High Levels Of Enantioselectivity Research Articles

Enantioselective Electrophilic Cyanation of Boron Enolates: Scope and Mechanistic Studies.

Chiral β-ketonitriles bearing a stereogenic carbon center at the α-position are an important class of compounds, many of which serve as useful synthetic intermediates for the preparation of chiral 1,3-aminoalcohols, β-hydroxy nitriles, and related derivatives. Although the enantioselective electrophilic cyanation of enolate equivalents is one of the most promising approaches for the synthesis of chiral β-ketonitriles, the available methods are largely limited to reactions of 1,3-dicarbonyl compounds. Herein, we report on enantioselective electrophilic cyanation of boron enolates, which are readily prepared from α,β-unsaturated ketones and diisopinocampheylborane (Ipc2 BH) to afford chiral β-ketonitriles with a high level of enantioselectivity. The present method is scalable and provides facile access to both enantiomers of chiral β-ketonitriles. Analysis of the in situ generated boron enolates by NMR revealed that hydroboration proceeds in a stereospecific manner, providing α,α-disubstituted boron enolates in the form of single isomers. Furthermore, the results of DFT calculations suggest that the cyanation of the boron enolates with p-toluenesulfonyl cyanide (TsCN) proceeds in a highly enantioselective manner through a unique six-membered ring transition state.

Highly stereoselective construction of tetrahydroquinolines via cascade aza-Michael-Michael reaction: Formal [4+2] cycloaddition of β,γ-unsaturated α-ketoesters with 2-aminochalcones

An efficient cascade aza-Michael-Michael sequence for the preparation of tetrahydroquinolines has been established. Three contiguous stereogenic centers are created with high levels of enantioselectivities (79–99% ee) and exclusive diastereoselectivities in the presence of a bifunctional squaramide. This approach is compatible with a broad range of β,γ-unsaturated α-ketoesters and 2-aminochalcones. Our protocol indicated that β-site of β,γ-unsaturated α-ketoester is an available pro-nucleophilic site.

Copper(II)-Catalyzed Asymmetric Photoredox Reactions: Enantioselective Alkylation of Imines Driven by Visible Light

Asymmetric photoredox catalysis offers exciting opportunities to develop new synthetic approaches to chiral molecules through novel reaction pathways. Employing the first-row transition metal complexes as the chiral photoredox catalysts remains, however, a formidable challenge, although these complexes are economic, environmentally friendly, and often exhibit special reactivities. We report in this Article the development of one class of highly efficient asymmetric/photoredox bifunctional catalysts based on the copper(II) bisoxazoline complexes (CuII-BOX) for the light-induced enantioselective alkylation of imines. The reactions proceed under very mild conditions and without a need for any other photosensitizer. The simple catalytic system and readily tunable chiral ligands enable a significantly high level of enantioselectivity for the formation of chiral amine products bearing a tetrasubstituted carbon stereocenter (36 examples, up to 98% ee). Overall, the CuII-BOX catalysts initiate the radical generation, and also govern the subsequent stereoselective transformations. This strategy utilizing chiral complexes comprised of a first-row transition metal and a flexible chiral ligand as the asymmetric photoredox catalysts provides an effective platform for the development of green asymmetric synthetic methods.

Organocatalytic Enantioselective α‐Amination of Thiazol‐4‐one‐5‐carboxylates with Azodicarboxylates

AbstractAn effective method for the asymmetric synthesis of 5‐hydrazinothiazol‐4‐one‐5‐carboxylates was developed. The tetrasubstituted chiral carbon center was generated by asymmetric amination of thiazol‐4‐one‐5‐carboxylate with azodicarboxylate catalyzed by a bifunctional squaramide‐based (1R,2R)‐cyclohexane‐1,2‐diamine backbone in good to excellent yields (40–96%) with high levels of enantioselectivity (92–98% ee). A representative transformation of the amination product to a biologically important 1,3,4‐oxadiazol‐2(3H)‐one is achieved without any appreciable loss in enantioselectivity. Additionally, upon treatment with NaBH3CN, the amination product could also be converted into a biologically important thiazolidin‐4‐one derivative in good yield without any loss of stereochemical integrity.

