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 2003First 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 Introduction2 Muscarine alkaloids3 Imidazole alkaloids4 Oxazole and isoxazole alkaloids5 Thiazole alkaloids6 References

1 Introduction

Living organisms have proven to be a rich source of noveland structurally diverse natural products containing imidazole-, oxazole-, or thiazole-derived units and displaying a widevariety of biological activities. In particular, molecules iso-lated from marine organisms constitute an ever-growingsubset of all natural products collected, and among themare some of the most potent antitumor and cytotoxic agentsyet discovered.1 The structural challenge and significant bio-logical importance of these secondary metabolites havedriven the search for ever more efficient approaches to theirsynthesis.

This review covers the literature from the middle of 2001 tothe end of 2002, following on from the previous review 2 in theseries.

Born in Nanjin, P. R. China in 1973, Zhong Jin started to studyorganic chemistry at Nankai University in 1991. After graduationfrom Nankai University in 2000, he joined the research group ofProfessor Runqiu Huang as a lecturer. His research interestsinclude the discovery of novel bioactive substances, thedevelopment of selective and efficient organic syntheticmethodologies, and the total syntheses of natural products,especially alkaloids.

Zhong Jin

2 Muscarine alkaloids

During the past decades, much attention has been paid to themuscarine alkaloids, which were first isolated from Amanitamuscaria, a poisonous mushroom found in pinewoods, byreason of their ability to act as an acetylcholine agonist in theperipheral nervous system. More recently, the characterizationof many subtypes of muscarinic receptors has further enhancedthis interest. The naturally occurring diastereomers ofmuscarine 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 activityand simple but challenging structure has interested chemistsand biologists over the years.

A formal short synthesis of (�)-muscarine 1 has beenaccomplished starting from methyl (S )-lactate.3 The O-silylaldehyde 5 was prepared from methyl (S )-lactate in two efficientsteps by sequential O-silylation and DIBAL-H reduction. Non-chelation controlled and highly anti-selective addition of lithi-ated O-TBDPS propargyl alcohol favoured formation of theprotected yne-diol 6. Lindlar reduction then provided the keyanti-(Z ) cyclization precursor 7. 5-endo-Trig iodocyclisation ofthe protected (Z )-ene-diol 7, without removal of the protectinggroup, gave almost exclusively the iodo-tetrahydrofuran 8.Removal of the iodine by hydrogenolysis proceeded unevent-fully to give the trisubstituted tetrahydrofuran 9a, which wasfinally deprotected to give the tetrahydrofuran-2-methanol 9b.The diol 9b was converted efficiently into (�)-muscarine bysequential selective tosylation of the primary alcohol andthermolysis with trimethylamine in methanol at 80 �C (Scheme1). A stereoselective synthesis of tetrahydrofurans has beenachieved by formal [3 � 2]-cycloaddition of allyl and crotyl-silanes with α-triethylsilyloxy aldehydes.4 The methodologyprovided a concise pathway for the synthesis of (�)-allo-muscarine 2 and (�)-epi-muscarine 3.

3 Imidazole alkaloids

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

584 Nat. Prod. Rep., 2003, 20, 584–605 DOI: 10.1039/b304142p

This journal is © The Royal Society of Chemistry 2003

has been used in China for more than 500 years to treat spas-modic contractions.5 To confirm their structures and ensure anadequate supply for further biological studies, catharsitoxins Aand D were synthesized.

Alkaloid 16 has been isolated from the aerial part of Nitrariasibirica Pall., along with a decahydroquinoline alkaloid.6 Theirstructures were determined using chemical transformations andspectral data.

Enantiomeric marine natural products are uncommon, and itis rare to find enantiomers with two or more chiral centers.Bioassay-directed fractionation of extracts of the delicate pinkstalked ascidian, Hypsistozoa fasmeriana collected at Tutukaka,North Island, New Zealand, afforded the new (�)-enantiomerof trans-5-hydroxy-4-(4-hydroxy-3-methoxyphenyl)-4-(2-imid-azolyl)-1,2,3-trithiane 17.7 A second collection of H. fasmerianamade at Leigh Harbor, Northland, afforded (�)-17 and twonovel dithiane alkaloids 18 and 19. All spectroscopic dataobserved for (�)-17 were identical to the literature valuesoriginally reported for (�)-17 isolated from Aplidium species

Scheme 1 Reagents and conditions: a) TBDPS propargyl ether, n-BuLi, 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 chiropticalproperties, which were equal in magnitude and opposite in signat every wavelength measured. Both enantiomers of 17 exhib-ited identical biological activities in a range of assays, includingmodest cytotoxicity and antimicrobial properties.

