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A concise synthetic approach to construct [6] , [6] , [6] -tricyclic core, bearing 14-membered carbocyclic skeleton and oxygen at C13 of lophotoxin, has been described. This approach features a diastereoselective intermolecular Diels−Alder furan reaction and intramolecular Michael reaction. N-methylmaleimide was found to be critical for achieving the stable intermolecular Diels−Alder furan outcome.

Our recent progress toward the synthesis of the furanocembranolide lophotoxin (1) is disclosed. Strategies for the stereoselective incorporation of the C13stereocenter by a catalytic desymmetrization of a cyclic meso-anhydride, as well as a novel 1,6-addition reaction of organocuprates to unsaturated [1,3]dioxin-4-ones are discussed. Preliminary results on the development of a rhodium-catalyzed asymmetric 1,6-addition reaction are also mentioned. Finally, modifications of a previously reported transition-metal-catalyzed cyclization reaction involving α-propargyl β-keto esters allow furan ring formation either under thermal conditions or by microwave irradiation.Key words: 1,6-addition, organocuprates, catalytic desymmetrization, furan cyclization, microwave.

A chronological summary of the contributions made by researchers in Nottingham, UK, to developing the scope for the intramolecular Stille reaction in target natural product syntheses, e.g. leinamycin, the virginiamycins, macrolactin A, rhizoxin, the amphidinolides, lophotoxin, and pateamine, is described.

A chronological summary of the contributions made by researchers in Nottingham, UK, to developing the scope for the intramolecular Stille reaction in target natural product syntheses, e.g. leinamycin, the virginiamycins, macrolactin A, rhizoxin, the amphidinolides, lophotoxin, and pateamine, is described.

A concise synthesis of the furan-containing macrocyclic (cembranoid) ring system 8 (10-isopropenyl-3,7,1 13-trimethyl-15-oxabicyclo[10.2.1] pentadeca-2,6,12,14-tetraene) found in lophotoxin (1) and other members of this family of irreversible nicotinic receptor antagonists, is described. The synthesis features a 14-endo trig cyclisation from an unsaturated acyl radical intermediate incor porating a terminal conjugated enone moiety, viz 10, leading to the macrocycle (5E,9E)-13-isopropenyl-2,6,10-trimethylcyclotetradeca-5,9-diene-2,4-dione (9), followed by acid-catalysed furan ring formation from the resulting 1,4-dione system in 9 (Scheme 1)

The chemical defenses of the Brazilian gorgonian octocoral Lophogorgia violacea Pallas have been investigated using feeding preference experiments performed in situ with an ecologically relevant, natural assemblage of predatory fishes. Feeding experiments incorporating the crude extract of the animal into palatable foods showed that the organic constituents of L. violacea provide a powerful chemical deterrence toward consumption by generalist fish carnivores. Bioassay-guided fractionation of the extract and evaluation of the fractions and purified compounds obtained in the same in situ assay revealed that a complex mixture of furanocembranolides was responsible for the overall feeding deterrence observed. The most potent feeding deterrent identified was lophotoxin (1), followed by two previously reported and structurally related compounds, deoxylophotoxin (2), and 13-acetoxy-11beta,12beta-epoxypukalide (3), as well as two new furanocembranolides: 7-acetoxy-8-hydroxylophotoxin (4) and 3-methoxy-8-hydroxylophotoxin (5). Lophotoxin (1), a neurotoxin originally isolated from the Pacific gorgonian L. rigida, was the most potent feeding deterrent among the furanocembranolides isolated. However, the four other related furanocembranolides (2-5) appear to contribute, in an additive manner, to the overall deterrent effects observed. These results add to earlier studies providing further evidence that compounds of this structural class provide effective chemical defenses against fish predators in both temperate and tropical environments. O mecanismo de defesa contra predadores no octocoral brasileiro Lophogorgia violacea foi investigado através de ensaios de preferência alimentar em campo frente a predadores. Os ensaios de palatabilidade com o extrato bruto da gorgônia demonstraram que seus metabólitos secundários possuem atividade deterrente significativa frente a peixes generalistas. O fracionamento do extrato bruto, guiado pelos ensaios em campo, revelou que uma mistura complexa de furanocembranolídeos é a responsável pela defesa química de L. violacea. O diterpeno lophotoxina (1) foi a principal substância isolada, seguida por outras duas similares, deoxilophotoxina (2) e 13-acetoxi-11beta,12beta-epoxipukalídeo (3), além de dois furanocembranolídeos inéditos na literatura, 7-acetoxi-8-hidroxilophotoxina (4) e 3-metoxi-8-hidroxilophotoxina (5). A lophotoxina (1), uma importante neurotoxina, originalmente isolada de L. rigida do Pacífico, demonstrou ser a mais potente dentre as substâncias fagoinibidoras presentes no extrato bruto. Por outro lado, os outros quatro furanocembranolídeos isolados também parecem contribuir, de maneira aditiva, para a atividade total observada. Estes resultados corroboram estudos prévios, confirmando que furanocembranolídeos são uma classe de substâncias de defesa frente ao consumo por peixes em ambientes tropicais e temperados.

