Amaryllidaceae muscarine imidazole oxazole thiazole and peptide alkaloids and other miscellaneous alkaloids John R. Lewis Department of Chemistry University of Aberdeen Meston Walk Old Aberdeen UK AB24 3UE Received (in Cambridge UK) 20th August 1999 Covering July 1997 to June 1998 Previous review 1999 16 389 1 Introduction 2 Amaryllidaceae alkaloids 3 Muscarine imidazole oxazole and thiazole alkaloids 4 Peptide alkaloids 5 Miscellaneous alkaloids 6 References 1 Introduction This article now contains a section on amaryllidaceae alkaloids. In recent years the paucity of information on this alkaloid group suggested that it did not warrant a chapter in its own right. Even so there are annual fluctuations as to the quantity and the quality of publications of this alkaloid family.The remaining groups of alkaloids reviewed herein namely muscarine imidazole oxazole and thiazole alkaloids are grouped into the second section while peptide alkaloids continue to require their own section. Needless to say some overlap occurs in this section as the amide grouping is sometimes only a minor functionality compared to a more significant nitrogen–heteroatom arrangement where consequently classification requires it to be elsewhere in this review. 2 Amaryllidaceae alkaloids A comprehensive review on amaryllidaceae alkaloids has appeared in the 1998 edition of ‘Alkaloids’ vol. 51 by O. Hoshino it contains two hundred and three references to their biological sources and their synthesis.1 Galanthamine 1 continues to dominate the literature mostly in investigations into the search for better sources either in tissue culture or in new Narcissus cultivars and in synthesis.Four Narcissus cultivars have been evaluated for galanthamine production. The investigation showed that planting depth density bulb size or flower bud removal did not effect the galanthamine 1 content.2 It is now possible to evaluate the quantities of galanthamine 1 and related alkaloids in wild plants Dr Lewis graduated at University College Swansea; was Fulbright Fellow in 1958 at University of Iowa Ames later becoming Senior Lecturer in Organic Chemistry at Aberdeen University. He is now retired. This journal is © The Royal Society of Chemistry 2000 or tissue cultures of Narcissus confusus using HPLC.An isocratic system employing water–acetonitrile as mobile phase supplemented with octanesulfonic acid enabled alcoholic extracts of wild Narcissus confusus bulbs leaves scapes roots and flowers to be analysed while the buds from in vitro cultures were also included in the survey.3 Narcissus confusus cultures have been examined for their galanthamine 1 content. When grown with different amounts of sucrose the alkaloid content varied with sugar concentration (8–18% w/v) optimising after fourteen days growth in a sugar concentration of 9%.4 As reported in earlier reviews on amaryllidaceae alkaloids5,6 several syntheses of chiral (2)-galanthamine 1 depend upon the synthesis of its precursor (2)-narwedine 2.Recently two syntheses have been reported for the conversion of 3,4-dimethoxybenzaldehyde into (2)-galanthamine 1 one in kilogram quantities. Basically using the same steps the first report7 57 Nat. Prod. Rep. 2000 17 57–84 coupling steps only gave a less than 2% yield. Surely this step will be even further improved in the near future. A resolution of racemic narwedine type compounds has been achieved through formation of a salt of the alkaloid with a chirally enriched organic acid e.g. di-p-toluoyl-d-tartaric acid. Thus (+)-narwedine 2 gave predominantly the (2)-narwedine salt in 83% yield which upon reduction with l-selectride gave a 73% yield of (2)-galanthamine 1. The method is applicable to numerous narwedine derivatives.9 Brunsvigia littoralis bulbs have been shown to contain four alkaloids.10 They were identified as lycorine 6 1,2-di-Oacetyllycorine 7 ambelline 8 and crinine 9.Two studies on the constituents of Crinum latifolium have reported that the leaves contain a new alkaloid 6-hydroxycrinamidine 10,11 while the dried powdered bulbs obtained also from Crinum latifolium12 have been shown to contain two pyrrolophenanthridine alkaloids namely lycorine 6 and pratosine 11. In another study13 on this plant the rhizomes have been shown to contain lycorine 6 and 3a-1,2-didehydroxycrinan- 3-ol 12. The leaves of Crinan oliganthum native to Cuba has been studied phytochemically and a new alkaloid isolated.14 Called cribetamine its structure was determined by spectroscopic measurements and comparisons with nerbowdin 13.A second report15 on this plant describes a new alkaloid called crinatine 14. It is also a member of the crinidine group of alkaloids. The recognition that cripowelline 1 14 and cripowelline 2 15 have anti-insect repellent properties has led to their being patented.16 Both these naturally occurring alkaloids were obtained from Crinum powellii. The alkaloids have also been reported in detail with the bulbs being identified as a good source for them.17 describes the half molar quantity preparation of 6-bromoisovanillin in a one-pot procedure. The oxidative cyclisation which was carried out on 4 used potassium ferricyanide in toluene– aqueous sodium bicarbonate and gave yields of ~ 30% of (+)-bromonarwedine 3.Debromination and resolution gave an overall yield of about 19% of (2)-galanthamine 1. In the second method8 a tonne quantity of 6-bromoisovanillin was produced and twelve kilogram quantities employed in the oxidative coupling step now using 5 led to an efficient conversion into (+)-bromonarwedine 3 and thence to (2)-galanthamine 1. The quantity production of this alkaloid can be seen as one of the highlights of organic chemistry since originally the oxidative Lycorine 6 has been isolated from the leaves of the tropical plant Eucharis grandiflora.18 Nat. Prod. Rep. 2000 17 57–84 58 Hymenocallis cayamansis seeds have been shown to contain four members of the tazettine group of alkaloids.19 They are marconine 16 tazettine 17 criwelline 18 and pretazattine 19.An extraction of the plant Narcissus asturiensis has shown20 that it contains hemanthamine 20 hemanthidine 21 tazettine 17 and epimacronine 22. An X-ray crystallographic study of the alkaloid ismine obtained from Narcissus asturiensis and crystallised from n-hexane–chloroform shows that it has two non-equivalent molecules in the asymmetric unit 23 through intermolecular hydrogen bonding involving the hydroxy groups.21 Pancratium foetidum has been examined for its alkaloid content and trispheradine 24 crinamine 25 haemanthidine 21 lycorine 6 and crinine 9 were found to be present.22 Many of the amaryllidaceae alkaloids are biosynthetically created by a phenol activated oxidative coupling reaction. In the laboratory a large number of oxidising agents have been successful in emulating nature.One of merit is the relatively non-toxic phenyliodine(iii) bis(trifluoroacetate) (PIFA). This hypervalent iodine reagent in poorly nucleophilic polar solvents can induce ortho–para and para–para coupling. Thus beladine derivative 26 cyclised intramolecularly to give 27 in 61% yield at 240 °C in five