Muscarine, imidazole, oxazole, and thiazole alkaloids

Zhong Jin Institute and State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China. E-mail: jinzhong2000@263.net; Fax: (00)86-(0)22-23503438 Received (in Cambridge, UK) 14th April 2003 First published as an Advance Article on the web 16th October 2003
Covering: July 2001–December 2002. Previous review: Nat. Prod. Rep., 2002, 19, 454 The occurrence, structure determination, biological activities, as well as total syntheses of muscarine, imidazole, oxazole and thiazole alkaloids have been reviewed. The literature covers from the middle of 2001 to the end of 2002, and 149 references are cited. 1 2 3 4 5 6 1 Introduction Muscarine alkaloids Imidazole alkaloids Oxazole and isoxazole alkaloids Thiazole alkaloids References Introduction 2 Muscarine alkaloids

Living organisms have proven to be a rich source of novel and structurally diverse natural products containing imidazole, oxazole-, or thiazole-derived units and displaying a wide variety of biological activities. In particular, molecules isolated from marine organisms constitute an ever-growing subset of all natural products collected, and among them are some of the most potent antitumor and cytotoxic agents yet discovered.1 The structural challenge and significant biological importance of these secondary metabolites have driven the search for ever more efficient approaches to their synthesis. This review covers the literature from the middle of 2001 to the end of 2002, following on from the previous review 2 in the series.

During the past decades, much attention has been paid to the muscarine alkaloids, which were first isolated from Amanita muscaria, a poisonous mushroom found in pinewoods, by reason of their ability to act as an acetylcholine agonist in the peripheral nervous system. More recently, the characterization of many subtypes of muscarinic receptors has further enhanced this interest. The naturally occurring diastereomers of muscarine are ( )-(2S,3R,5S )-muscarine 1, ( )-(2S,3R,5R)allo-muscarine 2, ( )-(2S,3S,5S )-epi-muscarine 3, and ( )(2S,3S,5R)-epiallo-muscarine 4. Their cholinomimetic activity and simple but challenging structure has interested chemists and biologists over the years.

Born in Nanjin, P. R. China in 1973, Zhong Jin started to study organic chemistry at Nankai University in 1991. After graduation from Nankai University in 2000, he joined the research group of Professor Runqiu Huang as a lecturer. His research interests include the discovery of novel bioactive substances, the development of selective and efficient organic synthetic methodologies, and the total syntheses of natural products, especially alkaloids.

A formal short synthesis of ( )-muscarine 1 has been accomplished starting from methyl (S )-lactate.3 The O-silyl aldehyde 5 was prepared from methyl (S )-lactate in two efficient steps by sequential O-silylation and DIBAL-H reduction. Nonchelation controlled and highly anti-selective addition of lithiated O-TBDPS propargyl alcohol favoured formation of the protected yne-diol 6. Lindlar reduction then provided the key anti-(Z ) cyclization precursor 7. 5-endo-Trig iodocyclisation of the protected (Z )-ene-diol 7, without removal of the protecting group, gave almost exclusively the iodo-tetrahydrofuran 8. Removal of the iodine by hydrogenolysis proceeded uneventfully to give the trisubstituted tetrahydrofuran 9a, which was finally deprotected to give the tetrahydrofuran-2-methanol 9b. The diol 9b was converted efficiently into ( )-muscarine by sequential selective tosylation of the primary alcohol and thermolysis with trimethylamine in methanol at 80 C (Scheme 1). A stereoselective synthesis of tetrahydrofurans has been achieved by formal [3 2]-cycloaddition of allyl and crotylsilanes with α-triethylsilyloxy aldehydes.4 The methodology provided a concise pathway for the synthesis of ( )-allomuscarine 2 and ( )-epi-muscarine 3. 3 Imidazole alkaloids

Zhong Jin

Six novel imidazole compounds, catharsitoxins A-F 10–15, have been isolated from the Chinese remedy qiung laug, which DOI: 10.1039/b304142p

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Scheme 1 Reagents and conditions: a) TBDPS propargyl ether, nBuLi, 12-crown-4, 78 C, 4 h; b) H2, 5% Pd–CaCO3, quinoline, MeOH, 20 C, 1 h; c) IBr (2 eq.), MeCN, 10 C, 5 h; d) H2, 5% Pd–C, Et3N, MeOH, 20 C, 5 h; e) NH4F, MeOH, 20 C, 12 h.

and Distaplia stylifera, with the exception of the chiroptical properties, which were equal in magnitude and opposite in sign at every wavelength measured. Both enantiomers of 17 exhibited identical biological activities in a range of assays, including modest cytotoxicity and antimicrobial properties. The symmetrical disulfide-linked marine alkaloid, polycarpine 20, which has a significant inhibitory effect on the reverse transcriptase of avian myeloblastosis virus (and is therefore a potential anti-HIV agent) and moderate antitumor activity, has been isolated from the tropical ascidian Polycarpa aurata.8 The cytotoxic and antitumor activities of polycarpine were compared with those of some synthetic analogues.

has been used in China for more than 500 years to treat spasmodic contractions.5 To confirm their structures and ensure an adequate supply for further biological studies, catharsitoxins A and D were synthesized. Alkaloid 16 has been isolated from the aerial part of Nitraria sibirica Pall., along with a decahydroquinoline alkaloid.6 Their structures were determined using chemical transformations and spectral data.

Enantiomeric marine natural products are uncommon, and it is rare to find enantiomers with two or more chiral centers. Bioassay-directed fractionation of extracts of the delicate pink stalked ascidian, Hypsistozoa fasmeriana collected at Tutukaka, North Island, New Zealand, afforded the new ( )-enantiomer of trans-5-hydroxy-4-(4-hydroxy-3-methoxyphenyl)-4-(2-imidazolyl)-1,2,3-trithiane 17.7 A second collection of H. fasmeriana made at Leigh Harbor, Northland, afforded ( )-17 and two novel dithiane alkaloids 18 and 19. All spectroscopic data observed for ( )-17 were identical to the literature values originally reported for ( )-17 isolated from Aplidium species

A series of novel antibiotics with activity against methicillinresistant staphylococci and vancomycin-resistant enterococci has been purified from a strain of Streptomyces hygroscopicus, LL-AC98, and their structures have been characterized using spectroscopic analyses and chemical conversions.9 These antibiotics, designated mannopeptimycins α–ε 21–25, are glycosylated cyclic hexapeptides containing two stereoisomers of an unprecedented amino acid, α-amino-β-[4 -(2 -iminoimidazolidinyl)]-β-hydroxypropionic adid (Aiha), as a distinguishing feature. The cyclic peptide core of these antibiotics is attached to a mannosyl monosaccharide moiety in 22 and to mannosyl monosaccharide and disaccharide moieties in 21, 23, 24, and 25. The presence and position of an isovaleryl group in the terminal mannose (Man-B) in 23–25 are critical for retaining antibacterial potency. Wainunuamide 26, isolated from the Fijian marine sponge Stylotella aurantium, is a new histidine-containing cyclic peptide.10 The peptide contains three proline residues and a histidine residue, which is rare in cyclic peptides and has only previously been reported in a cyclic peptide isolated from the cyanobacterium Oscillatoria agardhii, suggesting a possible source of the peptide.

