Asymmetric catalysis for the synthesis of planar chiral ferrocene derivatives

Asymmetric catalysis for the synthesis of planar chiral ferrocene derivatives

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Haitao Liu, Youlin Deng, Dan Ling, Lingzhu Chen, Zhichao Jin

Chinese Chemical Letters | 2026, 37(3) : 111793

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Chinese Chemical Letters | 2026, 37(3): 111793

• Review •

Asymmetric catalysis for the synthesis of planar chiral ferrocene derivatives

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Haitao Liu, Youlin Deng, Dan Ling, Lingzhu Chen, Zhichao Jin

Affiliations

State Key Laboratory of Green Pesticide, Guizhou University, Guiyang 550025, China

About Author:

CRediT authorship contribution statement

Haitao Liu: Writing – original draft.

Youlin Deng: Investigation.

Dan Ling: Investigation.

Lingzhu Chen: Writing – review & editing.

Zhichao Jin: Writing – review & editing.

Published: 2026-03-15 doi: 10.1016/j.cclet.2025.111793

Outline

Abstract

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The asymmetric catalytic synthesis of planar chiral ferrocene derivatives has received dramatic attention in recent years. Transition metal-catalyzed asymmetric cross-coupling reactions and CH functionalization reactions have played significant roles in the stereoselective construction of planar chiral ferrocene derivatives. Transition metals such as copper, palladium, rhodium, iridium, gold, and platinum have been adopted as the effective catalysts in combination with various chiral ligands to achieve satisfactory yields and stereoselectivity. Organic catalysts have also shown great potential in the synthesis of planar chiral ferrocenes. Chiral amines and N-heterocyclic carbenes (NHCs) have been the key catalysts for facile access to multi-functional ferrocene derivatives. Some of the planar chiral ferrocene molecules obtained from the above methods have demonstrated promising applications in the development of novel ligands for asymmetric synthesis and pesticides for plant protection. This review provides an overview on the key progresses in the catalytic synthesis of planar chiral ferrocene derivatives using transition metal catalysts and organic catalysts. The merits, challenges and potential directions in the future development within this highly active research field are also discussed at the end of this review.

Key words

Ferrocene derivatives / Planar chirality / Asymmetric catalysis / Desymmetrization / Kinetic resolution

Cite this Article

Haitao Liu, Youlin Deng, Dan Ling, Lingzhu Chen, Zhichao Jin. Asymmetric catalysis for the synthesis of planar chiral ferrocene derivatives[J]. Chinese Chemical Letters, 2026 , 37 (3) : 111793 - . DOI: 10.1016/j.cclet.2025.111793

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1　Introduction

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Ferrocene derivatives have been widely used in material sciences [1-4], organic synthesis [5,6], and pharmaceutical chemistry [7-9] (Scheme 1). For example, ferrocene derivatives have exhibited anticancer [10-15], antimalarial [16], antibacterial [17,18], antifungal and other interesting bioactivities in drug development [19]. Enantio-pure planar chiral ferrocene structures have been extensively used as excellent ligands and catalysts for asymmetric synthesis in both scientific research and industrial production [20-27]. Therefore, the development of efficient and enantioselective catalytic methods for the synthesis of novel planar chiral ferrocene structures has attracted great interest of scientists focusing on various disciplines.

The preparation of optically pure planar chiral ferrocene derivatives has long relied on chiral resolutions [28-31], desymmetrization, enantio– and diastereoselective directed o-metalation reactions [32-36]. The last decade has witnessed prosperous development in the enantioselective catalytic methods for the synthesis of various planar chiral ferrocene molecules, with both transition metal complexes and organic molecules used as the chiral catalysts [37]. The asymmetric catalytic methods that have been developed possess certain advantages in the atom economy, environmental friendly and increased synthetic efficiency. It is therefore significant and urgent for scientists to get an overview on the development of catalytic methods for the facile synthesis of planar chiral ferrocene structures. Herein, we aim to provide a systematic summary on the transition metal- and organocatalyzed desymmetrizations and kinetic resolutions that have been developed in the recent decade for the establishment of the planar chirality based on ferrocene structures. The merits, challenges and potential directions in the future development within this highly active research field are also discussed at the end of this review.

