Reactivity Controlling Factors for an Aromatic Carbon‐Centered σ,σ,σ‐Triradical: The 4,5,8‐Tridehydroisoquinolinium Ion

The chemical properties of the 4,5,8‐tridehydroisoquinolinium ion (doublet ground state) and related mono‐ and biradicals were examined in the gas phase in a dual‐cell Fourier‐transform ion cyclotron resonance (FT‐ICR) mass spectrometer. The triradical abstracted three hydrogen atoms in a consecutive manner from tetrahydrofuran (THF) and cyclohexane molecules; this demonstrates the presence of three reactive radical sites in this molecule. The high (calculated) electron affinity (EA=6.06 eV) at the radical sites makes the triradical more reactive than two related monoradicals, the 5‐ and 8‐dehydroisoquinolinium ions (EA=4.87 and 5.06 eV, respectively), the reactivity of which is controlled predominantly by polar effects. Calculated triradical stabilization energies predict that the most reactive radical site in the triradical is not position C4, as expected based on the high EA of this radical site, but instead position C5. The latter radical site actually destabilizes the 4,8‐biradical moiety, which is singlet coupled. Indeed, experimental reactivity studies show that the radical site at C5 reacts first. This explains why the triradical is not more reactive than the 4‐dehydroisoquinolinium ion because the C5 site is the intrinsically least reactive of the three radical sites due to its low EA. Although both EA and spin–spin coupling play major roles in controlling the overall reactivity of the triradical, spin–spin coupling determines the relative reactivity of the three radical sites.     

First Stereoselective Total Synthesis of a Dimeric Naphthoquinonopyrano‐γ‐lactone: (+)‐γ‐Actinorhodin

We have accomplished the first total synthesis of an isomerically pure naphthoquinonopyrano‐γ‐lactone dimer, γ‐actinorhodin, in eleven steps. Two steps exploit pairs of peri‐MeO groups as unusual selectivity controls. The respective MeO groups convey the steric bulk of a bromo or iodo substituent located ortho to one MeO group as steric hindrance into the vicinity of the second MeO group. This relay effect was indispensable for exerting regiocontrol in an aromatic bromination and diastereocontrol in an oxa‐Pictet–Spengler cyclization. The absolute configuration of our target compound was established in an asymmetric Sharpless dihydroxylation of a β,γ‐unsaturated ester, which was synthesized in a Heck coupling of a bromoiodonaphthalene with ethyl vinylacetate. The dihydroxylation provided the γ‐hydroxylactone moiety of the bromonaphthalene that was used as the substrate in the oxa‐Pictet–Spengler cyclization. Dimerization to the core of γ‐actinorhodin occurred by two Suzuki couplings.     

An Optimised Small‐Molecule Stabiliser of the 14‐3‐3–PMA2 Protein–Protein Interaction

Modulation of protein–protein interactions (PPIs) is a highly demanding, but also a very promising approach in chemical biology and targeted drug discovery. In contrast to inhibiting PPIs with small, chemically tractable molecules, stabilisation of these interactions can only be achieved with complex natural products, like rapamycin, FK506, taxol, forskolin, brefeldin and fusicoccin. Fusicoccin stabilises the activatory complex of the plant H⁺‐ATPase PMA2 and 14‐3‐3 proteins. Recently, we have shown that the stabilising effect of fusicoccin could be mimicked by a trisubstituted pyrrolinone (pyrrolidone1, 1 ). Here, we report the synthesis, functional activity and crystal structure of derivatives of 1 that stabilise the 14‐3‐3–PMA2 complex. With a limited compound collection three modifications that are important for activity enhancement could be determined: 1) conversion of the pyrrolinone scaffold into a pyrazole, 2) introduction of a tetrazole moiety to the phenyl ring that contacts PMA2, and 3) addition of a bromine to the phenyl ring that exclusively contacts the 14‐3‐3 protein. The crystal structure of a pyrazole derivative of 1 in complex with 14‐3‐3 and PMA2 revealed that the more rigid core of this molecule positions the stabiliser deeper into the rim of the interface, enlarging especially the contact surface to PMA2. Combination of the aforementioned features gave rise to a molecule ( 37 ) that displays a threefold increase in stabilising the 14‐3‐3–PMA2 complex over 1 . Compound 37 and the other active derivatives show no effect on two other important 14‐3‐3 protein–protein interactions, that is, with CRaf and p53. This is the first study that describes the successful optimisation of a PPI stabiliser identified by screening.     

