Studies on the Biosynthesis of Spirostaphylotrichin A

Incorporation of ¹⁴C-labelled acetate and amino acids as well as of [1-¹³C]-, [2-¹³C]-, and [1,2-¹³C₂] acetate, L -[methyl¹³C] methionine, [2,3-¹³C₂] succinate, and L -[2,3-¹³C₂] aspartate into spirostaphylotrichin A ( 1 ) by Staphylotrichum coccosporum demonstrates that the building blocks of 1 are 5 units of acetate/malonate, 1 unit of methionine, and a C₄-dicarboxylic acid. The latter is most likely aspartate and derived from the citric-acid cycle. Using [2-¹³C, 2-²H₃] acetate as a precursor, the starter unit of the polyketide chain was identified.     

Modular and Selective Arylation of Aryl Germanes (C−GeEt3) over C−Bpin,C−SiR3 and Halogens Enabled by Light-Activated Gold Catalysis

Selective C –C couplings are powerful strategies for the rapid and programmable construction of bi- or multiaryls. To this end, the next frontier of synthetic modularity will likely arise from harnessing the coupling space that is orthogonal to the powerful Pd-catalyzed coupling regime. This report details the realization of this concept and presents the fully selective arylation of aryl germanes (which are inert under Pd⁰/Pd^II catalysis) in the presence of the valuable functionalities C−BPin, C−SiMe₃, C−I, C−Br, C−Cl, which in turn offer versatile opportunities for diversification. The protocol makes use of visible light activation combined with gold catalysis, which facilitates the selective coupling of C−Ge with aryl diazonium salts. Contrary to previous light-/gold-catalyzed couplings of Ar–N₂⁺, which were specialized in Ar–N₂⁺ scope, we present conditions to efficiently couple electron-rich, electron-poor, heterocyclic and sterically hindered aryl diazonium salts. Our computational data suggest that while electron-poor Ar–N₂⁺ salts are readily activated by gold under blue-light irradiation, there is a competing dissociative deactivation pathway for excited electron-rich Ar–N₂⁺, which requires an alternative photo-redox approach to enable productive couplings.     

Synthesis of New,Unnatural Macrocyclic Trichothecenes: 3-isoverrucarin A ((1″-O)(3→4)abeo-verrucarin A), verrucinol,and verrucene. 46th Communication on verrucarins and roridins

A new unnatural macrocyclic trichothecene, an analogue of verrucarine A ( 1 ), which was named 3-Isoverrucarin A ((1″-O)(3→4)abeo-verrucarin A; 3 ) was synthesized starting from anguidine ( 5 ). The two key reactions were the removal of the 4β-acetoxy group of anguidine ( 5 ) by a Barton deoxygenation and the final macrolactonization. During the cyclization procedure, two unexpected new macrocyclic by-products, which were named verrucinol ( 19 ) and verrucene ( 20 ), were formed. They represent novel types of macrocyclic trichothecenes, the macrolidic moiety of verrucene ( 20 ) consisting only of the (Z,E)-muconic-acid residue. The formation of the analogous macrolide 26 of verrucene ( 20 ) was not possible, probably because the ring strain is too strong.     

The effect of pressure on hydrogen transfer reactions with quinones

The effect of pressure on the oxidation of hydroarenes 3-9 with 2,3-dichloro-5,6-dicyano-1,4-quinone (DDQ; 1 a) or o-chloranil (10), leading to the corresponding arenes, has been investigated. The activation volumes were determined from the pressure dependence of the rate constants of these reactions monitored by on-line UV/Vis spectroscopic measurements in an optical high-pressure cell (up to 3500 bar). The finding that they are highly negative and only moderately dependent on the solvent polarity (DeltaV( not equal ) = -13 to -25 in MTBE and -15 to -29 cm(3) mol(-1) in MeCN/AcOEt, 1:1) rules out the formation of ionic species in the rate-determining step and is good evidence for a hydrogen atom transfer mechanism leading to a pair of radicals in the rate-determining step, as was also suggested by kinetic measurements, studies of kinetic isotope effects, and spin-trapping experiments. The strong pressure dependence of the kinetic deuterium isotope effect for the reaction of 9,10-dihydroanthracene 5/5-9,9,10,10-D(4) with DDQ (1 a) can be attributed to a tunneling component in the hydrogen transfer. In the case of formal 1,3-dienes and enes possessing two vicinal C--H bonds, which have to be cleaved during the dehydrogenation, a pericyclic hydrogen transfer has to considered as one mechanistic alternative. The comparison of the kinetic deuterium isotope effects determined for the oxidation of tetralin 9/9-1,1,4,4-D(4)/9-2,2,3,3-D(4)/9-D(12) either with DDQ (1 a) or with thymoquinone 1 c indicates that the reaction with DDQ (1 a) proceeds in a stepwise manner through hydrogen atom transfer, analogously to the oxidations of 1,4-dihydroarenes, whereas the reaction with thymoquinone 1 c is concerted, following the course of a pericyclic hydrogen transfer. The difference in the mechanistic courses of these two reactions may be explained by the effect of the CN and Cl substituents in 1 a, which stabilize a radical intermediate better than the alkyl groups in 1 c. The mechanistic conclusions are substantiated by DFT calculations.     

