Asymmetric Cross-coupling Reaction Research Articles

Development of a chiral TPr# ligand and application for asymmetric palladium and copper catalysis

We report the design and synthesis of chiral triazolylidene-metal complexes with bulky substituents at the triazole ring. The palladium complex could be applied to the asymmetric Suzuki-Miyaura cross coupling reaction of 1-naphthaleneboronic acid and 1-bromo-2-methoxynaphthalene to afford the coupling product with good enantioselectivity. The reaction was found to proceed even at 10 mol ppm catalyst loading, leading to high turnover numbers of up to 2300. The chiral triazolylidene-copper complex was employed as an asymmetric catalyst for the borylation of methyl cinnamate to provide the borylated product with good enantioselectivity.

Nickel-Catalyzed Asymmetric Propargyl-Aryl Cross-Electrophile Coupling.

Performing asymmetric cross-coupling reactions between propargylic electrophiles and aryl nucleophiles is a well-established method to build enantioenriched benzylic alkynes. Here, a catalytic enantioselective propargyl-aryl cross-coupling between two electrophiles was achieved for the first time in a stereoconvergent manner. Propargylic chlorides were treated with aryl iodides as well as heteroaryl iodides in the presence of a chiral nickel complex, and manganese metal was used as a stoichiometric reductant, allowing for the construction of a propargyl C-aryl bond under mild conditions. An alternative dual nickel/photoredox catalytic protocol was also developed for this cross-electrophile coupling in the absence of a metal reductant. The potential utility of this conversion is demonstrated in the facile construction of stereoenriched bioactive molecule derivatives and medicinal compounds based on the diversity of acetylenic chemistry. Detailed experimental studies have revealed the key mechanistic features of this transformation.

Catalytic Asymmetric Imine Cross-Coupling Reaction

Catalytic asymmetric cross-coupling of imines constitutes a particularly desirable method for the synthesis of chiral vicinal diamines directly from readily available achiral precursors. The potential of this method lies in the possibility of utilizing a variety of imines as reacting partners. However, the realization of highly stereoselective cross-coupling of two different imines proved to be a formidable challenge. Herein we report an unprecedented catalytic asymmetric cross-coupling reaction that tolerates a variety of ketimines and aldimines as nucleophiles and electrophiles, respectively. The realization of this reaction resulted from the development of a new chiral ammonium catalyst, which was guided by insights from studies of catalyst-substrate interactions. With a 0.5 mol % loading of an organocatalyst, this reaction proceeded in a highly diastereo- and enantioselective manner to afford a diverse range of chiral vicinal diamines as nearly single stereoisomers. This catalytic reaction establishes a new approach for the asymmetric synthesis of chiral vicinal diamines.

An Efficient Asymmetric Cross-Coupling Reaction in Aqueous Media Mediated by Chiral Chelating Mono Phosphane Atropisomeric Biaryl Ligand

The enantiomerically pure ligand BisNap-Phos was obtained in a straightforward sequence of reactions beginning with inexpensive starting materials under the readily affordable conditions in high overall yield. An asymmetric BisNap-Phos-palladium complex-catalyzed Suzuki–Miyaura coupling leading to axially chiral biaryl compounds was described. The reactions were carried out under mild conditions in aqueous and organic media. A series of atropisomeric biaryls were synthesized with excellent yields and high enantioselectivities (up to 86% ee). The methodology provides an efficient and practical strategy for the synthesis of novel multifunctionalized axially chiral biaryl compounds under mild environmentally friendly and easily affordable conditions.

A Ni-catalyzed asymmetric C(sp)-P cross-coupling reaction for the synthesis of P-stereogenic alkynylphosphines.

Due to the high reactivity of the triple bond, P-stereogenic alkynylphosphines could be easily derivatized, serving as universal building blocks for structurally diverse phosphine compounds. However, the synthesis of alkynylphosphines via direct P-C bond formation was unprecedented. Here, we report an efficient method for the synthesis of P-stereogenic alkynylphosphines with high enantioselectivity via a Ni-catalyzed asymmetric cross-coupling reaction. The reaction could tolerate a variety of functional groups, affording products that can be converted into useful phosphine derivatives.