2　Transition metal-catalyzed planar chiral ferrocene synthesis

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Significant progress has been made in the field of transition metal-catalyzed synthesis of planar chiral ferrocene derivatives (Scheme 2). Various asymmetric cross-coupling reactions and C—H bond activation reactions of ferrocenes have been developed with the catalysis of transition metals, which generally require the introduction of directing groups and the combination of chiral ligands to achieve regio- and stereoselectivity. For example, asymmetric C—H alkylation, C—H vinylation, C—H alkynylation, C—H acylation, C—H borylation, C—H acyloxylation, and C—H thiolation reactions have been adopted to establish planar chiralities on ferrocene frameworks. Pd catalysts and other transition metal catalysts such as Rh, Ir, Au, Pt, Cu, and Co have been explored to expand reaction conditions and substrate scope.

2.1　Intramolecular cyclization reactions

In 2014, Kang and Gu’s group achieved the ferrocene-based indanone derivatives 2 through palladium-catalyzed asymmetric cyclization reaction with chiral 1,1′-bi-2,2′-naphthol (BINAP) L1 used as the ligand (Scheme 3) [38]. The o-C-H bond on the cyclopentadienyl ring was coupled with the o-C-I bond on the phenyl group, exhibiting excellent diastereo- and enantioselectivity. The reaction featured mild reaction condition and broad substrate scope. Noteworthily, the iron center in the ferrocene structure could also be switched into a ruthenium atom, providing an efficient route for the synthesis of various planar chiral metallocene compounds.

In 2018, Duan and co-workers used as the chiral biaryl-bisphosphine (R)-L2 as the ligand in the Pd-catalyzed enantioselective cyclization of the ferrocene aryl sulfides 3, affording the ferrocene-derived planar chiral thiophene compounds in good to excellent yields and enantioselectivities (Scheme 4) [39]. The sulfur atom in the reaction substrate could be switched into an oxygen atom without much erosion on the reaction outcomes. The current method could also be adopted in the synthesis of the ferrocene-based thiophene compounds bearing two stereogenic planes as single diastereomers.

In 2021, Mao and co-workers reported a Pd-catalyzed desymmetric C—H functionalization of the ferrocene cyclopentadienyl ring with the intramolecular bromophenyl group for enantioselective synthesis of planar chiral isoquinolinone-ferrrocene compounds (Scheme 5) [40]. The chiral L3 that developed by the Tang’s group was used as the ligand [41], with a variety of ferrrocene-based isoquinolinone products afforded in generally good to excellent yields and enantioselectivities under mild conditions.

In 2015, He and co-workers reported a Rh(Ⅲ)-catalyzed enantio–selective C—H bond silylation reaction of the ferrocenes 7 (Scheme 6) [42]. The chiral diphosphine ligand (S)-L4 was used in combination with the Rh(Ⅲ) catalyst, and a broad scope of planar chiral ferrocene-fused silole products 8 were afforded in good to excellent yields and optical purity. Noteworthily, the iron center in the ferrocene structure can be replaced with a ruthenium atom, offering a versatile and efficient strategy for the synthesis of diverse planar chiral metallocene derivatives.

In 2016, Carreno, Urbano and co-workers developed an Au(Ⅰ)-catalyzed cycloisomerization of o-alkynylaryl ferrocenes 9, using the selenium-phosphine (R)-L5 as the chiral ligand and AgSbF₆ as the halide scavenger (Scheme 7) [43]. A broad scope of planar-chiral aromatic ferrocene products with different substituents were afforded in good to excellent yields and enantioselectivities.

In 2024, Liu, Fan, Gao and co-workers utilized the Tang’s bisphosphine L6 as the ligand to coordinate with the Au(Ⅰ) catalyst for the desymmetric intramolecular hydroarylation reaction of N-ferroceneyl propiolamides (Scheme 8a) [44]. A broad scope of planar chiral ferrocenepyridin-2(1H)-one products bearing various substituents on the phenyl moieties were efficiently afforded in good to excellent optical purity. The proposed reaction mechanism is depicted in Scheme 8c. Initially, the chiral gold catalyst formed from the AuCl(Me₂S) and the chiral ligand coordinates with the triple bond of the N-ferrocenylpropanylamide substrate to give the chiral Au(Ⅰ)-π complex Ⅰ-1. The o-position of the ferrocene moiety then attacks the π-activated alkyne group through a conjugate addition process to produce the Au(Ⅰ)-enamide intermediate Ⅰ-2, which then undergoes a protodemetalation step to give the final product 12 and regenerate the Au(Ⅰ) catalyst for additional catalytic cycles.

