Enantioselective Three-component Reaction Research Articles

Palladium-catalyzed enantioselective three-component synthesis of α-arylglycine derivatives from glyoxylic acid, sulfonamides and aryltrifluoroborates.

A palladium-catalyzed enantioselective three-component reaction of glyoxylic acid, sulfonamides and aryltrifluoroborates is described. This process provides modular access to the important α-arylglycine motif in moderate to good yields and enantioselectivies. The formed α-arylglycine products constitute useful building blocks for the synthesis of peptides or arylglycine-containing natural products.

Construction of Chiral Quaternary Carbon Centers via Asymmetric Metal Carbene gem-Dialkylation.

The catalytic asymmetric construction of all-carbon quaternary stereocenters has received tremendous interest over the past decades, and numerous efficient protocols have been disclosed based on the formation of one C-C bond between two assembling reactants. However, the use of asymmetric multi-component reactions that build two C-C bonds on the same carbonic center with concomitant assembly of quaternary stereocenters is rare and remains challenging. Herein, we disclose an enantioselective three-component reaction of α-diazo ketones with alkenes and 1,3,5-triazines under dirhodium/chiral phosphoric acid cooperative catalysis, which leads to a practical and atom-economic synthesis of poly-functionalized chiral ketones that bear a α-quaternary stereocenter in generally good to high yields with excellent enantioselectivities. In comparison to the previous method for the construction of tertiary and quaternary stereocenters via carbene gem-difunctionalization reactions, this reaction features an unprecedented gem-dialkylation process via sequential installation of two C-C bonds on the carbene center in one reaction, providing an essential complement to the asymmetric construction of all-carbon quaternary stereocenters using common and readily available starting materials.

Enantioselective three-component reaction to access chiral α-vinyl phosphonates

Enantioselective three-component reaction to access chiral α-vinyl phosphonates

Organocatalytic Enantioselective Diels-Alder Reaction of 2-Trifluoroacetamido-1,3-dienes with α,β-Unsaturated Ketones.

We report herein the first examples of chiral phosphoric acid-catalyzed enantioselective Diels-Alder reactions between 2-trifluoroacetamido-1,3-dienes 1 and α,β-unsaturated carbonyl compounds 2. Polysubstituted 1-acetamido cyclohexenes 3 were formed in high yields with excellent diastereo- and enantioselectivities. The reaction proceeds through a stepwise process as shown by deuterium labelling experiments. A catalytic enantioselective three-component reaction of 1, 2 and ortho-hydroxybenzhydryl alcohols 4 was subsequently developed furnishing the densely functionalized hexahydroxanthenes 5 in a highly stereoselective manner. This multicomponent reaction generates four chemical bonds with concurrent creation of five contiguous stereocenters.

Highly Enantioselective Three-Component Povarov Reaction for Direct Construction of Azaspirocycles.

An asymmetric organocatalyzed three-component Povarov reaction to construct azaspirocycles has been developed. A chiral phosphoric acid OCF-CPA bearing o-CF3-aryl on the H8-BINOL-framework is highly efficient in the reaction. The reaction was carried out under mind conditions for synthesis of a range of azaspirocycles in high yields and high to excellent enantioselectivities, thus expending the substrate scope of the traditional Povarov reaction.

Pd/Ming-Phos-Catalyzed Asymmetric Three-Component Arylsilylation of N-Sulfonylhydrazones: Enantioselective Synthesis of gem-Diarylmethine Silanes.

A Pd-catalyzed enantioselective three-component reaction of N-sulfonylhydrazones, aryl bromides, and silylboronic esters is developed, enabling the synthesis of chiral gem-diarylmethine silanes in high enantioselectivity with the use of a newly identified Ming-Phos. Compared with N-tosyl, the more easily decomposed N-mesitylsulfonyl is more suitable as the masking group of electron-rich hydrazone to improve the reaction efficiency. The reaction features a broad scope concerning both coupling partners, high enantioselectivity, and mild reaction conditions. The ready access to enantiomers and utility of this catalytic method are also presented.

Enantioselective Propargylation of Oxonium Ylide with α-Propargylic-3-Indolymethanol: Access to Chiral Propargylic Indoles.

