Wolfdieter A. Schenk

Platelet Polyphosphates Are Proinflammatory and Procoagulant Mediators In Vivo

Platelets play a central role in thrombosis, hemostasis, and inflammation. We show that activated platelets release inorganic polyphosphate (polyP), a polymer of 60-100 phosphate residues that directly bound to and activated the plasma protease factor XII. PolyP-driven factor XII activation triggered release of the inflammatory mediator bradykinin by plasma kallikrein-mediated kininogen processing. PolyP increased vascular permeability and induced fluid extravasation in skin microvessels of mice. Mice deficient in factor XII or bradykinin receptors were resistant to polyP-induced leakage. PolyP initiated clotting of plasma via the contact pathway. Ablation of intrinsic coagulation pathway proteases factor XII and factor XI protected mice from polyP-triggered lethal pulmonary embolism. Targeting polyP with phosphatases interfered with procoagulant activity of activated platelets and blocked platelet-induced thrombosis in mice. Addition of polyP restored defective plasma clotting of Hermansky-Pudlak Syndrome patients, who lack platelet polyP. The data identify polyP as a new class of mediator having fundamental roles in platelet-driven proinflammatory and procoagulant disorders.

The lactone concept—a novel approach to the metal-assisted atroposelective construction of axially chiral biaryl systems

The atroposelective synthesis of axially chiral biaryls via configurationally unstable, lactone-bridged biaryls is reviewed. These key molecules are easily accessible by regioselective intramolecular cross-coupling of ester-linked, even sterically hindered aromatic portions and can be cleaved highly atropo-enantio- or -diastereoselectively by three principal options, either (a) by using a wide range of chiral metalated nucleophiles (usually with external asymmetric induction), (b) after Lewis acid activation of the lactone CO function using uncharged chiral or achiral nucleophiles, or (c) with internal asymmetric induction, using the stereoelement of planar chirality originating from η6-coordination (typically involving Cr or Ru complexes). The resulting ring-opened configurationally stable biaryls are obtained in mostly excellent chemical and optical yields. By the choice of the respective enantiomer of the nucleophile, the method allows the atropo-divergent synthesis of both atropisomers from the same immediate biaryl precursor and, if required, a recycling of the undesired minor atropisomer is possible, too. Such advantages are otherwise well-known for the stereoselective preparation of centrochiral compounds.

Catalytic oxidations by peroxy, peroxo and oxo metal complexes: an interdisciplinary account with a personal view

Abstract In this account, we present a brief overview of our interdisciplinary efforts on the metal-assisted selective oxyfunctionalization of organic substrates in the ‘Sonderforschungsbereich (SFB 347): Selektive Reaktionen Metall-aktivierter Molekule’. The reactivity and selectivity of peroxy-, peroxo-, and oxo-type metal oxidants have been studied to gain insight into the mechanism of the oxygen transfer by such catalytic oxidants. Based on our mechanistic work, effective catalytic oxyfunctionalization methods have been developed by employing Ti, V, Re, Mn or Cr complexes as catalysts for the chemo-, regio-, diastereo- and enantioselective synthesis of hydroxy epoxides (from olefins), sulfoxides (from sulfides), and silanols (from silanes). We show that the stoichiometric dimethyldioxirane (DMD) oxidation of ligands in selected transition-metal complexes provides an useful tool for the synthesis of oxyfunctionalized compounds.

Tetracarbonylwolfram-komplexe mit zwei unterschiedlichen donorliganden : I. Darstellung und mechanismus der thermischen isomerisierung

Abstract cis- and trans -tetracarbonyltungsten complexes (R 3 P)(R′ 3 E)W(CO) 4 (R 3 P,R′ 3 E = i-Pr 3 P, Ph 2 -i-PrP, Ph 3 P, Ph 2 HP, (Me 2 n) 3 P, Ph(i-PrO) 2 P, (i-PrO) 3 P, (PhO) 3 P, Ph 3 As, Ph 3 Sb) are obtained from the chlortetracarbonyltungstates [(R 3 P)W-(CO) 4 Cl] - by several different routes. a cis—trans equilibrium is attained at 20–30°C with the trans isomer being thermodynamically more stable in nearly all cases. The cis-trans isomerisation of the phosphine—arsine and phosphine—stibine complexes is shown by ligand exchange experiments to occur via dissociation of the arsine and stibine ligand, respectively. The bis(phosphine) complexes, however, isomerise intramolecularly without bond cleavage.