minutes.23 A variant in intramolecular ring closures is the dehydrobromination of phenylamine 28 by palladium acetate to give crinasiadine 29. If a palladium chloride catalyst was used triphaeridine 30 resulted.24 A rather well thought out procedure for the synthesis of (+)-narciclasine 33 involves a cyclisation of amide 31 which incorporated an epoxide grouping as a synthon for the 3,4-dihydroxy functions.This together with a hydrogen bonded carbonyl group so as to exert conformational control promoted photocyclisation. A 43% conversion to the tricyclic trans-fused phenanthridone also produced only a single diastereoisomer 32. Further manipulation resulted in (+)-narciclasine 33 in 37% overall yield.25 Pancratistatin 36 and related alkaloids such as narciclasine lycoricidine and its 7-deoxy-derivative all possess excellent antitumour properties. A new synthesis of (+)-pancratistatin 36 employs an intramolecular electrophilic aromatic substitution procedure resulting in ether 34 being converted into a diastereomeric mixture 35 upon treatment with Tf2O in base.26 Further manipulation most of which has already been published, 27 gave the natural product.Benzo[c]phenanthridine alkaloid chelerythrine 39 is also synthesised by an intramolecular ring closing reaction involving an amide. In this case 6-halo-2,3-dimethoxy-N-methyl-N-(6,7-methylenedioxy- 1-naphthyl)benzamide 37 upon treatment with Heck reagent palladium(iii) acetate with ligand POT in DMF under reflux gave oxychelerythrine 38 in < 90% yield. A small improvement in yield was achieved with the iodo-precursor rather than using the bromo-amide. Reductive deoxygenation gave chelerythrine 39.28 An intramolecular concerted pericyclic allenesilane imino ene cycloaddition is the key step in the synthesis of the 5,11-methanomorphanthridine alkaloids (2)-montanine 44 (2)-coccinine 45 and (2)-pancracine 46. Thus 40 prepared from 41 and 42 by heating in mesitylene at 50 °C followed by TBAF treatment at 0 °C and deprotection enabled reduction to ene 43 which could be converted into natural products 44 45 and 46.29,30 Tetracyclic tazettine 17 has been synthesised in sixteen steps and in 11% yield.31 Several synthetic steps deserve mention in the creation of the stereochemistry required for this alkaloid.Firstly acyl azide 47 reacted with an excess of Warkentin oxadiazoline 48 to give 49. Acid hydrolysis of the acetal gave a 59 Nat. Prod. Rep. 2000 17 57–84 cyclic alcohol which after acid treatment and methylation gave enone 50. Samarium iodide HMPA–NaBH4 reduction gave the trans fused product 51 which on reintroduction of the double bond affording 52 and manipulation of ring A via 53 gave racemic tazettine 17 It appears that tazettine is not a natural product but an artefact derived from pretazettine 19 during work up.Pavine alkaloid thalimonine 55 has been synthesised by an acid-mediated cyclisation of the 1,2-dihydroisoquinoline 54. The resulting racemic mixture being resolved to give the natural (2)-enantiomer.32 3 Muscarine imidazole oxazole and thiazole alkaloids A facile synthesis of (2)-allomuscarine 58 has been reported33 which starts from easily obtainable 1-dimethylamino-1,3,6-trideoxyhexitol 56 whereby HF treatment gives the 2,5-anhydride 57 that upon methylation produces (2)-allomuscarine 58. In principle (+)-allomuscarine could be synthesised utilising the enantiomer of 56.A number of marine sponge metabolites contain the imidazole ring system and frequently it is substituted in the two position by an amino-grouping. It has now been established that NCS oxidation of 59 in methanol gives the trans adduct 60 predominantly (99%). Thermal elimination of methanol gives diene 61 which can be acylated with brominated pyrrole carboxylic acids to give a variety of natural products.34 Employing a Stille coupling procedure it has been found that the protected bromoindolylmaleimide 62 reacts with 5-tributylstannyl-1-methyl-1H-imidazole to give 63 which was subsequently converted into didemnimide C 64. Irradiation of 63 with a halogen lamp in the presence of iodine gave pentacyclic 65 and it is thought that these cyclodidemnimides will soon be found as natural products.35 A Streptomyces species isolated from a soil sample has been found to produce a novel amino acid.36 Designated TU-185 it has an imidazole-ornithine structure 66.Nat. Prod. Rep. 2000 17 57–84 60 (2)-Phenylahistin 67 is a new type of mammalian cell cycle inhibitor obtained as a racemic mixture from the fungus Aspergillus ustus.37 Separation of the enantiomeric mixture by HPLC gave the S-enantiomer which was active but the R-isomer was not. In a series of Caribbean sponges belonging to the Agelas family all four namely Agelas clathrodes Agelas conifera Agelas dispar and Agelas longissima contained a number of known bromopyrrolo imidazole alkaloids interestingly they all contained the novel alkaloid dispacamide C 68.38 Taurocidin A and taurocidin B are bioactive constituents of a marine sponge of the Hymeniacidon family.Their structures were elucidated by spectroscopic measurements and they have both been shown to have a taurine residue attached to the 2-amino-imidazole ring i.e. 69 and 70.39 A synthesis of the marine imidazole alkaloids croidine 72 clathrodine 73 and hymenidine 74 has established a general synthetic route to imidazole alkaloids starting with the ‘trans’ propene amine 71 whereby condensation with the appropriate brominated pyrrole-2-carboxylic acid led to each of the natural products. A synthesis of the ‘cis’ propene amine 75 ultimately led to the first formal synthesis of keramadin 76.40 2-Thiohydantoin 77 is the starting point for the first synthesis of the marine sponge natural product dispacamide 81.41 Its condensation with aldehyde 78 in the presence of piperidine afforded stereochemically (Z) pure alkylidene thiohydantoin 79.Regioselective S-methylation produced 80 and thence to dispacamide 81 by heating to 60 °C in a sealed tube with ammonia. Alternatively thiohydantoin 79 could be directly converted into 81 by treatment with tert-butyl hydroperoxide in aqueous ammonia at room temperature. A synthesis of polycarpine 83 the sulfur containing alkaloid found in the ascidian Polycarpa aurata has been achieved first through the synthesis of key intermediate 82. Reaction with Sethylthiourea in base followed by treatment with S2Cl2 in acetic acid gave polycarpine 83 as its dihydrochloride salt.42 The Micronesian sponge Leucetta cf chagosensis contains four new imidazole alkaloids as well as the known isonaamidine B 84.The new ones are isonaamine B 86 and isonaamidine D 85 together with the zinc complex of isonaamidine B 87 and a mixed zinc complex 88 containing both isonaamidine B and isonaamidine D.43 Pyronaamidine 9-(N-methylimine) 89 is a new imidazole alkaloid isolated from a sponge of the Leucetta family. This coloured sponge was characterised as Leucetta sp cf chagosensis and was located in Micronesia near Rota Island. It is made up of small bright lemon coloured semispherical masses.44 A total synthesis of the imidazole alkaloid kealiiquinone 91 has resulted in a