Catalytic Asymmetric Reaction Research Articles

Stereoselective Access to Spirooxindoles and Bisoxindoles Through Organocatalyzed Asymmetric Divergent Transformations of Isatin-derived MBH Carbonates.

An interesting β-isoquinidine catalyzed divergent reaction was developed to produce either spirocyclopentene oxindoles, spirocyclopentadiene oxindoles or bisoxindoles in a high enantioselective fashion. The utility of this protocol was demonstrated by the versatile transformations of the products. This work not only represents the first highly stereoselective intermolecular catalytic asymmetric allylic alkylation reaction between two isatin-derived MBH carbonate molecules but also constitutes a rare example of isatin-derived MBH carbonate-based enantioselective and α-regioselective [3+2] cycloaddition reactions.

A Unified Catalytic Asymmetric (4+1) and (5+1) Annulation Strategy to Access Chiral Spirooxindole-Fused Oxacycles.

A unified catalytic asymmetric (N+1) (N=4, 5) annulation reaction of oxindoles with bifunctional peroxides has been achieved in the presence of a chiral phase-transfer catalyst (PTC). This general strategy utilizes peroxides as unique bielectrophilic four- or five-atom synthons to participate in the C-C and the subsequent umpolung C-O bond-forming reactions with one-carbon unit nucleophiles, thus providing a distinct method to access the valuable chiral spirooxindole-tetrahydrofurans and -tetrahydropyrans with good yields and high enantioselectivities under mild conditions. DFT calculations were performed to rationalize the origin of high enantioselectivity. The gram-scale syntheses and synthetic utility of the resultant products were also demonstrated.

Silver‐Catalyzed Asymmetric Dearomatization of Electron‐Deficient Heteroarenes via Interrupted Barton–Zard Reaction

AbstractHerein we report a catalytic asymmetric dearomatization reaction of electron‐deficient heteroarenes with α‐substituted isocyanoacetates through an interrupted Barton–Zard reaction. A range of optically active pyrrolo[3,4‐b]indole derivatives was obtained in good yields (up to 97 %) with high stereoselectivities (up to >20:1 dr and 97 % ee), using a catalytic system consisting of a cinchona‐derived amino‐phosphine and silver oxide. This reaction features wide substrate scope and mild conditions, and provides a new strategy for developing asymmetric dearomatization reactions.

Silver‐Catalyzed Asymmetric Dearomatization of Electron‐Deficient Heteroarenes via Interrupted Barton–Zard Reaction

Herein we report a catalytic asymmetric dearomatization reaction of electron-deficient heteroarenes with α-substituted isocyanoacetates through an interrupted Barton-Zard reaction. A range of optically active pyrrolo[3,4-b]indole derivatives was obtained in good yields (up to 97 %) with high stereoselectivities (up to >20:1 dr and 97 % ee), using a catalytic system consisting of a cinchona-derived amino-phosphine and silver oxide. This reaction features wide substrate scope and mild conditions, and provides a new strategy for developing asymmetric dearomatization reactions.

Frontispiece: Extended Enolates: Versatile Intermediates for Asymmetric C‐H Functionalization via Noncovalent Catalysis

Extended enolates, particularly dienolates, may be generated upon deprotonation of α,β(and most usually β,γ)-unsaturated carbonyl compounds by treatment with base. While known for more than half a century, their use in catalytic asymmetric bond-forming reactions has remained underdeveloped until recently. The Minireview by M. Oiarbide and C. Palomo on page 10226 highlights the reactivity and selectivity problems encountered during their catalytic generation and subsequent reaction control, and how both metallic and organic catalysts complement to make direct and enantioselective C−H functionalization of various categories of enolizable compounds via dienolate intermediates feasible.

Catalytic stereoselective Mannich-type reactions for construction of fluorinated compounds.

For its unique role in developing and designing new bioactive materials and healthcare products, fluoro-organic compounds have attracted remarkable interest. Along with ever-increasing demand for a wider availability of fluorine-containing structural units, a large diversity of methods has been introduced to incorporate fluorine atoms specially in a stereoselective fashion. Among them, catalytic Mannich reaction can proceed with a broad variety of reactants and open clear paths for the synthesis of versatile amine synthons in the synthesis of natural product and pharmaceutical molecules. This review provides an overview of the employment of catalytic asymmetric Mannich reactions in the synthesis of fluorine-containing amine compounds and highlights the conceivable distinct mechanisms.

