Marine natural products

Contents

• 1 Introduction

• 2 Marine microorganisms and phytoplankton

• 3 Green algae

• 4 Brown Algae

• 5 Red algae

• 6 Sponges

• 7 Coelenterates

• 8 Bryozoans

• 9 Molluscs

• 10 Tunicates (ascidians)

• 11 Echinoderms

• 12 Miscellaneous

• References

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Abstract

Covering: 1999. Previous review: 2000, 17, 7.

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D. John Faulkner

D. John Faulkner, born in England in 1942, received his BSc and PhD degrees from Imperial College, London, where he studied synthetic organic chemistry under the guidance of Sir Derek Barton. He received postdoctoral training from R. B. Woodward at Harvard University and W. S. Johnson at Stanford University before joining the faculty of the Scripps Institution of Oceanography, University of California at San Diego, in 1968. Recognizing the need to ‘do something more marine’, he began a new career in marine natural products chemistry. He is currently Professor of Marine Chemistry

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1 Introduction

This report is a review of the marine natural products literature for 1999. Earlier reports published in this journal cover the period from 1977 to December 1998. In comparison with 1998,¹ the last year was relatively quiet although steady progress was reported on most fronts. Once again, sponges were the favourite organisms for natural product studies, with tunicates and coelenterates following close behind. The accelerating advances in marine biotechnology have made their mark on marine natural products chemistry in the form of a steady increase in papers emphasizing marine microorganisms and symbiotic relationships involving marine microbes.² Studies of the biosynthesis of marine natural products, which also bear the mark of the latest genetic techniques, are reviewed elsewhere in this journal.³ Marine natural products continue to be prime targets for synthesis although papers reporting partial and formal syntheses, which are not included in this review, far outnumber the more useful papers that record total syntheses and, in particular, synthetic studies that redefine the structures of marine natural products. This report continues to emphasize the bioactivity of new marine natural products while specifically excluding biochemical and pharmacological studies of known marine natural products. The patent literature, which is not covered in detail in this report, was the subject of a review entitled “Marine natural products as therapeutic agents”.⁴ The format for this review is identical to its predecessor.

A number of reviews of specific topics appeared during 1999. An excellent review of “Marine opisthobranch molluscs: Chemistry and ecology in sacoglossans and dorids” ⁵ covered the period 1988–1998 while the mini review “Chemical defence and evolutionary trends in biosynthetic capacity among dorid nudibranchs (Mollusca: Gastropoda: Opisthobranchia)” ⁶ explores the complex relationships between taxonomy and natural products chemistry. Different families of marine natural products are highlighted in “Pyrroloquinoline and pyridoacridine alkaloids from marine sources”,⁷ “The dolastatins, a family of promising antineoplastic agents”,⁸ “Biogenesis and biological function of marine algal oxylipins” ⁹ and “Total synthesis and chemical biology of the sarcodictyins”.¹⁰ Topics of more general interest include “Toxins from sea cucumbers (Holothuroids): chemical structures, properties, taxonomic distribution, biosynthesis and evolution”,¹¹ “Emerging harmful algal blooms and human health: Pfiesteria and related organisms”,¹² “Steroids from sponges: Recent reports”,¹³ and “Discovery and development of antineoplastic agents from natural sources”.¹⁴ Broader-based reviews that include many marine natural products include “The diversity of naturally occurring organobromine compounds” ¹⁵ and “Peroxy natural products”.¹⁶ Three reviews that are intended for general audiences are “Testing the water”,¹⁷ “Products of chemistry – Exploring the ocean – Stating the case for chemistry” ¹⁸ and “Chemistry of marine natural products: yesterday, today and tomorrow”.¹⁹ Forty-two articles on various aspects of marine biotechnology, some of which review aspects of marine natural products chemistry, were featured in a special issue of the Journal of Biotechnology.²⁰

2 Marine microorganisms and phytoplankton

Marine microorganisms continue to be the subject of vigorous chemical investigation although studies of marine bacteria may be decreasing in comparison with those of other microorganisms. A mixture of four monoacyldiglycosyl-monoacylglycerols 1–4 were obtained from Flavobacterium marinotypicum (ATCC 19260) but the positions of the different ester groups were not well defined.²¹ Flavocristamides A 5 and B 6, which are sulfonolipids from a Chryseobacterium (= Flavobacterium) sp.,²² have been synthesized from L-cysteine.²³ Two lysophosphatidyl inositols 7 and 8 were obtained as antifungal agents from a Streptomyces sp. (strain # M428) isolated from a marine sediment.²⁴ A phosphatidyl glyceride 9 and four quinolone derivatives 10–13 were isolated from a Pseudomonas sp. cultured from the sponge Homophymia sp. from New Caledonia.²⁵ Arenaric acid 14 is a pentacyclic polyether, isolated as its sodium salt from an unidentified marine Streptomyces sp. (isolate # CNH-248) from a San Diego estuarine sediment sample.²⁶ The antiinflammatory macrolides lobophorins A 15 and B 16 were obtained from cultures of a tropical marine actinomycete (strain # CNB-837) that was isolated from the surface of the brown alga Lobophora variegata from Belize.²⁷ Two aromatic tetraols, luisols A 17 and B 18, were produced by an unidentified Streptomyces sp. (isolate # CHN-370) cultured from a sediment sample from an estuary near San Diego.²⁸ The cytotoxic thiazole alkaloid agrochelin 19, which was obtained from a marine Agrobacterium sp., formed a complex with Zn²⁺ ions.^29,30 Cultures of an unidentified marine bacterium MK-PNG-276A obtained from the reefs off Loloata Island, Papua New Guinea, have yielded a series of cyclic decapeptide antibiotics, loloatins A–D 20–23, that inhibit methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and drug-resistant Streptococcus pneumoniae.³¹ Salinamides A–E 24–28 are minor antiinflammatory bicyclic depsipeptides from a marine Streptomyces sp. (isolate # CNB-091) isolated from the surface of the jellyfish Cassiopeia xamachana from the Florida Keys.³² The absolute configurations of the previously-reported ³³ salinamides A 24 and B 25 have been revised using chiral capillary electrophoresis of the derivatized hydrolysates. The prenylated cyclic peptides, cyclomarins A–C 29–31 were isolated as cytotoxins from an unidentified Streptomyces sp. (isolate # CNB-982) from a Mission Bay, San Diego, sediment sample but cyclomarin A 30 was later found to possess significant antiinflammatory activity.³⁴ Holyrines A 32 and B 33 are possible intermediates in staurosporine biosynthesis from an actinomycete (strain # N96C-47) from a sediment core sample from Newfoundland.³⁵ The absolute stereochemistry of korormicin 34, which is an antibiotic from a Pseudomonas sp. F-420,³⁶ has been determined by total synthesis.³⁷

Studies of marine fungi appear to be expanding at a much faster rate than those of other unicellular organisms. Roselipins 1A 35, 1B 36, 2A 37 and 2B 38, from the marine fungus Gliocladium roseum KF-1040, are highly methylated glycolipids, possibly polypropionates, that inhibit the enzyme diacylglycerol acyl transferase (DGAT).^38–40 The absolute stereochemistries of penostatins A–E 39–43, earlier reported from a Penicillium sp. isolated from the alga Enteromorpha intestinalis,⁴¹ have been determined using the modified Mosher’s method and CD measurements.⁴² A marine Penicillium sp. (isolate # 386) from the South China Sea contained the pyranolactone 44.⁴³ A Coniothyrium sp. isolated from the sponge Ectyoplasia ferox contained (3S )-(3,5-dihydroxyphenyl)butan-2-one 45 and 2-(1(E )-propenyl)-octa-4(E ),6(Z )-diene-1,2-diol 46 while a Microsphaeropsis sp. isolated from the sponge Myxilla incrustans produced microsphaeropsin 47.⁴⁴ The absolute stereochemistries of trichodenones A–C 48–50, which are metabolites of Trichoderma harzianum (OUPS-N115) from the sponge Halichondria okadai,⁴⁵ have been determined by total synthesis.⁴⁶ A marine derived strain of Emericella unguis, obtained from both a mollusc and a medusa, produced the chlorinated depside guisinol 51, which exhibited mild antibacterial activity.⁴⁷ Five DNA cleaving antitumour antibiotics, spiroxins A–E 52–56, were obtained from a marine fungal strain LL-37H248 that had been isolated from an orange soft coral from Vancouver Island.⁴⁸ An unidentified fungus cultured from the Okinawan red alga Ceratodictyon spongiosum produced seragakinone A 57, which possessed mild antimicrobial activity.⁴⁹ The Callyspongia vaginalis derived fungus Ulocladium botrytis produced the tyrosine kinase (p56^lck) inhibitor ulocladol 58 and the known antifungal agent 1-hydroxy-6-methyl-8-(hydroxymethyl)xanthone.⁵⁰ The culture medium of Asteromyces cruciatus contained (+)-2,4-dimethyl-4,5-dihydrofuran-3-carboxaldehyde 59, while Varicosporina ramulosa produced two new macrodiolides, (6R,11S,12S,14R)-colletodiol 60 and (6R,11R,12R,14R)-colletodiol 61.⁵⁰ The structure of colletoketol 62, which is a metabolite of the same obligate marine mitosporic fungus Varicosporina ramulosa, obtained from an unidentified alga of the genus Cystoseira from Tenerife, Spain, was determined by X-ray crystallography.⁵¹

A Penicillium sp. (strain # CNC-350) from the surface of the Caribbean green alga Avrainvillea longicaulis produced two diketopiperazine dimers, 11,11′-dideoxyverticillin A 63 and 11′-deoxyverticillin A 64, both of which exhibited potent in vitro cytotoxicity against the HCT-116 cell line.⁵² A full account of the synthesis of tryprostatin B 65, which is a metabolite of Aspergillus fumigatus (strain # BM939),⁵³ has been presented.⁵⁴ The cyclic pentadepsipeptide sansalvamide 66 was produced by a Fusarium sp. (isolate # CNL-292) collected from the surface of the seagrass Halodule wrightii from Little San Salvador Island, Bahamas.⁵⁵ Sansalvamide 66 was initially reported as having selective cytotoxicity against the COLO 205 and SK-MEL-2 cell lines but was later shown to inhibit molluscum contagiosum virus (MCV) topoisomerase.⁵⁶ Unguisins A 67 and B 68 are GABA-containing cyclic heptapeptides from the same culture of Emericella unguis described above.⁵⁷ The fermentation broth of the facultative marine fungus Hypoxylon croceum, which was isolated from driftwood in a mangrove estuary in the Everglades, Florida, produced hypoxysordarin 69, which is a potent antifungal metabolite, and hypoxylactone 70.⁵⁸ Nine compounds were isolated from the marine fungus Hypoxylon sp. but some of these appear to be possible contaminants.⁵⁹ The rearranged sterol dankasterone 71, which exhibits significant cytotoxicity, was obtained from a Gymnascella dankaliensis (strain # OUPS-N134) isolated from the sponge Halichondria japonica.⁶⁰ Ergosteryl myristate 72 was isolated from an unidentified fungus cultured from the alga Sargassum thunbergii from Korea.⁶¹ Dendryphiellin C 73, which is a trinor-sesquiterpene from the deuteromycete Dendryphiella salina,⁶² has been synthesized in a convergent manner.⁶³ The marine protist Thraustochytrium globosum, collected from the surface of the seagrass Thalassia testudinum in the Bahamas, contained the glycosphingolipids thraustochytrosides A–C 74–76.⁶⁴