The ambident electrophilic behavior of 5‐nitro‐3‐X‐thiophenes in σ‐complexation processes

Kinetics of the reactions of 3,5‐dinitrothiophene 1 and 3‐cyano‐5‐nitrothiophene 2 with a series of parasubstituted phenoxide anions 3a–c have been investigated in aqueous solution at 20°C. Two unsubstituted electrophilic centers (C(2) and C(4)) of the two thiophenes have been identified. The Fukui functions correctly predict the C(2) and C(4) atoms as the most electrophilic centers of these electron‐deficient thiophenes 1 and 2 . Analysis of the experimental data in terms of Brønsted relationships reveals that the reaction mechanism likely involves a single‐electron transfer (SET) process. The excellent correlations upon plotting the rate constants versus the oxidation potentials E^o values is an additional evidence that reactions between thiophenes and phenoxide anions are proceeding through an initial electron transfer. It is of particular interest to note that the systems studied in this paper provide a rare example of a SET mechanism in σ‐complexation reactions. According to the free energy relationship log k = s(N + E) (Angew. Chem., Int. Ed. Engl., 1994, 33, 938–957), the electrophilicity parameters E of the C‐4 and C‐2 positions of the thiophenes have been determined and compared with the reactivities of other ambident electrophiles. On the other hand, the second‐order rate constants for the reactions of these thiophenes with the hydroxide ion has been measured in water and 50% water–50% acetonitrile and found to agree with those calculated theoretically using Mayr's equation from the E values determined in this work and from the previously published N and s parameters of OH⁻.     

Ultrasound‐Driven Secondary Self‐Assembly of Amphiphilic β‐Cyclodextrin Dimers

The controlled secondary self‐assembly of amphiphilic molecules in solution is theoretically and practically significant in amphiphilic molecular applications. An amphiphilic β‐cyclodextrin (β‐CD) dimer, namely LA‐(CD)₂, has been synthesized, wherein one lithocholic acid (LA) unit is hydrophobic and two β‐CD units are hydrophilic. In an aqueous solution at room temperature, LA‐(CD)₂ self‐assembles into spherical micelles without ultrasonication. The primary micelles dissociates and then secondarily form self‐assemblies with branched structures under ultrasonication. The branched aggregates revert to primary micelles at high temperature. The ultrasound‐driven secondary self‐assembly is confirmed by transmission electron microscopy, dynamic light scattering, ¹H NMR spectroscopy, and Cu²⁺‐responsive experiments. Furthermore, 2D NOESY NMR and UV/Vis spectroscopy results indicate that the formation of the primary micelles is driven by hydrophilic–hydrophobic interactions, whereas host–guest interactions promote the formation of the secondary assemblies. Additionally, ultrasonication is shown to be able to effectively destroy the primary hydrophilic–hydrophobic balances while enhancing the host–guest interaction between the LA and β‐CD moieties at room temperature.     

(E)‐3‐{4‐[(7‐Chloroquinolin‐4‐yl)oxy]‐3‐methoxyphenyl}‐1‐(4‐methylphenyl)prop‐2‐en‐1‐one: a ladder‐like structure resulting solely from π–π stacking interactions

In the title compound, C₂₆H₂₀ClNO₃, the quinoline fragment is nearly orthogonal to the adjacent aryl ring, while the rest of the molecular skeleton is close to being planar. The crystal structure contains no hydrogen bonds of any sort, but there are two π–π stacking interactions present. One, involving the quinoline ring, links molecules related by inversion, while the other, involving the two nonfused aryl rings, links molecules related by translation, so together forming a ladder‐type arrangement     

A–π–D–π–A Electron‐Donating Small Molecules for Solution‐Processed Organic Solar Cells: A Review

Organic solar cells based on semiconducting polymers and small molecules have attracted considerable attention in the last two decades. Moreover, the power conversion efficiencies for solution‐processed solar cells containing A–π–D–π–A‐type small molecules and fullerenes have reached 11%. However, the method for designing high‐performance, photovoltaic small molecules still remains unclear. In this review, recent studies on A–π–D–π–A electron‐donating small molecules for organic solar cells are introduced. Moreover, the relationships between molecular properties and device performances are summarized, from which inspiration for the future design of high performance organic solar cells may be obtained.     

Sensing Remote Chirality: Stereochemical Determination of β‐, γ‐, and δ‐Chiral Carboxylic Acids

Determining the absolute stereochemisty of small molecules bearing remote nonfunctionalizable stereocenters is a challenging task. Presented is a solution in which appropriately substituted bis(porphyrin) tweezers are used. Complexation of a suitably derivatized β‐, γ‐, or δ‐chiral carboxylic acid to the tweezer induces a predictable helicity of the bis(porphyrin), which is detected as a bisignate Cotton Effect (ECCD). The sign of the ECCD curve is correlated with the absolute stereochemistry of the substrate based on the derived working mnemonics in a predictable manner.     