Asymmetric Alkoxy‐ and Hydroxy‐Carbonylations of Functionalized Alkenes Assisted by β‐Carbonyl Groups

AbstractAs a fundamental type of carbonylation reaction, the alkoxy‐ and hydroxy‐carbonylation of unsaturated hydrocarbons constitutes one of the most important industrial applications of homogeneous catalysis. However, owing to the difficulties in controlling multi‐selectivities for asymmetric hydrocarbonylation of alkenes, this reaction is typically limited to vinylarenes and analogues. In this work, a highly efficient asymmetric alkoxy‐ and hydroxy‐carbonylation of β‐carbonyl functionalized alkenes was developed, providing practical and easy access to various densely functionalized chiral molecules with high optical purity from broadly available alkenes, CO, and nucleophiles (>90 examples, 84–99 % ee). This protocol features mild reaction conditions and a broad substrate scope, and the products can be readily transformed into a diverse array of chiral heterocycles. Control experiments revealed the key role of the β‐carbonyl group in determining the enantioselectivity and promoting the activity, which facilitates chiral induction by coordination to the transition metal as rationalized by DFT calculations. The strategy of utilizing an innate functional group as the directing group on the alkene substrate might find further applications in catalytic asymmetric hydrocarbonylation reactions.

Asymmetric Alkoxy- and Hydroxy-Carbonylations of Functionalized Alkenes Assisted by β-Carbonyl Groups.

As a fundamental type of carbonylation reaction, the alkoxy- and hydroxy-carbonylation of unsaturated hydrocarbons constitutes one of the most important industrial applications of homogeneous catalysis. However, owing to the difficulties in controlling multi-selectivities for asymmetric hydrocarbonylation of alkenes, this reaction is typically limited to vinylarenes and analogues. In this work, a highly efficient asymmetric alkoxy- and hydroxy-carbonylation of β-carbonyl functionalized alkenes was developed, providing practical and easy access to various densely functionalized chiral molecules with high optical purity from broadly available alkenes, CO, and nucleophiles (>90 examples, 84-99 % ee). This protocol features mild reaction conditions and a broad substrate scope, and the products can be readily transformed into a diverse array of chiral heterocycles. Control experiments revealed the key role of the β-carbonyl group in determining the enantioselectivity and promoting the activity, which facilitates chiral induction by coordination to the transition metal as rationalized by DFT calculations. The strategy of utilizing an innate functional group as the directing group on the alkene substrate might find further applications in catalytic asymmetric hydrocarbonylation reactions.

Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction

Synthesis of Dihydroisoquinoline and Dihydropyridine Derivatives via Asymmetric Dearomative Three-Component Reaction

Mechanistic insights into entropy-driven 1,2-type Friedel-Crafts reaction with conformationally flexible guanidine-bisthiourea bifunctional organocatalysts

In some asymmetric catalytic reactions, the enantio-discrimination step is dominated by the change in entropy, in contrast to the usual enthalpy-driven process, but the origin of this entropy-dependent behavior is unclear. Here, we first conducted Eyring analysis to confirm the entropy-driven character of our previously reported 1,2-type Friedel-Crafts (FC) reaction of sesamol with imine, catalyzed by conformationally flexible guanidine-bisthiourea bifunctional organocatalyst, and then we carried out computational studies to compare the transition states leading to the two enantiomers. We found no significant temperature dependence of ΔH or -TΔS for TS-R, the transition state leading to the R enantiomer. In TS-S, on the other hand, -TΔS was increased at higher temperature, although ΔH was unchanged. Furthermore, the benzyl groups of the catalyst increase the contribution of the enthalpy term to the enantioselectivity, albeit with retention of the entropy-driven behavior arising from the conformationally flexible catalyst structure.

