Enantioselective Cross-coupling Research Articles

An Electroreductive Approach to Nickel-Catalyzed Enantioselective Cross-Coupling of Aryl Aziridines

Key words aryl aziridines - electrochemistry - homoallylic amines - nickel catalysis - reductive cross-coupling - vinyl bromides

Site- and enantioselective cross-coupling of saturated N-heterocycles with carboxylic acids by cooperative Ni/photoredox catalysis

Site- and enantioselective cross-coupling of saturated N-heterocycles and carboxylic acids—two of the most abundant and versatile functionalities—to form pharmaceutically relevant α-acylated amine derivatives remains a major challenge in organic synthesis. Here, we report a general strategy for the highly site- and enantioselective α-acylation of saturated N-heterocycles with in situ-activated carboxylic acids. This modular approach exploits the hydrogen-atom-transfer reactivity of photocatalytically generated chlorine radicals in combination with asymmetric nickel catalysis to selectively functionalize cyclic α-amino C−H bonds in the presence of benzylic, allylic, acyclic α-amino, and α-oxy methylene groups. The mild and scalable protocol requires no organometallic reagents, displays excellent chemo-, site- and enantioselectivity, and is amenable to late-stage diversification, including a modular synthesis of previously inaccessible Taxol derivatives. Mechanistic studies highlight the exceptional versatility of the chiral nickel catalyst in orchestrating (i) catalytic chlorine elimination, (ii) alkyl radical capture, (iii) cross-coupling, and (iv) asymmetric induction.

Enantioselective Suzuki cross-coupling of 1,2-diboryl cyclopropanes.

Herein, we describe the catalytic enantioselective cross-coupling of 1,2-bisboronic esters. Prior work on group specific cross coupling is limited to the use of geminal bis-boronates. This desymmetrization provides a novel approach to prepare enantioenriched cyclopropyl boronates with three contiguous stereocenters, that could be further derivatized through selective functionalization of the carbon-boron bond. Our results suggest that transmetallation, which is the enantiodetermining step, takes place with retention of stereochemistry at carbon.

Enantioselective construction of ortho-sulfur- or nitrogen-substituted axially chiral biaryls and asymmetric synthesis of isoplagiochin D

Axially chiral biaryl motifs possessing ortho-heteroatom-substituted functionalities exist widely in the structures of natural products and have served as foundation for constructing prominent chiral organocatalysts, ligands, functional materials, and even bioactive molecules. However, a general and enantioselective synthesis of such chiral structures with high synthetic value is rare. Taking advantage of the BaryPhos-facilitated asymmetric Suzuki-Miyaura cross-coupling, we have established a general, efficient and enantioselective construction of the ortho sulfur- or nitrogen-substituted axially chiral biaryls. The protocol shows excellent compatibility to various functional groups and structural features, delivering chiral biaryl structures with ortho-sulfonyl groups or with ortho-nitro groups at a broad range of molecular diversity and complexity. The immobilization of BaryPhos on polyethylene glycol (PEG) support has enabled homogeneous enantioselective cross-coupling in aqueous media and the palladium catalyst recycling for multiple times. The method has enabled a concise 10-step asymmetric synthesis of isoplagiochin D as well as the construction of chiroptical molecules with circularly polarized luminescence (CPL) properties.

Modular Access to Chiral α-(Hetero)aryl Amines via Ni/Photoredox-Catalyzed Enantioselective Cross-Coupling.

Chiral α-aryl N-heterocycles are commonly found in natural products, pharmaceutical agents, and chiral catalysts but remain challenging to access via asymmetric catalysis. Herein, we report a general and modular approach for the direct enantioselective α-arylation of saturated azacycles and acyclic N-alkyl benzamides via nickel/photoredox dual catalysis. This process exploits the hydrogen atom transfer ability of photoeliminated chlorine radicals to convert azacycles to the corresponding α-amino alkyl radicals that then are coupled with ubiquitous and inexpensive (hetero)aryl chlorides. These coupling reactions require no oxidants or organometallic reagents, feature feedstock starting materials, a broad substrate scope, and high enantioselectivities, and are applicable to late-stage diversification of medicinally relevant complex molecules. Mechanistic studies suggest that the nickel catalyst uncommonly plays multiple roles, accomplishing chlorine radical generation, α-amino radical capture, cross-coupling, and asymmetric induction.