Reports of metabolites from marine cyanobacteria were restricted to filamentous species. Lyngbya majuscula from the French Mediterranean coast yielded (−)-7-methoxydodec-4(E )-enoic acid 77, the structure of which was confirmed by synthesis.⁶⁵ Two serinol-derived malyngamides 78 and 79 were isolated from an unidentified estuarine cyanobacterium from the King George River in Northwestern Australia.⁶⁶ Tanikolide 80 is a toxic and antifungal lactone from a Madagascan collection of L. majuscula.⁶⁷ Two nitrogenous macrolides, madangolide 81 and laingolide A 82, a lower homolog of laingolide 83,⁶⁸ were isolated from L. bouillonii collected in Papua New Guinea.⁶⁹ The same specimen of L. bouillonii also contained the modified tetrapeptide lyngbyapeptin A 84, the stereochemistry of which was not determined.⁷⁰

A mixed assemblage of L. majuscula and Schizothrix calcicola from Tumon Bay, Guam, contained five acyl depsipeptides, tumonic acids A–C 85–87 and methyl tumonoates A 88 and B 89.⁷¹

The cytotoxic cyclic depsipeptides lyngbyastatin 2 90 and norlyngbyastatin 2 91, which are analogs of the sea hare cytotoxins dolastatin G 92 and nordolastatin G 93,⁷² were isolated from L. majuscula from Guam.⁷³ Symplostatin 2 94, which is somewhat similar in structure to dolastatin 13 95, a metabolite of the sea hare Dolabella auricularia,⁷⁴ was isolated from Symploca hydnoides from Guam.⁷⁵ The structure of antillatoxin, which is an ichthyotoxic metabolite of L. majuscula from Curacao,⁷⁶ has been revised from 96 to 97 as a result of total syntheses of both the reported and corrected structures.^77,78 The epilithic encrusting cyanobacterium Kyrtuthrix maculans from the shores of Hong Kong contained maculactone L 98 and three halogenated carbazoles 99–101, which had not been reported previously as natural products.⁷⁹ Hyellazole 102, which is a carbazole alkaloid from Hyella caespitosa,⁸⁰ has been synthesized using an organometallic approach.⁸¹

The cultured marine dinoflagellate Amphidinium sp., collected from the coast of NW Spain, contained a monogalactosyl triacylglycerol 103.⁸² Two very long, highly unsaturated fatty acids 104 and 105 were isolated from seven marine dinoflagellate species.⁸³ Amphidinolide U 106 is a 20-membered macrolide from a cultured Amphidinium sp. (Y-56) isolated from the flatworm Amphiscolops sp. from Okinawa.⁸⁴ A different strain of Amphidinium sp. (Y-5) produced colopsinols A–C 107–109, of which colopsinol A 107 inhibited DNA polymerases α and β and colopsinol C 109 exhibited cytotoxicity.^85,86 The absolute configuration of amphidinol 3 110, which is a metabolite of A. klebsii,⁸⁷ was determined by analysis of carbon–hydrogen spin-coupling constants.⁸⁸

Cultures of the toxin-producing dinoflagellate Prorocentrum hoffamnnianum contained the non-cytotoxic macrolide, hoffmanniolide 111.⁸⁹ The absolute configuration of gambierol 112, a toxic polyether from Gambierdiscus toxicus,⁹⁰ was determined by application of Mosher’s method.⁹¹ The structures and partial stereochemical assignments of prymnesins-1 113 and -2 114, which are hemolytic and icthyotoxic glycosides from Prymnesium parvum,⁹² have been determined.⁹³ The total synthesis of brevetoxin A 115 from the dinoflagellate Gymnodinium breve ⁹⁴ has been described in detail.⁹⁵ The structure of 7-deoxyokadaic acid 116, which is a potent serine/threonine-specific protein phosphatase inhibitor from Prorocentrum lima, has been confirmed by total synthesis.⁹⁶

Vannusals A 117 and B 118 were isolated from an Indonesian specimen of the ciliate Euplotes vannus.⁹⁷

3 Green algae

The green macro alga Ulvella lens contains a bromoperoxidase that produces dibromomethane and bromoform.⁹⁸ A survey of the metabolites of Ulva lactata led to the proposal that 4-hydroxybenzoic acid is the most likely biosynthetic precursor of 2,4,6-tribromophenol 119.⁹⁹ Kahalalide K 120 is an additional cyclic depsipeptide from a Hawaiian species of Bryopsis.¹⁰⁰ The structure of caulersin 121, a metabolite of Caulerpa serrulata,¹⁰¹ has been confirmed by total synthesis.¹⁰²

4 Brown Algae

The sulfonoglycolipid 122 from the Australian brown alga Dictyota ciliolata was active in the constitutive nitric oxide synthetase assay.¹⁰³Iyengaria stelleta from Pakistan was reported to contain a very interesting cyclopropyl ether but the spectral data do not support the proposed structure.¹⁰⁴ An additional synthesis of (6S,7S,9R,10R)-6,9-epoxynonadec-18-ene-7,10-diol 123, which is a metabolite of Notheia anomola,¹⁰⁵ has been accomplished using an oxiranyl anion strategy.¹⁰⁶ After peracetylation, forty-five phloroglucinol derivatives, including 2,4,6-triacetoxychlorobenzene 124, 2[D′]-iododiphlorethol pentaacetate 125, 3[A]-chlorobifuhalol hexaacetate 126, 3[A₄]-chlorodifucol hexaacetate 127, and larger compounds such as trihydroxyheptaphlorethol-A octadecaacetate 128 were isolated from Carpophyllum angustifolium from New Zealand.^107,108 An additional three phlorethols, ten fucophlorethols, ten halogenated phlorethols, exemplified by 129, and two chlorinated fucophlorethols were isolated as their peracetates from Cystophora retroflexa.^109,110 An unusual eleven-membered heterocyclic metabolite 130 was isolated from Sargassum vachellianum ¹¹¹ from the South China Sea.¹¹² A specimen of Spatoglossum variabile from Karachi, Pakistan contained spatazoate 131.¹¹³ Stypoquinonic acid 132 is a tyrosine kinase inhibitor from Stypopodium zonale from the Canary Islands.¹¹⁴ Methoxybifurcarenone 133 is an antifungal and antibacterial meroditerpenoid from a Moroccan specimen of Cystoseira tamariscifolia.¹¹⁵ (−)-Sporochnol A 134, which is the enantiomer of a fish feeding deterrent from Sporochnus bolleanus,¹¹⁶ has been synthesized using an enantiospecific route from (R)-(+)-malonic acid benzyl ester.¹¹⁷

Three additional diterpenes 135, 136, isolated as their corresponding acetates, and 137 were obtained from specimens of Bifurcaria bifurcata from two locations in Brittany.¹¹⁸ An enantioselective synthesis of the cytotoxic diterpenoid (−)-bifurcadiol 138, obtained from Bifurcaria bifurcata,¹¹⁹ has been reported.¹²⁰ A specimen of Stoechospermum marginatum contained 5(R),16(S )-diacetoxyspata-13,17-diene 139, the absolute stereochemistry of which was established using Mosher’s method.¹²¹ Secospatacetals A–E 140–144 were obtained from Dilophus okamurai from Japan and the structure of a spatane derivative previously reported from an Australian specimen of S. marginatum ¹²² was revised from 145 to 146.¹²³ A different specimen of D. okamurai ¹²⁴ from Japan contained dilkamural 147, which may be a hydrolysis product of secospatacetal B 141.¹²⁵

Spatosterol 148 and varninasterol 149 are new fucosterol derivatives from Spatoglossum variabile from Pakistan.^126,113 Six additional fucosterol derivatives, 150–155, were obtained from Turbinaria conoides from Taiwan.¹²⁷

5 Red algae

Interest in red algae continues to decline slowly, probably due to the paucity of bioactivity reported for the halogenated metabolites that make up the bulk of their metabolites. As part of a chemotaxonomic study, two C₁₅ acetogenins, japonenynes A 156 and B 157, were isolated from Laurencia japonensis from Japan,¹²⁸ while an undescribed Laurencia sp. from Japan contained bisezakynes A 158 and B 159.¹²⁹ Laurencienyne B 160 is an additional halogenated acetogenin from a Greek specimen of L. obtusa.¹³⁰L. obtusa from Turkey contained the brominated acetogenin acetate 161.¹³¹ The structure of (+)-obtusenyne 162, which is a metabolite of L. obtusa,^132,133 has been confirmed by total synthesis.¹³⁴ The absolute configuration of Norte’s obtusenynes 163 (a mixture of 3Z and 3E isomers) from L. pinnatifida ¹³⁵ has also been determined by total synthesis.¹³⁶ (−)-Kumausallene 164, a metabolite of L. nipponica,¹³⁷ has been synthesized in an enantioselective manner.¹³⁸ A total synthesis of (+)-laurencin 165, isolated from L. glandulifera,¹³⁹ was accomplished using an olefin metathesis to form the 8-membered ring.¹⁴⁰ A brominated diphenyl ether 166 and a brominated dibenzyl ether 167 that were isolated from Odonthalia corymbifera were shown to inactivate α-glucosidase.¹⁴¹

