Chiral Metal Complexes Research Articles

Ligand-Enabled Cu-Catalyzed Stereoselective Synthesis of P-Stereogenic ProTides.

Nucleoside analogues have seen significant advancements in treating viral infections and cancer through ProTide technology, leading to a series of FDA-approved drugs such as sofosbuvir, tenofovir alafenamide, and remdesivir. The stereochemical configuration at the phosphorus center of ProTides significantly influences their pharmacological properties, necessitating efficient stereoselective synthesis. Traditional methods using chiral auxiliaries or nonracemic phosphorylating agents are labor-intensive and inefficient, while recent organocatalytic approaches, despite their promise, still face limitations. Herein, we present a novel approach employing chiral metal complexes for the stereoselective assembly of P-stereogenic ProTides via asymmetric P-O bond formation. This approach leverages a chiral metal catalyst to activate the electrophilic phosphorylating reagent, facilitating a base-promoted nucleophilic replacement pathway. Our protocol, featuring mild reaction conditions and broad applicability, enables the highly stereoselective synthesis of previously inaccessible (S,RP) and (R,SP)-ProTide derivatives. The practical utility of this method is demonstrated through the preparation of pharmaceutically relevant ProTide targets and mechanistic studies were conducted to elucidate the reaction pathway, offering significant advancements for drug development and pharmaceutical research.

Metallo-supramolecular complexes enantioselectively target monkeypox virus RNA G-quadruplex and bolster immune responses against MPXV

Abstract Mpox viruses (MPXV) has emerged as a formidable orthopoxvirus, posing an immense challenge to global public health. Understanding the regulatory mechanisms of MPXV infection, replication and immune evasion will benefit the development of novel antiviral strategies. Despite the involvement of G-quadruplexes (G4s) in modulating infection and replication processes of multiple viruses, their roles in MPXV life cycle remain largely unknown. Here, we found a highly conservative and stable G4 in MPXV, which acts as a positive regulatory element for viral immunodominant protein expression. Furthermore, by screening 42 optically pure chiral metal complexes, we identified the Λ enantiomer of a pair of chiral helical compounds can selectively target mRNA G4 and enhance expression of the 39-kDa core protein encoded by the MPXV A5L gene. Mechanistically, RNA G4-specific helicase DHX36 inhibits A5L protein expression by unwinding G4. In contrast, MH3 Λ enhanced mRNA stability by specifically targeting G4 structures and subsequently increased protein expression. Furthermore, given the pivotal role of the 39-kDa core protein in activating immune responses and facilitating virion maturation, modulation of MPXV G4 folding by MH3 Λ exhibited inhibitory effects on MPXV replication through enhancing immune response. Our findings underscore the critical involvement of G4 in MPXV life cycle and offer potential avenues for developing antiviral drugs targeting G4.

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.

Synergistic Catalysis Involving Palladium for Stereodivergent Csp3-Csp3 Coupling Reactions.

