Combining single electron transfer between a donor substrate and a catalyst-activated acceptor substrate with a stereocontrolled radical–radical recombination enables the visible-light-driven catalytic enantio- and diastereoselective synthesis of 1,2-amino alcohols from trifluoromethyl ketones and tertiary amines. With a chiral iridium complex acting as both a Lewis acid and a photoredox catalyst, enantioselectivities of up to 99 % ee were achieved. A quantum yield of <1 supports the proposed catalytic cycle in which at least one photon is needed for each asymmetric CC bond formation mediated by single electron transfer.

A bis-cyclometalated rhodium(III) complex catalyzes a visible-light-activated enantioselective α-amination of 2-acyl imidazoles with up to 99 % yield and 98 % ee. The rhodium catalyst is ascribed a dual function as a chiral Lewis acid and, simultaneously, as a light-activated smart initiator of a radical-chain process through intermediate aminyl radicals. Notably, related iridium-based photoredox catalysts reported before were unsuccessful in this enantioselective radical C−N bond formation. The surprising preference for rhodium over iridium is attributed to much faster ligand-exchange kinetics of the rhodium complexes involved in the catalytic cycle, which is crucial to keep pace with the highly reactive and thus short-lived nitrogen-centered radical intermediate.

Combining single electron transfer between a donor substrate and a catalyst-activated acceptor substrate with a stereocontrolled radical–radical recombination enables the visible-light-driven catalytic enantio- and diastereoselective synthesis of 1,2-amino alcohols from trifluoromethyl ketones and tertiary amines. With a chiral iridium complex acting as both a Lewis acid and a photoredox catalyst, enantioselectivities of up to 99 % ee were achieved. A quantum yield of <1 supports the proposed catalytic cycle in which at least one photon is needed for each asymmetric CC bond formation mediated by single electron transfer.

Chiral bis-cyclometalated octahedral organoiridium(III) complexes were designed to target different classes of enzymes, namely carbonic anhydrases, histone deacetylases, and serine proteases. The stereoselective non-racemic synthesis of selected complexes was used to study the chiral discrimination of enzyme active sites for enantiomers of propeller-type octahedral metal complexes. Cases for negligible, modest, and significant chiral discrimination in the interaction of iridium propeller complexes with enzyme active sites were identified.

A single chiral octahedral iridium(III) complex is used for visible light activated asymmetric photoredox catalysis. In the presence of a conventional household lamp and under an atmosphere of air, the oxidative coupling of 2-acyl-1-phenylimidazoles with N,N-diaryl-N-(trimethylsilyl)methylamines provides aminoalkylated products in 61–93 % yields with high enantiomeric excess (90–98 % ee). Notably, the iridium center simultaneously serves three distinct functions: as the exclusive source of chirality, as the catalytically active Lewis acid, and as a central part of the photoredox sensitizer. This conceptionally simple reaction Scheme may provide new avenues for the green synthesis of non-racemic chiral molecules.

Octahedral iridium(III) complexes containing two bidentate cyclometalating 5-tert-butyl-2-phenylbenzoxazole (IrO) or 5-tert-butyl-2-phenylbenzothiazole (IrS) ligands in addition to two labile acetonitrile ligands are demonstrated to constitute a highly versatile class of asymmetric Lewis acid catalysts. These complexes feature the metal center as the exclusive source of chirality and serve as effective asymmetric catalysts (0.5–5.0 mol % catalyst loading) for a variety of reactions with α,β-unsaturated carbonyl compounds, namely Friedel–Crafts alkylations (94–99 % ee), Michael additions with CH-acidic compounds (81–97 % ee), and a variety of cycloadditions (92–99 % ee with high d.r.). Mechanistic investigations and crystal structures of an iridium-coordinated substrates and iridium-coordinated products are consistent with a mechanistic picture in which the α,β-unsaturated carbonyl compounds are activated by two-point binding (bidentate coordination) to the chiral Lewis acid.

Hexacoordinate (arenediolato)silicon(IV) complexes that contain two additional 2,2′-bipyridine or 1,10-phenanthroline ligands are surprisingly stable against aqueous hydrolysis and therefore constitute attractive and novel templates for the design of bioactive compounds. In this article, we report the synthesis of (arenediolato)bis(polypyridyl)silicon(IV) complexes, including a case of diastereoselective synthesis of a nonracemic hexacoordinate (binaphtholato)silicon(IV) complex, and methods for their post-coordinative functionalization with halides, nitro, and carbonyl groups. Several X-ray crystal structures are provided and demonstrate the octahedral coordination of silicon in these complexes.

