Dual-Responsive Chiroptical Switching in Chiral Ferrocene Derivatives

Chiral 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

This chapter contains sections titled: Central and Planar Chirality in Metallocenes α-Ferrocenylalkyl Carbocations Central Chiral Ferrocene Derivatives Planar Chiral Ferrocene Derivatives Applications of Chiral Ferrocene Derivatives

The enantioselective synthesis of β-amino-β-ferrocenyl alcohols, a new class of chiral ferrocene derivatives suitable for the elaboration of auxiliaries and ligands for asymmetric synthesis, can be efficiently achieved by the catalytic asymmetric dihydroxylation of 1-ferrocenylalkenes, followed by the regio- and stereoselective substitution of the hydroxy group adjacent to the ferrocene moiety by nitrogen nucleophiles. En route to these compounds, several previously unknown metallocene derivatives such as α-ferrocenyl epoxides, interannularly cyclopalladated ferrocenyloxazolines, and α-amino-α-ferrocenyl acids have been obtained. The first examples of an organocatalytic approach to the enantioselective synthesis of chiral ferrocenes are also presented.

In recent years, transition-metal-catalyzed C-H functionalization has gradually developed into a powerful tool for the synthesis of ferrocenes in an atom- and step-economic fashion. However, despite significant achievements, the vast majority of these C-H functionalizations required precious 4d or 5d transition metal catalysts. The use of inexpensive and sustainable 3d metals in the C-H functionalization of ferrocenes remains challenging, especially the development of asymmetric versions. Herein, we summarize the remarkable recent progress in the synthesis of ferrocenes by 3d transition metal-catalyzed C-H activation until December 2021.

Asymmetric dihydroxylation reactions leading to novel chiral ferrocene derivatives

Examples of organometallic compounds as nucleoside analogues are rare within the field of medicinal bioorganometallic chemistry. We report on the synthesis and properties of two chiral ferrocene derivatives containing a nucleobase and a hydroxyalkyl group. These so-called ferronucleosides show promising anticancer activity, with cytostatic studies on five different cancer cell lines indicating that both functional groups are required for optimal activity.

An operationally simple colorimetric method for enantioselective detection of chiral secondary alcohols via hydrogen bonding interactions using a chiral ferrocene derivative is reported.

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The chiral ferrocene derivative (R,Rp)‐2‐[1‐(diphenylphosphanyl)ethyl]ferrocenecarboxylic acid (1) is prepared together with selected derivatives resulting from modification at the phosphane moiety [P‐oxide (5) and P‐sulfide (4)] and the carboxyl group {amides bearing benzyl (6) and (R)‐ or (S)‐1‐phenylethyl substituents [(R)‐7 and (S)‐7] at the amide nitrogen atom}. Acid 1 and amide 6 are studied as ligands in rhodium and palladium complexes. Bridge cleavage of the dimer [{Rh(μ‐Cl)Cl(η5‐C5Me5)}2] with 1 gives [RhCl2(η5‐C5Me5)(1‐κP)] (9) containing P‐monodentate 1, which undergoes smooth conversion to the (phosphanylalkyl)ferrocenecarboxylato complex [RhCl(η5‐C5Me5){Fe(η5‐C5H5)(η5‐C5H3‐1‐CH(Me)PPh2‐2‐COO‐κ2O,P}] (10) upon treatment with silica gel or alumina. Yet another O,P‐chelate complex,[Rh{Fe(η5‐C5H5)(η5‐C5H3‐1‐CH(Me)PPh2‐2‐COO‐κ2O,P}(CO)(PCy3)] (11; Cy = cyclohexyl) is obtained directly by an acid‐base reaction between the acetylacetonato complex [Rh(acac)(CO)(PCy3)] and 1. Amide 6 reacts with [{Pd(μ‐Cl)(η3‐C3H5)}2] to give the expected phosphane complex [PdCl(η3‐C3H5)(6‐κP)] (12), while the replacement of the cyclooctadiene (cod) ligand in [PdCl(Me)(cod)] affords the chelate complex [PdCl(Me)(6‐κ2O,P)] (13). All compounds are characterised by spectroscopic methods and the solid‐state structures of 5, 9, 11, 13, (R,Sp)‐2‐[1‐(diphenylphosphoryl)ethyl]‐1‐[N‐(R)‐(1‐phenylethyl)carbamoyl]ferrocene [(R)‐8; phosphane oxide from (R)‐7], and the synthetic precursors (R,Sp)‐1‐bromo‐2‐[1‐(diphenylphosphanyl)ethyl]ferrocene (2) and (R,Sp)‐1‐bromo‐2‐[1‐(diphenylthiophosphoryl)ethyl]ferrocene (3) determined by single‐crystal X‐ray diffraction. The catalytic properties of 1 and the amides are probed in enanatioselective rhodium‐catalysed hydrogenation and palladium‐catalysed asymmetric allylic alkylation. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

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Chiral ferrocene derivatives containing a 2,2′-bridged binaphthyl moiety

While the functions of carbon materials with precisely controlled nanostructures have been reported in many studies, their chiral discriminating abilities have not been reported yet. Herein, chiral discrimination is achieved using helical carbon materials devoid of chiral attachments. A Fe3O4 nanoparticle template with ethyl cellulose (carbon source) is self-assembled on dispersed multiwalled carbon nanotubes (MWCNTs) fixed in a lamellar structure, with helical nanoparticle alignment induced by the addition of a binaphthyl derivative. Carbonization followed by template removal produces helically aligned fused carbon hollow nanospheres (CHNSs) with no chiral molecules left. Helicity is confirmed using vacuum-ultraviolet circular dichroism spectroscopy. Chiral discrimination, as revealed by the electrochemical reactions of binaphthol and a chiral ferrocene derivative in aqueous and nonaqueous electrolytes, respectively, is attributable to the chiral space formed between the CHNS and MWCNT surfaces.

N,N‘-Diisopropylferrocenecarboxamide is utilized for an asymmetric, directed metalation approach to several planar chiral bifunctional ferrocene derivatives. Directed metalation using n-butyllithium-(−)-sparteine on N,N‘-diisopropylferrocenecarboxamide can be achieved to give high yields of the corresponding boronic acid; however, it was found that a sequence involving asymmetric directed metalation−bromination, followed by lithium−halogen exchange, was more convenient to access the same derivatives since this allowed straightforward determination of the enantiomeric excess. (pR)-2-[(N,N-Diisopropylamino)methyl]ferrocenylboronic acid and derivatives thereof could be readily accessed with high enantiomeric excess, followed by amide reduction.

Structures and antitumor activities of planar chiral cyclopalladated ferrocene derivatives

Structures and Synthetic Strategies of Chiral Oxazolinyl Ferrocene Derivatives