Catalytic Asymmetric Addition Research Articles

Direct Catalytic Asymmetric Conjugate Addition of Benzofuran‐3(2H)‐Ones to α,β‐Unsaturated Thioamides: Stereodivergent Synthesis of Rocaglaol

AbstractRocaglaol, a representative flavagline, has attracted significant attention because of its unique chemical structure and biological activities. This paper reports a mild and scalable copper‐catalyzed enantioselective conjugate addition of benzofuran‐3(2H)‐ones to α,β‐unsaturated thioamides. This method allows for the concise synthesis of all possible stereoisomers of a key intermediate of rocaglaol and its derivatives in a highly diastereo‐ and enantioselective manner using different chiral phosphine ligands. Theoretical insights into the reaction mechanism and the origin of ligand‐dependent diastereodivergence were obtained using density functional theory calculations.

Direct Catalytic Asymmetric Conjugate Addition of Benzofuran-3(2H)-Ones to α,β-Unsaturated Thioamides: Stereodivergent Synthesis of Rocaglaol.

Rocaglaol, a representative flavagline, has attracted significant attention because of its unique chemical structure and biological activities. This paper reports a mild and scalable copper-catalyzed enantioselective conjugate addition of benzofuran-3(2H)-ones to α,β-unsaturated thioamides. This method allows for the concise synthesis of all possible stereoisomers of a key intermediate of rocaglaol and its derivatives in a highly diastereo- and enantioselective manner using different chiral phosphine ligands. Theoretical insights into the reaction mechanism and the origin of ligand-dependent diastereodivergence were obtained using density functional theory calculations.

Catalytic Asymmetric Aza-Electrophilic Additions of 1,1-Disubstituted Styrenes.

Electrophilic addition of alkenes is a textbook reaction that plays a pivotal role in organic chemistry. In the past decades, catalytic asymmetric variants of this important type of reaction have witnessed great achievements by the development of novel catalytic systems. However, enantioselective aza-electrophilic additions of unactivated alkenes, which could provide a transformative strategy for the preparation of synthetically significant nitrogen-containing compounds, still remain a formidable challenge. Herein, we have developed unprecedented Au(I)/NHC-catalyzed asymmetric aza-electrophilic additions of unactivated 1,1-disubstituted styrenes by the utilization of readily available dialkyl azodicarboxylates as electrophilic nitrogen sources. Based on this approach, a series of transformations, including [2 + 2] cycloaddition, intermolecular 1,2-oxyamination, and several types of intramolecular hydrazination-induced cyclizations, have been realized. These transformations provide a previously unattainable platform for the divergent synthesis of hydrazine derivatives, which could also be converted to other nitrogen-containing chiral synthons. Experimental and computational studies support the idea that carbocation intermediates are involved in reaction pathways.

Asymmetric 2,3-Addition of Sulfinylamines with Arylboronic Acids Enabled by Nickel Catalysis.

Sulfinamides have been widely used in organic synthesis, with research on their preparation spanning more than a century. Despite advancements in catalytic methodologies, creating sulfur stereocenters within these molecules remains a significant challenge. In this study, we present an effective and versatile method for synthesizing a diverse range of S-chirogenic sulfinamides through catalytic asymmetric aryl addition to sulfinylamines. By utilizing a nickel complex as a catalyst, this process exhibits impressive enantioselectivity and can incorporate various arylboronic acids at the sulfur position. The resulting synthetic sulfinamides are stable and highly adaptable, allowing for their conversion to a variety of sulfur-containing compounds. Our study also incorporates detailed experimental and computational studies to elucidate the reaction mechanism and factors influencing enantioselectivity.

Metal-Free Enantioselective 1,4-Addition of Diarylphosphine Oxides to α,β-Unsaturated Carboxylic Esters.