Rhenium(I) pyridocarbazole complexes with photoinduced antiproliferative activity are reported. The substitutionally inert complexes induce cell death by singlet oxygen generation upon irradiation with red light (λ ≥ 620 nm), whereas only weak background cytotoxicity is observed in the dark. Owing to their ability to inhibit protein kinases (nanomolar IC₅₀ values against Pim1 at 10 μM ATP), this class of rhenium complexes point in the direction of dual function antiproliferative therapy with a single drug in which photodynamic therapy is combined with the inhibition of cancer-related protein kinases.

Die Katalyse von bioorthogonalen Transformationen in Lebewesen ist eine enorme Herausforderung – allerdings birgt sie auch großes Potenzial für zukünftige Anwendungen. Wir berichten hier über Rutheniumkomplexe, die in der bioorthogonalen Katalyse unter biologisch relevanten Bedingungen und in lebenden Zellen eingesetzt werden können. Die Katalysatoren aktivieren Allylcarbamat-geschützte Amine mit bisher unerreicht hoher Aktivität (270 Zyklen) in Gegenwart von Wasser, Luft und millimolaren Thiolkonzentrationen. Durch Fluoreszenzmikroskopie lebender HeLa-Zellen und mithilfe einer aktivierbaren Fluoreszenzsonde konnten wir eine intensive Fluoreszenzentwicklung im Zytoplasma nachweisen und damit die vermutete Bioorthogonalität der Katalysatoren bekräftigen. Zur Illustration der möglichen Anwendungsbreite bioorthogonaler Organometallkatalyse entwickelten wir eine Methode zur intrazellulären, katalytischen Aktivierung einer Zytostatikavorstufe, welche die Apoptose effizient einleitete.

Due to the relationship between structure and function in chemistry, access to novel chemical structures ultimately drives the discovery of novel chemical function. In this light, the formidable utility of the octahedral geometry of six-coordinate metal complexes is founded in its stereochemical complexity combined with the ability to access chemical space that might be unavailable for purely organic compounds. In this Minireview we wish to draw attention to inert octahedral chiral-at-metal complexes as an emerging class of metal-templated asymmetric “organocatalysts” which exploit the globular, rigid nature and stereochemical options of octahedral compounds and promise to provide new opportunities in the field of catalysis.

Aufgrund der Beziehung zwischen Struktur und Funktion in der Chemie ist der Zugang zu neuartigen chemischen Strukturen ein treibender Faktor für die Entdeckung neuer chemischer Funktionen. Unter diesem Blickwinkel betrachtet, liegt die beachtliche Nützlichkeit der oktaedrischen Geometrie sechsfach koordinierter Metallkomplexe darin begründet, dass ihre stereochemische Vielseitigkeit mit der Fähigkeit gepaart wird, Zugang zu chemischem Raum zu ermöglichen, der für rein organische Verbindungen möglicherweise nicht erreichbar ist. In diesem Kurzaufsatz möchten wir inerte oktaedrische Metallkomplexe mit metallzentrierter Chiralität als aufkommende Klasse metallgestützten asymmetrischer “Organokatalysatoren” vorstellen. Die Ausnutzung der oftmals starren und globulären Gerüste sowie die vielfältige Stereochemie versprechen neue Anwendungsmöglichkeiten auf dem Gebiet der Katalyse.

The catalysis of bioorthogonal transformations inside living organisms is a formidable challenge—yet bears great potential for future applications in chemical biology and medicinal chemistry. We herein disclose highly active organometallic ruthenium complexes for bioorthogonal catalysis under biologically relevant conditions and inside living cells. The catalysts uncage allyl carbamate protected amines with unprecedented high turnover numbers of up to 270 cycles in the presence of water, air, and millimolar concentrations of thiols. By live-cell imaging of HeLa cells and with the aid of a caged fluorescent probe we could reveal a rapid development of intense fluorescence within the cellular cytoplasm and therefore support the proposed bioorthogonality of the catalysts. In addition, to illustrate the manifold applications of bioorthogonal catalysis, we developed a method for catalytic in-cell activation of a caged anticancer drug, which efficiently induced apoptosis in HeLa cells.