2.2　Intermolecular reactions

In 2013, Cui, Wu and co-workers reported an asymmetric dehydrogenative Heck reaction between the N,N-dimethylaminomethylferrocene 13 and the alkene 14, with the Pd(Ⅱ) salt used as the reaction catalyst and the chiral amino acid L7 used as the chiral ligand (Scheme 9) [45]. A broad scope of functional groups could be tolerated on the alkene 14, and the planar chiral ferrocenyl phosphine products were facilely achieved in generally excellent optical purity. The proposed reaction mechanism is depicted in Scheme 9c. Initially, the chiral palladium catalyst formed by the Pd(Ⅱ) salt and the chiral ligand coordinates with the N atom of substrate 13 to give the cyclopalladated complex Ⅰ-3, and subsequently undergoes enantioselective electrophilic attack at the o-position carbon atom (via bicycle-intermediate Ⅰ-3) to produce the cyclopalladated complex Ⅰ-4. The cyclopalladated complex Ⅰ-4 can be coordinated with alkene 14 under mild conditions to give the intermediate Ⅰ-5. Then the intermediate Ⅰ-5 goes through the β-hydride elimination process to give the target product 15 and liberate the Pd(0). Noteworthily, the N,N-dimethylaminomethylferrocene 13 can be oxidized by O₂ to give N,N-dimethylaminomethylferrocenium, which can oxidize Pd(0) to regenerate Pd(Ⅱ) for the next catalytic cycle.

In 2020, Cui, Wu and co-workers demonstrated that the planar chiral ferrocene structures could be achieved from the achiral ferrocenecarboxylic acid 16 with alkene 14 through a Pd(Ⅱ)-catalyzed C—H alkenylation reaction (Scheme 10) [46]. The mono-protected amino acid L8 was used as the single chiral ligand and the oxygen was used as the oxidant for this reaction. Both electron-donating and electron-withdrawing groups could be installed on the alkene substrate 14, with the target planar chiral 2-alkenyl ferrocenecar-boxylic acids 17 afforded in good to excellent enantioselectivities.

In 2019, You, Gu and co-workers demonstrated that the planar chiral ferrocene structures could be achieved from the achiral aminomethylferrocenes 13 and the oxazoles 18 through a Pd(Ⅱ)-catalyzed asymmetric oxidative C—H/C—H cross-coupling reaction (Scheme 11) [47]. The mono-protected natural amino acid L9 was used as the single chiral ligand and the 1,4-benzoquinone was used as the oxidant for this reaction. Oxazole and thiazoles bearing various functional groups worked well in this process, and the optically pure planar chiral ferrocene products were given in moderate to good yields. Mechanistically, the chiral amino acid and the palladium acetate could form the catalytically reactive complex, which could promote the C—H bond cleavage process of the aminomethylferrocene substrate 13 to generate the chiral Pd(Ⅱ) intermediate Ⅰ-7. Then, an electrophilic palladation of the azole substrate 18 into the intermediate Ⅰ-7 affords the intermediate Ⅰ-8, which could go through a reductive elimination to afford the planar chiral product 19 and released a Pd(0) species. The Pd(0) is oxidized by air to regenerate Pd(Ⅱ) for the next catalytic cycle.

In 2021, You and co-workers succeeded to use the indolizine derivative 21 as the arylation reagent to participate in the regio- and enantioselective C—H functionalization reaction of the aminomethylferrocene 20 (Scheme 12) [48]. The palladium acetate was used as the reaction catalyst in combination with the Boc-L-Val-OH (L10) used as the chiral ligand. The reaction exhibited good functional group tolerance on both the indolizine and the aminomethylferrocene substrates, with the corresponding arylated planar chiral aminomethylferrocene products afforded in good yields with excellent optical purities.

In 2019, You, Gu and co-workers reported an asymmetric cross-coupling reaction between the thiocarbonylferrocene 23 and the iodobenzene 24, with the Rh(Ⅰ) salt used as the reaction catalyst and the (4R,5R)-(2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol) (TADDOL)-derived phosphonite (R,R)-L11 used as the chiral ligand (Scheme 13) [49]. The reaction showed good functional group tolerance, with a diversity of aryl iodides and thiocarbonylferrocene substrates worked well to give the target planar chiral ferrocenes in good to excellent yields and enantioselectivity.

