Light-dependent Reactivity of Heavy Pnictogen Double Bonds.

The chemistry of light dipnictenes has been widely investigated in the last century with remarkable achievements especially for azobenzene derivatives. In contrast, distibenes and dibismuthenes are relatively rare and show very limited reactivity. Herein, we have designed a protocol using visible light to enhance the reactivity of heavy dipnictenes. Exploiting the distinctive π-π* transition, we have been able to isolate unique examples of dipnictene-cobalt complexes. The reactivity of the distibene complex was further exploited using red light in the presence of a diazoolefin to access an unusual four-membered bicyclo[1.1.0]butane analog, containing only a single carbon atom. These findings set the bases to a conceptually new strategy in heavy element double bonds chemistry where visible light is at the front seat of bond activation.

A General Iron-Catalyzed Decarboxylative Oxygenation of Aliphatic Carboxylic Acids.

We report an iron-catalyzed decarboxylative C(sp3)-O bond-forming reaction under mild, base-free conditions with visible light irradiation. The transformation uses readily available and structurally diverse carboxylic acids, iron photocatalyst, and 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) derivatives as oxygenation reagents. The process exhibits a broad scope in acids possessing a wide range of stereoelectronic properties and functional groups. The developed reaction was applied to late-stage oxygenation of a series of bio-active molecules. The reaction leverages the ability of iron complexes to generate carbon-centered radicals directly from carboxylic acids by photoinduced carboxylate-to-iron charge transfer. Kinetic, electrochemical, EPR, UV-Vis, HRMS and DFT studies revealed that TEMPO has a triple role in the reaction: as an oxygenation reagent, an oxidant to turn over the Fe-catalyst, and an internal base for the carboxylic acid deprotonation. The obtained TEMPO adducts represent versatile synthetic intermediates that were further engaged in C-C and C-heteroatom bond-forming reactions using commercial organo-photocatalysts and nucleophilic reagents.

Synthesis of tricyclic 1,4-dihydro-1,4-phosphagermines - trying to establish molecular fencing of reactive centers.

Novel tricyclic 1,4-dihydro-1,4-phosphagermines (3a and 4a) were synthesised from Ge(NR2)2-bridged 1,3-imidazole-2-thione derivative 2a; all structures were crystallographically confirmed. In going from rather small alkyl substituents (Me, nBu) at the nitrogen centers of the 1,3-imidazole-2-thione units to sterically more demanding R = Mes and changing the employed Ge reagent from (R2N)2GeCl2 to R2NGeCl3 we achieved access to mixed functional bis(1,3-imidazole-2-thione)-substituted germanium derivative 2c. The latter was treated with MeLi and, subsequently, with PCl3 to yield a pentacyclic P,Ge-heterocycle (5); its formation was rationalized using DFT theoretical calculations.

Application of phosphorus-bridged rigid, bent bis(NHCs) as dipodal ligands in main group and transition metal chemistry.

Phosphorus-bridged rigid, bent bis(N-heterocyclic) carbenes have not been reported, so far, despite having structural features that could make them interesting ligands in coordination and main group element chemistry. In previous reports, we had demonstrated that tuning of σ3- and σ4-phosphorus environments in planarised bis(NHCs) affects electronic properties and can provide additional coordination sites. Herein, we report on first examples of synthesis and conversion of 1,4-diphosphabarrelene-related compounds into rigid bent, doubly P-bridged bis(NHCs). The formation of main group element adducts with substrates from group 13, 14 and 15 illustrates opportunities to access novel scaffolds and to create nonplanar branching points. DFT calculations reveal the new bis(NHCs) to be good candidates as novel soft/hard ligands with up to four coordination sites. The synthesis of a dinuclear Fe(CO)4 complex is demonstrated. The thermal retro-[4 + 2] cycloaddition was theoretically and experimentally explored for a variety of ionic and zwitterionic 1,4-diphosphabarrelenes, and the generation and trapping of a dinuclear Fe(0) bis(NHC) complex with a tricyclic 1σ2,4 σ2-diphosphinine scaffold is presented.

Arbuzov meets 1,2-oxaphosphetanes: transient 1,2-oxaphosphetan-2-iums as an entry point to beta-halo phosphane oxides and P-containing oligomers.