Many coelenterate species produce toxins in order to capture prey or for defence. Most of them are polypeptides and proteins excepting palytoxin, lophotoxin and a few physiologically less active organic compounds e.g. tetramine,serotonin and histamine. Coelenterates also contain other biologically active compounds e.g. prostaglandins with hormonecembrene derivates with antitumor activities and proteinase inhibitors.The present state of knowledge on the most important biologically active compounds from coelenterates is reviewed and a new method for the isolation of the caribbean palytoxin (C-PTX) is described.

Three new diketone cembrenolides have been isolated from the Pacific sea whip Lophogorgia alba. The structure of lophodione (1) was assigned by X-ray crystallography, and isolophodione (2) and epoxylophodione (3) have been assigned based upon interconversion with (1) and by proton difference decoupling and nOe experiments. The previously reported neurotoxin, lophotoxin (4) was also isolated from L. alba. Since L. alba does not contain the endo-symbiotic algae (zooxanthellae), which are well-known in the Caribbean and Indo-Pacific corals, compounds 1–4 would appear to be of animal origin.

Pd(0)-catalysed coupling between various furyl zinc or tin compounds and vinyl iodides is demonstrated to be a versatile method for the synthesis of 2,3-dialkyl-5-alkenylfurans like 3, as potential precursors of the ring system of lophotoxin and pukalide. A possible cyclisation substrate was successfully prepared by glycol cleavage, 21 → 24, when alcohol oxidation failed.

The effects of a structurally novel paralytic substance (lophotoxin) on quantal transmission parameters and the time course of synaptic potentials have been examined. This substance completely abolished potentials by reducing quantal size without affecting the release of quanta. Nerve conduction, membrane potential, and the passive electrical properties of the muscle end-plate remained unaffected. Lophotoxin appears to act directly on the acetylcholine receptor-channel complex, although perhaps not the cholinoreceptive site itself, as suggested by the unusual chemistry and onset kinetics of this toxin.

An hypothesis based on molecular modeling is presented concerning the molecular mode of interaction between two newly described curare-like agents — lophotoxin and conotoxin GI — and the acetylcholine receptor at the neuromuscular junction. An experiment critically to test the hypothesis is described.

A furanocembranolide, 11 beta, 12 beta-epoxypukalide (1), C21H24O7, was isolated in trace quantities from the gorgonian Leptogorgia setacea. The structure was determined from detailed 1H-nmr and 13C-nmr analyses and comparison of these spectral data with those of the closely related compounds pukalide (2) and lophotoxin (3). The ultimate origin of 1 is discussed briefly.

A new neuromuscular toxin, lophotoxin, has been isolated from several pacific gorgonians of the genus Lophogorgia. The structure of lophotoxin was deduced by combined spectrochemical methods, and belongs to the well-known cembrene class of diterpenoid molecules. Lophotoxin contains furanoaldehyde and alpha, beta-epoxy-gamma-lactone functional groups, in sharp contrast to the cationic ammonium functional groups of the established neurotoxins.

Pd(0)-Catalyzed coupling of furyl zinc or tin compounds and vinyl iodides is found to be a versatile method for the preparation of 2,3-dialkyl-5-alkenylfurans (cf.

The soft coral Sinularia polydactyla has yielded six highly functionalized diterpenes. The known diterpenes pukalide (2) and 1-epithunbergol (3) were readily identified by spectral comparison with authentic samples. The new natural products 13 α-acetoxy-11β, 12β-epoxypukalide (4),13 α-acetoxypukalide (5) and its allylically rearranged isomer (6) were identified on the basis of 2D-n.m.r. experiments at 300 MHz and by spectral comparison with the known compounds pukalide (21, lophotoxin (8) and epoxypukalide (9). A minor, relatively unstable metabolite (7) is tentatively identified as a 3,4:5,6-bisepoxy derivative of (6). The biological implications of these findings are discussed.