Soon later, the same group successfully adopted the aryl cross-coupling strategy in the enantioselective C—H arylation of ferrocenylpyridines (Scheme 14) [50]. The 2-pyridyl group on the ferrocene scaffold functionalized as a directing group to regio- and enantioselectively introduce the aryl group onto the o-position of the cyclopentadienyl ring under the promotion of the Rh(Ⅰ)/(R,R)-L12 catalytic system. Various aryl halides worked smoothly as the arylation reagent, with most of the o-substituted planar chiral ferrocenylpyridine products efficiently afforded as single enantiomers.

The authors intensively studied the reaction mechanism of the above C—H arylation of ferrocenylpyridines through both experimental and computational methods (Scheme 15) [51]. The elementary steps in the catalytic cycle were elucidated, and the structures of several key intermediates were identified. The results revealed that the reaction initiates with the C—H activation of the ferrocene by the Rh(Ⅰ)/(R,R)-L13 complex via the intermediate Ⅰ-9, followed by the oxidative addition of the intermediate Ⅰ-10 with aryl bromide to give the intermediate Ⅰ-11. Reductive elimination of the Rh(Ⅰ) catalyst from the intermediate Ⅰ-11 led to the formation of the final product. The final reductive elimination step is identified as the rate-limiting step of the catalytic cycle. Leveraging the mechanistic insights gained, the authors successfully utilized isoquinoline, pyrimidine, oxazoline, imidazole and pyrazole as the directing groups in this ferrocene o-C-H arylation protocol [6-8]-ferrocenophanes bearing unique molecular topology were efficiently afforded through this strategy in exclusive enantioselectivity.

In 2023, You’s group discolsed an enantioselective arylation reaction of the commercially available ferroceneformaldehydes with aryl bromides (Scheme 16) [52]. The benzylamine was used to overcome the weak coordinating ability of the aldehyde group through in situ formation of the imine intermediate. With the Rh(Ⅰ) used as the reaction catalyst and the phosphonite (R,R)-L13 used as the chiral ligand, the arylated planar chiral ferroceneformaldehyde products could be formed in up to 83% yield and as almost single enantiomers.

In 2024, Shi’s group made a breakthrough in the facile preparation of planar chiral ferrocenyl phosphines (Scheme 17) [53]. They used the ferrocenyl phosphine 34 as the reaction substrate, with diverse aryl groups introduced to the o-position of the ferrocene moiety. The triarylphosphine group attached to the substrate 34 acted as an innovative directing group, which cooperated with the palladium catalyst and the chiral phosphine ligand L14 to achieve both regio- and enantioselectivities during the ferrocene C—H activation reaction. A broad scope of functional groups could be tolerated on both the ferrocene substrate 34 and the arylbromide substrate 35, and the planar chiral ferrocenyl phosphine products were facilely achieved in generally excellent optical purity.

In 2023, Zhou’s group succeeded in introducing an aryl group to the m-position of the ferrocene scaffold in both regio- and enantioselective fashion (Scheme 18a) [54]. An aminomethyl group was pre-installed on the ferrocene substrate 13 as the directing group. The Pd(OAc)₂ was used as the reaction catalyst, the mono-protected amino acid L15 was used as the chiral ligand and the norbornene was used as the transent mediator. A diversity of aryliodides or arylbromides worked smoothly in this protocol as the aryl group donor, with the corresponding planar chiral 1,3-disubstituted ferrocene products 38 afforded in moderate to good yields as single enantiomers (Scheme 18b). The proposed mechanism involves the Pd(Ⅱ)/L15 complex-catalyzed, amino-directed regio-selective activation of the ferrocene o-C-H bond, followed by the insertion of norbornene to generate the intermediate Ⅰ-13. Then the m-C-H bond of the ferrocene substrate could be activated through the formation of the intermediate Ⅰ-14, which could go through oxidative addition with the aryl halide substrate 37 and reductive elimination of the Pd(Ⅱ) complex to give the intermediate Ⅰ-15. Then a β-carbon elimination process within the intermediate Ⅰ-15 extrudes the norbornene moiety and gives the intermediate Ⅰ-16, which can produce the final product 38 via a protodepalladation step and liberate the This strategic placement of the Pd(Ⅱ) catalyst at the 3-position enables the of electrophiles and subsequent reductive elimination, thereby establishing the critical meta C—C bond. The catalytic cycle is completed through β-carbon elimination, which liberates the NBE 1 mediator, followed by the depalladation of intermediate Ⅰ-16, leading to the release of the final product 38 and regenerate the Pd(Ⅱ)/L15 complex for additional catalytic cycles (Scheme 18c).