Front Cover Picture: Pyrazoleamides in Catalytic Asymmetric Reactions: Recent Advances (Adv. Synth. Catal. 14/2021)

The front cover picture, designed by Sara and Luca Meninno, illustrates poorly reactive carboxylic acids and their ester and amide derivatives transformed into pyrazoleamides super-molecules with superpowers. Where carboxylic acids, esters and amides fail pyrazoleamides succeed, allowing the transition from a world with limited possibilities to a rich and futuristic world, meeting the increasing needs of the society. The super-powers consist in: i) easy one-step synthesis from readily available carboxylic acids; ii) easy metal and H-bonding coordination with catalysts, unlocking otherwise inaccessible reactions on carboxylic acid derivatives; iii) exceptional leaving group ability which enables several post-functionalizations with different nucleophiles. Pyrazoleamides, unlike carboxylic acid derivatives have proven increasingly useful starting materials in a variety of diastereo- and enantioselective metal-, organocatalytic and photoinduced transformations, giving access to valuable intermediates, heterocycles and pharmaceuticals. Details can be found in the Review by Meninno, Franco, Benaglia, and Lattanzi. (S. Meninno, F. Franco, M. Benaglia, A. Lattanzi, Adv. Synth. Catal. 2021, 363, 3380–3410; DOI: 10.1002/adsc.202100006)

Asymmetric Catalytic Ketimine Mannich Reactions and Related Transformations.

The catalytic enantioselective ketimine Mannich and its related reactions provide direct access to chiral building blocks bearing an α-tertiary amine stereogenic center, a ubiquitous structural motif in nature. Although ketimines are often viewed as challenging electrophiles, various approaches/strategies to circumvent or overcome the adverse properties of ketimines have been developed for these transformations. This review showcases the selected examples that highlight the benefits and utilities of various ketimines and remaining challenges associated with them in the context of Mannich, allylation, and aza-Morita-Baylis-Hillman reactions as well as their variants.

Catalytic asymmetric Nakamura reaction by gold(I)/chiral N,N\u02b9-dioxide-indium(III) or nickel(II) synergistic catalysis

Intermolecular addition of enols and enolates to unactivated alkynes was proved to be a simple and powerful method for carbon-carbon bond formation. Up to date, a catalytic asymmetric version of alkyne with 1,3-dicarbonyl compound has not been realized. Herein, we achieve the catalytic asymmetric intermolecular addition of 1,3-dicarbonyl compounds to unactivated 1-alkynes attributing to the synergistic activation of chiral N,N′-dioxide-indium(III) or nickel(II) Lewis acid and achiral gold(I) π-acid. A range of β-ketoamides, β-ketoesters and 1,3-diketones transform to the corresponding products with a tetra-substituted chiral center in good yields with good e.r. values. Besides, a possible catalytic cycle and a transition state model are proposed to illustrate the reaction process and the origin of chiral induction based on the experimental investigations.

Asymmetric Catalytic Vinylogous Addition Reactions Initiated by Meinwald Rearrangement of Vinyl Epoxides.

The first catalytic asymmetric multiple vinylogous addition reactions initiated by Meinwald rearrangement of vinyl epoxides were realized by employing chiral N,N'-dioxide/ScIII complex catalysts. The vinyl epoxides, as masked β,γ-unsaturated aldehydes, via direct vinylogous additions with isatins, 2-alkenoylpyridines or methyleneindolinones, provided a facile and efficient way for the synthesis of chiral 3-hydroxy-3-substituted oxindoles, α,β-unsaturated aldehydes and spiro-cyclohexene indolinones, respectively with high efficiency and stereoselectivity. The control experiments and kinetic studies revealed that the Lewis acid acted as dual-tasking catalyst, controlling the initial rearrangement to match subsequent enantioselective vinylogous addition reactions. A catalytic cycle with a possible transition model was proposed to illustrate the reaction mechanism.