Plocamium costatum from Tasmania contained an additional halogenated monoterpene 168 in addition to the known tribromotrichloromonoterpene 169 from P. cartilagineum,¹⁴² the  ¹³C NMR spectrum of which was recorded for the first time.¹⁴³ Eleven known compounds, one of which 170 was obtained pure for the first time, were isolated from a Great Barrier Reef specimen of P. hamatum: the structure of the anti-algal metabolite 171 was confirmed by X-ray analysis.¹⁴⁴ Apakaochtodenes A 172, the structure of which was determined by X-ray analysis, and B 173 were obtained from a specimen of Portieria hornemannii from Guam.¹⁴⁵ Claviol 174 is a tricyclic brominated sesquiterpene that was isolated along with five known metabolites from Laurencia claviformis from Easter Island.¹⁴⁶ A total of fourteen chamigrane derivatives, only two of which, 175 and 176, were previously undescribed, were isolated from L. nidifica from Oahu.¹⁴⁷ The cultivated edible seaweed Porphyra yezoensis from Japan contained two isomeric diterpenes 177 and 178, which did not appear to be photooxidation products of phytol.¹⁴⁸ Aplysin 179, debromoaplysin 180, aplysinol 181, debromoaplysinol 182, isoaplysin 183, isolaurenterol 184 and debromoisolaurinterol 185, all of which are metabolites of Laurencia spp.,^149–151 were synthesized using a diastereoselective radical to polar crossover sequence,¹⁵² while aplysin 179 and debromoaplysin 180 were constructed using a similar sulfur mediated cyclization strategy.¹⁵³ A “symmetrical” total synthesis of teurilene 186, which is a polyether metabolite of L. obtusa,¹⁵⁴ required only ten steps from a commercially available compound.¹⁵⁵ The structure of (−)-polycavernosamide A 187, a toxin isolated from Polycavernosa tsudai,¹⁵⁶ was confirmed by two total syntheses.^157,158 An additional total synthesis of (−)-kainic acid 188, which is an anthelmintic metabolite from Digenea simplex,¹⁵⁹ utilizes a short, efficient and highly stereoselective approach.¹⁶⁰

6 Sponges

Once again, sponges have provided the largest number of new marine natural products, many of which have interesting biomedical potential. A series of phospholipids that included four previously undescribed representatives, 189–192, were obtained as inhibitors of cholesterol biosynthesis from a Korean specimen of Spirastrella abata.¹⁶¹ A Petrosia sp. from Korea contained a cyclitol derivative 193 that inhibited in vitro SV40 DNA replication.¹⁶² Oceanapiside 194 is an antifungal bis-aminohydroxylipid glycoside from a Southern Australian specimen of Oceanapia phillipensis.¹⁶³ A Caribbean specimen of Plakortis simplex contained the simplexides 195, a group of immunosuppressive glycolipids that inhibit proliferation of activated T-cells by a non-cytotoxic mechanism.¹⁶⁴ Agelagalastatin 196 is a cytotoxic glycosphingolipid from an Agelas sp. from Papua New Guinea.¹⁶⁵ Myrmekiosides A 197 and B 198 from a Japanese Myrmekioderma sp. are mono-O-alkyl-diglycosylglycerols that reverse the phenotype of melanoma H-ras transformed NIH3T3 cells.¹⁶⁶ Penaresidin A 199, which is a potent actomyosin ATPase inhibitor from an Okinawan Penares sp.,^167,168 was synthesized in an enantioselective manner.¹⁶⁹ The asymmetric synthesis of (−)-aplysillamide B 200, which is an antimicrobial agent from Psammaplysilla purpurea,¹⁷⁰ illustrated the use of a ‘superquat’ reagent as a chiral auxiliary.¹⁷¹ The (2S,3R,4S,6R,12R) configuration of (+)-rottnestol 201, which is a metabolite of a Haliclona sp. from Rottnest Island, Western Australia,¹⁷² has been proposed on the basis of total synthesis.¹⁷³

Six additional acetylenic enol ethers, petroraspailynes A1 202, A2 203, A3 204, B1 205, B2 206 and B3 207, and the alcohol 208, the absolute configurations of which were determined by Mosher’s method, have been isolated from a Korean species of Petrosia.¹⁷⁴ Seven additional cytotoxic polyacetylenes, (3S,14S )-petrocortyne A 209, petrotetrayndiols A 210, B 211 and C 212, dideoxypetrosynols E 213 and F 214, and nor-3S,14S-petrocortyne A 215, were also isolated from a Petrosia sp. from Korea.^175,176 The isolation of pellynols E–H 216–219, together with swinholides, from an undescribed Theonella sp. from Chuuk Atoll, Micronesia, was unexpected from a chemotaxonomic viewpoint.¹⁷⁷ The xestosterol esters 220 and 221 of two brominated acetylenic acids were obtained from an Australian specimen of Xestospongia testudinaria.¹⁷⁸ A chemoenzymatic synthesis of both the (4E,15Z ) and (4E,15E ) isomers ¹⁷⁹ resulted in assignment of the (3S,4E,15Z ) stereochemistry to (+)-docosa-4,15-dien-1-yn-3-ol 222, which is a cytotoxic metabolite of Cribrochalina vasculum.^180–182 The proposed stereochemistry at C-3 for both (3S,4E )-eicos-4-en-1-yn-3-ol 223 and (3S,4E )-19-methylicos-4-en-1-yn-3-ol 224, which are also metabolites of C. vasculum,¹⁸⁰ has been confirmed by two independent total syntheses.^183,184 Petrofuran 225, from an Okinawan Petrosia sp.,¹⁸⁵ (aka adociaacetylene B from an Okinawan Adocia sp.) ¹⁸⁶ has been synthesized using an enantioselective reduction to produce the two chiral alcohols.¹⁸⁷

Studies of Plakortis simplex from the Caribbean resulted in the isolation of the cyclic peroxide dihydroplakortin 226 and two related furans 227 and 228, as well as providing the absolute stereochemistry of plakortin 229.¹⁸⁸ A subsequent report of metabolites from P. simplex described four additional lactones, plakortones E 230 and F 231 and simplactones A 232 and B 233.¹⁸⁹ The structures and absolute stereochemistries of the cyclic peroxides chondrillin 234 from a Great Barrier Reef Chondrilla sp.¹⁹⁰ and plakorin 235 from Plakortis spp.^191,192 have been confirmed by syntheses of (+)- and (−)-chondrillin and (+)- and (−)-plakorin.¹⁹³ Elenic acid 236, which is a topoisomerase II inhibitor from an Indonesian Plakinastrella sp.,¹⁹⁴ was synthesized by a short efficient route.¹⁹⁵Homo-plakotenin 237 and its sodium salt 238, nor-plakotenin sodium salt 239 and plakotenin sodium salt 240, some of which significantly reduced proliferation of rheumatoid synovial fibroblasts, are additional members of the plakotenin family from a Palauan specimen of Plakortis lita.¹⁹⁶ Benzylthiocrellidone 241, the structure of which was confirmed by synthesis, was isolated from Crella spinulata: it should be noted that the Australian group has previously studied the use of synthetic dimedone derivatives as sunblocks.¹⁹⁷ Five additional antifungal and cytotoxic metabolites, theopederins F–J 242–246, were isolated from a Japanese specimen of Theonella swinhoei.¹⁹⁸ (+)-Discodermolide 247, a potentially important antimitotic agent from the Caribbean deep-water sponge Discodermia dissoluta,¹⁹⁹ has been synthesized on a scale that will enable future development as an antimitotic agent.²⁰⁰

The bicyclic macrolides, amphilactams A–D 248–251, are nematocides from the Southern Australian Amphimedon sp.²⁰¹ A Geodia sp. from Southern Australia contained geodin A magnesium salt 252, which also has nematocidal activity.²⁰² Haterumalides NA 253, NB 254, NC 255, ND 256 and NE 257 are cytotoxic chlorinated macrolides from an Okinawan species of Ircinia.²⁰³ The calcareous sponge Leucascandra caveolata from New Caledonia contained an additional macrolide, leucascandrolide B 258.²⁰⁴ Four additional cytotoxic macrolides, sphinxolides E–G 259–261 and reidispongiolide C 262, were isolated from the New Caledonian sponges Neosiphonia superstes and Reidispongia coerulea, respectively.²⁰⁵ The relative and absolute stereochemistry of the mycalolides, exemplified by mycalolide A 263 from a Japanese Mycale sp.,²⁰⁶ were determined by chemical synthesis, degradation and spectroscopic analyses.²⁰⁷ An additional tetramic acid glycoside, aurantoside C 264, was isolated from the lithistid sponge Homophymia conferta from the Philippines ²⁰⁸ while aurantosides D–F 265–267, which possessed antifungal activity, were isolated from the Japanese lithistid Siliquariaspongia japonica.²⁰⁹S. japonica also contained a related series of tetramic acid glycosides, rubrosides A–H 268–275, that induced large intracellular vacuoles in 3Y1 rat fibroblasts.²¹⁰

The synthesis of macrolides and related complex molecules from sponges has attracted much attention. The absolute configuration of (+)-miyakolide 276, which is a weakly cytotoxic tetracyclic macrolide from a Japanese Polyfibrospongia sp.,²¹¹ was established by a very efficient synthesis of its enantiomer.²¹² The potent cytotoxin altohyrtin C 277 from Hyrtios altum,²¹³ also known as spongistatin 2 from Spongia sp.,²¹⁴ has been synthesized by an enantioselective route.²¹⁵ A stereocontrolled total synthesis of (+)-halichlorine 278, which is an inhibitor of VCAM-1 expression from Halichondria okadai from Japan,²¹⁶ has been accomplished.²¹⁷ (−)-Hennoxazole A 279, which is an antiviral agent from a Polyfibrospongia species,²¹⁸ has been synthesized using a convergent enantio-controlled strategy.²¹⁹ A convergent total synthesis ²²⁰ led to the antipodes of calyculin A 280 and calyculin B 281, which are serine-threonine phosphatase inhibitors from a Japanese specimen of Discodermia calyx.^221,222 The solution structures of calyculin A 280 and dephosphonocalyculin A 282 have been determined using NMR methods.²²³