The symmetrical disulfide-linked marine alkaloid, poly-carpine 20, which has a significant inhibitory effect on thereverse transcriptase of avian myeloblastosis virus (and is there-fore a potential anti-HIV agent) and moderate antitumoractivity, has been isolated from the tropical ascidian Polycarpaaurata.8 The cytotoxic and antitumor activities of polycarpinewere compared with those of some synthetic analogues.

A series of novel antibiotics with activity against methicillin-resistant staphylococci and vancomycin-resistant enterococcihas been purified from a strain of Streptomyces hygroscopicus,LL-AC98, and their structures have been characterized usingspectroscopic analyses and chemical conversions.9 These anti-biotics, designated mannopeptimycins α–ε 21–25, are glyco-sylated cyclic hexapeptides containing two stereoisomers of anunprecedented amino acid, α-amino-β-[4�-(2�-iminoimidazol-idinyl)]-β-hydroxypropionic adid (Aiha), as a distinguishingfeature. The cyclic peptide core of these antibiotics is attachedto a mannosyl monosaccharide moiety in 22 and to mannosylmonosaccharide and disaccharide moieties in 21, 23, 24, and25. The presence and position of an isovaleryl group in theterminal mannose (Man-B) in 23–25 are critical for retainingantibacterial potency.

Wainunuamide 26, isolated from the Fijian marine spongeStylotella aurantium, is a new histidine-containing cyclicpeptide.10 The peptide contains three proline residues and ahistidine residue, which is rare in cyclic peptides and has onlypreviously been reported in a cyclic peptide isolated fromthe cyanobacterium Oscillatoria agardhii, suggesting a possiblesource of the peptide.

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Further investigation of the extract of the seeds of Celosiaargentea (Amaranthaceae) resulted in the isolation of three newbicyclic peptides, celogentins A 27, B 28, and C 29, togetherwith a known related bicyclic peptide, moroidin 30, originallyisolated from Laportea moroides (Labiatae).11 A structure–activity relationship study using moroidin derivatives as well ascelogentins A–C and moroidin indicates that the bicyclic ringsystem, including the unusual connections between Leu, Trp,and His residues, the ring size and the conformation areimportant for their interaction with tubulin.

Bromopyrrole alkaloids are characteristic secondary metab-olites found in marine Porifera belonging to several generaincluding Axinella, Agelas, Acanthella, Pseudaxinyssa andHymeniacidon. Bioassay-guided fractionation of the methanolextract of the marine sponge Stylissa caribica, collected off thecoast of Sweetings Cay, Bahamas, resulted in the isolation oftwo known bromopyrrole alkaloids containing 2-amino-imidazole or -imidazoline rings: dibromoisophakellin 31 andageliferin 32, as well as a new compound N-methyl dibromo-isophakellin 33.12 Dibromoisophakellin 31 has also beenisolated from the marine sponge Axinella carteri, collected on areed slope of Talakanen Island, Phillipines, along with a newisomeric 9,10-seco derivative, called ugibohlin.13 Bioassay-

monitored isolation of marine sponge Axinella brevistylaafforded four new alkaloids: 3-bromomaleimide, 3,4-dibromo-maleimide, 12-chloro-11-hydroxydibromoisophakellin 34 andN-methylmanzacidin C along with the known dibromo-isophakellin 31, tauroacidin 35, taurodispacamide A 36, girol-line 37 and 4,5-dibromopyrrole-2-carboxylic acid.14 Thedichloromethane–methanol extract of the sponge Agelassventres, 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-carboxylicacid, and a new bromopyrrole-derived alkaloid, sventrin 40.15

Four brominated compounds have been isolated from a Carrib-bean specimen of Agelas sp. and one of them was identified as anew bromopyrrole metabolite, monobromoisophakellin 41.16 Anew dimeric bromopyrrole alkaloid, bromosceptrin 42, hasbeen obtained from a Florida keys specimen of Agelas coniferaalong with five other known dimeric bromopyrrole alkaloids.17

Their structures were established by MS spectrometry, and 1Dand 2D NMR spectroscopy.

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A short synthesis of the bromopyrrole-derived alkaloidsdibromoisophakellin 31 and dibromophakellstatin 43 hasbeen described.18 The highlight of the synthetic route is aputative biomimetic oxidative cyclization of imidazolone 44.Monoenolates of C2-symmetric, proline-derived piperazine-2,5-diones were generated and trapped with a variety ofelectrophiles to produce, in a highly diastereoselectivefashion, functionalized diketopiperazines 45 (DKPs).19 Thesereactions provide the basis for an asymmetric, desymmetriz-ation strategy toward the marine alkaloids phakellstatin 46 andphakellin 47.

