Confirmation of the Structures of Lutein and Zeaxanthin

A series of new esters of lutein ( 1a ) have been prepared with the aim of confirming the structure of lutein via an X‐ray crystal‐structure analysis. Although well crystallized, only one of the derivatives, the (?)‐(1R)‐menthyl carbonate ( 1i ) proved to be useful for a complete structure analysis. The same derivative of zeaxanthin ( 2a ) also allowed its crystal structure to be determined. Both analyses represent the first successful X‐ray crystal structure analyses of the most important xanthophylls. At the same time, they confirm both the constitution and absolute configuration of 1a and 2a that had been deduced earlier by classical methods.     

Interaction of nonionic detergents and swelling clays

Summary The 25° sorption isotherms of a polyoxyethylated n-dodecanol with 14 ethylene oxide units (C₁₂EO₁₄) on sodium and calcium montmorillonite were determined. Sorption complexes of the two clays were also prepared with C₁₂EO₃₀, n-dodecanol, polyethylene glycol and polypropylene glycol. X-ray powder diagrams show that the sorbed organic molecules are intercalated with their chains parallel to the montmorillonite lamellae, in layers one or two molecules thick. Sodium montmorillonite sorbs C₁₂ EO₁₄ and C₁₂EO₃₀ in excess of close-packed double layers: the excess detergent is occluded in interstices and absorbs moisture at 85% relative humidity to the same extent as the bulk detergents. The double layer complexes are not swelled by water; the single layer complexes sorb a single layer of water molecules at 85% relative humidity.Apparent densities of the sorbed organic molecules decrease with increasing EO content while bulk densities increase. This is explained in terms of chain flexibility and polarity.

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Zusammenfassung Die 25°-Absorptions-Isothermen von polyoxyäthyliertem n-Dodekanol mit 14Äthylenoxyd-Einheiten(C₁₂EO₁₄) an Na- und Ca-Montmorillonit wurden bestimmt. Sorptions-Komplexe der 2 Tone wurden ebenfalls mit nDodekanol, Polyäthylenglykol und Polypropylenglykol präpariert. Pulverdiagramme zeigen, daß die sorbierten organischen Moleküle mit ihren Ketten parallel zu den Montmorillonitlamellen eingelagert sind, in Schichten 1 oder 2 Moleküle dick. Na-Montmorillonit sorbiert C₁₂EO₁₄ und C₁₂EO₃₀ im Überschuß zur dichtgepackten Doppelschicht. Der Überschuß ist in Hohlräumen eingelagert und absorbiert Wasser bei 85° relativer Feuchtigkeit im selben Ausmaß wie die reinen Detergentien. Die Doppelschichtkomplexe werden nicht durch Wasser gequollen. Die Einschichtkomplexe sorbieren eine Monoschicht von Wasser-Molekülen bei 85° relativer Luftfeuchtigkeit.Scheinbare Dichten der sorbierten organischen Moleküle nehmen mit steigendem Äthylenoxydgehalt ab, während die Dichten der reinen Substanz ansteigen. Dies läßt sich auf Grund der Kettenbeweglichkeit und Polarität erklären.

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Presented at the 145^th Meeting of the American Chemical Society, New York, N. Y., September 1963.     

Zur Kenntnis der anomalen Reaktionen bei der Aminostickstoff-Bestimmung. IX. Die Reaktionen der Pyrrolin- und Oxazolinverbindungen mit salpetriger Säure