Herein, we describe the synthesis of a 1,2σ3λ3-oxaphosphetane from ethylene oxide and its reactions with alkyl halides to form ß-halo phosphane oxides in an Arbuzov-type reaction. When methyl triflate was used as a hard electrophile, cationic oligomerisation of 1,2-oxaphosphetanes was observed. DFT calculations indicate 1,2-oxaphosphetan-2-iums as intermediates and reveal differences between the Arbuzov and the potential Perkow reaction pathway.

NHC-Supported 2-Sila and 2-Germavinylidenes: Synthesis, Dynamics, First Reactivity and Theoretical Studies.

2-tetrelavinylidenes (C=EH2 ; E=Si, Ge) are according to quantum chemical studies the least stable isomers on the [E,C,2H] potential energy hypersurface isomerizing easily via the trans-bent tetrelaacetylenes HE≡CH to the thermodynamically most stable 1-tetrelavinylidenes (E=CH2 ). Consequently, experimental studies on 2-tetrelavinylidenes (C=ER2 ) and their derivatives are lacking. Herein we report experimental and theoretical studies of the first N-heterocyclic carbene (NHC) supported 2-silavinylidene (NHC)C=SiBr(Tbb) (1-Si: NHC=C[N(Dipp)CH]2 , Dipp=2,6-diisopropylphenyl, Tbb=2,6-bis[bis(trimethylsilyl)methyl]-4-tert-butylphenyl) and the isovalent 2-germavinylidenes (NHC)C=GeBr(R) (1-Ge, 1-GeMind: R=Tbb, Mind (1,1,3,3,5,5,7,7-octamethyl-s-hydrindacene-4-yl)). The NHC-supported 2-tetrelavinylidenes were obtained selectively from the 1,2-dibromoditetrelenes (E)-(R)BrE=EBr(R) using the diazoolefin (NHC)CN2 as vinylidene transfer reagent. 1-E (E=Si, Ge) have a planar vinylidene core, a bent-dicoordinated vinylidene carbon atom (CVNL ), a very short E=CVNL bond and an almost orthogonal orientation of the NHC five-membered ring to the vinylidene core. Quantum chemical analysis of the electronic structures of 1-E suggest a significantly bent 1-tetrelaallene and tetrelyne character. NMR studies shed light into the dynamics of 1-E involving NHC-rotation around the CVNL -CNHC bond with a low activation barrier. Furthermore, the synthetic potential of 1-E is demonstrated by the synthesis and full characterization of the unprecedented NHC-supported bromogermynes BrGe=C(EBr2 Tbb)(NHC) (2-SiGe: E=Si; 2-GeGe: E=Ge).

Access to ligand-stabilized PH-containing phosphenium complexes.

While the chemistry of phosphenium compounds, including metal complexes thereof, is very well established, few derivatives having a P-H bond have been described, yet. This work describes rational access to donor-stabilised phosphenium metal complexes possessing a P-H bond using protonation reactions of stable phosphinidene complex adducts. While most Brønsted-Lowry acids yield formal 1,1-addition products at the phosphorus centre under the loss of the donor, super-strong acids having weakly coordinating anions enable access to donor-stabilised P-H phosphenium complex salts. The latter possess N-methylimidazole as a donor (to phosphorus) and the N-P interaction has been studied theoretically.

Subrutilane-A Hexacyclic Sesterterpene from Streptomyces subrutilus.

Mining of a terpene synthase from Streptomyces subrutilus resulted in the identification of the hexacyclic sesterterpene subrutilane, besides eight pentacyclic side products. Subrutilane represents the first case of a saturated sesterterpene hydrocarbon. Its structure, including the absolute configuration, was unambiguously determined through X-ray crystallographic analysis and stereoselective deuteration. The cyclisation mechanism to subrutilane and its side products was investigated in all detail by isotopic labelling experiments and DFT calculations. The subrutilane synthase (SrS) also converted (2Z)-GFPP into one major product. Additional compounds were obtained from the substrate analogues (7R)-6,7-dihydro-GFPP and (2Z,7R)-6,7-dihydro-GFPP with blocked reactivity at the C6-C7 bond. Interestingly, the early steps of the cyclisation cascade with (2Z)-GFPP and the saturated substrate analogues were analogous to those of GFPP, but then deviations from the natural cyclisation mode occur.