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Further investigation of the extract of the seeds of Celosia argentea (Amaranthaceae) resulted in the isolation of three new bicyclic peptides, celogentins A 27, B 28, and C 29, together with a known related bicyclic peptide, moroidin 30, originally isolated from Laportea moroides (Labiatae).11 A structure– activity relationship study using moroidin derivatives as well as celogentins A–C and moroidin indicates that the bicyclic ring system, including the unusual connections between Leu, Trp, and His residues, the ring size and the conformation are important for their interaction with tubulin.

monitored isolation of marine sponge Axinella brevistyla afforded four new alkaloids: 3-bromomaleimide, 3,4-dibromomaleimide, 12-chloro-11-hydroxydibromoisophakellin 34 and N-methylmanzacidin C along with the known dibromoisophakellin 31, tauroacidin 35, taurodispacamide A 36, girolline 37 and 4,5-dibromopyrrole-2-carboxylic acid.14 The dichloromethane–methanol extract of the sponge Agelas sventres, collected off the coast of North Cat Cay, Bimini, Bahamas, resulted in the isolation of three known alkaloids: hymenidin 38, oroidin 39, 4,5-dibromopyrrole-2-carboxylic acid, and a new bromopyrrole-derived alkaloid, sventrin 40.15 Four brominated compounds have been isolated from a Carribbean specimen of Agelas sp. and one of them was identified as a new bromopyrrole metabolite, monobromoisophakellin 41.16 A new dimeric bromopyrrole alkaloid, bromosceptrin 42, has been obtained from a Florida keys specimen of Agelas conifera along with five other known dimeric bromopyrrole alkaloids.17 Their structures were established by MS spectrometry, and 1D and 2D NMR spectroscopy.

Bromopyrrole alkaloids are characteristic secondary metabolites found in marine Porifera belonging to several genera including Axinella, Agelas, Acanthella, Pseudaxinyssa and Hymeniacidon. Bioassay-guided fractionation of the methanol extract of the marine sponge Stylissa caribica, collected off the coast of Sweetings Cay, Bahamas, resulted in the isolation of two known bromopyrrole alkaloids containing 2-aminoimidazole or -imidazoline rings: dibromoisophakellin 31 and ageliferin 32, as well as a new compound N-methyl dibromoisophakellin 33.12 Dibromoisophakellin 31 has also been isolated from the marine sponge Axinella carteri, collected on a reed slope of Talakanen Island, Phillipines, along with a new isomeric 9,10-seco derivative, called ugibohlin.13 Bioassay586 Nat. Prod. Rep., 2003, 20, 584–605

A short synthesis of the bromopyrrole-derived alkaloids dibromoisophakellin 31 and dibromophakellstatin 43 has been described.18 The highlight of the synthetic route is a putative biomimetic oxidative cyclization of imidazolone 44. Monoenolates of C2-symmetric, proline-derived piperazine2,5-diones were generated and trapped with a variety of electrophiles to produce, in a highly diastereoselective fashion, functionalized diketopiperazines 45 (DKPs).19 These reactions provide the basis for an asymmetric, desymmetrization strategy toward the marine alkaloids phakellstatin 46 and phakellin 47.

The total syntheses of natural agelastatin A 48 and agelastatin B 49 have been accomplished via a strategy that utilized an alkynyliodonium salt–alkylidenecarbene–cyclopentene transformation to convert a relatively simple amino alcohol derivative to the functionalized core of the agelastatin system.20,21 The route started with the known alkynyloxirane 50, which is readily available in two steps from (R)-epichlorohydrin. Introduction of N-6 employed azide and the reductive cyclization conditions of Vilarrasa to deliver the oxazolidinone 51 in good yield. N-Acylation of 51 with o-nitrobenzylamineprotected N-methylcarbamoyl chloride, followed by the usual Si-to-Sn alkyne terminus transformation, afforded the oxidative cyclization precursor 52. Treatment of 52 with Stang’s reagent (PhI(CN)OTf ) and then TolSO2Na in DME provided the C-H insertion product 53 along with a byproduct of 1,2-sulfone shift product. Conjugate addition of o-nitrobenzylamine to the electron-deficient alkene of 53 proceeded without interference from the oxazolidinone carbonyl as expected, and acylation of the resulting secondary amine with acid chloride 54 furnished the bicycle 55 bearing a pendant pyrrole carboxamide moiety. Subsequent oxazolidinone hydrolysis and oxidation/cyclization afforded the tricycle 56 in good overall yield. The photochemical cleavage of both nitrogen protecting groups and cyclization gave the product debromoagelastatin ( )-57. Electrophilic pyrrole bromination with one equivalent of NBS delivered ( )-agelastatin A 48 in good yield with no more than 4% of agelastatin B 49. Use of an excess of NBS under otherwise identical conditions afforded the dibromide product ( )-agelastatin B 49 (Scheme 2). A short total synthesis for the ( )-antipode of slagenin B 58 and the ( )-antipode of slagenin C 59 has been achieved utilizing the condensation of a glyoxal hydrate and urea as the key step.22 The absolute structures of naturally isolated slagenins B and C were established as (9R,11R,15R)-58 and (9R,11S,15S )59, respectively, by comparison with the enantioselectively synthesized antipodes of slagenins B and C. The first enantioselective total syntheses of slagenins B and C have been described starting from -arabinose as a chiral precursor.23 Shortly after, a total synthesis of slagenins A-C 60, 58, 59 was accomplished in which their absolute stereochemistries were

Scheme 2 Reagents and conditions: a) i. NaN3, NH4Cl, ii. n-BuLi, CO2, PMe3; b) i. NaN(TMS)2, ClC(O)N(CH3)oNB, ii. Bu4NF, HOAc, iii. LiN(TMS)2, Bu3SnCl; c) PhI(CN)OTf, TolSO2Na; d) i. oNB-NH2, ii. 54, Et3N; e) i. Cs2CO3, MeOH, H2O, ii. (COCl)2, DMSO, Et3N; f ) hν (350 nm); g) 1 eq. NBS, CH3OH, THF; h) 2 eq. NBS, CH3OH, THF.

