High Levels Of Enantioselectivity Research Articles

Nickel/Copper‐Cocatalyzed Asymmetric Benzylation of Aldimine Esters for the Enantioselective Synthesis of α‐Quaternary Amino Acids

AbstractThe first asymmetric Ni/Cu cocatalyzed benzylation of aldimine esters is reported. A series of benzyl‐substituted α‐quaternary amino acids could be synthesized in high yield and with high levels of enantioselectivity (up to 90 % yield and 99 % ee). The experimental and theoretical calculation results suggested that the strong electrophilicity of the η3‐benzylnickel intermediate is crucial for the high reactivity, enabling the reaction under base‐free conditions. Furthermore, this method has been applied to the synthesis of the cell adhesion inhibitor BIRT‐377 analogues, and the key intermediate of the NK1 receptor antagonist PD154075 and CCK‐B receptor antagonist CI‐988.

Chiral Sulfide/Phosphoric Acid Cocatalyzed Enantioselective Intermolecular Oxysulfenylation of Alkenes with Phenol and Alcohol O -Nucleophiles

Chiral Sulfide/Phosphoric Acid Cocatalyzed Enantioselective Intermolecular Oxysulfenylation of Alkenes with Phenol and Alcohol <i>O</i> -Nucleophiles

Atropoenantioselective palladaelectro-catalyzed anilide C-H olefinations viable with natural sunlight as sustainable power source.

Enantioselective electrocatalyzed transformations represent a major challenge. We herein achieved atropoenantioselective pallada-electrocatalyzed C–H olefinations and C–H allylations with high efficacy and enantioselectivity under exceedingly mild reaction conditions. With (S)-5-oxoproline as the chiral ligand, activated and non-activated olefins were suitable substrates for the electro-C–H activations. Dual catalysis was devised in terms of electro-C–H olefination, along with catalytic hydrogenation. Challenging enantiomerically-enriched chiral anilide scaffolds were thereby obtained with high levels of enantio-control in the absence of toxic and cost-intensive silver salts. The resource-economy of the transformation was even improved by directly employing renewable solar energy.

Regio- and Enantioselective Iridium-Catalyzed Amination of Alkyl-Substituted Allylic Acetates with Secondary Amines.

Robust air-stable cyclometalated π-allyliridium C,O-benzoates modified by (S)-tol-BINAP catalyze the reaction of secondary aliphatic amines with racemic alkyl-substituted allylic acetates to furnish products of allylic amination with high levels of enantioselectivity. Complete branched regioselectivities were observed despite the formation of more highly substituted C-N bonds.

Organocatalysis: A Tool of Choice for the Enantioselective Nucleophilic Dearomatization of Electron-Deficient Six-Membered Ring Azaarenium Salts

Nucleophilic dearomatization of azaarenium salts is a powerful strategy to access 3D scaffolds of interest from easily accessible planar aromatic azaarene compounds. Moreover, this approach yields complex dihydroazaarenes by allowing the functionalization of the scaffold simultaneously to the dearomatization step. On the other side, organocatalysis is nowadays recognized as one of the pillars of the asymmetric catalysis field of research and is well-known to afford a high level of enantioselectivity for a myriad of transformations thanks to well-organized transition states resulting from low-energy interactions (electrostatic and/or H-bonding interactions…). Consequently, in the last fifteen years, organocatalysis has met great success in nucleophilic dearomatization of azaarenium salts. This review summarizes the work achieved up to date in the field of organocatalyzed nucleophilic dearomatization of azaarenium salts (mainly pyridinium, quinolinium, quinolinium and acridinium salts). A classification by organocatalytic mode of activation will be disclosed by shedding light on their related advantages and drawbacks. The versatility of the dearomatization approach will also be demonstrated by discussing several chemical transformations of the resulting dihydroazaarenes towards the synthesis of structurally complex compounds.

Synthesis of Chiral Spirolactams via Sequential C−H Olefination/Asymmetric [4+1] Spirocyclization under a Simple CoII/Chiral Spiro Phosphoric Acid Binary System

AbstractAn unprecedented enantioselective synthesis of spiro‐γ‐lactams via a sequential C−H olefination/asymmetric [4+1] spirocyclization under a simple CoII/chiral spiro phosphoric acid (SPA) binary system is reported. A range of biologically important spiro‐γ‐lactams are obtained with high levels of enantioselectivity (up to 98 % ee). The concise, asymmetric synthesis of an aldose reductase inhibitor was successfully achieved. Notably, contrast to previous reports that relied on the use of cyclopentadienyl or its derivatives (achiral Cp*, CptBu, or chiral Cpx) ligated CoIII complexes requiring tedious steps to prepare, cheap and commercially available cobalt(II) acetate tetrahydrate was used as an efficient precatalyst.

Synthesis of Chiral Spirolactams via Sequential C-H Olefination/Asymmetric [4+1] Spirocyclization under a Simple CoII /Chiral Spiro Phosphoric Acid Binary System.