Challenging an old paradigm by demonstrating transition metal-like chemistry at a neutral nonmetal center.

We describe nonmetal adducts of the phosphorus center of terminal phosphinidene complexes using classical C- and N-ligands from metal coordination chemistry. The nature of the L-P bond has been analyzed by various theoretical methods including a refined method on the variation of the Laplacian of electron density ∇2ρ along the L-P bond path. Studies on thermal stability reveal stark differences between N-ligands such as N-methyl imidazole and C-ligands such as tert-butyl isocyanide, including ligand exchange reactions and a surprising formation of white phosphorus. A milestone is the transformation of a nonmetal-bound isocyanide into phosphaguanidine or an acyclic bisaminocarbene bound to phosphorus; the latter is analogous to the chemistry of transition metal-bound isocyanides, and the former reveals the differences. This example has been studied via cutting-edge DFT calculations leading to two pathways differently favored depending on variations in steric demand. This study reveals the emergence of organometallic from coordination chemistry of a neutral nonmetal center.

First-Row Transition Metal Complexes Incorporating the 2-(2'-pyridyl)quinoxaline Ligand (pqx), as Potent Inflammatory Mediators: Cytotoxic Properties and Biological Activities against the Platelet-Activating Factor (PAF) and Thrombin.

Inflammatory mediators constitute a recently coined term in the field of metal-based complexes with antiplatelet activities. Our strategy targets Platelet-Activating Factor (PAF) and its receptor, which is the most potent lipid mediator of inflammation. Thus, the antiplatelet (anti-PAF) potency of any substance could be exerted by inhibiting the PAF-induced aggregation in washed rabbit platelets (WRPs), which internationally is a well-accepted methodology. Herein, a series of mononuclear (mer-[Cr(pqx)Cl3(H2O]) (1), [Co(pqx)Cl2(DMF)] (2) (DMF = N,N'-dimethyl formamide), [Cu(pqx)Cl2(DMSO)] (3) (DMSO = dimethyl sulfoxide), [Zn(pqx)Cl2] (4)) and dinuclear complexes ([Mn(pqx)(H2O)2Cl2]2 (5), [Fe(pqx)Cl2]2 (6) and [Ni(pqx)Cl2]2 (7)) incorporating the 2-(2'-pyridyl)quinoxaline ligand (pqx), were biologically evaluated as inhibitors of the PAF- and thrombin-induced aggregation in washed rabbit platelets (WRPs). The molecular structure of the five-co-ordinate analog (3) has been elucidated by single-crystal X-ray diffraction revealing a trigonal bipyramidal geometry. All complexes are potent inhibitors of the PAF-induced aggregation in WRPs in the micromolar range. Complex (6) displayed a remarkable in vitro dual inhibition against PAF and thrombin, with IC50 values of 1.79 µM and 0.46 µM, respectively. Within the series, complex (5) was less effective (IC50 = 39 µM) while complex (1) was almost 12-fold more potent against PAF, as opposed to thrombin-induced aggregation. The biological behavior of complexes 1, 6 and 7 on PAF's basic metabolic enzymatic pathways reveals that they affect key biosynthetic and catabolic enzymes of PAF underlying the anti-inflammatory properties of the relevant complexes. The in vitro cytotoxic activities of all complexes in HEK293T (human embryonic kidney cells) and HeLa cells (cervical cancer cells) are described via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The results reveal that complex 3 is the most potent within the series.

A Case of Convergent Evolution: The Bacterial Sesquiterpene Synthase for 1-epi-Cubenol from Nonomuraea coxensis.

A terpene synthase from Nonomuraea coxensis was identified as (+)-1-epi-cubenol synthase. The enzyme is phylogenetically unrelated to the known enzyme of the same function that is widespread in streptomycetes. Isotopic labelling experiments were performed to unambiguously assign the NMR data and to investigate hydrogen migrations during terpene cyclisations. Epoxidations of (+)-1-epi-cubenol and of the plant derived compounds (-)-cubenol and (-)-1-epi-cubenol confirmed the structure of a natural product isolated from the brown alga Dictyopteris divaricata and allowed to conclude on its absolute configuration. The crystal structures of the epoxides from (+)- and (-)-1-epi-cubenol and the acid catalysed conversion into an isomeric ketone are reported.