Invited for the cover of this issue is the team of Prof. Meggers. The cover image shows the Λ and Δ enantiomers of a bis-cyclometalated iridium(III) complex and their corresponding mirror-imaged CD spectra.

A practical strategy for the generation of virtually enantiomerically pure bis-cyclometalated iridium(III) complexes is reported. Accordingly, the reactions of [Ir(μ-Cl)(ppy)₂]₂ (ppy = cyclometalating 2-phenylpyridine) with (S)-4-tert-butyl-2-(2′-hydroxyphenyl)-2-oxazoline [(S)-1a], [Ir(μ-Cl)(pq)₂]₂ (pq = cyclometalating 2-phenylquinoline) with (S)-2-(2′-hydroxyphenyl)-4-isopropyl-2-oxazoline [(S)-1b], and [Ir(μ-Cl)(pbt)₂]₂ (pbt = cyclometalating 2-phenylbenzothiazole) with (S)-2-(2′-hydroxyphenyl)-4-isopropyl-2-thiazoline [(S)-1d] afforded diastereomeric mixtures of salicyloxazolinato or salicylthiazolinato complexes Λ/Δ-[Ir(ppy)₂{(S)-1a–H}]PF₆, Λ/Δ-[Ir(pq)₂{(S)-1b–H}]PF₆, and Λ/Δ-[Ir(pbt)₂{(S)-1d–H}]PF₆, respectively, which could be resolved by silica gel flash chromatography. With the individual diastereomers in hand, an acid-induced substitution of the chiral auxiliaries by achiral bidentate ligands with retention of configuration afforded several iridium complexes Λ- or Δ-[Ir(C^∧N)₂(N^∧N)]PF₆ (C^∧N = cyclometalating ppy, pq, or pbt; N^∧N = 2,2′-bipyridine, 1,10-phenanthroline, or 2,2′-biquinoline) with enantiomeric ratio (er) values of 24:1 to 230:1.

The reactivity of an exemplary ruthenium(II)–azido complex towards non-activated, electron-deficient, and towards strain-activated alkynes at room temperature and low millimolar azide and alkyne concentrations has been investigated. Non-activated terminal and internal alkynes failed to react under such conditions, even under copper(I) catalysis conditions. In contrast, as expected, rapid cycloaddition was observed with electron-deficient dimethyl acetylenedicarboxylate (DMAD) as the dipolarophile. Since DMAD and related propargylic esters are excellent Michael acceptors and thus unsuitable for biological applications, we investigated the reactivity of the azido complex towards cycloaddition with derivatives of cyclooctyne (OCT), bicyclo[6.1.0]non-4-yne (BCN), and azadibenzocyclooctyne (ADIBO). While no reaction could be observed in the case of the less strained cyclooctyne OCT, the highly strained cyclooctynes BCN and ADIBO readily reacted with the azido complex, providing the corresponding stable triazolato complexes, which were amenable to purification by conventional silica gel column chromatography. An X-ray crystal structure of an ADIBO cycloadduct was obtained and verified that the formed 1,2,3-triazolato ligand coordinates the metal center through the central N2 atom. Importantly, the determined second-order rate constant for the ADIBO cycloaddition with the azido complex (k₂=6.9 × 10⁻² M⁻¹ s⁻¹) is comparable to the rate determined for the ADIBO cycloaddition with organic benzyl azide (k₂=4.0 × 10⁻¹ M⁻¹ s⁻¹). Our results demonstrate that it is possible to transfer the concept of strain-promoted azide–alkyne cycloaddition (SPAAC) from purely organic azides to metal-coordinated azido ligands. The favorable reaction kinetics for the ADIBO-azido-ligand cycloaddition and the well-proven bioorthogonality of strain-activated alkynes should pave the way for applications in living biological systems.