further established.24 The key to the synthesis involved an efficient condensation of 2-methoxy-dihydrofuran-3-one and urea to prepare the cis-fused tetrahydrofuro[2,3-d]imidazolidin-2one skeleton. A concise total synthesis of the tricyclic pyrrole marine metabolites, axinohydantoins 61–66, isolated from various genera of marine sponges, has been described.25 The key feature of the synthesis is a putative biomimetic, intramolecular cyclization of α-functionalized imidazolone 67, which affords the tricyclic pyrroloazepinone framework 68. Chemical investigation of two sponges, Leucetta chagosensis and Leucetta cf chagosensis, collected from the Great Barrier Reef and the Fiji Islands, respectively, has led to the isolation of three new imidazole alkaloids 69, 70, and 71, together with the known compounds isonaamine 72 and naamine A 73.26 Compounds 69 and 70 were found to be cytotoxic toward several tumor cell lines (GI50 values ranged from 1.3 to 7.0 µg mL 1). The first total synthesis of naamine C 74 and pyronaamidine 75, isolated from marine sponge Leucetta chagosensis, has been achieved through an eight-step reaction starting from 1-methyl2-phenylthio-1H-imidazole 76.27 The benzyl alcohol 77 Nat. Prod. Rep., 2003, 20, 584–605 587

prepared from 76 and the aldehyde 78 was smoothly reduced to the 5-benzylimidazole 79 by treatment with triethylsilane in the presence of trifluoroacetic acid according to Kobayashi’s

procedure. Bromination of 79 by NBS gave the 4-bromoimidazole 80, which was treated with tert-butyllithium in the presence of p-anisaldehyde to yield the required 4-alkylated product 81 in excellent yield. Reductive removal of the hydroxyl group

Scheme 3 Reagents and conditions: a) n-BuLi, 2,2,6,6-tetramethylpiperidine, THF; b) Et3SiH, TFA, DCM; c) NBS, THF; d) tert-BuLi (6 eq.), p-anisaldehyde (5 eq.), THF; e) NaBH4, NiCl2 6H2O, THF, MeOH; f ) i. tert-BuLi, THF, ii. trisyl azide; g) i. TBAF, THF, ii. H2, 10% Pd–C, EtOH; h) 85, (iPr)2NEt, TMSCl, CHCl3.

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of 81 with nickel boride gave successfully the 2-unsubstituted 4,5-dibenzylimidazole 82 in good yield. The imidazole 82 was brominated by NBS to give the 2-bromoimidazole 83, which was subjected to lithiation with tert-butyllithium followed by treatment with trisyl azide to afford the 2-azidoimidazole 84. Removal of the protecting group was smoothly effected by treatment with TBAF, and the subsequent hydrogenation over 10% Pd–C gave naamine C 74. The naamine C was further treated with 85 in the presence of TMSCl and N,Ndiisopropylethylamine to give pyronaamidine 75 (Scheme 3). 1,3-Dialkyl-2,3-dihydro-2-imino-1H-imidazole derivatives have been synthesized by treatment of 1,3-dialkyl-2-(phenylsulfanyl)imidazolium salts with primary carbamates or amides in the presence of a base such as LDA or NaH, and the first total synthesis of naamine B 86 has been achieved by application of this reaction as a key step.28

Chemical investigation of a Fijian ascidian, Polyandrocarpa sp., has resulted in the isolation of two new 2-aminoimidazolone-derived alkaloids, named polyandrocarpamines A 87 and B 88.29 To confirm the spectroscopically assigned structures, the syntheses of both polyandrocarpamines A and B have been accomplished utilizing aldol condensation chemistry to generate an arylidene thiohydantoin that was subsequently transaminated to yield polyandrocarpamine A 87. Demethylation of 87 afforded polyandrocarpamine B 88.

A new synthetic route to the marine alkaloid granulatimide 98 and its structural analogues, isolated from the Brazilian ascidian Didemnum granulatum, has been established by the construction of the indole-imidazole nucleus based on the Stille coupling reaction.33

Marine environments are a rich source of indole and bis(indole) alkaloids with various structures. Numerous compounds belonging to these classes have been isolated from diverse origins, e.g. sponge, ascidian, tunicates and algae, and display a wide spectrum of biological activities. Bioassayguided fractionation of the extract of the sponge of the order Haplosclerida, collected in Palau, yielded a novel tryptaminederived alkaloid, haploscleridamine 89, along with two known alkaloids, tryptamine and halitoxin.30 Haploscleridamine has been found to be an inhibitor of cathepsin K with an IC50 value of 26 µM. Kottamides A–D 90–93, novel 2,2,5-trisubstituted imidazolone-containing alkaloids, have been isolated from the endemic ascidian Pycnoclavella kottae collected at the Three Kings Islands, New Zealand.31 The structures of these kottamides, exhibiting anti-inflammatory and anti-metabolic activity as well as cytotoxicity toward tumor cell lines, have been characterized by using 15N natural abundance 2D NMR in addition to standard spectroscopic techniques. The total synthesis of the marine alkaloids rhopaladins A–D 94–97, isolated from the Okinawan marine tunicate Rhopalaea sp., has been achieved involving an imidate based cyclization with tryptophan esters as the key step to afford the appropriately substituted imidazolinone unit.32

The first total synthesis of the biologically significant alkaloid dragmacidin D 99, obtained from a deep-water marine sponge of the genus Spongosorites, has been developed.34 The first room-temperature Suzuki coupling of dihalopyrazine 100 and indole 101 proceeded selectively to the coupled indolylpyrazine 102. Under carefully controlled conditions, the critical second Suzuki coupling of dibromide 102 with indoleboronate 103 gave the desired bis-indole alkoxypyrazine 104 in good yield with complete selectivity for coupling of the pyrazinyl bromide in the presence of the indolyl bromide. Selective cleavage of the silyl ether in 104 was accomplished by the action of HF– pyridine, and the resulting primary alcohol was oxidized to aldehyde 105 using the Dess–Martin periodinane reagent. Nitromethane addition and subsequent oxidation to nitroketone 106 proceeded smoothly. Scrupulously deoxygenated ethanolic KOH facilitated the removal of the N-tosyl group of 106, and LiBF4 followed by aqueous NaOH effected complete hydrolysis of the 2-(trimethylsilyl)ethoxymethyl (SEM) group. Selective reduction of nitroketone 107 using stannous chloride and removal of the benzyl and methyl ethers with Nat. Prod. Rep., 2003, 20, 584–605 589

