Dications of fluorenylidenes. The effect of substituent electronegativity and position on the antiaromaticity of substituted tetrabenzo[5.5]fulvalene dications

Oxidation of 3,6-disubstituted tetrabenzo[5.5]fulvalenes by SbF(5) results in the formation of dications that behave like two antiaromatic fluorenyl cations connected by a single bond. Both fluorenyl systems exhibit the paratropic shifts and nucleus independent chemical shifts (NICS) characteristic of antiaromatic species. Comparison with analogous 2,7-disubstituted tetrabenzo[5.5]fulvalenes reveals that the antiaromaticity of the substituted ring system can be altered substantially by changes in the placement of the substituents, possibly due to changes in the delocalization of charge in the system. Substituents in the 3,6-position decrease the antiaromaticity because of the increase in the benzylic resonance compared to 2,7-substituents.     

Einfluß zweiwertiger Anionen auf die Filmdruck-Flächenbedarfs-Isothermen von gespreiteten Octadecylamin-Monoschichten

Zusammenfassung Durch den Einsatz zweiwertiger Ionen in der wäßrigen Subphase kann die Packungsdichte gespreiteter Monoschichten wasserunlöslicher Tenside pH-abhän-gig erhöht werden. Ergebnisse für Octadecylamin auf einer Lösung von Natriumhydrogensphosphat werden angegeben.

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Summary The packing density of spread monolayers of waterinsoluble surface-active agents can be increased by use of bivalent ions in the aqueous subphase. Results for octadecyl amine spread on a solution of sodium hydrogen phosphate are given.

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Mit 2 Abbildungen     

Forwards and backwards – synthesis of Laurencia natural products using a biomimetic and retrobiomimetic strategy incorporating structural reassignment of laurefurenynes C–F

Laurefurenynes C–F are four natural products isolated from Laurencia species whose structures were originally determined on the basis of extensive nuclear magnetic resonance experiments. On the basis of a proposed biogenesis, involving a tricyclic oxonium ion as a key intermediate, we have reassigned the structures of these four natural products and synthesized the four reassigned structures using a biomimetic approach demonstrating that they are the actual structures of the natural products. In addition, we have developed a synthesis of the enantiomers of the natural products laurencin and deacetyllaurencin from the enantiomer of (E)-laurefucin using an unusual retrobiomimetic strategy. All of these syntheses have been enabled by the use of tricyclic oxonium ions as pivotal synthetic intermediates.

The synthesis and structural reassignment of laurefurenynes C–F has been achieved, with the new structures fitting with a proposed biosynthesis. Also reported is the synthesis of ent-laurencin and ent-deacetyllaurencin via a retrobiomimetic approach.     

Dications of fluorenylidenes. The relationship between redox potentials and antiaromaticity for meta- and para-substituted diphenylmethylidenefluorenes

[reaction: see text] Electrochemical oxidation of meta-substituted diphenylmethylidenefluorenes (3a-g) results in the formation of fluorenylidene dications that are shown to be antiaromatic through calculation of the nucleus independent chemical shift (NICS) for the 5- and 6-membered rings of the fluorenyl system. There is a strong linear correlation between the redox potential for the dication and both the calculated NICS and sigma(m). Redox potentials for formation of dications of analogously substituted tetraphenylethylenes shows that, with the exception of the p-methyl derivative, the redox potentials for these dications are less positive than for formation of the dications of 3a-g and for dications of p-substituted diphenylmethylidenefluorenes, 2a-g. The greater instability of dications of 2a-g and 3a-g compared to the reference system implies their antiaromaticity, which is supported by the positive NICS values. The redox potentials for formation of the dications of meta-substituted diphenylmethylidenes (3a-g) are more positive than for the formation of dications of para-substituted diphenylmethylidenes (2a-g), indicating their greater thermodynamic instability. The NICS values for dications of 3a-g are more antiaromatic than for dications of 2a-g, which is consistent with their greater instability of the dications of 3a-g. Although the substituted diphenylmethyl systems are not able to interact with the fluorenyl system through resonance because of their geometry, they are able to moderate the antiaromaticity of the fluorenyl cationic system. Two models have been suggested for this interaction, sigma to p donation and the ability of the charge on the substituted ring system to affect delocalization. Examination of bond lengths shows very limited variation, which argues against sigma to p donation in these systems. A strong correlation between NICS and sigma constants suggests that factors that affect the magnitude of the charge on the benzylic (alpha) carbon of the diphenylmethyl cation affect the antiaromaticity of the fluorenyl cation. Calculated atomic charges on carbons 1-8 and 10-13 show an increase in positive charge, and therefore greater delocalization of charge in the fluorenyl system, with increasing electronegativity of the substituent. The change in the amount of positive charge correlated strongly with NICS, supporting the model in which the amount of delocalization of charge is related to the antiaromaticity of the species. Thus, both aromatic and antiaromatic species are characterized by extensive delocalization of electron density.     