(4S)-2-(4-Isopropyl-4,5-dihydrooxazol-2-yl)-4-nitrobenzenethiol {(S)-TS} and its tert-butyl derivative {(S)-TS′} were developed as chiral auxiliaries for the asymmetric synthesis of polypyridyl ruthenium complexes. In their deprotonated form, these (mercaptophenyl)oxazolines were used as bidentate ligands and allowed the efficient transfer of chirality from the oxazoline moiety to the ruthenium stereocenter. After the induction of the absolute metal-centered configuration, the auxiliaries were labilized by converting the coordinated thiolate into a thioether ligand upon methylation with Meerwein salt, followed by the thermal replacement with 2,2′-bipyridine or 1,10-phenanthroline ligands under retention of configuration to afford octahedral polypyridyl ruthenium complexes with high enantiomeric excesses. These thiol-based auxiliaries complement our previously developed acid-labile chiral auxiliaries and thus expand the toolbox for the asymmetric synthesis of chiral ruthenium complexes.

Inert metal complexes are sophisticated structural scaffolds for the design of enzyme inhibitors. Whereas previous work from our laboratory was predominantly based on ruthenium(II), this study evaluates the suitability of rhodium in the +3 oxidation state to serve as a structural centre for the design of inert metal-based enzyme inhibitors. Based on our established staurosporine-inspired metallo-pyridocarbazole scaffold, strategies for the convenient synthesis of rhodium(III)-pyridocarbazole complexes were developed and applied to the synthesis of protein kinase inhibitors. The structures of several rhodium complexes were investigated by X-ray crystallography. A stability study confirmed the high kinetic inertness of such rhodium complexes under biologically relevant conditions, such as the presence of millimolar concentrations of thiols. Finally, an extremely potent, picomolar rhodium inhibitor for the protein kinase Pim1 was discovered. Thus, it can be concluded that rhodium(III) expands the toolbox for the design of inert metal complexes with biological activity.

In the quest for the identification of catalytic transformations to be used in chemical biology and medicinal chemistry, we identified iron(III) meso-tetraarylporphines as efficient catalysts for the reduction of aromatic azides to their amines. The reaction uses thiols as reducing agents and tolerates water, air, and other biological components. A caged fluorophore was employed to demonstrate that the reduction can be performed even in living mammalian cells. However, in vivo experiments in nematodes (Caenorhabditis elegans) and zebrafish (Danio rerio) revealed a limitation to this method: the metabolic reduction of aromatic azides.

In contrast to stereoselective organic chemistry, which has established sophisticated synthetic strategies to control the relative and absolute configuration at tetrahedral carbon atoms, the stereochemical control of octahedral coordination spheres is much less understood. This microreview reflects on the state of the art of asymmetric coordination chemistry of octahedral complexes within the historical context, including asymmetric coordination chemistry evolved by nature, the predetermination of metal-centered chirality with tailored chiral ligands, chiral-anion-mediated asymmetric synthesis, chiral-auxiliary-mediated asymmetric coordination chemistry, and finally, very recent work on the catalytic asymmetric synthesis of an octahedral coordination complex. The stereocontrolled synthesis of octahedral metal complexes is an important problem of contemporary coordination chemistry and will ultimately provide the necessary synthetic tools to fully exploit the opportunities provided by the rich stereochemistry of octahedral coordination geometries.

The cover picture shows a selection of transition-metal complexes in which tailored chiral ligands or auxiliaries control the metal-centered configuration; the background highlights Alfred Werner's historical publication 100 years ago regarding the first experimental verification of metal-centered chirality in octahedral metal complexes. Nowadays, highly preorganized chiral motifs in multidentate ligands, such as the 1,1′-binaphthyl moiety of the shown bis(8-quinolinolato)chromium(III) complex (top-left corner) or the (bipyrrolidine)iron(III) complex shown in the bottom-right corner, are capable of efficiently controlling the relative and absolute stereochemistry upon metal complexation. Alternatively, aromatic face-to-face π-stacking can be exploited for the implementation of the metal-centered chirality as demonstrated by the bis(iminobipyridine)iron(II) complex displayed in the bottom-left corner. The ruthenium(II) complex on the top right is an intermediate in the auxiliary-mediated asymmetric synthesis of (polypyridyl)ruthenium complexes. Further details are presented in the Microreview by E. Meggers on p. 2911 ff, which provides an overview of the asymmetric synthesis of octahedral metal complexes, ranging from the first experiments to the current state of the art. The structures of the metal complexes shown were created with PyMOL (DeLano Scientific LLC).