Scheme 4 Reagents and conditions: a) i. Pd(PPh3)4, MeOH, PhH, ii. Na2CO3, H2O, 23 C, 72 h; b) i. Pd(PPh3)4, MeOH, PhH, ii. Na2CO3, H2O, 50 C, 72 h; c) i. HF, pyridine, ii. Dess–Martin reagent; d) i. Et3N, CH3NO2, ii. Dess–Martin reagent; e) i. KOH, EtOH, ii. LiBF4, CH3CN, then NaOH, H2O; f ) i. SnCl2 2H2O, EtOAc, ii. TMSI, CH3CN, 50 C; g) H2NCN, EtOH, 60 C, then TFA, H2O, CH3CN.

iodotrimethylsilane revealed the fully deprotected aminoketone 108. Final installation of the aminoimidazolium unit with cyanamide followed by treatment with trifluoroacetic acid provided dragmacidin D 99 (Scheme 4). An enantioselective synthesis of 2-aminoimidazole sidechain of dragmacidin D has been developed involving the regio- and stereoselective opening of a chiral epoxide.35 By the regioselective introduction of two indole units using sequential palladium-catalyzed Suzuki and Stille cross-coupling reactions, a direct approach for selective construction of properly substituted bis(indole) pyrazine, the central skeleton of dragmacidin D, has been developed.36 α-Alkylidene-γ-butyrolactams have been prepared efficiently via the Pd()-catalyzed cyclization of acyclic N-allylic 2-alkynamides followed by halopalladation, intramolecular olefin insertion, and β-heteroatom elimination.37 The total syntheses of (±)-isocynodine 109 and (±)-isocynometrine 110, imidazole alkaloids isolated from Cynometra sp., have been realized using the above-mentioned cyclized product as the key intermediate.

The total syntheses of the ( )-fumiquinazolines C 111, E 112, and H 113 have been completed efficiently in 13–14 steps.38 The strategy features the use of Fmoc-NHCH(CH2SePh)CO2H as a dehydroalanine precursor that spontaneously eliminates benzeneselenol without oxidation under the cyclization conditions. -( )-Biotin (vitamin H) 114, a biocatalyst of reversible metabolic reactions of carbon dioxide transport in organisms, 590 Nat. Prod. Rep., 2003, 20, 584–605

is one of the B-complex group of vitamins and has immense commercial importance in poultry feeds and animal nutrition. A short synthesis of -( )-biotin has been achieved from -cystine involving a facile intramolecular cyclization to furnish the 5,5-fused system as a key step.39 Another highly stereocontrolled total synthesis of ( )-biotin has been completed

from readily accessible -cysteine.40 Highlights of the synthetic strategy were a Lewis base-catalyzed highly diastereoselective cyanosilylation of (2R,4R)-N-Boc-2-phenylthiazolidine-4carbaldehyde and a ring closure of a cis-allylic carbonate utilizing a palladium-catalyzed intramolecular allylic amination. Isoroquefortine C 116, the 3,12-double bond isomer of roquefortine C 115 isolated from Penicillium roqueforti Thom strain, has been synthesized for the first time in eight linear steps from -tryptophan methyl ester hydrochloride in an overall yield of 16%.41 The three fragments necessary to perform this synthesis were easily prepared on a large scale, allowing for preparation of quantities of isoroquefortine C suitable for biological testing.

Cylindrospermopsin 117 and its C7 epimer 118 are potent, naturally occurring hepatotoxins from cyanobacteria which contain a guanidinium unit embedded in a unique tricyclic skeleton.42 Two stereoselective total syntheses of cylindrospermopsin and 7-epicylindrospermopsin have been completed by two independent groups.43,44 As a result, the stereochemistry of the natural products has been revised and the absolute configuration of natural epicylindrospermopsin is 7S,8R,10S,12S, 13R,14S, as shown in 118.

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Oxazole and isoxazole alkaloids

Two structurally isomeric siderophores, namely anachelin 127 and anachelin-2 128, have been isolated from the freshwater cyanobacterium Anabaena cyclindrica (NIES-19).48 Their structures were elucidated by FABMS analysis and 1H–1H, 1H–13C, and 1H–15N 2D NMR analyses.

The syntheses of two imidazole derivatives, fungerin 119 and its isomer 120 have been described.45 As a result, it has been concluded that visoltricin, isolated from the strain of Fusarium tricinctum and previously thought to have structure 120, is in fact identical to fungerin.

A model study directed toward the total synthesis of sarcodictyn A 121 and B 122, eleutheside A 123 and B 124, and eleutherobin 125, fused oxacyclononane-dihydrofurane diterpenes isolated from gorgonian and soft corals, has been undertaken.46 The strategy features a NiCl2–CrCl2-mediated intramolecular condensation (Nozaki–Hiyama condensation) leading to a 10-membered ring eleutheside analog. The first total synthesis of exochelin MN 126, an extracellular siderophore isolated from the culture broth of Mycobacteria neoaurum, has been described utilizing a Sharpless asymmetric aminohydroxylation reaction and an asymmetric aldol reaction of imidazolidinone as key steps.47

Investigation of cancer cell growth inhibitory constituents from Pseudomonas syringae pv. coronafaciens led to the isolation of labradorins 1 129 and 2 130, related to pimprinine 131.49 Labradorin 1 showed GI50 values against human cancer cell lines of 9.8 µg mL 1 for NCI–H 460 (lung-NSC) and 6.2 µg mL 1 for BXPC-3 (pancreas-a).

Geometricin A 132, a new cytotoxic calyculinamide derivative, has been isolated from the methanol extract of the Australian sponge Luffariella geometrica along with the known Nat. Prod. Rep., 2003, 20, 584–605 591

compounds (7E,12E,18S,20Z )-variabilin, clathryimine A, tryptophol, and -tryptophan.50 Geometricin A showed moderately cytotoxic activity toward the cell lines HM02 and HEPG2, with GI50 values of 1.7 and 2.8 µg mL 1, respectively, and antialgal activity (growth inhibition zone 5 mm at 50 µg,/ mL). Two novel metabolites, ajudazoles A 133 and B 134 have been isolated from several strains of C. drocatus in a screening of the mycobacterial genus Chondromyces.51 Both are unique isochromanone derivatives with an extended side chain containing an oxazole, a Z,Z-diene, and a 3-methoxybutenamide as characteristic structural features.

related alkaloid in which the isoxazole ring is opened, have been isolated from the Fijian marine sponge Druinella sp. along with eight known bromotyrosine derivatives.54 Leucamide A 139, a bioactive cyclic heptapeptide containing a unique mixed 4,2-bisheterocycle tandem pair consisting of a methyloxazole and thiazole subunit has been isolated from the extract of the Australian marine sponge Leucetta microraphis.55 The structure of leucamide A was elucidated using standard spectroscopic techniques and the absolute stereochemistries of the chiral centres was established by chemical degradation, derivatisation, and chiral GC-MS analysis. Localization studies of bioactive cyclic peptides patellamides A–C 140–142 in the ascidian Lissoclinum patella have been undertaken.56 In contrast to previous reports, it has been demonstrated that these cyclic peptides were not located in the symbiotic cyanobacterium Prochloron sp. but were instead distributed throughout the ascidian tunic.