Zusammenfassung Es wurde die Reaktion von Pyrrolin- und Oxazolinverbindungen mit salpetriger Säure näher studiert, zumalTh. Wagner- Jauregg die Beobachtung machte, daß diese Verbindungen mit salpetriger Säure 1 Mol Stickstoff entwickeln, ohne daß eine primäre Aminogruppe vorhanden ist. Es zeigte sich, daß die Stickstoffentwicklung wie bei einem leicht desaminierbaren Amin schon bei 20° C schnell und vollständig vonstatten geht (Reaktion 1). Bei den Pyrrohnverbindungen ist ab 50° C noch eine weitere gasbildende Reaktion feststellbar, die bei 80 °C 1,40 Mole (N₂ + N₂O) liefert (Reaktion 2). Für die Reaktion 1 wird wahrscheinlich gemacht, daß sich zunächst eine in wäßriger Lösung unbeständige N-Nitrosoverbindung bildet. Bei deren Hydrolyse entsteht ein Diazoniumsalz, das unter Stickstoffentwicklung zerfällt. Dieses Reaktionsschema wird durch die Tatsache gestützt, daß bei Nitrosierung inwasserfreier Phase keine Stickstoffentwicklung erfolgt.Es wird weiters gezeigt, daß die Reaktion 2 (Gasentwicklung bei erhöhter Temperatur) durch die Folgeprodukte der Reaktion 1 verursacht wird. Bei diesen Folgeprodukten handelt es sich, wieWagner-Jauregg fand, um Acetonylverbindungen. Diese werden, wie wir bereits früher gezeigt haben, nitrosiert, wobei sich Isonitrosoverbindungen bilden. Die Isonitrosogruppe wird von überschüssiger salpetriger Säure unter Bildung von N₂ und N₂O zersetzt.Für die Aminostickstoffbestimmung ergibt sich daraus, daß Pyrrolinund Oxazolinverbindungen nur mit Nitrosylbromid in Eisessig (vgl.Kainz, Huber undKasler ¹⁵) richtig analysiert werden künnen, während die Bestimmung mit wäßriger Nitritlösung(van Slyke) ein Fehlresultat verursacht.

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Summary A study was made of the reaction of pyrrolin- and oxazoline compounds with nitrous acid, especially sinceTh. Wagner- Jauregg observed that these compounds generate 1 mol of nitrogen with nitrous acid, though no primary amino group is present. It was observed that the evolution of nitrogen, as in the case of a readily deaminable amine, occurs rapidly and completely even at 20° C (reaction 1). With the pyrroline compounds, it was possible to demonstrate another gas-producing reaction from 50° C on, which yields 1.40 mols (N₂ + N₂O) at 80° C (reaction 2). It is probable that in reaction (1) there is formation of a N-nitroso compound instable in water solution, and that the hydrolysis of this primary product yields a diazonium salt, which decomposes with evolution of nitrogen. This reaction scheme is supported by the fact that no formation of nitrogen is observed on nitrosation in solutions containing no water.It was also shown that the reaction (2) (evolution of gas at raised temperature) is caused by the secondary product of reaction (1). In these latter products there are involved, as shown byWagner- Jauregg, acetonyl compounds, which as we have proved previously, are nitrosated with formation ofiso-nitroso compounds. Theiso-nitroso group is decomposed by excess nitrous acid with production of N₂ and N₂O.With respect to the determination of amino nitrogen, it was found that pyrroline- and oxazoline compounds can be correctly analyzed only with nitrosyl bromide in glacial acetic acid (compareKainz, Huber, andKasler ¹⁵), whereas the determination with aqueous nitrite solution(van Slyke) brings about an incorrect result.

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Résumé Les auteurs ont poussé l'étude de la réaction des dérivés de la pyrroline et de l'oxazoline avec l'acide nitreux à partir de l'observation deTh. Wagner-Jauregg suivant laquelle ces combinaisons réagissent sur l'acide nitreux en dégageant une molécule d'azote en l'absence de tout groupe aminé primaire. Il est apparu que le dégagement d'azote se produit rapidement et complètement à 20° C comme pour une amine réagissant facilement (Réaction 1). Pour les combinaisons de la pyrroline une autre réaction commençant à partir de 50° C et donnant lieu à la formation de gaz a pu être établie; à 80° C, elle donne naissance à 1,40 molécule du mélange (N₂ + N₂O) (Réaction 2). Pour la réaction 1 il est vraisemblable qu'il se produit tout d'abord en solution aqueuse une combinaison N-nitrosée instable. Son hydrolyse produit un sel de diazonium qui se décompose avec dégagement d'azote. Ce schéma réactionnel est confirmé par le fait que par nitrosation en phase non aqueuse il ne se produit aucun dégagement d'azote.Il a été en outre montré que la réaction 2 (dégagement de gaz par élévation de température) est dûe aux produits formés dans la réaction 1. Parmi ces produits, se trouvent, comme l'ont montréWagner-Jauregg, des combinaisons acétonylées. Ces dernières, comme nous l'avons déjà montré antérieurement, se nitrosent en donnant lieu à la formation de combinaisons isonitrosées. Le groupement isonitrosé est décomposé par l'acide nitreux en excès avec formation de N₂ et de N₂O. Pour la détermination de l'azote aminé, il en résulte que les dérivés de la pyrroline et de l'oxazoline ne peuvent être correctement analysés qu'en employant du bromure de nitrosyle en solution dans l'acide acétique (cf.Kainz, Huber etKasler ¹⁵) tandis que la détermination par action d'une solution aqueuse de nitrite (van Slyke) fournit un résultat erroné.