A method is presented for the asymmetric synthesis of chiral ruthenium polypyridyl complexes that starts from racemic cis-[Ru(pp)₂Cl₂] (pp=2,2′-bipyridine or 1,10-phenanthroline ligands). The chiral bidentate ligands (R)-2-(isopropylsulfinyl)phenol, (R)-SO, and preferably the more electron-rich derivative (R)-2-(isopropylsulfinyl)-4-methoxyphenol, (R)-A, serve as convenient chiral auxiliaries for the conversion of racemic starting complexes (1a: pp=2,2′-bipyridine; 1b: pp=5,5′-dimethyl-2,2′-bipyridine; 1c: pp=1,10-phenanthroline) into single diastereomers Λ-[Ru(pp)₂{(R)-SO}]PF₆ (Λ-(S)-2a, 2b, 2c) or Λ-[Ru(pp)₂{(R)-A}]PF₆ (Λ-(S)-2a′) under a thermodynamically controlled dynamic transformation. The complexes Λ-(S)-2a, 2b, 2c and Λ-(S)-2a′ themselves are direct precursors for the generation of optically active ruthenium–polypyridyl complexes by trifluoroacetic-acid-induced replacement of the sulfinylphenolate auxiliaries with bidentate pp ligands under retention of configuration, thereby affording Λ-[Ru(pp)₃](PF₆)₂ (3a, 3b, 3c) complexes with high enantiomeric ratios of ≥98:2. In particular, by employing the methoxy-modified chiral auxiliary (R)-A, enantiomeric ratios of >99:1 were reached. In the strategy introduced here, the high steric crowding of an octahedral coordination sphere was exploited by placing a sulfur-based stereocenter in direct proximity to the ruthenium stereocenter, thereby leading to a large difference in the stabilities of the intermediate Λ-S and Δ-S diastereomers and thus providing the opportunity to find suitable reaction conditions for conversion of the destabilized diastereomer into the thermodynamically more-stable one. This method should be of high practical value for the asymmetric synthesis of ruthenium–polypyridyl complexes because it allows one to use readily available racemic ruthenium complexes as starting materials.

In dieser Arbeit wird eine Methode zur asymmetrischen Synthese von chiralen Rutheniumpolypyridyl-Verbindungen ausgehend von den racemischen Komplexen cis-[Ru(pp)₂Cl₂] (pp=2,2′-Bipyridin- oder 1,10-Phenanthrolin-Liganden) vorgestellt. Dabei dienen die chiralen zweizähnigen Liganden (R)-2-(Isopropylsulfinyl)phenol, (R)-SO, und bevorzugt das elektronenreichere Derivat (R)-2-(Isopropylsulfinyl)-4-methoxyphenol, (R)-A, als bequeme chirale Auxiliare für die Umsetzung der racemischen Edukte (1a: pp=2,2′-Bipyridin, 1b: pp=5,5′-Dimethyl-2,2′-bipyridin, 1c: pp=1,10-Phenanthrolin) in die reinen Diastereomeren Λ-[Ru(pp)₂{(R)-SO}]PF₆ (Λ-(S)-2a, 2b, 2c) oder Λ-[Ru(pp)₂{(R)-A}]PF₆ (Λ-(S)-2a′) in thermodynamisch-kontrollierten dynamischen Transformationen. Die Komplexe Λ-(S)-2a, 2b, 2c and Λ-(S)-2a′ sind ihrerseits direkte Vorläufer für die Herstellung von optisch-aktiven Rutheniumpolypyridin-Komplexen Λ-[Ru(pp)₃](PF₆)₂ (3a, 3b, 3c) im Zuge einer Trifluoressigsäure-induzierten Substitution der koordinierten Sulfinylphenolate gegen zweizähnigen Liganden pp unter Retention der Konfiguration und mit hohen Enantiomerenverhältnissen von ≥98:2. Mit dem Methoxyderivat (R)-A werden sogar e.r.-Werte von >99:1 erreicht. In der hier vorgestellten Strategie wird also die hohe Ligandendichte eines oktaedrischen Metallzentrums ausgenutzt, indem ein Schwefel-zentriertes tetraedrisches Stereozentrum als koordinierender Ligand in direkte Nachbarschaft zu diesem Metallzentrum gebracht wird, was zu großen Unterschieden in den Stabilitäten der beiden möglichen Λ-(S)- und Δ-(S)-Diastereomeren führt. Geeignete Reaktionsbedingungen erlauben es dabei, das labile Diastereomer zu zersetzen und in das stabilere umzuwandeln. Diese Methode sollte von großem praktischen Nutzen für die asymmetrische Synthese von Rutheniumpolypyridyl-Komplexen sein, da sie von leicht zugänglichen racemischen Edukten ausgeht.

