Chiral Copper Complexes Research Articles

Selectivity Control in Nitroaldol (Henry) Reaction by Changing the Basic Anion in a Chiral Copper(II) Complex Based on (S)-2-Aminomethylpyrrolidine and 3,5-Di-tert-butylsalicylaldehyde.

This article is a continuation of our previous research on the catalytic capability of a chiral copper complex based on commercially available (S)-2-aminomethylpyrrolidine and 3,5-di-tert-butylsalicylaldehyde with various counter-anions in the asymmetric Henry reaction. Our findings indicate that depending on the type of base used, chiral nitroalcohols with yields up to 98% and ee values up to 77%, as well as β-nitrostyrenes with yields up to 88%, can be produced. Additionally, it has been found that the outcome of the reaction and the catalytic properties of copper (II) complexes (S)-Cu1 and (S)-Cu2 are influenced by the structure of the aldehyde used.

Co-assembly of chiral copper(I) complexes and achiral polymer for enhanced circularly polarized luminescence

Co-assembly of chiral copper(I) complexes and achiral polymer for enhanced circularly polarized luminescence

Copper-Catalyzed Enantioselective [4π + 2σ] Cycloaddition of Bicyclobutanes with Nitrones.

The selective construction of bridged bicyclic scaffolds has garnered increasing attention because of their extensive use as saturated bioisosteres of arene in pharmaceutical industry. However, in sharp contrast to their racemic counterparts, assembling chiral bridged bicyclic structures in an enantioselective and regioselective manner remains challenging. Herein, we describe our protocol for constructing chiral 2-oxa-3-azabicyclo[3.1.1]heptanes (BCHeps) by enantioselective [4π + 2σ] cycloadditions of bicyclo[1.1.0]butanes (BCBs) and nitrones taking advantage of a chiral copper(II) complex as a Lewis acid catalyst. This method features mild conditions, good functional group tolerance, high yield (up to 99%), and excellent enantioselectivity (up to 99% ee). Density functional theory (DFT) calculation elucidates the origin of the reaction's enantioselectivity and the mechanism of BCB activation by Cu(II) complex.

A comprehensive review on the development of chiral Cu, Ni, and Zn complexes as pharmaceutical agents over the past decades: Synthesis, molecular structure and biological activity.

Chirality is a fundamental and widespread geometric structural property in living organisms that most biomacromolecules including nucleic acids, proteins and enzymes, possess. Consequently, the development of chiral drugs capable of binding specific targets have gradually gained wide attention in recent decades due to their selective effects on a broad spectrum of biological events ranging from cell metabolism to cell fate. In this context, the synthesis of chiral compounds as promising therapeutic candidates has assumed a major role in drug discovery. Among them, chiral metal complexes have attracted considerable interest due to their unique and intriguing structural features that could enable overcoming side effects and drug-resistance phenomena of metal-based drugs currently in the market such as cisplatin. In the current scenario, an in-depth overview of non-platinum chiral complexes needs to be presented and carried forward. Therefore, in this perspective article, an update of the scientific development of bioactive chiral copper, zinc and nickel complexes have been reported since they have not been thoroughly reviewed so far. Specifically, we focused the article mainly on metal complexes containing chiral ligands (type 2 chirality) as in literature they are more numerous than those with chirality at the metal center (type 1 chirality). Herein, not only their biological activity but also their mechanism of action is summarized. Furthermore, in the final section of the article we have highlighted copper-based complexes as those with a superior biological activity profile and greater prospects for development as a drug.

Photoinduced Copper-Catalyzed Asymmetric Three-Component Radical 1,2-Azidooxygenation of 1,3-Dienes.

Radical-involved multicomponent difunctionalization of 1,3-dienes has recently emerged as a promising strategy for rapid synthesis of valuable allylic compounds in one-pot operation. However, the expansion of radical scope and enantiocontrol remain two major challenges. Herein, we describe an unprecedented photoinduced copper-catalyzed highly enantioselective three-component radical 1,2-azidooxygenation of 1,3-dienes with readily available azidobenziodazolone reagent and carboxylic acids. This mild protocol exhibits a broad substrate scope, high functional group tolerance, and exceptional control over chemo-, regio- and enantioselectivity, providing practical access to diverse valuable azidated chiral allylic esters. Mechanistic studies imply that the chiral copper complex is implicated as a bifunctional catalyst in both the photoredox catalyzed azidyl radical generation and enantioselective radical C-O cross-coupling.

