Reactivity of Anodically Generated 4-Methoxystilbene Cation Radicals: The Influence of Ortho-Substituted Hydroxymethyl, Aminomethyl, and Carboxylic Acid Groups

The effect of ortho′-substituted side chains bearing nucleophilic groups such as CH 2 OH, CH 2 NHR, and CO 2 H on the reactivity of anodically generated 4-methoxy- and 3,4-dimethoxystilbene cation radicals was investigated, and results were compared with those of substrates where the nucleophilic groups such as OH and NHR are directly attached to the aromatic ring. It was found that when ortho′-substituted groups such as CH 2 OH or CH 2 NHR are present in the other ring, only direct intramolecular cation-nucleophile reactions occur to give bisbenzopyrans or bisisoquinolines. Crossover products (previously obtained when the ortho′ substituents were OH and NH 2 ) such as the fused benzoxepanes/fused benzoazepanes were not formed. When the ortho′ substituent is COOH, direct intramolecular cation-nucleophile reaction occurs to give the corresponding bis-δ-lactones in high yield. The presence of an additional 3-methoxy substituent resulted in the formation of other fused polycyclic products due to competing aromatic substitution reactions. Reaction pathways leading to the different products and reasons for the difference in behavior shown by the present stilbenes are presented. The results have provided additional insight into the reactivity and behavior of anodically generated stilbene cation radicals

Biomimetic Oxidative Dimerization of Anodically Generated Stilbene Radical Cations: Effect of Aromatic Substitution on Product Distribution and Reaction Pathways

A systematic study of the electrochemical oxidation of 1,2-diarylalkenes was carried out with the focus on detailed product studies and variation of product type as a function of aromatic substitution. A reinvestigation of the electrochemical oxidation of 4,4′-dimethoxystilbene under various conditions was first carried out, and all products formed were fully characterized and quantitated. This was followed by a systematic investigation of the effect of aromatic substitution on the nature and distribution of the products. The aromatic substituents were found to fall into three main categories, viz., substrates in which the nature and position of the aromatic substituents gave rise to essentially the same products as 4,4′-dimethoxystilbene, for example, tetraaryltetrahydrofurans, dehydrotetralins, and aldehydes (<i>p</i>-MeO or <i>p</i>-NMe₂ on one ring and X on the other ring, where X = <i>o</i>-MeO or <i>p</i>-alkyl, or <i>m</i>- or <i>p</i>-EWG; e.g., 4-methoxy-4′-trifluoromethylstilbene); those that gave rise to a mixture of indanyl (or tetralinyl) acetamides and dehydrotetralins (or pallidols) (both or one ring substituted by alkyl groups, e.g., 4,4′-dimethylstilbene); and those where strategic placement of donor groups, such as OMe and OH, led to the formation of ampelopsin F and pallidol-type carbon skeletons (e.g., 4,3′,4′-trimethoxystilbene). Reaction pathways to rationalize the formation of the different products are presented

Verso sistemi sanitari orientati alle patologie croniche: il caso spagnolo

Le crescenti spese della sanità destano grande preoccupazione in particolare nei paesi Ocse, soprattutto in relazione ai driver alla base di tale incremento tra cui l’invecchiamento della popolazione, l’innovazione medica e i cambiamenti nelle priorità e nel carico di malattia, che vede una costante crescita nella prevalenza di patologie croniche. La maggior parte dei sistemi sanitari nei paesi sviluppati è stata creata per ‘curare’ episodi acuti piuttosto che ‘gestire’ condizioni croniche e, di conseguenza, non è adeguatamente ed efficientemente organizzata per rispondere alle esigenze e alle preferenze, in costante cambiamento ed evoluzione, dei consumatori. Nuovi modelli per meglio rispondere ai bisogni dei pazienti cronici sono stati proposti e sviluppati e vi sono già esperienze pratiche in diversi paesi che ne dimostrano i vantaggi, ma anche le difficoltà di implementazione. In questo articolo ci focalizziamo sull’esperienza spagnola, ed in particolare sulle politiche e gli studi pilota atti a testare la fattibilità del passaggio da modelli di ‘cura’ a modelli di ‘gestione’ delle patologie croniche. In particolare, utilizziamo una struttura concettuale che identifica e analizza 10 prerequisiti dei sistemi sanitari basati sulla gestione delle patologie croniche con prestazioni di alta qualità e li applichiamo all’attuale sistema sanitario nazionale spagnolo. Dalla nostra analisi emerge che il sistema sanitario spagnolo soddisfa già alcuni prerequisiti. Tuttavia, altri prerequisiti sono ancora in fase embrionale di sviluppo o vengono applicati in contesti clinici o geografici limitati. Proponiamo, quindi, un percorso per delineare i passaggi cruciali verso un sistema sanitario orientato alla cura delle patologie croniche

