Planar Chiral Ferrocene Research Articles

Enantioselective Synthesis of Planar Chiral Ferrocene Triflones

AbstractA multi‐gram scale synthesis of ferrocenetriflone was optimised from ferrocenesulfonyl fluoride and Me3SiCF3 (Ruppert reagent). Enantioselective deprotolithiations were then optimised using alkyllithiums in the presence of catalytic (+)‐sparteine to afford 2‐substituted ferrocene triflones in 79–84% ee. The use of chiral lithium amides in the presence of in situ traps was also optimised and was found to outperform alkyllithium⋅chiral diamine chelates for the first time in the ferrocene series, with 89–93% ee. Crystallisation of derivatives afforded enantiopure compounds that were engaged in deprotolithiation‐electrophilic trapping sequences, a halogen ‘dance’ reaction and transition metal‐promoted coupling to afford a wide range of variously polysubstituted ferrocene triflones.

Synthesis of Planar Chiral Ferrocenes by Catalytic Desymmetrization Reactions

Synthesis of Planar Chiral Ferrocenes by Catalytic Desymmetrization Reactions

Synthesis of Planar Chiral Compounds Containing α-Amino Phosphonates for Antiplant Virus Applications against Potato Virus Y.

An unprecedented study of the application of planar chiral compounds in antiviral pesticide development is reported. A class of multifunctional planar chiral ferrocene derivatives bearing α-amino phosphonate moieties was synthesized. These compounds, exhibiting superior optical purities, were subsequently subjected to antiviral evaluations against the notable plant pathogen potato virus Y (PVY). The influence of the absolute configurations of the planar chiral compounds on their antiviral bioactivities was significant. A number of these enantiomerically enriched planar chiral molecules demonstrated superior anti-PVY activities. Specifically, compound (Sp, R)-9n displayed extraordinary curative activities against PVY, with a 50% maximal effective concentration (EC50) of 216.11 μg/mL, surpassing the efficacy of ningnanmycin (NNM, 272.74 μg/mL). The protective activities of compound (Sp, R)-9n had an EC50 value of 152.78 μg/mL, which was better than that of NNM (413.22 μg/mL). The molecular docking and defense enzyme activity tests were carried out using the planar chiral molecules bearing different absolute configurations to investigate the mechanism of their antiviral activities against PVY. (Sp, R)-9n, (Sp, R)-9o, and NMM all showed stronger affinities to the PVY-CP than the (Rp, S)-9n. Investigations into the mechanisms revealed that the planar chiral configurations of the compounds played pivotal roles in the interactions between the PVY-CP molecules and could augment the activities of the defense enzymes. This study contributes substantial insights into the role of planar chirality in defending plants against viral infections.

Construction of Planar Chiral Ferrocenes by Cobalt-Catalyzed Enantioselective C–H Acyloxylation Enabled by Dual Ligands

Construction of Planar Chiral Ferrocenes by Cobalt-Catalyzed Enantioselective C–H Acyloxylation Enabled by Dual Ligands

Enantioselective synthesis of planar chiral ferrocenes via gold(I)-catalyzed hydroarylation of N-ferrocenyl propiolamides

Herein, we report an intramolecular 6-endo-dig cyclization of N-ferrocenyl propiolamides for the synthesis of planar chiral ferrocenes enabled by gold(I)-catalyzed hydroarylation. By using this protocol, a variety of planar chiral ferrocenopyridin-2(1H)-ones were obtained in good yields and excellent enantioselectivities (up to 96% ee).

Copper/BINOL-Catalyzed Enantioselective C–H Functionalization toward Planar Chiral Ferrocenes Under Mild Conditions

Copper/BINOL-Catalyzed Enantioselective C–H Functionalization toward Planar Chiral Ferrocenes Under Mild Conditions

Molybdenum-Catalyzed Enantioselective Ring-Closing Metathesis/Kinetic Resolution of Racemic Planar-Chiral 1,1′-Diallylferrocenes

The molybdenum-catalyzed enantioselective ring-closing metathesis/kinetic resolution of a series of racemic planar-chiral 1,1′-diallylferrocene derivatives was reinvestigated utilizing the method of generating catalytically active chiral molybdenum-alkylidene species in situ, which allowed us to examine a variety of chiral molybdenum-alkylidene metathesis precatalysts in the present asymmetric reaction. With the catalyst screening experiments conducted in this study, the more practical reaction conditions, including a choice of a proper chiral molybdenum precatalyst, giving planar-chiral ferrocenes of higher enantiomeric purity and better chemoselectivity could be optimized.