Enantioselective construction of axially chiral cyclohexylidene scaffolds via Pd-catalyzed asymmetric coupling reaction

Axially chiral cyclohexylidenes exhibit unique chirality because of the restricted rotation of the C=C bond. Compared with other axially chiral compounds, they are much less explored, and their efficient construction remains a synthetic challenge. Herein, we report the first palladium-catalyzed asymmetric coupling reaction of aryl iodides with 4-substituted cyclohexanol-derived α-diazocarbonyl compounds to give tetrasubstituted cyclohexylidenes in good yields (up to 92%) with excellent enantioselectivities (up to 96% ee ) under mild conditions. This protocol provides a general access to axially chiral cyclohexylidenes. The utility of this unique scaffold was demonstrated by the carboxylic acid serving as a useful chiral ligand in transition-metal-catalyzed C–H bond activation, which showed great promise as a new type of olefin ligand. • Pd-catalyzed asymmetric cross-coupling reaction • Facile access to enantioenriched axially chiral tetrasubstituted alkenes • Broad scope, good yields, and excellent enantioselectivities • Develop skeleton applications Tetrasubstituted alkenes are important building blocks in many natural products, drugs, and functional materials. Their efficient regio- and stereoselective synthesis poses a significant challenge to synthetic organic chemists due to the crowded nature of the double bonds. The reported palladium/Xu-Phos-catalyzed asymmetric coupling reaction of this method allows the use of readily available simple aryl iodides and 4-substituted cyclohexanol-derived α-diazocarbonyl compounds under mild conditions, furnishing a variety of tetrasubstituted cyclohexylidenes in good yields with excellent enantioselectivities. The utility of this unique scaffold was demonstrated by the carboxylic acid serving as a useful chiral ligand in transition-metal-catalyzed C–H bond activation, which showed great promise as a new type of olefin ligand. The first Pd/Xu-Phos-catalyzed asymmetric coupling reaction of aryl iodides with β -hydroxy α -diazocarbonyl compounds has been established to construct axially chiral cyclohexylidene skeletons (up to 92% yield, up to 96% ee ). This protocol provides easy access to axially chiral cyclohexylidenes, one rarely explored class of the atropisomeric family. The carboxylic acid derivatives could serve as a useful chiral ligand in transition-metal-catalyzed C–H bond activation. The proposed mechanism involves palladium carbene asymmetric migration insertion, β -hydroxyl elimination, and reduction of Pd(II) to Pd(0).

Asymmetric Suzuki Cross‐Coupling Reactions Catalyzed by Chiral Surfactant‐Stabilized Palladium Nanoparticles

AbstractWe report the synthesis of cinchonine and hydrocinchonine derived surfactants by reacting with various mono alkylating agents (hexyl, octyl, octadecyl, dodecyl bromides) and di‐alkylating agent such as α,α’‐p‐xylene‐di‐bromide. A series of chiral surfactants have been used to stabilize palladium nanoparticles (NPs) which are water soluble. These Pd NPs were utilized in asymmetric Suzuki cross coupling reaction of naphthalene boronic acids with substituted naphthalene bromides to get binaphthalenes and terephenylenes. It was observed that, the surfactant's alkyl‐chain length and the palladium source played a major role in this catalytic reaction. The high solubility and positive zeta potential of gemini‐surfactant (GS) stabilized Pd NPs make them attractive as a potential candidate for the synthesis of binaphthalenes and terephenylenes with high yields.

Palladium-Catalyzed Asymmetric Cross-Coupling Reactions of Cyclobutanols and Unactivated Olefins.

Transition-metal-catalyzed activations of carbon-carbons bonds of small strained rings have widespread applications in synthetic and medicinal chemistry. However, coupling reactions of cyclobutanols involving β-carbon elimination to construct C(sp3)-C(sp3) bonds have scarcely been developed. Here, we demonstrate a highly enantioselective Pd-catalyzed intermolecular C(sp3)-C(sp3) coupling reaction of a broad range of cyclobutanol derivatives and unactivated alkenes, allowing convenient access to a series of chiral benzene-fused cyclic compounds in a highly regio-, chemo-, and enantioselective manner.

A catalytic asymmetric cross-coupling approach to the synthesis of cyclobutanes.

Stereodefined four-membered rings are common motifs in bioactive molecules and versatile intermediates in organic synthesis. However, the synthesis of complex, chiral cyclobutanes is a largely unsolved problem and there is a need for general and modular synthetic methods. Here we report a series of asymmetric cross-coupling reactions between cyclobutenes and arylboronic acids which are initiated by Rh-catalysed asymmetric carbometallation. After the initial carborhodation, Rh-cyclobutyl intermediates undergo chain-walking or C-H insertion so that overall a variety of additions such as reductive Heck reactions, 1,5-addition and homoallylic substitution are observed. The synthetic applicability of these highly stereoselective transformations is demonstrated in the concise syntheses of the drug candidates Belaperidone and PF-04862853. We anticipate this approach will be widely adopted by synthetic and medicinal chemists. While the carbometallation approach reported here is exemplified with Rh and arylboronic acids, it is likely to be applicable to other metals and nucleophiles.