The total syntheses of natural agelastatin A 48 and agela-statin B 49 have been accomplished via a strategy that util-ized an alkynyliodonium salt–alkylidenecarbene–cyclopentenetransformation to convert a relatively simple amino alcoholderivative to the functionalized core of the agelastatin sys-tem.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 cycliz-ation conditions of Vilarrasa to deliver the oxazolidinone 51in good yield. N-Acylation of 51 with o-nitrobenzylamine-protected N-methylcarbamoyl chloride, followed by the usualSi-to-Sn alkyne terminus transformation, afforded the oxidativecyclization precursor 52. Treatment of 52 with Stang’s reagent(PhI(CN)OTf ) and then TolSO2Na in DME provided the C-Hinsertion product 53 along with a byproduct of 1,2-sulfone shiftproduct. Conjugate addition of o-nitrobenzylamine to theelectron-deficient alkene of 53 proceeded without interferencefrom the oxazolidinone carbonyl as expected, and acylation ofthe resulting secondary amine with acid chloride 54 furnishedthe bicycle 55 bearing a pendant pyrrole carboxamide moiety.Subsequent oxazolidinone hydrolysis and oxidation/cyclizationafforded the tricycle 56 in good overall yield. The photo-chemical cleavage of both nitrogen protecting groups andcyclization gave the product debromoagelastatin (�)-57.Electrophilic pyrrole bromination with one equivalent of NBSdelivered (�)-agelastatin A 48 in good yield with no morethan 4% of agelastatin B 49. Use of an excess of NBS underotherwise identical conditions afforded the dibromide product(�)-agelastatin B 49 (Scheme 2).

A short total synthesis for the (�)-antipode of slagenin B 58and the (�)-antipode of slagenin C 59 has been achieved util-izing the condensation of a glyoxal hydrate and urea as the keystep.22 The absolute structures of naturally isolated slagenins Band C were established as (9R,11R,15R)-58 and (9R,11S,15S )-59, respectively, by comparison with the enantioselectively syn-thesized antipodes of slagenins B and C. The first enantio-selective total syntheses of slagenins B and C have beendescribed starting from -arabinose as a chiral precursor.23

Shortly after, a total synthesis of slagenins A-C 60, 58, 59 wasaccomplished in which their absolute stereochemistries were

further established.24 The key to the synthesis involved an effi-cient condensation of 2-methoxy-dihydrofuran-3-one and ureato prepare the cis-fused tetrahydrofuro[2,3-d]imidazolidin-2-one skeleton.

A concise total synthesis of the tricyclic pyrrole marinemetabolites, axinohydantoins 61–66, isolated from various gen-era of marine sponges, has been described.25 The key feature ofthe synthesis is a putative biomimetic, intramolecular cycliz-ation of α-functionalized imidazolone 67, which affords thetricyclic pyrroloazepinone framework 68.

Chemical investigation of two sponges, Leucetta chagosensisand Leucetta cf chagosensis, collected from the Great BarrierReef and the Fiji Islands, respectively, has led to the isolation ofthree new imidazole alkaloids 69, 70, and 71, together with theknown compounds isonaamine 72 and naamine A 73.26 Com-pounds 69 and 70 were found to be cytotoxic toward severaltumor cell lines (GI50 values ranged from 1.3 to 7.0 µg mL�1).The first total synthesis of naamine C 74 and pyronaamidine75, isolated from marine sponge Leucetta chagosensis, has beenachieved through an eight-step reaction starting from 1-methyl-2-phenylthio-1H-imidazole 76.27 The benzyl alcohol 77

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.

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

procedure. Bromination of 79 by NBS gave the 4-bromoimid-azole 80, which was treated with tert-butyllithium in the pres-ence of p-anisaldehyde to yield the required 4-alkylated product81 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-unsubstituted4,5-dibenzylimidazole 82 in good yield. The imidazole 82was brominated by NBS to give the 2-bromoimidazole 83,which was subjected to lithiation with tert-butyllithium fol-lowed by treatment with trisyl azide to afford the 2-azido-imidazole 84. Removal of the protecting group was smoothlyeffected by treatment with TBAF, and the subsequent hydro-genation over 10% Pd–C gave naamine C 74. The naamine Cwas further treated with 85 in the presence of TMSCl and N,N-diisopropylethylamine to give pyronaamidine 75 (Scheme 3).1,3-Dialkyl-2,3-dihydro-2-imino-1H-imidazole derivatives havebeen synthesized by treatment of 1,3-dialkyl-2-(phenylsulfanyl)-imidazolium salts with primary carbamates or amides in thepresence of a base such as LDA or NaH, and the first totalsynthesis of naamine B 86 has been achieved by application ofthis reaction as a key step.28

Chemical investigation of a Fijian ascidian, Polyandrocarpasp., has resulted in the isolation of two new 2-aminoimid-azolone-derived alkaloids, named polyandrocarpamines A 87and B 88.29 To confirm the spectroscopically assigned struc-tures, the syntheses of both polyandrocarpamines A and B havebeen accomplished utilizing aldol condensation chemistry togenerate an arylidene thiohydantoin that was subsequentlytransaminated to yield polyandrocarpamine A 87. Demethyl-ation of 87 afforded polyandrocarpamine B 88.

