Enantioselective Annulation Research Articles

Enantioselective Synthesis of Cyclopentenes by (3+2) Annulation via a 2‐Carbon Phosphonium

AbstractHerein we report a catalytic enantioselective (3+2) annulation, in which a vinyl phosphonium intermediate serves as the 2‐carbon component. The reaction involves an α‐umpolung β‐umpolung coupling sequence, enabled by β‐haloacrylates and chiral enantioenriched phosphepine catalysts. The reaction shows good generality, providing access to an array of cyclopentenes, with mechanistic studies supporting stereospecific formation of the vinyl phosphonium intermediate which, then undergoes annulation with turn over limiting catalyst elimination. Beyond defining a new approach to cyclopentenes, these studies demonstrate that β‐haloacrylates can replace ynoates in reaction designs that require exclusive umpolung coupling at the α‐ and β‐positions.

Enantioselective (3+2) Annulation of Donor-Acceptor Cyclopropanes with Aldehydes and Ketones Catalyzed by Brønsted Bases.

The substituted tetrahydrofuran core is a structural motif in many biologically active and natural compounds. However, the scarcity of enantioselective methods developed towards its synthesis makes this field challenging and attractive to explore. Herein, the first Brønsted-base catalyzed enantioselective (3+2) annulation of donor-acceptor cyclopropanes with aldehydes and ketones affording enantioenriched 2,3,5-substituted tetrahydrofurans is reported. The reaction concept is based on activation of racemic β-cyclopropyl ketones by a chiral bifunctional Brønsted base which catalyzes the (3+2) annulation for a range of aldehydes and ketones. For aldehydes, the annulation furnished tetrahydrofurans in excellent yield, good diastereoselectivity and with excellent enantioselectivity up to >99 % ee. Surprisingly, aromatic aldehydes afforded the cis-2,5-substituted tetrahydrofurans as the major diastereoisomer, while for aliphatic aldehydes the trans-cycloadduct was favored. The reaction also proceeds well for ketones affording spiro tetrahydrofurans in excellent yields and enantioselectivities (up to 99 % ee). Hammett studies have been conducted to elucidate the influence of the electronic nature of benzaldehydes on the stereoselectivity. Based on the diastereochemical outcome for the aldehydes, two reaction paths for aromatic and aliphatic aldehydes are proposed. Finally, two diastereoselective synthetic transformations have been conducted to demonstrate the synthetic potential of the obtained products.

Enantioselective (3+2) Annulation of Donor‐Acceptor Cyclopropanes with Aldehydes and Ketones Catalyzed by Brønsted Bases

The substituted tetrahydrofuran core is a structural motif in many biologically active and natural compounds. However, the scarcity of enantioselective methods developed towards its synthesis makes this field challenging and attractive to explore. Herein, the first Brønsted‐base catalyzed enantioselective (3+2) annulation of donor‐acceptor cyclopropanes with aldehydes and ketones affording enantioenriched 2,3,5‐substituted tetrahydrofurans is reported. The reaction concept is based on activation of racemic β‐cyclopropyl ketones by a chiral bifunctional Brønsted base which catalyzes the (3+2) annulation for a range of aldehydes and ketones. For aldehydes, the annulation furnished tetrahydrofurans in excellent yield, good diastereoselectivity and with excellent enantioselectivity up to >99% ee. Surprisingly, aromatic aldehydes afforded the cis‐2,5‐substituted tetrahydrofurans as the major diastereoisomer, while for aliphatic aldehydes the trans‐cycloadduct was favored. The reaction also proceeds well for ketones affording spiro tetrahydrofurans in excellent yields and enantioselectivities (up to 99% ee). Hammett studies have been conducted to elucidate the influence of the electronic nature of benzaldehydes on the stereoselectivity. Based on the diastereochemical outcome for the aldehydes, two reaction paths for aromatic and aliphatic aldehydes are proposed. Finally, two diastereoselective synthetic transformations have been conducted to demonstrate the synthetic potential of the obtained products.

