Enamine Catalysis Research Articles

Enantioselective SN1-type reaction via electrochemically generated chiral α-Imino carbocation intermediate

Electrochemical reactions via carbocation intermediates remain fundamental transformations that build up molecular functionality and complexity in a sustainable manner. Enantioselective control of such processes is a great challenge in a highly ionic electrolyte solution. Here, we report an anodic generation of chiral α-imino carbocation intermediates by enamine catalysis. The chiral carbocation intermediates can be intercepted by a variety of nucleophiles such as alcohols, water and thiols with high stereoselectivity. The key SN1 step proceeds via a tertiary amine-mediated proton shuttle that facilitates facial selection in reacting with carbocation.

Frontispiece: Design and Evolution of an Enzyme for the Asymmetric Michael Addition of Cyclic Ketones to Nitroolefins by Enamine Catalysis

Frontispiece: Design and Evolution of an Enzyme for the Asymmetric Michael Addition of Cyclic Ketones to Nitroolefins by Enamine Catalysis

Frontispiz: Design and Evolution of an Enzyme for the Asymmetric Michael Addition of Cyclic Ketones to Nitroolefins by Enamine Catalysis

Frontispiz: Design and Evolution of an Enzyme for the Asymmetric Michael Addition of Cyclic Ketones to Nitroolefins by Enamine Catalysis

Visible-Light-Promoted Enantioselective α-Amidation of Aldehydes by Harnessing Organo-Iron Dual Catalysis.

The strategic integration of organocatalysis with transition-metal catalysis to achieve otherwise unattainable stereoselective transformations may serve as a powerful synthetic tool. Herein, we present a synthetically versatile α-amidation of aldehydes by leveraging dual iron and chiral enamine catalysis in an enantioselective manner (up to >99:1 er). Experimental and computational studies have led us to propose a new mechanistic platform, wherein visible-light-promoted LMCT generates [Fe(II)Cl3-], which effectively activates dioxazolones to form an iron-acylnitrenoid radical that inserts into chiral enamine intermediates.

Design and Evolution of an Enzyme for the Asymmetric Michael Addition of Cyclic Ketones to Nitroolefins by Enamine Catalysis.

Consistent introduction of novel enzymes is required for developing efficient biocatalysts for challenging biotransformations. Absorbing catalytic modes from organocatalysis may be fruitful for designing new-to-nature enzymes with novel functions. Herein we report a newly designed artificial enzyme harboring a catalytic pyrrolidine residue that catalyzes the asymmetric Michael addition of cyclic ketones to nitroolefins through enamine activation with high efficiency. Diverse chiral γ-nitro cyclic ketones with two stereocenters were efficiently prepared with excellent stereoselectivity (up to 97 % e.e., >20 : 1 d.r.) and good yield (up to 86 %). This work provides an efficient biocatalytic strategy for cyclic ketone functionalization, and highlights the usefulness of artificial enzymes for extending biocatalysis to further non-natural reactions.

Design and Evolution of an Enzyme for the Asymmetric Michael Addition of Cyclic Ketones to Nitroolefins by Enamine Catalysis

AbstractConsistent introduction of novel enzymes is required for developing efficient biocatalysts for challenging biotransformations. Absorbing catalytic modes from organocatalysis may be fruitful for designing new‐to‐nature enzymes with novel functions. Herein we report a newly designed artificial enzyme harboring a catalytic pyrrolidine residue that catalyzes the asymmetric Michael addition of cyclic ketones to nitroolefins through enamine activation with high efficiency. Diverse chiral γ‐nitro cyclic ketones with two stereocenters were efficiently prepared with excellent stereoselectivity (up to 97 % e.e., >20 : 1 d.r.) and good yield (up to 86 %). This work provides an efficient biocatalytic strategy for cyclic ketone functionalization, and highlights the usefulness of artificial enzymes for extending biocatalysis to further non‐natural reactions.

Direct Transamidation of Thioamides with Amines via Acetophenone-Promoted Enamine Catalysis under Metal-Free Conditions.

Herein, we developed a highly selective, efficient, and simple method for direct transamidation of thioamides with amines, promoted by commercially available acetophenone under metal-/solvent-free conditions. The reaction tolerated a wide range of functional groups and substrates, including single- or double-thioamides, benzylamines, or alkyl/cycloalkyl-substituted aliphatic amines. The present protocol can be applied to gram-scale in good yields. In addition, the Pt-/Ni-complexes of double-transamidation products were obtained in good to excellent yields. The investigation of photophysical properties indicated that the fluorescence spectra of Pt-complexes showed an emission band centered at 550-750 nm and exhibited red fluorescence when irradiated by a UV lamp (365 nm).

Enamine/Iminium-based Dual Organocatalytic Systems for Asymmetric Catalysis and Synthesis.