Thirteen additional 5-alkylpyrrole-2-carboxaldehydes 283–295 were isolated from the Caribbean sponges Mycale microsigmatosa and Desmapsamma anchorata from Venezuela.²²⁴ A general method has been reported for the synthesis of mycalazol 11 296 from Mycale micracanthoxea ²²⁵ and related pyrroles.²²⁶ Pyrinodemin A 297, the structure of which was elucidated largely on the basis of its EIMS fragmentation pattern, is a cytotoxic pyridine alkaloid from a Japanese species of Amphimedon.²²⁷ Echinoclathrines A–C 298–300, which show weak immunosuppressive activity, are members of a new class of pyridine alkaloids from an Okinawan species of Echinoclathria.²²⁸ Bengamides Y 301 and Z 302 and bengazole Z 303, which were isolated from an Australian Jaspis sp., showed striking differential cytotoxicity patterns against a panel of human tumour cell lines.²²⁹ Bengamide L 304 and six additional bengazoles 305–310 were isolated from a Pachastrissa sp. from the Djibouti coast.²³⁰ The first total synthesis of bengazole A 311, which is an antifungal agent from a Jaspis sp.,²³¹ employed consecutive regiocontrolled metalation–addition reactions.²³² Neofolitispates 1–3 312–314 are additional pentacyclic guanidine alkaloids from Neofolitispa dianchora from the Andaman Islands, India, that inhibited the hepatitis B virus.²³³ 13,14,15-Isocrambescidin 800 315, a rare metabolite of Crambe crambe,²³⁴ has been synthesized in an enantioselective manner.²³⁵ The ring junction stereochemistry of the left-hand portion of batzelladine F, a metabolite of a Caribbean Batzella sp. that induces p56 ^lck-CD4 dissociation,²³⁶ has been revised from anti316 to syn317 as the result of partial synthesis.^237,238 An enantioselective total synthesis of batzelladine D 318, from the same Batzella sp.,²³⁹ has been described.²⁴⁰ A new manzamine alkaloid, 1,2,3,4-tetrahydromanzamine B 319, was obtained from a Japanese species of Amphimedon.²⁴¹ An enantioselective total synthesis of ircinal A 320, which is a metabolite of a Japanese Ircinia sp.,²⁴² also completes a formal synthesis of manzamine A 321.²⁴³ Studies on the biomimetic synthesis of the manzamine alkaloids resulted in the total synthesis of keramaphidin B 322,²⁴⁴ which was obtained from an Okinawan species of Amphimedon. ²⁴⁵ Halitulin 323 is an unusual cytotoxic alkaloid from Haliclona tulearensis from South Africa.²⁴⁶ Two groups have synthesized motuporamines A 324 and B 325,^247,248 which are metabolites of Xestospongia exigua,²⁴⁹ and one of these groups also determined the position of the double bond in motuporamine C 326.²⁴⁸ A new 1,2-dihydroisoquinoline 327 was isolated from Petrosia similis from the Mandapam coast of India.²⁵⁰ Renierol 328, which is a metabolite of Xestospongia caycedoi,²⁵¹ and the corresponding acetate and propionate esters 329 and 330 were synthesized using a thermal electrocyclic reaction as the key step.²⁵² A deep-water Caribbean sponge of the genus Batzella contained secobatzellines A 331 and B 332, both of which were cytotoxic and inhibited calcineurin, while only secobatzelline A 331 inhibited the peptidase activity of CPP32.²⁵³ Similar bioactivity was ascribed to discorhabdin P 333, the structure of which was determined by X-ray crystallography, which was isolated from a similar deep-water Batzella sp. from the Bahamas.²⁵⁴ Discorhabdin Q 334 was isolated as a cytotoxic constituent from Latrunculia purpurea and at least three Zyzzya species.²⁵⁵ The biomimetic syntheses of discorhabdins C 335 and E 336, which are metabolites of Latrunculia species from New Zealand,^256,257 employ cupric chloride-catalyzed oxidative cyclizations of suitably substituted indoloquinonimines.²⁵⁸ Batzellines A 337 and B 338 and isobatzellines A 339 and B 340, which are metabolites of a deep-water Caribbean Batzella sp.,^259,260 have all been synthesized using a similar strategy.²⁶¹ The total synthesis of the cytotoxic agent makaluvamine F 341 from Zyzzya cf. marsailis ²⁶² was accomplished using hypervalent iodine(III)-induced reactions.^263,264 Veiutamine 342, which is a cytotoxic constituent of Zyzzya fuliginosa from Fiji,²⁶⁵ has been synthesized for the first time.²⁶⁶ Neoamphimedine 343, which was obtained from a Xestospongia sp. from the Philippines and from X. cf. carbonaria from Palau, is a pyridoacridine topoisomerase II inhibitor that catenates DNA.²⁶⁷

The structure of dysibetaine 344, which is an α,α-disubstituted α-amino acid derivative from Dysidea herbacea from Yap, Micronesia, was determined by X-ray crystallography.²⁶⁸ Two additional jaspamide derivatives, jaspamides B 345 and C 346, were obtained as moderately active cytotoxic agents from a specimen of Jaspis splendens from Vanuatu ²⁶⁹ while the related metabolites, geodiamolides J–P 347–353 and R 354, were isolated as minor metabolites of a Cymbastela sp. from Papua New Guinea.²⁷⁰ In a paper that compares the cytotoxicity of the hemiasterlins with other linear peptides, hemiasterlin C 355 was reported as an additional cytotoxic linear peptide from an Auletta sp. and two collections of Siphonochalina species.²⁷¹ Tokaramide A 356 was isolated as a cathepsin B inhibitor with potential anticancer activity from a Japanese specimen of Theonella aff. mirabilis.²⁷² A Japanese Theonella sp. contained the cytotoxic linear peptide koshikamide A₁357.²⁷³ A mixture of linear and cyclic peptides, pseudotheonamides A₁358, A₂359, B₂360, C 361 and D 362, and dihydrocyclotheonamide A 363, were obtained as serine protease inhibitors from a Japanese specimen of Theonella swinhoei.²⁷⁴ Three total syntheses of motuporin 364, which is a potent inhibitor of protein phosphatase type 1 (PP1) from a Papua New Guinea specimen of Theonella swinhoei,²⁷⁵ have been reported during 1999.^276–278 Arenastatin A 365, which is a cytotoxic depsipeptide from Dysidea arenaria,²⁷⁹ has been synthesized together with related cyanobacterial cytotoxins.²⁸⁰

Keramamides M 366 and N 367 are additional sulfated cyclic peptides from an Okinawan Theonella species.²⁸¹ A different Theonella sp. from Okinawa contained two additional theonellapeptolide congeners 368 and 369, one of which had methylsulfinylacetyl group at the N-terminus.²⁸² An X-ray study of theonellapeptolide Id 370 from an Okinawan specimen of T. swinhoei ²⁸³ revealed that the crystals were highly solvated.²⁸⁴ An Indonesian specimen of T. swinhoei contained the cyclic peptide barangamide A 371, which is related to the theonellapeptolides.²⁸⁵ The Papua New Guinea sponges T. mirabilis and T. swinhoei contained the cytotoxic and HIV-inhibitory depsipeptides papuamides A 372 and B 373 and papuamides C 374 and D 375, respectively.²⁸⁶ The cyclic heptapeptide phakellistatin 2 376, which is a cytotoxic constituent of Phakellia carteri from the Comoros Islands,²⁸⁷ has been synthesized in a stepwise manner but the synthetic product did not possess the biological activity of the natural product.²⁸⁸ Synthesis of the proposed structure of keramamide J 377, which was isolated from an Okinawan Theonella sp.,²⁸⁹ indicated that the structure of the natural product should be re-examined.²⁹⁰

Two bromotyrosine derivatives 378 and 379 were described as constituents of Aplysina cauliformis from the Bahamas.²⁹¹ 14-Oxo-aerophobin-2 380 was among fourteen bromoisoxazole alkaloids isolated from A. insularis from the Bahamas.²⁹² The diethyl ketal 381 was obtained from a Turkish specimen of Verongia aerophoba that had been extracted with ethanol.²⁹³ Two additional bromotyrosine-derived metabolites, araplysillin III 382 and hexadelin C 383, were isolated from Aiolochroia crassa (= Ianthella ardis) from Belize.²⁹⁴ A specimen of Aplysina fistularis insularis from Venezuela contained the cytotoxic metabolite 11-deoxyfistularin-3 384.²⁹⁵ 7-Hydroxyceratinamine 385 is an additional cyanoformamide from an Aplysinella sp. from Micronesia.²⁹⁶ The urethane 386 and the corresponding salt were isolated from Psammaplysilla purpurea from the Mandapam Coast of India.²⁹⁷ Iantheran A 387 is an unusual dimeric polybrominated benzofuran that was obtained as a Na,K-ATPase inhibitor from an Australian Ianthella species.²⁹⁸

Six additional bromopyrrole alkaloids, slagenins A–C 388–390 and mukanadins A–C 391–393 were isolated from Agelas nakamurai from Okinawa: the planar structure of mukanadin C 393 is the same as that previously reported for dispacamide D.^299,300A. wiedenmayeri from the Florida Keys contained an additional bromopyrrole alkaloid (4-bromopyrrole-2-carboxy)homoarginine 394.³⁰¹ Two dimeric bromopyrrole alkaloids, nakamuric acid 395 and the corresponding methyl ester 396 were obtained from a methanolic extract of A. nakamurai from Indonesia.³⁰²Stylissa carteri from Indonesia contained debromostevensine 397 and debromohymenin 398 together with known congeners.³⁰³ Axinellamides A–D 399–402 were obtained as antibacterial agents from an Australian Axinella species.³⁰⁴ The racemic forms of the pyrrolodiketopiperazines, longamide 403, longamide B 404, longamide B methyl ester 405 and hanishin 406, which were isolated from Agelas longissima, A. dispar and Acanthella carteri,^305–307 have all been synthesized in a concise manner.³⁰⁸ A second independent synthesis of (±)-longamide 403 was reported.³⁰⁹ Agelastatin A 407, a cytotoxic metabolite of Agelas dendromorpha from New Caledonia,³¹⁰ has been synthesized as its racemate.³¹¹