Substituierte halogenocarbonylmetallate des chroms, molybdäns und wolframs : III. Ligandensubstitution an halogenocarbonylmetallaten der VI. Nebengruppe☆

Abstract The halopentacarbonylmetal compounds of molybdenum and tungsten react with phosphines in polar aprotic solvents with CO substitution to give the ionic derivatives [LM(CO)4X]− (X = Cl, Br; M = Mo, W; L = i-PrnPh3−nP, (Me2N)nPh3−nP, (i-PrO)nPh3−nP, Ph2MeP, Et3P, (PhO)3P, n = 0, 1, 2, 3). The substitution of the halide ligand, which is catalysed by protic solvents, provides a convenient route to the neutral complexes LM(CO)5 and LL′M(CO)4 (L = phosphines; L′ = ammonia, acetonitrile, pyridine, piperidine). cis-(NH3)(i-Pr3P)W(CO)4 in solution is slowly deuterated by D2O. In this reaction all three hydrogen atoms appear to be exchanged simultaneously.

Schwefel(IV)-Verbindungen als liganden: III. Struktur- und bindungsisomerie bei elektronenreichen schwefeldioxidkomplexen

Abstract The synthesis of electron rich sulfur dioxide complexes of the types fac -M(CO) 3 -(dmpe)(η 2 -SO 2 ), mer -M(CO) 3 (dmpe)η 1 -SO 2 ), mer,trans -M(CO) 3 (PR 3 ) 2 (η 1 -SO 2 ) (M = Cr, Mo, W; PR 3 = PPh 2 Me, P(OMe) 3 , P(O-i-Pr) 3 ), trans -Mo(CO) 2 (dppe)-(PR 3 )(η 1 -SO 2 ) (PR 3 = PMe 3 , PPh 2 Me, P-i-Pr 3 ), as well as fac -Cr(CO) 3 (bipy)(η 2 -SO 2 ), and fac -Mo(CO) 3 (MeCN) 2 (η 2 -SO 2 ) is described. The structures of these compounds are derived on the basis of NMR and vibrational spectroscopy. The results allow for an analysis of the various factors which contribute to the stability of the η 1 and η 2 bonding modes in {MSO 2 } 6 complexes. In the tricarbonyl series SO 2 can be replaced by pyridine in a reaction which in certain cases is accompanied by a change of stereochemistry around the metal.

Sulfur(IV) compounds as ligands: Part XXV. Halfsandwich ruthenium thiosulfonato complexes. Crystal and molecular structure of [CpRu(dppe){SSO2(4-C6H4Cl)}]

Abstract Reaction of the hydrogen sulfido complexes [CpRu(PP)(SH)] (PP=dppm (1), dppe (2)) with sulfonyl chlorides RSO2Cl at −70°C in THF gave the ruthenium thiosulfonato complexes [CpRu(PP)(SSO2R)] (PP=dppm (3), dppe (4), R=Me (a), Ph (b), 4-C6H4Cl (c), 4-C6H4NO2 (d)). The structure of 4c was determined by X-ray crystallography. Important molecular geometry data are: RuS(1) 239.3(2), S(1)S(2) 203.2(2), S(2)O(1) 145.0(5), S(2)O(2) 144.1(5) pm; RuS(1)S(2) 104.23(8)°.

Die koordinationschemie CS-funktioneller verbindungen: X. kationische rutheniumthiobenzaldehyd-Komplexe: Synthese durch hydridabstraktion aus benzylthiolat-komplexen, struktur, dynamisches verhalten und reaktionen☆