ConspectusTransition-metal-catalyzed coupling reactions of dienes (such as 1,3-dienes, alkoxyallenes, and aminoallenes) with carbon nucleophiles have proven to be a highly effective method for creating Csp3-Csp3 bonds. These reactions have perfect atom economy and typically occur under mild reaction conditions. By using chiral metal complexes as catalysts, it is possible to create enantioenriched molecules bearing allylic stereocenters with high enantioselectivities. However, challenges arise when Csp3-Csp3 bonds bearing two vicinal stereocenters are constructed through this type of coupling reaction. Due to the inherent diastereoselectivities, only the kinetically favored diastereoisomers (either the syn- or anti-product) are usually obtained through the transition-metal catalyst system. Achieving complementary stereoisomers with high selectivity, which require complete control of both absolute and relative configurations of multiple chiral centers in a single chemical transformation, is usually impossible.Over the past decade, significant advancements have been made in stereodivergent synthesis. Notably, iridium-related synergistic catalysis has been rapidly developed for stereodivergent allylic alkylation reactions. However, these systems were limited to using allylic alcohol derivatives as electrophilic partners. Finding ways to extend the use of synergistic catalysis to other types of stereodivergent reactions is a crucial issue that needs to be addressed.In 2019, we reported the first palladium-mediated synergistic system for the stereodivergent Csp3-Csp3 coupling between 1,3-dienes and aldimine esters. Lately, this strategy has proven successful in accessing stereodivergent coupling with diverse substrate patterns. In this Account, we will summarize our laboratory's efforts in developing a range of palladium-involved synergistic catalysis systems for the stereodivergent Csp3-Csp3 coupling reactions of dienes. We discovered several synergistic catalysis systems, including Pd/Cu(Ag), Pd/amine, Pd/Lewis base, and Pd/PTC. Additionally, we developed diverse dienes, such as 1,3-dienes, alkoxyallenes, and aminoallenes, to serve as suitable coupling partners for stereodivergent coupling. These processes provide an efficient method for constructing a range of chiral scaffolds bearing vicinal stereocenters. Density functional theory (DFT) calculations have been performed to elucidate the reaction mechanism and to rationalize the origins of the stereochemistry for some of the synergistic catalyst systems. Finally, the synthetic application of these methods has been demonstrated in the concise total synthesis of a number of natural products and bioactive molecules. It is anticipated that an increasing number of chemists will join in the research on stereodivergent Csp3-Csp3 coupling reactions and contribute to more elegant examples in this area. We believe future development will further push the boundary of asymmetric catalysis and find more innovative applications soon for synthesizing complex chiral molecules.

Enantioseparation of organometallic compounds by electromigration techniques.

Over time, chiral organometallic compounds have attracted great interest in several fields, with applications going across several disciplines of chemical, biological, medical, and material sciences. In the last decades, due to advancements in molecular design and computational modeling, the chemistry of chiral transition metal complexes had a remarkable flowering, with the development of new structures for applications in asymmetric synthesis, bioinorganic chemistry, and molecular recognition. In these fields, fast chiral analysis to determine the enantiomeric purity of organometallic structures prepared by asymmetric synthesis, and for high-throughput screening of analytes, catalysts, and reactions, is very important. Capillary electrophoresis and related techniques proved to be extremely versatile for chiral analysis, showing unsurpassed advantages compared to chromatography like low consumption of materials, production of limited amounts of waste, fast equilibration, and possibility to replace easily type and concentration of the chiral selector, among others. Furthermore, electromigration techniques may be useful to gain details about the stereochemistry of the enantiomers of new compounds and to study analyte-selector noncovalent interactions at molecular level. On this basis, this short review aims to provide the reader with a comprehensive view on the enantioseparation of organometallic compounds by electromigration techniques, examining the topic from the historical perspective and showing what was made in this field so far, an essential know-how for developing new and advanced applications in the next future.

Asymmetric electrophilic functionalization of amino-substituted heteroaromatic compounds: a convenient tool for the enantioselective synthesis of nitrogen heterocycles.

The catalytic asymmetric electrophilic functionalization of the less reactive N-heteroaromatic compounds has been reported using the approach of the introduction of an exocyclic amino substituent. This strategy has allowed enantioselective Friedel-Crafts alkylation in pyrazoles, isoxazoles and isothiazoles, as well as in aminoindoles, aminobenzofurans and aminobenzothiophenes. Several stereoselective methods have been used for the 1,4-addition or 1,2-addition of these heteroaromatic compounds to different electrophiles employing organocatalysts or chiral metal complexes. The activating exocyclic amino substituent has also been used as a nucleophile in tandem reactions, including formal cycloadditions ([3+2] and [3+3]), for the synthesis of highly functionalized chiral nitrogen heterocycles.