Marine environments are a rich source of indole and bis-(indole) alkaloids with various structures. Numerous com-pounds belonging to these classes have been isolated fromdiverse origins, e.g. sponge, ascidian, tunicates and algae, anddisplay a wide spectrum of biological activities. Bioassay-guided fractionation of the extract of the sponge of the orderHaplosclerida, collected in Palau, yielded a novel tryptamine-derived alkaloid, haploscleridamine 89, along with two knownalkaloids, tryptamine and halitoxin.30 Haploscleridamine hasbeen found to be an inhibitor of cathepsin K with an IC50 valueof 26 µM. Kottamides A–D 90–93, novel 2,2,5-trisubstitutedimidazolone-containing alkaloids, have been isolated from theendemic ascidian Pycnoclavella kottae collected at the ThreeKings Islands, New Zealand.31 The structures of thesekottamides, exhibiting anti-inflammatory and anti-metabolicactivity as well as cytotoxicity toward tumor cell lines, havebeen characterized by using 15N natural abundance 2D NMRin addition to standard spectroscopic techniques.

The total synthesis of the marine alkaloids rhopaladins A–D94–97, isolated from the Okinawan marine tunicate Rhopalaeasp., has been achieved involving an imidate based cyclizationwith tryptophan esters as the key step to afford the appropri-ately substituted imidazolinone unit.32

A new synthetic route to the marine alkaloid granulatimide98 and its structural analogues, isolated from the Brazilianascidian Didemnum granulatum, has been established by theconstruction of the indole-imidazole nucleus based on the Stillecoupling reaction.33

The first total synthesis of the biologically significantalkaloid dragmacidin D 99, obtained from a deep-water marinesponge of the genus Spongosorites, has been developed.34 Thefirst room-temperature Suzuki coupling of dihalopyrazine 100and indole 101 proceeded selectively to the coupled indolyl-pyrazine 102. Under carefully controlled conditions, the criticalsecond Suzuki coupling of dibromide 102 with indoleboronate103 gave the desired bis-indole alkoxypyrazine 104 in good yieldwith complete selectivity for coupling of the pyrazinyl bromidein the presence of the indolyl bromide. Selective cleavage of thesilyl ether in 104 was accomplished by the action of HF–pyridine, and the resulting primary alcohol was oxidized toaldehyde 105 using the Dess–Martin periodinane reagent.Nitromethane addition and subsequent oxidation to nitro-ketone 106 proceeded smoothly. Scrupulously deoxygenatedethanolic KOH facilitated the removal of the N-tosyl group of106, and LiBF4 followed by aqueous NaOH effected com-plete hydrolysis of the 2-(trimethylsilyl)ethoxymethyl (SEM)group. Selective reduction of nitroketone 107 using stannouschloride and removal of the benzyl and methyl ethers with

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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 aminoketone108. Final installation of the aminoimidazolium unit withcyanamide followed by treatment with trifluoroacetic acidprovided dragmacidin D 99 (Scheme 4).

An enantioselective synthesis of 2-aminoimidazole side-chain of dragmacidin D has been developed involving theregio- and stereoselective opening of a chiral epoxide.35 By theregioselective introduction of two indole units using sequentialpalladium-catalyzed Suzuki and Stille cross-coupling reactions,a direct approach for selective construction of properly substi-tuted bis(indole) pyrazine, the central skeleton of dragmacidinD, has been developed.36

α-Alkylidene-γ-butyrolactams have been prepared efficientlyvia the Pd()-catalyzed cyclization of acyclic N-allylic 2-alkyn-amides followed by halopalladation, intramolecular olefininsertion, and β-heteroatom elimination.37 The total synthesesof (±)-isocynodine 109 and (±)-isocynometrine 110, imidazolealkaloids isolated from Cynometra sp., have been realized usingthe above-mentioned cyclized product as the key intermediate.

The total syntheses of the (�)-fumiquinazolines C 111, E112, and H 113 have been completed efficiently in 13–14 steps.38

The strategy features the use of Fmoc-NHCH(CH2SePh)CO2Has a dehydroalanine precursor that spontaneously eliminatesbenzeneselenol without oxidation under the cyclizationconditions.