An enantioselective three-component reaction of α-propargylic-3-indolymethanol with diazoindolinone and alcohol under cocatalysis of Rh(II) and chiral phosphoric acid (CPA) has been reported. It proceeds through the regio- and enantiospecific addition of the in situ formed oxonium ylide to the α-propargylic indole iminium ion that is generated from 3-indolyl propargylic alcohol with CPA. This work features an asymmetric counteranion-directed propargylation of oxonium ylide, and provides an efficient access to chiral propargylic indole derivatives with high yields and enantioselectivities.

Multicomponent Enantioselective Synthesis of Tetrahydropyridazinones Employing Chiral α,β-Unsaturated Acylammonium Salts.

An enantioselective three-component reaction was developed for the synthesis of tetrahydropyridazinones employing chiral α,β-unsaturated acylammonium salts, malonates, and azodicarboxylates. An initial α-amination of a malonate with an azodicarboxylate and a subsequent chiral Lewis-base-catalyzed Michael/proton transfer/lactamization process delivered optically active tetrahydropyridazinones (up to 99:1 er). Subsequent transformations of these adducts were explored, revealing some unexpected rearrangements, and the use of an allyl methyl malonate enabled a subsequent deallylative decarboxylation and the introduction of a second stereocenter.

Catalytic Asymmetric Hydroacyloxylation/Ring-Opening Reaction of Ynamides, Acids, and Aziridines.

A highly enantioselective three-component reaction of ynamides with carboxylic acids and 2,2'-diester aziridines has been realized by using a chiral N,N'-dioxide/Ho(OTf)3 complex as a Lewis acid catalyst. The process includes the formation of an α-acyloxyenamide intermediate through the addition of carboxylic acids to ynamides and the following enantioselective nucleophilic addition to in-situ-generated azomethine ylides induced by the chiral catalyst. A range of amino acyloxyenamides are delivered in moderate to good yields with good ee values. In addition, a possible catalytic cycle with a transition model is proposed to elucidate the reaction mechanism.

Asymmetric three-component olefin dicarbofunctionalization enabled by photoredox and copper dual catalysis.

The intermolecular three-component alkene vicinal dicarbofunctionalization (DCF) reaction allows installation of two different carbon fragments. Despite extensive investigation into its ionic chemistry, the enantioseletive radical-mediated versions of DCF reactions remain largely unexplored. Herein, we report an intermolecular, enantioselective three-component radical vicinal dicarbofunctionalization reaction of olefins enabled by merger of radical addition and cross-coupling using photoredox and copper dual catalysis. Key to the success of this protocol relies on chemoselective addition of acyl and cyanoalkyl radicals, generated in situ from the redox-active oxime esters by a photocatalytic N-centered iminyl radical-triggered C-C bond cleavage event, onto the alkenes to form new carbon radicals. Single electron metalation of such newly formed carbon radicals to TMSCN-derived L1Cu(II)(CN)2 complex leads to asymmetric cross-coupling. This three-component process proceeds under mild conditions, and tolerates a diverse range of functionalities and synthetic handles, leading to valuable optically active β–cyano ketones and alkyldinitriles, respectively, in a highly enantioselective manner (>60 examples, up to 97% ee).

Asymmetric Three-Component Propargyloxylation for Direct Assembly of Polyfunctionalized Chiral Succinate Derivatives

An enantioselective three-component propargyloxylation reaction of propargyl alcohols, pyridotriazoles, and imines has been realized by cooperative catalysis with dirhodium complex and chiral phosp...

Asymmetric Catalytic Synthesis of Epoxides via Three-Component Reaction of Diazoacetates, 2-Oxo-3-ynoates, and Nitrosoarenes.

An enantioselective three-component reaction of diazoacetates, 2-oxo-3-ynoates, and nitrosoarenes has been developed by using a chiral N,N'-dioxide/Ni(OTf)2 complex. This catalytic manifold allows rapid access to a series of multifunctional chiral epoxides containing an imino ketone substituent in moderate to good yields (up to 82%) and excellent diastereo- and enantioselectivities (up to >95/5 dr and 99% ee) with high levels of Z/E ratios (up to >95/5 Z/E) under mild reaction conditions.