Synthesis and Characterization of New 7‐Substituted 6,14‐Ethenomorphinane Derivatives: N‐{5‐[(5α,7α)‐4,5‐Epoxy‐3,6‐dimethoxy‐17‐methyl‐6,14‐ethenomorphinan‐7‐yl]‐1,3,4‐oxadiazol‐2‐yl}arenamines

In this study, (5α,7α)‐4,5‐epoxy‐3,6‐dimethoxy‐17‐methyl‐6,14‐ethenomorphinan‐7‐carboxylic acid hydrazide ( 5 ) was synthesized by the condensation of methyl (5α,7α)‐4,5‐epoxy‐3,6‐dimethoxy‐17‐methyl‐6,14‐ethenomorphinan‐7‐carboxylate ( 4 ) with NH₂NH₂⋅H₂O. The (5α,7α)‐4,5‐epoxy‐3,6‐dimethoxy‐17‐methyl‐6,14‐ethenomorphinan‐7‐carboxylic acid 2‐[(arylamino)carbonyl]hydrazides 6a – 6q were prepared by the reaction of 5 with corresponding substituted aryl isocyanates, and the N‐{5‐[(5α,7α)‐4,5‐epoxy‐3,6‐dimethoxy‐17‐methyl‐6,14‐ethenomorphinan‐7‐yl]‐1,3,4‐oxadiazol‐2‐yl}arenamines 7a – 7q were obtained via the cyclization reaction of 6a – 6q in the presence of POCl₃. The synthesized compounds have a rigid morphine structure, including the 6,14‐endo‐etheno bridge and the 5‐(arylamino)‐1,3,4‐oxadiazol‐2‐yl residue at C(7) adopting the (S)‐configuration (7α). The structures of the compounds were confirmed by high‐resolution mass spectrometry (HR‐MS) and various spectroscopic methods such as FT‐IR, ¹H‐NMR, ¹³C‐NMR, APT, and 2D‐NMR (HETCOR, COSY, INADEQUATE).     

N,N′‐Dioxide/Nickel(II)‐Catalyzed Asymmetric Inverse‐Electron‐Demand Hetero‐Diels–Alder Reaction of β,γ‐Unsaturated α‐Ketoesters with Enecarbamates

N,N′‐Dioxide/nickel(II) complexes have been developed to catalyze the inverse‐electron‐demand hetero‐Diels–Alder reaction of β,γ‐unsaturated α‐ketoesters with acyclic enecarbamates. After detailed screening of the reaction parameters, mild optimized reaction conditions were established, affording 3,4‐dihydro‐2H‐pyranamines in up to 99 % yield, 99 % ee and more than 95:5 d.r. The catalytic system was also efficient for β‐substituted acyclic enecarbamates, affording more challenging 2,3,4‐trisubstituted 3,4‐dihydro‐2H‐pyranamine with three contiguous stereogenic centers in excellent yields, diastereoselectivities, and enantioselectivities. The reaction could be scaled up to a gram scale with no deterioration of either enantioselectivity or yield. Based on these experiments and on previous reports, a possible transition state was proposed.     

6‐TIPS‐β‐Cyclodextrin‐Modified Fe3O4 for Facile Enantioseparation of 1‐(1‐Naphthyl)ethylamine

A new type of chiral magnetic nanoparticle was prepared from covalently linked magnetic nanoparticles (Fe₃O₄) and heptakis‐(6‐O‐triisopropylsilyl)‐β‐cyclodextrin (6‐TIPS‐β‐CD). The resulting selectors (TIPS‐β‐CD‐MNPs) combined the good magnetic properties Fe₃O₄ and efficient chiral recognition ability of 6‐TIPS‐β‐CD. The enantioselectivity of TIPS‐β‐CD‐MNPs towards 1‐(1‐naphthyl)ethylamine was six times higher than that of the parent β‐CD modified Fe₃O₄ particles.     

Palladium‐catalyzed cyclization of β‐bromo‐α,β‐unsaturated ketones with arylhydrazines leading to 3‐substituted 1‐aryl‐1 H‐pyrazoles

β‐Bromo‐α,β‐unsaturated ketones are condensed with arylhydrazines to form hydrazones, which are in situ intramolecularly cyclized into 3‐substituted 1‐aryl‐1 H‐pyrazoles under a catalytic system of Pd(OAc)₂/1,3‐bis(diphenylhosphino)propane (dppp)/NaO^tBu. Copyright © 2012 John Wiley & Sons, Ltd.     

Iron‐Catalyzed Aminomethyloxygenative Cyclization of Hydroxy‐α‐diazoesters with N,O‐Aminals

A new and efficient cyclization reaction has been developed to synthesize cyclic α,α‐disubstituted β‐amino esters via iron‐catalyzed intramolecular aminomethyloxygenative cyclization of diazo compounds with N,O‐aminal under mild reaction conditions. A broad range of hydroxy‐α‐diazoesters with different substituents and various N,O‐aminals were compatible with this protocol, affording the corresponding α,α‐disubstituted β‐amino esters bearing a five‐ to eight‐membered oxacycle in good yields.