Total synthesis of Comfreyn A and structural analogues via two photochemical key steps.

In this work the influence of o-fluorine substituents on the photo-dehydro-Diels-Alder (PDDA) reaction was investigated and the findings of this study were applied to the total synthesis of natural products. The reactant molecules consisted of two alkyl arylpropiolates, connected by a suberic acid tether and bearing fluorine substituents in each of the o-positions. While quantum chemical calculations suggested that a fluorine substituent prevents an attack of the adjacent carbon atom in the second C-C bond forming step of the PDDA reaction, this attack took place nevertheless. The subsequent fluoride elimination, assisted by protic solvents or trialkylsilanes, resulted in an "Umpolung" of the 4-position of the cycloallene intermediate enabling the introduction of nucleophiles at this position. The nucleophilic replacement of the second fluorine substituent could also be triggered photochemically. After removal of the tether, the two arene moieties stand nearly perpendicular to each other and a selective excitation of the naphthalene moiety was possible. This led to an intramolecular photoinduced electron transfer (PET) followed by a nucleophilic replacement of the fluoride according to a SR+N1Ar* mechanism. The formed phenolic hydroxyl group underwent spontaneous lactonization with the adjacent ester group. Based on these results, the first total synthesis of the lignan Comfreyn A and some structural analogues were developed.

Selective and pH-Independent Detection of Ba2+ in Water by a Benzo-21-crown-7-Functionalized BODIPY.

Herein, we report on highly Ba2+ selective fluorescence sensing in water by a fluorescent probe consisting of a benzo-21-crown-7 as a Ba2+ binding unit (ionophore) and a tetramethylated BODIPY fluorophore as a fluorescence reporter. This fluorescent probe showed a Ba2+ induced fluorescence enhancement (FE) by a factor of 12±1 independently of the pH value and a high Ba2+ sensitivity with a limit of detection (LOD) of (17.2±0.3) µM. Moreover, a second fluorescent probe consisting of the same BODIPY fluorophore, but a benzo-18-crown-6 as a cation-responsive binding moiety, showed an even higher FE upon Ba2+ complexation by a factor of 85±3 and a lower LOD of (13±3) µM albeit a lower Ba2+ selectivity. The fluorescence sensing mechanism of Ba2+ was further investigated by time-resolved fluorescence as well as transient absorption spectroscopy (TAS) and it turned out that within these probes a blocking of a photoinduced electron transfer (PET) by Ba2+ is very likely responsible for the FE.

The Suzuki-Miyaura Cross-Coupling-Claisen Rearrangement-Cross-Metathesis Approach to Prenylated Isoflavones.

Isoflavones were synthesized via Suzuki-Miyaura coupling of 3-iodochromones and para-methoxybenzene- and para-phenolboronic acid. In our hands, conditions commonly used for similar cross couplings turned out to be unsuccessful or difficult to reproduce, for example, due to the unplanned partial cleavage of MOM-protecting groups. Using Pd(dba)2 as a precatalyst and tricyclohexylphosphine as an activating ligand, reliable cross-coupling conditions were identified. In all cases, notably higher yields of isoflavones were obtained with para-phenolboronic acid than with para-methoxybenzene boronic acid. This observation and the commercial availability of para-phenolboronic acid suggest that for the synthesis of the important 3'-prenyl- or 3',5'-diprenylisoflavone substitution pattern a synthetic route that introduces the prenyl substituents after the Pd-catalyzed cross-coupling step, thereby avoiding laborious and protecting-group-intensive multistep syntheses of C-prenylated arene boronic acids, is advantageous.

Synthesis and Bioactivity of Isoflavones from Ficus carica and Some Non-Natural Analogues.

Ficucaricone D (1) and its 4'-demethyl congener 2 are isoflavones isolated from fruits of Ficus carica that share a 5,7-dimethoxy-6-prenyl-substituted A-ring. Both natural products were, for the first time, obtained by chemical synthesis in six steps, starting from 2,4,6-trihydroxyacetophenone. Key steps are a microwave-promoted tandem sequence of Claisen- and Cope-rearrangements to install the 6-prenyl substituent and a Suzuki-Miyaura cross coupling for installing the B-ring. By using various boronic acids, non-natural analogues become conveniently available. All compounds were tested for cytotoxicity against drug-sensitive and drug-resistant human leukemia cell lines, but were found to be inactive. The compounds were also tested for antimicrobial activities against a panel of eight Gram-negative and two Gram-positive bacterial strains. Addition of the efflux pump inhibitor phenylalanine-arginine-ß-naphthylamide (PAßN) significantly improved the antibiotic activity in most cases, with MIC values as low as 2.5 µM and activity improvement factors as high as 128-fold.

