A series of cage penta-arylated carboranes have been synthesized by palladium-catalyzed intermolecular coupling of the C-carboxylic acid of the monocarba-closo-dodecaborate anion [CB11H12]− with iodoarenes by direct cage B–H bond functionalization. These transformations set a record in terms of one-pot directing group-mediated activation of inert bonds in a single molecule. The methodology is characterized by high yields, good functional group tolerance, and complete cage regioselectivity. The directing group COOH can be easily removed during or after the intermolecular coupling reaction. The mechanistic pathways were probed using density functional theory calculations. A Pd(II)–Pd(IV)–Pd(II) catalytic cycle is proposed, in which initial coupling is followed by preferred B–H activation of the adjacent boron vertex, and continuation of this selectivity results in a continuous walking process of the palladium center. The methodology opens a new avenue toward building blocks with 5-fold symmetry.

Palladium-Catalyzed Selective Five-Fold Cascade Arylation of the 12-Vertex Monocarborane Anion by B-H Activation

Palladium-catalyzed dehydrogenative B–H/C–H cross coupling of monocarborane anions with alkenes is reported, allowing for the first time the isolation of selectively penta-alkenylated boron clusters. The reaction cascade is regioselective for the cage positions, leading directly to B2–6 functionalization. Under mild and convenient conditions, styrenes, benzylic alkenes and aliphatic alkenes are demonstrated to be viable coupling partners with exclusive vinyl-type B–C bond formation. Multiple subsequent transformations provide access to directing group-free products, chiral derivatives and penta-alkylated cages. The five-fold coupling, combined with the latter reactions, represents a powerful methodology for the straightforward synthesis of new classes of boron clusters.

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Highly selective palladium-catalyzed one-pot, five-fold B-H/C-H cross coupling of monocarboranes with alkenes.

An iridium-catalyzed alkenylation/annulation sequence between monocarba-closo-dodecaborate carboxylic acids and diarylacetylenes is reported. Regioselective activation of the B2 position, followed by B-C bond formation and ring closure, affords 3D bora-analogues of isocoumarins. The reaction tolerates a variety of functional groups on the aromatic rings and can be extended to B12-substituted derivatives. Furthermore, subsequent alkenylation of the B4 vertex has been achieved in high yields.

Fusing Carborane Carboxylic Acids with Alkynes: 3D Analogues of Isocoumarins via Regioselective B−H Activation

The five-membered, nitrogen-containing pyrroline ring is a privileged structure. This ring is present in many bioactive compounds from natural sources. Pyrrolines—the dihydro derivatives of pyrroles—have three structural isomer classes, depending on the location of the double bond: 1-pyrrolines (3,4-dihydro-2H-pyrroles), 2-pyrrolines (2,3-dihydro-1H-pyrroles) and 3-pyrrolines (2,5-dihydro-1H-pyrroles). This review aims to describe the latest advances for the synthesis of pyrrolines by transition metal-catalyzed cyclizations. Only reactions in which the pyrroline ring is formed by metal promotion are described. Transformations of the pyrroline ring in other heterocycles, and the structural manipulations of the pyrroline itself are not discussed. The review is organized into three parts, each covering the metal-mediated synthesis of the three pyrroline isomers. Each part is subdivided according to the metal involved, and concludes with a brief description of notable biological activities within the class.

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Metal-mediated synthesis of pyrrolines

The cysteine protease ATG4B is a key component of the autophagy machinery, acting to proteolytically prime and recycle its substrate MAP1LC3B. The roles of ATG4B in cancer and other diseases appear to be context dependent but are still not well understood. To help further explore ATG4B functions and potential therapeutic applications, we employed a chemical biology approach to identify ATG4B inhibitors. Here, we describe the discovery of 4–28, a styrylquinoline identified by a combined computational modeling, in silico screening, high content cell-based screening and biochemical assay approach. A structure-activity relationship study led to the development of a more stable and potent compound LV-320. We demonstrated that LV-320 inhibits ATG4B enzymatic activity, blocks autophagic flux in cells, and is stable, non-toxic and active in vivo. These findings suggest that LV-320 will serve as a relevant chemical tool to study the various roles of ATG4B in cancer and other contexts.

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A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B.

The first homoleptic cobalt phosphanido complex [K(thf)4][Co{1,2-(PtBu2)2C2B10H12}2] (1) was prepared by an unprecedented oxidative P‒P bond addition of an ortho-carborane-substituted 1,2-diphosphetane to cobalt(‒I) in [K(thf)0.2][Co(η4-cod)2)] (cod = 1,5-cycloctadiene). Compound 1 is a rare distorted tetrahedral d6 complex with a low-spin ground state configuration. Magnetic measurements revealed that the complex is diamagnetic between 2 to 270 K in the solid state and at 298 K in THF d8 solution. Based on DFT calculations, the unusual singlet ground state is caused by the strong σ-donor and moderate π-donor properties of the bis(phosphanido) ligand.