Photoinduced Copper‐Catalyzed Asymmetric Three‐Component Radical 1,2‐Azidooxygenation of 1,3‐Dienes

AbstractRadical‐involved multicomponent difunctionalization of 1,3‐dienes has recently emerged as a promising strategy for rapid synthesis of valuable allylic compounds in one‐pot operation. However, the expansion of radical scope and enantiocontrol remain two major challenges. Herein, we describe an unprecedented photoinduced copper‐catalyzed highly enantioselective three‐component radical 1,2‐azidooxygenation of 1,3‐dienes with readily available azidobenziodazolone reagent and carboxylic acids. This mild protocol exhibits a broad substrate scope, high functional group tolerance, and exceptional control over chemo‐, regio‐ and enantioselectivity, providing practical access to diverse valuable azidated chiral allylic esters. Mechanistic studies imply that the chiral copper complex is implicated as a bifunctional catalyst in both the photoredox catalyzed azidyl radical generation and enantioselective radical C−O cross‐coupling.

Enantioselective α-Boryl Carbene Transformations.

Carbenes, recognized as potent intermediates, enable unique chemical transformations, and organoborons are pivotal in diverse chemical applications. As a hybrid of carbene and the boryl group, α-boryl carbenes are promising intermediates for the construction of organoborons; unfortunately, such carbenes are hard to access and have low structural diversity with their asymmetric transformations largely uncharted. In this research, we utilized boryl cyclopropenes as precursors for the swift synthesis of α-boryl metal carbenes, a powerful category of intermediates for chiral organoboron synthesis. These α-boryl carbenes undergo a series of highly enantioselective transfer reactions, including B-H and Si-H insertion, cyclopropanation, and cyclopropanation/Cope rearrangement, catalyzed by a singular chiral copper complex. This approach opens paths to previously unattainable but easily transformable chiral organoborons, expanding both carbene and organoboron chemistry.

A copper-catalyzed asymmetric Friedel-Crafts hydroxyalkylation of pyrazole-4,5-diones with 5-aminoisoxazoles.

An asymmetric Friedel-Crafts hydroxyalkylation reaction of 5-aminoisoxazoles with pyrazole-4,5-diones was developed under the catalysis of 5% chiral copper complexes. This reaction exhibits functional group tolerance and excellent enantioselectivity. Moreover, the reaction can be scaled up and its mechanism was studied.

Streamlined synthetic assembly of α-chiral CAAC ligands and catalytic performance of their copper and ruthenium complexes.

The unique electronic and steric parameters of chiral cyclic alkyl amino carbene (CAAC) ligands render them appealing steering ligands for enantioselective transition-metal catalyzed transformations. Due to the lack of efficient synthetic strategies to access particularly attractive α-chiral CAACs assessment and exploitation of their full synthetic potential remain difficult. Herein, we report a streamlined strategy to assemble a library of diastereo- and enantiomerically pure CAAC ligands featuring the notoriously difficult to access α-quaternary stereogenic centers. A tailored Julia-Kocienski olefination reagent allows the Claisen-rearrangement to be leveraged as an expedient route to form the synthetically pivotal racemic α-chiral methallyl aldehydes. Subsequent condensation with chiral amines and further cyclization provided a library of diastereomeric mixtures of the targeted ligand precursors. The CAAC salts as well as their corresponding metal complexes are conveniently separable by standard silica gel flash chromatography closing a long-standing accessibility gap in chiral CAAC ligands with proximal α-chirality. The rapid availability of both diastereomers enables testing of the relevance and synergistic effects of two chiral centers on the ligand in catalytic applications. A broad range of metal complexes with copper, gold, rhodium and ruthenium were obtained and structurally analyzed. The catalytic performances of the corresponding chiral CAAC copper and ruthenium complexes were assessed in enantioselective conjugate borylations and asymmetric ring closing metathesis, displaying selectivities of up 95 : 5 er.

Chiral Bifunctional NHC–Guanidine Ligands for Asymmetric Hydrogenation

AbstractWe report the synthesis of chiral N-heterocyclic carbene/guanidine bifunctional ligands from readily available amino alcohols. The resulting chiral bifunctional copper(I) complexes are active catalysts in an asymmetric hydrogenation of ketones. We show that the chiral linker unit can be employed for the transfer of stereoinformation.

Copper-catalyzed generation of nitrogen-centered radicals and reactions thereof.

Nitrogen-centered radicals are reactive intermediates that can function in the formation of new C-N bonds or enable the formation of other bonds through their ability to abstract hydrogen atoms to generate carbon radical intermediates. Methods for the generation of nitrogen-centered radicals have traditionally involved application of radical initiators and propagators such as peroxides, AIBN and tin hydrides. More recently, approaches to nitrogen-centered radicals involving copper catalysis have been developed. In the transformations summarized herein, the copper catalyst either oxidizes or reduces the nitrogen-centered radical precursor. Some of these methods have been developed as catalytic enantioselective using chiral copper complexes.