Tetrahalidometallate(II) Ionic Liquids with More than One Metal: The Effect of Bromide versus Chloride.

Fifteen N-butylpyridinium salts - five monometallic [C4 Py]2 [MBr4 ] and ten bimetallic [C4 Py]2 [M0.5 a M0.5 b Br4 ] (M=Co, Cu, Mn, Ni, Zn) - were synthesized, and their structures and thermal and electrochemical properties were studied. All the compounds are ionic liquids (ILs) with melting points between 64 and 101 °C. Powder and single-crystal X-ray diffraction show that all ILs are isostructural. The electrochemical stability windows of the ILs are between 2 and 3 V. The conductivities at room temperature are between 10-5 and 10-6  S cm-1 . At elevated temperatures, the conductivities reach up to 10-4  S cm-1 at 70 °C. The structures and properties of the current bromide-based ILs were also compared with those of previous examples using chloride ligands, which illustrated differences and similarities between the two groups of ILs.

Studies toward the Total Synthesis of Arylnaphthalene Lignans via a Photo-Dehydro-Diels-Alder (PDDA) Reaction.

An efficient method for the preparation of arylnaphthalene lignans (ANLs) was developed, which is based on the Photo-Dehydro-Diels-Alder (PDDA) reaction. While intermolecular PDDA reactions turned out to be inefficient, the intramolecular variant using suberic acid as tether linking two aryl propiolic esters smoothly provided naphthalenophanes. The irradiations were performed with a previously developed annular continuous-flow reactor and UVB lamps. In this way, the natural products Alashinol D, Taiwanin C, and an unnamed ANL could be prepared.

[Nb6Cl14(pyrazine)4], a Versatile Precursor for Ligand-Supported Hexanuclear Niobium Cluster Compounds: Synthesis, Characterization, Follow-Up Reactions, and Intermolecular Interactions.

The compound [Nb6Cl14(pyrazine)4]·2CH2Cl2 (1) was investigated for its suitability as a starting compound for new ligand-supported hexanuclear niobium cluster compounds. The synthesis, stability to air and increased temperature, solubility and usability for subsequent reactions of 1, and purification and separation of the reaction products are discussed. The compounds with cluster units [Nb6Cl14L4], where L = iso-quinoline N-oxides (2), 1,1-dimethylethylenediamines (3), or thiazoles (4), and [Nb6Cl14(PEt3)3.76(Et3PO)0.24][Nb6Cl14(MeCN)4]·4MeCN (5) are presented as follow-up products. The crystal structures of compounds 1-5 are analyzed, and the structures are discussed with respect to their intra- and intermolecular bonding situations and crystal packing. In addition to hydrogen bonds and π-π interactions, the appearance of chalcogen and halogen bonds and lone pair-π interactions between Nb6 cluster units was observed for the first time.

Intraligand Charge Transfer Enables Visible-Light-Mediated Nickel-Catalyzed Cross-Coupling Reactions.

We demonstrate that several visible-light-mediated carbon-heteroatom cross-coupling reactions can be carried out using a photoactive NiII precatalyst that forms in situ from a nickel salt and a bipyridine ligand decorated with two carbazole groups (Ni(Czbpy)Cl2 ). The activation of this precatalyst towards cross-coupling reactions follows a hitherto undisclosed mechanism that is different from previously reported light-responsive nickel complexes that undergo metal-to-ligand charge transfer. Theoretical and spectroscopic investigations revealed that irradiation of Ni(Czbpy)Cl2 with visible light causes an initial intraligand charge transfer event that triggers productive catalysis. Ligand polymerization affords a porous, recyclable organic polymer for heterogeneous nickel catalysis of cross-coupling reactions. The heterogeneous catalyst shows stable performance in a packed-bed flow reactor during a week of continuous operation.

Scope and Applications of 2,3-Oxidative Aryl Rearrangements for the Synthesis of Isoflavone Natural Products.

