Enantioselective Cycloaddition Reactions Research Articles

A Class of Chiral‐Bridged Biphenyl Monophosphine Ligands with Benzofuran Moiety and The Application in Diastereo‐ and Enantioselective Au(I)‐Catalyzed Cycloaddition

AbstractA class of novel chiral‐bridged biphenyl monophosphine ligands with a benzofuran moiety (He‐phos) has been successfully synthesized and reported. These ligands exhibited good performance in the gold‐catalyzed enantioselective cycloaddition reaction of 2‐(1‐alkynyl)‐2‐en‐1‐ones with nitrones, resulting in the successful preparation of a series of polyaryl‐substituted heterocyclic compounds with high enantioselectivities (up to 99% yield, 98% ee). The wide substrate adaptability (53 examples) and mild reaction conditions demonstrate the practicability of He‐phos in this reaction.

Tandem Isomerization/α,β-Site-Selective and Enantioselective Addition Reactions of N-(3-Butynoyl)-3,5-dimethylpyrazole Induced by Chiral π-Cu(II) Catalysts.

Allenes are important building blocks, and derivatization of products via cycloadditions of allenes could become a powerful strategy for constructing carbocyclic and heterocyclic rings. However, the development of catalytic site-selective and enantioselective cycloaddition reactions of allenes still presents significant challenges. Here, we report chiral π-Cu(II)-complex-catalyzed isomerization of N-(3-butynoyl)-3,5-dimethyl-1H-pyrazole to generate N-allenoylpyrazole in situ and subsequent α,β-site-selective and enantioselective [3 + 2], [4 + 2], or [2 + 2] cycloaddition or conjugate addition reactions. The asymmetric environment created by the intramolecular π-Cu(II) interactions provides the corresponding adducts in moderate to high yield with excellent enantioselectivity. To the best of our knowledge, this is the first successful method for chiral-Lewis-acid-catalyzed tandem isomerization/α,β-site-selective and enantioselective cycloaddition or conjugate addition reactions of latent non-γ-substituted allenoyl derivative.

Copper-Catalyzed Enantioselective C1,N-Dipolar (3+2) Cycloadditions of 2-Aminoallyl Cations with Indoles.

2-Aminoallyl cations are versatile 1,3-dipoles that could potentially be used for diverse (3+n) cycloaddition reactions. Despite some preliminary studies, the asymmetric catalytic transformation of these species is still underdeveloped. We herein report a binuclear copper-catalyzed generation of 2-aminoallyl cations from ethynyl methylene cyclic carbamates and their enantioselective (3+2) cycloaddition reaction with indoles to construct chiral pyrroloindolines. This transformation features a novel C1,N-dipolar reactivity for 2-aminoallyl cations.

Copper‐Catalyzed Enantioselective C1,N‐Dipolar (3+2) Cycloadditions of 2‐Aminoallyl Cations with Indoles

Abstract2‐Aminoallyl cations are versatile 1,3‐dipoles that could potentially be used for diverse (3+n) cycloaddition reactions. Despite some preliminary studies, the asymmetric catalytic transformation of these species is still underdeveloped. We herein report a binuclear copper‐catalyzed generation of 2‐aminoallyl cations from ethynyl methylene cyclic carbamates and their enantioselective (3+2) cycloaddition reaction with indoles to construct chiral pyrroloindolines. This transformation features a novel C1,N‐dipolar reactivity for 2‐aminoallyl cations.

Chemodivergent, Regio- and Enantioselective Cycloaddition Reactions between 1,3-Dienes and Alkynes.

Alkynes and 1,3-dienes are among the most readily available precursors for organic synthesis. We report two distinctly different, catalyst-dependent, modes of regio- and enantioselective cycloaddition reactions between these classes of compounds providing rapid access to highly functionalized 1,4-cyclohexadienes or cyclobutenes from the same precursors. Complexes of an earth abundant metal, cobalt, with several commercially available chiral bisphosphine ligands with narrow bite angles catalyze [4+2]-cycloadditions between a 1,3-diene and an alkyne giving a cyclohexa-1,4-diene in excellent chemo-, regio- and enantioselectivities. In sharp contrast, complex of a finely tuned phosphino-oxazoline ligand promotes unique [2+2]-cycloaddition between the alkyne and the terminal double bond of the diene giving a highly functionalized cyclobutene in excellent regio- and enantioselectivities.