Two additional alkaloids, 408 and 409, of the topsentin class have been isolated as cytotoxic constituents of Spongosorites genitrix from Korea.³¹² A Southern Australian Echinodictyum sp. contained the antibacterial metabolites echinosulfonic acids A–C 410–412 and echinosulfone A 413.³¹³ The X-ray structure of 1,3-dimethylisoguanine 414 from Amphimedon viridis,³¹⁴ indicated that the compound crystallized as a trihydrate and in a different tautomeric form than that previously reported.^315,316 Coixol (6-methoxy-2(3H )-benzoxazolinone 415) was isolated from an Indian Oceanapia sp. as a toxin to brine shrimp.³¹⁷ A specimen of Dysidea sp. from Okinawa contained S1319 416, which was isolated as a β-adrenoceptor agonist.³¹⁸ A synthesis of homofascaplysin C 417 from Fascaplysinopsis reticulatus ³¹⁹ involved a ditryptophan intermediate.³²⁰ The bis-indole alkaloid hyrtiosin B 418,³²¹ from an Okinawan specimen of Hyrtios erecta, has been prepared in good yield.³²² Two different routes were used to synthesize the alkaloid leucettamine B 419, which was obtained from Leucetta microraphis,³²³ in good yields.³²⁴ Isonaamine A 420, which was isolated from L. chagosensis,³²⁵ has been synthesized using a condensation reaction involving tosyl isocyanate to prepare the 2-aminoimidazole ring system.³²⁶ The structure of niphatoxin B 421 from a Red Sea Niphates sp.³²⁷ was confirmed by total synthesis.³²⁸ Lamellarin O 422, which is a metabolite of Dendrilla cactos,³²⁹ has been synthesized using a Diels–Alder strategy.³³⁰

A Red Sea Smenospongia sp. contained smenotronic acid 423, which is an interesting tetronic acid thought to be derived from ilimaquinone.³³¹ A single methanol-addition product, 15α-methoxypuupehenol 424, crystallized from methanol during the work-up of a New Caledonian Hyrtios sp. known to contain puupehenone 425.³³² Puupehenone 425, first isolated from a Verongid sponge,³³³ was synthesized from (−)-sclareol in an enantiospecific manner.³³⁴ An efficient synthesis of ent-chromozonarol 426, which is a metabolite of Dysidea pallescens,³³⁵ also used (−)-sclareol as a starting material.³³⁶ Avarol 427 and the corresponding quinone, avarone 428, which are cytotoxic metabolites of Dysidea avara,³³⁷ have been synthesized in an enantioselective manner using a radical addition reaction to incorporate the aromatic ring.³³⁸ The structure of isoavarol 429, also known as neoavarol,³³⁹ which is a merosesquiterpene from a Pacific Dysidea sp.,³⁴⁰ has been confirmed by an X-ray crystallographic study of the corresponding diacetate 430.³⁴¹ The absolute configuration of (+)-hyatellaquinone 431, which is a metabolite of Hyatella intestinalis,³⁴² has been revised as the result of a synthesis of (−)-hyatellaquinone from (+)-sclareolide.³⁴³ Nakijiquinone C 432, which is a selective inhibitor of the Her-2/Neu protooncogene from an unidentified sponge of the family Spongiidae,³⁴⁴ has been synthesized by an enantioselective route.³⁴⁵ Both a stereoselective total synthesis and an enantioselective formal synthesis of metachromin A 433, which is a metabolite of Hippospongia metachromia,³⁴⁶ have been accomplished.³⁴⁷

A number of meroterpenoid sulfates have recently been reported. An Australian Sarcotragus sp. contained octaprenylhydroquinone sulfate 434 and nonaprenylhydroquinone sulfate 435 as inhibitors of α1,3-fucosyltransferase VII.³⁴⁸ Two related but non-sulfated meroterpenoids, 1,4,44-trihydroxy-2-octaprenylbenzene 436 and 4-hydroxy-3-octaprenylbenzoic acid 437 were obtained from specimens of Spongia sp. and Ircinia sp., respectively, collected from the Aegean Sea.³⁴⁹ Adociasulfates 1–6 438–443 were obtained as inhibitors of kinesin motor proteins from a Palauan sponge of the genus Haliclona (aka Adocia).³⁵⁰ An Adocia sp. from the Great Barrier Reef contained adociasulfates 1 438, 7 444 and 8 445, which inhibit vacuolar H⁺-ATPase.³⁵¹ Adociasulfates 5 442 and 9 446 were obtained from Adocia aculeata from the Great Barrier Reef.³⁵² The structure of adociasulfate 1 438 has been confirmed by an enantioselective total synthesis.³⁵³ The relative stereochemistry of the ring junction in the upper decalin moiety of akaterpin 447, which is an inhibitor of phosphatidylinositol-specific phospholipase C from a Callyspongia sp.,³⁵⁴ was shown to be cis by synthesis of model compounds.³⁵⁵

A new furanosesquiterpene, iso-dehydrodendrolasin 448, was obtained from Euryspongia deliculata from the Great Barrier Reef.³⁵⁶ The sequiterpenoids (−)-14-methoxy-14-deacetoxyspirodysin-1 449 and the corresponding 12,13-dihydro derivative 450 were isolated from an Indian specimen of Dysidea fragilis.³⁵⁷ The tricyclic sesquiterpene γ-hydroxybutenolide 451 was obtained as an antifouling agent from D. herbacea from Palau.³⁵⁸ Dysifragin 452 and caparrapi oxide 453 were isolated from a Taiwanese specimen of D. fragilis.³⁵⁹ Tavacpallescensin 454 from D. avara contaminated with Pleraplysilla spinifera ³⁶⁰ was synthesized as the racemate from a symmetrical precursor.³⁶¹ Pallescensin B 455, which was isolated from Dysidea pallescens,³⁶² has been synthesized as its racemate.³⁶³ 1,5-Cyclooctadiene was employed as the starting material for a stereoselective total synthesis of kelsoene 456,³⁶⁴ which is a metabolite of Cymbastela hooperi.³⁶⁵ A Taiwanese sponge of the genus Parahigginsia contained parahigginols A–D 457–460, parahigginic acid 461, parahigginine 462 and parahigginone 463, of which 458–461 were moderately cytotoxic.^365,367 Three 3-formamidobisabolene derivatives 464–466 were isolated from an Axinyssa sp. from Yap, Micronesia.³⁶⁸ The first total synthesis of 9-isocyanoneopupukeanane 467, a metabolite of Ciocalypta sp.,³⁶⁹ has been reported.³⁷⁰ (−)-4-Thiocyanatoneopupukaenane 468, which is a metabolite of an unidentified sponge from Pohnpei,³⁷¹ has been synthesized in an enantiospecific manner.³⁷² The guanidinoimidazole alkaloid stellettazole A 469 is an antibacterial and Ca ²/calmodulin-dependent phosphodiesterase inhibitor from a Japanese species of Stelletta.³⁷³ The same Stelletta sp. also yielded stellettazoles B 470 and C 471, stellettamide C 472, and bistellettadines A 473 and B 474, which also inhibited Ca ²/calmodulin-dependent phosphodiesterase.^374,375

It is interesting that the cytotoxic diterpene 475, which is closely related to metabolites of brown algae, was obtained from Sigmosceptrella quadrilobata from the Comoros Islands.³⁷⁶ Two cytotoxic cembranoids, flabellatenes A 476 and B 477, which are compounds that are normally associated with soft corals, were isolated from the Antarctic sponge Lissodendoryx flabellata.³⁷⁷ Together with the known major metabolite, (+)-spongia-13(16),14-diene-19-oic acid 478, six additional spongian diterpenes, the epimeric γ-methoxybutenolides 479–481, the di(methoxy ketal) 482 and the epimeric butenolides 483 and 484 were isolated from Spongia matamata from Yap, Micronesia.³⁷⁸ A Spongia sp. from the Philippines contained spongiabutenolides A–D 485–488 in addition to the known major metabolite (+)-spongia-13(16),14-diene-19-oic acid 478: the structure of spongiabutenolide A 485 was confirmed by synthesis from the furan 478 using singlet oxygen oxidation.³⁷⁹ The X-ray crystallographic data for ent-isocopal-12-ene-15,16-dialdehyde 489, which is a metabolite of S. officinalis,³⁸⁰ has been presented.³⁸¹ (−)-Spongia-13(16),14-diene 490, which is also a metabolite of S. officinalis,³⁸² was synthesized in a diastereoselective manner.³⁸³ A trio of amphilectene isonitriles, 491–493, and the bicyclic diterpene hydrocarbon 494 were obtained from a Caribbean Cribochalina sp.³⁸⁴ The absolute configuration of kalihinol A 495, which is a metabolite of an Acanthella sp. from Guam,³⁸⁵ was determined by application of the CD exciton chirality method to a bis-p-bromobenzoate derivative.³⁸⁶

An additional C₂₁ terpene lactone 496, that is possibly derived from cacospongionolide B 497, with which it was found in a Mediterranean specimen of Fasciospongia cavernosa, was identified by interpretation of spectral data.³⁸⁷ Methylation of the crude extract of a Sigmosceptrella sp. from Southern Australia with diazomethane produced a mixture of products from which nuapapuin methyl ester 498 and sigmosceptrellin D and E methyl esters 499 and 500 were isolated and identified.³⁸⁸ The methyl ester 501, which is a metabolite of Latrunculia brevis from Australia,³⁸⁹ has been synthesized in an enantiospecific manner.³⁹⁰

Halisulfate 7 502 is a sesterterpene sulfate from a species of Coscinoderma from Yap, Micronesia.³⁹¹ An additional sesterterpene, cacospongionolide F 503, was isolated from Fasciospongia cavernosa from the Northern Adriatic Sea and its absolute stereochemistry was determined using the modified Mosher’s method.³⁹² The X-ray crystallographic data for scalarolide 504 and scalarin 505, which are metabolites of sponges of the family Thorectidae,^393,394 have been reported.³⁹⁵ A specimen of Coscinoderma mathewsi from Pohnpei contained two sesterterpenes 506 and 507 that have an unusual cis geometry about the B/C ring junction.³⁹⁶ Bilosespens A 508 and B 509, which were isolated as an inseparable mixture from an Eritrean sample of Dysidea cinerea, are cytotoxic sesterterpenes having an unprecedented carbon skeleton.³⁹⁷ (−)-Wistarin 510 from a Red Sea Ircinia sp. is the enantiomer of a metabolite previously isolated ³⁹⁸ from I. wistaria.³⁹⁹ Phyllofolactones C 511 and D 512 are minor homoscalarane sesterterpenes from a Chinese specimen of Phyllospongia foliascens.⁴⁰⁰ Three additional sesterterpenes 513–515 were isolated from Strepsichordaia lendenfeldi from the Great Barrier Reef.⁴⁰¹ The polar material from a Great Barrier Reef Carteriospongia sp. contained (−)-3-hydroxypentanoic acid 516 which is sometimes found as an ester group on scalaranes.⁴⁰² Manoalide 517, which is an antiinflammatory agent from Luffariella variabilis,⁴⁰³ has been synthesized in an enantioselective manner.⁴⁰⁴ A synthesis of ircinin-4 518, a metabolite of Ircinia oros,⁴⁰⁵ employed a palladium-catalyzed reaction as the key step.⁴⁰⁶ The absolute configuration of (−)-spongianolide A 519, which is a cytotoxic sesterterpene from a Spongia sp.,⁴⁰⁷ was determined by total synthesis.⁴⁰⁸

