Chemical Predictive Modelling and Natural Product-based Divergent Synthesis - Design of Type B PPAPs with Nanomolar Activities against MRSA.

In response to the pressing global challenge of antibiotic resistance, time efficient design and synthesis of novel antibiotics are of immense need. Polycyclic polyprenylated acylphloroglucinols (PPAP) were previously reported to effectively combat a range of gram-positive bacteria. Although the exact mode of action is still not clear, we conceptualized a late-stage divergent synthesis approach to expand our natural product-based PPAP library by 30 additional entities to perform SAR studies against methicillin-resistant Staphylococcus aureus (MRSA). Although at this point only data from cellular assays are available and understanding of molecular drug-target interactions are lacking, the experimental data were used to generate 3D-QSAR models via an artificial intelligence training and to identify a common pharmacophore model. The experimentally validated QSAR model enabled the estimation of anti-MRSA activities of a virtual compound library consisting of more than 100.000 in-silico generated B PPAPs, out of which the 20 most promising candidates were synthesized. These novel PPAPs revealed significantly improved cellular activities against MRSA with growth inhibition down to nanomolar concentrations.

Olefin Metathesis in Confinement: Towards Covalent Organic Framework Scaffolds for Increased Macrocyclization Selectivity.

Covalent organic frameworks (COFs) offer vast structural and chemical diversity enabling a wide and growing range of applications. While COFs are well-established as heterogeneous catalysts, so far, their high and ordered porosity has scarcely been utilized to its full potential when it comes to spatially confined reactions in COF pores to alter the outcome of reactions. Here, we present a highly porous and crystalline, large-pore COF as catalytic support in α,ω-diene ring-closing metathesis reactions, leading to increased macrocyclization selectivity. COF pore-wall modification by immobilization of a Grubbs-Hoveyda-type catalyst via a mild silylation reaction provides a molecularly precise heterogeneous olefin metathesis catalyst. An increased macro(mono)cyclization (MMC) selectivity over oligomerization (O) for the heterogeneous COF-catalyst (MMC:O=1.35) of up to 51 % compared to the homogeneous catalyst (MMC:O=0.90) was observed along with a substrate-size dependency in selectivity, pointing to diffusion limitations induced by the pore confinement.

Iron-Catalyzed Cycloisomerization and C-C Bond Activation to Access Non-canonical Tricyclic Cyclobutanes.

Cycloisomerizations are powerful skeletal rearrangements that allow the construction of complex molecular architectures in an atom-economic way. We present here an unusual type of cyclopropyl enyne cycloisomerization that couples the process of a cycloisomerization with the activation of a C-C bond in cyclopropanes. A set of substituted non-canonical tricyclic cyclobutanes were synthesized under mild conditions using [(Ph3 P)2 Fe(CO)(NO)]BF4 as catalyst in good to excellent yields with high levels of stereocontrol.

Mild, Selective Ru-Catalyzed Deuteration Using D2 O as a Deuterium Source.

A method for the selective deuteration of polyfunctional organic molecules using catalytic amounts of [RuCl2 (PPh3 )3 ] and D2 O as a deuterium source is presented. Through variation of additives like CuI, KOH, and various amounts of zinc powder, orthogonal chemoselectivities in the deuteration process are observed. Mechanistic investigation indicates the presence of different, defined Ru-complexes under the given specific conditions.

ß-Ketoesters as Mono- or Bisnucleophiles: A Concise Enantioselective Total Synthesis of (-)-Englerin†A and B.

A short enantioselective total synthesis of englerin A, a guaiane sesquiterpene with significant in vitro antitumor activity, is reported. Key features of this total synthesis are an organocatalytic asymmetric decarboxylative aldol reaction, a neighboring-group-participating [4+3] cycloaddition, a novel one-pot Heck coupling/regioselective 1,4-hydrosilylation/Tamao-Fleming oxidation cascade, and a kinetic CBS reduction, generating the optically pure natural product in 6.7 % overall yield over twelve steps starting from methylglyoxal. Selective saponification of the more reactive glycolic ester moiety of englerin A also gave (-)-englerin B.

Annelated Cyclobutanes by Fe-Catalyzed Cycloisomerization of Enyne Acetates.

Cationic Fe complexes of the general type [(Ph3 P)2 Fe(CO)(NO)]X (X=BF4 , BArF4 ) catalyze the redox-neutral cycloisomerization of 1,6- and 1,7-enyneacetates to afford bicyclic cyclobutanes under mild conditions in good yields and diastereoselectivities.

Detection and Characterization of Hydride Ligands in Iron Complexes by High-Resolution Hard X-ray Spectroscopy and Implications for Catalytic Processes.