Catalytic (4+2) Annulation via Regio- and Enantioselective Interception of in-situ Generated Alkylgold Intermediate.

A regio- and stereoselective stepwise (4+2) annulation of N-propargylamides and α,β-unsaturated imines/ketones has been accomplished with synergetic catalysis by a combination of a gold-complex and a chiral quinine-derived squaramide (QN-SQA), leading to highly functionalized chiral tetrahydropyridines/dihydropyrans in good to high yields with generally excellent enantioselectivity. Mechanistic studies and DFT calculations indicate that the in situ formed alkylgold species is the key intermediate in this transformation, and the amide group served as a traceless directing group in this highly selective transformation. This method complements the enantioselective (4+2) annulation of allene reagents, providing the formal internal C-C π-bond cycloaddition products, which is challenging and remains elusive.

Catalytic (4+2) Annulation via Regio‐ and Enantioselective Interception of in‐situ Generated Alkylgold Intermediate

AbstractA regio‐ and stereoselective stepwise (4+2) annulation of N‐propargylamides and α,β‐unsaturated imines/ketones has been accomplished with synergetic catalysis by a combination of a gold‐complex and a chiral quinine‐derived squaramide (QN‐SQA), leading to highly functionalized chiral tetrahydropyridines/dihydropyrans in good to high yields with generally excellent enantioselectivity. Mechanistic studies and DFT calculations indicate that the in situ formed alkylgold species is the key intermediate in this transformation, and the amide group served as a traceless directing group in this highly selective transformation. This method complements the enantioselective (4+2) annulation of allene reagents, providing the formal internal C−C π‐bond cycloaddition products, which is challenging and remains elusive.

Enantioselective Synthesis of Cyclopentenes by (3+2) Annulation via a 2-Carbon Phosphonium.

Herein we report a catalytic enantioselective (3+2) annulation, in which a vinyl phosphonium intermediate serves as the 2-carbon component. The reaction involves an α-umpolung β-umpolung coupling sequence, enabled by β-haloacrylates and chiral enantioenriched phosphepine catalysts. The reaction shows good generality, providing access to an array of cyclopentenes, with mechanistic studies supporting stereospecific formation of the vinyl phosphonium intermediate which, then undergoes annulation with turn over limiting catalyst elimination. Beyond defining a new approach to cyclopentenes, these studies demonstrate that β-haloacrylates can replace ynoates in reaction designs that require exclusive umpolung coupling at the α- and β-positions.

Organocatalytic Enantioselective (4+2) Annulation of Cyclopropane Carbaldehydes with 2‐Mercapto‐1‐Arylethanones

AbstractHere, we report the organocatalytic enantioselective synthesis of dihydrothiopyran derivatives from trans racemic donor–acceptor cyclopropane carbaldehydes (DACCs) and 2‐mercapto‐1‐arylethanone via formal thio (4+2) cycloaddition involving thia‐Michael aldol condensation and annulation. Mechanistic studies indicate a typical kinetic resolution (KR) is involved in this transformation, which results in moderate yields and enantiomeric ratios. Remarkably, this method is characterized by its one‐pot simplicity, mild reaction conditions, and resilience towards air and moisture interference.

Rhodium/Ming-Phos-catalyzed asymmetric annulation reaction of silacyclobutanes with terminal alkynes

Asymmetric ring-expansion reactions of silacyclobutanes (SCBs) with alkynes have evolved as one of the powerful protocols for the construction of silicon-stereogenic compounds. However, the achievement of highly enantioselective annulation of SCBs with terminal alkynes remains a challenge. Herein, we report a rhodium-catalyzed asymmetric annulation reaction of SCBs with terminal alkynes, which relies on the newly identified chiral sulfinamide phosphine ligand Ming-Phos. This catalytic system exhibits unique effects under mild conditions, leading to the direct synthesis of structurally diverse chiral silacycles in moderate to good yields with high enantioselectivities (up to 95% ee).

