Metabolites with a Novel C30 Backbone from Marine Ciliates

Guella, Graziano; Dini, Fernando; Pietra, Francesco

doi:10.1002/(sici)1521-3773(19990419)38:8<1134::aid-anie1134>3.0.co;2-u

Cited by 57 publications

(71 citation statements)

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“…Structure 3a was originally assigned to this natural product 40,41 . As is often the case in contemporary natural product isolation and structure determination campaigns, the quantity of sufficiently pure material for structural analysis was limited.…”

Section: Box 1 | Two Case Studies: Hexacyclinol (Constitution) and Vamentioning

confidence: 51%

A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts

2014

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this protocol is intended to provide chemists who discover or make new organic compounds with a valuable tool for validating the structural assignments of those new chemical entities. experimental 1 H and/or 13 c nMr spectral data and its proper interpretation for the compound of interest is required as a starting point. the approach involves the following steps: (i) using molecular mechanics calculations (with, e.g., MacroModel) to generate a library of conformers; (ii) using density functional theory (DFt) calculations (with, e.g., Gaussian 09) to determine optimal geometry, free energies and chemical shifts for each conformer; (iii) determining Boltzmann-weighted proton and carbon chemical shifts; and (iv) comparing the computed chemical shifts for two or more candidate structures with experimental data to determine the best fit. For a typical structure assignment of a small organic molecule (e.g., fewer than ~10 non-H atoms or up to ~180 a.m.u. and ~20 conformers), this protocol can be completed in ~2 h of active effort over a 2-d period; for more complex molecules (e.g., fewer than ~30 non-H atoms or up to ~500 a.m.u. and ~50 conformers), the protocol requires ~3-6 h of active effort over a 2-week period. to demonstrate the method, we have chosen the analysis of the cis-versus the trans-diastereoisomers of 3-methylcyclohexanol (1-cis versus 1-trans). the protocol is written in a manner that makes the computation of chemical shifts tractable for chemists who may otherwise have only rudimentary computational experience. this method certainly has value, the example described next shows that when one moves to the consideration of molecules bearing more than one stereocenter, this approach is no longer adequate.Consider the case of the trans-versus the cis-diastereomers of 3-methylcyclohexanol (1-trans and 1-cis, respectively). The experimental 1 H NMR spectra for 1-trans and 1-cis are shown in Figure 1a,b (see Supplementary Data 1 for a full listing of actual chemical shift values). There are substantial differences in these two spectra, especially within the upfield 0.7-2.1 p.p.m. range. Clearly, it would be valuable if computational approaches could reproduce these sorts of differences sufficiently well to allow confident assignment of structure.Common software packages that use empirical (often increment-based) compilations of chemical shift information (e.g., tabulated shift increments or databases of known spectral data) allow users to predict the chemical shifts of a given input structure. These include 'ChemNMR' within ChemBioDraw (also known as ChemDraw) and 'C+H NMR Predictor and DB' within the ACD/Labs software suite. These methods sometimes can be sufficient for the task of resolving constitutional structural assignments. However, when issues associated with relative configuration are considered, increment-based methods are decidedly ill-equipped. Analysis of structures 1-trans and 1-cis by each of these programs quickly reveals these limitations, even for these simple structures. Namely, because Che...

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Section: Box 1 | Two Case Studies: Hexacyclinol (Constitution) and Vamentioning

confidence: 51%

A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts

2014

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“…Considering that naturally produced terpenes and terpenoids, particularly those from plants (5,6), demonstrated a certain antileishmanial activity and a moderate cytotoxic activity against mammalian cells, the effect observed with EC could be linked to the structure of this metabolite. Since other terpenes were obtained (20,21,22) from other species of Euplotes (Euplotes raikovi, Euplotes rariseta, and Euplotes focardii), and other compounds were obtained from E. vannus (23), it would be interesting to analyze the effects of these different molecules on microorganisms, and in particular on leishmaniae.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial Activity of Euplotin C, the Sesquiterpene Taxonomic Marker from the Marine Ciliate Euplotes crassus

Savoia

Avanzini

Allice

et al. 2004

Antimicrob Agents Chemother

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Strains of the marine ciliate protist Euplotes crassus produce exclusive terpenoids called euplotins that play an ecological role. Among these derivatives, euplotin C is the main of four secondary metabolites isolated from cultures of this protozoon and represents the sesquiterpene taxonomic marker from E. crassus. Because different terpenoid metabolites of plant origin showed a certain antimicrobial activity, we assessed the compound euplotin C, purified by high-pressure liquid chromatography and solubilized in two solubility enhancers, against the protozoa Leishmania major and Leishmani infantum, the fungus Candida albicans, and nine strains of gram-positive and gram-negative microorganisms. An activity of euplotin C against Leishmania promastigotes was demonstrated (50% lethal doses were 4.6 or 8.1 g/ml depending on the agent used to solubilize the compound), while the effect was less evident on Candida and nearly absent on bacteria. A nonsignificant cytotoxicity (50% lethal dose, >200 g/ml) against the J774 cell line was observed. A leishmanicidal activity was also shown by the living, euplotin-producing cells of E. crassus cultured together with promastigotes; this activity increased with time from 10 min to 6 h of incubation. This study provides an initial rationale for the evaluation of euplotin C and other similar natural products as alternative or possibly synergistic compounds for current antiprotozoon chemotherapeutics.In recent years, several reports have been published on the scientifically confirmed antimicrobial activity of some natural products derived from plants (1,8,13,14,30,34,38,39) or of bioactive metabolites of microbial origin (26,32,33,35,40). Natural products showing effective action of pharmaceutical and medical relevance have also been recovered from marine organisms. Some bioactive antiviral, antitumor, antimicrobial, or generally cytotoxic compounds have been extracted from species of starfish and sponges. For example, extracts from the starfish Asterina pectifera are active against Aspergillus spp. and Cryptococcus neoformans (7), while various sponges exhibit antibacterial properties which are due to the presence of a metabolic product or to host microorganisms (12,25).Recently, four sesquiterpenes-euplotin A, euplotin B, euplotin C (EC), and their biogenetic precursor preuplotinhave been isolated from Euplotes crassus, a eukaryotic unicellular marine ciliate (16,19). All strains of this ciliate morphospecies (taxonomically described by microscopic, outwardly identifying features) produce the same compounds. Notably, euplotins, and in particular EC, are biosynthesized in relative large amounts, suggesting an important ecological role of this substance in the adaptive strategy of the organism. A similar terpenoid (udoteatrial hydrate) was isolated from Udotea flabellum (36), a tropical seaweed belonging to the phylum Chlorophyta that contributes to the structure of coral reefs. Indeed, it has been suggested that strong similarities in anthozoan metabolite biosynthesis reveal the ev...