The catalytic asymmetric conjugate addition of phosphorus nucleophiles to unsaturated compounds, catalyzed by metallic or nonmetallic catalysts, has been extensively developed. However, the enantioselective transformations involving α,β-unsaturated carboxylic esters for constructing chiral c-p bonds have been rarely reported, particularly in metal-free processes. In this study, we present a novel metal-free methodology for enantioselective 1,4-addition of diarylphosphine oxides to α,β-unsaturated carboxylic esters using classical chiral oxazaborolidine catalysts. Remarkably high yields and enantioselectivities were obtained for most of the products. Furthermore, these valuable chiral phosphorus esters serve as crucial intermediates that can be transformed into various derivatives including amides, acids, and alcohols in a single step.

Carbene-Catalyzed Enantioselective Addition of Sulfinate to Ketones.

A carbene-catalyzed enantioselective addition of sulfinate to ketones between 2-benzoylbenzaldehyde and sulfonyl chloride is disclosed. Up to now, the carbon and heteroatom nucleophiles have effectively undergone catalytic enantioselective addition to carbonyl molecules to introduce functionalities and chirality. Sulfone, as an important class of sulfur-containing functional groups, represents highly valuable motifs in medicines and natural products. It remains undeveloped for the catalytic asymmetric addition of sulfinate to carbonyls. Herein we disclosed the first catalytic enantioselective addition of sulfinate to ketones for the synthesis of sulfones via N-heterocyclic carbene (NHC) catalysis. The sulfonyl chloride behaves both as an oxidant and as a nucleophilic substrate in this carbene-catalyzed process. Experimental studies suggested that the Breslow intermediate can be SET oxidized by sulfonyl chloride to generate the sulfonyl radical. This novel synthetic approach for the asymmetric addition of sulfinate to carbonyls can also be used to modify the commercially available functional molecules.

Synthesis of Chiral Diarylmethylamides via Catalytic Asymmetric Aza-Michael Addition of Amides to ortho-Quinomethanes.

Chiral diarylmethylamides are a privileged skeleton in many bioactive molecules. However, the enantioselective synthesis of such molecules remains a long-standing challenge in organic synthesis. Herein, we report a chiral bifunctional squaramide catalyzed asymmetric aza-Michael addition of amides to in situ generated ortho-quinomethanes, affording enantioenriched diarylmethylamides in good yields with excellent enantioselectivities. This work not only provides a new strategy for the construction of the diarylmethylamides but also represents the practicability of amides as nitrogen-nucleophiles in asymmetric organocatalysis.

Organocatalytic Enantioselective Nucleophilic Addition of Indole Imine 5-Methides.

Despite the enormous developments in the asymmetric transformations of indole imine methides (IIMs), the remote asymmetric induction involving IIMs remains challenging due to the spatial interaction requirement between the substrate and catalyst. Herein we report the first catalytic asymmetric nucleophilic addition to indole imine 5-methide (5-IIM), the only topological isomer of IIMs whose asymmetric addition remains unknown. Despite the challenging remote stereocontrol, high efficiency and respectable enantioselectivity were achieved to provide access to a range of enantioenriched indole-containing triaryl alkanes.

Catalytic asymmetric conjugate addition of coumarins to unsaturated ketones catalyzed by a chiral-at-metal Rh(III) complex.

The first catalytic asymmetric vinylogous Michael addition of coumarins to unsaturated ketones catalyzed by chiral rhodium catalysts has been established. This strategy allowed the synthesis of a variety of highly enantioenriched compounds containing coumarin skeletons in 41-99% yields and 84-99% ee. The developed reaction enriches the chemistry of catalytic asymmetric vinylogous Michael additions of 3-cyano-4-methylcoumarins. Furthermore, the protocol showed obvious advantages in reaction enantioselectivity. When the chiral rhodium catalyst was reduced to 0.06 mol%, a Gram-level reaction was still achieved to provide the desired products with 99% ee.