tautomeric compound 92 being prepared.45 This may be due to the penultimate step of oxidation of phenol 90 in the presence of salcomine and oxygen in acetonitrile giving preferentially 92.There is an equilibrium between 91 and 92 which depends upon the solvent. The synthesis of a number of sarcodictyins which includes the first total synthesis of sarcodictyin B 93 has allowed some structure–activity relation- 61 Nat. Prod. Rep. 2000 17 57–84 ships to be made of the antitumour activity of these marine natural products and to relate this to the eleutherobins.46 The antitumour active metabolite obtained from Streptomyces species NA 22598 has been identified as 94.47 The oxazoline ring system has been found in the secondary metabolite obtained from the culture broth of Actinomadura species MJ502-77F-8.Methyl 2-(2A-hydroxyphenyl)-4,5-dihydro-oxazole-4-carboxylate 95 was identified by spectroscopic methods and was reported to be an antibiotic.48 Two novel oxazole alkaloids have been isolated from two species of ladybirds.49 Both insects Epilachna varivestis and Epilachna borealis contain bicyclic alkaloids 96 and 98 together with their cogeners 97 and 99. Martefragin A 100 is a metabolite found in the red alga Martensia fragilis. Structure elucidation was achieved by spectroscopic measurements on its methyl ester.50 A total synthesis of rhizoxin D 109 employs a convergent enantiocontrolled procedure.51 The difficult macrolactonization steps 106 to 107 were circumvented by first assembling 106 through Wittig reaction of aldehyde 101 with bromodiene 102 which gave a mixture of epimeric alcohols which could be separated by flash chromotography to give the required epimer 103.Its enantiomer 104 could be recyclised to 103 by oxidation and reduction using (R)-2-methyl-CBS-oxazaborolidine. Extension to the ester 105 was followed by release of aldehyde 106 so that an intramolecular ring closure employing the Horner– Emmons procedure created macrocycle 107. Modification via deprotection and attachment of the oxazole terminus completed the synthesis (Scheme 1). Two papers52,53 describe approaches to the synthesis of rhizoxin 110 in convergent terms by dividing the molecule into two sections as indicated in structure 110 (wavy lines). The synthesis is yet to be completed.Verongida sponges Aplysina acrophoba and Aplysina cavernicota contain a number of modified tyrosine derivatives related to the bromotyrosines. Two new metabolites recently found are oxohomoaerothionin 111 and 11-hydroxyfistularin 112.54 The marine sponge Discodermia calx contains the bioactive marine metabolite dephosphonocalyculin A 113.55 Its absolute stereochemistry was determined by converting 113 and calyculin A56 into a common compound. A new antimicrobial and cytotoxic substance 16-methyloxazolomycin 114 has been obtained from a species of Streptomyces. 57 The Horner–Emmons procedure for intramolecular cyclisation through lactone formation has also been successfully applied58 in the synthesis of the antibiotic (2)-madumycin 115.The determination of the absolute configuration of natural products normally involves X-ray crystallographic measurements or chemical degradation. Using hennoxazole A 116 it has been shown that applying ab initio calculations it is possible to combine molar rotation angles for ‘molecular fragments’ of the parent molecule and so determine which stereochemical arrangement is correct. Thus fragments 117 118 and 119 gave the required data for hennoxazole A’s absolute stereochemistry. 59 A synthesis of (+)-nostocyclamide 120 has supported the stereochemical assignment as 2S,12R even though the optical rotation of the synthetic product is +51° while the natural product was +25°. The discrepancy is possibly due to the fact that only a small quantity of the natural product has been available.60 Scheme 1 Reagents i BuLi (2 equiv.) THF–Et2O–pentane (4+1+1); 2120 °C to 90 °C then 102 290 °C to 278 °C; ii TPAP NMO 4 Å sieves CH2Cl2; iii (R)-2-methyl-CBS-oxazaborolidine BH3 THF 210 °C; iv SEMCl iPrEtN CH2Cl2; v TBAF THF; vi diisopropylphosphonoacetic acid 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide methyl toluene-psulfonate DMAP 4 Å series CH2Cl2; vii HOAc–H2O (4+1) 48 h; viii NaIO4 THF–H2O; ix DBu (2 equiv.) CH3CN; LiCl (15 equiv.) 4.6 31024 M; x Horner–Emmons cyclization; DDQ H2O CH2Cl2; xi MnO2; xii KHMDS 4-(3-diphenylphosphinoyl)-2-(methylpropenyl)-2-methyloxazole; xiii Me Dolastin 1 121 is a cyclic hexapeptide isolated from the Japanese sea hare Dolabella auricularia and it has been identified by spectroscopic analysis.61 Its absolute stereochemistry came from its hydrolysis and identification of the chirality of the amino-acid components so released.Dolastin 18 122 has been isolated also from the sea-hare Dolabella auricularia but 2BBr THF–CH2Cl2 0 °C. Nat. Prod. Rep. 2000 17 57–84 62 by using a cancer cell growth inhibitor test62 so as to focus on the active constituent. (+)-Curacin A 123 is a relatively unstable molecule and consequently is unlikely to become a drug for cytotoxic purposes. Its mode of action through colchicine binding and consequently causing tubulin polymerisation inhibition has prompted several synthetic procedures. The latest63 offers yet another route to the natural product and its modification will lead to analogues.A series of bactericidal and antimycotic agents have been obtained from the culture broth of strain DSM10320 of Sorangium cellulosum.64 Two such metabolites are thuggacin A 124 and thuggacin B 125. The total synthesis of (2)-pateamine A 128 the novel immunosuppressive agent found in the Mycale sponge family has been reported.65 A novel feature involves the use of a blactam functionality so that its hydrolysis causes an intramolecular lactonisation to take place. Thus 126 upon treatment with 9 equiv. of Et4NCN in chloroform at room temperature gave a 68% yield of 127. Although epothilone A 129 and epothiline B 130 have been synthesised previously the newest approach employs solid state methodology. This enables a variety of analogues to be created and to be assessed66 for their effectiveness against taxol resistant cancer cell lines.Oriamide 131 is a cyclic peptide containing the unprecedented amino acid 4-propenoyl-2-tyrosylthiazole. This unusual thiazole containing alkaloid was obtained from a sponge of the Theonella family.67 In the convergent synthesis of (2)-mirabazole B 133 a linear tripeptide amide 132 which contains three S-benzyl-2-methylcysteine residues could be converted into the thiazoline/thiazole rings using titanium tetrachloride and thence to 133.68 A bioassay guided fractionation has led to the isolation of a new cyclic peptide preulithiacyclamide 134 from the ascidian Lissoclinium patella. It has a high macrophage scavenger receptor inhibitor property but it was not as active as ulithiacyclamide69 135 which was also present in the extract.70 Thiostrepton Sch40832 is a new minor component found in the antibiotic complex produced by Micromonospora carbonacea africana. This disaccharide containing sulfur rich metabolite 136 is an active Gram-positive