-(�)-Biotin (vitamin H) 114, a biocatalyst of reversiblemetabolic reactions of carbon dioxide transport in organisms,

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

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from readily accessible -cysteine.40 Highlights of the syntheticstrategy were a Lewis base-catalyzed highly diastereoselectivecyanosilylation of (2R,4R)-N-Boc-2-phenylthiazolidine-4-carbaldehyde and a ring closure of a cis-allylic carbonate util-izing a palladium-catalyzed intramolecular allylic amination.

Isoroquefortine C 116, the 3,12-double bond isomer ofroquefortine C 115 isolated from Penicillium roqueforti Thomstrain, has been synthesized for the first time in eight linearsteps from -tryptophan methyl ester hydrochloride in an over-all yield of 16%.41 The three fragments necessary to performthis synthesis were easily prepared on a large scale, allowingfor preparation of quantities of isoroquefortine C suitable forbiological testing.

Cylindrospermopsin 117 and its C7 epimer 118 are potent,naturally occurring hepatotoxins from cyanobacteria whichcontain a guanidinium unit embedded in a unique tricyclicskeleton.42 Two stereoselective total syntheses of cylindro-spermopsin and 7-epicylindrospermopsin have been completedby two independent groups.43,44 As a result, the stereochemistryof the natural products has been revised and the absolute con-figuration of natural epicylindrospermopsin is 7S,8R,10S,12S,13R,14S, as shown in 118.

The syntheses of two imidazole derivatives, fungerin 119 andits isomer 120 have been described.45 As a result, it has beenconcluded that visoltricin, isolated from the strain of Fusariumtricinctum and previously thought to have structure 120, is infact identical to fungerin.

A model study directed toward the total synthesis of sarco-dictyn A 121 and B 122, eleutheside A 123 and B 124,and eleutherobin 125, fused oxacyclononane-dihydrofuranediterpenes isolated from gorgonian and soft corals, has beenundertaken.46 The strategy features a NiCl2–CrCl2-mediatedintramolecular condensation (Nozaki–Hiyama condensation)leading to a 10-membered ring eleutheside analog.

The first total synthesis of exochelin MN 126, an extra-cellular siderophore isolated from the culture broth of Myco-bacteria neoaurum, has been described utilizing a Sharplessasymmetric aminohydroxylation reaction and an asymmetricaldol reaction of imidazolidinone as key steps.47

4 Oxazole and isoxazole alkaloids

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

Investigation of cancer cell growth inhibitory constituentsfrom Pseudomonas syringae pv. coronafaciens led to the iso-lation of labradorins 1 129 and 2 130, related to pimprinine131.49 Labradorin 1 showed GI50 values against human cancercell lines of 9.8 µg mL�1 for NCI–H 460 (lung-NSC) and 6.2 µgmL�1 for BXPC-3 (pancreas-a).

Geometricin A 132, a new cytotoxic calyculinamide deriv-ative, has been isolated from the methanol extract of theAustralian sponge Luffariella geometrica along with the known

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compounds (7E,12E,18S,20Z )-variabilin, clathryimine A,tryptophol, and -tryptophan.50 Geometricin A showedmoderately cytotoxic activity toward the cell lines HM02 andHEPG2, 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 beenisolated from several strains of C. drocatus in a screening of themycobacterial genus Chondromyces.51 Both are unique iso-chromanone derivatives with an extended side chain containingan oxazole, a Z,Z-diene, and a 3-methoxybutenamide as char-acteristic structural features.

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

related alkaloid in which the isoxazole ring is opened, have beenisolated from the Fijian marine sponge Druinella sp. along witheight known bromotyrosine derivatives.54

Leucamide A 139, a bioactive cyclic heptapeptide containinga unique mixed 4,2-bisheterocycle tandem pair consisting of amethyloxazole and thiazole subunit has been isolated from theextract of the Australian marine sponge Leucetta microraphis.55

The structure of leucamide A was elucidated using standardspectroscopic techniques and the absolute stereochemistries ofthe chiral centres was established by chemical degradation,derivatisation, and chiral GC-MS analysis.

Localization studies of bioactive cyclic peptides patellamidesA–C 140–142 in the ascidian Lissoclinum patella have beenundertaken.56 In contrast to previous reports, it has beendemonstrated that these cyclic peptides were not located in thesymbiotic cyanobacterium Prochloron sp. but were insteaddistributed throughout the ascidian tunic.

592 Nat. Prod. Rep., 2003, 20, 584–605

Telomestatin 143 has been shown to be a very potent telo-merase inhibitor, by virtue of its ability to facilitate the form-ation of, or stabilize, G-quadruplex structures. Simulatedannealing docking calculations were used to predict the bindingmodes of 143 to the intramolecular G-quadruplex producedfrom the human telomeric sequence d[T2AG3]4.