An unprecedented enantioselective synthesis of spiro-γ-lactams via a sequential C-H olefination/asymmetric [4+1] spirocyclization under a simple CoII /chiral spiro phosphoric acid (SPA) binary system is reported. A range of biologically important spiro-γ-lactams are obtained with high levels of enantioselectivity (up to 98 % ee). The concise, asymmetric synthesis of an aldose reductase inhibitor was successfully achieved. Notably, contrast to previous reports that relied on the use of cyclopentadienyl or its derivatives (achiral Cp*, CptBu , or chiral Cpx ) ligated CoIII complexes requiring tedious steps to prepare, cheap and commercially available cobalt(II) acetate tetrahydrate was used as an efficient precatalyst.

Enantioselective Catalytic Synthesis of α-Halogenated α-Aryl-β2,2-amino Acid Derivatives.

The enantioselective synthesis of a broad variety of novel differently functionalized α-halogenated α-aryl-β2,2-amino acid derivatives by means of an ammonium-salt-catalyzed asymmetric α-halogenation of isoxazolidin-5-ones was accomplished. Key to success to obtain high levels of enantioselectivities was the use of Maruoka’s spirocyclic binaphthyl-based ammonium salts, and detailed accompanying mechanistic studies using density functional theory methods revealed the key features for the catalyst–substrate interactions.

Organocatalysis for the Asymmetric Michael Addition of Cycloketones and α, β-Unsaturated Nitroalkenes

Michael addition is one of the most important carbon–carbon bond formation reactions. In this study, an (R, R)-1,2-diphenylethylenediamine (DPEN)-based thiourea organocatalyst was applied to the asymmetric Michael addition of nitroalkenes and cycloketones to produce a chiral product. The primary amine moiety in DPEN reacts with the ketone to form an enamine and is activated through the hydrogen bond formation between the nitro group in the α, β-unsaturated nitroalkene and thiourea. Here, the aim was to obtain an asymmetric Michael product through the 1,4-addition of the enamine to an alkene to form a new carbon–carbon bond. As a result, the primary amine of the chiral diamine was converted into an enamine. The reaction proceeded with a relatively high level of enantioselectivity achieved using double activation through the hydrogen bonding of the nitro group and thiourea. Michael products with high levels of enantioselectivity (76–99% syn ee) and diastereoselectivity (syn/anti = 9/1) were obtained with yields in the range of 88–99% depending on the ketone.

Enantioselective α-Chlorination Reactions of in Situ Generated C1 Ammonium Enolates under Base-Free Conditions.

The asymmetric α-chlorination of activated aryl acetic acid esters can be carried out with high levels of enantioselectivities utilizing commercially available isothiourea catalysts under base-free conditions. The reaction, which proceeds via the in situ formation of chiral C1 ammonium enolates, is best carried out under cryogenic conditions combined with a direct trapping of the activated α-chlorinated ester derivative to prevent epimerization, thus allowing for enantioselectivities of up to e.r. 99:1.

Copper(II) Acetate-Induced Oxidation of Hydrazones to Diazo Compounds under Flow Conditions Followed by Dirhodium-Catalyzed Enantioselective Cyclopropanation Reactions.

A tandem system comprising in-line diazo compound synthesis and downstream consumption in a rhodium-catalyzed cyclopropanation reaction has been developed. Passing hydrazone through a silica column absorbed with Cu(OAc)2-H2O/N,N-dimethylaminopyridine oxidized the hydrazone to generate an aryldiazoacetate in flow. The crude aryldiazoacetate elutes from this column directly into a downstream cyclopropanation reaction, catalyzed by the chiral dirhodium tetracarboxylates, Rh2(R-p-Ph-TPCP)4 and Rh2(R-PTAD)4. This convenient flow to batch method was applied to the synthesis of a range of 1,2-diarylcyclopropane-1-carboxylates in high yields and with high levels of enantioselectivity.

Enantioselective Intermolecular C-H Amination Directed by a Chiral Cation.

The enantioselective amination of C(sp3)–H bonds is a powerful synthetic transformation yet highly challenging to achieve in an intermolecular sense. We have developed a family of anionic variants of the best-in-class catalyst for Rh-catalyzed C–H amination, Rh2(esp)2, with which we have associated chiral cations derived from quaternized cinchona alkaloids. These ion-paired catalysts enable high levels of enantioselectivity to be achieved in the benzylic C–H amination of substrates bearing pendant hydroxyl groups. Additionally, the quinoline of the chiral cation appears to engage in axial ligation to the rhodium complex, providing improved yields of product versus Rh2(esp)2 and highlighting the dual role that the cation is playing. These results underline the potential of using chiral cations to control enantioselectivity in challenging transition-metal-catalyzed transformations.

Ground-State Electron Transfer as an Initiation Mechanism for Biocatalytic C-C Bond Forming Reactions.