bacteriostat.71 4 Peptide alkaloids A succinylanthranilic acid ester 137 has been obtained from the methanolic extract of the dark brown alga Jolyna laminarioides. This metabolite exhibited chymotrypsin inhibitory activity and some antifungal activity.72 Circinamide 138 is a novel and the first papain inhibitor to be isolated from the cyanobacterium Anabaena circinalis which was cultured on a CB medium under aerobic conditions and the freeze dried cells extracted with ether–water.Activity was 63 Nat. Prod. Rep. 2000 17 57–84 metabolites namely myxopyronin A 141 and myxopyronin B 142 differ only in one of the side chains and consequently a found in the aqueous layer and 138 was isolated as a bright yellow solid.73 A new ceramide 139 isolated from the epiphylic dinoflagellate Coolia monolis has an unusual side chain in that it is branched. This also gives rise to the recognition of a new type of fatty acid one with nineteen carbon atoms.74 Inhibitor activity in vitro is displayed by metabolite 140 isolated from a Fusarium mycotoxin both Gram-positive and Gram-negative bacteria being affected. Its synthesis was easily undertaken by the condensation of 5-ethoxyfuran-2(5H)-one with acetamide which occurred in hot concentrated hydrochloric acid to give the natural product.Synthetic analogues only showed minimal biological activity.75 Myxopyronins were the RNA polymerase inhibitors isolated from gliding bacteria in the early 1980’s. Two of these Nat. Prod. Rep. 2000 17 57–84 64 synthesis has been devised to introduce side chains onto a core pyrone. This procedure however resulted in racemic products. 76 Giganticine 143 is a novel nonprotein amino acid isolated from the root bark of Calotropis gigantea. It has some antifeedant properties as well as a variety of homeopathic applications.77 cis-p-Coumaroylaginatine 144 is a genuine leaf opening substance isolated from Albizzia julibrissin. As it easily opens the leaves of this plant it has stimulated the research for an unknown substance that causes its leaf closing.78 Nat.Prod. Rep. 2000 17 57–84 Radiosumin 149 is a trypsin inhibitor obtained from the fresh water blue–green alga Plectonema radiosum. Its synthesis79 was based primarily on the assumption that both amino-acid components possessed the same stereochemistry namely S at C- 7. Thus the synthesis of methyl 2-amino-3-(4-acetylaminocy- 65 clohex-2-en-1-ylidene)propionate 145 and of methyl 2-methoxyimino-3-(4-aminocyclohexylidene)propionic acid 146 protected respectively as the benzyloxycarbonyl group 147 and with the tert-butoxycarbonyl group 148 thus enabled condensation to be achieved with diethyl phosphorocyanidate [DEPC(EtO)2P(O)CN].Diastereoisomer separation gave 150 whereupon deprotection produced the natural product 149. Epoxyquinomicins A B C and D 154 are new antibiotics isolated from the fungal broth of an Amycolatopsis fungus. Their structures80 and biological properties81 have been described in some detail. Rufulamide 155 is an oligopeptide analogue isolated from the liverwort Metzgeria rufula. Its structure consists of two anthranilic acid units coupled through l-glutamic and malonic acids. Its synthesis was achieved by normal peptide procedures. 82 Korormicin 156 had been isolated from the marine bacterium Pseudoalteromonas species F-420 found on the surface of a species of a macroalga of the Halimeda family. It appears to exhibit antimicrobial activity against marine Gram-negative bacteria.83 Substance FA-70D 157 is produced by a Strepto- Nat.Prod. Rep. 2000 17 57–84 66 myces species called strain FA-70D. It has been reported and patented84 as useful for the treatment of osteoporosis due to its ability to inhibit specifically cathepsin proteases. Malyngamides M and N have been isolated from the Hawaiian red alga Gracilaria coronopifolia. This alga had been previously found to have been associated with an unusual food poisoning epidemic in Hawaii but these two new metabolites 158 and 159 are not thought to be the causative agents.85 The three gymnastatins namely A B and C are produced by a strain of the fungus Gymnascella dankaliensis obtained from the sponge Halichondria japonica.86 Structural modification occurs mainly in the six membered ring A is 160 B is 161 and C 162.A novel antibiotic has been produced by shake culture of species 2128 of a Penicillium fungus. Designated E-2128-1 163 shows an inhibitory effect on 1L-1 production.87 Andrimide (164) isolated from the natural bacterium Pseudomonas fluorescens has been found to be bacteriostatic towards Gram-(+) and Gram-(2) bacteria and preferentially inhibited RNA polymerase and UMP kinase activities.88 Microginin 299A and microginin 299B are metabolites produced by the cyanobacterium Microcystis aeruginosa which is a causative agent for bloom in fresh water lakes. Both these 4 dioxane reflux 20 h; vi 70% HClO4 Scheme 2 Reagents i (i) EtOH EtONa reflux 2 h then acrylonitrile H2O dioxane reflux 2.5 h; ii CH2N2 ether then NaBH4 CeCl3 MeOH 0 °C to rt 3 h then H+; iii (CH2OH)2 TsOH benzene reflux 8 h; iv LiAlH4 ether 0 °C 3 h; v 17% HClO dioxane reflux 20 h.colourless amorphous compounds 165 and 166 have leucine aminopeptidase inhibitor properties.89 A glutamate receptor antagonist called kaitecephalin 167 has been isolated from the fungus Eupenicillium shearii species PF 1191.90 Yunnanmycin antibiotics which are claimed to have low toxicity are produced by culturing Streptomyces species strain 2321.91 Typical is yunnanmycin 168 R = H but other antibiotics found in this culture fluid are its acid derivatives where R = H Na K NH2 Me or Et. Dipeptides TAN A B C and D are antibiotics successful in the treatment of methicillin resistant Strephylococcus aureus.92 These metabolites isolated from the bacterium Flexibacter species PK-72 and PK-176 have been synthesised and their structures thus confirmed.A and B are stereochemically related at C-5 (169) as are C and D at C-2 (170). Two cytotoxic macrolides found in the common Caribbean sea whip Eunicea succinea possess a salicyl grouping involved in a twelve membered ring 171. Structurally they are related by being geometric isomers at C-17. Salicylihalamide A is the Eisomer and salicylihalamide B is the Z-isomer. From an analysis of structures recorded on the NCI data base these metabolites represent a new class of cytotoxic agents.93 Celenamide E 172 is a tripeptide alkaloid obtained from the Patagonian sponge Cliona chilensis.An unusual feature structurally is its dehydro amino-acid moiety.94 Cherinonaine is a novel dimeric amide found in the stems of the plant Annona cherimola.95 It has a unique ether bridge between two monomeric amides 173. Amonabactin 174 is the name given to a family of novel siderophores isolated from a pathogenic bacterium. These iron chelating compounds found in Aeromonas hydrophilia are thought to be paramount in the organisms growth under low iron concentrations.96 Cymbimicin A 175 and cymbimicin B 176 possess novel cyclophilin binding behaviour; A being one hundred times more active than B; they were isolated from a strain of Micromonospora by a bioassay monitored