In 2024, Kapur, Madhavan and co-workers reported a Pd(Ⅱ)-catalyzed regio- and stereoselective distal C—H activation of the chiral N,N-dimethyl-1-ferrocenylethylamine 39 with various aryl iodides 24 (Scheme 19) [55]. The chiral N-acetyl phenylalanine L8 and the NBE 2 were used as the dual ligands in combination with the Pd(OAc)₂ catalyst for this reaction. A broad range of ferrocene-1,3-derivatives featuring both central and planar chirality, with varying substituents, were synthesized in good to excellent yields with high enantio– or diastereoselectivities.

In 2021, Hou and Luo’s group reported a highly enantioselective C—H alkenylation reaction of quinoline-substituted ferrocene 41 with alkynes 42 using scandium complex C1 as the chiral catalyst (Scheme 20a) [56]. A series of o-alkenylated planar-chiral ferrocenyl quinoline products were afforded in good to excellent yields and optical purity (Scheme 20b). It was attractive that no atoms were lost during the catalytic reaction, and the planar chiral ferrocene products obtained from this protocol could be applied as chiral ligand for the asymmetric rhodium-catalyzed hydroarylation of the cyclohexanone (Scheme 20c).

In 2022, You, Zheng and co-workers reported a Rh(Ⅲ)-catalyzed enantioselective C—H activation/annulation reaction of substituted ferrocenecarboxamides with internal alkynes (Scheme 21) [57]. The chiral CpRh(Ⅲ) complex C2 was used as the reaction catalyst, yielding the planar chiral ferrocene-fused pyridone products in moderate to excellent yields and enantioselectivities.

In 2023, Yu, Wang and co-workers reported a Cu-mediated enantioselective ferrocene C—H alkynylation reaction with terminal alkynes (Scheme 22) [58]. The chiral DDBINOL derivative (S)-L16 was used as the ligand for the enantioselective induction during the oxidative cross-coupling process. An oxazoline-aniline group was pre-installed on the ferrocene scaffold as the directing group, introducing the external alkynyl groups onto the o-position of the ferrocene moiety.

In 2024, Shi, Yao and co-workers reported a novel copper-catalyzed enantioselective o-C-H alkynylation reaction of ferrocene carboxamides (Scheme 23a) [59]. The 8-aminoquinoline in the amide moiety of the substrate 53 was adopted as the directing group for the o-induction of the alkynyl group with the promotion of the copper catalyst and the chiral BINOL ligand (S)-L17. Both electron-donating and electron-withdrawing groups could be installed on the arylalkyne substrate 51, with the target planar chiral alkynyl ferrocenes 54 afforded in good to excellent enantioselectivities. Noteworthily, the stoichiometric external oxidant TBHP that used for the oxidative C—H cross coupling process could be replaced with renewable electricity (Scheme 23b). The asymmetric reaction between the substrates 53 and 51 could be carried out under electrochemical conditions in an undivided cell in presence of the same copper catalyst and chiral ligand. The corresponding products were generally afforded in higher yields without much loss of the optical purity.

In 2024, You, Zheng and co-workers reported a cobalt-catalyzed asymmetric C(sp²)-C(sp³) cross-coupling reaction between the ferrocene thioamides 55 and the allyl carbonates 56 for the facile preparation of enantio–enriched o-allyl substituted ferrocene thioamide products 57 (Scheme 24) [60]. The binaphthyl-based chiral cobalt complex C3 was used as the reaction catalyst and the target products were given in up to 81% yield and 95% ee value. Noteworthily, the iron center in the ferrocene structure could also be switched into a ruthenium atom.

In 2022, Xu, Ke and colleagues achieved the enantioselective dual borylation of ferrocenes through an amide-directed iridium-catalyzed C—H activation reaction (Scheme 25) [61]. The chiral bidentate boryl ligand L18 was used in combination with the Ir(Ⅰ) catalyst, and a series of planar chiral borylated ferrocene products bearing various substituents were afforded in good to excellent yields and optical purity. Mechanistic studies demonstrate that the C—H borylation of the N-methyl group in the amide moiety plays a crucial role in enhancing enantioselectivity.