Platinum/Copper Dual-Catalyzed Asymmetric Vinylogous Addition Reactions for the Synthesis of Functionalized Indoles.

The development of multicomponent ligands to improve catalytic reactivity and selectivity remains a significant challenge for the synthesis of chiral building blocks. Here, a modular synthesis of structurally diverse multiligated platinum complexes, characterized by X-ray crystallography, was revealed to open up a previously inaccessible reaction space. A library of more than 16 binary component-ligated platinum complexes was identified as a practical toolkit to enable faster screening. The isolated bench-stable Pt(II)(oxazoline)(phosphine) complex paired with a chiral copper complex exhibits fundamentally new cooperative reactivity. The newly designed Pt/Cu dual catalytic system contributed to the development of highly enantioselective vinylogous addition reactions between a Pt-activated electrophilic α,β-unsaturated carbene and a Cu-activated nucleophile, resulting in a reliable process for the asymmetric synthesis of valuable functionalized indoles in good yields and excellent enantioselectivities.

Platinum/Copper Dual‐Catalyzed Asymmetric Vinylogous Addition Reactions for the Synthesis of Functionalized Indoles

AbstractThe development of multicomponent ligands to improve catalytic reactivity and selectivity remains a significant challenge for the synthesis of chiral building blocks. Here, a modular synthesis of structurally diverse multiligated platinum complexes, characterized by X‐ray crystallography, was revealed to open up a previously inaccessible reaction space. A library of more than 16 binary component‐ligated platinum complexes was identified as a practical toolkit to enable faster screening. The isolated bench‐stable PtII(oxazoline)(phosphine) complex paired with a chiral copper complex exhibits fundamentally new cooperative reactivity. The newly designed Pt/Cu dual catalytic system contributed to the development of highly enantioselective vinylogous addition reactions between a Pt‐activated electrophilic α,β‐unsaturated carbene and a Cu‐activated nucleophile, resulting in a reliable process for the asymmetric synthesis of valuable functionalized indoles in good yields and excellent enantioselectivities.

Copper-Catalyzed Enantioselective Aerobic Alkene Aminooxygenation and Dioxygenation: Access to 2-Formyl Saturated Heterocycles and Unnatural Proline Derivatives.

Alkene aminooxygenation and dioxygenation reactions that result in carbonyl products are uncommon, and protocols that control absolute stereochemistry are rare. We report herein catalytic enantioselective alkene aminooxygenation and dioxygenation that directly provide enantioenriched 2-formyl saturated heterocycles under aerobic conditions. Cyclization of substituted 4-pentenylsulfonamides, catalyzed by readily available chiral copper complexes and employing molecular oxygen as both oxygen source and stoichiometric oxidant, directly provides chiral 2-formyl pyrrolidines efficiently. Reductive or oxidative workup of these aldehydes provides their respective amino alcohols or amino acids (unnatural prolines). Enantioselective synthesis of an indoline and isoquinolines is also demonstrated. Concurrently, cyclization of various alkenols under similar conditions provides 2-formyl tetrahydrofurans, phthalans, isochromans, and morpholines. The nature of the copper ligands, the concentration of molecular oxygen, and the reaction temperature all impact the product distribution. Chiral nitrogen and oxygen heterocycles are common components of bioactive small molecules, and these enabling technologies provide access to saturated heterocycles functionalized with ready-to-use carbonyl electrophiles.

Asymmetric Sulfoxidation by a Tyrosinase Biomimetic Dicopper Complex with a Benzimidazolyl Derivative of L-Phenylalanine.

A challenge in mimicking tyrosinase activity using model compounds is to reproduce its enantioselectivity. Good enantioselection requires rigidity and a chiral center close to the active site. In this study, the synthesis of a new chiral copper complex, [Cu2(mXPhI)]4+/2+, based on an m-xylyl-bis(imidazole)-bis(benzimidazole) ligand containing a stereocenter with a benzyl residue directly bound on the copper chelating ring, is reported. Binding experiments show that the cooperation between the two metal centers is weak, probably due to steric hindrance given by the benzyl group. The dicopper(II) complex [Cu2(mXPhI)]4+ has catalytic activity in the oxidations of enantiomeric couples of chiral catechols, with an excellent discrimination capability for Dopa-OMe enantiomers and a different substrate dependence, hyperbolic or with substrate inhibition, for the L- or D- enantiomers, respectively. [Cu2(mXPhI)]4+ is active in a tyrosinase-like sulfoxidation of organic sulfides. The monooxygenase reaction requires a reducing co-substrate (NH2OH) and yields sulfoxide with significant enantiomeric excess (e.e.). Experiments with 18O2 and thioanisole yielded sulfoxide with 77% incorporation of 18O, indicating a reaction occurring mostly through direct oxygen transfer from the copper active intermediate to the sulfide. This mechanism and the presence of the chiral center of the ligand in the immediate copper coordination sphere are responsible for the good enantioselectivity observed.