Catalytic reductive ring opening of epoxides enabled by zirconocene and photoredox catalysis

Catalytic reductive ring opening of epoxides enabled by zirconocene and photoredox catalysis

Enantioselective Cross-Coupling of Alkenyl Boronates and Carbamoyl Chlorides

Enantioselective Cross-Coupling of Alkenyl Boronates and Carbamoyl Chlorides

An atom economical approach for enantioselective cross dehydrogenative coupling

Asymmetric C−H/C−H cross coupling offers an efficient strategy for direct synthesis of enantioriched molecules. In this issue of Chem Catalysis, You and coworkers disclosed a Pd catalyzed approach for enantioselective cross coupling between indolizines and dialkylaminomethylferrocenes. Using this protocol, a range of chiral planar ferrocenes have been accessed under mild condition.

Nickel-Catalyzed Stereo- and Enantioselective Cross-Coupling of gem-Difluoroalkenes with Carbon Electrophiles by C—F Bond Activation

Nickel-Catalyzed Stereo- and Enantioselective Cross-Coupling of <i>gem</i>-Difluoroalkenes with Carbon Electrophiles by C—F Bond Activation

Recent Advances in Cross-Couplings of Functionalized Organozinc Reagents

AbstractCross-couplings involving organozinc reagents usually require a Pd-catalyst (Negishi cross-coupling), however, uncatalyzed cross-couplings of zinc organometallics proceed well in the absence of transition-metal catalysts with reactive electrophiles such as benzal 1,1-diacetates, benzhydryl acetates, and iminium trifluoroacetates. Organozinc compounds also undergo C–N bond formation with O-benzoylhydroxylamines or organic azides in the presence of cobalt- or iron-catalysts. Highly diastereoselective and enantioselective cross-couplings can be readily performed with room-temperature configurationally stable alkylzinc species, producing diastereoselectively and enantiomerically enriched products. Finally, highly regioselective magnesiations of functionalized arenes and heteroarenes undergo Negishi (after transmetalation with ZnCl2) or Cu-catalyzed cross-couplings.1 Introduction2 Uncatalyzed Cross-Couplings of Organozinc Reagents with Highly Electrophilic Partners3 Iron- and Cobalt-Catalyzed Aminations using Organozinc Reagents4 Stereo- and Regioselective Cross-Couplings of Organozinc Reagents5 Conclusion

Enantioselective Cross-Coupling of Electron-Deficient Alkenes via Ir-Catalyzed Vinylic sp2 C-H Alkylation.

A chiral Ir-catalyzed reaction of α-aryl-α,β-unsaturated amides with β-substituted acrylates proceeded to give formal conjugate adducts in high yield and ee (up to 99% yield and up to 95% ee). This is the first example of the enantioselective cross-coupling of two different electron-deficient alkenes via vinylic sp2 C-H activation, and polyfunctionalized chiral compounds were obtained.

Frontispiece: Enantioselective Cross‐couplings between Halide Derivatives and Organometallics by Using Iron and Cobalt Catalysts: Formation of C−C Bonds

Recent achievements of iron- and cobalt-catalyzed enantioselective cross-couplings of halide derivatives with organometallic reagents for the construction of C−C bonds are discussed. Synthetic applications of enantioselective cross-couplings to natural products and biologically active compounds are also covered showing the power of these cross-couplings in organic synthesis. Read more in the Minireview by T. Shu and J. Cossy on page 11021 ff.

Enantioselective Cross-couplings between Halide Derivatives and Organometallics by Using Iron and Cobalt Catalysts: Formation of C-C Bonds.

This review highlights the recent achievements of iron- and cobalt-catalyzed enantioselective cross-couplings of halide derivatives with organometallic reagents for the construction of C-C bonds. Synthetic applications of enantioselective cross-couplings to natural products and biologically active compounds are also covered showing the power of these cross-couplings in organic synthesis.

Enantioselective C(sp3)-C(sp3) cross-coupling of non-activated alkyl electrophiles via nickel hydride catalysis.