In addition to known sesterterpenes, an inseparable mixture of two epimeric epidioxy sterols 520 and 521 was obtained as an antifouling agent from Lendenfeldia chondrodes from Palau.⁴⁰⁹ An Indian specimen of Petrosia testudinaria yielded an unusual 27-nor sterol 522.⁴¹⁰ Two C₃₀ sterols, thymosiosterol 523 and 24,27-dehydrothymosiosterol 524 were isolated from an undescribed Thymosiopsis sp. from France.⁴¹¹ As part of a study of multidrug resistance reversal, six new agosterol derivatives, agosterols B 525, C 526, A₄527, D₂528, A₅529 and C₆530 were isolated from a Japanese species of Spongia.⁴¹² An unusual sterol enol ether 531, derived by cyclization of a 9,11-secosterol, was obtained from an Australian specimen of Euryspongia arenaria.⁴¹³ Glaciasterol B 3-monoacetate 532 is a 9,11-secosterol from Fasciospongia cavernosa from the Mediterranean that was toxic to brine shrimp.⁴¹⁴ A Corticium sp. from Vanuatu contained plakinamines C 533 and D 534 and three other steroidal alkaloids 535–537, all of which showed significant cytotoxicity.⁴¹⁵ Tamasterone sulfates 538 and 539 are a C-14 epimeric pair of polyhydroxylated sterols from a new species of the genus Oceanapia.⁴¹⁶ Although haplosamates A 540 and B 541, which are inhibitors of HIV-1 integrase from two Philippines Haplosclerid sponges, were reported to be the first naturally occurring sulfamates,⁴¹⁷ re-examination of the spectral data has revealed that they are in fact phosphate esters and that the structures must be revised to 542 and 543, respectively.⁴¹⁸ Crellastatins B–M 544–555 are twelve additional cytotoxic dimeric 4,4′-dimethylsterols from a Crella sp. from Vanuatu.^419,420 A two sponge association of Poecillastra wondoensis and Jaspis wondoensis contained three cytotoxic and antimicrobial steroidal glycosides, wondosterols A–C 556–558.⁴²¹ The Caribbean sponge Ectyoplasia ferox contained two triterpene oligoglycosides, ectyoplasides A 559 and B 560, that showed moderate cytotoxicity.⁴²² Xestobergsterol A 561, which is a metabolite of Xestospongia bergquistii that inhibits the release of histamine from rat mast cells,⁴²³ has been synthesized in 24 steps from stigmasterol.⁴²⁴

The symmetrical diketotriterpenoid 562 was obtained from an Indonesian specimen of Hyrtios erectus.⁴²⁵ The revised structure of hippospongic acid 563,⁴²⁶ which is a metabolite of a Japanese Hippospongia sp.,⁴²⁷ has been synthesized as the racemate.^428,429 Three additional triterpenes, 22-dihydroyardenone 564, abudinol B 565 and muzitone 566, together with possible degradation products nakorone 567 and durgamone 568, were obtained from a Red Sea specimen of Ptilocaulis spiculifer and five new triterpenes, sodwanones N–R 569–573 were reported from Axinella weltneri from South Africa.⁴³⁰

7 Coelenterates

Although the chemistry of coelenterates continues to be dominated by terpenoids, there are a few interesting lipids and alkaloids to be reported. The scleractinian coral Madrepora oculata contained a mixture of 10-hydroxydocosapolyenoic acids that was methylated to obtain the methyl esters 574 and 575.⁴³¹ Montiporic acids A 576 and B 577, which are cytotoxic polyacetylenes from the scleractinian coral Montipora digitata,⁴³² have been synthesized in good yields.⁴³³ Three additional butenolides 578–580 related to ancepsenolide ⁴³⁴ were obtained from the Caribbean gorgonian Pterogorgia anceps.⁴³⁵ The Okinawan soft coral Clavularia viridis has yielded a number of new prostanoids: 17,18-dehydroclavulone I 581 and clavulactone I 582,⁴³⁶ 4-epiclavulones II 583 and III 584,⁴³⁷ and the truncated derivatives clavirins I 585 and II 586.⁴³⁸ Batyl alcohol-3-O-α-L-fucoside 587 was obtained from a new species of Sinularia from Rangat Island in the Andaman group.⁴³⁹ An Indian specimen of Sinularia dissecta contained the known ⁴⁴⁰ sponge metabolite 588.⁴⁴¹ Five additional alkaloids, zoanthenol 589, 3-hydroxynorzoanthamine 590, 30-hydroxynorzoanthamine 591, 11-hydroxynorzoanthamine 592 and 11-hydroxyzoanthamine 593 have been isolated from a Zoanthus sp. from the Canary Islands.⁴⁴² An Indian Zoanthus sp. contained known bases together with thyminol 594.¹²⁶ The deep-water briareid soft coral Lignopsis spongiosum from South Georgia Island yielded the β-carboline alkaloid 595.⁴⁴³ The H,K-ATPase inhibitor sinulamide 596 is a tetraprenylated spermine derivative from a Japanese soft coral of the genus Sinularia.⁴⁴⁴ Two sphingosine derivatives, N-hexadecanoyl-1,3-dihydroxy-2-amino-4,8-octadecadiene 597 and N-heneicosanoyl-1,3,4-trihydroxy-2-aminotetradecane 598, were isolated from S. crassa from the Andaman and Nicobar Islands.⁴⁴⁵ As part of a pharmacological study that reported the cytotoxicity of africanene 599, it was shown that S. leptaclados from Southern India contained two new sphingolipids, 600 and 601.⁴⁴⁶

Three additional africanene derivatives, 10(S )-hydroxy-9(15)-africanene 602, 9(S ),15-epoxyafricanane 603 and 9(S ),15-dihydroxyafricanane 604 were isolated as minor constituents of Sinularia dissecta from Southern India.⁴⁴⁷ 10(S )-Hydroxy-9(15)-africanene 602 and 9(S ),15-epoxyafricanane 603 were also obtained by microbial oxidation of 9(15)-africanene 599 using Aspergillus niger and Rhizopusoryzae.⁴⁴⁸S. intacta from India contained four additional africanane derivatives, (9R)-9,15-dihydroxyafricanane 605, (9R)-9-methoxy-15-hydroxyafricanane 606, (9S )-9,15-dihydroxyafricanane 607 and the seco-diketone 608.^449,450 A specimen of Gorgonia ventalina from the Bahamas contained 5,10-epoxymuurolane 609.⁴⁵¹ During studies of fish feeding deterrents from the Brazilian gorgonian Heterogorgia uatumani, a new sesquiterpene, heterogorgiolide 610, was isolated as an active agent.⁴⁵² Alertenone 611 is a dimer of the cytotoxin suberosenone 612, previously isolated from Subergorgia suberosa,⁴⁵³ that was obtained from an Alertigorgia sp. from Australia.⁴⁵⁴ Euplexides A–E 613–617 are cytotoxic farnesylhydroquinone glycosides from the Korean gorgonian Euplexaura anastomosans.⁴⁵⁵ Curcuhydroquinone 618, which is a metabolite of Pseudopterogorgia rigida,⁴⁵⁶ has been synthesized as its racemate.⁴⁵⁷ The absolute configuration of the secosesquiterpene (−)-anthoplalone 619, which is a cytotoxic constituent of the sea anemone Anthopleura pacifica,⁴⁵⁸ was determined by total synthesis.⁴⁵⁹ Clavularin B 620, which is a metabolite of the soft coral Clavularia koellikeri,⁴⁶⁰ has been synthesized by an enantio- and diastereo-controlled route.⁴⁶¹

In addition to several known compounds, a Taiwanese specimen of the soft coral Nephthea brassica contained both the sesquiterpene (−)-4α-O-acetylselin-11-ene 621 and the diterpenes brassicolide 622 and brassicolide acetate 623.⁴⁶² Three additional cembranoids, sartol acetate B 624, epoxysartone B 625 and sartone E 626, were obtained from a Japanese Sarcophyton species.⁴⁶³ Sarcophytols A 627 and B 628, which are metabolites of the Okinawan soft coral S. glaucum,⁴⁶⁴ were synthesized in a concise and efficient manner.⁴⁶⁵ The synthesis of racemic sinulariol B 629, isolated from a Japanese specimen of Sinularia mayi,⁴⁶⁶ was accomplished in 10 steps and ca. 10% yield from geraniol.⁴⁶⁷ A subsequent paper recorded the synthesis of (−)-sinulariol B 629 from geraniol.⁴⁶⁸ Preverecynarmin 630, which was isolated from both Veretillum cynomorium and its specific predator, the opisthobranch mollusc Armina maculata,⁴⁶⁹ was synthesized from (E,E )-farnesol.⁴⁷⁰ Lobatrienolide 631 and lobatrientriol 632, which are metabolites of an Okinawan specimen of S. flexibilis,⁴⁷¹ were prepared from (+)-nopinone.⁴⁷²

The Indonesian sea pen Veretillum malayense contained four diterpenes, malayenolides A–D 633–636, that were toxic to brine shrimp.⁴⁷³ Sandresolides A 637 and B 638 are nor-diterpenes that were isolated from the gorgonian Pseudopterogorgia elisabethae from Columbia.⁴⁷⁴ An Okinawan soft coral of the genus Xenia contained three additional xenicane diterpenes, xeniadiol 639, xeniaol 640 and xeniatriol 641.⁴⁷⁵ In addition to known metabolites, the Indian soft coral Sinularia maxima produced two furanocembranoids, sethukarailin 642 and sethukarailide 643.⁴⁷⁶ A specimen of the gorgonian Pseudopterogorgia bipinnata from Columbia contained bipinnapterolide A 644, bipinnatins G–I 645–647 and bipinnatolides F–J 648–652, among which the structures of bipinnapterolide A 644 and bipinnatolide F 648 were determined by X-ray crystallography.⁴⁷⁷ Bisgersolanolide 653 is a diterpenoid dimer that was also obtained from a specimen of P. bipinnata from the same location.⁴⁷⁸ A full account of the synthesis of eleutherobin 654, which is an anti-tumour agent from an Australian Eleutherobia sp.,⁴⁷⁹ has appeared.⁴⁸⁰

