15‐Hydroperoxy‐PGE2: Intermediate in Mammalian and Algal Prostaglandin Biosynthesis

Arachidonic‐acid‐derived prostaglandins (PGs), specifically PGE₂, play a central role in inflammation and numerous immunological reactions. The enzymes of PGE₂ biosynthesis are important pharmacological targets for anti‐inflammatory drugs. Besides mammals, certain edible marine algae possess a comprehensive repertoire of bioactive arachidonic‐acid‐derived oxylipins including PGs that may account for food poisoning. Described here is the analysis of PGE₂ biosynthesis in the red macroalga Gracilaria vermiculophylla that led to the identification of 15‐hydroperoxy‐PGE₂, a novel precursor of PGE₂ and 15‐keto‐PGE₂. Interestingly, this novel precursor is also produced in human macrophages where it represents a key metabolite in an alternative biosynthetic PGE₂ pathway in addition to the well‐established arachidonic acid‐PGG₂‐PGH₂‐PGE₂ route. This alternative pathway of mammalian PGE₂ biosynthesis may open novel opportunities to intervene with inflammation‐related diseases.     

Highly Conjugated π-Systems Arising from Cannibalistic Hexadehydro-Diels–Alder Couplings: Cleavage of C−C Single and Triple Bonds

We have investigated the cannibalistic self-trapping reaction of an ortho-benzyne derivative generated from 1,11-bis(p-tolyl)undeca-1,3,8,10-tetrayne in an HDDA reaction. Without adding any specific trapping agent, the highly reactive benzyne is trapped by another bisdiyne molecule in at least three different modes. We have isolated and characterized the resulting products and performed high-level calculations concerning the reaction mechanism. During the cannibalistic self-trapping process, either a C≡C triple bond or an sp–sp³ C−C single bond is cleaved. Up to seven rings and nine C−C bonds are formed starting from two 1,11-bis(p-tolyl)undeca-1,3,8,10-tetrayne molecules. Our experiments and calculations provide considerable insight into the variety of reaction pathways which the ortho-benzyne derivative, generated from a bisdiyne, can take when reacting with another bisdiyne molecule.     

Dynamic control of volume phase transitions of poly(N‐isopropylacrylamide) based microgels in water using hydrazide‐aldehyde chemistry

We demonstrate that the volume phase transition temperature (VPTT) of copolymer microgel particles made from N‐isopropylacrylamide (NIPAm) and methacryloyl hydrazide (MH) can be tailored in a reversible manner upon the reaction of the hydrazide functional groups with aldehydes. The microgels were synthesized by precipitation polymerization in water. Due to the water‐soluble nature of the MH monomer, the VPTT at which the microgel particles contract shifts to higher values by increasing the incorporated amounts of methacryloyl hydrazide from 0 to 5.0 mol %. The VPTT of the copolymer microgel dispersions in water can be fine‐tuned upon addition of hydrophobic/hydrophilic aldehydes, which react with the hydrazide moiety to produce the hydrazone analogue. This hydrazone formation is reversible, which allows for flexible, dynamic control of the thermo‐responsive behavior of the microgels. The ability to “switch” the VPTT was demonstrated by exposing hydrophilic streptomycin sulfate salt incubated microgel particles to an excess of a hydrophobic aldehyde, that is benzaldehyde. The temperature at which these microgels contracted in size upon heating was markedly lowered in these aldehyde exchange experiments. Transformation into benzaldehyde hydrazone derivatives led to assembly of the microgel particles into small colloidal clusters at elevated temperatures. This control of supracolloidal cluster formation was also demonstrated with polystyrene particles which had a hydrazide functionalised microgel shell. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 1745–1754     

Redox‐Active Tetraruthenium Macrocycles Built from 1,4‐Divinylphenylene‐Bridged Diruthenium Complexes

Metallamacrocylic tetraruthenium complexes were generated by treatment of 1,4‐divinylphenylene‐bridged diruthenium complexes with functionalized 1,3‐benzene dicarboxylic acids and characterized by HR ESI‐MS and multinuclear NMR spectroscopy. Every divinylphenylene diruthenium subunit is oxidized in two consecutive one‐electron steps with half‐wave potential splittings in the range of 250 to 330 mV. Additional, smaller redox‐splittings between the +/2+ and 0/+ and the 3+/4+ and 2+/3+ redox processes, corresponding to the first and the second oxidations of every divinylphenylene diruthenium entity, are due to electrostatic effects. The lack of electronic coupling through bond or through space is explained by the nodal properties of the relevant molecular orbitals and the lateral side‐by‐side arrangement of the divinylphenylene linkers. The polyelectrochromic behavior of the divinylphenylene diruthenium precursors is retained and even amplified in these metallamacrocyclic structures. EPR studies down to T=4 K indicate that the dications 1‐H²⁺ and 1‐OBu²⁺ are paramagnetic. The dications and the tetracation of macrocycle 3‐H display intense (dications) or weak ( 3‐H⁴⁺ ) EPR signals. Quantum chemical calculations indicate that the four most stable conformers of the macrocycles are largely devoid of strain. Bond parameters, energies as well as charge and spin density distributions of model macrocycle 5‐H^Me were calculated for the different charge and spin states.     

Tyrosine nitration of human ERK1 introduces an intra-hydrogen bond by molecular dynamics simulations

Structural Chemistry - ERK1 is an important kinase in Ras–Raf–MEK signaling. We have recently demonstrated by mass spectrometry that Tyr210 of ERK1 can be nitrated, and the nitration...     

Controlling 6-endo-selectivity in oxidation/bromocyclization cascades for synthesis of aplysiapyranoids and other 2,2,6,6-substituted tetrahydropyrans

A cascade, composed of (i) oxovanadium(V)-catalyzed oxidation of bromide by tert-butyl hydroperoxide and (ii) stereoselective 6-endo-bromocyclization, affords 3-bromo-2-aryl-2,6,6-trimethyltetrahydropyrans from styrene-type tertiary alkenols in synthetically useful yields. (E)-Alkenols add the bromo- and the alkoxy substituent anti-selectively across the double bond, indicating a bromonium ion-mechanism for the ring closure. 6-endo-control of the alkenol cyclization thereby arises from the polar effect of the aryl substituent. Two methyl substituents bound to the alkene terminus are not similarly able to favor 6-endo-cyclization, because strain arising from methyl group repulsion, as the bromonium-activated π-bond and the hydroxyl oxygen approach, directs bromocyclization of tertiary prenyl-type substrates toward tetrahydrofuran formation. A hexasubstituted bromotetrahydropyran prepared from the oxidation/bromocyclization cascade served as starting material for synthesis of racemic aplysiapyranoid A, in a sequence of free radical and polar functional group interconversion.