Cascade Processes of Metallo Carbenoids

Cyclizations of N-acyliminium ions.

Intramolecular reactions of N-acyliminium intermediates

In this tutorial review, the rhodium(II)-catalyzed domino reactions of α-diazo carbonyl compounds are summarized. The article will emphasize some of the more recent synthetic applications of the rhodium carbenoid cyclization/cycloaddition domino cascade for alkaloid synthesis. The many structurally diverse and highly successful examples of both oxa and azapolycyclic ring formation cited in this tutorial review clearly demonstrate that the domino cyclization/cycloaddition cascade of metallo carbenoids has evolved as an important strategy for the synthesis of nitrogen containing natural products.

Domino reactions of rhodium(II) carbenoids for alkaloid synthesis

Ornamental flower growers know that placing a cut daffodil (a.k.a. narcissus) in a vase with other flowers has a negative effect on the quality of those flowers and significantly shortens their vase life. Furthermore, a common horticultural practice for the cultivation of narcissus flowers involves the introduction of cuts on the bulbs before immersing them into water. The mucilage that leaches out from the cuts is constantly removed by frequent changing of water and this leads to sprouting. These observations raise speculation that specific components in the mucilage of the narcissus bulbs may have powerful growth-inhibitory effects. Historical use of narcissus flowers, as well as at least thirty other plants of the Amaryllidaceae family, in folk medicine for the management of cancer1 speaks volumes to validate this conjecture.

Indeed, powerful anticancer properties of Narcissus poeticus L. were already known to the Father of Medicine, Hippokrates of Kos (ca. B.C. 460–370), who recommended a pessary prepared from narcissus oil for the treatment of uterine tumors.2 His successors, the ancient Greek physicians Pedanius Dioscorides (ca. A.D. 40–90) and Soranus of Ephesus (A.D. 98–138) continued using this therapy in the first and second centuries A.D.3,4 In addition, the topical anticancer uses of extracts from this plant5,6 as well as from N. pseudonarcissus7–9 were recorded in the first century A.D. by the Roman natural philosopher Gaius Plinius Secundus, (A.D. 23–79), better known as Pliny the Elder.10 Even the Bible provides multiple references to the Mediterranean N. tazetta L., which has a long history of use against cancer.11 The applications of narcissus oil in cancer management continued in the middle ages in Chinese, North African, Central American and Arabian medicine.1,12 The uses of other genera of the Amaryllidaceae family were also common, e. g. Hymenocallis caribaea (L. emend Gawler) Herbert, utilized by early European medical practitioners for inflammatory tumors.13

More recently, the plants of the Amaryllidaceae have been under intense scrutiny for the presence of the specific metabolites responsible for the medicinal properties associated with this plant family. The study began in 1877 with the isolation of alkaloid lycorine from Narcissus pseudonarcissus14 and since then more than 100 alkaloids, exhibiting diverse biological activities, have been isolated from the Amaryllidaceae plants.

Based on the present scientific evidence, it is likely that isocarbostyril constituents of the Amaryllidaceae, such as narciclasine, pancratistatin and their congeners, are the most important metabolites responsible for the therapeutic benefits of these plants in the folk medical treatment of cancer. Notably, N. poeticus L. used by the ancient Greek physicians, as was eluded before, is now known to contain some 0.12 g of narciclasine per kg of fresh bulbs.15 Continuing along this intriguing path, the focus of the present review is a comprehensive literature survey and discussion of the chemistry and biology of these compounds as specifically relevant to their potential use in medicine. The examination of the synthetic organic chemistry, more specifically the total synthesis efforts inspired by the challenging chemical structures of narciclasine, pancratistatin and their congeners, will be reduced to a minimum in view of the two very recent excellent reviews published on this subject.16,17

/pdf/chemistry-biology-and-medicinal-potential-of-narciclasine-1ngnxqunxc.pdf

Chemistry, biology, and medicinal potential of narciclasine and its congeners.