Asymmetric Catalytic Vinylogous Addition Reactions Initiated by Meinwald Rearrangement of Vinyl Epoxides

AbstractThe first catalytic asymmetric multiple vinylogous addition reactions initiated by Meinwald rearrangement of vinyl epoxides were realized by employing chiral N,N′‐dioxide/ScIII complex catalysts. The vinyl epoxides, as masked β,γ‐unsaturated aldehydes, via direct vinylogous additions with isatins, 2‐alkenoylpyridines or methyleneindolinones, provided a facile and efficient way for the synthesis of chiral 3‐hydroxy‐3‐substituted oxindoles, α,β‐unsaturated aldehydes and spiro‐cyclohexene indolinones, respectively with high efficiency and stereoselectivity. The control experiments and kinetic studies revealed that the Lewis acid acted as dual‐tasking catalyst, controlling the initial rearrangement to match subsequent enantioselective vinylogous addition reactions. A catalytic cycle with a possible transition model was proposed to illustrate the reaction mechanism.

Catalytic Asymmetric [4+1] Spiroannulation of α-Bromo-β-Naphthols with Azoalkenes by an Electrophilic Dearomatization/S RN 1-Debromination Approach

Catalytic Asymmetric [4+1] Spiroannulation of α-Bromo-β-Naphthols with Azoalkenes by an Electrophilic Dearomatization/S _RN 1-Debromination Approach

Surface enhanced Raman spectroscopic (SERS) behavior of phenylpyruvates used in heterogeneous catalytic asymmetric cascade reaction

The strength and geometry of adsorption of substituted phenylpyruvates on silver surface was studied by means of surface enhanced Raman spectroscopy (SERS) using silver sol. 2′-nitrophenylpyruvates were used as starting materials in a newly developed heterogeneous catalytic asymmetric cascade reaction to produce substituted quinoline derivatives. Substituents on the aromatic ring of the starting materials had significant influence on the yield of the desired quinoline derivatives. Product selectivity of the transformation of nitrophenylpyruvates were enhanced by the acid added. The geometry and the strength of the adsorption are assumed to play an important role in the outcome of this reaction, so we have tried to find correlation between the structure of adsorbed phenylpyruvates and their catalytic performance. Based on the results of our spectroscopic measurements, the enol form is predominant in the series of phenylpyruvates in solid form and methanol solutions. Stronger adsorption of phenylpyruvates in acidic media through oxygen atoms was indicated by the increased enhancement in the SERS spectrum. The nitro group of 2′-nitrophenylpyruvates has no direct role in the adsorption on Ag surface. This observation has explained why the hydrogenation of the keto group (presumably via the enol form) occurs preferentially and why the formation of the undesired indole derivatives requiring reduction of the nitro group is suppressed. The SERS behavior has helped to get a closer look on the first step of adsorption of starting materials contributing to a better understanding of the cascade reaction studied, thus providing a better flexibility in catalyst design.

Au(I)/(R)-BINOL-Ti(IV) Concerted Catalyzed Asymmetric Cascade Cycloaddition Reaction of Arylalkynols.

An efficient catalytic asymmetric cascade cycloaddition reaction of arylalkynols with dioxopyrrolidines was developed. This reaction was achieved using Au(I) and (R)-BINOL-Ti(IV) bimetallic catalysts and exclusively delivered a series of chiral oxo-bridged bicyclic benzooxacine compounds in up to 86% yield with 96% ee as well as >33:1 dr. Meanwhile, three new σ bonds and three new stereogenic centers were formed in a one-pot process.

Enantiodivergent synthesis of tricyclic chromans: Remote nucleophilic groups switch selectivity in catalytic asymmetric cascade reactions of trifunctional substrates

An efficient and unified approach to the enantioselective synthesis of two important yet challenging classes of tricyclic chroman scaffolds by site-selective organocatalytic asymmetric cascade reactions of newly designed phenol-based trifunctional substrates bearing two reactive nucleophilic groups is described. The enantioselectivities of this reaction can be switched by altering the remote nucleophilic groups of the substrates.

Photoredox-Mediated Asymmetric Cross-Dehydrogenative Coupling of Enones and Tertiary Amines by Chiral Primary Amine Catalysis

AbstractA catalytic asymmetric dehydrogenative cross-coupling reaction between enones and tertiary amines enabled by synergistic photoredox and chiral primary amine catalysis is reported. The reaction was proposed to proceed via the interception of iminium ion intermediate, in situ generated from photoredox oxidation, by dienamine at α-position, followed by isomerization, leading to aza-Morita–Baylis–Hillman-type products with good diastereo- and enantioselectivity.