In 2014, Cui, Wu and co-workers reported a Pd(Ⅱ)-catalyzed enantioselective C—H activation of N,N-dimethylaminomethylferrocene 13 with diphenyl diketone 61 (Scheme 26) [62]. The chiral amino acid ligand L8 was used in combination with the Pd(Ⅱ) catalyst, and a series of planar chiral 2-acyl-1-dimethylaminomethylferrocene products were afforded in good to excellent yields and optical purity. The afforded products could be easily converted to various chiral ligands via simple trans-formations.

In 2023, Ming, Chen and co-workers reported a Rh-catalyzed conjugate addition/cyclization cascade reaction between the symmetric ferrocene diketone substrate 63 and the organoboronic acid 64 for access to the ferrocene-fused cyclopentane molecules bearing both planar and central chirality (Scheme 27) [63]. The chiral ferrocene-derived diene molecule (S,S)-L19 was used as the ligand to achieve high efficiencies and selectivities. A diversity of substituents and substitution patterns were well tolerated on the organoboronic acid substrates, with the ferrocene-fused cyclopentane products afforded in good to excellent yields and optical purity as single diastereomers.

In 2025, Ming and co-workers reported a Rh-catalyzed asymmetric aryl addition reaction between the 1,2-diformylferrocene 66 and the arylboronic acid 67 (Scheme 28) [64]. The chiral (R,R)-L19 was used as the ligand for this reaction. A broad scope of planar-chiral formylferroccene products with different substituents were afforded in good to excellent yields and enantioselectivities.

In 2024, Shi, Yao and co-workers reported a cobalt-catalyzed enantioselective C—H acyloxylation of the ferrocene amides 53 with various carboxylic acids 69 (Scheme 29) [65]. The chiral salicyloxazoline (R)-L20 and the in situ-formed tricyclohexylphosphine oxide were used as the dual ligands in combination with the Co(SCN)₂ catalyst for this dehydrogenative C—H acyloxylation reaction. The planar chiral o-acyloxylated ferrocene amide products bearing various substitution patterns were afforded in moderate to good yields with excellent optical purity.

In 2025, Shi and colleagues reported a copper-mediated enantioselective C—H thiolation of ferrocenes via a Cu(Ⅰ)-catalyzed C—H activation process (Scheme 30) [66]. The reaction used a chiral 1,1′-bi-2,2′-naphthol ligand (S)-L21 in combination with a Cu(Ⅰ) catalyst, enabling the synthesis of a diverse array of planar chiral sulfur-substituted ferrocenes with various substituents. The products were obtained in good to excellent yields with high optical purity, highlighting the efficacy of the catalytic system and expanding the synthetic toolbox for access to chiral organosulfur compounds.

3　Organocatalyzed planar chiral ferrocene syntheses

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The field of organocatalytic synthesis of planar chiral ferrocene derivatives is still in its infancy. Researchers have explored the use of chiral amines and N-heterocyclic carbenes (NHCs) as organocatalysts for asymmetric monoesterification and kinetic resolution strategies (Scheme 31).

In currently, the constructions of planar chiral ferrocenes via organocatalytic methods have been relatively less developed. In 2016, Torre, Sierra and co-workers disclosed an asymmetric mono-esterification reaction of the meso–ferrocene anhydride 73 (Scheme 32) [67]. Chiral bifunctional organic catalysts bearing both an amino group and an H-bond donor fragment were evaluated for this desymmetric esterification process. The planar chiral ferrocenyl dicarboxylic acid mono ethylate product 74 could be afforded in up to 98% ee value under the catalysis of the quinine-derived squaramide catalyst C4.