Enantioselective three-component aminomethylation of \u03b1-diazo ketones with alcohols and 1,3,5-triazines

Enantioselective α-aminomethylation of carbonyl compounds constitutes a powerful protocol for introducing aminomethyl groups to simple organic molecules. However, current strategies rely on nucleophile-based enantioselective activation with inherently activated substrates only, and enantioselective protocol based on the activation of in situ-generated unstable formaldimines remains elusive, probably owing to their unstable nature and the lack of steric environment for efficient stereocontrols. Here, based on a rhodium/chiral phosphoric acid cooperative catalysis, we achieved an enantioselective three-component reaction of α-diazo ketones with alcohols and 1,3,5-triazines. A dual hydrogen bonding between the chiral phosphoric acid catalyst and two distinct active intermediates was proposed to be crucial for the efficient electrophile-based enantiocontrol. A series of chiral β-amino-α-hydroxy ketones including those derived from simple aliphatic alcohols, allylic alcohol, propargyl alcohol, complicated natural alcohols and water could all be prepared in high efficiency and enantioselectivity.

Chiral-at-Metal Rh(III) Complex Catalyzed Cascade Reduction-Michael Addition Reaction.

An enantioselective three-component cascade reduction-Michael addition reaction catalyzed by chiral-at-metal Rh(III) complexes has been developed. With a Hantzsch ester as the hydride source, a number of malononitrile derivatives were prepared in good yields and excellent enantioselectivities. A model that accounts for the origin and influence factors of the stereoselectivity has been proposed based on experiments.

Enantioselective three-component Ugi reaction catalyzed by chiral phosphoric acid

A catalytic enantioselective three-component Ugi reaction was developed. SPINOL-derived phosphoric acid with bulky 2,4,6-tricyclohexylphenyl groups at the 6,6′ positions was found to be the best catalyst to afford α-amino amide derivatives in good to excellent yields (62% to 99%) and enantiocontrol (81% to >99% enantiomeric excess). This asymmetric reaction was applicable well to an array of aliphatic aldehydes. The gram-scale synthesis, modification of dapsone, and enantioselective synthesis of ( R )-Lacosamide underline the general utility of this methodology. Influence of dihedral angles and substituents of the chiral phosphoric acids on the enantioselectivity was also discussed in this article.

Asymmetric Synthesis of Heterocyclic γ-Amino-Acid and Diamine Derivatives by Three-Component Radical Cascade Reactions.

An enantioselective three-component radical reaction of quinolines or pyridines with enamides and α-bromo carbonyl compounds by dual photoredox and chiral Brønsted acid catalysis is presented. A range of valuable chiral γ-amino-acid derivatives are accessible in high chemo-, regio-, and enantioselectivity from simple, readily available starting materials under mild reaction conditions. Using the same strategy, the asymmetric synthesis of 1,2-diamine derivatives is also reported.

Merging Asymmetric [1,2]-Additions of Lithium Acetylides to Carbonyls with Type II Anion Relay Chemistry.

An enantioselective three-component coupling reaction has been developed, enabling the union of a variety of lithium acetylides and electrophiles exploiting an achiral linchpin via an anionic reaction cascade. This Type II Anion Relay Chemistry tactic is initiated via an enantioselective [1,2]-carbonyl addition exploiting BINOL catalysis to access an enantioenriched alkoxide intermediate. Migration of charge across the linchpin via a [1,4]-Brook rearrangement with electrophile capture affords a three-component propargyl ether adduct. Herein, we report the development, scope, and limitations of this reaction sequence.

Asymmetric Mannich Reaction: Synthesis of Novel Chiral 5-(substituted aryl)-1,3,4-Thiadiazole Derivatives with Anti-Plant-Virus Potency

Abstract A series of novel chiral 5-(substituted aryl)-1,3,4-thiadiazole derivatives was synthesized in an enantioselective three-component Mannich reaction using cinchona alkaloid squaramide catalyst with excellent enantioselectivities (up to >99% enantiomeric excess (ee)). The bioassay results showed that these derivatives possessed good to excellent activities against tobacco mosaic virus (TMV).

Dinuclear zinc cooperative catalytic three-component reactions for highly enantioselective synthesis of 3,3'-dihydrofuran spirooxindoles.

A new dinuclear zinc cooperative catalytic enantioselective three-component reaction via a domino Knoevenagel /Michael/cyclization sequence has been developed. A series of chiral 3,3'-dihydrofuran spirooxindoles are obtained in excellent yields (up to 99%) and enantioselectivities (up to 99% ee). In addition, the reaction is carried out smoothly on a gram scale under mild conditions.

Chiral phosphoric acid-catalyzed enantioselective three-component Mannich reaction of acyclic ketones, aldehydes and anilines

Chiral phosphoric acid-catalyzed enantioselective three-component Mannich reaction of acyclic ketones, aldehydes and anilines