Expanding the Structural Diversity at the Phenylene Core of Ligands for the von Hippel-Lindau E3 Ubiquitin Ligase: Development of Highly Potent Hypoxia-Inducible Factor-1α Stabilizers.

Hypoxia-inducible factor-1α (HIF-1α) constitutes the principal mediator of cellular adaptation to hypoxia in humans. The HIF-1α protein level and activity are tightly regulated by the ubiquitin E3 ligase von Hippel-Lindau (VHL). Here, we performed a structure-guided and bioactivity-driven design of new VHL inhibitors. Our iterative and combinatorial strategy focused on chemical variability at the phenylene unit and encompassed further points of diversity. The exploitation of tailored phenylene fragments and the stereoselective installation of the benzylic methyl group provided potent VHL ligands. Three high-resolution structures of VHL-ligand complexes were determined, and bioactive conformations of these ligands were explored. The most potent inhibitor (30) exhibited dissociation constants lower than 40 nM, independently determined by fluorescence polarization and surface plasmon resonance and an enhanced cellular potency, as evidenced by its superior ability to induce HIF-1α transcriptional activity. Our work is anticipated to inspire future efforts toward HIF-1α stabilizers and new ligands for proteolysis-targeting chimera (PROTAC) degraders.

A novel access to phosphanylidene-phosphorane complexes via P-donor substitution and a detailed bonding analysis.

Phospha-Wittig reagents such as phosphanylidene-phosphoranes and their transition metal complexes are of great interest as sources of P1 building blocks but the access is still limited. Herein, we describe a new access to phosphanylidene-phosphorane complexes starting from the N-methylimidazole-to-phosphinidene complex adduct. The complexes were studied electrochemically and theoretically, also with respect to their 31P NMR data, and the P-P bonds were evaluated by various DFT-derived descriptors.

Synthesis of a 1-aza-2-phospha-acenaphthene complex profiting from coordination enabled chloromethane elimination.

Despite debate on intramolecular N→P interactions in peri-substituted naphthalene derivatives their coordination chemistry has not yet been reported. Herein, we describe bonding in and reactivity of dichloro(8-dimethylamino-1-naphthyl)phosphane towards pentacarbonyltungsten(0) reagents. A 1-aza-2-phospha-acenaphthene complex was obtained via the unexpected elimination of chloromethane enabled through P-coordination. Theoretical DFT calculations provide insights into P⋯N pnictogen bonding interaction as well as the reaction pathway of the elimination reaction.

Mechanistic Characterisation of the Bacterial Sesterviridene Synthase from Kitasatospora viridis.

A gene coding for a terpene synthase homolog from Kitasatospora viridis was cloned and expressed in Escherichia coli. The purified recombinant protein possessed sesterterpene synthase activity and efficiently converted geranylfarnesyl diphosphate (GFPP) with 19 % yield into the sesterterpene hydrocarbon sesterviridene A. Large scale enzymatic conversions also allowed for the isolation of two side products that are generated with very low yields of ca. 0.1 %. Several derivatives of sesterviridene A were obtained by chemical transformations, securing the NMR-based structural assignments. The absolute configuration of sesterviridene A was determined by chemical correlation using stereoselectively deuterated precursors and by anomalous dispersion X-ray crystallography. The cyclisation mechanism from GFPP to sesterviridene A was extensively studied through isotopic labelling experiments and DFT calculations.

Enantio- and Diastereomerically Pure Titanocenes by Dynamic Conformational Locking.

The synthesis of enantiomerically pure titanocenes is limited to cases with enantiomerically pure substituents at the cyclopentadienyl ligands and to ansa-titanocenes. For the latter complexes, the use of achiral ligands requires a resolution of enantiomers and frequently also a separation of the diastereoisomers obtained after metalation. Here, we introduce a new synthetic method that relies on the use of enantiomerically pure camphorsulfonate (CSA) ligands as control elements for the absolute and relative configuration of titanocene complexes. Starting from the conformationally flexible (RC5 H4 )2 TiCl2 , the desired conformationally locked and hence enantio- and diastereomerically pure complexes (RC5 H4 )2 Ti(CSA)2 are obtained in just two steps. According to X-ray crystallography the (RC5 H4 )2 Ti fragment is essentially C2 -symmetric and nuclear magnetic resonance displays overall C2 -symmetry. We applied density functional theory methods to unravel the dynamics of the complexes and the mechanisms and selectivities of their formation.