Biologically Active Palladium(II), Zinc(II), and Copper(II) Complexes with Terpene Ligands as Potential Pharmaceutical Drugs

A final review of the results of studies of versatile biological activities (in vitro) of chiral metal complexes with benzylamine and ethylenediamine derivatives of terpenes is presented. The cytotoxic profiles of palladacycles containing a Pd–C bond and palladium and zinc chelate complexes were determined. For a number of compounds, the possible mechanisms of potential anticancer action were analyzed, such as modulation of mitochondrial functioning and effect on the parameters of glycolytic function of tumor cells. The antibacterial and antifungal activities of palladium complexes of different types and copper chelate complexes were investigated. A correlation between high antimicrobial activity and antioxidant properties was found for a number of copper complexes. The material is supplemented by an extended analysis of publications in relevant subjects.

Chiral Organocatalysts in Enantioselective CO2 Utilization Reactions

AbstractThe development of efficient CO2 utilization reactions has gained a significant amount of attention in recent years. Although transformations of CO2 to produce basic chemicals have been extensively investigated, the development of catalytic enantioselective CO2 utilization reactions for the preparation of fine chemicals remains limited at this stage. Several excellent methods for catalytic enantioselective CO2 utilization using chiral metal complex catalysts have been reported. Many researchers have also focused on developing organocatalyzed approaches to enantioselective CO2 utilization, and several excellent examples have appeared in recent years. Herein, recent advances in catalytic enantioselective CO2 utilization reactions using chiral organocatalysts are reviewed to provide a forecast for organocatalyzed enantioselective CO2 utilization research.

Photoenzymatic Hydrosulfonylation for the Stereoselective Synthesis of Chiral Sulfones.

Chiral sulfones are recurrent motifs in pharmaceuticals and bioactive molecules. Although chemical methods have been developed to afford α- or β- chiral sulfones, these protocols rely heavily on the pre-synthesis of structurally complicated starting materials and chiral metal complexes. Herein, we described a photoenzymatic approach for the radical-mediated stereoselective hydrosulfonylation. Engineered variants of ene reductases provide efficient biocatalysts for this transformation, enabling to achieve a series of β-chiral sulfonyl compounds with high yields (up to 92%) and excellent e.r. values (up to 99:1).

Photoenzymatic Hydrosulfonylation for the Stereoselective Synthesis of Chiral Sulfones

AbstractChiral sulfones are recurrent motifs in pharmaceuticals and bioactive molecules. Although chemical methods have been developed to afford α‐ or β‐ chiral sulfones, these protocols rely heavily on the pre‐synthesis of structurally complicated starting materials and chiral metal complexes. Herein, we described a photoenzymatic approach for the radical‐mediated stereoselective hydrosulfonylation. Engineered variants of ene reductases provide efficient biocatalysts for this transformation, enabling to achieve a series of β‐chiral sulfonyl compounds with high yields (up to 92 %) and excellent e.r. values (up to 99 : 1).

Metal Stereogenicity in Asymmetric Transition Metal Catalysis.

Chiral transition metal catalysts represent a powerful and economic tool for implementing stereocenters in organic synthesis, with the metal center providing a strong chemical activation upon its interaction with substrates or reagents, while the overall chirality of the metal complex achieves the desired stereoselectivity. Often, the overall chiral topology of the metal complex implements a stereogenic metal center, which is then involved in the origin of the asymmetric induction. This review provides a comprehensive survey of reported chiral transition metal catalysts in which the metal formally constitutes a stereocenter. A stereogenic metal center goes along with an overall chiral topology of the metal complex, regardless of whether the ligands are chiral or achiral. Implications for the catalyst design and mechanism of asymmetric induction are discussed for half-sandwich, tetracoordinated, pentacoordinated, and hexacoordinated chiral transition metal complexes containing a stereogenic metal center. The review distinguishes between chiral metal catalysts originating from the coordination to chiral ligands and those which are solely composed of optically inactive ligands (achiral or rapidly interconverting enantiomers) prior to complexation (dubbed "chiral-at-metal" catalysts).