Die enorme Herausforderung der spezifischen molekularen Erkennung einzelner biomakromolekularer Ziele innerhalb komplexer biologischer Systeme erfordert neuartige und kreative Strategien. Dieser Kurzaufsatz beschäftigt sich sowohl mit einigen konventionellen als auch mit ungewöhnlichen Herangehensweisen an die Entwicklung von selektiven Enzyminhibitoren mit besonderem Augenmerk auf die dazu verwendeten chemischen Grundgerüste. Diese beinhalten zum Beispiel komplizierte naturproduktähnliche organische Moleküle, stabile oktaedrische Metallkomplexe, Fullerene, Carborane, polymetallische Cluster und sogar Polymere. Somit ist das ganze Repertoire der organischen, anorganischen und makromolekularen Chemie verfügbar, um die Herausforderung der zielspezifischen Enzyminhibition anzugehen.

The tremendous challenge presented by the specific molecular recognition of single biomacromolecular targets within complex biological systems demands novel and creative design strategies. This Minireview discusses some conventional and unusual approaches for the design of target-selective enzyme inhibitors with a focus on the underlying chemical scaffolds. These include complicated natural-product-like organic molecules, stable octahedral metal complexes, fullerenes, carboranes, polymetallic clusters, and even polymers. Thus the whole repertoire of organic, inorganic, and macromolecular chemistry can be applied to tackle the problem of target-specific enzyme inhibition.

Screening of a library of structurally unusual osmacyclic complexes for their antiproliferate properties in HeLa cells led to the discovery of a highly cytotoxic η²-allene osmacycle. In this remarkably stable complex, osmium constitutes part of a metallacycle through the formation of a σ-bond to a carbon in combination with coordination to an allene moiety. The osmacycle strongly induces apoptosis in Burkitt-like lymphoma cells at submicromolar concentrations. The reduction of the mitochondrial membrane potential, the induction of DNA fragmentation, and the activation of caspases-9 and -3 reveal that programmed cell death occurs through the intrinsic mitochondrial pathway. From the lipophilic and cationic nature of the osmacycle, in addition to a low oxidation potential (E_1/2=+0.27 V vs. Fc/Fc⁺, Fc=ferrocene) it is proposed that mitochondria are the cellular target where oxidative decomposition initiates apoptosis.

New methods for the stereocontrolled synthesis of octahedral metal complexes are needed in order to fully exploit the stereochemical richness of the octahedron in the fields of catalysis, materials sciences, and life sciences. Whereas a large body of work exists regarding the diastereoselective coordination chemistry with chiral ligands, such efforts are restricted to certain carefully designed chiral ligands which remain in the coordination sphere. The emerging strategy of chiral-auxiliary-mediated asymmetric synthesis holds promise to solve the problem of controlling relative and absolute configuration in octahedral metal complexes in a general fashion, thus hopefully in the future providing access to any desired optical active octahedral metal complex without the need for chiral separations. This short review will summarize reported examples of chiral auxiliaries applied to the asymmetric synthesis of octahedral metal complexes.

In this study, we probe and verify the concept of designing unreactive bioactive metal complexes, in which the metal possesses a purely structural function, by investigating the consequences of replacing ruthenium in a bioactive half-sandwich kinase inhibitor scaffold by its heavier congener osmium. The two isostructural complexes are compared with respect to their anticancer properties in 1205 Lu melanoma cells, activation of the Wnt signaling pathway, IC₅₀ values against the protein kinases GSK-3β and Pim-1, and binding modes to the protein kinase Pim-1 by protein crystallography. It was found that the two congeners display almost indistinguishable biological activities, which can be explained by their nearly identical three-dimensional structures and their identical mode of action as protein kinase inhibitors. This is a unique example in which the replacement of a metal in an anticancer scaffold by its heavier homologue does not alter its biological activity.