57

The mycalolides are macrocyclic lactones belonging to aunique family of tris-oxazole containing marine metabolites.Other members of this family include ulapualides, kabiramides,halichondramides, jaspisamides, and halishigamides. Bioassay-directed fractionation of the lipophilic extract of the marinesponge Mycale izuensis, collected in the Amakusa Islands 1700km southwest of Tokyo, led to the isolation of six cytotoxicmycalolides 144–149 and one of them is a new compound,named 30,32-dihydroxymycalolide A 144, which showed anIC50 value of 2.6 ng mL�1 against Hela cells.58 The synthesisof an advanced C1–C19 fragment of ulapualide A 150, whichconstitutes the tris-oxazole linked to the C1–C9 tether, hasbeen accomplished.59 The absolute stereochemistry of the C3-hydroxyl bearing stereocenter and the C9-methyl bearing stereo-center of the ulapualides has been unambiguously assignedthrough experimental methods for the first time.

The diazonamides A 151 and B 152 were first isolated fromthe colonial ascidian Diazona angulata, collected from theceilings of caves along the northwest coast of Siquijor Island,Philippines in 1991. The unusual structural features and potentactivity of the diazonamides have stimulated intensive syntheticefforts directed at 151,60 including photo-Fries rearrangementto give the complete diazonamide core skeleton,61 imino-Dieckmann cyclization to close the C29–C30 bond,62and use ofNegishi coupling to fashion diazonamide-related biaryls withdefined axial chirality.63 A fully synthetic pathway to theoriginal structure proposed for (�)-diazonamide A 153 has

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proven that it was in error, and advanced a revised structure 151for (�)-diazonamide A instead.64,65 Shortly after, a path waschartered for the total synthesis of the newly proposed struc-ture of (�)-diazonamide A which confirmed its structure as151.66

A convergent total synthesis of (�)-hennoxazole A 154, anti-viral marine natural product isolated from the marine spongePolyfibrospongia sp., has been efficiently achieved.67 The stereo-selective synthesis of the functionalized tetrahydropyran frag-ment has been accomplished by the Mukaiyama aldol reaction,chelation-controlled 1,3-syn reduction, Wacker oxidation, andacid catalyzed intramolecular ketalization. The non-conjugatedtriene fragment was synthesized by SN2 displacement ofan allylic bromide with vinyllithium and the CrCl2-mediatediodoolefination followed by palladium-catalyzed cross couplingwith MeMgBr. The final steps include fragment coupling usingdiethyl phosphorocyanidate (DEPC) and oxazole synthesis viaan oxidation/cyclodehydration process.

Cytoxazone 155, a novel 4,5-disubstituted-2-oxazolidinonecompound recently isolated from Streptomyces sp., has showncytokine modulating activity. Two novel stereoselective syn-theses of (�)-cytoxazone have been reported and both affordedthe target alkaloid in enantiopure form.68,69

(�)-Streptazolin 156, a lipophilic neutral tricyclic compoundfirst isolated from cultures of Streptomyces viridochromogenes,has been shown to possess antibiotic and antifungal activities.Its unique structural features as well as its promising biologicalactivity profile have thus far led to several synthetic efforts. Atotal synthesis of (�)-4a,5-dihydrostreptazolin 157 has beenachieved in nine steps from -glyceraldehyde acetonide.70

Key steps involved a diastereoselective addition of a vinylicGrignard reagent to an imine derived from -glyceraldehydeacetonide, a ring-closing metathesis and a stereoselectiveradical-mediated enyne cyclization. The intramolecularPauson–Khand reaction of 2-oxazolone derivatives with a suit-able pentynyl appendage exclusively gave the corresponding 4-hydroxy-6-substituted-9-oxa-1-azatricyclo[6.2.1.0 5,11]undec-5-ene-7,10-diones. Based on this newly developed Pauson–Khandreaction of 2-oxazolone-alkyne derivatives, the first total syn-theis of (±)-8α-hydroxystreptazolone 158 has been accom-plished in a highly stereoselective manner.71

The total syntheses of the novel antitumor agent calli-peltoside A 159, isolated from the shallow-water lithistid

sponge Callipelta sp., and of its deschloro derivative 160 havebeen accomplished.72,73 A convergent strategy was employedwherein the target was dissected into three units–the coremacrolactone, the sugar callipeltose, and a cyclopropyl bearingchain.