Palladium-Catalyzed Asymmetric (3 + 2) Cycloaddition of 5-Allenyloxazolidine-2,4-Diones with Barbiturate-Derived Alkenes: Synthesis of Spirobarbiturate-γ-Lactams.

The 5-allenyloxazolidine-2,4-diones had been synthesized as novel precursors of π-allyl palladium zwitterion and were applied in a palladium-catalyzed enantioselective (3 + 2) annulation by using barbiturate-derived alkenes as the reaction partner in the presence of an axially chiral phosphoramidite ligand. This reaction proceeded smoothly under mild reaction conditions, affording highly functionalized spirobarbiturate-γ-lactam derivatives in excellent yields along with high diastereo- and enantioselectivities. The scale-up reaction and further transformation of the product were also successful.

Electrooxidative Cobalt-Catalyzed Regio- and Enantioselective Annulation of Benzamides with Alkenes

Electrooxidative Cobalt-Catalyzed Regio- and Enantioselective Annulation of Benzamides with Alkenes

Rigid P-Chiral Phosphorus Ligands for Highly Selective Palladium-Catalyzed (4+2) and (4+4) Annulations.

We developed novel shackled P-chiral ligands based on 1-phosphanorbornenes and oxazolines. They were subsequently evaluated in palladium-catalyzed (4+2) annulations, producing enantioenriched tetrahydropyran scaffolds in good yields with high site selectivity and enantioselectivity. Moreover, chemoselective (4+4) products were also achieved by using acyclic imines. In addition, density functional theory calculations were performed to afford the energy profile of the Michael addition step and ring formation step. This demonstrated that the enantioselective (4+2) annulations and the chemoselective reaction between (4+2) and (4+4) products were mostly under thermodynamic control.

Enantioselective Annulation of α,β-Unsaturated N-Acyliminium Ions with β-Keto Ester Enolates via Cooperative Palladium and Brønsted Acid Catalysis.

We herein report a cooperative palladium- and Brønsted acid-catalyzed strategy toward the first enantioselective annulation of in situ generated α,β-unsaturated N-acyliminium ions with chiral metal enolates. Novel polycyclic oxoisoindoles featuring three contiguous stereogenic centers have been obtained with typically good yields, outstanding enantiocontrol, and moderate to good diastereoselectivity. The utility of the process was further demonstrated by their conversion to synthetically valuable scaffolds.

Phosphine-Catalyzed Enantioselective (3+2) Annulation of Vinylcyclopropanes with Imines for the Synthesis of Chiral Pyrrolidines.

A phosphine-catalyzed highly enantioselective and diastereoselective (up to 98 % ee and >20 : 1 dr) (3+2) annulation between vinylcyclopropanes and N-tosylaldimines has been developed, which allows facile access to a range of highly functionalized chiral pyrrolidines. Notably, this method makes use of vinylcyclopropanes as a synthon for phosphine-mediated asymmetric annulation reaction, which will offer new opportunities for potential applications of cyclopropanes substrates in phosphine-catalyzed organic transformations.

Phosphine‐Catalyzed Enantioselective (3+2) Annulation of Vinylcyclopropanes with Imines for the Synthesis of Chiral Pyrrolidines

AbstractA phosphine‐catalyzed highly enantioselective and diastereoselective (up to 98 % ee and >20 : 1 dr) (3+2) annulation between vinylcyclopropanes and N‐tosylaldimines has been developed, which allows facile access to a range of highly functionalized chiral pyrrolidines. Notably, this method makes use of vinylcyclopropanes as a synthon for phosphine‐mediated asymmetric annulation reaction, which will offer new opportunities for potential applications of cyclopropanes substrates in phosphine‐catalyzed organic transformations.

Phosphine-Catalyzed Asymmetric Tandem Isomerization/Annulation of Allyl Amines with Allenoates: Enantioselective Annulation of a Saturated C-N Bond.

Under catalysis by chiral phosphine, an asymmetric isomerization/annulation cascade reaction of allylamines with allenoates was realized. A wide range of γ-substituted allenoates were tolerated to afford chiral pyrroline derivatives in high yields with excellent enantioselectivities. In the reaction, isomerization of readily available N-allylamines to reactive aliphatic imines through a 1,4-proton shift is a key step, which circumvents the isolation of highly unstable alkyl N-sulfonylimines.

