1. Advantages of Chemical Redox Agents 878 2. Disadvantages of Chemical Redox Agents 879 C. Potentials in Nonaqueous Solvents 879 D. Reversible vs Irreversible ET Reagents 879 E. Categorization of Reagent Strength 881 II. Oxidants 881 A. Inorganic 881 1. Metal and Metal Complex Oxidants 881 2. Main Group Oxidants 887 B. Organic 891 1. Radical Cations 891 2. Carbocations 893 3. Cyanocarbons and Related Electron-Rich Compounds 894

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Chemical Redox Agents for Organometallic Chemistry

4.2.8. Reductive Coupling 3109 5. Reaction of Aromatic Compounds 3110 5.1. Electrophilic Substitutions 3110 5.2. Radical Substitution 3111 5.3. Oxidative Coupling 3111 5.4. Photochemical Reactions 3111 6. Reaction of Carbonyl Compounds 3111 6.1. Nucleophilic Additions 3111 6.1.1. Allylation 3111 6.1.2. Propargylation 3120 6.1.3. Benzylation 3121 6.1.4. Arylation/Vinylation 3121 6.1.5. Alkynylation 3121 6.1.6. Alkylation 3121 6.1.7. Reformatsky-Type Reaction 3122 6.1.8. Direct Aldol Reaction 3122 6.1.9. Mukaiyama Aldol Reaction 3124 6.1.10. Hydrogen Cyanide Addition 3125 6.2. Pinacol Coupling 3126 6.3. Wittig Reactions 3126 7. Reaction of R,â-Unsaturated Carbonyl Compounds 3127

Organic Reactions in Aqueous Media with a Focus on Carbon−Carbon Bond Formations: A Decade Update

Ru-, Rh-, and Pd-Catalyzed C-C Bond Formation Involving C-H Activation and Addition on Unsaturated Substrates: Reactions and Mechanistic Aspects

Transition-metal-catalyzed addition of heteroatom-hydrogen bonds to alkynes.

The quest for alternative drugs to the well-known cisplatin and its derivatives, which are still used in more than 50% of the treatment regimes for patients suffering from cancer, is highly needed.1,2 Despite their tremendous success, these platinum compounds suffer from two main disadvantages: they are inefficient against platinum-resistant tumors, and they have severe side effects such as nephrotoxicity. The latter drawback is the consequence of the fact that the ultimate target of these drugs is ubiquitous: It is generally accepted that Pt anticancer drugs target DNA, which is present in all cells.3,4 Furthermore, as a consequence of its particular chemical structure, cisplatin in particular offers little possibility for rational improvements to increase its tumor specificity and thereby reduce undesired side effects.

In this context, organometallic compounds, which are defined as metal complexes containing at least one direct, covalent metal−carbon bond, have recently been found to be promising anticancer drug candidates. Organometallics have a great structural variety (ranging from linear to octahedral and even beyond), have far more diverse stereochemistry than organic compounds (for an octahedral complex with six different ligands, 30 stereoisomers exist!), and by rational ligand design, provide control over key kinetic properties (such as hydrolysis rate of ligands). Furthermore, they are kinetically stable, usually uncharged, and relatively lipophilic and their metal atom is in a low oxidation state. Because of these fundamental differences compared to “classical coordination metal complexes”, organometallics offer ample opportunities in the design of novel classes of medicinal compounds, potentially with new metal-specific modes of action. Interestingly, all the typical classes of organometallics such as metallocenes, half-sandwich, carbene-, CO-, or π-ligands, which have been widely used for catalysis or biosensing purposes, have now also found application in medicinal chemistry (see Figure ​Figure11 for an overview of these typical classes of organometallics).



Figure 1

Summary of the typical classes of organometallic compounds used in medicinal chemistry.



In this Perspective, we report on the recent advances in the discovery of organometallics with proven antiproliferative activity. We are emphasizing those compounds where efforts have been made to identify their molecular target and mode of action by biochemical or cell biology studies. This Perspective covers more classes of compounds and in more detail than a recent tutorial review by Hartinger and Dyson.(5) Furthermore, whereas recent reviews and book contributions attest to the rapid development of bioorganometallic chemistry in general,6,7 this Perspective focuses on their potential application as anticancer chemotherapeutics. Another very recent review article categorizes inorganic anticancer drug candidates by their modes of action.(8) It should be mentioned that a full description of all currently investigated types of compounds is hardly possible anymore in a concise review. For example, a particularly promising class of organometallic anticancer compounds, namely, radiolabeled organometallics, has been omitted for space limitations. Recent developments of such compounds have been reviewed in detail by Alberto.(9)

http://pubs.acs.org/doi/pdf/10.1021/jm100020w

Organometallic Anticancer Compounds

In Vitro Evaluation of Rhodium and Osmium RAPTA Analogues: The Case for Organometallic Anticancer Drugs Not Based on Ruthenium