A concise route to the aminocyclopentital core of(�)-allosamizoline 161, a potent glycosidase inhibitor, has beenrealized featuring a photochemical synthesis of the amino-cyclopentene core from a pyridinium salt, enzymatic desym-metrization, Wittig rearrangement to introduce the hydroxy-methyl 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 methodfor the formation of the allylic amine precursor to an azo-methine ylide has been developed and exploited in an efficient[1,3]-dipolar cycloaddition to afford the key tetracyclic inter-mediate used in the synthesis of (�)-tetrazomine.

A concise synthesis of the oxazole alkaloid texamine 163 hasbeen described starting from piperonylic acid.76 The strategyhas proven to be highly convergent and efficient for analogues.

Rhizoxin 164 and rhizoxin D 165, novel macrolides isolatedfrom the pathogenic fungus Rhizopus chinensis, showedpowerful antitumour and antifungal activities. A conciseenantioselective total synthesis of rhizoxin D has beendescribed featuring a Wadsworth–Emmons olefination and afacile intramolecular Stille reaction between a vinyl iodide anda vinyl stannane as key steps to elaborate the 16-memberedmacrocyclic core.77 Another convergent strategy for rhizoxin Dhas been employed wherein rhizoxin D was synthesized fromfour 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 agentsisolated from Phorbas sp. of marine sponge, feature three

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substituted tetrahydropyran units embedded with a 21-membered lactone ring. In addition to exhibiting antifungalactivity against Candida albicans, both phorboxazoles inhibitthe growth of most of the 60 tumor cell lines in the NCI panelat concentrations < 8 × 10�10 M (e.g. the GI50 againstCCRFCBM leukemia is 2.45 × 10�10 M). This level of activityplaces phorboxazoles among the most potent cytostatic agentsknown. The outstanding biological activity of phorboxazoles,combined with their complex structural architecture, has led toever-growing synthetic interest. The two analogs of phorb-oxazole A C32–C43 have been prepared and their absolute con-figurations were assigned.79 By spectroscopic comparisons withphorboxazoles, the C38 absolute configuration of these naturalproducts was verified to be R. In studies directed toward thetotal synthesis of the phorboxazoles, the syntheses of a C3–C15

bisoxane segment and a C9–C32 bisoxazole segment have beendeveloped.80,81

A masked segment of the antimitotic agents disorazolesA1 168 and C1 169, a family of 29 unique macrocyclicpolyketides isolated from the bacteria Sorangium cellulosum,has been synthesized in a highly convergent manner in 12 linearsteps.82 Synthesis of protected tetradehydro-(6,6�-S ),(14,14�-S ),(16,16�-R)-disorazole 170, a potential precursor to thenatural product disorazole C1, has been described.83 Keyfeatures of this work include: (a) an unprecedented sequential1,5 OØO silyl rearrangement/Horner–Wadsworth–Emmonsreaction, (b) a highly convergent Sonogashira reaction, and(c) selective cyclizations to give either the cyclic monomer or thedimer 170.

Leucascandrolide A 171 is a structurally unique macrolideisolated from the marine sponge Keucascandra caveolata. Thissynthetically appealing structure, in combination with itsremarkable biological activity, has solicited considerable inter-est in the synthetic community. The formal total synthesis ofleucascandrolide A has been achieved independently by threeresearch groups.84,85,86

An alternative structure of pyrinodemin A 172 has been syn-thesized.87 The 13C NMR of the synthetic product was in betteragreement with the original literature data and as a resultthe position of the double bond in the natural product wasreassigned as being between C14�–C15�.

The C9–C23 subunit of the group A treptogramin antibioticssuch as virginiamycin 173, madumycin 174, and griseoviridin175, a family of natural products isolated from strains ofStreptomyces in soil organisms, has been synthesized.88 Thestrategy incorporated a palladium-catalysed sp–sp coupling(Trost coupling reaction) and a catalytic asymmetric vinylogousMukaiyama aldol reaction to induce the chiral center at C14.

5 Thiazole alkaloids

Pyridoacridine alkaloids have been isolated from sponges,ascidians, anemones, and a prosobranch. From a 1 : 1 CH2Cl2–MeOH extract of a Singaporean ascidian, seven pyridoacridinealkaloids have been identified and two of them were newthiazole-containing compounds, namely kuanoniamine E 176and kuanoniamine F 177.89 Bioassay-guided fractionation ledto isolation of the new pyridoacridine alkaloid, lissoclinidine178 from the New Zealand ascidian Lissoclinum notti togetherwith other known alkaloids.90

A potent inhibitor of actin polymerization, 16-epi-latrunculin B 179, has been isolated from the sponge Negom-bata magnifica collected from the Red Sea near Hurghada,

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Egypt.91 This new natural product has been determined to be anepimer of latrunculin B 180, which was found in the samesponge collection. A computational method applicable to thisclass of stereochemical problems has been established and thestrategy represented a general, powerful, and readily adaptabletool for determining the relative configuration of complexmolecules.