Cross-coupling of two alkyl fragments is an efficient method to produce organic molecules rich in sp3-hybridized carbon centers, which are attractive candidate compounds in drug discovery. Enantioselective C(sp3)–C(sp3) coupling is challenging, especially of alkyl electrophiles without an activating group (aryl, vinyl, carbonyl). Here we report a strategy based on nickel hydride addition to internal olefins followed by nickel-catalyzed alkyl-alkyl coupling. This strategy enables enantioselective cross-coupling of non-activated alkyl halides with alkenyl boronates to produce chiral alkyl boronates. Employing readily available and stable olefins as pro-chiral nucleophiles, the coupling proceeds under mild conditions and exhibits broad scope and high functional group tolerance. Applications for the functionalization of natural products and drug molecules, as well as the synthesis of chiral building blocks and a key intermediate to (S)-(+)-Pregabalin, are demonstrated.

Diastereo- and Enantioselective Cross-Couplings of Secondary Alkylcopper Reagents with 3-Halogeno-Unsaturated Carbonyl Derivatives.

Chiral secondary alkylcopper reagents were prepared from the corresponding alkyl iodides with retention of configuration by an I/Li‐exchange using tBuLi (−100 °C, 1 min) followed by a transmetalation with CuBr⋅P(OEt)3 (−100 °C, 20 s). These stereodefined secondary alkylcoppers underwent stereoretentive cross‐couplings with several 3‐iodo or 3‐bromo unsaturated carbonyl derivatives leading to the corresponding γ‐methylated Michael acceptors in good yields and with high diastereoselectivities (dr up to 96:4). The method was extended to enantiomerically enriched alkylcoppers, providing optically enriched advanced natural product intermediates with up to 90 % ee.

General Synthesis of Chiral α,α-Diaryl Carboxamides by Enantioselective Palladium-Catalyzed Cross-Coupling

A general synthesis of chiral α,α-diaryl carboxamides is developed by enantioselective cross-coupling between 2-bromo-2-aryl carboxamides and arylboronic acids, leading to a series of chiral α,α-diaryl carboxamides with various electronic properties and functionalities in moderate to excellent enantioselectivities and yields. The employment of a sterically bulky chiral P,P═O ligand L2 is critical for the reactivity and selectivity. This protocol is applied to an efficient asymmetric synthesis of a key intermediate of dopamine receptor agonist SKF 38393.

Cobalt-Bisoxazoline-Catalyzed Enantioselective Cross-Coupling of α-Bromo Esters with Alkenyl Grignard Reagents.

The first catalytic asymmetric Kumada cross-coupling of organic halides with alkenyl Grignard reagents has been developed. The reaction was promoted by the cobalt-bisoxazoline catalyst and afforded various α-alkyl-β,γ-unsaturated esters with excellent enantioselectivities and moderate to good yields (≤95% ee and ≤82% yields). The formal synthesis of the California red scale pheromone using this method was investigated, and radical clock experiments were performed.

Enantioselective Conjunctive Cross-Couplings Leading to α-Boryl Allenes

Enantioselective Conjunctive Cross-Couplings Leading to α-Boryl Allenes

Enantioselective Conjunctive Cross-Coupling Strategy for the Formation of anti-1,2-Dimetalloid Compounds

Enantioselective Conjunctive Cross-Coupling Strategy for the Formation of anti-1,2-Dimetalloid Compounds

Enantioselective Cross-Coupling for Axially Chiral Tetra-ortho-Substituted Biaryls and Asymmetric Synthesis of Gossypol.

The axially chiral tetra-ortho-substituted biaryl skeleton exists in numerous biologically important natural products, pharmaceutical molecules, chiral catalysts, and ligands. The efficient synthesis of chiral tetra-ortho-substituted biaryl structures remains a challenging but unsolved problem. Among various asymmetric synthetic protocols, enantioselective Suzuki-Miyaura cross-coupling represents one of the most straightforward and versatile approaches. Herein we describe a powerful Suzuki-Miyaura coupling enabled by a P-chiral monophosphorus ligand BaryPhos, providing a broad range of synthetically challenging chiral tetra-ortho-substituted biaryls in excellent enantioselectivities and yields. In addition to the enhanced reactivity for sterically hindered cross-coupling, the rational design of BaryPhos also enabled a new catalysis mode of asymmetric cross-coupling involving noncovalent interactions between the ligand and two coupling partners to effect efficient stereoinduction. This protocol is robust and practical, allowing for a concise enantioselective synthesis of therapeutically valuable male contraceptive and antitumor agent gossypol.