P(III)-Directed Asymmetric C-H Arylation toward Planar Chiral Ferrocenes by Palladium Catalysis.

Planar chiral ferrocenyl phosphines have been employed as highly valuable ligands in metal-catalyzed asymmetric reactions. However, their preparation remains a formidable challenge due to the requirement for intricate, multistep synthetic sequences. In addressing this issue, we have developed a groundbreaking enantioselective C-H activation strategy facilitated by P(III) directing groups, enabling the efficient construction of planar chiral ferrocenyl phosphines in a single step. Our innovative approach entails the combination of a palladium catalyst, a parent ferrocenyl phosphine, and a chiral phosphoramidite ligand, leading to exceptional reactivity and enantioselectivity. Remarkably, these novel ligands exhibit remarkable efficacy in silver-catalyzed asymmetric 1,3-dipolar cycloadditions. We carried out a combination of experimental and computational studies to obtain a more comprehensive understanding of the reaction pathway and the factors contributing to enantioselectivity.

P(III)-Directed Asymmetric C—H Arylation toward Planar Chiral Ferrocenes by Palladium Catalysis

P(III)-Directed Asymmetric C—H Arylation toward Planar Chiral Ferrocenes by Palladium Catalysis

Enantioselective construction of planar, axially and central chiral ferrocenyl phosphines via a Pd-catalyzed domino reaction and diastereoselective phosphination

A family of both axially and planar chiral ferrocenes was prepared through a Pd-catalyzed domino reaction.

Palladium-catalyzed intramolecular C–H arylation of ferrocenyl-sulfides, sulfoxide and its application in metal ion recognition

An intramolecular C–H arylation of ferrocenyl ortho-bromophenyl sulfide and sulfoxide has been developed with a palladium/non-chiral monophosphine ligand. Under mild reaction conditions, a wide range of ferrocene cyclosulfide and ferrocene cyclosulfoxide were obtained in up to 90 ​% yield. Moreover, planar chiral ferrocene cyclosulfide with enantioselectivities (up to 45 ​% ee) was synthesized utilizing chiral phosphine ligands. Furthermore, the compound 4a and 6a can be used as novel chemosensors to detect Cu2+ ion.

Cu-mediated enantioselective C–H alkynylation of ferrocenes with chiral BINOL ligands

A wide range of Cu(II)-catalyzed C–H activation reactions have been realized since 2006, however, whether a C–H metalation mechanism similar to Pd(II)-catalyzed C–H activation reaction is operating remains an open question. To address this question and ultimately develop ligand accelerated Cu(II)-catalyzed C–H activation reactions, realizing the enantioselective version and investigating the mechanism is critically important. With a modified chiral BINOL ligand, we report the first example of Cu-mediated enantioselective C–H activation reaction for the construction of planar chiral ferrocenes with high yields and stereoinduction. The key to the success of this reaction is the discovery of a ligand acceleration effect with the BINOL-based diol ligand in the directed Cu-catalyzed C–H alkynylation of ferrocene derivatives bearing an oxazoline-aniline directing group. This transformation is compatible with terminal aryl and alkyl alkynes, which are incompatible with Pd-catalyzed C–H activation reactions. This finding provides an invaluable mechanistic information in determining whether Cu(II) cleaves C–H bonds via CMD pathway in analogous manner to Pd(II) catalysts.

Enantioselective Rh(I)-Catalyzed C-H Arylation of Ferroceneformaldehydes.