The Senegalese gorgonian Eunicella labiata contained two additional eunicellin-type diterpenes, labiatins D 655 and E 656.⁴⁸¹ Obtained from E. cavolinii from the Mediterranean, massileunicellins A–C 657–659 are cytotoxic eunicellin-type diterpenes that contain a second ether bridge.⁴⁸² The briarane class of diterpenoids have dominated reports of new metabolites from coelenterates. Five such compounds, (−)-4-deacetyljunceellolide D 660, (+)-11α,20α-epoxyjunceellolide D 661, (−)-11α,20α-epoxy-4-deacetyljunceellolide D 662, (−)-11α,20α-epoxy-4-deacetoxyjunceellolide D 663 and (+)-junceellolide A 664, an antipode of a known metabolite, were obtained from an Indonesian specimen of Junceella fragilis.⁴⁸³Erythropodium caribaeorum from Jamaica contained three additional briaranes, erythrolide E 3-acetate 665, erythrolide F 3-acetate 666 and erythrolide H 16-acetate 667.⁴⁸⁴ Violides C–I 668–674 are additional briarane diterpenes from a Japanese species of Briareum (aka Pachyclavularai violacea): ⁴⁸⁵ the authors propose that two previously reported ⁴⁸⁶ analogs be renamed violides A and B. A subsequent paper reported the isolation of violides J -M 675–678 from the same organism and the X-ray crystallographic structure determination of violide J 675.⁴⁸⁷ Excavatolides F–M 679–686 and U–Z 687–692, some of which were cytotoxic, were isolated from a Taiwanese specimen of Briareum excavatum ^488,489 while excavatolides N–T 693–699 were obtained from a Western Australian specimen of B. excavatum.⁴⁹⁰ Having reached the end of the alphabet for the excavatolides, the next series of compounds from B. excavatum were named briaexcavatolides A–J 700–709 and the structure of briaexcavatolide B 701 was determined by X-ray crystallography.⁴⁹¹

Bishomoisomandapamate 710, which was isolated from a new species of Sinularia from the Indian Ocean, is an analog of a known metabolite.⁴⁹²Sarcophyton elegans from the Indian Ocean has yielded an additional diterpene, 7-dehydrosarcophytin 711.⁴⁹³ A full paper has described the isolation of sarcophytin 712, 7-dehydrosarcophytin 711, 7(15)-dehydrosarcophytin 713 and isosarcophytin 714 from S. elegans.⁴⁹⁴ The structure of an unusual cytotoxic norditerpenoid, ineleganolide 715, which was obtained from Sinularia inelegans from Formosa, was determined by X-ray crystallography.⁴⁹⁵ Pseudopteroxazole 716, and to a lesser extent, secopseudopteroxazole 717 are inhibitors of Mycobacterium tuberculosis H37Rv that were isolated from Pseudopterogorgia elizabethae from Columbia.⁴⁹⁶P. elizabethae from the same location also contained elisabatins A 718 and B 719.⁴⁹⁷

Two 19-oxygenated polyhydroxy steroids, 24-methylenecholest-5-en-1α,3β,19-triol 720 and 24-methylenecholest-5-en-3β,7β,9α,19-tetraol 721, were isolated from an Indian Ocean specimen of Nephthea chabroli ⁴⁹⁸ while a Chinese specimen of N. brassica contained 24-methylenecholest-3β,6β,9α,19-tetraol 722.⁴⁹⁹ A specimen of N. brassica from the Indian Ocean contained 4α-methyl-24-methylenecholest-3β,8β-diol 723.⁵⁰⁰ A Formosan Sinularia sp. contained 7β-hydroperoxy-24-methylenecholesterol 724 together with a number of known compounds.⁵⁰¹ A Sinularia sp. from Southern India yielded 11α,12α-epoxy-24-methylenecholest-1α,3β,6β-triol 725 ⁵⁰² while Lobophytum crassum from the same region contained 23,24(S )-dimethylcholest-5,22-dien-3β,7α-diol 726, which was isolated as the corresponding diacetate.⁵⁰³ Four polyhydroxy steroids from an Indian specimen of S. dissecta, cholest-1β,3β,5α,6β,11α-pentaol 727, 24-methylenecholest-1β,3β,5α,6β,11α-pentaol 728, 24-methylenecholest-1β,3β,5α,6α,11α-pentaol 729 and 11α,12α-epoxy-24-β-methylcholest-1α,3β,6β-triol 730, were identified as their peracetate derivatives.⁵⁰⁴ Palythoalones A 731 and B 732 are ecdysteroids from an Okinawan specimen of the zoanthid Palythoa australiae.⁵⁰⁵ A Dendronephthya sp. from Japan contained four 13,17-secosteroids, isogosterones A–D 733–736, that inhibited settlement of the cyprid larvae of the barnacle Balanus amphitrite.⁵⁰⁶ Subsequently, methyl 3-oxochola-1,4,22-trien-24-oate 737 from the Dendronephthya sp. and 3-methoxy-19-norpregna-1,3,5(10),20-tetraene 738, 22,23-dihydroxycholesta-1,24-dien-3-one 739 and 3-(4-O-acetyl-6-deoxy-β-galactopyranosyloxy)-19-norpregna-1,3,5(10),20- tetraene 740 from a Japanese specimen of Alcyonium gracillimum were shown to be toxic to the cyprid larvae of B. amphitrite.⁵⁰⁷ Two norpregnane glycosides, 19-norpregna-1,3,5(10),20-tetraen-3-O-α-fucopyranoside 741 and 19-norpregna-1,3,5(10),20-tetraen-3-O-β-arabinopyranoside 742, were obtained from the soft coral Scleronephthya pallida from Thailand.⁵⁰⁸Sinularia gravis from Southern India contained (24S)-methylcholest-5-en-3β,25-diol-3-O-α-fucopyranoside 743.⁵⁰⁹

8 Bryozoans

Recent research on natural products from bryozoans has centered as much on synthesis as on structural elucidation. Six new brominated alkaloids, amathaspiramides A–F 744–749, were isolated from Amathia wilsoni from New Zealand.⁵¹⁰ Convalutamines F 750, which is cytotoxic, and G 751 and convolutamydine E 752 are additional alkaloids from A. convoluta from Florida.⁵¹¹ Convalutamydine A 753, an alkaloid from A. convoluta,⁵¹² has been synthesized from isatin as the racemate.^513,514 Debromoflustramines A 754 and B 755, the latter of which is a metabolite of Flustra foliacea,⁵¹⁵ have been synthesized using a strategy that can be applied to other alkaloids in this group.⁵¹⁶ A detailed account of the convergent synthesis of bryostatin 2 756, which is a cytotoxic macrolide from Bugula neritina,⁵¹⁷ has been published.⁵¹⁸

9 Molluscs

There was only one new paper on the isolation of sea hare metabolites. In addition to known algal metabolites, four halogenated sesquiterpenes, algoane 757, the structure of which was established by X-ray crystallography, 1-deacetoxyalgoane 758, 1-deacetoxy-8-deoxyalgoane 759 and ibhayinol 760 were isolated from Aplysia dactylomela from the Eastern Cape of South Africa.⁵¹⁹ Dolastatin 15 761, which is a cytotoxic depsipeptide from the Indian Ocean sea hare Dolabella auricularia,⁵²⁰ was prepared using a convergent synthesis.⁵²¹ The stereostructure of dolastatin I 762, a cytotoxic metabolite of a Japanese specimen of D. auricularia,⁵²² was confirmed by an enantioselective synthesis.⁵²³

The absolute stereochemistry of kahalalide F 763, which is a bioactive metabolite of the Hawaiian sacoglossan Elysia rufescens and its food source Bryopsis sp.,⁵²⁴ has been determined by acid hydrolysis and hydrazinolysis, followed by chiral analysis of the fragments.⁵²⁵ Volvatellin 764 is an unstable sesquiterpene from the Indian sacoglossan Volvatella sp. that is formally related to the green algal metabolite caulerpenyne.⁵²⁶

In the process of defining the de novo biosynthesis of drimane terpenoids in dorid nudibranchs, an additional sesquiterpene, 7-deacetoxyolepupuane 765, was isolated from Dendrodoris arborescens.⁵²⁷ 2-Isocyanoallopupukeanane 766, which is a metabolite of the nudibranch Phyllidia pustulosa from Japan,⁵²⁸ has been synthesized in good yield using an intramolecular Diels–Alder reaction to fuse the bridging cyclopentane ring to a bicyclo[3.2.1]octane unit.⁵²⁹ The Okinawan nudibranch Reticulidia fungia contained two additional members of a rare class of sponge metabolites, the carbonimidic dichlorides reticulidins A 767 and B 768.⁵³⁰ The absolute stereochemistry of the farnesic acid glyceride derivatives 769–771 from Archidoris odhneri ⁵³¹ and the drimane derivatives 772 and 773 from A. montereyensis ⁵³² were determined by total synthesis.⁵³³ Austrodorins A 774 and B 775 are tricyclic diterpenoid 2′-monoglyceryl esters from the skin of the Antarctic nudibranch Austrodoris kerguelenensis.⁵³⁴ Two additional glycerides 776 and 777 were isolated from A. kerguelenensis and the absolute configurations of 776 and the known ⁵³⁵ glyceride 778 were established using the modified Mosher method.⁵³⁶ Similar compounds, anisidorins 1–5 779–783, were obtained from the Patagonian dorid Anisodoris fontaini.⁵³⁷ The absolute configuration of anisodorin 5 783 was established by synthesis of the enantiomer.⁵³⁸ The Japanese nudibranch Chromodoris inornata contained three cytotoxic sesterterpenes, inorolides A 784, B 785 and C 786, as well as five new scalaranes 787–791.⁵³⁹ Two additional scalaranes 792 and 793 were obtained from mantle dermal formation-like structures of the Indian nudibranch Glossodoris atromarginata and from the sponge, tentatively identified as a Spongia sp., on which it was grazing.⁵⁴⁰

Three new polypropionates, capensinone 794, capensifurannone 795 and (2E,4S,6S,8S )-2,4,6,8-tetramethyl-2-undecenoic acid 796, were obtained from the South African pulmonate mollusc Siphonaria capensis.⁵⁴¹ The prosobranch mollusc Coriocella nigra contained an additional cytotoxic staurosporine analog, 4′-N-demethyl-11-hydroxystaurosporine 797.⁵⁴² The synthesis of both dorimidazole A 798 and preclathridine A 799, which were isolated from the Indo-Pacific nudibranch Notodoris gardneri,^543,544 have been reported.³²⁶