Design of 1-Phosphanorbornene Derivatives as Chiral Organocatalysts for Enantioselective (4 + 2) Annulation Reactions of γ-Benzyl Allenoates.

Two novel diastereoisomeric P-chirogenic phosphine catalysts, i.e., JiaPhos, which can be easily derived from inexpensive and commercially available starting materials in five chemical operations (totally 4.16g scale), are introduced. To our delight, the JiaPhos catalysts display good performance in enantioselective (4 + 2) annulations involving 3-methylene-2-oxindoles and γ-benzyl allenoates, providing a wide range of 3,3'-spirocyclic oxindoles with good efficiency and enantioselectivity.

Gold-Catalyzed [3+2]-Annulations of α-Aryl Diazoketones with the Tetrasubstituted Alkenes of Cyclopentadienes: High Stereoselectivity and Enantioselectivity.

This work reports gold-catalyzed [3+2]-annulations of α-diazo ketones with highly substituted cyclopentadienes, affording bicyclic 2,3-dihydrofurans with high regio- and stereoselectivity. The reactions highlights the first success of tetrasubstituted alkenes to undergo [3+2]-annulations with α-diazo carbonyls. The enantioselective annulations are also achieved with high enantioselectivity using chiral forms of gold and phosphoric acid. Our mechanistic analysis supports that cyclopentadienes serve as nucleophiles to attack gold carbenes at the more substituted alkenes, yielding gold enolates that complex with chiral phosphoric acid to enhance the enantioselectivity.

Gold‐Catalyzed [3+2]‐Annulations of α‐Aryl Diazoketones with the Tetrasubstituted Alkenes of Cyclopentadienes: High Stereoselectivity and Enantioselectivity

AbstractThis work reports gold‐catalyzed [3+2]‐annulations of α‐diazo ketones with highly substituted cyclopentadienes, affording bicyclic 2,3‐dihydrofurans with high regio‐ and stereoselectivity. The reactions highlights the first success of tetrasubstituted alkenes to undergo [3+2]‐annulations with α‐diazo carbonyls. The enantioselective annulations are also achieved with high enantioselectivity using chiral forms of gold and phosphoric acid. Our mechanistic analysis supports that cyclopentadienes serve as nucleophiles to attack gold carbenes at the more substituted alkenes, yielding gold enolates that complex with chiral phosphoric acid to enhance the enantioselectivity.

Carbene-catalyzed enantioselective annulation of dinucleophilic hydrazones and bromoenals for access to aryl-dihydropyridazinones and related drugs.

4,5-Dihydropyridazinones bearing an aryl substituent at the C6-position are important motifs in drug molecules. Herein, we developed an efficient protocol to access aryl-dihydropyridazinone molecules via carbene-catalyzed asymmetric annulation between dinucleophilic arylidene hydrazones and bromoenals. Key steps in this reaction include polarity-inversion of aryl aldehyde-derived hydrazones followed by chemo-selective reaction with enal-derived α,β-unsaturated acyl azolium intermediates. The aryl-dihydropyridazinone products accessed by our protocol can be readily transformed into drugs and bioactive molecules.

Synergistic N-Heterocyclic Carbene/Palladium-Catalyzed [3 + 2] Annulation of Vinyl Enolates with 1-Tosyl-2-vinylaziridine.

The synergistic combination of N-heterocyclic carbene organocatalysis and transition-metal catalysis for a formal [3 + 2] annulation between 3-substituted but-2-enoates and 1-tosyl-2-vinylaziridine was developed. This cooperative strategy provides a facile and efficient access to various functionalized (E)-3-ethylidene-4-vinylpyrrolidin-2-ones in a regioselective and stereoselective manner. The preliminary asymmetric studies were also performed, which indicated a potential for enantioselective annulation of vinyl enolate intermediates with transition-metal-π-allyl species.