Electrochemically Mediated Oxidative Transformations of Substituted 4‑Methoxystilbenes: Effect of Ortho-Substituted Nucleophilic Groups

A systematic study was undertaken to determine the influence of ortho′-substituted nucleophilic groups (OH, NH₂, or NHR) on the reactivity of anodically generated 4-methoxy- and 3,4-dimethoxystilbene cation radicals. The results showed that when ortho-substituted nucleophilic groups such as OH and NHR are present in the other ring, both direct and crossover intramolecular cation–nucleophile reactions occur to give bisbenzofurans/bisindoles or fused bisbenzopyrans/bisquinolines, respectively. Where an additional 3-methoxy substituent is present, bridged oxocine/azocine products are formed in addition to the bisbenzopyrans/bisquinolines and bisbenzofurans/bisindoles. Mechanistic rationalization of the observed behavior is presented based on a generalized pathway involving fast cation radical dimerization following electron transfer, followed by direct and crossover trapping of the benzylic cations by the ortho-substituted oxygen and nitrogen nucleophilic groups. In the instances where an additional 3-methoxy group is present, the bridged oxocine/azocine products are also formed as a result of competing aromatic substitution (Friedel–Crafts reaction). The results have shed further light and provided additional clarification on the reactivity of anodically generated stilbene cation radicals

Ibogan, Aspidosperman, Vincamine, and Bisindole Alkaloids from a Malayan <i>Tabernaemontana corymbosa</i>: Iboga Alkaloids with C‑20α Substitution

Ten new indole alkaloids (<b>1</b>–<b>10</b>) comprising five ibogan, two aspidosperman, one vincamine, and two bisindole alkaloids, in addition to 32 known alkaloids, were isolated from the stem-bark extract of a Malayan <i>Tabernaemontana corymbosa</i>. The structures of these alkaloids were determined based on analysis of the NMR and MS data and, in five instances (<b>1</b>, <b>3</b>, <b>5</b>, <b>6</b>, <b>8</b>), confirmed by X-ray diffraction analysis. Two of the iboga alkaloids, conodusines B (<b>2</b>) and C (<b>3</b>), and the iboga-containing bisindole tabernamidine B (<b>10</b>) are notable for the presence of an α-substituted acetyl group at C-20 of the iboga carbon skeleton. The iboga alkaloid (+)-conodusine E (<b>5</b>) had MS and NMR data that were identical to those of (−)-ervatamine I, recently isolated from <i>Ervatamia hainanensis</i>. Establishment of the absolute configuration of (+)-conodusine E (<b>5</b>) was based on analysis of the ECD data, correlation with (−)-heyneanine, and X-ray analysis, which showed that (+)-<b>5</b> belongs to the same enantiomeric series as exemplified by (−)-coronaridine. The configuration at C-20′ of the previously reported <i>Tabernaemontana</i> bisindole alkaloid 19′-oxotabernamine (renamed tabernamidine B) required revision based on the present results. Several of the bisindoles showed pronounced in vitro growth inhibitory activity against drug-sensitive and vincristine-resistant KB cells

Arborisidine and Arbornamine, Two Monoterpenoid Indole Alkaloids with New Polycyclic Carbon–Nitrogen Skeletons Derived from a Common Pericine Precursor

Two new monoterpene indole alkaloids, characterized by previously unencountered natural product skeletons, viz., arborisidine (<b>1</b>), incorporating indolizidine and cyclohexanone moieties fused to an indole unit, and arbornamine (<b>2</b>), incorporating an unprecedented 6/5/6/5/6 “arbornane” skeleton (distinct from the eburnan or tacaman skeleton), were isolated from a Malayan Kopsia arborea. The structures of the alkaloids were determined based on analysis of the NMR and MS data. Possible biogenetic pathways to these alkaloids from a common pericine precursor (<b>3</b>) are presented