Aus Narciclasin (2a) wird das Acetonid 8a und dessen Oxidationsprodukt 10 dargestellt. 10 wird leicht zu 11 isomerisiert. Das bei der katalytischen Hydrierung von 2a anfallende Gemisch der Dihydronarciclasine wird uber die Tetraacetate in die cis- und trans-Verbindungen 14a und 15a aufgetrennt. Als Nebenprodukt der katalytischen Hydrierung entsteht Isonarciclasin (16a). Mit Hilfe der NMR-Spektren von 15b und 16b last sich die relative Konfiguration des Narciclasins entsprechend 2a beweisen. Lycoricidin und Margetin sind identisch und haben die Konfiguration 2b. Uber einige biologische Teste wird berichtet.



Chemistry of Nariciclasine



From narciclasine (2a), the acetonide 8a and its oxidation product 10 are prepared. 10 isomerizes easily to give 11. Catalytic hydrogenation of 2a yields a mixture of dihydronarci-clasines from which the pure cis- and trans-isomers 14a and 15a can be obtained via the tetraacetates. As a by-product of the hydrogenation, isonarciclasine (16a) is isolated. The relative configuration of narciclasine (as represented by formula 2a) is established by the n. m. r. spectra of 15b and 16b. Lycoricidine and margetine are shown to be identical; their configuration is as shown in formula 2b. Some biological tests are reported.

Zur Kenntnis des Narciclasins

Zum Aufbau neuer Erythrinane wird die Glyoxylester-Synthese auf C-4-Substituierte Cyclo-hexanone ubertragen. Der Ringschlus der Enamin-Vorstufen 1b, c und d fuhrt glatt zu den Erythrinan-Derivaten 2b, c und d, wahrend die Vorstufe 33 zum Isatin-Derivat 37 aromatisiert und dehydriert wird. Im Mittelpunkt der Arbeit steht der cyclische Ather 10 mit fixierter cis-Verknupfung des Ringsystems. Seine Aufspaltungsprodukte 12a und 13a, deren Struktur durch Hilfssynthesen bewiesen wurde, ermoglichten die Losung des gesamten Stereoproblems der gesattigten Erythrinane. Die Enamin-Vorstufen liefern mit Sauren tieffarbige Kationen, deren Chromophor dem des Bisnor-hexahydrocurarins ahnelt.



Syntheses of Aromatic Erythrina Alkaloids, XI Applications of the Glyoxylic Ester Synthesis



The glyoxylic ester synthesis of erythrinanes has been further developed and transferred to C-4-substituted cyclohexanones. Cyclisation of the precursors 1b, c and d, stabilized by enamine formation, leads smoothly to the erythrinane derivatives 2b, c and d, whereas 33 yields the isatin 37 by aromatisation and dehydrogenation. The key compound is the cyclic ether 10 with fixed cis-arrangement of the ring system. Its cleveage products 12a and 13a, the structures of which have been proved by independent syntheses, were used to solve all stereochemical problems of the saturated erythrinanes. The enamine type precursors react with acids to yield deeply coloured cations, the chromophore of which is very similar to that of bisnor-hexahydrocurarine.

Synthetische Arbeiten in der Reihe der aromatischen Erythrina-Alkaloide, XI Anwendungen der Glyoxylester-Synthese

racem. trans-15.16-Dimethoxy-erythrinan last sich durch eine einfache Synthese aus Homoveratrylamin und Cyclohexanon-(2)-essigsaure in guter Ausbeute gewinnen.

Albert Mondon

Papers

Zur Kenntnis des Narciclasins

Synthetische Arbeiten in der Reihe der aromatischen Erythrina-Alkaloide, XI Anwendungen der Glyoxylester-Synthese

Synthetische Arbeiten in der Reihe der aromatischen Erythrina‐Alkaloide, I. Synthese des racem. trans‐15.16‐Dimethoxy‐erythrinans

Der Aufbau von Olefinen aus 1.4-Dibrombutan Nach der Methode von Wittig†

Die Totalsynthese des Tetrahydro-desoxycodeins