Double cycloaromatization of (Z,Z)-deca-3,7-diene-1,5,9-triyne: evidence for the intermediacy and diradical character of 2,6-didehydronaphthalene

Bharucha, Kamal N.; Marsh, Rebecca M.; Minto, Robert E.; Bergman, Robert G.

doi:10.1021/ja00034a059

Cited by 65 publications

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“…Both cyanosporasides A and B ( 7 / 8 ) and sporolides A and B ( 9 / 10 ) are equally represented in the respective fermentation extracts of the producing strains. This is what would be expected for the cycloaromatization of the enediyne precursors to Bergman diradical intermediates followed by nonspecific quenching with hydrogen15a or chloride, a process that has been experimentally verified 15b. Interestingly, chloride addition occurred primarily at the C-3 position in fijiolides A and B.…”

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confidence: 58%

Fijiolides A and B, Inhibitors of TNF-α-Induced NFκB Activation, from a Marine-Derived Sediment Bacterium of the Genus Nocardiopsis

et al. 2010

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Fijiolide A, a potent inhibitor of TNF-α induced NFκB activation, along with fijiolide B, were isolated from a marine-derived bacterium of the genus Nocardiopsis. The planar structures of fijiolides A (1) and B (2) were elucidated by interpretation of 2D NMR spectroscopic data, while the absolute configurations of these compounds were defined by interpretation of circular dichroism (CD) and 2D NMR data combined with application of the advanced Mosher's method. Fijiolides A and B are related to several recently isolated chloroaromatic compounds, which appear to be the Bergman cyclization products of enediyne precursors. Fijiolide A reduced TNF-α induced NFκB activation by 70.3%, with an IC 50 value of 0.57 µM. Fijiolide B demonstrated less inhibition, only 46.5%, without dose-dependence. The same pattern was also observed with quinone reductase (QR) activity: fijiolide A was found to induce quinone reductase-1 (QR1), with an induction ratio (IR) of 3.5 at a concentration of 20 µg/mL (28.4 µM). The concentration required to double activity (CD) was 1.8 µM. Fijiolide B did not affect QR1 activity, indicating the importance of the nitrogen substitution pattern for biological activity. Based on these data, fijiolide A is viewed as a promising lead for more advanced anticancer testing.Nature is an important resource for the discovery of anticancer drugs. The relevance of the marine environment as a source of novel anticancer compounds has been validated by discovery ca. 2,500 new metabolites with antiproliferative activity.1 Bacteria belonging to the order Actinomycetales, commonly known as actinomycetes, have provided nearly 50% of the bioactive microbial natural products discovered as of 2002.2 Although most microbial small molecule discovery efforts have focused on actinomycetes from terrestrial environments, marine-derived actinomycetes are proving to be an important resource that has led to the discovery of biologically active molecules with unique chemical structures.3 Excellent examples are the salinosporamides4a and marinomycins.4b Salinosporamide A, isolated from Salinispora tropica, is a potent 20S proteasome inhibitor that recently completed phase I clinical trials for treatment of solid tumors, lymphomas, and multiple myeloma. The marinomycins isolated from a "Marinispora" sp. showed significant antimicrobial activity against drug-resistant bacterial pathogens and selective cancer cell cytotoxicity against melanoma cell lines.4bCorresponding Author: Tel: 1-858-534-2133; Fax: 1-858-534-1318; wfenical@ucsd.edu. Supporting Information Available: The 1 H, 13 C, and 2D NMR spectra of fijiolide A (1) and 1 H spectrum of fijiolide B (2), and 1 H NMR spectrum of MTPA esters 3a, 3b, 4a, 4b, 6a, 6b, and 1 H NMR spectrum of acetonide 5 are available free of charge via the Internet at http://pubs.acs.org. As part of a program to explore marine bacterial metabolites as inhibitors of tumor initiation and promotion, we have targeted nuclear factor kappa B (NFκB), a transcription factor that regulates the expressi...

