Metabolite Ascidians

In an approach towards a total synthesis of the marine ascidian metabolite pero-phoramidine (6/1-96) [55], Weinreb and coworkers developed a domino Heck/car-bonylation process [56]. This allowed construction of the C,E,F-ring system of 6/1-96, together with the C-20 quaternary center and the introduction of a functionality at C-4 (Scheme 6/1.25). Thus, reaction of 6/1-97 in the presence of catalytic amounts of Pd(OAc)2 and P(oTol)3 under a CO atmosphere in DMA/MeOH led to 6/1-98 in 77% yield. 

Unlike carbazoles, haiogenated (3-carbolines are abundant in nature [1[. For example, the simple eudistomin O (7-bromo-(3-carboline) (40) is a ubiquitous marine ascidian metabolite [44[. Indeed, the tunicate genus Eudistoma has furnished most of the extant haiogenated (3-carbolines, some of which have significant antiviral (polio, herpes) and microbial activity. The Caribbean Eudistoma olivaceum produces at least 15 brominated carbolines [1[. A study of Eudistoma gilboverde uncovered the new eudistomins 41-43[45[, and the Australian ascidian Pseudodistoma aureum has... 

III trials in Europe) [70]. The biomedical potential of the ascidian metabolites has resulted in these primitive chordates. As part of our ongoing chemical and biological studies on Okinawan marine organisms, we investigated an ascidian Lissoclinum sp. collected off the coast of Hateruma Island. A lipophilic extract of the ascidian showed that it could inhibit the division of fertilized sea urchin eggs. 

The marine ascidian metabolite purine aplidiamine-9- 3-D-ribofuranoside was prepared by T. Itaya et al. by alkylation of 8-oxoadenosine with 4-benzyloxy-3,5-dibromobenzyl bromide followed by a Dimroth rearrangement and acid hydrolysis. The rearrangement was induced by treating the nucleoside in boiling IN NaOH for 1h. The desired rearranged nucleoside was formed in 58% overall yield. 

Much interest and research over the past 15 or so years has been directed towards ascidian metabolites because of the high incidence of pharmacological activity that they display. Few comprehensive reviews exist on the topic the only general ones being those produced by Davidson in 1993 [1,2] and the Marine Natural Product literature reviews by Faulkner which always contain a section on tunicate metabolites [3-13]. Although a number of non-nitrogenous metabolites have been isolated from the tunicates, the majority of compoimds isolated have been derived from amino acids. In particular, the two most commonly encountered classes are cyclic peptides and polycyclic aromatic alkaloids. 

Artman, G.D. Ill and Weinreb, S.M. (2003) An approach to the total s3mthesis of the marine ascidian metabolite perophoramidine via a halogen-selective tandem Heck/carbonylation strategy. Org. Lett., 5, 1523-6. 

Weinreb and colleagues reported the total synthesis of marine ascidian metabolite perphoramidine via a halogen-selective tandem Heck/carbonylation strategy [111]. 

Evans, M.A., Sacher, J.R., and Weinreb, S.M. (2009) Exploratory studies toward a total synthesis of the marine ascidian metabolite perophoramidine. Tetrahedron. 65, 6712-6719. 

Benzopentathiepins are stable solids. Varacin, a cytotoxic metabolite, was isolated from a marine ascidian.398 The parent benzopentathiepin exhibits infrared absorptions at 1620, 1570, 1235 and 1020 cm" 1.399 X-ray structure analyses of benzopentathiepin and 6-methylbenzopen-talhicpin show that the seven-membered ring in both compounds is nonplanar and that it adopts a chair conformation. The S-S bond lengths are in the range 204-206 pm.400... 

Little work has been reported on the biosynthesis of oxylipins in ascidians. One report describes the production of numerous oxidized AA metabolites by eggs... 

Like the South Pacific, the South Atlantic also scarcely contributed to the diversity of natural products. Pregnane steroids from ascidians of the Argentine coast are the most unusual metabolites. 

The list of natural product similarities from land and the sea is immense, with metabolites of all chemical classes. On land these mostly derive from bacteria, cyanobacteria, plants, fiingi, insects, amphibians, and mammals in the sea, besides bacteria and cyanobacteria, the sponges, cnidarians, bryozoans, moUusks, ascidians, and sharks produce most. The ascidians are exclusively marine, and the sponges, cnidarians, and bryozoans are productive only in the sea. Dietary metabolites are also... 

The relative contribution to the cup of natural products by marine and terrestrial organisms is outlined in Table 9.1. Column entries are the phylum, class or order, number of species, biogenetic class of metabolites produced, their bioactivity level, and a qualitative indication as to the average molecular complexity (Whitlock 1998). The latter property receives closer attention in Table 9.II for specific molecular skeletons. These data warrant several conclusions. First, unusual secondary metabolites on land derive mostly fi-om green plants and arthropods, while in the sea are the algae, sponges, cnidarians, bryozoans, and ascidians that give most. This is true no matter if the molecular skeleton, or the actual metabolite, or even the bioactivity, is examined. 

Antifeedant/fish various dietary metabolites Paul 1992 marine dietary metabolites from spmges, cnidarians, bryozoans, and ascidians in carnivorous Q)isthobr., Moll. 

However, pyrroloquinolines and pyridoacridines are the alkaloids of major interest as metabolites in sponges and ascidians [227], Many of these compounds have generated interest both as challenging problems for structure elucidation and synthesis as well as for their cytotoxicities [228-230],... 

Aminoacids occur in plants and animals, both in the free state and as the basic units of proteins and other metabolites. Aminoacid derivatives have been reported in marine environment, such as from marine sponges of the genus Jaspis sp. [371,372], from Suberea creba, a Coral Sea marine sponge [373], and the marine ascidian Leptoclinides dubius [374], Some of these compounds have been shown to possess interesting biological properties, e g., cytostatic activity exhibited by axinastatin-4, an aminoacid derivative isolated from a marine sponge [375],... 

Ecological studies indicate that the Australian sponge Stylotella aurantium inhibits the settlement of ascidian larvae. A dichloroimine metabolite, stylotellane B (132), was isolated which displayed weak P-388 activity [105],... 

The ascidian Lissoclinum japonicum from Palau contained the antimicrobial and antifungal metabolites N,N-dimethyl-5-(methylthio)varacin and 3,4-dimethoxy-6-(2 -iV,./V-dimethylaminoethyl)-5-(methylthio)benzotrithiane, both of which were isolated as the trifluoroacetate salts <1994T12785>. They selectively inhibit protein kinase. Also, varacin and three new antimicrobial marine polysulfides, varacins A-C, were isolated from the Far Eastern ascidian Polycitor sp. <1995JNP254>, extracted from the New Zealand ascidian Lissoclinum notti <2002T9779>. 

Smith CJ, Hettich RL, Jompa J, Tahir A, Buchanan MV, Ireland CM (1998) Cadiolides A and B, New Metabolites from an Ascidian of the Genus Botryllus. J Org Chem 63 4147... 

Makarieva TN, Dmitrenok AS, Dmitrenok PS, Grebnev BB, Stonik VA (2001) Pibocin B, the First A -O-Methylindole Marine Alkaloid, a Metabolite from the Far-Eastern Ascidian Eudistoma Species. J Nat Prod 64 1559... 

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