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VIII. Mitteilung: Anomalie einiger Aminosäuren¹.     

Potent and selective structure-based dibenzofuran inhibitors of transthyretin amyloidogenesis: kinetic stabilization of the native state

Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation and partial monomer denaturation to produce a misassembly competent species. This process has been followed by turbidity to identify transthyretin amyloidogenesis inhibitors including dibenzofuran-4,6-dicarboxylic acid (1). An X-ray cocrystal structure of TTR.1(2) reveals that it only utilizes the outer portion of the two thyroxine binding pockets to bind to and inhibit TTR amyloidogenesis. Herein, structure-based design was employed to append aryl substituents at C1 of the dibenzofuran ring to complement the unused inner portion of the thyroxine binding pockets. Twenty-eight amyloidogenesis inhibitors of increased potency and dramatically increased plasma TTR binding selectivity resulted. These function by imposing kinetic stabilization on the native tetrameric structure of TTR, creating a barrier that is insurmountable under physiological conditions. Since kinetic stabilization of the TTR native state by interallelic trans suppression is known to ameliorate disease, there is reason to be optimistic that the dibenzofuran-based inhibitors will do the same. Preventing the onset of amyloidogenesis is the most conservative strategy to intervene clinically, as it remains unclear which of the TTR misassembly intermediates results in toxicity. The exceptional binding selectivity enables these inhibitors to occupy the thyroxine binding site(s) in a complex biological fluid such as blood plasma, required for inhibition of amyloidogenesis in humans. It is now established that the dibenzofuran-based amyloidogenesis inhibitors have high selectivity, affinity, and efficacy and are thus excellent candidates for further pharmacologic evaluation.     

Synthese des Dysidins

Synthesis of Dysidin The synthesis of dysidin ((?)- 1 ), the enantiomer of a metabolite of the marine sponge Dysidea herbacea, is described. To effect the synthesis, (±)-5-isopropyl-4-methoxy-3-pyrrolin-2-one ( 7 ) is converted to its lithium salt and reacted with (?)-(5R,2E)-3-methoxy-5-trichloromethyl-2-hexenoyl chloride ((-)- 11 ) to give (?)- 1 and its diastereoisomer (+)-5-epidysidin ((+)- 12 ) epimeric at C(5) of the pyrrolinone ring. The (?)-acyl chloride (?)- 11 has been synthesized from (+)-(R)-3-(trichloromethyl)butanoic acid ((+)- 8 ) via the intermediates (+)- 9 and (?)- 10 , the pyrrolinone 7 from N-benzyl-oxycarbonyl-L-valine via the intermediate 5 . The enantiomers of acid 8 have been resolved by fractional crystallization of their diastereoisomeric N-(1-phenylethyl)amides. The (R)-chirality of (+)- 8 was determined by comparing the ¹H-NMR spectra of the diastereoisomeric N-(1-phenylethyl)amides 16 and 17 , made from (+)- 8 by substituting deuterium for chlorine, with the spectra of the N-(1-phenylethyl)amides 14 and 15 of known absolute configuration. This correlation shows that literature value (R) for (?)- 8 is in error. Therefore, the structural formulae of (?)-dysidenin and (+)-isodysidenin, two other metabolites of D.herbacea, have to be changed to their mirror images as shown in formulae (?)- 3 and (+)- 4 , respectively.     

Wismutmonojodid BiJ,eine Verbindung mit Bi(O) und Bi(II)

Bismuth Monoiodide, a Compound with Bi(O) and Bi(II) Bismuth monoiodide was synthesized in closed tubes from the elements as well as from Bi and HgI₂ as a black coloured crystalline compound. With increasing temperature BiI passes two transitions. α-BiI is stable below 370 K and changes to β-BiI by a martensitic transition. γ-BiI is the stable modification above 564 K and decomposes at 585 K peritectically to BiI₃ and a lower iodide. All three modification crystallize in the monoclinic space group C2/m. The structures (single crystal studies) of α-BiI and β-BiI are characterized by onedimensional infinite chains [Bi₄I₄] with covalent bonds but only weak interactions in between. The [Bi₄I₄]-chains are built up by two completely different Bi atoms. Bi(A) is only bonded to three Bi whereas Bi(B) has bonds to one Bi and four I. The average bond lengths are Bi? Bi = 304.5 pm and Bi? I = 313.7 pm respectively. The configuration of the Bi(A) atoms is typical for Bi^O and that one of the Bi(B) atoms is characteristic for Bi²⁺ with the electron configuration s²p¹. Therefore, α-BiI and β-BiI are mixed valence compounds [Bi^OBi²⁺I₄]. The structures are variants of the simple cubic polonium type of structure and differ in the stacking of connected units. The structures and their transitions, the possible configurations for monohalides BiX on principle as well as the energy balances of the disproportionation of Bi⁺ are discussed together in detail.     