Octahydrocyclopenta[c]pyridine Scaffold – Enantioselective Synthesis and Indole Annulation

An optically active hexahydrocyclopenta[c]pyridine derivative with quaternary stereocenter was prepared as a new heterocyclic scaffold. Key reaction was the Pd‐catalyzed asymmetric allylic alkylation of a piperidine‐based β‐oxoester, which proceeded in very good yield with high level of enantioselectivity (90 %, 95 % ee). The α‐allyl moiety was transformed into a 1,4‐diketone by Pd‐catalyzed Wacker oxidation with molecular oxygen (89 %). This intermediate was cyclized in an intramolecular aldol reaction furnishing the cyclopentenone motif (86 %). Hydrogenation of the C–C double bond gave the cis‐annulated octahydrocyclopenta[c]pyridine (86 %), which was submitted to Fischer indolization (85 %). Although two regioisomers could be expected, only the angular constitution was observed. Relative and absolute configurations were established by X‐ray crystallography of a para‐iodo benzamide derivative. The utility of the title compound as scaffold is further highlighted by a number of synthetically useful transformations, for instance formation of carboxamides, sulfonamides, ureas and reductive aminations with aldehydes.

Enantioselective α-Allylation of Aryl Acetic Acid Esters via C1-Ammonium Enolate Nucleophiles: Identification of a Broadly Effective Palladium Catalyst for Electron-Deficient Electrophiles.

We have identified a generally effective Pd catalyst for the highly enantioselective cooperative Lewis base/Pd-catalyzed α-allylation of aryl acetic esters using electron-deficient electrophiles. Changing between aldehyde, ketone, ester, and amide substituents at the terminus of intermediate cationic π-(allyl)Pd species affects both the efficiency of the reaction and, in the case of amides, control over the stereochemistry of the product alkene, as a function of the ligand. Tris[tri(2-thienyl)phosphino]Pd(0) serves as a broadly effective catalyst and overcomes these challenges to provide a general, high-yielding, and operationally simple C(sp3)-C(sp3) bond-forming method that gives products with high levels of enantioselectivity.

Enantioselective α‐Benzylation of Acyclic Esters Using π‐Extended Electrophiles

AbstractThe first asymmetric cooperative Lewis base/palladium catalyzed benzylic alkylation of acyclic esters is reported. This reaction proceeds via stereodefined C1‐ammonium enolate nucleophiles. Critical to its success was the identification of benzylic phosphate electrophiles, which were uniquely reactive. Alkylated products were obtained with very high levels of enantioselectivity, and this method has been applied toward the synthesis of the thrombin inhibitor DX‐9065a.

A Straightforward Sequential Approach for the Enantioselective Synthesis of Optically Active α‐Arylmethanol‐1,2,3‐Triazoles

Herein we describe a compelling sequential methodology for obtaining optically active α‐arylmethanols‐1,2,3‐triazoles. The approach is based on the enantioselective alkynylation of aldehydes followed by a one‐pot two‐step desilylation/CuI‐catalyzed azide‐alkyne 1,3‐dipolar cycloaddition (CuAAC), providing the corresponding products with excellent yields and high levels of enantioselectivity. Furthermore, the click chemistry can be performed without affecting the enantiomeric excess. The application of the reaction has been demonstrated in the synthesis of a 1,2,3‐triazole analog of antihistaminic and anticholinergic drug (R)‐orphenadrine.

Enantioselective α-Benzylation of Acyclic Esters Using π-Extended Electrophiles.

The first asymmetric cooperative Lewis base/palladium catalyzed benzylic alkylation of acyclic esters is reported. This reaction proceeds via stereodefined C1-ammonium enolate nucleophiles. Critical to its success was the identification of benzylic phosphate electrophiles, which were uniquely reactive. Alkylated products were obtained with very high levels of enantioselectivity, and this method has been applied toward the synthesis of the thrombin inhibitor DX-9065a.

Paracyclophane‐based Silver Phosphates as Catalysts for Enantioselective Cycloisomerization/Addition Reactions: Synthesis of Bicyclic Furans

AbstractThis manuscript discloses the first use of chiral phosphates based on C2‐symmetric paracyclophane scaffolds as chiral counterions in transition metal catalysis, showing that they may compare favorably with other known chiral phosphates, such as the TRIP phosphate. The targeted catalytic reaction is a silver(I) promoted domino heterocyclization of 2‐(1‐alkynyl)‐2‐alken‐1‐one derivatives, in the presence of C‐, or N‐nucleophiles, which provides an efficient access to substituted bicyclic furans. Results show that high levels of enantioselectivity can be attained with either paracyclophane‐based phosphates or TRIP phosphates, when the nucleophilic reactants display N‐H functions in appropriate positions, near to the nucleophilic center. Therefore, the involvement of H‐bonding between the NH function and the phosphate in the enantiodetermining step is postulated.magnified image

Enantioselective Decarboxylative Propargylation/Hydroamination Enabled by Organo/Metal Cooperative Catalysis.