separating procedure.97 67 Nat. Prod. Rep. 2000 17 57–84 The tunicate Aplidium lobatum contains two novel cytotoxic macrolides99 Lobatamide A 178 occurs with its isomer B.A mixture of antimycin A5 and A6 can now be produced in a shake culture of Streptomyces species POL-129. A6 179 is marginally in excess.100 Antifungal antibiotic UK-3A has the novel structure 180 although somewhat related structurally to Nat. Prod. Rep. 2000 17 57–84 68 The structural elucidation of YM-75518 an antibiotic isolated from Pseudomonas species Q 38009 was obtained by extensive NMR spectroscopy revealing the novel macrolide structure 177.98 2 Pd–C CH2Cl2–MeOH (90+10) rt 10 h; vii Scheme 3 Reagents i EDCl DMAP CH2Cl2 rt 4 h; ii O3 CH2Cl2 278 °C 0.5 h; iii H-Leu-OBut CH2Cl2 278 °C 1 h; iv AgNO3 THF– H2O (4+1) rt 24 h; v TFA–CH2Cl2 (1+1) rt 1.5 h then DPPA NaHCO3 DMF 215 °C 40 h; vi H 6-methylhept-2-enoic acid EDCl rt 3 h.antimycin A it is much weaker in activity. It was found in the mycelial cake of Streptomyces species 571-02.101 Another chaetoglobosin designated P 181 has been obtained from a fungus of the genus Discosia.102 dioxane to give cyanide 185. Protection of the diketone as its enol ether enabled reduction of one keto group which was dehydrated in situ to produce a,b-unsaturated ketone 186. Ketalization allowed reduction to amine 187 and thence to dienamine 188. A tandem Michael addition and intramolecular Hannich reaction between 188 and 189 gave the tetracyclic molecule 190 which could then be manipulated to create (+)-huperzine B 191 Scheme 2.105 Puberulin A 192 is a new diketopiperazine alkaloid isolated from the fungus Penicillium regulosum.106 Xylaria hypoxylon is a fungus isolated from soil containing decayed wood chips.On cultivation it produced six new cytochalasins.107 They are designated 19,20-epoxycytochalasin R 193 18-deoxy- 19,20-epoxycytochalasin R 194 18-deoxy-19,20-epoxycytochalasin Q 195 19,20-epoxycytochalasin N 196 19,20-epoxycytochalasin C 197 and 19,20-epoxycytochalasin D 198. Two known bengamides A and B together with five related new amino acid derivatives have been isolated from the marine sponge Jaspia carteri.108 Designated bengamides G H I J and K they are 199 200 201 202 while K is a relative of bengamide B having a shorter side chain 203. Four thirteen membered ring spermidine alkaloids have been synthesised using a common synthon namely the diazalactam 204.109 Addition of the appropriate acyl residue was introduced using the Mukaiyama procedure i.e.the carboxylic acid Nmethyl-2-chloropyridinium iodide in triethylamine–methylene chloride was stirred at room temperature prior to the addition of synthon 204. After several hours the reaction mixture was worked up to give the natural product (2)-(S)-celacinnine 205 (2)-(S)-celabenzine 206 or (2)-(S)-celafurine 207. Acetylation of (2)-(S)-celacinnine 205 gave its N-acetyl derivative namely (2)-(S)-viburnine 208. Using the established synthetic strategy for spermidine alkaloids reported in a previous review,110 the spermidine alkaloids (+)-(2S)-dihydromyricoidine 209 and (+)-(2S)-myricoidine 210 have been synthesised.111 Apochalasins are antibiotic metabolites produced by the fungus Aspergillus.A new species FO-4282 has been cultivated and it produced two new metabolites apochalasin F 211 and apochalasin G 212.112 A biamide with an unusual structure called bahamamide 213 has been isolated from an undescribed marine bacterium designated CNE-852.113 Antitumour metabolite FE 399 214 is produced by cultivating the filamentous fungus Ascochyla.114 The synthesis of eurystatin A 223 has been achieved using an acyl cyanophosphorane methodology first to produce the a,b-diketo-amide group necessary for its synthesis. Thus protected alanine 215 upon treatment with cyanophosphorane 216 gave 217 which on ozonolysis gave diketonitrile 218 which reacted in situ with leucine tert-butyl ester.Further peptide extension with ornithine gave 219. This was followed by deprotection of 219 and intramolecular cyclisation of this peptide 220 to give macrocycle 221 which on further deprotection gave amine 222 whereby 6-methylhept-2-enoic acid could be attached via EDCl mediation115 to give the natural product 223 (Scheme 3). A methanol extract of the seeds of Albizia lebbek contained three new macrocyclic alkaloids belonging to the budmuchiamine family. They are budmuchiamine L4 224 budmuchiamine L5 225 and budmuchiamine L6 226. Budmuchiamines A B C and D were also found in this extract.116 Verballoscenine 227 is the Z-isomer of verbascenine 228 and was found in the leaves of the plant Verbascum phoeniceum.117 Also present were the N-unacetylated analogues verbacine and verballocine.Using a new test procedure for identifying mitotic inhibitors it has been possible to isolate a new mammalian cell cycle inhibitor in the culture fluid of a Phoma species (SNF 1778). Compound 182 belongs to the cytochalasin group of natural products and is accompanied by its 6,7-deepoxy compound which is presumably its biogenetic precursor.103 Rubrobramide 183 is a cytotoxic and phytoxic metabolite found in the culture filtrate of Cladobotryum rubrobrunnesceus.104 The first total synthesis of huperzine-B 191 produced this Lycopodium alkaloid in racemic form. It took twelve steps with an overall 6.6% yield.Thus ketoester 184 via an intramolecular Dieckmann condensation added to acrylonitrile in refluxing Antitumour substances designated BE 42303 229 are manufactured with a Streptomyces species A42303. In all four metabolites A B C and D were isolated and the patent describes the synthesis of C and D from A and B respectively.118 A synthesis of both antitumour macrolides cryptophycin 1 233 and cryptophycin 8 234 has been described.119 The procedure is 69 Nat. Prod. Rep. 2000 17 57–84 70 Nat. Prod. Rep. 2000 17 57–84 efficient and enantiospecific and a particularly interesting feature is the creation of the epoxide grouping using reagent 4-azido-1,1,1-trimethoxybutane so as to give the ester 230 which was employed to stereospecifically create chloro-ester 231 which could then be hydrolysed under mild conditions so as to create chloro-alcohol 234 and thence cryptophycin D 233.Lebstatin 235 is a cell cycle inhibitor manufactured from Streptomyces hygroscopicus.120 An expeditious synthesis of geodiamolide A 236 has employed an efficient combination of tripeptide and polypropionate units using an Evans asymmetric alkylation the Mitsunobu esterification and the macrolactamization proceeded through use of di-phenylphosphorazidate.121 Cremimycin 237 is a novel nineteen membered macrocyclic lactam antibiotic isolated from a Sreptomyces strain.122 A total synthesis by solid phase methodology of oscillamide Y 239 has been reported.123 An aminomethyl polystyrene resin was used as the core and subsequently six amino acids were connected to give the protected open chain peptide precursor 238.Deprotection allowed cyclisation to be induced using PyBroP and DIPEA in DMF and the resulting cyclic peptide was cleaved from its core suport using weakly diluted trifluoroacetic acid. Since all four enantiomeric