Photochemistry of 3-Substituted 1-Iminopyridinium Ylides. Regiospecific versus non-regiospecific photoisomerization patterns [1]

3-Substituted 1-iminopyridinium ylides 1 undergo photo-induced ring enlargement to 1H-1,2-diazepines. With strongly electron-withdrawing substituents the ring expansion process is regiospecific and leads exclusively to 4-substituted 1 H-1, 2-diazepines. Weak electron-donating substituents, like a methyl group and halogen atoms, do not have any directing effect since both 4- and 6-substituted 1 H -1,2-diazepines are obtained. With strong electron-donating substituents no diazepines are formed; instead one observes photo-induced isomerization to the 2-aminopyridine derivatives, the process being non-regiospecific. Regiospecific photo-induced ring expansion processes are explained in terms of a simple HMO model.     

Electrocatalytic oxidation of reduced nicotinamide coenzymes by graphite electrodes modified with an adsorbed phenoxazinium salt,meldola blue

Meldola Blue (7-dimethylamino-1,2-benzophenoxazine) can be adsorbed on graphite to give chemically modified electrodes. The electrochemical redox reactions of the phenoxazine are fairly reversible at low coverages with an E′^o of ?175 mV vs. SCE at pH 7.0. The electrode was most stable in acid solutions, at pH 6.0 its electrochemical activity decreased by 15% during 2h. The adsorbed compound mediated electron transfer in the electrocatalytic oxidation of the nicotinamide coenzymes (NADH and NADPH). The formation of a charge transfer complex between Meldola Blue and the coenzyme is demonstrated by experiments with a rotating disk electrode. The complex decomposes in a rate limiting step (k₊₂=30 s^?1) to the oxidized coenzyme and the reduced Meldola Blue. The latter can be reoxidized in a fast electrochemical step. The overall result is an electrocatalytic oxidation at a voltage which is about 500 mV lower than at an unmodified electrode.     

Abbau von Palustrin zu (−)-Dihydropalustraminsäure ((2R, 6S, 1′S)-[6-(1′-Hydroxypropyl)-2-piperidyl]essigsäure) und Struktur von Palustrin und Palustridin. Mitteilung über Schachtelhalmalkaloide

Degradation of palustrin to (?)-dihydropalustramic acid ((2R,6S,1′S)-[6-(1′-hydroxypropyl)-2-piperidyl]acetic acid), and the structure of palustrin and palustridin The structure of the macrocyclic alkaloid palustrin is shown to be 1a . Its piperidine unit can be obtained as (?)-dihydropalustramic acid ( 6a ) by the following sequence of degradation reactions (Scheme 1): catalytic hydrogenation of 1a followed by methylation and Hofmann degradation provides the allyl base 4 . the regioselectivity of the Hofmann elimination is explained by intramolecular proton abstraction at C(3) by C(18)-O^?. Catalytic reduction of 4 and subsequent acidic hydrolysis yielded 6a and N, N-dimethylputrescine (?N,N-dimethyl-1,4-butanediamine; 7 ). Loss of the N-alkyl group in the formation of 6a occurs during the catalytic hydrogenation step. This interpretation is supported by the results of model experiments. The position of the double bond in 1a is deduced from the IR. spectrum of the bromo-δ-lactone 19 prepared by treatment of 1a with N-bromosuccinimide at pH 4 (Scheme 3). Some of our previously published results on the degradation of dihydropalustrin ( 2a ) are obviously at variance with the newly proposed structure for palustrin ( 1a ). They can easily be explained by assuming a partial hydrogenolysis of the C(17)-N(1) bond during the preparation of dihydropalustrin from palustrin. Periodate cleavage of dihydropalustramic acid methyl ester ( 6b ) liberates propionaldehyde, which can be trapped by working at pH 7.5 (Scheme 2); at lower pH values it condenses rapidly with the simultaneously generated 3,4,5,6-tetrahydropyridine derivative 15 . The structure of the condensation product is proposed to be 16 on the basis of the isolation of its hydrogenation product, an isomeric dihydropalustramic acid ( 17 ).