N-Heterocyclic carbenes (NHCs) have also been applied as effective catalysts in the desymmetric mono-esterification reactions of ferrocene derivatives [68-71]. In 2022, Chi, Jin and co-workers reported the NHC-catalyzed oxidative mono-esterification reaction of diformylferrocenes 66 with electron-deficient phenols 75 (Scheme 33) [72]. The chiral NHC C5 was used as the reaction catalyst and the diphenoquinone (DQ) was used as the external oxidant. Electron-withdrawing groups were well tolerated on the phenol substrate 75 to give the planar chiral ferrocene mono-ester products 76 in good to excellent yields and enantioselectivities. Electron-donating and electron-neutral groups led to little formation of the desired products under the current catalytic condition. However, the phenol substrates 75 could be replaced with mercaptans 75c to give the ferrocene mono-thioesters 76c in satisfactory results under the same catalytic condition, regardless of the substitution patterns of the mercaptan scaffolds. The possible mechanism was briefly illustrated as shown in Scheme 33c. The addition of the chiral NHC C5 to the ferrocene dicarbaldehyde 66 gives two diastereomeric intermediates Ⅰ-18 and Ⅰ-19 in reversible fashion. Due to steric hindrance, the intermediate Ⅰ-18 is more easily formed than the intermediate Ⅰ-19 and can be oxidized under mild conditions to give the intermediate Ⅰ-20. Then, nucleophiles such as phenols and mercaptans can react with the intermediate Ⅰ-20 to ultimately yield the planar chiral product 76a or 76c, liberating the NHC catalyst and completing the cycle. In vitro inhibitive activities of the planar chiral products 76 against Xanthomonas axonopodis pv. citri (Xac) have been examined. The products 76b (100 µg/mL) and 76d (100 µg/mL) exhibited Xac inhibition rate of 85.86% ± 0.65% and 84.19% ± 0.75%, which were better than that of the thiodiazole copper (46.08% ± 3.91%) (Scheme 33b).

Recently, the same group reported an NHC-catalyzed kinetic resolution reaction of the racemic ferrocenyl carbaldehyde substrate 77 bearing a phosphinyl group (Scheme 34) [73]. The toluenesulfonamide 78 (TsNH₂) was used as the N source to convert the aldehyde group into the cyanide group through a cascade amide formation/de-sulfination process. The ferrocenyl nitriles (R_p)-79 were generally afforded in good yields and optical purity. Meanwhile, the NaBH₄ was added at the end of this reaction to reduce the unreacted imine intermediate into the Ts-protected ferrocenylmethylamines (S_p)-80. It was interesting to find that the afforded planar chiral ferrocene derivatives showed promising antibacterial bioactivities against the bacterial plant pathogens.

4　Summary and outlook

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The development of catalytic methods for facile and enantioselective construction of planar chiral ferrocene-based multi-functional molecules has received considerable interest in the recent decade. Transition metal-catalysis has been dominating in the desymmetrization of mono-substituted ferrocene structures. Asymmetric ferrocene C(sp²)-H activation reactions have been extensively studied in the transition metal-catalyzed planar chiral ferrocene synthesis. The pre-installation of suitable directing groups and the design of effective chiral ligands are critical for the regio- and stereoselectivities in these transformations. Organic catalysts such as chiral amines and NHCs have recently been used to promote the enantioselective desymmetrization and kinetic resolution of ferrocene derivatives. The introduction of suitable electron-withdrawing functional groups onto the ferrocene structures and the selection of suitable nucleophilic organic catalysts have played crucial roles in the organocatalytic ferrocene synthesis. Based on the abundant catalytic methods developed in the recent decade, diverse planar chiral ferrocene molecules bearing alkyl, aryl, heteroaryl, alkenenyl, alkynyl, and other functional groups have been efficiently obtained in optically enriched forms.

However, challenges and limitations remain in the asymmetric catalytic synthesis of planar chiral ferrocenes. The reaction modes have long been dominated by transition metal-catalyzed C(sp²)-H activations. Asymmetric additions, oxidations, hydrogenations and substitution reactions have been relatively less developed in the construction of planar chiral ferrocenes. Most of C(sp²)-H activation reactions in planar chiral ferrocenes have taken place on the o-position to the directing groups, with limited success in the m-selective C(sp²)-H activation of ferrocene structures. Comparing with the transition metal catalysis, organocatalytic reactions have been rarely used in the asymmetric synthesis of ferrocene derivatives.

Therefore, great efforts are still needed in the development of efficient and stereoselective catalytic methods for planar chiral ferrocene synthesis. For instance, the introduction of novel directing groups with practical synthetic significance represents an interesting strategy in the stereoselective ferrocene functionalization. The development of novel catalytic systems to realize novel reaction modes and further enhance the reaction selectivity is still of great significance in this research field. Multi-component cascade reactions, co-operative catalysis with different catalysts and relay activations may bring new breakthroughs to the construction of planar ferrocene derivatives. The development of novel catalytic methods will undoubtedly further promote the application of planar chiral ferrocene derivatives in drug development and material sciences.