The hydration of phenylacetylene in the presence of the complex mer,trans-(PNP)RuCl2(PPh3) in THF at 60 °C leads to the cleavage of the C−C triple bond with formation of the carbonyl complex fac,cis-(PNP)RuCl2(CO) and toluene [PNP = CH3CH2CH2N(CH2CH2PPh2)2]. A study under different experimental conditions, the use of model and isotope labeling experiments, and the detection of several intermediates, taken altogether, show that the C−C bond cleavage reaction comprises a number of steps, among which the most relevant to the mechanism are 1-alkyne to vinylidene tautomerism, conversion of a vinylidene ligand to hydroxycarbene by intramolecular attack of water, deprotonation of hydroxycarbene to σ-acyl, deinsertion of CO from the acyl ligand, and hydrocarbon elimination by protonation of the metal-alkyl moiety. The following intermediate species have been isolated and characterized:  the vinylidene fac,cis-(PNP)RuCl2{CC(H)Ph}, the (aquo)(σ-alkynyl) complex fac-(PNP)RuCl(C⋮CPh)(OH2), and the (benzyl)carbonyl me...

The Mechanism of the Ru-Assisted C−C Bond Cleavage of Terminal Alkynes by Water

We report that the selective coupling of terminal alkynes to Z-1,4-disubstituted butenynes can be achieved in a catalytic way by using either the Ru(II) η 2 -H 2 complex [(PP 3 )Ru-(H)(H 2 )]BPh 4 (1) or the η 1 -dinitrogen derivative [(PP 3 )Ru(H)(N 2 )]BPh 4 (2) [PP 3 =P(CH 2 CH 2 PPh 2 ) 3 ]. We describe in detail the reaction sequence leading to 1,4-bis(trimethylsilyl)-but-3-1-yne, but comparisons with other 1-alkynes are given in the text showing the applicability of our method to the catalytic homo coupling and stoichiometric cross coupling of 1-alkynes

A ruthenium(II) enynyl complex mediates the catalytic dimerization of 1-alkynes to Z-1,4-disubstituted enynes

Regio- and stereoselective dimerization of phenylacetylene to (z)-1,4-diphenylbut-3-en-1-yne by ruthenium(ii) catalysis. reaction mechanism involving intermolecular protonation of sigma -alkynyl by 1-alkyne

A new family of Cs- and C1-symmetric 2,6-bis(imino)pyridyl ligands has been synthesised. These ligands, which differ from their known counterparts in the contemporaneous presence of alkyl and aryl substituent at the ketimine nitrogen atoms, form stable, five-coordinate complexes with FeCl2 and CoCl2. All ligands and catalysts have been fully characterised both in the solid state and in solution. A single-crystal X-ray analysis of [CoCl2{2-[CMe=N−(2,6-dimethylphenyl)]-6-(CMe=N−C6H11)C5H3N}]·H2O shows the metal centre to adopt a highly distorted square-pyramidal geometry. In combination with methylaluminoxane (MAO), both iron and cobalt compounds act as effective and selective (> 99%) catalysts for the oligomerisation of ethylene to a Schulz−Flory distribution of α-olefins, with the α factor ranging from 0.61 to 0.91. The iron catalysts exhibit TOFs as high as 7·105 mol C2H4 (mol of cat × h)−1 and are much more active than their cobalt analogues. Experiments at different ethylene pressures with the iron catalysts showed that both the propagation rate and the chain transfer rate are first order in ethylene pressure. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2003)

Fabrizio Zanobini

Papers

In Vitro Evaluation of Rhodium and Osmium RAPTA Analogues: The Case for Organometallic Anticancer Drugs Not Based on Ruthenium

The Mechanism of the Ru-Assisted C−C Bond Cleavage of Terminal Alkynes by Water

A ruthenium(II) enynyl complex mediates the catalytic dimerization of 1-alkynes to Z-1,4-disubstituted enynes

Regio- and stereoselective dimerization of phenylacetylene to (z)-1,4-diphenylbut-3-en-1-yne by ruthenium(ii) catalysis. reaction mechanism involving intermolecular protonation of sigma -alkynyl by 1-alkyne

Oligomerisation of Ethylene to Linear α‐Olefins by new Cs‐ and C1‐Symmetric [2,6‐Bis(imino)pyridyl]iron and ‐cobalt Dichloride Complexes