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Section: Introductionmentioning

confidence: 99%

“…Their structures have been assigned on the basis of mass spectrometric and NMR spectroscopic data and chemical transformations. [1,2] Herein we report the total synthesis of structure 1b that proved that it does not represent the true structure of vannusal B.Our retrosynthetic analysis of the vannusal molecule dissected it as shown in Figure 2, revealing vinyl iodide 2 and aldehyde 3 as the key building blocks required for the projected total synthesis. The devised strategy anticipated their fusion through two carbon-carbon bond forming reactions, namely lithiation of 2 followed by addition of 3 to join them, and a samarium-induced ring closure of a subsequent intermediate to forge the final ring of the target molecule.…”

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Total Synthesis of the Originally Assigned Structure of Vannusal B

et al. 2008

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Keywordsnatural products; vannusals A and B; samarium diiodide; ketyl-olefin cyclization Vannusals A (1a, Figure 1) and B (1b) are two marine natural products notable for their unusual molecular architectures. Isolated from the tropical interstitial ciliate Euplotes vannus strains Si121 and BUN3, these intriguing molecules include in their C30 molecular framework seven rings and thirteen stereogenic centers, three of which are quaternary. Their structures have been assigned on the basis of mass spectrometric and NMR spectroscopic data and chemical transformations. [1,2] Herein we report the total synthesis of structure 1b that proved that it does not represent the true structure of vannusal B.Our retrosynthetic analysis of the vannusal molecule dissected it as shown in Figure 2, revealing vinyl iodide 2 and aldehyde 3 as the key building blocks required for the projected total synthesis. The devised strategy anticipated their fusion through two carbon-carbon bond forming reactions, namely lithiation of 2 followed by addition of 3 to join them, and a samarium-induced ring closure of a subsequent intermediate to forge the final ring of the target molecule.Scheme 1 summarizes the construction of vinyl iodide 2 from the commercially available meso diol 4. Thus, dehydration of 4 through the action of POCl 3 (py, 90 °C) furnished conjugated diene 5 (97 % yield), [3] which was regio-and stereoselectively converted to the new meso diol 6 by a hydroboration-oxidation process (CyBH 2 ; H 2 O 2 , NaOH, 50 % yield). The latter compound was then desymmetrized through the enantioselective hydrolytic action of Lipase Amano PS[4] on its bis-acetate (prepared in quantitative yield by reaction of 6 with Ac 2 O in the presence of 4-DMAP), leading to the monoacetate 7 in 100 % yield and 99 % ee (determined by Mosher ester analysis). Silylation of 7 (TBDPSCl, imid., 98 % yield), followed by acetate cleavage (DIBAL-H, 98 % yield) and treatment of the resulting alcohol with Martin's sulfurane (Et 3 N, CH 2 Cl 2 , 91 % yield) afforded enantiomerically pure cyclopentene derivative 8. The planned stereoselective epoxidation of 8 was achieved through a two-step procedure that involved first iodohydrin formation (NIS, H 2 O), and then ring closure (K 2 CO 3 , MeOH) to give β-epoxide 9 in 90 % overall yield. This epoxide was then regio-and stereoselectively opened with 2-lithiopropene (generated from the corresponding bromide and tBuLi) in the presence of BF 3 •Et 2 O to afford hydroxy compound 10 (83 % yield), whose stereochemistry Figure 3) [7] of the crystalline p-bromophenyl carbamate 14 (m.p. 136-138 °C, EtOAc / hexanes) prepared from hydroxy compound 10 through reaction with pbromophenyl isocyanate, followed by TBAF-induced desilylation, in 80 % overall yield as shown in Scheme 1.Scheme 2 outlines the construction of building block 3 starting from intermediate 15 (racemic) [8] or 15a (enantiopure).[9] Thus, exposure of dihydroxy methyl ether 15 to Bbromocatecholborane, followed by selective monosilylation of the resulting triol (TIPS...

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Metabolites with a Novel C30 Backbone from Marine Ciliates

Abstract: Challenging questions are raised about the biosynthetic origin of vannusal A (1), a metabolite that is isolated from the tropical marine ciliate Euplotes vannus and contains an unusual C30 backbone.

Cited by 57 publications

References 5 publications

A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts

A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts

Antimicrobial Activity of Euplotin C, the Sesquiterpene Taxonomic Marker from the Marine Ciliate Euplotes crassus

Total Synthesis of the Originally Assigned Structure of Vannusal B

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