Marine sponges of the order Verongida have been known to be one of the richest sources of naturally occurring bromotyrosine alkaloids with interesting biological activities. Zamamistatin 135, a significant antibacterial bromo-tyrosine metabolite, has been isolated from the Okinawan sponge Pseudoceratina purpurea.52 By 2D NMR spectral analysis and comparison of its 1H NMR spectrum with those of structurally related compounds, it was deduced to be a novel bromotyrosine derivative. From the Brazilian endemic marine sponge Aplysina caissara, two new bromotyrosine-derived alkaloids, caissarine A 136 and B 137, along with three known biogenetically related alkaloids, have been isolated.53 Two new bromotyrosine alkaloids, purealidin S 138 and purpuramine J, a

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Telomestatin 143 has been shown to be a very potent telomerase inhibitor, by virtue of its ability to facilitate the formation of, or stabilize, G-quadruplex structures. Simulated annealing docking calculations were used to predict the binding modes of 143 to the intramolecular G-quadruplex produced from the human telomeric sequence d[T2AG3]4.57

The diazonamides A 151 and B 152 were first isolated from the colonial ascidian Diazona angulata, collected from the ceilings of caves along the northwest coast of Siquijor Island, Philippines in 1991. The unusual structural features and potent activity of the diazonamides have stimulated intensive synthetic efforts directed at 151,60 including photo-Fries rearrangement to give the complete diazonamide core skeleton,61 iminoDieckmann cyclization to close the C29–C30 bond,62and use of Negishi coupling to fashion diazonamide-related biaryls with defined axial chirality.63 A fully synthetic pathway to the original structure proposed for ( )-diazonamide A 153 has

The mycalolides are macrocyclic lactones belonging to a unique family of tris-oxazole containing marine metabolites. Other members of this family include ulapualides, kabiramides, halichondramides, jaspisamides, and halishigamides. Bioassaydirected fractionation of the lipophilic extract of the marine sponge Mycale izuensis, collected in the Amakusa Islands 1700 km southwest of Tokyo, led to the isolation of six cytotoxic mycalolides 144–149 and one of them is a new compound, named 30,32-dihydroxymycalolide A 144, which showed an IC50 value of 2.6 ng mL 1 against Hela cells.58 The synthesis of an advanced C1–C19 fragment of ulapualide A 150, which constitutes the tris-oxazole linked to the C1–C9 tether, has been accomplished.59 The absolute stereochemistry of the C3hydroxyl bearing stereocenter and the C9-methyl bearing stereocenter of the ulapualides has been unambiguously assigned through experimental methods for the first time.

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proven that it was in error, and advanced a revised structure 151 for ( )-diazonamide A instead.64,65 Shortly after, a path was chartered for the total synthesis of the newly proposed structure of ( )-diazonamide A which confirmed its structure as 151.66 A convergent total synthesis of ( )-hennoxazole A 154, antiviral marine natural product isolated from the marine sponge Polyfibrospongia sp., has been efficiently achieved.67 The stereoselective synthesis of the functionalized tetrahydropyran fragment has been accomplished by the Mukaiyama aldol reaction, chelation-controlled 1,3-syn reduction, Wacker oxidation, and acid catalyzed intramolecular ketalization. The non-conjugated triene fragment was synthesized by SN2 displacement of an allylic bromide with vinyllithium and the CrCl2-mediated iodoolefination followed by palladium-catalyzed cross coupling with MeMgBr. The final steps include fragment coupling using diethyl phosphorocyanidate (DEPC) and oxazole synthesis via an oxidation/cyclodehydration process.

sponge Callipelta sp., and of its deschloro derivative 160 have been accomplished.72,73 A convergent strategy was employed wherein the target was dissected into three units–the core macrolactone, the sugar callipeltose, and a cyclopropyl bearing chain.

Cytoxazone 155, a novel 4,5-disubstituted-2-oxazolidinone compound recently isolated from Streptomyces sp., has shown cytokine modulating activity. Two novel stereoselective syntheses of ( )-cytoxazone have been reported and both afforded the target alkaloid in enantiopure form.68,69 ( )-Streptazolin 156, a lipophilic neutral tricyclic compound first isolated from cultures of Streptomyces viridochromogenes, has been shown to possess antibiotic and antifungal activities. Its unique structural features as well as its promising biological activity profile have thus far led to several synthetic efforts. A total synthesis of ( )-4a,5-dihydrostreptazolin 157 has been achieved in nine steps from -glyceraldehyde acetonide.70 Key steps involved a diastereoselective addition of a vinylic Grignard reagent to an imine derived from -glyceraldehyde acetonide, a ring-closing metathesis and a stereoselective radical-mediated enyne cyclization. The intramolecular Pauson–Khand reaction of 2-oxazolone derivatives with a suitable pentynyl appendage exclusively gave the corresponding 4hydroxy-6-substituted-9-oxa-1-azatricyclo[6.2.1.0 5,11]undec-5ene-7,10-diones. Based on this newly developed Pauson–Khand reaction of 2-oxazolone-alkyne derivatives, the first total syntheis of (±)-8α-hydroxystreptazolone 158 has been accomplished in a highly stereoselective manner.71 The total syntheses of the novel antitumor agent callipeltoside A 159, isolated from the shallow-water lithistid

A concise route to the aminocyclopentital core of ( )-allosamizoline 161, a potent glycosidase inhibitor, has been realized featuring a photochemical synthesis of the aminocyclopentene core from a pyridinium salt, enzymatic desymmetrization, Wittig rearrangement to introduce the hydroxymethyl side chain, and regiocontrolled epoxide ring opening.74 The first total synthesis of the potent antitumor antibiotic ( )-tetrazomine 162 has been accomplished.75 A new method for the formation of the allylic amine precursor to an azomethine ylide has been developed and exploited in an efficient [1,3]-dipolar cycloaddition to afford the key tetracyclic intermediate used in the synthesis of ( )-tetrazomine. A concise synthesis of the oxazole alkaloid texamine 163 has been described starting from piperonylic acid.76 The strategy has proven to be highly convergent and efficient for analogues.