As an important class of platform molecules, planar chiral ferrocene carbonyl compounds could be transformed into various functional groups offering facile synthesis of chiral ligands and catalysts. However, developing efficient and straightforward methods for accessing enantiopure planar chiral ferrocene carbonyl compounds, especially ferroceneformaldehydes, remains highly challenging. Herein, we report a rhodium(I)/phosphoramidite-catalyzed enantioselective C-H bond arylation of ferroceneformaldehydes. Readily available aryl halides such as aryl iodides, aryl bromides, and even aryl chlorides are suitable coupling partners in this transformation, leading to a series of planar chiral ferroceneformaldehydes in good yields and excellent enantioselectivity (up to 83% yield and >99% ee). The aldehyde group could be transformed into diverse functional groups smoothly, and enantiopure Ugi's amine and PPFA analogues could be synthesized efficiently. The latter was found to be a highly efficient ligand in Pd-catalyzed asymmetric allylic alkylation reactions. Mechanistic experiments supported the formation of imine intermediates as the key step during the reaction.

Comparison of Diastereoselective ortho-Metalations and C–H ­Activations of Chiral Ferrocenes

AbstractChiral ferrocene derivatives possessing a planar stereogenic unit are important as chiral catalysts and materials. The principle method to obtain 1,2-disubstituted planarly chiral ferrocenes is base-mediated ortho-metalation performed on a chiral ferrocene derivative, typically using organolithium bases. A multitude of chiral ligands and other useful compounds have been synthesized by using this methodology. Newer methodologies employing transition-metal-catalyzed C–H bond activation strategies complement ortho-metalation methods and affords access to different types of planar chiral ferrocene derivatives.1 Introduction2 Base-Mediated ortho-Deprotonations3 Diastereoselective C–H Activations4 Examples of Enantioselective C–H Activations5 Conclusions

Pd-Catalyzed Asymmetric Oxidative C-H/C-H Cross-Coupling Reaction between Ferrocenes and Azoles.

The asymmetric C-H bond functionalization reaction is one of the most efficient and straightforward methods for the synthesis of optically active molecules. Herein, our work discovered a Pd-catalyzed asymmetric oxidative C-H/C-H cross-coupling reaction of ferrocenes with azoles such as oxazoles and thiazoles. Mono-N-protected amino acid as chiral ligands with palladium(II) has been demonstrated as an effective catalytic system in a weakly azine-directed asymmetric C-H bond functionalization reaction. This method offers a powerful strategy for constructing various substituted planar chiral ferrocenes via a dual C-H bond activation pathway in medium yields (up to 70%) with good enantioselectivity (up to 95.3:4.7 er) under mild conditions.

Synthesis of planar chiral ferrocenes via enantioselective remote C-H activation.

Planar chiral ferrocenes are widely studied structures in asymmetric catalysis, materials science and medicinal chemistry. Although synthetic methods for 1,2-disubstituted planar chiral ferrocenes are well known, methods for the direct construction of 1,3-disubstituted planar chiral ferrocenes remain elusive. Here we report a modular platform for the construction of planar chirality in 1,3-disubstituted ferrocenes/ruthenocenes via an enantioselective relay remote C-H activation strategy. This method demonstrates a mechanism for remote enantiocontrol via enantiodetermining initial C‒H activation at the C2 position, enabled by a chiral mono-N-protected natural amino-acid ligand, and subsequent relay to the remote C3 position by a bridgehead-substituted norbornene mediator. A wide variety of 1,3-disubstituted planar chiral metallocenes are prepared with high enantioselectivity (96‒99% e.e.). The reaction shows good functional-group tolerance and high step-economy, and aryl iodides/bromides are compatible as coupling partners. The resulting metallocenes can be readily derivatized to yield planar chiral ligands and catalysts for asymmetric catalysis as well as building blocks for other applications.

Design and synthesis of a new family of planar and central chiral ferrocenyl phosphine ligands.