amino acids were used in this synthesis individually the natural products’ structure was confirmed as having l-N-methylalanine and lhomotyrosine incorporated in the metabolite. Cyclocinamide A 240 is an unusual cytotoxic halogenated hexapeptide isolated from the marine sponge Psammocinia. One of its unusual features is its tetrapeptide core.124 A total synthesis of (2)-mycotrienol 242 and (+)-mycotrenin-1 243 used as a penultimate step a tandem Stille coupling procedure to produce configurationally pure (E,E,E)triene 241 which could be oxidised with ceric nitrate to quinone and then to 242.If addition of the cyclohexylcarbonyl-d-alanine entity proceeded CAN oxidation it produced (+)-mycotrenin 1 243.125 The total synthesis of macbecin-1 245 was also obtained by elaboration of an aromatic carboxylic acid precursor 244 which was cyclised and oxidised to the quinone macbecin-1 245.126 A total synthesis of (+)-damavaricin D 246 a member of the streptovaricin group of antibiotic alkaloids also used the amide link as the macrolide forming step.127 Goniothalactam 247 is a new alkaloid found in the bark of Goniothalamus borneensis.128 In all twelve natural products were isolated in this investigation but the other eleven were nonalkaloidal.A novel cinnamide dimer 248 has been isolated as a minor component of the Indian Ocean soft coral Sinularia flexibilis. 129 More cyclopeptide alkaloids have been isolated from Scutia buxifolia found in South America. Scutianine K 249 and scutianine 250 have been characterised by spectroscopic analysis.130 71 Nat. Prod. Rep. 2000 17 57–84 Exumolides A and B are cyclic hexadepsipeptides possessing antimicrobial activity. Isolated from a species of the marine fungus Scytalidium they have been characterized as 251 and 252 respectively.131 A further examination of the sea hare Dolabella auricularia guided by bioassay has located another human cancer cell growth inhibitor called dolastin 16 it has structure 253.132 Dolastin 17 (254) isolated from the same species of sea hare is reported to have an unusual alkyne feature.It also exhibited significant human cancer cell growth inhibitory activity.133 An examination of the metabolites of the mollusc Philinopsis speciosa has yielded information into the interrelationships of their diet. This latest study134 has found five new depsipeptides namely kulolide-2 255 kulolide-3 256 kulokainalide-1 257 kulomo’opunalide-1 258 kulomo’opunalide-2 259 together with linear peptide pupukeamide 260 and macrolide tolytoxin 23-acetate 261. From these metabolites it has been suggested that the algal diet of sea hares and molluscs plays an important part in the creation of these more structurally complex metabolites.Cupolamide A 262 is a cytotoxic cyclic heptapeptide found in two samples of the sponge Theonella cupola.135 Another total synthesis of cyclotheonamide B 265 uses two key intermediates 263 and 264 in a flexible convergent procedure. The yield being 1.8% over seventeen steps.136 Mozamide A 266 and moxamide B 267 are new metabolites found in a sponge belonging to the Theonellid family.137 Thiocoraline 268 is a novel depsipeptide alkaloid found in the mycelium of the marine fungus Micromonospora species l- 13-ACM2 = 092. This interesting cyclic thiodepsipeptide has antitumour antibiotic properties.138 Octapeptide cyclogossine B 269 is found in the latex of the Euphorbiaceae tree Jatropha gossypifolia.139 Omphalotin is a new cyclic peptide alkaloid isolated from Omphalotus oleaurius.Its structure has been determined as 270 the structure of the decapeptide ring being established by hydrolysis followed by Nat. Prod. Rep. 2000 17 57–84 72 HMBC and NOESY correlations to determine the sequence of amino acids.140 A cyclic peptide named RP-1776 (271) has been obtained from the aerobic culture fluid of a Streptomyces species.141 Compound 271 possesses antibacterial activity. The total synthesis of himastatin 272 has resulted in a revision of its previous stereochemistry.142 Complestatin 273 and chloropectin 274 its isomeric congener are both bicyclic hexapeptides isolated from a Streptomyces species.143 Acid treatment of 273 results in the formation of 273 and it has been suggested that this transformation occurs through a cyclopropane intermediate 275.5 Miscellaneous alkaloids The fresh pods of Moringa oleifera contain an unusual glycoside called miazidin it contains an O-nitrile thiocarbamate grouping 276.144 The new lysine derivative 277 has been found in two species of marine sponges. The first was Axinyssa terpnis and the second source of this zwitterion was Axinella carteri.145 A new juvenile hormone biosynthesis inhibitor called brevioxime 278 has been isolated from the microorganism Penicillium brevicompactum. This unusual heterobicyclic ring system was identified primarily by X-ray crystallography and as the first inhibitor produced by a fungus with this type of activity.146 Macrocyclic polyamines are defence substances associated with the pupal stage of the coccinellid beetle Epitachna borealis.These are made up of large ring lactonic structures derived from a set of 2-(hydroxyethylamino)alkanoic acids. Epiachnene 279 is the simplest and the most abundant macrocyclic metabolite isolated.147 Of the more complex polyamines is 280 where n m o p and q can have values of five six or seven. The growth stimulator produced by the fungus Propiolacterium freudenreichii was found to be 2-amino-3-carboxynaphtho-1,4-quinone 281.148 (+)-Norlumicine’s structure 282 has been completely elucidated by X-ray analysis.149 73 Nat. Prod. Rep. 2000 17 57–84 Nat. Prod. Rep. 2000 17 57–84 74 3N 2Cl2 0 °C 1 h; iii NaI acetone reflux 3–4 h; iv DMPU–THF (1+1) Sixteen alkaloids have been identified as being present in the roots of Aristolochia triangularis.150 The new ones are triangularine A 283 and triangularine B 284.Lissoclin disulfide 285 is a novel dimeric alkaloid found in a bioassay guided fractionation of a methanol extract of an ascidian of the Lissoclinum family.151 The phenazine alkaloid from a marine Streptomycete species is new,152 it is 5,10-dihydrophencomycin methyl ester 286. Two phenazine alkaloids produced by a new halophilic marine bacterium called culture LL-141352 were Scheme 4 Reagents i NaH BnBr DMF 0 °C > rt 15 h; ii MsCl Et CH 215 °C 30 min to rt overnight; v excess Na ButOH NH3 Et2O 240 °C 3–4 days; vi LDA 3-picoline 307 THF 278 °C 30 min then 309 or 310; vii MCPBA CH2Cl2 0 °C 5 h to rt overnight; viii KI CH3CN reflux 4 days.identified as pelagiomicin A 287 and pelagiomicin B 286. Both are quite toxic substances.153 The tunicate Ritterella tokioka is a prolific producer of alkaloids of the ritterazine group some twenty nine compounds have been isolated. The most recent publication describes thirteen new ones namely ritterazines N to Z.154 Their structures are based largely on two hexacyclic ring systems connected through nitrogen. Thus ritterazine N is 287 O is 290 P is 291 75 Nat. Prod. Rep. 2000 17 57–84 Q is 292 while Z is 293. All thirteen alkaloids have been evaluated for cytotoxic activity and some structure activity assessment