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confidence: 58%

Fijiolides A and B, Inhibitors of TNF-α-Induced NFκB Activation, from a Marine-Derived Sediment Bacterium of the Genus Nocardiopsis

et al. 2010

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“…18,19 Some other less stable isomers, in particular both 2,6-and 1,5-naphthynes, were found as reaction intermediates and their diradical character was documented. [20][21][22] Unfortunately, as far as we know, there are no reliable experimental data concerning the electronic spectra of these species, in particular the magnitude of the S-T splittings, or the spin multiplicity of their ground states. Yet, this type of information is of crucial importance for a rational drug design, since it has been established (see, e.g., refs.…”

Section: Introductionmentioning

confidence: 99%

Energetics of naphthynes — Performance of reduced multi-reference coupled-cluster methods for diradicals

Paldus

2009

Can. J. Chem.

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The energetics of all the possible isomers of the didehydronaphthalene (naphthalyne or naphthyne) diradical has been examined using the reduced multi-reference (RMR) coupled-cluster (CC) method with singles and doubles (RMR CCSD) that employs a modest size MR CISD wave function as an external source of the most important (primary) triples and quadruples to account for nondynamic correlation effects in the presence of quasi-degeneracy, as well as by its perturbatively corrected version for the secondary triples, the RMR CCSD(T) method. The resulting energies are compared with those obtained by the standard single-reference (SR) CCSD and CCSD(T) approaches. In all cases, we used both the ccpVDZ basis set, as well as its restricted version cc-pVDZ* with deleted p-functions on hydrogens. Once the optimal geometry for each isomer was found, we computed the energy of the lowest-lying singlet and triplet states using the above mentioned CC methods, as well as the implied singlet-triplet splittings. These results enabled us to classify the isomers into three groups according to their stability and to determine, whenever possible, the spin multiplicity of the ground state. Finally, we point out the relationship between the extent of the diradical character of naphthyne isomers, the degree of their MR nature, the distance separating the radical centers, and, finally, the size of the largest doubly-excited cluster amplitude in their CC wave functions.Résumé : On a examiné les énergétiques de tous les isomères possibles du biradical du didéhydronaphtalène (naphtalyne ou naphtyne) en faisant appel à la méthode des agrégats couplés (AC) à multiréférence réduite (MRR) avec des simples et des doubles (MRR ACSD) qui utilise une fonction d'onde de taille modeste (MR CISD) comme source externe des triples et quadruples les plus importants (primaires) afin de tenir compte des effets de corrélation non dynamique en présence de quasi-dégénérescence; on a aussi fait appel à sa version corrigée d'un point de vue des perturbations pour les triples secondaires, la méthode MRR ACSD(T). On a comparé les énergies ainsi obtenues avec celles obtenues par les approches à ré-férence simple ACSD (RS) et ACSD(T). Dans tous les cas, on a utilisé l'ensemble de base cc-pVDZ ainsi que la version restreinte cc-pVDZ* desquelles les fonctions p de l'hydrogène ont été éliminées. Une fois que la géométrie optimale de chaque isomère a été trouvée, on a calculé les états singulet et triplet de plus basse énergie en utilisant les méthodes d'agrégats couplés mentionnées plus haut et on a aussi calculé la sèparation des niveaux de singulet et triplet qu'ils impliquent. Ces résultats permettent de classifier les isomères en trois groupes suivant leur stabilité et de déterminer, lorsque cela est possible, la multiplicité de spin de l'état fondamental. Enfin, on signale la relation entre le degré du caractère biradicalaire des isomères du naphtyne, le degré de leur nature de multiréférence, la distance qui sépare les centres radicalaires et enfin la taille de l'am...