The development of non-natural reaction mechanisms is an attractive strategy for expanding the synthetic capabilities of substrate promiscuous enzymes. Here, we report an "ene"-reductase catalyzed asymmetric hydroalkylation of olefins using α-bromoketones as radical precursors. Radical initiation occurs via ground-state electron transfer from the flavin cofactor located within the enzyme active site, an underrepresented mechanism in flavin biocatalysis. Four rounds of site saturation mutagenesis were used to access a variant of the "ene"-reductase nicotinamide-dependent cyclohexanone reductase (NCR) from Zymomonas mobiles capable of catalyzing a cyclization to furnish β-chiral cyclopentanones with high levels of enantioselectivity. Additionally, wild-type NCR can catalyze intermolecular couplings with precise stereochemical control over the radical termination step. This report highlights the utility for ground-state electron transfers to enable non-natural biocatalytic C-C bond forming reactions.

Catalytic Asymmetric [4+1] Spiroannulation of α-Bromo-β-Naphthols with Azoalkenes by an Electrophilic Dearomatization/S RN 1-Debromination Approach

Catalytic Asymmetric [4+1] Spiroannulation of α-Bromo-β-Naphthols with Azoalkenes by an Electrophilic Dearomatization/S _RN 1-Debromination Approach

Enantioselective Ruthenium-Catalyzed C-H Alkylations by a Chiral Carboxylic Acid with Attractive Dispersive Interactions.

Asymmetric ruthenium-catalyzed C-H alkylations were enabled by a chiral C2-symmetric carboxylic acid. The mild cooperative ruthenium(II) catalysis set the stage for the assembly of chiral tetrahydrocarbazoles and cyclohepta[b]indoles with high levels of enantioselectivity at room temperature. Mechanistic studies by experiment and computation identified a fast C-H ruthenation, along with a rate- and enantio-determining proto-demetalation. The asymmetric induction was governed by weak attractive secondary dispersion interactions as found in NCI analysis of the key transition states.

Rapid Construction of Polycyclic Ketones and the Divergent Kinetic Resolution Using Ruthenium‐Catalyzed Transfer Hydrogenation

AbstractA unique cascade sequence of vinylogous Michael addition‐Michael addition‐oxa‐Michael addition using dienone substrates was reported for the first time, achieving the rapid construction of 5/6/5 fused ring compounds in good yields with good to high stereoselectivities under mild conditions. Enantioenriched polycyclic rings can be obtained with high level of enantioselectivity by the stereodivergent resolution using ruthenium‐catalyzed transfer hydrogenation. The protocol provides a concise approach for the construction of the related fused ring substances.magnified image

Asymmetric Catalysis of Chiral Bifunctional Selenides and Selenonium Salts Bearing a Urea Group

AbstractCatalytic asymmetric reactions with chiral organoselenium catalysts have become one of the most important research topics in the field of organocatalysis. Despite the presence of several effective chiral selenium catalysts, further developments of new chiral organoseleniums are still desired due to their remarkable potential as asymmetric organocatalysts. Herein, we report the synthesis and asymmetric catalysis of chiral bifunctional selenides and selenonium salts bearing a urea group. The new chiral bifunctional selenide organocatalysts promote asymmetric halocyclizations with good to high levels of enantioselectivity. Furthermore, we report a reaction involving a precious example of a chiral tertiary selenonium salt‐catalyzed asymmetric phase‐transfer conjugate addition.

Chiral-Anion-Mediated Asymmetric Heck-Matsuda Reaction of Acyclic Alkenyl Alcohols.

Acyclic internal alkenes are a class of challenging substrates in asymmetric Heck-type reactions due to difficulties related to both reactivity and selectivity control. Employing acyclic alkenyl alcohols, an asymmetric Heck-Matsuda reaction is developed through the strategy of chiral anion phase transfer. Various chiral ketones could be obtained in high levels of enantioselectivity. A catalytic amount of dimethyl sulfoxide (DMSO) as an additive is crucial for the reaction to suppress the palladium-hydride-mediated side reactions.

Designing successful monodentate N-heterocyclic carbene ligands for asymmetric metal catalysis.

Chiral ligands are of particular importance in asymmetric transition-metal catalysis. Although the development of effective chiral monodentate N-heterocyclic carbenes (NHCs) has been slow, a growing amount of papers have been published in recent years showing their unique efficiency as chiral ancillary ligands. Herein we provide an overview of NHC structures that accomplish high levels of enantioselectivity (≥90% ee) and give guidelines to their use and thoughts on the future of this field.

Effective synthesis of bicyclodienes via palladium-catalyzed asymmetric allylic alkylation and ruthenium-catalyzed cycloisomerization.

[n.3.0]Bicycles (n = 3–6) can be synthesized using palladium-catalyzed asymmetric allylic alkylation followed by ruthenium-catalyzed cycloisomerization. New types of triarylphosphino-1,2-diaminooxazoline ligands show the same high levels of enantioselectivity observed with Trost ligand when employed in Pd-catalyzed allylic alkylation reactions. The enyne products of these allylic alkylation reactions were further elaborated using a Ru-catalyzed redox isomerization process, for which a mechanism is proposed.