The rational combination of two catalysts to expedite the construction of chiral complex biologically and pharmacologically relevant chiral compounds has widely gained momentum over the past decade. In particular, enamine or iminium catalysis ensuing from the activation of aldehyde or ketone by chiral amine catalysts in conjugation with other organocatalytic cycles has facilitated several asymmetric transformations to yield the enantioenriched products. Regardless of the considerable discussion on the various dual catalytic approaches, literature lacks a comprehensive review focusing on the enamine and iminium-based dual organocatalytic systems. Thus, this review article has discussed the noteworthy achievements in the field of asymmetric catalysis and synthesis catalyzed by the enamine and iminium-based dual organocatalytic systems.

Ligating Catalytically Active Peptides onto Microporous Polymers: A General Route Toward Specifically-Functional High Surface Area Platforms.

A versatile post-synthetic modification strategy to functionalize a high surface area microporous network (MPN-OH) by bio-orthogonal inverse electron-demand Diels-Alder (IEDDA) ligation is presented. While the polymer matrix is modified with a readily accessible norbornene isocyanate (Nor-NCO), a series of functional units presenting the robust asymmetric 1,2,4,5-tetrazine (Tz) allows easy functionalization of the MPN by chemoselective Nor/Tz ligation. A generic route is demonstrated, modulating the internal interfaces by introducing carboxylates, amides or amino acids as well as an oligopeptide d-Pro-Pro-Glu organocatalyst. The MPN-Pz-Peptide construct largely retains the catalytic activity and selectivity in an enantioselective enamine catalysis, demonstrates remarkable availability in different solvents, offers heterogeneous organocatalysis in bulk and shows stability in recycling settings.

Highly efficient morpholine-based organocatalysts for the 1,4-addition reaction between aldehydes and nitroolefins: an unexploited class of catalysts.

Many studies have demonstrated how the pyrrolidine nucleus is more efficient than the corresponding piperidine or morpholine as organocatalysts in the condensation of aldehydes with electrophiles via enamine. Focussing on morpholine-enamines, their low reactivity is ascribed to the presence of oxygen on the ring and to the pronounced pyramidalisation of nitrogen, decreasing the nucleophilicity of the enamine. Thus, the selection of efficient morpholine organocatalysts appears to be a difficult challenge. Herein, we reported on the synthesis of new organocatalysts belonging to the class of ß-morpholine amino acids that were tested in a model reaction, i.e., the 1,4-addition reaction of aldehydes to nitroolefins. Starting from commercially available amino acids and epichlorohydrin, we designed an efficient synthesis for the aforementioned catalysts, controlling the configuration and the substitution pattern. Computational studies indeed disclosed the transition state of the reaction, explaining why, despite all the limitations of the morpholine ring for enamine catalysis, our best catalyst works efficiently, affording condensation products with excellent yields, diastereoselection and good-to-exquisite enantioselectivity.

Short Synthesis of a Biphenyl-Based Amino Triflamide Catalyst and Its Application in Enamine Catalysis

AbstractA novel axially chiral biphenyl-based amino triflamide has been designed and successfully synthesized from 1-nitropyrene in 6 steps. This chiral amino triflamide functions as effective catalyst for asymmetric Mannich reaction through enamine intermediates.

Visible Light-Promoted Enantioselective Aerobic Hydroxylation of β-Ketocarbonyls by Chiral Primary Amine Catalysis

Highly effective and stereoselective enamine-singlet oxygen coupling was achieved by synergistic chiral primary amine and photocatalysis in hexafluoroisopropanol. The current enamine catalysis enables α-hydroxylation of β-ketocarbonyls with good yields and high enantioselectivity across a broad range of substrates. Mechanistic studies revealed a direct participation of solvents in the critical enamine coupling step, and a solvent-1O2 H-bonding mode was invoked to account for the dramatic solvent effect.

α‐Benzylation of Carbonyl Compounds Enabled by Synergistic Copper/Amine Catalyzed Decarboxylation of Arylacetic Acids

AbstractHerein, we report synergistic copper/amine‐catalyzed reactions for directly α‐benzylating carbonyl compounds with arylacetic acids. These reactions represent the first examples of decarboxylative oxidative synergistic transition‐metal/enamine catalysis for α‐functionalizing carbonyl compounds. The process features starting‐material availability, good functional group tolerance, mild reaction conditions, and good‐to‐excellent yields. Dibenzylated products were formed in moderate yields under slightly altered reaction conditions, and some products were transformed into 1,2,3,4‐tetrahydrocyclopenta[b]indole derivatives by acid‐catalyzed intermolecular cyclization reactions with indoles. Moreover, biological studies revealed that some products have anticancer properties and may be useful in drug‐discovery studies.magnified image

Highly Enantioselective Construction of Multifunctional Silicon-Stereogenic Silacycles by Asymmetric Enamine Catalysis.