The first catalytic enantioselective decarboxylative propargylation/hydroamination reaction of ethynyl benzoxazinanones with malononitriles enabled by organo/copper cooperative catalysis was established. Various 3-indolin-malononitrile derivatives, displaying a high tolerance for functional groups, could be obtained in good yields with high levels of enantioselectivity (up to 85% yield, 96:4 er). More importantly, this organo/metal cooperative catalytic system will provide a powerful synthetic strategy for new reaction development.

Arylketone π-Conjugation Controls Enantioselectivity in Asymmetric Alkynylations Catalyzed by Centrochiral Ruthenium Complexes.

The origin of enantioselectivity in the asymmetric alkynylation of trihalomethyl ketones catalyzed by octahedral stereogenic-at-ruthenium complexes has been investigated through density functional theory calculations. Computational results support a mechanism involving formation of a ruthenium acetylide, followed by pre-coordination of the trihalomethyl ketone through the carbonyl oxygen and intramolecular attack of the acetylide via a compact four-membered transition state. Differences in computed free energies of activation for the formation of the major and minor propargyl alcohol enantiomers are in good agreement with the experimentally observed levels of asymmetric induction. Analysis of fragment distortion energies shows that disfavored transition states are destabilized due to the more severe distortion and loss of π-conjugation in the coordinated arylketone fragments. Examination of the different substitution patterns in the ketone substrate and the catalyst reveals the key steric factors that control the enantioselectivity. Finally, calculations indicate promising directions for the simplification of the catalyst scaffold while preserving the high levels of enantioselectivity of these alkynylation reactions.

Asymmetric synthesis of \u03b3-branched amines via rhodium-catalyzed reductive amination

Amines bearing γ-stereocenters are highly important structural motifs in many biologically active compounds. However, reported enantioselective syntheses of these molecules are indirect and often require multiple steps. Herein, we report a general asymmetric route for the one-pot synthesis of chiral γ-branched amines through the highly enantioselective isomerization of allylamines, followed by enamine exchange and subsequent chemoselective reduction. This protocol is suitable for establishing various tertiary stereocenters, including those containing dialkyl, diaryl, cyclic, trifluoromethyl, difluoromethyl, and silyl substituents, which allows for a rapid and modular synthesis of many chiral γ-branched amines. To demonstrate the synthetic utility, Terikalant and Tolterodine are synthesized using this method with high levels of enantioselectivity.

Enantioselective Synthesis of α-(Hetero)aryl Piperidines through Asymmetric Hydrogenation of Pyridinium Salts and Its Mechanistic Insights.

Enantioselective synthesis of α-aryl and α-heteroaryl piperidines is reported. The key step is an iridium-catalyzed asymmetric hydrogenation of substituted N-benzylpyridinium salts. High levels of enantioselectivity up to 99.3:0.7 er were obtained for a range of α-heteroaryl piperidines. DFT calculations support an outersphere dissociative mechanism for the pyridinium reduction. Notably, initial protonation of the final enamine intermediate determines the stereochemical outcome of the transformation rather than hydride reduction of the resultant iminium intermediate.

Enantioselective Synthesis of Pyrroloindolines via Noncovalent Stabilization of Indole Radical Cations and Applications to the Synthesis of Alkaloid Natural Products.

While interest in the synthetic chemistry of radical cations continues to grow, controlling enantioselectivity in the reactions of these intermediates remains a challenge. Based on recent insights into the oxidation of tryptophan in enzymatic systems, we report a photocatalytic method for the generation of indole radical cations as hydrogen-bonded adducts with chiral phosphate anions. These noncovalent open-shell complexes can be intercepted by the stable nitroxyl radical TEMPO· to form alkoxyamine-substituted pyrroloindolines with high levels of enantioselectivity. Further elaboration of these optically enriched adducts can be achieved via a catalytic single-electron oxidation/mesolytic cleavage sequence to furnish transient carbocation intermediates that may be intercepted by a wide range of nucleophiles. Taken together, this two-step sequence provides a simple catalytic method to access a wide range of substituted pyrroloindolines in enantioenriched form via a standard experimental protocol from a common synthetic intermediate. The design, development, mechanistic study, and scope of this process are presented, as are applications of this method to the synthesis of several dimeric pyrroloindoline natural products.

Aminocatalyzed Synthesis of Enantioenriched Phenalene Skeletons through a Friedel-Crafts/Cyclization Strategy.