Cytotoxic Vobasine, Tacaman, and Corynanthe-Tryptamine Bisindole Alkaloids from <i>Tabernaemontana</i> and Structure Revision of Tronoharine

Seven new indole alkaloids (<b>1</b>–<b>7</b>) comprising four vobasine, two tacaman, and one corynanthe-tryptamine bisindole alkaloid were isolated from the stem-bark extract of a Malayan <i>Tabernaemontana</i>. Two of the new vobasine alkaloids (<b>1</b>, <b>3</b>), as well as 16-epivobasine (<b>15</b>) and 16-epivobasenal (<b>17</b>), showed appreciable cytotoxicity toward KB cells (IC₅₀ ca. 5 μg/mL). The structure of the known <i>Tabernaemontana</i> alkaloid tronoharine (<b>8</b>) was revised based on newly acquired NMR data, as well as X-ray diffraction analysis

Cytotoxic Vobasine, Tacaman, and Corynanthe-Tryptamine Bisindole Alkaloids from <i>Tabernaemontana</i> and Structure Revision of Tronoharine

Seven new indole alkaloids (<b>1</b>–<b>7</b>) comprising four vobasine, two tacaman, and one corynanthe-tryptamine bisindole alkaloid were isolated from the stem-bark extract of a Malayan <i>Tabernaemontana</i>. Two of the new vobasine alkaloids (<b>1</b>, <b>3</b>), as well as 16-epivobasine (<b>15</b>) and 16-epivobasenal (<b>17</b>), showed appreciable cytotoxicity toward KB cells (IC₅₀ ca. 5 μg/mL). The structure of the known <i>Tabernaemontana</i> alkaloid tronoharine (<b>8</b>) was revised based on newly acquired NMR data, as well as X-ray diffraction analysis

Biosynthetic Enantiodivergence in the Eburnane Alkaloids from <i>Kopsia</i>

Reexamination of the absolute configuration of recently isolated eburnane alkaloids from Malaysian <i>Kopsia</i> and <i>Leuconotis</i> species by X-ray diffraction analysis and ECD/TDDFT has revealed the existence of biosynthetic enantiodivergence. Three different scenarios are discerned with respect to the composition of the enantiomeric eburnane alkaloids in these plants: first, where the new eburnane congeners possess the same C-20, C-21 absolute configurations as the common eburnane alkaloids (eburnamonine, eburnamine, isoeburnamine, eburnamenine) occurring in the same plant; second, where the new eburnane congeners possess opposite or enantiomeric C-20, C-21 absolute configurations compared to the common eburnane alkaloids found in the same plant; and, third, where the four common eburnane alkaloids were isolated as racemic or scalemic mixtures, while the new eburnane congeners were isolated as pure enantiomers with a common C-20, C-21 configuration (20α, 21α). Additionally, the same <i>Kopsia</i> species (<i>K. pauciflora</i>) found in two different geographical locations (Peninsular Malaysia and Malaysian Borneo) showed different patterns in the composition of the enantiomeric eburnane alkaloids. Revision of the absolute configurations of a number of new eburnane congeners (previously assigned based on the assumption of a common biogenetic origin to that of the known eburnane alkaloids co-occurring in the same plant) is required based on the present results

Unusual phenethylamine-containing alkaloids from Elaeocarpus tectorius

From the leaves of Elaeocarpus tectorius (Lour.) Poir. four previously undescribed phenethylamine-containing alkaloids were isolated, namely, tectoricine, possessing an unprecedented isoquinuclidinone ring system incorporating a phenethylamine moiety, tectoraline, representing a rare alkamide incorporating two phenethylamine moieties, and tectoramidines A and B, representing the first naturally occurring trimeric and dimeric phenethylamine alkaloids incorporating an amidine function. The structures of these alkaloids were established by detailed spectroscopic analysis. The absolute configuration of tectoricine was determined by comparison of the experimental and calculated ECD spectra. Plausible biosynthetic pathways to the four alkaloids are proposed