We report the first highly enantioselective construction of silicon-stereocenters by asymmetric enamine catalysis. An unprecedented desymmetric intramolecular aldolization of prochiral siladials was thus developed for the facile access of multifunctional silicon-stereogenic silacycles in high to excellent enantioselectivity. With an enal moiety, these adducts could be readily elaborated for the diverse synthesis of silicon-stereogenic compounds, and for late-stage modification.

Highly Enantioselective Construction of Multifunctional Silicon‐Stereogenic Silacycles by Asymmetric Enamine Catalysis

AbstractWe report the first highly enantioselective construction of silicon‐stereocenters by asymmetric enamine catalysis. An unprecedented desymmetric intramolecular aldolization of prochiral siladials was thus developed for the facile access of multifunctional silicon‐stereogenic silacycles in high to excellent enantioselectivity. With an enal moiety, these adducts could be readily elaborated for the diverse synthesis of silicon‐stereogenic compounds, and for late‐stage modification.

Synthesis of biphenyl-based chiral amine catalysts from dibromopyrenes and their application in enamine catalysis.

Novel axially chiral biphenyl-based amine catalysts have been designed and synthesized from dibromopyrenes. These chiral amines function as effective catalysts for asymmetric reactions through enamine intermediates.

Enantioselective Michael Addition/Cyclization/Desymmetrization Sequence of Prochiral Cyclic Hemiacetals and Nitroolefins: Synthesis of Chiral Oxygen-Bridged Bicyclic Compounds.

The organocatalytic enantioselective Michael addition of functionalized prochiral cyclic hemiacetals and nitroolefins has been developed under cooperative enamine and hydrogen bond catalysis. The obtained chiral hemiacetal intermediates could be used in the subsequent diastereocontrolled cyclization/desymmetrization divergent process to access (1) 9-oxabicyclo[3.3.1]nonane or 8-oxabicyclo[3.2.1]octane frameworks via oxocarbenium ion-mediated Friedel-Crafts cyclization, and (2) 2,9-dioxabicyclo[3.3.1]nonane frameworks via intramolecular nucleophilic cyclization. Experimental results suggest that there is neighboring group participation controlling the diastereoselectivities of the desymmetrization process.

Asymmetric Alkylation of Cyclic Ketones with Dehydroalanine via H-Bond-Directing Enamine Catalysis: Straightforward Access to Enantiopure Unnatural α-Amino Acids.

The growing importance of structurally diverse and functionalized enantiomerically pure unnatural amino acids in the design of drugs, including peptides, has stimulated the development of new synthetic methods. This study reports the challenging direct asymmetric alkylation of cyclic ketones with dehydroalanine derivatives via a conjugate addition reaction for the synthesis of enantiopure ketone-based α-unnatural amino acids. The key to success was the design of a bifunctional primary amine-thiourea catalyst that combines H-bond-directing activation and enamine catalysis. The simultaneous dual activation of the two relatively unreactive partners, confirmed by mass spectrometry studies, results in high reactivity while securing high levels of stereocontrol. A broad substrate scope is accompanied by versatile downstream chemical modifications. The mild reaction conditions and consistently excellent enantioselectivities (>95 % ee in most cases) render this protocol highly practical for the rapid construction of valuable noncanonical enantiopure α-amino-acid building blocks.

A Desaturative Approach for Aromatic Aldehyde Synthesis via Synergistic Enamine, Photoredox and Cobalt Triple Catalysis

AbstractAromatic aldehydes are fundamental intermediates that are widely utilised for the synthesis of important materials across the broad spectrum of chemical industries. Accessing highly substituted derivatives can often be difficult as their functionalizations are generally performed via electrophilic aromatic substitution, SEAr. Here we provide an alternative and mechanistically distinct approach whereby aromatic aldehydes are assembled from saturated precursors via a desaturative process. This novel strategy harnesses the high‐fidelity of Diels–Alder cycloadditions to quickly construct multi‐substituted cyclohexenecarbaldehyde cores which undergo desaturation via the synergistic interplay of enamine, photoredox and cobalt triple catalysis.

A Desaturative Approach for Aromatic Aldehyde Synthesis via Synergistic Enamine, Photoredox and Cobalt Triple Catalysis.

Aromatic aldehydes are fundamental intermediates that are widely utilised for the synthesis of important materials across the broad spectrum of chemical industries. Accessing highly substituted derivatives can often be difficult as their functionalizations are generally performed via electrophilic aromatic substitution, SEAr. Here we provide an alternative and mechanistically distinct approach whereby aromatic aldehydes are assembled from saturated precursors via a desaturative process. This novel strategy harnesses the high‐fidelity of Diels–Alder cycloadditions to quickly construct multi‐substituted cyclohexenecarbaldehyde cores which undergo desaturation via the synergistic interplay of enamine, photoredox and cobalt triple catalysis.