Chemodivergent, Regio‐ and Enantioselective Cycloaddition Reactions between 1,3‐Dienes and Alkynes

AbstractAlkynes and 1,3‐dienes are among the most readily available precursors for organic synthesis. We report two distinctly different, catalyst‐dependent, modes of regio‐ and enantioselective cycloaddition reactions between these classes of compounds providing rapid access to highly functionalized 1,4‐cyclohexadienes or cyclobutenes from the same precursors. Complexes of an earth abundant metal, cobalt, with several commercially available chiral bisphosphine ligands with narrow bite angles catalyze [4+2]‐cycloadditions between a 1,3‐diene and an alkyne giving a cyclohexa‐1,4‐diene in excellent chemo‐, regio‐ and enantioselectivities. In sharp contrast, complex of a finely tuned phosphino‐oxazoline ligand promotes unique [2+2]‐cycloaddition between the alkyne and the terminal double bond of the diene giving a highly functionalized cyclobutene in excellent regio‐ and enantioselectivities.

Chiral nickel(II) complex catalyzed asymmetric (3 + 2) cycloaddition of α‐diazo pyrazoleamides with 2‐siloxy‐1‐alkenes

A highly efficient asymmetric (3 + 2) cycloaddition of α-diazo pyrazoleamides with silyl enol ethers was realized by employing a chiral N,N'-dioxide-Ni(II) complex catalyst. The process includes the formation of chiral nickel carbenoid intermediate and the following enantioselective cycloaddition reaction. The desired dihydrofuran O,O-acetal derivatives were obtained in good yields (up to 90%) with high enantioselectivity (up to 99% ee) under mild reaction conditions within short reaction time. On the basis of the determination of the catalyst structure, a possible transition state mode was proposed.

Asymmetric Umpolung (3+2) Cycloadditions of Iminoesters with α,β-Unsaturated-2-acyl Imidazoles for the Synthesis of Substituted Pyrrolidines.

An enantioselective (3+2) cycloaddition reaction of iminoesters occurring with opposite regioselectivity is reported. This reaction provides chiral polysubstituted pyrrolidines with high enantioselectivities (up to 97%), diastereoselectivities (>20:1), and yields (up to 99%). Interestingly, changing the alpha-substituents of the iminoesters from an aryl to an aliphatic (benzyl) group or hydrogen resulted in the formation of normal (3+2) cycloaddition products, also in excellent enantioselectivities.

Enantioselective Inverse Electron Demand (3 + 2) Cycloaddition of Palladium-Oxyallyl Enabled by a Hydrogen-Bond-Donating Ligand.

Cycloaddition reactions between oxyallyl cations and alkenes are important transformations for the construction of ring systems. Although (4 + 3) cycloaddition reactions of oxyallyl cations are well-developed, (3 + 2) cycloadditions remain rare, and an asymmetric version has not yet been developed. Moreover, because oxyallyl cations are highly electrophilic, only electron-rich olefins can be used as cycloaddition partners. We herein report a method for enantioselective (3 + 2) cycloaddition reactions between palladium-oxyallyl species and electron-deficient nitroalkenes. This transformation was enabled by a rationally designed hydrogen-bond-donating ligand (FeUrPhos) and proceeded via an inverse electron demand pathway. Using this method, we could assemble cyclopentanones with up to three contiguous stereocenters with high enantioselectivity and good to excellent diastereoselectivity.

Electron-Deficient Alkynes as Dipolarophile in Pd-Catalyzed Enantioselective (3 + 2) Cycloaddition Reaction with Vinyl Cyclopropanes.

The activated alkynes have been used successfully for the first time as the dipolarophile in the palladium-catalyzed asymmetric (3 + 2) cycloaddition, affording highly functionalized cyclopentenes in good to high yields with high chemoselectivities and good to high enantioselectivities. The introduction of an additional carbonyl group at the α-position of the alkynyl esters is the key to activating the carbon-carbon triple bond. The reaction process was investigated, and an inverse process of Pd-catalyzed (3 + 2) cycloaddition was observed.

Synthesis of α-alkylated γ-butyrolactones with concomitant anhydride kinetic resolution using a sulfamide-based catalyst.

The Kinetic Resolution (KR) of α-alkylated enolisable disubstituted anhydrides has been shown to be possible for the first time. In the presence of an ad hoc designed novel class of bifunctional sulfamide organocatalyst, a regio-, diastereo- and enantioselective cycloaddition reaction between the enolisable anhydride and benzaldehydes provides densely functionalised γ-butyrolactones in one pot (up to 19 : 1 dr, 94% ee) with control over three contiguous stereocentres. The concomitant resolution of the starting material anhydride, provides access to a range of chiral succinate derivatives with selectivity factors up to S* = 10.5.

Ni-Al Bimetallic Catalyzed Enantioselective Cycloaddition of Cyclopropyl Carboxamide with Alkyne.

A Ni-Al bimetallic catalyzed enantioselective cycloaddition reaction of cyclopropyl carboxamides with alkynes has been developed. A series of cyclopentenyl carboxamides were obtained in up to 99% yield and 94% ee. The bifunctional-ligand-enabled bimetallic catalysis proved to be an efficient strategy for the C-C bond cleavage of unreactive cyclopropanes.