Rhizoxin 164 and rhizoxin D 165, novel macrolides isolated from the pathogenic fungus Rhizopus chinensis, showed powerful antitumour and antifungal activities. A concise enantioselective total synthesis of rhizoxin D has been described featuring a Wadsworth–Emmons olefination and a facile intramolecular Stille reaction between a vinyl iodide and a vinyl stannane as key steps to elaborate the 16-membered macrocyclic core.77 Another convergent strategy for rhizoxin D has been employed wherein rhizoxin D was synthesized from four subunits, A, B, C, and D representing C3–C9, C10–C13, C14– C19, and C20–C27, respectively.78 Phorboxazoles A 166 and B 167, powerful cytotoxic agents isolated from Phorbas sp. of marine sponge, feature three 594 Nat. Prod. Rep., 2003, 20, 584–605

substituted tetrahydropyran units embedded with a 21membered lactone ring. In addition to exhibiting antifungal activity against Candida albicans, both phorboxazoles inhibit the growth of most of the 60 tumor cell lines in the NCI panel at concentrations < 8 × 10 10 M (e.g. the GI50 against CCRFCBM leukemia is 2.45 × 10 10 M). This level of activity places phorboxazoles among the most potent cytostatic agents known. The outstanding biological activity of phorboxazoles, combined with their complex structural architecture, has led to ever-growing synthetic interest. The two analogs of phorboxazole A C32–C43 have been prepared and their absolute configurations were assigned.79 By spectroscopic comparisons with phorboxazoles, the C38 absolute configuration of these natural products was verified to be R. In studies directed toward the total synthesis of the phorboxazoles, the syntheses of a C3–C15 bisoxane segment and a C9–C32 bisoxazole segment have been developed.80,81

Leucascandrolide A 171 is a structurally unique macrolide isolated from the marine sponge Keucascandra caveolata. This synthetically appealing structure, in combination with its remarkable biological activity, has solicited considerable interest in the synthetic community. The formal total synthesis of leucascandrolide A has been achieved independently by three research groups.84,85,86 An alternative structure of pyrinodemin A 172 has been synthesized.87 The 13C NMR of the synthetic product was in better agreement with the original literature data and as a result the position of the double bond in the natural product was reassigned as being between C14 –C15 . The C9–C23 subunit of the group A treptogramin antibiotics such as virginiamycin 173, madumycin 174, and griseoviridin 175, a family of natural products isolated from strains of Streptomyces in soil organisms, has been synthesized.88 The strategy incorporated a palladium-catalysed sp–sp coupling (Trost coupling reaction) and a catalytic asymmetric vinylogous Mukaiyama aldol reaction to induce the chiral center at C14. 5 Thiazole alkaloids

A masked segment of the antimitotic agents disorazoles A1 168 and C1 169, a family of 29 unique macrocyclic polyketides isolated from the bacteria Sorangium cellulosum, has been synthesized in a highly convergent manner in 12 linear steps.82 Synthesis of protected tetradehydro-(6,6 -S ),(14,14 S ),(16,16 -R)-disorazole 170, a potential precursor to the natural product disorazole C1, has been described.83 Key features of this work include: (a) an unprecedented sequential 1,5 OØO silyl rearrangement/Horner–Wadsworth–Emmons reaction, (b) a highly convergent Sonogashira reaction, and (c) selective cyclizations to give either the cyclic monomer or the dimer 170.

Pyridoacridine alkaloids have been isolated from sponges, ascidians, anemones, and a prosobranch. From a 1 : 1 CH2Cl2– MeOH extract of a Singaporean ascidian, seven pyridoacridine alkaloids have been identified and two of them were new thiazole-containing compounds, namely kuanoniamine E 176 and kuanoniamine F 177.89 Bioassay-guided fractionation led to isolation of the new pyridoacridine alkaloid, lissoclinidine 178 from the New Zealand ascidian Lissoclinum notti together with other known alkaloids.90 A potent inhibitor of actin polymerization, 16-epilatrunculin B 179, has been isolated from the sponge Negombata magnifica collected from the Red Sea near Hurghada, Nat. Prod. Rep., 2003, 20, 584–605 595

Lizard Island.93 It is most probable that these compounds are actually derived from a symbiotic cyanobacterium found in close association with the Dysidea sp.

Marine cyanobacteria, in particular those of the genus Lyngbya sp., have yielded a number of bioactive secondary metabolites over the past decades. Two new apratoxins B 192 and C 193, natural analogues of apratoxins A 191, have been isolated from the marine cyanobacterium Lyngbya sp., originating from Guam and Palau, USA.94

Egypt.91 This new natural product has been determined to be an epimer of latrunculin B 180, which was found in the same sponge collection. A computational method applicable to this class of stereochemical problems has been established and the strategy represented a general, powerful, and readily adaptable tool for determining the relative configuration of complex molecules. Chemical investigation of a marine sponge Dysidea sp., collected at Bararin Island, Philippines, has afforded eight polychlorinated secondary metabolites, termed dysideaprolines A–F 181–186 and barbaleucamides A 187 and B 188.92 Two new polychlorinated metabolites 189 and 190 have been isolated from the sponge Dysidea herbacea sp. 1524 collected from 596 Nat. Prod. Rep., 2003, 20, 584–605

From Palauan collections of the apratoxin-producing marine cyanobacterium Lyngbya sp., three new nitrogenous metabolites, lyngbyabellin C 194 and lyngbyapeptins B 195 and C 196, have been obtained together with known lyngbyabellin A 197 and lyngbyapeptin A 198.95 The first total syntheses of lyngbyabellins A and B have been reported recently.96 The synthetic

strategy involved the oxidative dehydrogenation of thiazolidines to thiazoles using manganese dioxide, efficient fragment condensation, macrolactamization, and finally formation of the sensitive thiazoline ring. Six new β-amino acid-containing cyclic depsipeptides, termed ulongamides A–F 199–204, have been isolated from collections of apratoxin-producing cyanobacteria Lyngbya sp. NIH309 from Palau.97 Obyanamide 205, a novel cytotoxic cyclic depsipeptide, has been obtained from a variety of the marine cyanobacterium Lyngbya confervoides collected in Saipan, Commonwealth of the Northern Mariana Islands.98 Curacin D 206 is a potent antimitotic agent which was isolated from the cyanobacterium Lyngbya majuscular collected off the coast of Curacao and also from the Hawaiian cyanobacterium Symploca hydnoides.99 A total synthesis of curacin A 207 has been achieved.100 Formation of the thiazoline ring, which completed the synthesis, involved selective thioacylation of the amino group of a 2-amino-alcohol with a 1-thioacyl benzotriazole followed by cyclodehydration using Burgess’s reagent. The total synthesis of hectochlorin 208, a novel secondary metabolites of the marine cyanobacterium Lyngbya majuscula collected in Hector Bay, Jamaica, has been accomplished.101 Nat. Prod. Rep., 2003, 20, 584–605 597

Numerous naturally occurring marine cyclopeptides containing thiazole and/or oxazole units have been isolated from various origins, and almost all show significant biological activities such as cytotoxic, immunosuppressive, antifungal and enzyme inhibitory activity. Lissoclinum sp. and Didemnum sp. ascidians are a prolific source of such cyclic peptides. A new cycloheptapeptide, termed cyclodidemnamide B 209, has been isolated from the marine ascidian Didemnum molle, collected at Ibo Island, Mozambique.102 The structure of the bisthiazolecontaining macrocyclic peptide was initially assigned using 2D NMR analysis and spectroscopic data comparisons with cyclodidemnamide 210. The unambiguous structure and stereochemistry of cyclodidemnamide B have been validated through the total synthesis.