Oxidative P-P Bond Addition to Cobalt(-I): Formation of a Low-Spin Cobalt(III) Phosphanido Complex.

Racemic carborane-based bisphosphanes were obtained by dismutation reactions between a carborane-based diphosphetane and diaryl dichalogenides. NMR spectroscopic and theoretical studies revealed a two-step mechanism explaining the high stereoselectivity of these reactions. The coordination chemistry of the multidentate P,N ligands 6c and 6d in copper(I) and silver(I) complexes was studied. While 6d acted exclusively as tetradentate ligand, 6c showed either tridentate or tetradentate coordination depending on the metal and the counterion.

C2-Symmetric P,N Ligands Derived from Carborane-Based Diphosphetanes: Synthesis and Coordination Chemistry

The modular syntheses of C3-symmetric tris(ferrocenyl)arene-based tris-phosphanes and their homotrinuclear gold(I) complexes are reported. Choosing the arene core allows fine-tuning of the exact oxidation potentials and thus tailoring of the electrochemical response. The tris[chloridogold(I)] complexes were investigated in the catalytic ring-closing isomerisation of N-(2-propyn-1-yl)benzamide, showing cooperative behaviour vs. a mononuclear chloridogold(I) complex. Adding one, two, or three equivalents of 1,1′-diacetylferrocenium[tetrakis(perfluoro-tert-butoxy)aluminate] as an oxidant during the catalytic reaction (in situ) resulted in a distinct, stepwise influence on the resulting catalytic rates. Isolation of the oxidised species is possible, and using them as (pre-)catalysts (ex situ oxidation) confirmed the activity trend. Proving the intactness of the P–Au–Cl motif during oxidation, the tri-oxidised benzene-based complex has been structurally characterised.

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Triple the fun: tris(ferrocenyl)arene-based gold(I) complexes for redox-switchable catalysis

The principle of stereotopic face differentiation was successfully applied to 2H-phospholes which undergo a very efficient and highly stereoselective Diels–Alder reaction giving phosphorus-chiral 1-phosphanorbornenes with up to 87% yield. The observed reaction pathway has been supported by theoretical calculations showing that the cycloaddition reaction between 2H-phosphole 3a and the dienophile (5R)-(−)-menthyloxy-2(5H)-furanone (8) is of normal electron demand. Optically pure phosphanes were obtained by separation of the single diastereomers and subsequent desulfurisation of the sulfur-protected phosphorus atom. Finally, divergent ligand synthesis is feasible by reduction of the chiral auxiliary, subsequent stereospecific intramolecular Michael addition, and various functionalisations of the obtained key compound 13a. Furthermore, the unique structural properties of phospanorbornenes are presented and compared to those of phosphanorbornanes.

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P-chiral 1-phosphanorbornenes: from asymmetric phospha-Diels–Alder reactions towards ligand design and functionalisation

Die oxidative P-P-Bindungsaddition eines ortho-Carboran-substituierten 1,2-Diphosphetans an Cobalt(−I) in [K(thf)0.2][Co(η4-cod)2)] (cod=1,5-Cycloctadien) ermoglichte die Darstellung des ersten homoleptischen Cobalt(III)-Phosphanidokomplexes [K(thf)4][Co{1,2-(PtBu)2C2B10H12}2] (1). Diese Verbindung ist ein seltenes Beispiel eines verzerrt tetraedrisch koordinierten 3d6-Komplexes mit einem Low-spin-Grundzustand. Magnetische Messungen ergaben, dass 1 zwischen 2 und 270 K im Festkorper und bei 298 K in einer [D8]THF-Losung diamagnetisch ist. Dichtefunktionalrechnungen zeigten, dass der diamagnetische Grundzustand durch die starken σ-Donor- und die moderaten π-Donoreigenschaften der Bisphosphanidoliganden verursacht wird.

Peter Coburger

Papers

Oxidative P-P Bond Addition to Cobalt(-I): Formation of a Low-Spin Cobalt(III) Phosphanido Complex.

C2-Symmetric P,N Ligands Derived from Carborane-Based Diphosphetanes: Synthesis and Coordination Chemistry

Triple the fun: tris(ferrocenyl)arene-based gold(I) complexes for redox-switchable catalysis

P-chiral 1-phosphanorbornenes: from asymmetric phospha-Diels–Alder reactions towards ligand design and functionalisation

Oxidative P-P-Bindungsaddition an Cobalt(−I): Bildung eines Low-spin-Cobalt(III)-Phosphanidokomplexes