A de novo synthesis of the bisindole alkaloid geissolosimine: collective synthesis of geissoschizoline, akuammicine, (16S)-deshydroxymethylstemmadenine and Aspidospermatan alkaloids

Collective synthesis of geissolosimine, geissoschizoline, akuammicine, (16S)-deshydroxymethylstemmadenine and Aspidospermatan alkaloids was achieved based on a catalytic asymmetric double Michael addition.

Catalytic Asymmetric Vinylogous Conjugate Addition of Butenolide to 2-Ester-Substituted Chromones: Access to Chiral Chromanone Lactones via Trapping of a Copper(I) Enolate by Trimethyl Borate.

A copper-catalyzed asymmetric vinylogous conjugate addition of butenolide to 2-ester-substituted chromones is described, and it delivers syn- or anti-chromanone lactones with high stereoselectivities. The enantioselectivity-determining step varied with the use of B(OMe)3 as an additive, resulting in enhanced stereoselectivities, as revealed by density functional theory calculations, which also provided theoretical insight into the origin of the ligand-dependent diastereodivergence.

Chiral Lewis Acid-Catalyzed Asymmetric Multicomponent Michael Reaction through [1,2]-Phospha-Brook Rearrangement.

The multicomponent catalytic asymmetric Pudovik addition/[1,2]-phospha-Brook rearrangement/Michael reaction sequence of isatins, phosphites, and 4-oxobutenoates was realized. A series of oxindole derivatives containing two contiguous stereocenters was obtained in high yields and excellent stereoselectivities (up to >99% yield, >95:5 dr, >99% ee) using a chiral Lewis acid catalyst. A possible catalytic model is presented to illustrate the stereocontrol.

W-Phos Ligand Enables Copper-Catalyzed Enantioselective Alkylation of N-Sulfonyl Ketimines with Grignard Reagents

Catalytic asymmetric addition of reactive Grignard reagents to ketimines poses a considerable challenge. Herein, a PNP-type W-Phos ligand developed recently by our group showed a unique effect toward this end, paving the way to a Cu(I)-catalyzed asymmetric alkylation reaction of N-sulfonyl ketimines, delivering optically active α-tertiary amines in high enantioselectivities. This catalytic protocol shows an unprecedented substrate scope with more than 80 examples, not only compatible with benzo five- and six-membered cyclic N-sulfonyl ketimines but also suitable for geometrically unstable (E or Z) acyclic N-sulfonyl ketimines. The application potential of the protocol is featured by the extensive presence of α-tertiary amines in natural products and pharmaceutical compounds and also demonstrated by downstream transformations with maintenance of the enantioselectivity.

Confronting the Challenge of Asymmetric Carbonyl Addition to Sterically Bulky Isatins: Upgrading Dirhodium(II)/Biphosphine Catalytic System

Catalytic asymmetric addition of arylboronic acids to ketones is a powerful transformation for directly delivering chiral tertiary alcohols. However, there is no successful example of enantioselective addition to steric bulky isatins, which contain bulky substituent at the 4-position. To confront this challenge, in this work a dirhodium/(BTFM-Garphos) system was developed that showed extremely high activity and stereoselectivity, and the reactions were usually finished within a few minutes.

Catalytic Asymmetric Conjugate Addition of 1,4-Dienes to β-Substituted Alkenyl Azaarenes

Key words asymmetric conjugate addition - azaarenes - copper catalysis - 1,4-dienes

Multicatalysis protocol enables direct and versatile enantioselective reductive transformations of secondary amides.