made. A stereoselective synthesis of penaresidin A 300 has been achieved starting with the Gamer aldehyde 294.155 It was first converted into its extended aldehyde 295 and when condensed with Wittig reagent 296 it gave a diastereomeric mixture at C15 and C16 297.Ring opening of the N,O-acetonide gave after protection and mesylation of the hydroxy groups 298. Ring closure of the azetane 299 then proceeded to give penaresidin A 300. Several amino acids of a non-protein nature have been isolated from the seeds of Cycas revoluta.156 Two new ones are Nat. Prod. Rep. 2000 17 57–84 76 cycasindene 301 and cycasthioamide 302. Haliclamine A 316 is said to be biogenetically related to the manzamines in that it is the nearest bisdihydropyridine so far found naturally. Its total synthesis has been reported.157 Butane-1,4-diol (303) was modified to the protected mesylate 304 which could be condensed with lithioalkyne 305 to give 306 which upon reduction with sodium metal in tert-butyl alcohol simultaneously removed the protecting group and produced E-alkene 307 which was mesylated and iodinated to give 309.In a similar manner related alkyl chain 310 was prepared and it remained for both to be attached to 3-methylpyridine (311). This was achieved by LDA activation of the methyl-group on 311 and attachment occurred by iodide displacement to give 312 and thence to the mesylate 314. Similarly 316 was prepared from 310 and 3-methylpyridine (311). Protection of the heterocyclic nitrogen in 314 by N-oxide formation 315 enabled it to condense with 316 giving 317. Mesylation and N-deoxygenation allowed ring closure where upon sodium borohydride reduction resulted in the formation of haliclamine A 318 (Scheme 4).Malonylniphimycin 319 is a macrolide antibiotic obtained from the culture fluid of Streptomyces hygroscopicus B-7.158 Polaramycin A 320 and polaramycin B 321 are two new antifungal antibiotics isolated from the culture fluid of hygroscopicus species LP-93.159 Some fourteen alkaloids have been isolated from the prosobranch mollusc Lamellaria in the past fourteen years and now the first synthesis of lamarin class marine alkaloids namely laminarin D 327 and laminarin H 328 has been reported.160 Firstly benzylisoquinoline 322 synthesised in a conventional procedure was condensed with ester 323 through the use of LDA to give 324.Quaternization of 324 with ethyl bromoacetate gave 325 which could be cyclised to the laminarin type structure 326 through removal of the MOM protecting group and treatment of the resulting phenol with triethylamine – all in a one pot procedure. Finally removal of the benzyl protecting groups gave laminarin D 327. Lamarin H 328 was also synthesised from 326 through simultaneous Odemethylation and deprotection with BBr3. A different synthetic approach is the convergent synthesis of lamellarin K 333. In this procedure161 an intramolecular [3+2] cycloaddition of 331 occurred in situ when 329 and 330 were mixed in dichloroethane in the presence of Hunig’s base and heated to 83 °C giving 332. Removal of the isopropyl ether groups with aluminium trichloride produced alkaloid 333.The shrub originating from Lijiang in China Cephalotaxus forturnei has been found to contain three alkaloids;162 the new one is called fortunine and its structure is 334. A stereocontrolled synthesis of (±)-9,10-dideoxynorribasine 338 an alkaloid found in Fumariaceae plants was successfully completed163 by treating cis-2-amino-1-inandol 335 to aqueous basic conditions whereupon the nitrile group was hydrolysed and intramolecularly cyclised to 336. This lactam was reduced to aminoindanol 336 which with Fremy’s salt produced indanobenzazepine 338 and thence to alkaloid 339. This synthetic procedure has also been applied to the synthesis of (±)-ribasin 340.164 Makaluvic acid A 341 and makaluvic acid B 342 are novel alkaloids found in the sponge Zyzzya fuliginosus.165 Hanishin 343 is a semi-racemic bioactive C9 alkaloid found in the axinellid sponge Acanthella carterie.166 It is thought that this metabolite is a degradation product of other metabolites found in this sponge as these are all C11 containing metabolites e.g.oroidin. Nothapodytine A 344 and nothapodytine B 345 are constituents of the stems of Nothapodytes foetida. Although this stem extract displayed significant cytotoxic activity no assess- Nat. Prod. Rep. 2000 17 57–84 77 ment of these alkaloids activity was reported.167 Two new pyrroloquinqaolinoquinoline alkaloids have been isolated from the ariel parts of Peganum nigellastrum. Called luotonins A and luotonius B they are 346 and 347 respectively.168 Nat.Prod. Rep. 2000 17 57–84 78 Four alkaloids obtained from the marine sponge Aaptos aaptos have been identified as dimethyl(oxy)aaptamine 348 and aaptosine 349 and the known alkaloids aaptamine and isoaaptamine. 169 The first reported synthesis of isotatzelline B 353 is based on the creation of the ring system 1,3,4,5-tetrahydropyrrolo- [4,3,2,de]quinoline common to a wide range of marine alkaloids. Reduction of 350 (i NaBH4 NiCl2 ii HCO2H) and ring closure gave 351. This was followed by introduction of the methylthio group (MeSSMe SO2Cl2) and oxidation to quinone 352 which enabled the amino group to be introduced leading to isobatzelline B 353.170 Eupomatidines are alkaloids containing the iminoquinoline quinone structure e.g.eupomatidine 2 354. Through an aza Diels–Alder reaction between 355 and 356 followed by condensation with DMF–diethyl acetal the crude imine 357 so Scheme 5 Reagents i NaI acetone 50 °C 16 h filter then tetrahydrothiophene AgBF4 rt 1 h; ii ButLi THF 278 °C 15 min then 9-bromononanal 278 °C to rt; iii Methyl (phenylsulfonyl)acetate KH 3 mmol DMF rt then 394 DMF rt 72 h; iv Pd(PPh 6 h reflux; v TBAF NH 3)4 dppe THF then 395 4F THF rt 30 min; vi Dess–Martin periodane reagent; vii BnNH2 Pd(Ph3P) THF 35 °C 1.5 h; viii 1-(N,N- 2Cl2 2 h rt; ix ZnCl2 dimethylamino)-1-chloro-2-methylprop-1-ene CH TMEDA THF MeLi 0 °C 15 min then PriMgCl THF 5 min then 400; x Ca liq NH3 THF 230 °C 2 h; xi KH DMF rt 5 min then SEMCl 45 min rt; xii BunLi THF 278 °C argon 30 min rt ZnCl2 278 °C to 0 °C then Pd(PPh3)4 THF and 403; xiii pyridinium toluene-p-sulfonate MeOH 55 °C 14 h; xiv KH THF 0 °C TIPSCl 30 min rt; xv BunLi THF 250 °C 5 h; xvi CeCl3 THF 278 °C 5 h then 401 2 h 278 °C to rt; xvii TBAF THF rt 10 min; 60 °C 45 min.produced could be cyclised to 354. Modification of naphthoquinone 355 led to the other eupomatidines.171 An extension of this synthetic procedure using azadiene 359 and a quinoline dione 358 has resulted in the synthesis of the pentacyclic azaaromatic alkaloid cystodamine 360.172 Plakinidine D 361 is a new pyrroloacridine alkaloid found in a previously undescribed red coloured Didemnum species.173 Extraction of Didemnum rubeus produced not only plakinidine D but also 3,5-diiodo-4-methoxyphenylethylamine.A consecutive publication174 also describes the isolation of this alkaloid together with 11-deoxyplakinidine D 362. Three steps were used to synthesis the pentacyclic alkaloid kuanoniamine A 365.175 Condensation of 6-methoxybenzothiazole-4,7-dione 