Advances in the synthesis of chiral cyclopentadienyl ligands and metal complexes

Advances in the synthesis of chiral cyclopentadienyl ligands and metal complexes

On the nature of optical activity in chiral transition metal complexes: [Pd(Me)2(BINAP)

Induced circular dichroism study of an asymmetric homogeneous catalyst reveals chirality transfer from ligands to the catalytically active metal centre.

Chiral-at-Metal Silver-Mediated Base Pairs: Metal-Centred Chirality versus DNA Helical Chirality.

When covalently incorporating ligands capable of forming chiral metal complexes into a DNA oligonucleotide duplex, an enantiospecific formation of metal-mediated base pairs is possible. We have been investigating the chirality of the silver-mediated base pair P-AgI -P (P, 1H-imidazo[4,5-f][1,10]phenanthroline) depending on the number of consecutive P : P pairs within a series of duplexes. Towards this end, both enantiomers of the nucleoside analogue 3-(1H-imidazo[4,5-f][1,10]phenanthrolin-1-yl)propane-1,2-diol comprising an acyclic backbone were introduced into DNA duplexes, resulting in diastereomeric metal-mediated base pairs. The same chiral-at-metal complex is formed inside the duplex for up to five neighbouring P-AgI -P pairs, irrespective of whether (S)-P or (R)-P is used. With six silver-mediated base pairs, the chirality of the metal complex is inverted for (S)-P but not for (R)-P. This indicates an intricate balance of what determines the configuration of the metal complex, the intrinsically preferred metal-centred chirality or the DNA helical chirality.

Recent Advances in the Catalytic Asymmetric Friedel-Crafts Reactions of Indoles.

Functionalized chiral indole derivatives are privileged and versatile organic frameworks encountered in numerous pharmaceutically active agents and biologically active natural products. The catalytic asymmetric Friedel–Crafts reaction of indoles, catalyzed by chiral metal complexes or chiral organocatalysts, is one of the most powerful and atom-economical approaches to access optically active indole derivatives. Consequently, a wide range of electrophilic partners including α,β-unsaturated ketones, esters, amides, imines, β,γ-unsaturated α-keto- and α-ketiminoesters, ketimines, nitroalkenes, and many others have been successfully employed to achieve a plethora of functionalized chiral indole moieties. In particular, strategies for C–H functionalization in the phenyl of indoles require incorporation of a directing or blocking group in the phenyl or azole ring of indole. The discovery of chiral catalysts which can control enantiodiscrimination has gained a great deal of attention in recent years. This review will provide an updated account on the application of the asymmetric Friedel–Crafts reaction of indoles in the synthesis of diverse chiral indole derivatives, covering the timeframe from 2011 to today.

Palladium-catalyzed asymmetric allylic 4-pyridinylation via electroreductive substitution reaction.

The enantioselective pyridinylation is important for providing chiral compounds bearing heterocycles of pharmaceutical interests. 4-CN-pyrinde is extensively applied in the radical pyridinylation reaction, however, its’ enantioselective application is highly challenging. To achieve this goal, we propose an electrochemical catalytic activation of 4-CN-pyridine with a chiral transition metal complex instead of direct cathodic reduction. The chiral catalyst acts as the electron mediator and the transition metal catalysis in turn. The radical species from 4-CN-pyridine is captured via radical rebound by chiral catalyst, and undergoes enantioselective pyridinylation reaction. Here, we show the first method for catalytic asymmetric allylic 4-pyridinylation reactions using 4-CN-pyridine under electrochemical conditions.

