under mild conditions and shows broad substrate scope, providing a variety of heterocycles containing tetrasubstituted alkenylboronate moieties in synthetically useful yields with excellent chemoselectivity and regioselectivity. This transformation features the catalytic generation of β-borylalkenylcopper intermediates and their use in Pd-catalyzed Heck cyclization/cross-couplings. An enantioselective cascade cyclization/cross-coupling process has also been developed for the synthesis of enantiomerically enriched oxindole bearing a tetrasubstituted alkenylboronate moiety.

Zinc-Catalyzed Asymmetric Cascade Michael/Acyl Transfer Reaction between α-Hydroxy Aryl Ketones and Enynones.

We described herein a neoteric enantioselective cascade Michael/acyl transfer reaction of enynones and α-hydroxy aryl ketones catalyzed by dinuclear zinc cooperative catalysis. A series of structurally diverse chiral 1,5-dicarbonyl compounds were synthesized in good yields with excellent stereoselectivities. This strategy features broad substrate scope, high atom economy, as well as enynones as efficient electrophilic acyl transfer reagents in asymmetric cascade reactions for the first time.

Catalytic Site-, Diastereo-, and Enantioselective Cascade Iodocyclization of 2-Geranylarenols.

A chiral amidophosphate-N-iodosuccinimide cooperative catalysis has been developed for the site-, diastereo-, and enantioselective iodocyclization of 2-geranylarenols with molecular iodine to give the corresponding iodo-containing polycyclic compounds with good levels of selectivity. This is the first example of a catalytic enantioselective iodocarbocyclization. A reactive chiral iodonium species is generated from molecular iodine via the dual halogen-bonding interactions with a chiral Lewis base and Lewis acid. The sterically demanding 3,3'-substituents of the chiral BINOL-derived amidophosphate are critical to induce the site-selective iodination at the less-hindered terminal alkenyl moiety of 2-geranylarenols.

Asymmetric Cascade Carbonylation/Annulation of Benzyl Bromides, CO, and Vinyl Benzoxazinanones Enabled by Pd/Chiral Lewis-Base Relay Catalysis.

A highly enantioselective cascade carbonylation/annulation of benzyl bromides, CO, and vinyl benzoxazinanones under mild conditions has been established by Pd/chiral Lewis base relay catalysis, providing an efficient method to assemble chiral quinolinones from readily available starting materials in good yields with excellent diastereo- and enantioselectivities. The palladium catalyst plays two roles in this reaction, enabling both the carbonylation process and the generation of the zwitterionic π-allyl palladium intermediate.

Enantioselective Cascade Michael/Hemiaminal Formation of α,β-Unsaturated Iminoindoles with Aldehydes Using a Chiral Aminomethylpyrrolidine Catalyst Bearing a SO2C6F5 Group as a Strongly Electron Withdrawing Arylsulfonyl Group

Enantioselective Cascade Michael/Hemiaminal Formation of α,β-Unsaturated Iminoindoles with Aldehydes Using a Chiral Aminomethylpyrrolidine Catalyst Bearing a SO₂C₆F₅ Group as a Strongly Electron Withdrawing Arylsulfonyl Group

Organocatalytic Enantioselective Cascade Process for Constructing Azabicyclo[3.3.1]nonane Scaffolds

Organocatalytic Enantioselective Cascade Process for Constructing Azabicyclo[3.3.1]nonane Scaffolds

Enantioselective Synthesis of Spiroketals and Spiroaminals via Gold and Iridium Sequential Catalysis.

The enantioselective cascade reaction between racemic 2-(1-hydroxyallyl)phenols and alkynols/alkynamides was realized by using a gold and iridium sequential catalytic system. In this procedure, the in situ generated exocyclic vinyl ethers or enamides undergo the asymmetric allylation/spiroketalization with π-ally-Ir amphiphilic species, which provides an efficient and straightforward access to spiroketals and spiroaminals with excellent enantioselectivities. Moreover, racemic 2-(1-hydroxyallyl)anilines were also suitable in this reaction along with a kinetic resolution process, affording enantioenriched spiroaminals and 2-(1-hydroxyallyl)anilines in good yields. The synthetic utility of this method has been demonstrated by efficient enantioselective synthesis of the analogue of Paecilospirone.

Enantioselective Synthesis of Spiroketals and Spiroaminals via Gold and Iridium Sequential Catalysis

AbstractThe enantioselective cascade reaction between racemic 2‐(1‐hydroxyallyl)phenols and alkynols/alkynamides was realized by using a gold and iridium sequential catalytic system. In this procedure, the in situ generated exocyclic vinyl ethers or enamides undergo the asymmetric allylation/spiroketalization with π‐ally‐Ir amphiphilic species, which provides an efficient and straightforward access to spiroketals and spiroaminals with excellent enantioselectivities. Moreover, racemic 2‐(1‐hydroxyallyl)anilines were also suitable in this reaction along with a kinetic resolution process, affording enantioenriched spiroaminals and 2‐(1‐hydroxyallyl)anilines in good yields. The synthetic utility of this method has been demonstrated by efficient enantioselective synthesis of the analogue of Paecilospirone.

Enantioselective Cascade Annulation of α‐Amino‐ynones and Enals Enabled by Gold and Oxidative NHC Relay Catalysis

AbstractWe report herein an unprecedented gold and oxidative NHC relay catalysis that enables highly enantioselective cascade annulation between readily available α‐amino‐ynones with enals. This method utilizes the in situ‐generated pyrrolin‐4‐ones as a novel and versatile synthon, which engage with α,β‐unsaturated acylazolium intermediates generated from enals by oxidative NHC catalysis to produce pyrrole‐fused lactones in high yield and excellent enantioselectivity. Synthetic utility of the lactone products is also demonstrated by facile conversion to densely functionalized pyrroles and pyrrolin‐4‐ones in high yields with excellent stereopurity.