363 with 2-aminoacetophenone gave the anilinoquinone 364 directly when CeCl3 was used in the presence of air. 79 Nat. Prod. Rep. 2000 17 57–84 Introduction of the aminoethylene side chain 365 was followed by ring closure to kuanoniamine 366. Using quinolinedione 367 resulted in the synthesis of neocalliactine acetate 368. Bioactive pyridoacridine alkaloids have been found in a species of the Micronesian sponge Oceanapia. All belong to the kuanoniamine type.176 Known kuanoniamine C 369 and kuanoniamine D 370 were found together with a new one Ndeacetylkuanoniamine 371.Asperazine 372 is a selective cytotoxic alkaloid obtained from a culture of Aspergillus niger growing on a saltwater Caribbean sponge belonging to the Hyrtios family.177 Antibiotic RF-1061 373 and its analogues can be prepared from the fungus Streptomyces species SN-1061M which is a mutant of Streptomyces species RK-1061.178 Dragmacidin E 374 is the newest member of metabolites obtained from the deep water Australian marine sponge of the Spongosorites species. It possesses a fluorescent yellow colour and is an active inhibitor of protein phosphatase.179 Moschamide 375 is an alkaloid found in the seeds of Centaurea moschata.Extensive spectroscopic analysis revealed its unusual structure.180 A series of antibacterial agents have been manufactured using an Actunomadura fungus species A45722. The active principal metabolite is BE-45772 376. Derivatives include substitution at the pyrrole itself.181 Callipeltoside A and callipeltoside B are two novel cytotoxic metabolites obtained from the marine lithistid sponge Callipelta.182 Both contain macrolide rings with heterocyclic appendages as indicated by 377 for A and 378 for B. A novel platelet activating factor and acetyltransferase inhibitor has been obtained from Penicillium rubrum.183 Extensive NMR studies on ZG-1494a have suggested it to have structure 379. Callipeltoside A 380 is a cytotoxic macrolide of a new type isolated from the marine lithistida sponge of the Callipelta family.184 Scheme 6 The sponge Batzella after a large scale extraction and examination has produced nineteen guanidine alkaloids;185 typical are the three new ones 8a,8b,dehydro-ptilocaulin 381 8a,8b-dehydro-8-hydroxyptilocaulin 382 and 1,8a;8b,3a-dihydro-8-hydroxyptilocaulin 383.Hydroxyakalone 384 is a novel xanthine oxidase inhibitor produced by the marine bacterium Agrobacterium aurantiacum.186 Some new saxitoxin analogues have been obtained from the fresh water mat-forming filamentous cyanobacterium Lyngbya wollei.188 All are based on saxitoxin 386 itself. Agelastatin C 387 and agelastatin D 388 are two new tetracyclic pyrroles found in a marine sponge of the Cymbastela family.189 The ‘living fossil’ sponge Astrosclera willeyana has been found to contain a metabolite with an unprecedented structure.Called A new purine metabolite erinacean 385 was found in the sponge Isodictya erinecea with antifeedant properties towards the antartic sponge predator Perknaster fuscus.187 Nat. Prod. Rep. 2000 17 57–84 80 manzacidin D 389 it contains the unusual unbrominated non Nmethylated pyrrole addendum.190 Konbu’acidin A 390 is an alkaloid isolated from an Hymeniacidon sponge.191 Compound 390 showed inhibitory activity against cyclin dependent kinase 4. A new member of the banumycin group of antibiotics has the ability to convert rastransformed cells NiH3T3 and T cells back into normal. The toxicology isolation biological characterisation and structure of 391 are described in detail.192 The first total synthesis of roseophilin 410 an antitumour agent produced by Streptomyces griseoviridis has been reported.193 The molecule can be made up of two entities a macrotricyclic component and a furanopyrrole. In the first case protected chlorobutene 392 condensed with tetrahydrothiophene via a halide exchange (chlorine to iodine) to give 393 which upon treatment with base gave the ylide for reaction with 9-bromononanal thereby generating oxirane 394. Introduction of the methyl(sulfonyl)acetate grouping gave 395 which was found to smoothly cyclise to the eighteen membered ring by treatment with a Pd[0] reagent. Desilylation gave the strained lactone 397 which upon Dess–Martin oxidation and treatment of the ketone 398 with another Pd[0] catalyst and benzylamine produced pyrrole 399 which could be cyclised to ketone 400.A 1,4-elimination and concomitant introduction of an isopropyl group created 401 which was deprotected and reprotected by the SEM group 402. The thiophenepyrrole synthon 405 was made from acid chloride 403 and pyrrolester 404 which combined to give 405 and hence 406. Combination of 402 and 406 occurred by converting the chloropyrrole 406 into its cerium derivative 408 thus giving the protected natural product 409 whereupon deprotection gave the red coloured salt of roseophilin hydrochloride 410 Scheme 5. The dried rhizomes of the Nuphar pumilum plant have been shown to contain four new thiasperane sulfoxide type dimeric alkaloids called nupharpumilamine A 411 nupharpumilamine B 412 nupharpumilamine C 413 and nupharpumilamine D 414 they all possess immunosuppressive activity.194 A revised structure for araguspongine B 415 and araguspongine E 416 has been suggested in that the C-9 stereochemistry is reversed.195 The absolute stereochemistry of isosaraine-1 417 and isosaraine 2 418 has been determined by applying the Mosher procedure.196 Two new alkaloids have been obtained from the roots of Isatis indigolica.197 X-Ray measurements combined with spectral analyses established the structures of isaindigotidione 1 as 419 and isaindigotone 2 as 420.Spirotryprostatin 421 is a cell cycle inhibitor and an antitumour agent which was produced by Aspergillus fumigatus.198 Lymphostin (LK6-A) is a novel immunosuppressant isolated from the culture broth of Streptomyces SP KY11783.199 Its structure contains the novel aromatic tricyclic ring system 422.Madangamines B to E are pentacyclic alkaloids obtained from the marine sponge Xestospongia ingens.200 Structural variation occurs in the ring designated X thus B is 423 C is 424 D is 425 and E is 426. A novel hexacyclic manzamine related alkaloid has been isolated from an Amphimedon sponge.201 Structurally it has been shown to have a novel furan ring 427 and it is proposed that it is biosynthesised from ircinol A 428. The first total synthesis of a number of these manzamine and related alkaloids has been reported.202 The novel pentacyclic ring system common to these alkaloids is based on ircinol A 428 which was synthesised rather elegantly starting from the secondary amine 429 which combined with 430 to give vinylogous amide 431.This amide 431 upon irradiation induced a photoaddition and retro-Mannich fragmentation through O-closure of the ketoiminium intermediate 432 to give aminal 434 presumably via 433. On treatment with pyridinium acetate this aminal 434 isomerized to the mangamine tetracycle 435. Manipulation of the substituents on ring B created 436 which could be ring closed to 437 and thence to manzamine A 438. 6 References 1 O. 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