Copper-Catalyzed Tandem Cross-Coupling and Alkynylogous Aldol Reaction: Access to Chiral Exocyclic α-Allenols.

An enantioselective copper-catalyzed tandem cross-coupling/alkynylogous aldol reaction has been developed. The tetrasubstituted allenoates containing both central and axial chirality have been obtained in moderate to good yields and excellent enantio- and diastereoselectivity. Distinct from the previous use of Cu(I) salts, this protocol features the use of copper(II) salts as a catalytic precursor in this asymmetric cross-coupling reaction.

Low-Temperature Nickel-Catalyzed C-N Cross-Coupling via Kinetic Resolution Enabled by a Bulky and Flexible Chiral N-Heterocyclic Carbene Ligand.

The transition-metal-catalyzed C-N cross-coupling has revolutionized the construction of amines. Despite the innovations of multiple generations of ligands to modulate the reactivity of the metal center, ligands for the low-temperature enantioselective amination of aryl halides remain a coveted target of catalyst engineering. Designs that promote one elementary reaction often create bottlenecks at other steps. We here report an unprecedented low-temperature (as low as -50 °C), enantioselective Ni-catalyzed C-N cross-coupling of aryl chlorides with sterically hindered secondary amines via a kinetic resolution process (s factor up to >300). A bulky yet flexible chiral N-heterocyclic carbene (NHC) ligand is leveraged to drive both oxidative addition and reductive elimination with low barriers and control the enantioselectivity. Computational studies indicate that the rotations of multiple σ-bonds on the C2 -symmetric chiral ligand adapt to the changing needs of catalytic processes. We expect this design would be widely applicable to diverse transition states to achieve other challenging metal-catalyzed asymmetric cross-coupling reactions.

Additions to Racemates: A Strategy for Developing Asymmetric Cross-Coupling Reactions

AbstractIn this Account, the authors describe their progress in developing catalytic asymmetric C(sp3)–C(sp3) and C(sp3)–C(sp2) cross-coupling reactions. Whereas most catalytic enantioselective transformations rely on prochiral or meso starting materials, strategies that use racemic starting materials are rare. Key features of these reactions are efficient mechanisms for deracemization. Here, the authors present copper-catalyzed alkylation and rhodium-catalyzed Suzuki–Miyaura-type arylation reactions, their underlying mechanisms, and their applications in complex-molecule syntheses.

Cobalt-Catalyzed Asymmetric Cross-Coupling Reaction of Fluorinated Secondary Benzyl Bromides with Lithium Aryl Boronates/ZnBr2.

A cobalt-catalyzed asymmetric cross-coupling of α-bromo-α-fluorotoluene derivatives with a variety of aryl zincates derived from lithium aryl n-butyl pinacol boronates and ZnBr2 under mild reaction conditions was described. In addition to mild reaction conditions, another advantage includes the compatibility of various common functional groups such as fluoride, chloride, bromide, cyano, or ester groups. Furthermore, this protocol was successfully applied to the enantioselective synthesis of three fluorinated derivatives of biologically active compounds or drug molecules.

Nickel/Photoredox-Catalyzed Asymmetric Reductive Cross-Coupling of Racemic α-Chloro Esters with Aryl Iodides.

A unique nickel/organic photoredox co-catalyzed asymmetric reductive cross-coupling between α-chloro esters and aryl iodides is developed. This cross-electrophile coupling reaction employs an organic reductant (Hantzsch ester), whereas most reductive cross-coupling reactions use stoichiometric metals. A diverse array of valuable α-aryl esters is formed under these conditions with high enantioselectivities (up to 94 %) and good yields (up to 88 %). α-Aryl esters represent an important family of nonsteroidal anti-inflammatory drugs. This novel synergistic strategy expands the scope of Ni-catalyzed reductive asymmetric cross-coupling reactions.

