Antillatoxin

Antillatoxin is a 15-membered cycHc Hpodepsipeptide isolated from the marine cyanobacterium Lynghya majuscula [135], A strong ichthyotoxicity and neurotoxicity agent, its structure 63b was determined by nuclear magnetic resonance (NMR) spectral studies, and the absolute configurations at of NMeVal and Ala were deduced 

64 oxidation was subjected to anti-aldol reaction with the (f )-enolate generated from the propionate ester of mesitylenesuUbnyl (MesS02) norephedrine derivative. After protection of the secondary alcohol with TESOTf, the resulting anti-aldol adduct 

65 was converted to 66 with diisobutylaluminum hydride (DIBAL-H). The primary alcohol 66 was oxidized and subjected to Still-Horner-Wadsworth-Emmons olefination to render 67. Further, acid-catalyzed lactonization followed by introduction of phenylselenomethyl group gave 69. Compound 71 was isolated in next three steps saponification, allylation of carboxylic acid, and condensation with the tripeptide 70. Subsequent oxidative deselenylation, global deprotection, and cyclization gave (4R,5R)-antillatoxin 63a, which was found to be identical to the natural antillatoxin. 

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Indium-mediated allylation of an unreactive halide with an aldehyde132 was used to synthesize an advanced intermediate in the synthesis of antillatoxin,133 a marine cyanobacteria (Lyngbya majus-cula) that is one of the most ichthyotoxic compounds isolated from a marine plant to date. In the presence of a lanthanide triflate, the indium-mediated allylation of Z-2-bromocrotyl chloride and aldehyde in saturated NH4C1 under sonication yielded the desired advanced intermediate as a 1 1 mixture of diastereomers in 70% yield. Loh et al.134 then changed the halide compound to methyl (Z)-2-(bromomethyl)-2-butenoate and coupled it with aldehyde under the same conditions to yield the desired homoallylic alcohol in 80% yield with a high 93 7 syn anti selectivity (Eq. 8.55). 

Fig. 10.7. DPFGSE NOE of H5 of antillatoxin (3) showing good selection and clean NOE enhancements.

Pept barbamide and (lipopept.l microcolins and antillatoxin (Lyngbya majvscula Oomont, Cyanobact. Yokokawa 2000) salinamides (depsipept. from Streptomyces sp. Actinom., Bact. from jellyfish Cassiopeia xamachana from Florida keys Trischman 1994A). 

Yokokawa, F. Fujiwara, H. Shioiri, T. (2000) Total synthesis and revision of absolute staeochemistry of antillatoxin. Tetrahedron, 56, 1759-75. 

Subsequently, shallow water collections of Lyngbya majuscula from Puerto Rico and the Dry Tortugas yielded additional supplies of ATX as well as a new congener termed antillatoxin B (Figure 6.10) [149]. The structure of the new metabolite was determined largely by comparison with the spectroscopic data set for ATX, and stereochemistry deduced by Marfey s analysis for L-alanine while the i-N-methyl homophenylalanine was proposed based on nuclear Overhauser effect (nOe) and bioassay results. Substitution of i-N-methyl homo-phenylalanine, an intriguing amino acid of quite rare occurrence in natural products, for i-N-methyl valine... 

Fig. 6.10 Structures of natural antillatoxin, three synthetic C-4 and C-5 stereoisomers, and antillatoxin B.

The simultaneous deprotection of both an allyl ester and an Aloe group is a popular tactic for liberating an amino and carboxyl function prior to formation of a lactam ring. The strategy is exemplified in Scheme 8.83 en route to a derivative of the ichthyotoxic cyclic lipopeptide Antillatoxin.196... 

Bioactivity-guided fractionation of organic extracts from two Lyngbya majuscula collections led to the isolation of a new secondary metabolite, antillatoxin B 356, an unusual A -methyl homophenyl-alanine analogue of the potent neurotoxin antillatoxin 357. Compound 356 exhibited significant sodium channel-activating (ECso = 1-77 pM) and ichthyotoxic (LCso = 1 pM) properties. 

Antillatoxin (Fig.50), discovered by Orjala et al. in 1995, is produced by the pantropical marine cyanobacterium Lyngbya majuscula. Blooms of L. majuscula have been associated with adverse effects on human health, including respiratory irritation, eye inflammation, and severe contact dermatitis in exposed individuals. Antillatoxin has been reported to be among the most ichthyotoxic metabolites isolated to date from marine microalgae and is exceeded in potency only by the brevetoxins l... 

Orjala, J., Nagle, D. G., Hsu,V., Gerwick, W. H., Antillatoxin An Exceptionally Ichthyotoxic Cyclic Lipopeptide from the Tropical Cyanobacterium Lyngbya majuscule, J. Am. Chem. Soc. 1995, 117, 8281-8282. 

Total synthesis of antillatoxin, an ichthyotoxic cyclic lipopeptide from marine cyanobacterium Lyngbya majuscula 00YGK634. 

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