The reaction of flavanones with hypervalent iodine reagents was investigated with a view to the synthesis of naturally occurring isoflavones. In contrast to several previous reports in the literature, we did not observe the formation of any benzofurans via a ring contraction pathway, but could isolate only isoflavones, resulting from an oxidative 2,3-aryl rearrangement, and flavones, resulting from an oxidation of the flavanones. Although the 2,3-oxidative rearrangement allows a synthetically useful approach toward some isoflavone natural products due to the convenient accessibility of the required starting materials, the overall synthetic utility and generality of the reaction appear to be more limited than previous literature reports suggest.

Matsuda-Heck arylation of itaconates: a versatile approach to heterocycles from a renewable resource.

Itaconic acid esters and hemiesters undergo Pd-catalyzed coupling reactions with arene diazonium salts in high to excellent yields. The coupling products of ortho-nitro arene diazonium salts can be converted in one or two steps to benzazepine-2-ones.

Ionic Liquids with More than One Metal: Optical and Electrochemical Properties versus d-Block Metal Combinations.

Thirteen N-butylpyridinium salts, including three monometallic [C4 Py]2 [MCl4 ], nine bimetallic [C4 Py]2 [M1-x a Mx b Cl4 ] and one trimetallic compound [C4 Py]2 [M1-y-z a My b Mz c Cl4 ] (M=Co, Cu, Mn; x=0.25, 0.50 or 0.75 and y=z=0.33), were synthesized and their structure and thermal and electrochemical properties were studied. All compounds are ionic liquids (ILs) with melting points between 69 and 93 °C. X-ray diffraction proves that all ILs are isostructural. The conductivity at room temperature is between 10-4 and 10-8  S cm-1 . Some Cu-based ILs reach conductivities of 10-2  S cm-1 , which is, however, probably due to IL dec. This correlates with the optical bandgap measurements indicating the formation of large bandgap semiconductors. At elevated temperatures approaching the melting points, the conductivities reach up to 1.47×10-1  S cm-1 at 70 °C. The electrochemical stability windows of the ILs are between 2.5 and 3.0 V.

Total Syntheses of Prenylated Isoflavones from Erythrina sacleuxii and Their Antibacterial Activity: 5-Deoxy-3'-prenylbiochanin A and Erysubin F.

The prenylated isoflavones 5-deoxyprenylbiochanin A (7-hydroxy-4'-methoxy-3'-prenylisoflavone) and erysubin F (7,4'-dihydroxy-8,3'-diprenylisoflavone) were synthesized for the first time, starting from mono- or di-O-allylated chalcones, and the structure of 5-deoxy-3'-prenylbiochanin A was corroborated by single-crystal X-ray diffraction analysis. Flavanones are key intermediates in the synthesis. Their reaction with hypervalent iodine reagents affords isoflavones via a 2,3-oxidative rearrangement and the corresponding flavone isomers via 2,3-dehydrogenation. This enabled a synthesis of 7,4'-dihydroxy-8,3'-diprenylflavone, a non-natural regioisomer of erysubin F. Erysubin F (8), 7,4'-dihydroxy-8,3'-diprenylflavone (27), and 5-deoxy-3'-prenylbiochanin A (7) were tested against three bacterial strains and one fungal pathogen. All three compounds are inactive against Salmonella enterica subsp. enterica (NCTC 13349), Escherichia coli (ATCC 25922), and Candida albicans (ATCC 90028), with MIC values greater than 80.0 µM. The diprenylated natural product erysubin F (8) and its flavone isomer 7,4'-dihydroxy-8,3'-diprenylflavone (27) show in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300) at MIC values of 15.4 and 20.5 µM, respectively. In contrast, the monoprenylated 5-deoxy-3'-prenylbiochanin A (7) is inactive against this MRSA strain.

Tetra-kis(tri-ethyl-enediamin-1-ium) dodeca-µ2-chlorido-hexakis(thio-cyanato-κN)hexa-octa-hedro-niobate.

The crystal structure of the cluster complex salt, (C6H13N2)4[Nb6(NCS)6Cl12] or (H-DABCO)4[Nb6Cl12(NCS)6] (DABCO = tri-ethyl-enedi-amine or 1,4-di-aza-bicyclo-[2.2.2]octa-ne), comprises octa-hedral Nb6 cluster cores, which are µ2-coordinated by 12 chloride ligands (bridging the octa-hedral edges, inner ligand sphere). Furthermore, each Nb atom is N-bonded to a terminal thio-cyanate ligand (outer ligand sphere). The discrete clusters carry a charge of -4, which is compensated by four monoprotonated DABCO mol-ecules. These are arranged in rows, which are N-H⋯Cl and N-H⋯N hydrogen bonded to the anions and among each other.