A series of enantioenriched phenalene-derived compounds were accessed by a Friedel-Crafts/cyclization strategy. Starting from α,β-unsaturated aldehydes and 2-naphthol derivatives, high levels of enantioselectivity were obtained through iminium-enamine catalysis. The catalytic system composed of a diphenylprolinol silyl ether organocatalyst and triethylamine as a base was applied to a combination of diversely functionalized substrates. The obtained phenalene-derived architectures are promising building blocks for reaching natural products and exhibit fluorescence properties.

CuH-Catalyzed Asymmetric Reduction of α,β-Unsaturated Carboxylic Acids to β-Chiral Aldehydes.

The copper hydride (CuH)-catalyzed enantioselective reduction of α,β-unsaturated carboxylic acids to saturated aldehydes is reported. This protocol provides a new method to access a variety of β-chiral aldehydes in good yields, with high levels of enantioselectivity and broad functional group tolerance. A reaction pathway involving a ketene intermediate is proposed based on preliminary mechanistic studies and density functional theory calculations.

Desymmetrizing Enantio- and Diastereoselective Selenoetherification through Supramolecular Catalysis

Selenofunctionalization is used for the introduction of aryl- or alkylseleno moieties, which can then be transformed into other functional groups (such as alkenes and carbonyls). However, asymmetric selenofunctionalization of unactivated olefins is often difficult to realize, as aryl- and alkylseleno cations rapidly interchange between olefinic partners. Recently, it has been demonstrated that Lewis bases, assisted by Bronsted acids, induce high levels of enantioselectivity in selenocyclization reactions. The Bronsted acid serves as an activator for the reaction. In this work, we demonstrate an asymmetric selenoetherification and desymmetrization of olefinic 1,3-diols, driven by a unique chiral pairing between a C2-symmetric cyclic selenide catalyst and a chiral Bronsted acid. The resulting substituted tetrahydrofurans contain a phenylselenoether handle and can be transformed into synthetically useful building blocks. A series of experimental and computational investigations suggest that the reaction proc...

Synthesis and kinetic resolution of substituted tetrahydroquinolines by lithiation then electrophilic quench.

Treatment of N-Boc-2-aryl-1,2,3,4-tetrahydroquinolines with n-butyllithium in THF at -78 °C resulted in efficient lithiation at the 2-position and the organolithiums were trapped with a variety of electrophiles to give substituted products. Variable temperature NMR spectroscopy gave kinetic data that showed that the rate of tert-butoxycarbonyl (Boc) rotation was fast (ΔG‡ ≈ 45 kJ mol-1 at -78 °C) and in situ ReactIR spectroscopy showed fast lithiation at -78 °C. By carrying out the lithiation in the presence of the chiral ligand sparteine, kinetic resolutions with very high levels of enantioselectivity were achieved. The resulting enantioenriched N-Boc-2-aryltetrahydroquinolines were converted to 2,2-disubstituted products without significant loss in enantiopurity. Most electrophiles add at the 2-position and the chemistry provides a way to access tetrahydroquinolines that are fully substituted alpha to the nitrogen atom. Notably, either enantiomer of the 2,2-disubstituted tetrahydroquinolines can be obtained with high selectivity from the same enantiomer of the chiral ligand. Unusually, when methyl cyanoformate was used as the electrophile, substitution occurred in the ortho position of the aryl ring attached at C-2. This change in regioselectivity on changing the electrophile was probed by deuterium isotope studies and by DFT calculations which suggested that the binding of the cyanoformate altered the structure of the intermediate organolithium. Secondary amine products can be prepared by removing the Boc group with acid or by inducing the Boc group to rearrange to the 2-position in the presence of triethylborane and this carbonyl N-to-C rearrangement occurs with retention of configuration from the intermediate enantiomerically enriched organolithium species.

Asymmetric Synthesis of Allylic Fluorides via Fluorination of Racemic Allylic Trichloroacetimidates Catalyzed by a Chiral Diene-Iridium Complex

The ability to use racemic allylic trichloroacetimidates as competent electrophiles in a chiral bicyclo[3.3.0]octadiene-ligated iridium-catalyzed asymmetric fluorination with Et3N·3HF is described. The methodology represents an effective route to prepare a wide variety of α-linear, α-branching, and β-heteroatom substituted allylic fluorides in good yields, excellent branched-to-linear ratios, and high levels of enantioselectivity. Additionally, the catalytic system is amendable to the fluorination of optically active allylic trichloroacetimidate substrates to afford the fluorinated products in good yields with exclusively branched selectivity. Excellent levels of catalyst-controlled diastereoselectivities using either (R,R) or (S,S)-bicyclo[3.3.0]octadiene ligand are observed. The synthetic utility of the fluorination process is illustrated in the asymmetric synthesis of 15-fluorinated prostaglandin and neuroprotective agent P7C3-A20.