Helical Induction, Chiroptical Properties, and Quantitative Prediction of the Dissymmetry Factor on the Circularly Polarized Phosphorescence of Iminopyrrolyl Platinum(II) Complexes

Chiral transition metal complexes have attracted significant attention for the development of optoelectrical materials, such as circularly polarized phosphorescence (CPP)-emitting devices. In this paper, we report the helicity induction of d-π-conjugated platinum(II) complexes by the point chirality on 1,2-diaminocyclohexane and their CPP properties. The obtained C2-helical complexes exhibited excellent chiroptical properties with high dissymmetry factors (circular dichroism: gabs = 1.2 × 10–2, CPP: gphos = 3.2 × 10–3). Moreover, we conducted a theoretical investigation of the dissymmetry factor of CPP, gphos,calc, using a kinetic model of triplet state sublevels. The ab initio calculations represented the experimental gphos values, as well as the impact of helical chirality on the CPP.

Asymmetric Hydrophosphonylation of α,β-Unsaturated Ketones Catalyzed by Rare-Earth Metal Complexes Bearing Trost Ligands.

Chiral dinuclear rare-earth metal complexes RE2Ln2 (n = 1, RE = Y(1), Eu(2), Nd(3), La(4), Gd(5); n = 2, RE = Eu(6), Gd(7)) stabilized by the corresponding Trost ligands H3L1 or H3L2 (H3L1 = (S,S)-2,6-bis[2-(hydroxydiphenylmethyl)pyrrolidin-1-ylmethyl]-4-methylphenol, H3L2 = (S,S)-2,6-bis[2-(hydroxydiphenylmethyl)pyrrolidin-1-ylmethyl]-4-chlorophenol) were prepared and three unknown complexes 5-7 were characterized by X-ray diffraction analysis. The chiral rare-earth metal complexes 1-7 displayed high reactivity in the asymmetric hydrophosphonylation of α,β-unsaturated ketones, and 5 mol % of complex 7 together with 10 mol % of chiral diamine (1S,2S)-1,2-cyclohexanediamine were proved to be the optimal catalyst combination. Various hydrophosphonylation products with excellent yields and high to excellent enantiomeric excess (ee) values were obtained in toluene (up to 99% yield, >99% ee).

Circularly Polarized Luminescence from Uranyl Improves Resolution of Electronic Transitions.

The first reported example of circularly polarized luminescence from a chiral, molecular uranyl (UO22+) complex in solution is presented. This uranyl chiroptical activity is enabled by complexation with ibuprofen, an enantiopure chiral carboxylate ligand. Salt metathesis between [UO2Cl2(thf)2]2 and the sodium ibuprofenate salts results in the formation of the anionic tris complexes; these complexes are found to be luminescent in solution, both under visible excitation, directly targeting the metal, and through sensitization by UV absorption and energy transfer from the ligand. Each enantiomer displays both circular dichroism and circularly polarized luminescence (CPL) with |gabs| ≤ 8.1 × 10-2 and |glum| ≤ 8.0 × 10-3 under UV excitation, comparable to chiral transition metal complexes or purely organic emitters. The strength of the CPL emission is found to be comparable following excitation of either the ligand or metal directly. Further, use of CPL allows for resolution of subcomponents of the emission spectrum not previously possible at room temperature using standard fluorescence techniques. Observation of CPL following direct uranyl excitation presents a new tool for probing speciation of uranyl complexes when chiral ligands are used, without the need for synthetic modification to incorporate a suitable chromophore, and could enable the design of improved ligands for uranyl extraction from wastewater.

Resolving Resonant Electronic States in Chiral Metal Complexes by Raman Optical Activity Spectroscopy.

Chiral metal complexes exhibit rich photophysical properties and are important for applications ranging from biosensing to photocatalysis. We present a combined experimental and computational approach leading to information about energies and transition moments of excited electronic states, documented on two chiral metal complexes. The experimental protocol for measurement of the resonance Raman optical activity comprises multiple techniques, i.e., absorption, circular dichroism, and polarized and differential Raman scattering. An accurate formula for subtraction of the interfering circular dichroism/polarized Raman scattering effect is given. An analysis of the spectra based on density functional theory calculations unveils the geometric and electronic structures of the molecules. Such insight into molecular electronic states of chromophores may be useful for understanding and tuning photochemical properties of metal-containing complexes, biomolecules, and supramolecules.