Asymmetric Synthesis Using Chiral Crystals of Coumarin-3-carboxamides and Carbenoids

Unprecedented absolute asymmetric synthesis was carried out using frozen chirality derived from chiral crystals of achiral coumarin-3-carboxamide and carbenoids. An enantioselective cycloaddition reaction with a sulfur ylide gave an optically active cyclopropane up to 97% ee. Furthermore, a cycloaddition reaction with dichlorocarbene gave dihydrofuran in 93% ee. Nucleophilic addition of ylide or carbene occurs from the side of the carbonyl oxygen atom to avoid steric hindrance of substituents on the nitrogen atom.

ChemInform Abstract: Cationic Chiral Fluorinated Oxazaborolidines. More Potent, Second‐Generation Catalysts for Highly Enantioselective Cycloaddition Reactions.

AbstractA new, second‐generation family of chiral oxazaborolidinium cationic species is used as catalyst in a range of Diels—Alder reactions with catalyst loadings at a 1‐2 mol% level.

ChemInform Abstract: Enantioselective Cycloaddition Reactions Catalyzed by BINOL‐Derived Phosphoric Acids and N‐Triflyl Phosphoramides: Recent Advances

AbstractReview: 37 refs.

ChemInform Abstract: Asymmetric Cycloaddition Reactions Catalyzed by Bifunctional Thiourea and Squaramide Organocatalysts: Recent Advances

AbstractReview: 64 refs.

Cationic Chiral Fluorinated Oxazaborolidines. More Potent, Second-Generation Catalysts for Highly Enantioselective Cycloaddition Reactions.

The coordination of chiral ligands to Lewis acid metal derivatives, a useful strategy for enantioselective, electrophilic catalysis, generally leads to a lower level of catalytic activity than that of the original uncomplexed compound. Activation by further attachment of a proton or strong Lewis acid to the complex provides a way to overcome the deactivating effect of a chiral ligand. The research described herein has demonstrated that further enhancement of catalytic activity is possible by the judicious placement of fluorine substituents in the chiral ligand. This approach has led to a new, second-generation family of chiral oxazaborolidinium cationic species which can be used to effect many Diels-Alder reactions in >95% yield and >95% ee using catalyst loadings at the 1-2 mol % level. The easy recovery of the chiral ligand makes the application of these new catalysts especially attractive for large-scale synthesis.

Organocatalytic Strategy for the Enantioselective Cycloaddition to Trisubstituted Nitroolefins to Create Spirocyclohexene-Oxetane Scaffolds.

The first catalytic enantioselective cycloaddition reaction to α,β,β-trisubstituted nitroolefins is reported. For this purpose, nitroolefin oxetanes were employed in the reaction with 2,4-dienals promoted by trienamine catalysis. This methodology provides a facile and efficient strategy for the synthesis of highly functionalized chiral spirocyclohexene-oxetanes with two adjacent tetrasubstituted carbon atoms in high yields and excellent selectivities. This strategy also enabled access to chiral spirocyclohexene-cyclobutanes and -azetidines. Additionally, the obtained scaffolds can undergo diverse transformations leading to complex structures with up to four stereocenters, and we demonstrate that the nitro group, under nucleophilic conditions, can be applied for ring-opening of the oxetane.

Organocatalytic Strategy for the Enantioselective Cycloaddition to Trisubstituted Nitroolefins to Create Spirocyclohexene‐Oxetane Scaffolds

AbstractThe first catalytic enantioselective cycloaddition reaction to α,β,β‐trisubstituted nitroolefins is reported. For this purpose, nitroolefin oxetanes were employed in the reaction with 2,4‐dienals promoted by trienamine catalysis. This methodology provides a facile and efficient strategy for the synthesis of highly functionalized chiral spirocyclohexene‐oxetanes with two adjacent tetrasubstituted carbon atoms in high yields and excellent selectivities. This strategy also enabled access to chiral spirocyclohexene‐cyclobutanes and ‐azetidines. Additionally, the obtained scaffolds can undergo diverse transformations leading to complex structures with up to four stereocenters, and we demonstrate that the nitro group, under nucleophilic conditions, can be applied for ring‐opening of the oxetane.

Enantioselective Cycloaddition Reactions Catalyzed by BINOL-Derived Phosphoric Acids and N-Triflyl Phosphoramides: Recent Advances.

Over the last several years there has been a huge increase in the development and applications of new efficient organocatalysts for enantioselective pericyclic reactions, which represent one of the most powerful types of organic transformations. Among these processes are cycloaddition reactions (e.g., [3+2]; formal [3+3]; [4+2]; vinylogous [4+2] and 1,3-dipolar cycloadditions), which belong to the most utilized reactions in organic synthesis of complex nitrogen- and oxygen-containing heterocyclic molecules. This review presents the breakthrough realized in this field using chiral BINOL-derived phosphoric acids and N-triflyl phosphoramide organocatalysts.