Copper-Catalyzed Asymmetric Dearomative [3+2] Cycloaddition of Nitroheteroarenes with Azomethines.

Catalytic asymmetric dearomative [3+2] cycloaddition of α-imino γ-lactones with either 3-nitroindoles or 2-nitrobenzofurans by using a chiral copper complex as the catalyst was developed. A wide range of structurally diverse polyheterocyclic compounds containing spirocyclic-fused butyrolactone-pyrrolidine-indoline and butyrolactone-pyrrolidine-dihydrobenzofuran skeletons could be smoothly obtained with excellent results (>99:1 dr and 98% ee). The potential synthetic applications of this methodology were also demonstrated by the scale-up experiment and by the diverse transformations of one product. This method is characterized by high asymmetric induction, wide functional group tolerance and scalability, and attractive product diversification.

Mechano-Stimulus and Environment-Dependent Circularly Polarized TADF in Chiral Copper(I) Complexes and Their Application in OLEDs

Molecular emitters that combine circularly polarized luminescence (CPL) and high radiative rate constants of the triplet exciton decay are highly attractive for electroluminescent devices (OLEDs) or next-generation photonic applications, such as spintronics, quantum computing, cryptography, or sensors. However, the design of such emitters is a major challenge because the criteria for enhancing these two properties are mutually exclusive. In this contribution, we show that enantiomerically pure {Cu(CbzR)[(S/R)-BINAP]} [R = H (1), 3,6-tBu (2)] are efficient thermally activated delayed fluorescence (TADF) emitters with high radiative rate constants of kTADF up to 3.1 × 105 s-1 from 1/3LLCT states according to our temperature-dependent time-resolved luminescence studies. The efficiency of the TADF process and emission wavelengths are highly sensitive to environmental hydrogen bonding of the ligands, which can be disrupted by grinding of the crystalline materials. The origin of this pronounced mechano-stimulus photophysical behavior is a thermal equilibrium between the 1/3LLCT states and a 3LC state of the BINAP ligand, which depends on the relative energetic order of the excited states and is prone to inter-ligand C-H···π interactions. The copper(I) complexes are also efficient CPL emitters displaying exceptional dissymmetry values glum of up to ±0.6 × 10-2 in THF solution and ±2.1 × 10-2 in the solid state. Importantly for application in electroluminescence devices, the C-H···π interactions can also be disrupted by employing sterically bulky matrices. Accordingly, we have investigated various matrix materials for successful implementation of the chiral copper(I) TADF emitters in proof-of-concept CP-OLEDs.

Construction of a Chiral β-Fluoroamine by Asymmetric Mannich Reaction of 2-Fluoroindanone with Pyrazolinone Ketimines.

The asymmetric Mannich reaction of 2-fluoroindanone with ketimine was developed under the catalysis of a kind of chiral copper complex, affording a chiral tetrahedral center containing fluorine. A series of β-fluoroamine derivatives can be obtained in excellent yields (73-94%) with high diastereoselectivities (>99:1 dr) and enantioselectivities (89-99%). The possible transition state was supported by density functional theory calculation.

Construction of chiral N,O-hemiaminals via a copper-catalyzed enantioselective Michael/N-hemiacetalization cascade reaction.

An efficient Michael/N-hemiacetalization cascade reaction of 5-aminoisoxazoles with β,γ-unsaturated α-ketoesters was developed under the catalysis of a chiral copper complex. A series of optically pure six-membered ring N,O-hemiaminals were obtained with excellent yields (up to 96% yield) and high enantioselectivities (up to 98% ee). The possible transition state was supported by DFT calculations and thereby the corresponding mechanism was proposed.

Photoelectrochemical Asymmetric Catalysis Enables Direct and Enantioselective Decarboxylative Cyanation.

The development of efficient and sustainable methods for decarboxylative transformations is of great importance due to the ease of availability and nontoxicity of carboxylic acids. Despite tremendous efforts in this area, it remains challenging to develop enantioselective transformations direct from carboxylic acids. Herein we disclose a photoelectrocatalytic method for the direct and enantioselective decarboxylative cyanation. The photoelectrochemical reactions convert carboxylic acids to enantioenriched nitriles by employing cerium/copper relay catalysis with a cerium salt for catalytic decarboxylation and a chiral copper complex for stereoselective C-CN formation.