Abstract Hydride abstraction from [Cp(R3P)2Ru(SCH2C6H4X)] [R3PPh3P, Me3P, (MeO)3P; (R3P)2 Ph2PCH2PPh2 (dppm), Ph2PC2H4PPh2(dppe), Ph2PC2H4PMe2 (dpme), Me2PC2H4PMe2(dmpe); X  H, Cl, OMe] using triphenylcarbenium hexafluorophosphate yields ionic thiobenzaldehyde complexes [Cp(R3P)2Ru(S  CHC6H4X)]PF6. With bulky ligands R3P only η1(S) isomers are formed, whereas a dynamic η1/η2 equilibrium is observed for (R3P)2 = (Me3P)2, dmpe. An X-ray structure determination was carried out on [Cp(dppe)Ru(SCHC6 H4OMe)]PF6·0.5 Et2O (triclinic, space group P 1 , a= 11.372(4) A, b = 12.782(5)A, c = 14.548(4)A, α=70.33(1)°, β= 80.61(2)°, γ = 81.91(2)°, Z=2): Ru-Pl: 2.296(1) A, Ru-P2: 2.301(1) A, Ru-S: 2.314(1) A, S-C6: 1.632(5) A. Control experiments show that the s-hydride abstraction is initiated by single electron oxidation of the thiolate complex to give a radical cation intermediate. A fairly large kinetic isotope effect (KIE) of the H-transfer step (kH /kD = 5.6 using [Ph3C]+ and 7.4 using [Cp2Fe]+ as oxidant) demonstrates that the ruthenium atom is not involved. The thiobenzaldehyde complexes readily add nucleophiles such as H−, D−, PMe3, OR−, SR−, and carbanions. With (R3P) 2 = dpme, moderate diastereoselectivities are found in some of these reactions. [4 + 2]-Cycloadditions have been carried out with 2, 3-dimethylbutadiene and cyclopentadiene. The latter are moderately diastereoselective for (R3P)2 = dpme and highly exo-selective for (R3P)2 = dppm. An X-ray structure determination of [Cp(dppm)-Ru(SC6H7C6H4Cl)]PF6 · MeCN (monoclinic, space group P2 1/c, a = 13.463(6) A, b = 16.071(3) A, c = 20.813(9) A, s = 92.30(2)° , Z = 4) reveals that the E configuration of the CS bond is retained in the Diels-Alder adduct.

Die koordinationscheme CS-funktioneller verbindungen: VI. Reactionen an η1-, η2- und η3-dithioester-komplexen☆

Abstract The η 1 -dithioester complexes W(CO) 4 (L) (η 1 -SC(Me)SMe) (L  CO, P-i-Pr 3 ) add PMe 3 giving the betaines W(CO) 4 (L)(SC(Me)(SMe)(PMe 3 ). The uncoordinated dithioesters yield similar adducts − C(R)(SMe) P + Me 3 (R  Me, Ph) which can be alkylated to the phosphonium salts [RC(SMe) 2 PMe 3 ]I. Correspondingly, reaction with mer -W(CO) 3 )dmpe)(η 2 -SC(Me)SMe) produces inter alia a metal-coordinated thioacylphosphonium ion. Coordinately unsaturated metal fragments add to η 3 -dithioester complexes with formation of the binuclear compounds (CO) 3 (i-Pr 3 P)W(μ,η 3 -SC(Me)SMe)W(CO) 5 and (CO) 3 (Ph 3 P)Cr(μ,η 3 -SC(Me)SMe)Cr-(CO) 3 (dppe), respectively. With methyl iodide the η 2 -dithioester complexes yield the cations mer -[W(CO) 3 (dppe)(η 2 -MeSC(R)SMe)] + (R  Me, Ph), whereas the η 3 derivatives give the neutral compounds WI(CO) 3 (PR 3 )(η 2 -MeSC(Me)SMe) (R  i-Pr, Cy, Ph). The η 3 -dithiocarbenium complex WI(CO) 3 (η 3 -C(Me)(SMe) 2 ) which is formed as a side product for R  Ph was characterized by X-ray crystallography.

Die Koordinationscheme CS-funktioneller verbindungen: V. Dithioester als η1-, η2-und η3-liganden in übergangsmetallkomplexen☆

Abstract Esters of dithiocarboxylic acids SC(R)SMe (R  Me, Ph) coordinate to mononuclear transition metal fragments in three different ways. η 1 (S)-coordination of the CS group is found in cases of low electron density at the metal, e.g. M(CO) 5 (η 1 -SC(Me)SMe) (M  Cr, W) and cis -W(CO) 4 (PR 3 )(η 1 -SC(Me)SMe) (PR 3  P-i-Pr 3 , PPhMe 2 ). The more electron-rich tricabonyl complexes occur in two isomeric forms, fac -W(CO) 3 (R 2 PC 2 H 4 -PR 2 )(η 1 -SC(R)SMe) and mer -W(CO) 3 (R 2 PC 2 H 4 -PR 2 ) (η 2 -SC(R)(SMe) (R  Me, Ph) with the η 2 -dithioester acting as a good π-acceptor ligand. In the compounds fac -M(CO) 3 (PR) 3 (η 3 -SC(Me)SMe) (M  Cr, Mo, W) and cis -Mo(CO) 2 (dppe)(η 3 -SC(Me)SMe) the dithioester functions as a four-electron ligand with the SMe group also being coordinated to the metal. The three different bonding modes are readily distinguished by 13 C NMR spectroscopy A X-ray structure analysis of fac -W(CO) 3 (P-i-Pr 3 )(η 3 -SC(Me)SMe) reveals the allylic-type coordination of the dithioester ligand.