Micrococcin P1 (MP1) 213 is one of the structurally complex thiopeptide natural products. Due to persistent structural uncertainties, the synthetic activity in the thiopeptide area has been limited. An extensive NMR study has now validated the 1978 Bycroft–Gowland hypothesis, hitherto unsupported by experimental evidence, regarding the constitution of MP1.104

Several members of the thiopeptide class of antibiotics, thiazole- and/or oxazole-containing cyclic peptides, have been shown to induce production of certain proteins in Streptomyces lividans. One of these proteins, TipA, is a regulatory protein which binds to the ptipA promoter. Using an assay based on activation of this promoter as a screen, two thiopeptide antibiotics, promothiocins A 211 and B 212 were isolated from Streptomyces sp. SF2741. The absolute stereochemistry and solution conformation of promothiocins A and B have now been investigated by a combination of degradation and molecular modeling.103 These compounds contain characteristic dehydroalanine residues in their side chains that are necessary for high promoter inducing activity.

A method has been developed for the simultaneous detection and determination of the absolute configuration of amino acids following hydrolysis of a peptide. This involves HPLC-MS after derivatization with N-(5-fluoro-2,4-dinitrophenyl)--leucinamide (-FDLA) and, separately, with -FDLA. This method has now been successfully used to determine the absolute configuration of the constituent amino acids of three thiazole-containing peptides, microcyclamide 214, waiakeamide 215, and goadsporin 216.105 The method employed a brief acid hydrolysis to minimise the racemisation and this additionally allowed tryptophan and methionine sulfoxide, which are labile during normal acid hydrolysis, to be detected in intact form. Experiments to re-examine the spectral data of halipeptins A 217 and B 218 have resulted in the isolation, from the same Vanuatu species of Haliclona, of a new minor related compound, named halipeptin C 219.106 By comparing the spectral data of the natural products with an appropriate synthetic model, the heterocyclic structure of the halipeptins, previously incorrectly assigned as an oxazetidine ring, has been revised as a thiazoline unit. Theoretical calculations of 13C NMR chemical shifts for oxazetidine and thiazoline model compounds have provided additional evidence for the revised structure. The DNA-damaging natural product leinamycin 220 possesses a unique chemical structure and acts on DNA by a completely novel sequence of reactions. DNA damage by leinamycin is triggered by attack of thiols on the 1,2-dithiolan3-one 1-oxide heterocycle of the antibiotic. A theoretical study indicated that the most reasonable mechanism for thiolmediated activation of leinamycin involved initial attack of thiolate at the S2 -position of the antibiotic’s 1,2-dithiolan3-one 1-oxide heterocycle, followed by conversion to the 1,2-oxathiolan-5-one intermediate.107 During the screening of myxobacteria as a potential source of new antibiotics, a group of cyclic peptides were isolated from the Archangium gephyra strain and named argyrins A–H 221– 228.108 By established biological assays using both murine and human B-cell, argyrin B 222 was shown to be immunosuppressive and a potent inhibitor of T-cell independent antibody formation. Owing to its interesting biological activities, a total synthesis of argyrin B has been accomplished using modifications of known synthetic methods.109,110 Cystothiazoles A–F 229–234, previously isolated from the myxobacterium culture broth of Cystobacter fuscus, display potent antifungal activity and inhibit the growth of the phytopathogenic fungus Phytophthora capsici. Total syntheses of cystothiazoles A, C, and E have been achieved by several groups.111–113

598

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Epothilones are antifungal and cytotoxic secondary metabolites originally isolated from the Gram-negative myxobacterium Sorangium cellulosum. A recent study on the early enzymes of the epothilone biosynthesis cluster has suggested that combinatorial biosynthesis may be a viable means for producing a variety of epothilone analogues that incorporate diversity into the heterocycle starter unit.114 Thirty six natural epothilone variants 235–270 and six epothilone fragments 271–276 have been isolated from the culture broth of a 700 L fermentation of Sorangium cellulosum, strain So. ce90/B2 and So. ce90/D13.115 Of them, only the 12,13-desoxyepothilones, epothilone C 248 and D 249 were produced in significant amounts (3–6 mg/L), and most of the other epothilone variants were produced only in 1–100 µg/L. Further, epothilones 244–247 containing an

oxazole moiety in the side chain instead of a thiazole as well as ring-expanded 18-membered macrolides, epothilones I 264– 269, and a ring contracted 14-membered macrolide, epothilone K 270, were found as very minor metabolites. The biological Nat. Prod. Rep., 2003, 20, 584–605 599

activities of the epothilones A–K and the epothilone fragments have been determined by growth inhibition of the mouse fibroblast cell line L929. Several new natural epothilones showed activity comparable to epothilone A 235 and B 236, but in no case exceeded that of epothilone B 236.

A new epothilone, 10,11-didehydroepothilone D 277, has been isolated from a strain of the heterologous host Myxococcus xanthus genetically engineered to yield epothilone D 249.116 The cytotoxicity of 277 against a panel of tumor cell lines, including several with multidrug resistance, and its effect on tubulin polymerization were comparable to epothilone D 249. The introduction of the epothilone polyketide synthase (PKS) into Myxococcus xanthus has resulted in the heterologous production of epothilone D 249 on a large scale.117 An economical, scalable, and high-yielding purification process has been developed in order to isolate this valuable product from the fermentation medium. The unique structure of epothilones, as well as their potent antitumor activities closely related to that of paclitaxel (Taxol®), have evoked a great deal of interest from chemists and biologists. A review highlighting recent advances in the total synthesis, chemical biology and medicine of the epothilones over the last five years has been published.118 A convergent total synthesis of epothilone A 235 has been completed involving diastereoselective aldol condensation to form the C6–C7 bond, macrolactonization and Wadsworth– Emmons reaction of methyl ketone with a phosphonate reagent as key steps.119 Total synthesis of epothilone A has also been accomplished through sterospecific epoxidation of the p-methoxybenzyl ether of epothilone C 248.120 In addition, the asymmetric synthesis of two important synthetic precursors of epothilone A, the C1–C6 and C7–C15 fragments, has been achieved from commercially available starting materials.121 600 Nat. Prod. Rep., 2003, 20, 584–605