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“…Arenes with o-ethynyl substituents may undergo multiple, simultaneous cyclization induced by transition metals to give polycycles such as [3]phenylene. "4b1 It remains to be seen whether reaction of 24 will lead to the synthesis of [6]phenylene (antikekulene), as Vollhardt has predicted. In contrast to the previously mentioned ring closures of enediynes via diradicals, reactions providing the tive to that of the polymers, these compounds could be characterized.…”

Section: By R O Y Gleiter* and Detlej Kratzmentioning

confidence: 99%

Conjugated Enediynes—An Old Topic in a Different Light

Gleiter

Kratz

1993

Angew. Chem. Int. Ed. Engl.

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If Angewandte Chemie had published "Highlights" twenty years ago, the topic of this article would certainly have been addressed then. The most recent reports from the research groups led by Nicolaou,"] Diederich, I2] V~l l h a r d t , [~~ and MyersC4] prove that the chemistry of conjugated enediynes continues to flourish. What is more remarkable, however, is the difference in the goals of the investigations of enediynes then and now. Twenty years ago the syntheses of new 4n and (4n + 2) n-electron systems and tetrahedranes were the main points under consideration; today's motivation for examining these compounds comes from natural products chemistry and from interest in new modifications of carbon.Biologically Active Anticancer Antibiotics: Nicolaou et al. were not only the first to complete the synthesis of the anticancer antibiotic cdkheamycin indeed a preparative masterpiece, they also contributed to the understanding of the mode of action of the aglycon (1) responsible for the DNA cleavage.[' b, The incorporation of the enediyne unit in the ten-membered ring of the aglycon enhances the reactivity of the already labile planar 6n-electron system; after activation by attack of a nucleophile, the triple bonds are even closer together and ring closure to give a 1,4-diradical (Bergman c y~l i z a t i o n ) [~~ is induced. For the systematic study of the mechanism of DNA cleavage cyclodeca-3-ene-l,5-diyne (2) was prepared as the most strained member of a series of monocyclic conjugated enediynes; because of the short transannular distance between the triple bonds (d = 3.25 in l), its cyclization via the 1,4-diradical3 to give tetralin (4) proceeds even at 50 "C. By determining the strucwhich d < 3.2-3.31 A, spontaneous Bergman cyclizations can be expected.Kinetics and Mechanism: First evidence that cyclization of conjugated enediynes proceeds via 1,4-didehydrobenzene intermediates like 6 was reported by Bergman et al. about twenty years ago[*' in an elegant study of the dideuterated parent compound, cis-hexa-3-ene-I ,5-diyne (5). Recently, the same research group examined an expanded system, (Z,Z)-deca-3,7-diene-I ,5,9-triyne (7), and proved that the analogous double cycloaromatization gives rise to 2,6-didehydronaphthalene (9),16] which is isolated as naphthalene (10) after H abstraction from the solvent. The cyclizations of both 5 and 7 are first-order reactions. The rearrangement of 5 to give deuterated benzene proceeds almost quantitatively at 190 "C in dilute solution and has an activation energy of 32 kcalmolIn contrast, the reaction of 7 (at 190°C) provides naphthalene in only 10% yield. tures of a number of model compounds Nicolaou et al. were able to predict whether an enediyne would undergo Bergman cyclization at room temperature, and thus be a potential anticancer drug. The transannular separation of the triple bonds serves as the decisive parameter; in compounds in [lO]annulene is outlined in Scheme 1. Key steps include the Pd-catalyzed Heck coupling of 11 and 12 to give 13, the chain extension by mea...

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Double cycloaromatization of (Z,Z)-deca-3,7-diene-1,5,9-triyne: evidence for the intermediacy and diradical character of 2,6-didehydronaphthalene

Cited by 65 publications

References 2 publications

Fijiolides A and B, Inhibitors of TNF-α-Induced NFκB Activation, from a Marine-Derived Sediment Bacterium of the Genus Nocardiopsis

Fijiolides A and B, Inhibitors of TNF-α-Induced NFκB Activation, from a Marine-Derived Sediment Bacterium of the Genus Nocardiopsis

Energetics of naphthynes — Performance of reduced multi-reference coupled-cluster methods for diradicals

Conjugated Enediynes—An Old Topic in a Different Light

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