Two hydride catalysts [Fe(CO)(dppp)H(NO)] (dppp = 1,3-bis(diphenylphosphino)propane) and [Fe(CO)H(NO)(PPh3)2] in comparison with nonhydride analogues [Fe(dppe)(NO)2] (dppe = 1,3-bis(diphenylphosphino)ethane) and [Fe(NO)2(PPh3)2] are investigated with a combination of valence-to-core X-ray emission spectroscopy (VtC-XES) and high-energy resolution fluorescence detected X-ray absorption near-edge structure (HERFD-XANES). To fully understand the experiments and to obtain precise information about molecular levels being involved in the spectral signals, time-dependent density functional theory (TD-DFT) calculations and ground state density functional theory (DFT) calculations are necessary. An excellent agreement between experiment and theory allows the identification of particular spectral signals of the Fe-H group. Antibonding Fe-H interactions clearly contribute to pre-edge signals in HERFD-XANES spectra, while bonding Fe-H interactions cause characteristic signatures in the VtC-XES spectra. The sensitivity of both methods with respect to the Fe-H distance is demonstrated by a scanning simulation approach. The results open the way to study metal hydride complexes in situ, their formation, and their fate during catalytic reactions, using high-resolution XANES and valence-to-core X-ray emission spectroscopy.

Iron-Catalyzed Intramolecular Aminations of C(sp3 )-H Bonds in Alkylaryl Azides.

The nucleophilic iron complex Bu4 N[Fe(CO)3 (NO)] (TBA[Fe]) catalyzes the direct intramolecular amination of unactivated C(sp3 )-H bonds in alkylaryl azides, which results in the formation of substituted indoline and tetrahydroquinoline derivatives.

Polycyclic Polyprenylated Acylphloroglucinols: An Emerging Class of Non-Peptide-Based MRSA- and VRE-Active Antibiotics.

In the past 20 years, peptide-based antibiotics, such as vancomycin, teicoplanin, and daptomycin, have often been considered as second-line antibiotics. However, in recent years, an increasing number of reports on vancomycin resistance in pathogens appeared, which forces researchers to find novel lead structures for potent new antibiotics. Herein, we report the total synthesis of a defined endo-type B PPAP library and their antibiotic activity against multiresistant S. aureus and various vancomycin-resistant Enterococci. Four new compounds that combine high activities and low cytotoxicity were identified, indicating that the PPAP core might become a new non-peptide-based lead structure in antibiotic research.

Iron-Catalyzed Intramolecular C(sp(2))-H Amination.

The nucleophilic iron complex Bu4N[Fe(CO)3(NO)] (TBA[Fe]) catalyzes the direct intramolecular C-H amination of α-azidobiaryls and (azidoaryl)alkenes into the corresponding carbazoles and indoles, respectively, under mild conditions and with low catalyst loadings. These features and the broad functional-group tolerance render this method a particularly attractive alternative to established noble-metal-based procedures.

Total synthesis and absolute configuration assignment of MRSA active garcinol and isogarcinol.

A short total synthesis of (±)-garcinol and (±)-isogarcinol, two endo-type B PPAPs with reported activity against methiciline resistant Staphylococcus aureus (MRSA), is presented. The separation of framework-constructing from framework-decorating steps and the application of two highly regio- and stereoselective Pd-catalysed allylations, that is, the Pd-catalysed decarboxylative Tsuji-Trost allylation and the diastereoselective Pd-catalysed allyl-allyl cross-coupling, are key elements that allowed the total synthesis to be accomplished within 13 steps starting from acetylacetone. After separation of the enantiomers the absolute configurations of the four natural products (i.e., (-)-garcinol, (+)-guttiferone E (i.e., ent-garcinol), (-)-isogarcinol, and (+)-isoxanthochymol (i.e., ent-isogarcinol)) were assigned based on ECD spectroscopy.

General Stereodivergent Enantioselective Total Synthetic Approach toward Macrosphelides A-G and M.

A straightforward enantioselective total synthesis algorithm for the preparation of 8 out of 13 macrosphelides within 9-11 steps starting from tert-butyl sorbate is presented. The use of a cyclic sulfate as both protecting and reactivity directing group is the key element within this algorithm. A high-pressure transesterification allows for the selective ring-enlargement of the 15-membered macrosphelides into the 16-membered counterparts. The absolute configurations of the natural products were unambiguously assigned both by the chemical synthesis and by X-ray structure analysis.

The total syntheses of guttiferone A and 6-epi-guttiferone A.

Polyprenylated polycyclic acylphloroglucinols (PPAP) are a constantly growing class of natural products that exhibit a common bicyclo[3.3.1]nonatrione core and consist of currently more than 200 members. A subclassification among the various natural products of this class includes the position of the exocyclic acyl group, the prenylation grade of the core, and the relative configuration at C-7 within the core. About 10% of the reported structures, however, possess an additional chiral center at C-6. Herein we describe a straightforward access to guttiferone A and epi-guttiferone A, in which full control of stereoselectivity is achieved via conformational control, and a strict separation of framework decorating from framework constructing operations sets the stage for a short 13-step synthesis.