A family of planar chiral indene-fused ferrocenes were prepared through an intramolecular asymmetric C-H arylation in excellent yields (up to 99%) with excellent enantioselectivities (up to 99% ee). They were thereafter successfully transformed to chiral ferrocenyl phosphines, featuring both planar and central chiralities, in good yields (up to 83%) and excellent diastereoselectivities (up to 99% de) through highly diastereoselective phosphination. This protocol offers a general method for planar and central chiral ferrocenyl phosphines. The potential applications of the newly developed ligands were demonstrated by a Pd-catalyzed enantioselective allylic alkylation reaction, in which high enantioselectivity (92% ee) and good yield (89%) were obtained.

Stereoselective Synthesis of 1,1’,2,2’‐Tetrasubstituted Ferrocenes by Double Lithiation of a 1,1’‐Disubstituted Ferrocenyl Pyrroloimidazolone

AbstractA 1,1’‐disubstituted ferrocenyl pyrroloimidazolone with syn stereochemistry undergoes double lithiation–electrophile quench in a one‐pot procedure to give C2‐symmetric 1,1’,2,2’‐tetrasubstituted products in >95 : 5 diastereomeric ratio (dr). These results represent an extension of double lithiation to access tetrasubstituted planar chiral ferrocenes for the first time to a nitrogen‐linked (pyrroloimidazolone) chiral directing group. The stereochemistry of the products was determined by X‐ray crystallography of distannane and dibromide adducts in combination with deuteration, elimination, and transmetalation experiments. Results support that products arise from selective deprotonation of the pro‐Sp position of each cyclopentadienyl (Cp) ring.

Preparation of planar chiral oxazolinyl hydroxyl ferrocene silyl ethers and their desilylation derivatives

Featured by abundant derivation and powerful catalytic activities, chiral catalysts and ligands with oxazolinyl ferrocenes core play a vital role in the area of enantioselective transformations. Despite great researches on phosphine ligands with oxazolinyl ferrocene silyl ether core have been broadly explored, the example of N,O-ferrocene compounds with identical core is rare. We herein disclosed the practical approaches to the preparation of planar chiral oxazolinyl hydroxyl ferrocene silyl ethers. Several available methods were employed for the establishment of the configuration on planar chirality, which considered as key parameter for the subsequent relative products. Furthermore, an array of N,O,O-tridentate ferrocenes was obtained through desilylation treated with TBAF. The absolute stereochemical configuration of the synthesized ferrocene derivatives was determined by X-ray diffraction.

Enantioseparation of planar chiral ferrocenes on cellulose-based chiral stationary phases: Benzoate versus carbamate pendant groups.

In this study, the enantioseparation of 14 planar chiral ferrocenes containing halogen atoms, and methyl, iodoethynyl, phenyl, and 2-naphthyl groups, as substituents, was explored with a cellulose tris(4-methylbenzoate) (CMB)-based chiral column under multimodal elution conditions. n-Hexane/2-propanol (2-PrOH) 95:5 v/v, pure methanol (MeOH), and MeOH/water 90:10 v/v were used as mobile phases (MPs). With CMB, baseline enantioseparations were achieved for nine analytes with separation factors (α) ranging from 1.24 to 1.77, whereas only three analytes could be enantioseparated with 1.14 ≤ α ≤ 1.51 on a cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC)-based column, used as a reference for comparison, under the same elution conditions. Pendant group-dependent reversal of the enantiomer elution order was observed in several cases by changing CMB to CDMPC. The impact of analyte and chiral stationary phase (CSP) structure, and MP polarity on the enantioseparation, was evaluated. The two cellulose-based CSPs featured by different pendant groups were also compared in terms of thermodynamics. For this purpose, enthalpy (ΔΔH°), entropy (ΔΔS°) and free energy (ΔΔG°) differences, isoenantioselective temperatures (Tiso ), and enthalpy/entropy ratios (Q), associated with the enantioseparations, were derived from van 't Hoff plots by using n-hexane/2-PrOH 95:5 v/v and methanol/water 90:10 v/v as MPs. With the aim to disclose the functions of the different substituents in mechanisms and noncovalent interactions underlying analyte-selector complex formation at molecular level, electrostatic potential (V) analysis and molecular dynamics simulations were used as computational techniques. On this basis, enantioseparations and related mechanisms were investigated by integrating theoretical and experimental data.