The catalytic asymmetric geminal bis-nucleophilic addition to nonreactive functional groups is a type of highly desirable yet challenging transformation in organic chemistry. Here, we report the first catalytic asymmetric reductive/deoxygenative alkynylation of secondary amides. The method is based on a multicatalysis strategy that merges iridium/copper relay catalysis with organocatalysis. A further combination with the palladium-catalyzed alkyne hydrogenation allows the one-pot enantioselective reductive alkylation of secondary amides. This versatile protocol allows the efficient synthesis of four types of α-branched chiral amines, which are prevalent structural motifs of active pharmaceutical ingredients. The protocol also features excellent enantioselectivity, chemoselectivity, and functional group tolerance to be compatible with more reactive functional groups such as ketone and aldehyde. The synthetic utility of the method was further demonstrated by the late-stage functionalization of two drug derivatives and the concise, first catalytic asymmetric approach to the κ-opioid antagonist aticaprant.

Catalytic Asymmetric Synthesis of Axially Chiral 3,3'‐Bisindoles by Direct Coupling of Indole Rings

Comprehensive SummaryA new strategy for the enantioselective synthesis of axially chiral 3,3'‐bisindoles was devised by the direct coupling of two indole rings. This strategy makes use of the C3‐umpolung reactivity of 2‐indolylmethanols, which enables the catalytic asymmetric addition reaction of 2‐indolylmethanols with rationally designed 2‐substituted indoles, thus constructing axially chiral 3,3'‐bisindole scaffolds in overall excellent yields (up to 98%) with high enantioselectivities (up to 96 : 4 er). This approach not only has overcome the challenges in constructing axially chiral five‐five‐membered heterobiaryls, but also represents a new application of the C3‐umpolung reactivity of 2‐indolylmethanols in asymmetric catalysis. More importantly, this class of axially chiral 3,3'‐bisindoles can undergo a variety of post‐functionalizations to give axially chiral 3,3'‐bisindole‐based organocatalysts, which have found their preliminary applications in asymmetric catalysis.

Chiral Phosphoric Acid-Catalyzed Enantio- and Diastereoselective Allylboration of Aldehydes with β,γ-Substituted Allylboronates

The catalytic asymmetric addition of β,γ-substituted allylboronates to aldehydes has been described. Promoted by 5 mol % chiral phosphoric acid, the reactions were broadly applicable, scalable, and efficient, allowing for the formation of 3,4-anti/syn-homoallylic alcohols bearing adjacent tertiary or quaternary stereogenic centers in a highly enantio- and diastereoselective manner (≤99% ee and dr >20:1). The rigid chairlike transition state involving the chiral phosphoric acid contributed to the highly controlled reaction.

Synthesis of W‐Phos Ligand and Its Application in the Copper‐Catalyzed Enantioselective Addition of Linear Grignard Reagents to Ketones

AbstractThe asymmetric catalytic addition of linear Grignard reagents to ketones has been a long‐standing challenge in organic synthesis. Herein, a novel family of PNP ligands (W‐Phos) was designed and applied in copper‐catalyzed asymmetric addition of linear Grignard reagents to aryl alkyl ketones, allowing facile access to versatile chiral tertiary alcohols in good to high yields with excellent enantioselectivities (up to 94 % yield, 96 % ee). The process can also be used to synthesize chiral allylic tertiary alcohols from more challenging α,β‐unsaturated ketones. Notably, the potential utility of this method is demonstrated in the gram‐scale synthesis and modification of various densely functionalized medicinally relevant molecules.

Synthesis of W-Phos Ligand and Its Application in the Copper-Catalyzed Enantioselective Addition of Linear Grignard Reagents to Ketones.

The asymmetric catalytic addition of linear Grignard reagents to ketones has been a long-standing challenge in organic synthesis. Herein, a novel family of PNP ligands (W-Phos) was designed and applied in copper-catalyzed asymmetric addition of linear Grignard reagents to aryl alkyl ketones, allowing facile access to versatile chiral tertiary alcohols in good to high yields with excellent enantioselectivities (up to 94 % yield, 96 % ee). The process can also be used to synthesize chiral allylic tertiary alcohols from more challenging α,β-unsaturated ketones. Notably, the potential utility of this method is demonstrated in the gram-scale synthesis and modification of various densely functionalized medicinally relevant molecules.