The stereoselective routes to epothilones A 235 and B 236 based on the Kanemasa hydroxyl-directed nitrile oxide cycloaddition have been described.122 The synthetic efforts have led

to the development of new reaction methodologies and served as the proving ground for asymmetric carbon–carbon bond formation. A ring-closing alkyne metathesis reaction (RCM) catalyzed by a molybdenum complex, followed by a Lindlar reduction of the resulting cycloalkyne product, opened an efficient and stereoselective entry into epothilones A and C.123 A highly diastereoselective addition reaction of a titanium enolate offered an efficient entry to the total synthesis of the epothilone family such as epothilone B.124 Based on the subsequent Normant reaction, Wadsworth–Emmons reaction, diastereoselective aldol condensation and macrolactonization, a convergent and stereoselective total synthesis of epothilone B has been achieved.125 The selectively terminal epoxidation of 12,13-desoxyepothilone B (epothilone D 249) to epothilone B 236, using 2,2 -dimethyldioxirane (DMDO), has been investigated.126 The diastereoselectivity of the epoxidation has shown to be highly temperature dependent and the diastereoselectivity increases to > 20 : 1 when the reaction is performed at 78 C. A total synthesis of epothilones B 236 and D 249 has been reported in which the trisubstituted 12,13-double bond was introduced stereoselectively using the tin() bromide-promoted reaction between an allylstannane and an aldehyde.127 A Barton deoxygenation reaction and an aldol condensation were also applied to reach the target epothilones. The epothilones B and D have also been enantiospecifically synthesized from -glucose.128 Total synthesis of epothilone 490 277, which is 10,11didehydroepothilone D, has been accomplished by two routes, one utilizing a vinyl-boronate cross-metathesis followed by a Suzuki macrocyclization 129 and the other using ring-closing metathesis.130 With the hope of establishing a thorough understanding of epothilone structure–activity relationships (SAR), numerous epothilone analogues, including: C26-(1,3-dioxolanyl)-12,13desoxyepothilone B 278,131trans-12,13-cyclopropyl epothilone B analogues 279,132[17]- and [18]dehydrodesoxyepothilones B 280,1339,10-didehydroepothilone D isomers 281 and 282,134and 12α,13α-aziridinyl epothilone derivatives 283,135 have been prepared by total synthesis. Marine natural product trunkamide A 284 contains a thiazoline heterocycle and two residues of Ser and Thr with the hydroxy function modified as reverse prenyl (rPr). A total synthesis of trunkamide A has been presented, which used solidphase peptide chain elongation followed by cyclizations in solution.136 Several analogues of the naturally occurring antibiotic althiomycin 285, isolated from Streptomyces althioticus, have been synthesized by both total- and semi-synthetic methodologies.137 The antibacterial activity of these derivatives has been determined in whole cell assays and indicated that the natural product exhibits a restricted structure–activity relationship (SAR). The thiostrepton family of peptide antibiotics 286–289 was firstly isolated from the culture broth of Streptomyces azureus. Because of their complex structural features, synthetic studies on the thiostrepton family of antibiotics have scarcely been attempted. An enantioselective synthesis of the tetrasubstituted dehydropiperidine and piperidine cores, 290 and 291, of the thiostrepton family of antibiotics has been described.138 Thiazolyl peptide antibiotics nocathiacins I–IV 292–295, recently isolated from fermentation of Nocardia sp., show potent antimicrobial activity against Gram-positive bacteria in vitro, with promising activity against multi drug-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecium. Although nocathiacin IV 295 has been obtained from nocathiacin I 292 enzymatically,139an alternative efficient chemical method for converting nocathiacin I to nocathiacin IV by selective cleavage of the dehydroalanine unit has been developed.140 With the aim of improving the water-solubility of Nat. Prod. Rep., 2003, 20, 584–605 601

nocathiacins, several synthetic analogues have been prepared from nocathiacin IV by condensation with glycolaldehyde followed by tandem reductive amination.141 602 Nat. Prod. Rep., 2003, 20, 584–605

Marine cyclic peptides, a structurally diverse class of natural products, have shown a broad range of bioactivities such as cytotoxic, antiviral, and anti-inflammatory activities. Their biosynthesis has been thought to occur primarily through the action of nonribosomal peptide synthetases.142 Total synthesis of trans,trans- and cis,cis-ceratospongamide, 296a and b, bioactive cyclic heptapeptides recently isolated form a marine alga/sponge symbiont, has been accomplished and their comformations confirmed by X-ray crystal analysis.143,144 The bleomycins (BLMs), such as BLM A2 297 and A5 298, are a family of antitumor glycopeptide-derived antibiotics isolated from Streptomyces verticillus. Metabolic inactivation of the bleomycins is believed to be mediated exclusively via the action of bleomycin hydrolase, a cysteine proteinase that is widely distributed in nature. Total synthesis of deamido bleomycin A2 299, the major metabolite of bleomycin A2, has been reported.145 Synthetic deamido bleomycin A2 has shown to be identical to the product formed by treatment of bleomycin A2

bleomycins. A key intermediate toward the total synthesis of tallysomycins that contained the glycosylcarbinolamide moiety has been synthesized.147

The first racemic syntheses of cruciferous indole phytoalexins, 1-methoxyspirobrassinin 303, methoxyspirobrassinol 304, and 1-methoxyspirobrassinol methyl ether 305, as well as a new synthesis of spirobrassinin 302 have been achieved by spirocyclization of brassinin 306 and its 1-substituted derivatives using bromide in dioxane–water or dioxane–methanol.148

with human bleomycin hydrolase and although it retains significant DNA cleavage activity in DNA plasmid relaxation assays and has the same sequence selectivity of DNA cleavage as bleomycin A2, it has reduced ability to cleave double stranded DNA. To explore the influence on the sequence selectivity of DNA cleavage by the carbohydrate moiety of BLMs, BLM A5 298 and three monosaccharide analogues have been synthesized using a solid-phase synthetic methodology.146 Tallysomycins A 300 and B 301, firstly isolated from fermentation broths of Streptoalloteichus hindustanus, are glycopeptide-derived antitumor antibiotics structurally related to the

The 1,3-diene fragment present in mycothiazole 307, originally isolated from the Indo-Pacific sponge Spongia mycofijiensis collected from Vanuatu, has been synthesized using a key crossenyne metathesis in the presence of the Grubb’s ruthenium– carbene catalyst.149

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