The occurrence of human intoxication due to ingestion of shellfish is providing increasing opportunities for chemists to identify new toxins, which are often related to dinoflagellate metabolites. Turbotoxins A 800 and B 801 are toxic diiodotyramine derivatives from the (inedible) viscera of the Japanese gastropod Turbo marmorata.⁵⁴⁵ The Chinese bivalve Pinna attenuata contained isomeric bicyclic ketals, attenols A 802 and B 803, which exhibited moderate cytotoxicity.⁵⁴⁶ Azaspiracids-2 804 and -3 805 are additional toxins isolated from cultivated mussels (Mytilus edulis) that were the source of human intoxication in Ireland in 1995.⁵⁴⁷ An additional yessotoxin analog, 1-desulfoyessotoxin 806, was isolated from the digestive glands of Norwegian M. edulis.⁵⁴⁸ The major toxin involved in neurotoxic shellfish poisoning associated with the New Zealand greenshell mussel Perna canaliculus was identified as brevetoxin B4 807.⁵⁴⁹ Feeding experiments have shown that the scallop Patinopectin yessoensis converts dinophysistoxin-1 808 from the dinoflagellate Dinophysis fortii into dinophysistoxin-3 809.⁵⁵⁰

10 Tunicates (ascidians)

Although tunicates (ascidians) have yielded fewer new metabolites than usual during the last year, a greater variety of structural types has been described. For example, didemniserinols A–C 810–812 are an unprecedented group of serinolipids from an Indonesian species of Didemnum.⁵⁵¹ Lissoclinolide 813, which is an antimicrobial metabolite from a Lissoclinum patella,⁵⁵² has been synthesized in an efficient manner using organozirconium chemistry.⁵⁵³ A second stereoselective synthesis ⁵⁵⁴ of lissoclinolide 813 established that it was identical to ‘tetrenolin’, which had previously been isolated from the fungus Micropolyspora venezuelensis.⁵⁵⁵ An Okinawan species of Lissoclimum contained the cytotoxic macrolide haterumalide B 814 that inhibited cell division in fertilized sea urchin eggs.⁵⁵⁶ An additional monoterpene, hydroquinone 815, the geometrical isomer of a known metabolite, was isolated from Aplidium savignyi from the Comoro Islands.⁵⁵⁷ A specimen of A. longithorax from Palau contained the isomeric longithorols A 816 and B 817, which were isolated only as their pentaacetates,⁵⁵⁸ while longithorones J 818 and K 819 ⁵⁵⁹ and longithorols C–E 820–822 ⁵⁶⁰ were isolated from an Australian specimen of the same ascidian. Longithorone B 823 from A. logithorax ⁵⁶¹ has been synthesized as the racemate.⁵⁶²

Aplidioxins A 824, the structure of which was determined by X-ray analysis, and B 825 were isolated from Aplidiopsis ocellata from the Philippines.⁵⁶³ The Australian ascidian Synoicum prunum contained three weakly cytotoxic bis-spiroketals, prunolides A–C 826–828, together with the known metabolite rubrolide A.⁵⁶⁴ Five additional lamellarins, the 20-sulfates of lamellarin B 829, C 830 and L 831, lamellarin G 8-sulfate 832 and lamellarin Z 833 were isolated from Didemnum chartaceum from the Great Barrier Reef: unusually long relaxation times were observed for certain signals in their  ¹H NMR spectra.⁵⁶⁵ Having exhausted the regular alphabet, an inhibitor of HIV-1 integrase from an unidentified ascidian from India was named lamellarin α 20-sulfate 834.⁵⁶⁶ Ningalin A 835, which is a metabolite of a Western Australian Didemnum sp.,⁵⁶⁷ and lukianol A 836 from an unidentified tunicate ⁵⁶⁸ have been synthesized using a Diels–Alder strategy.³³⁰Distaplia regina from Palau contained the antibacterial agent 3,6-dibromoindole 837,⁵⁶⁹ a structure that had been erroneously proposed as a metabolite of acorn worms.⁵⁷⁰ The first marine ergoline alkaloid, pibocin 838, was isolated as a cytotoxic and antimicrobial agent from a Far-eastern Eudistoma species.⁵⁷¹ The cyclized didemnimide alkaloid 839, earlier reported as isogranulatimide from Didemnum granulatum,⁵⁷² was isolated in very low yield from D. conchyliatum from the Bahamas.⁵⁷³ Two additional staurosporine derivatives, 3′-demethoxy-3,3′-dihydroxystaurosporine 840 and 11-hydroxy-4′-N-demethylstaurosporine 841, were isolated from Eudistoma toealensis and a flatworm of the genus Pseudoceros that preys upon the ascidian.⁵⁷⁴ A Polycitorella sp. from Okinawa contained the cytotoxic alkaloids iheyamines A 842 and B 843, the latter being optically active and therefore unlikely to be an artifact of acetone extraction.⁵⁷⁵ Two pyrazine alkaloids, botryllazines A 844 and B 845, and 2-(p-hydroxybenzoyl)-4-(p-hydroxyphenyl)imidazole 846 were isolated from a Spanish specimen of Botryllus leachi.⁵⁷⁶ Trypargimine 847, 1-carboxytrypargine 848 and 3′,5′-dibromo-4′-methoxyphenylethylamine 849 were isolated from an undescribed Eudistoma sp. from Indonesia.⁵⁷⁷ Didemnolines A–D 850–853, which are β-carboline alkaloids from a Didemnum sp. from Rota, Northern Mariana Islands,⁵⁷⁸ have been synthesized in a straightforward manner.⁵⁷⁹

The New Zealand ascidian Botrylloides leachi contained a new purine base, 1,3-dimethylguanine 854.⁵⁸⁰ Another purine base, 6-methoxy-7-methyl-8-oxoguanine 855 was isolated from Symplegma rubra from the Southeastern Brazilian coast.⁵⁸¹ A total synthesis of aplidiamine, which was isolated from an Aplidiopsis sp.,⁵⁸² provided evidence that the structure should be revised from 856 to 857.⁵⁸³ Lumichrome 858 functions as a natural metamorphosis inducer in the larvae of Halocynthia roretzi.⁵⁸⁴

There have been a relatively large number of syntheses of ascidian alkaloids and peptides belonging to classes for which no new examples have appeared. The absolute configuration of lepadin B 859, which was obtained as a cytotoxic agent from Clavelina lepadiformis,⁵⁸⁵ was determined by total synthesis.^586,587 The structures and absolute configurations of clavepictines A 860 and B 861 and pictamine 862 from C. picta ^588,589 have been verified by total syntheses.^590,591 The racemates of cylindricines A 863 and B 864, which are tricyclic alkaloids from an Australian specimen of C. cylindrica,⁵⁹² have been synthesized in good yields.⁵⁹³ (−)-Cylindricine C 865 from C. cylindrica ⁵⁹⁴ has been synthesized in 12% overall yield from (S )-butane-1,2,4-triol.⁵⁹⁵ A convergent stereoselective synthesis of the putative structure of lepadiformine 866, which was isolated as a cytotoxic agent from C. lepadiformis,⁵⁹⁶ indicated the need to re-examine the structure, stereochemistry and the claim of a zwitterionic form.^597–599 In addition, syntheses of isomeric forms of lepidaformine indicate that it is not a stereoisomer at C-2 or C-13.⁵⁹⁸

Virenamide B 867, which is a cytotoxic thiazole-containing tripeptide from Diplosoma virens,⁶⁰⁰ has been synthesized and its optical rotation has been corrected.⁶⁰¹ The macrocyclic hexapeptide bistratamide D 868 from Lissoclinum bistratum ⁶⁰² has been synthesized using a convergent strategy using enantiomerically pure oxazole, thiazole and oxazoline segments.⁶⁰³ A total synthesis of the proposed structure of trunkamide A 869, which is a cyclic heptapeptide from a Lissoclinum sp.,⁶⁰⁴ revealed that the structure of the natural product should be reinvestigated.⁶⁰⁵ The total synthesis of mollamide 870, a cytotoxic cyclic peptide from Didemnum molle,⁶⁰⁶ has been reported.⁶⁰⁷ The synthesis of tamandarin A 871, which is a cyclic peptide related to the didemnins, was announced before the structural elucidation was published! ^608,609

11 Echinoderms

In comparison with recent years, very few new metabolites have been reported from echinoderms. Two major inositolphosphoceramides 872 and 873 were identified among the lipids of the crinoid Comanthus japonica.⁶¹⁰ The neuritogenic ganglioside LMG-2, the major component of which is 874, was isolated from the Japanese seastar Luidia maculata as a mixture of closely related compounds having different alkyl chains.⁶¹¹ A similar situation applies to the ganglioside LLG-3 875, which is a metabolite of Linckia laevigata from Okinawa.⁶¹² The Japanese sea cucumber Stichopus japonicus contained SJG-1 876 as the major neuritogenic ganglioside.⁶¹³ The lengths of the acyl chains in the ceramide moieties can be determined without chemical degradation by collision-induced dissociation mass spectrometry of the sodium ion complexes.⁶¹⁴ Four additional steroidal glycosides, mediasterosides M₁877, M₂878, M₃879 and M₄880, were isolated from the deep-water seastar Mediaster murrayi as inhibitors of cell division in fertilized sea urchin eggs.⁶¹⁵ Frondoside D 881 is an additional triterpenoid saponin from the holothurian Cucumaria frondosa.⁶¹⁶

12 Miscellaneous

Although there were no reports of novel compounds from marine worms, L-ovithiol A 882, which was isolated as the corresponding disulfide, was shown to be the egg release pheromone of the marine polychaete worm Platynereis dumerilii.⁶¹⁷ Hallachrome 883, which is a pigment of the marine worms Halla parthenopeia ⁶¹⁸ and Lumbriconereis impatiens,⁶¹⁹ has been synthesized using a Diels–Alder strategy.⁶²⁰ One of the few reports of a new natural product from fishes is the isolation of α-tocomonoenol 884 from the eggs of the Pacific salmon Oncorhynchus keta.⁶²¹ 5-Deoxytetrodotoxin 885 was isolated as a minor metabolite from the ovaries of the puffer fish Fugu poecilonotus.⁶²² Chinese studies of the puffer fish Fugu vermicularis described the isolation of tetrodoine 886 and a number of tetrodotoxin derivatives, which may or may not be artifacts.^623,624

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