Synthesis and characterisation of the platinum complexes [PtCl(CClPAr)(PPh3)2] and [PtCl(CClPAr′)(PPh3)2] as potential intermediates in the preparation of phosphaalkynes

Oxidative addition reactions of Cl₂CPR (R = 2,4,6-tris(trifluoromethyl)phenyl (Ar) or 2,6-bis(trifluoromethyl)phenyl (Ar′) with Pt(PPh₃)₄ yield the cis and trans (at platinum) complexes [PtCl(ClCPAr)(PPh₃)₂] and [PtCl(ClCPAr′)(PPh₃)₂]. All starting materials and intermediates have been characterised by NMR spectroscopy. The crystal and molecular structures of the trans-platinum complexes have been determined by single-crystal X-ray diffraction at low temperature.     

Electrospray ionization mass spectrometry studies of noncovalent myosin VI complexes reveal a new specific calmodulin binding site

Among the myosin superfamily, myosin VI differs from all others by a reverse directionality and a particular motility. Little structural information is available for myosin VI. It is known that it binds one calmodulin (CaM) by means of a single "IQ motif" and that myosin VI contains a specific insert located at the junction between the motor domain (MD) and the lever arm, likely to play a critical role for the unusual motility previously observed. Electrospray ionization mass spectrometry (MS) was used to determine the CaM and Ca2+ stoichiometries in several myosin VI constructs. In particular, the experimental conditions required for the observation of multiprotein/Ca2+ noncovalent assemblies are detailed for two truncated MD constructs (less than 20 kDa) and for three full MD constructs (more than 90 KDa). The specificity of the detected stoichiometries is discussed for each construct and the resolving power of Time of Flight mass spectrometry is stressed, in particular for the detection of metal ions binding to high molecular weight complexes. MS reveals a new CaM binding site for myosin VI and highlights a different behavior for the five myosin VI constructs versus Ca2+ binding. In addition to these stoichiometry based experiments, gas-phase dissociation analyses on intact complexes are described. They reveal that Ca2+ transfer between protein partners occurs during the dissociation process for one construct with a full MD. Charge-transfer and dissociation behavior has allowed to draw structural assumptions for the interaction of the MD with the CaM N-terminal lobe.     

α-CGRP disrupts amylin fibrillization and regulates insulin secretion: implications on diabetes and migraine

Despite being relatively benign and not an indicative signature of toxicity, fibril formation and fibrillar structures continue to be key factors in assessing the structure–function relationship in protein aggregation diseases. The inability to capture molecular cross-talk among key players at the tissue level before fibril formation greatly accounts for the missing link toward the development of an efficacious therapeutic intervention for Type II diabetes mellitus (T2DM). We show that human α-calcitonin gene-related peptide (α-CGRP) remodeled amylin fibrillization. Furthermore, while CGRP and/or amylin monomers reduce the secretion of both mouse Ins1 and Ins2 proteins, CGRP oligomers have a reverse effect on Ins1. Genetically reduced Ins2, the orthologous version of human insulin, has been shown to enhance insulin sensitivity and extend the life-span in old female mice. Beyond the mechanistic insights, our data suggest that CGRP regulates insulin secretion and lowers the risk of T2DM. Our result rationalizes how migraine might be protective against T2DM. We envision the new paradigm of CGRP : amylin interactions as a pivotal aspect for T2DM diagnostics and therapeutics. Maintaining a low level of amylin while increasing the level of CGRP could become a viable approach toward T2DM prevention and treatment.

CGRP concentration is elevated in migraine conditions. The protective effect of migraine against type 2 diabetes is attributed to the ability of CGRP to remodel human amylin aggregation and to suppress the secretion of mouse insulin 2 (the orthologue of human insulin).     

Formation of tryptanthrin compounds upon Oxone-induced dimerization of indole-3-carbaldehydes

Tryptanthrin is a natural product with numerous important pharmacological properties. Tryptanthrin and its analogs are commonly prepared by condensation of isatoic anhydride and isatin. In this Letter we investigate the formation of tryptanthrin derivatives upon Oxone-induced oxidative dimerization of indole-3-carbaldehydes.