Enantioselective benzylic C\u2013H arylation via photoredox and nickel dual catalysis

The asymmetric cross-coupling reaction is developed as a straightforward strategy toward 1,1-diaryl alkanes, which are a key skeleton in a series of natural products and bioactive molecules in recent years. Here we report an enantioselective benzylic C(sp3)−H bond arylation via photoredox/nickel dual catalysis. Sterically hindered chiral biimidazoline ligands are designed for this asymmetric cross-coupling reaction. Readily available alkyl benzenes and aryl bromides with various functional groups tolerance can be easily and directly transferred to useful chiral 1,1-diaryl alkanes including pharmaceutical intermediates and bioactive molecules. This reaction proceeds smoothly under mild conditions without the use of external redox reagents.

Asymmetric cross-coupling of alkyl, alkenyl and (hetero)aryl nucleophiles with racemic allyl halides.

Single enantiomer molecules are important for the pharmaceutical and agrochemical industries and increasingly so in materials science. Most strategies to obtain enantiomerically enriched molecules rely on either generating new stereogenic centres from prochiral substrates or resolving racemic mixtures of enantiomers. Dynamic asymmetric processes are powerful methods that use racemic mixtures of chiral substrates as starting material. This Feature Article focuses on asymmetric additions to racemic substrates using non-stabilized sp2- and sp3-hybridized nucleophiles. These reactions bear considerable resemblance to traditional sp2-sp2 cross-coupling reactions in terms of the starting materials used and the products obtained, but the reaction mechanisms are necessarily different.

Ni-Catalyzed C-C Couplings Using Alkyl Electrophiles.

Much effort has been devoted to developing new methods using Ni catalysts for the cross-coupling reaction of alkyl electrophiles with organometallic reagents, and significant achievements in this area have emerged during the past two decades. Nickel catalysts have enabled the coupling reaction of not only primary alkyl electrophiles, but also sterically hindered secondary and tertiary alkyl electrophiles possessing β-hydrogens with various organometallic reagents to construct carbon skeletons. In addition, Ni catalysts opened a new era of asymmetric cross-coupling reaction using alkyl halides. Recent progress in nickel-catalyzed cross-coupling reaction of alkyl electrophiles with sp(3)-, sp(2)-, and sp-hybridized organometallic reagents including asymmetric variants as well as mechanistic insights of nickel catalysis are reviewed in this chapter.

Counteranion-Controlled Unprecedented Diastereo- and Enantioselective Tandem Formal Povarov Reaction for Construction of Bioactive Octahydro-Dipyrroloquinolines

The asymmetric inverse-electron-demand hetero-Diels–Alder (IEHDA) reactions of imines and dienophiles have emerged as an attractive tool for derivatizing optically active complex azaheterocycles. In comparison, such reactions involving iminium ions remain great challenges because of low association of iminium ions with neutral catalytic centers. To overcome this, we report a metal-phosphate-catalyzed asymmetric tandem hydroamination/formal Povarov reaction of secondary aminoalkynes via a chiral counteranion-controlled iminium ion intermediate strategy. Critical to the success of this challenging strategy was chiral phosphate as an ion pair to achieve counteranion-controlled asymmetric reaction of in situ-generated iminium ions. This method enables a convenient, powerful, and atom-economical access to tetracyclic octahydro-dipyrroloquinoline frameworks bearing multiple contiguous stereogenic centers in good yields with diastereo- and enantioselectivities, from acyclic starting materials, and the catalyst loadings could be as low as 1 mol %. The asymmetric cross-coupling reaction of different aminoalkynes has further been demonstrated with good results. Furthermore, this methodology was applied to enantioselective synthesis of incargranine B aglycone epimer in only two steps. The reaction is demonstrated to proceed through a stepwise process for formal Povarov reaction.

Synthesis and reactivity of new aminophenolate complexes of nickel.

New well-defined, paramagnetic nickel complexes have been prepared and characterized by X-ray crystallography. The complexes were found to be active for the cross-coupling of alkyl electrophiles (especially ethyl 2-bromobutyrate) with alkyl Grignard reagents. The ligand architecture in these new complexes could potentially be rendered chiral, opening up future possibilities for performing asymmetric cross-coupling reactions.

Search for Ideal P-Chiral Phosphorus Ligands for Practical Asymmetric Hydrogenation and Asymmetric Suzuki–Miyaura Coupling

The synthesis of P-chiral phosphorus ligands with novel structures is important for the development of efficient asymmetric catalytic transformations. Here, we describe the development of P-chiral phosphorus ligands such as BIBOP, WingPhos, BI-DIME, and <b>8 </b>in our laboratory. Conformational rigidity, high tunability of electronic and steric properties, and convenient physical properties are the main features of our ligand design. Progress in developing practical asymmetric hydrogenation and asymmetric cross-coupling reactions are discussed.