Bromination of eudesmin isolated from araucaria araucana induces epimerization and give bromine derivatives with loss of anti-Candida activity.

Furofuran lignanes show important biological activities for the treatment of infectious diseases, inflammatory and metabolic pathologies. They have been isolated from leaves and barks of many plants. In Chile the native conifer Araucaria araucana produces eudesmin, matairesinol, secoisolariciresinol and lariciresinol in stemwood, branchwood and knotwood. These compounds were previously isolated by laborious flash chromatography on silica gel. Here we report the easy isolation of eudesmin by soxhlet extraction from milled knots of Araucaria araucana with hexane, followed by cryo-crystallization at -20 °C. Upon bromination of the isolated eudesmin epimerization at one benzylic position occurs, giving epieudesmin and the corresponding mono and di-brominated derivatives. The structures were determined by 1D, 2D NMR and X-ray diffraction. The analysis of products against Candida yeast showed that eudesmin has a moderate activity against different strains of Candida from 62.5 to 500 µg/mL. This activity decreases for epieudesmin, while bromine derivatives are not active.

Mixed chloridometallate(ii) ionic liquids with tunable color and optical response for potential ammonia sensors.

Eight d-metal-containing N-butylpyridinium ionic liquids (ILs) with the nominal composition (C4Py)2[Ni0.5M0.5Cl4] or (C4Py)2[Zn0.5M0.5Cl4] (M = Cu, Co, Mn, Ni, Zn; C4Py = N-butylpyridinium) were synthesized, characterized, and investigated for their optical properties. Single crystal and powder X-ray analysis shows that the compounds are isostructural to existing examples based on other d-metal ions. Inductively coupled plasma optical emission spectroscopy measurements confirm that the metal/metal ratio is around 50 : 50. UV-Vis spectroscopy shows that the optical absorption can be tuned by selection of the constituent metals. Moreover, the compounds can act as an optical sensor for the detection of gases such as ammonia as demonstrated via a simple prototype setup.

Cluster Salts [Nb6 Cl12 (HIm)6 ]An (with HIm=1H-imidazole and A=Mineral Acid Anion, n=1 or 2) Made in and with Brønsted-basic Ionic Liquids and Liquid Mixtures.

Four new hexanuclear niobium cluster compounds of the general formula [Nb6 Cl12 (HIm)6 ](A)n ⋅ x(solvent molecule) (HIm=1H-imidazole, A=mineral acid anion, Cl- (n=2) (1), (SO4 )2- (n=1) (2), (CrO4 )2- (n=1) (3), and (HAsO4 )2- (n=1) (4)) were prepared. Their synthesis can be done in basic ionic liquids, which form on the addition of a mineral acid, which also delivers the counter anion for the final cluster compound, to an excess of the 1H-imidazole. Some addition of an auxiliary solvent, like methanol, improves the speed of crystallisation. The cluster unit comprises a hexanuclear Nb6 unit of octahedral shape with the edges bridged by Cl atoms and the exo sites being occupied by N-bonded 1H-imidazole ligands. The cluster cation carries sixteen cluster-based electrons. Between the NH groups of the ligands of the cluster unit, the anions and the co-crystallised water (1), or 1H-imidazole and methanol molecules (2, 3, and 4) a network of hydrogen bonds exists.

Influence of Functional Groups on the Ene Reaction of Singlet Oxygen with 1,4-Cyclohexadienes.

The photooxygenation of 1,4-cyclohexadienes has been studied with a special focus on regio- and stereoselectivities. In all examples, only the methyl-substituted double bond undergoes an ene reaction with singlet oxygen, to afford hydroperoxides in moderate to good yields. We explain the high regioselectivities by a "large-group effect" of the adjacent quaternary stereocenter. Nitriles decrease the reactivity of singlet oxygen, presumably by quenching, but can stabilize proposed per-epoxide intermediates by polar interactions resulting in different stereoselectivities. Spiro lactams and lactones show an interesting effect on regio- and stereoselectivities of the ene reactions. Thus, singlet oxygen attacks the double bond preferentially anti to the carbonyl group, affording only one regioisomeric hydroperoxide. If the reaction occurs from the opposite face, the other regioisomer is exclusively formed by severe electrostatic repulsion in a perepoxide intermediate. We explain this unusual behavior by the fixed geometry of spiro compounds and call it a "spiro effect" in singlet oxygen ene reactions.