Pseudo-MS3 in a MALDI orthogonal quadrupole-time of flight mass spectrometer

Both the matrix selected and the laser fluence play important roles in MALDI-quadrupole/time of flight (QqTOF) fragmentation processes. "Hot" matrices, such as alpha-cyano4-hydroxycinnamic acid (HCCA), can increase fragmentation in MS spectra. Higher laser fluence also increases fragmentation. Typical peptide fragment ions observed in the QqTOF are a, b, and y ion series, which resemble low-energy CID product ions. This fragmentation may occur in the high-pressure region before the first mass-analyzing quadrupole. Fragment ions can be selected by the first quadrupole (Q1), and further sequenced by conventional MS/MS. This allows pseudo-MS3 experiments to be performed. For peptides of higher molecular weight, pseudo-MS3 can extend the mass range beyond what is usually accessible for sequencing, by allowing one to sequence a fragment ion of lower molecular weight instead of the full-length peptide. Peptides that predominantly show a single product ion after MS/MS yield improved sequence information when this technique is applied. This method was applied to the analysis of an in vitro phosphorylated peptide, where the intact enzymatically-generated peptide showed poor dissociation via MS/MS. Sequencing a fragment ion from the phosphopeptide enabled the phosphorylation site to be unambiguously determined.     

Novel rhenium chelate system derived from dimercaptosuccinic acid for the selective labeling of biomolecules

This work is part of an effort to develop chelating agents for stable binding and easy conjugation of Re-188 to biologically interesting structures. Starting from the well-known in vivo stability of [(188)ReO(DMSA)(2)](-), we want to exploit this coordination system for the design of (188)ReO(V) chelates, which are stable toward reoxidation to perrhenate and toward ligand exchange under all conditions of radiopharmaceutical development. Therefore, a new type of tetradentate ligand has been synthesized by bridging two molecules of N,N'-diisobutyl-2,3-dimercaptosuccinamide with N-(3-aminopropyl)propane-1,3-diamine. The resulting stereoisomeric tetrathiolato S(4) ligand of composition ((i)()Bu)(2)N(O)C-C(SH)-C(SH)-C(O)NH-(CH(2))(3)-NH-(CH(2))(3)-NHC(O)-C(SH)-C(SH)-C(O)N((i)Bu)(2) forms anionic five-coordinate oxorhenium(V) complexes by a ligand-exchange reaction of NBu(4)[ReOCl(4)] in methanol. In the absence of a base, the compounds were isolated as "betaine", [ReO(S(4))], with the protonated nitrogen of the bridge serving as an internal "counterion". Two representatives have been fully characterized in both the solid and solution states and found to adopt the expected square-pyramidal coordination geometry. The equatorial plane is formed by four thiolate sulfur atoms, whereas the oxygen occupies the apical position. The orientation of the metal oxo group is exo in relation to the carbamido groups in both isomers. Both complexes are stereoisomeric regarding the junction of the triamine chain.     

Combining fixed- and moving-grid methods to study direct dissociation processes involving nonadiabatic transitions

We present a novel quantum-dynamics approach suitable for computing direct dissociation processes, including electronic transitions. This approach combines quantum trajectories in the Lagrangian reference frame with standard fixed-grid wave packets in order to overcome the limitations and difficulties of both techniques. As a model application, we consider the ultrafast photodissociation of H2 excited by a femtosecond extreme UV laser pulse.     

Desoxaphomin,das erste [13]Cytochalasan,ein möglicher biogenetischer Vorläufer der 24-Oxa-[14]cytochalasane

From cultures of a Phoma species (strain S 298) the hitherto unknown metabolite deoxaphomine has been isolated. On the basis of the spectral data, structure 1 of the (7S, 16R, 20R)-7,20-dihydroxy-16-methyl-10-phenyl-[13]cytochalasa-6(12),13^t,21^t-triene-1,23-dione is assigned to deoxaphomine. This structure is confirmed by the chemical degradation of 1 , yielding the products 4 and 6 which are identical with derivatives of phomine ( 2 )((7S,16R,20R)-7,20-dihydroxy-16-methyl-10-phenyl-24-oxa-[14]cytochalasa-6(12), 13^t,21^t-triene-1,23-dione) and cytohalasin D ( 8 ) ((7S,16S,18R,21R)-21-acetoxy-7,18-dihydroxy-16,18-dimethyl-10-phenyl-[11]sytochalasa-6(12),13^t,19^t-triene-1,17-dione). Deoxaphomine ( 1 ) is a potential biogenetic precursor of the 24-oxa-[14]cytochalasans. Preliminary results of the biological activity of deoxaphomine are reported.     

Heats of formation of [2.2]paracyclophane-1-ene and [2.2]paracyclophane-1,9-diene - an experimental study

The enthalpies of formation [Delta(g)] of tricyclo[8.2.2.2(4,7)]hexadeca-1(13),2,4(16),5,7(15),10(14),11-heptaene (2, 1,2-dehydro[2.2]paracyclophane or [2.2]paracyclophane-1-ene) and tricyclo[8.2.2.2(4,7)]hexadeca-1(13),2,4(16),5,7(15),8,10(14),11-octaene (3, 1,2,9,10-dehydro[2.2]paracyclophane or [2.2]paracyclophane-1,9-diene) have been determined by measuring their heats of combustion in a microcalorimeter and their heats of sublimation by the transpiration method. Values of the strain energies (SE) [SE(2) = 34.7 kcal mol(-)(1), SE(3) = 42.0 kcal mol(-)(1)] have been derived from the gas-phase heats of formation and are compared with those from MM3 and PM3 calculations and with the corresponding value SE(1) = 30.1 kcal mol(-)(1) for the parent tricyclo[8.2.2.2(4,7)]hexadeca-1(13),4(16),5,7(15),10(14),11-hexaene (1, [2.2]paracyclophane). The higher strain energies of 2 and 3 (by 4.6 and 11.9 kcal mol(-)(1)) are in accord with the well-known increased reactivities of their aromatic rings as a consequence of their increased bending. As revealed by an X-ray crystal structure analysis, the bending in the monoene 2 corresponds to that of 1 and 3 at one of two bridging corners.