Access to and reactions of P-functional 1,4-dihydro-1,4-diphosphinines fused to two TTF units.

P-Functional phosphanylated tetrathiafulvalenes 3a-f were synthesised via stepwise lithiation and phosphanylation of TTF derivatives, and then reacted with PCl3 to form the related P-chloro compounds 4a-f. Reactions of 4c-f with LDA resulted in the formation of the corresponding 1,4-dihydro-1,4-diphosphinines 5c-f. As a case in point, P-oxidation reactions of 5d,f with elemental chalcogens were performed, and the former were also converted into 1,4-dichloro-1,4-dihydro-1,4-diphosphinine 9f. The latter was reduced to form the related 1,4-diphosphinine 10f which could not be isolated but formed the corresponding 1,4-diphosphabarrelene 11f in a [4 + 2]-cycloaddition with 1-hexene. All compounds were characterised by multinuclear NMR spectroscopy and mass spectrometry and also by single crystal X-ray diffraction studies in some cases. Intensive cyclic voltammetry studies were performed for all isolated compounds with the special focus on using TTF units as sensors to study the substituent effects on oxidation potentials and, hence, the degree of electronic communication between redox active moieties in the bis-TTF species. E.g., 5d possesses four quasi-reversible one-electron oxidation steps thus forming a tetracation species at highest potential (+0.54 V vs. Fc+/0). Additionally, high level DFT calculations were undertaken to get a deeper understanding of various aspects of this novel combination of phosphorus and TTF chemistry.

Fragmentation and [4 + 3] cycloaddition in sodorifen biosynthesis.

Terpenes constitute the largest class of natural products. Their skeletons are formed by terpene cyclases (TCs) from acyclic oligoprenyl diphosphates through sophisticated enzymatic conversions. These enzyme reactions start with substrate ionization through diphosphate abstraction, followed by a cascade reaction via cationic intermediates. Based on isotopic-labelling experiments in combination with a computational study, the cyclization mechanism for sodorifen, a highly methylated sesquiterpene from the soil bacterium Serratia plymuthica, was resolved. A peculiar problem in its biosynthesis lies in the formation of several methyl groups from chain methylene carbons. The underlying mechanism involves a methyltransferase-mediated cyclization and unprecedented ring contraction with carbon extrusion from the chain to form a methyl group. A terpene cyclase subsequently catalyses a fragmentation into two reactive intermediates, followed by hydrogen transfers between them and recombination of the fragments by [4 + 3] cycloaddition. This study solves the intricate mechanistic problem of extra methyl group formation in sodorifen biosynthesis.

P-Centred redox reactions of a 1,4-dihydro-1,4-phosphasiline.

Tricyclic 1,4-dihydro-1,4-phosphasilines 3a,b were synthesized from Si(NR2)2-bridged imidazole-2-thione compounds 2a,b. Based on calculated FMOs of 3b, forecasting a possible P-selective P-N bond cleavage reduction, a redox cycle could be established using solutions of P-centred anionic derivative K[4b]. The cycle started with the oxidation of the latter to give the P-P coupled product 5b which could be chemically reduced by KC8 to yield K[4b], again. All new products have been unambiguously confirmed in solution and solid state.

Twelve-membered ring photoswitches with excellent Z → E conversion under ambient light.

Incorporation of azobenzenes into macrocycles is an intriguing approach for fine tuning the photophysical properties of these photoswitches and tailoring them to specific applications. A versatile synthesis of macrocyclic azobenzenes has been developed that allows for facile modification of these photoswitches. One example shows high chemical stability, long half-life of its Z-isomers, quantitative Z → E conversion under white light, and excellent separation of excitation bands to address either the E or Z-state selectively. The near quantitative Z → E conversion under white light is a unique feature with an important impact on applications, in which the configuration under ambient light needs to be close to 100%.