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doi: 10.1016/j.cclet.2025.111793

Receive Date：2025-05-20
Online Date：2026-10-29
Published：2026-03-15

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Received：2025-05-20
Revised：2025-08-19
Accepted：2025-09-04

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State Key Laboratory of Green Pesticide, Guizhou University, Guiyang 550025, China

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E-mail addresses: lzchen@gzu.edu.cn (L. Chen)

zcjin@gzu.edu.cn (Z. Jin)

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表12种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Scheme 1 Representative planar chiral ferrocene derivatives.

Scheme 2 Transition metal-catalyzed asymmetric synthesis of planar chiral ferrocene derivatives.

Scheme 3 Pd(Ⅱ)-catalyzed intramolecular cyclization to form indenone derivatives.

Scheme 4 Pd(Ⅱ)-catalyzed intramolecular cyclization to form planar chiral thiophene compounds.

Scheme 5 Pd-catalyzed the intramolecular cyclization to form soquinolinone-fused ferrocenes.

Scheme 6 Rh(Ⅲ)-catalyzed C—H silylation reaction to form planar chiral thiophene compounds.

Scheme 7 Au(Ⅰ)-catalyzed cycloisomerization to form planar chiral aromatic ferrocene compounds.

Scheme 8 Au(Ⅰ)-catalyzed intramolecular cyclization to form planar chiral ferrocenepyridin-2(1H)-one products.

Scheme 9 Pd(Ⅱ)-catalyzed enantioselective alkenylation of N,N-dimethylaminomethylferrocene.

Scheme 10 Pd(Ⅱ)-catalyzed C—H alkenylation reaction between ferrocenecarboxylic acid with alkene.

Scheme 11 Pd(Ⅱ)-catalyzed cross-coupling reaction between ferrocenes and azoles.

Scheme 12 Pd(Ⅱ)-catalyzed cross-coupling reaction between dialkylaminomethylferrocenes and indolizines.

Scheme 13 Rh(Ⅰ)-catalyzed thioketone-directed enantioselective C—H bond arylation of ferrocenes.

Scheme 14 Rh(Ⅰ)-catalyzed coupling reaction to form planar chiral ferrocene-based pyridine derivatives.

Scheme 15 Rh(Ⅰ)-catalyzed asymmetric C—H arylation reac-tion to form planar chiral ferrocenophanes.

Scheme 16 Rh(Ⅰ)-catalyzed C—H arylation of ferrocenefor-maldehydes.

Scheme 17 Pd(Ⅱ)-catalyzed and P(Ⅲ)-directed asymmetric C—H arylation to form planar chiral ferrocenyl phosphines.

Scheme 18 Pd(Ⅱ)-catalyzed enantioselective C—H activationto form 1,3-disubstituted planar chiral ferrocenes.

Scheme 19 Pd(Ⅱ)-catalyzed enantioselective C3-arylation.

Scheme 20 Sc-catalyzed C—H alkenylation reaction between ferrocenes and alkynes.

Scheme 21 Rh(Ⅲ)-catalyzed C—H cycloaddition reaction between ferrocenecarboxamides and internal alkynes.

Scheme 22 Cu-mediated enantioselective C—H activation reaction to form planar chiral ferrocenophanes.

Scheme 23 Cu(Ⅱ)-catalyzed enantioselective C—H alkynylation reaction to form planar chiral ferrocene carboxamides.

Scheme 24 Co-catalyzed the coupling reaction to form planar chiral allylation products.

Scheme 25 Rh(Ⅰ)-catalyzed asymmetric C—H arylation reaction to form planar chiral ferrocenophanes.

Scheme 26 Pd(Ⅱ)-catalyzed enantioselective C—H direct acylation of ferrocene derivatives.

Scheme 27 Rh-catalyzed the desymmetric cyclization reaction to form planar and central chirality in metallocenes.

Scheme 28 Rh-catalyzed asymmetric addition of the 1,2-diformylmetallocenes.

Scheme 29 Co-catalyzed enantioselective C—H acyloxylation reaction to form oxy-substituted planar chiral ferrocenes.

Scheme 30 Cu(Ⅰ)-catalyzed enantioselective C—H thiolation of ferrocenes.

Scheme 31 Asymmetric organocatalysis for the synthesis of planar chiral ferrocenes.

Scheme 32 Organocatalytic desymmetrization of meso–ferrocene anhydride.

Scheme 33 NHC-catalyzed desymmetrization of ferrocene-derived dicarbaldehydes.

Scheme 34 NHC-catalyzed a kinetic resolution process to form ferrocene-derived phosphine carbonitrile and phosphinesulfonamide.

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