Selective transfer hydrogenation and hydrogenation of ketones using a defined monofunctional (P

A defined (P^N^N^P)-Ru complex possessing tertiary amines within the ligand backbone proved to be highly active both in transfer hydrogenations and hydrogenations of a variety of ketones. As compared to the existing catalytic systems, no bifunctional activation of H2 or of the substrate by the metal center and a secondary amine within the ligand backbone is required to obtain high activities at catalyst loadings of down to 10 ppm.

Fe or Fe-NO catalysis? A quantum chemical investigation of the [Fe(CO)3(NO)](-)-catalyzed Cloke-Wilson rearrangement.

A quantum chemical investigation of the Bu4N[Fe(CO)3(NO)]-catalyzed Cloke-Wilson rearrangement of vinyl cyclopropanes is reported. It was found that allylic C-C bond activation can proceed through a SN2' or SN2-type mechanism. The application of the recently reported intrinsic bond orbital (IBO) method for all structures indicated that one Fe-N π bond is directly involved. Further analysis showed that during the reaction oxidation occurs at the NO ligand exclusively.

A rechargeable hydrogen battery based on Ru catalysis.

Apart from energy generation, the storage and liberation of energy are among the major problems in establishing a sustainable energy supply chain. Herein we report the development of a rechargeable H2 battery which is based on the principle of the Ru-catalyzed hydrogenation of CO2 to formic acid (charging process) and the Ru-catalyzed decomposition of formic acid to CO2 and H2 (discharging process). Both processes are driven by the same catalyst at elevated temperature either under pressure (charging process) or pressure-free conditions (discharging process). Up to five charging-discharging cycles were performed without decrease of storage capacity. The resulting CO2/H2 mixture is free of CO and can be employed directly in fuel-cell technology.

The electronic ground state of [Fe(CO)3 (NO)](-) : a spectroscopic and theoretical study.

During the past 10 years iron-catalyzed reactions have become established in the field of organic synthesis. For example, the complex anion [Fe(CO)3 (NO)](-) , which was originally described by Hogsed and Hieber, shows catalytic activity in various organic reactions. This anion is commonly regarded as being isoelectronic with [Fe(CO)4 ](2-) , which, however, shows poor catalytic activity. The spectroscopic and quantum chemical investigations presented herein reveal that the complex ferrate [Fe(CO)3 (NO)](-) cannot be regarded as a Fe(-II) species, but rather is predominantly a Fe(0) species, in which the metal is covalently bonded to NO(-) by two π-bonds. A metal-N σ-bond is not observed.

A Ru-catalyzed desulfonylative C-arylation of O-tosyl-hydroxamates.

Benzylic amine derivatives are ubiquitous structural motifs in organic chemistry. Herein we report a direct synthesis of these compounds via a direct desulfonylative C-arylation of O-tosyl hydroxamates. The applicability of this Ru-catalyzed aminoalkylation is being exemplified by a set of late-stage functionalizations of natural products.

Key to High Performance Ion Hybrid Capacitor: Weakly Solvated Zinc Cations.

Zinc ion hybrid capacitors suffer from lack of reversibility and dendrite formation. An electrolyte, based on a solution of a zinc salt in acetonitrile and tetramethylene sulfone, allows smooth zinc deposition with high coulombic efficiency in a Zn||stainless steel cell (99.6% for 2880 cycles at 1.0 mA cm-2 , 1.0 mAh cm-2 ). A Zn||Zn cell operates stably for at least 7940 h at 1.0 mA cm-2 with an area capacity of 10 mAh cm-2 , or 648 h at 90% depth of discharge and 1 mA cm-2 , 9.0 mAh cm-2 . Molecular dynamics simulations reveal the reason for the excellent reversibility: The zinc cation is only weakly solvated than in pure tetramethylene sulfone with the closest atoms at 3.3 to 3.8 Å. With this electrolyte, a zinc||activated-carbon hybrid capacitor exhibits an operating voltage of 2.0 to 2.5 V, an energy-density of 135 Wh kg-1 and a power-density of 613 W kg-1 at 0.5 A g-1 . At the very high current-density of 15 A g-1 , 29.3 Wh kg-1 and 14 250 W kg-1 are achieved with 81.2% capacity retention over 9000 cycles.

Tosylazide as N1-Synthon: Iron-Catalyzed Nitrogenative Dimerization of Indoles to p-Bisindolopyrazine Derivatives.

We present a straightforward one-step process to access a range of novel p-diindolepyrazines via an unprecedented [n-Bu4N][Fe(CO)3(NO)] (TBA[Fe])-catalyzed intermolecular nitrogenative dimerization of various indole derivatives. Remarkably, tosylazide functions as a N1-synthon forming the central pyrazine unit that joins the two indole subunits. The catalytic transformation shows a good substrate scope, and the obtained products show interesting electronic properties.