Chemical investigation of a marine sponge Dysidea sp.,collected at Bararin Island, Philippines, has afforded eightpolychlorinated secondary metabolites, termed dysideaprolinesA–F 181–186 and barbaleucamides A 187 and B 188.92 Twonew polychlorinated metabolites 189 and 190 have been isolatedfrom the sponge Dysidea herbacea sp. 1524 collected from

Lizard Island.93 It is most probable that these compounds areactually derived from a symbiotic cyanobacterium found inclose association with the Dysidea sp.

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

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

596 Nat. Prod. Rep., 2003, 20, 584–605

strategy involved the oxidative dehydrogenation of thiazolid-ines to thiazoles using manganese dioxide, efficient fragmentcondensation, macrolactamization, and finally formation of thesensitive thiazoline ring.

Six new β-amino acid-containing cyclic depsipeptides,termed ulongamides A–F 199–204, have been isolated fromcollections of apratoxin-producing cyanobacteria Lyngbya sp.NIH309 from Palau.97 Obyanamide 205, a novel cytotoxiccyclic depsipeptide, has been obtained from a variety ofthe marine cyanobacterium Lyngbya confervoides collectedin Saipan, Commonwealth of the Northern MarianaIslands.98

Curacin D 206 is a potent antimitotic agent which was iso-lated from the cyanobacterium Lyngbya majuscular collectedoff the coast of Curacao and also from the Hawaiian cyano-bacterium Symploca hydnoides.99 A total synthesis of curacin A207 has been achieved.100 Formation of the thiazoline ring,which completed the synthesis, involved selective thioacylationof the amino group of a 2-amino-alcohol with a 1-thioacylbenzotriazole followed by cyclodehydration using Burgess’sreagent.

The total synthesis of hectochlorin 208, a novel secondarymetabolites of the marine cyanobacterium Lyngbya majusculacollected in Hector Bay, Jamaica, has been accomplished.101

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Numerous naturally occurring marine cyclopeptides contain-ing thiazole and/or oxazole units have been isolated from vari-ous origins, and almost all show significant biological activitiessuch as cytotoxic, immunosuppressive, antifungal and enzymeinhibitory activity. Lissoclinum sp. and Didemnum sp. ascidiansare a prolific source of such cyclic peptides. A new cyclo-heptapeptide, termed cyclodidemnamide B 209, has been isol-ated from the marine ascidian Didemnum molle, collected atIbo Island, Mozambique.102 The structure of the bisthiazole-containing macrocyclic peptide was initially assigned using2D NMR analysis and spectroscopic data comparisons withcyclodidemnamide 210. The unambiguous structure andstereochemistry of cyclodidemnamide B have been validatedthrough the total synthesis.

Several members of the thiopeptide class of antibiotics,thiazole- and/or oxazole-containing cyclic peptides, have beenshown to induce production of certain proteins in Streptomyceslividans. One of these proteins, TipA, is a regulatory proteinwhich binds to the ptipA promoter. Using an assay based onactivation of this promoter as a screen, two thiopeptide anti-biotics, promothiocins A 211 and B 212 were isolated fromStreptomyces sp. SF2741. The absolute stereochemistry andsolution conformation of promothiocins A and B have nowbeen investigated by a combination of degradation and molecu-lar modeling.103 These compounds contain characteristicdehydroalanine residues in their side chains that are necessaryfor high promoter inducing activity.

Micrococcin P1 (MP1) 213 is one of the structurally com-plex thiopeptide natural products. Due to persistent struc-tural uncertainties, the synthetic activity in the thiopeptidearea has been limited. An extensive NMR study has nowvalidated the 1978 Bycroft–Gowland hypothesis, hithertounsupported by experimental evidence, regarding the consti-tution of MP1.104

A method has been developed for the simultaneous detectionand determination of the absolute configuration of amino acidsfollowing hydrolysis of a peptide. This involves HPLC-MS afterderivatization with N-(5-fluoro-2,4-dinitrophenyl)--leucin-amide (-FDLA) and, separately, with -FDLA. Thismethod has now been successfully used to determine theabsolute configuration of the constituent amino acids ofthree thiazole-containing peptides, microcyclamide 214,waiakeamide 215, and goadsporin 216.105 The methodemployed a brief acid hydrolysis to minimise the racemisationand this additionally allowed tryptophan and methioninesulfoxide, which are labile during normal acid hydrolysis, to bedetected in intact form.

Experiments to re-examine the spectral data of halipeptinsA 217 and B 218 have resulted in the isolation, from the sameVanuatu species of Haliclona, of a new minor related com-pound, named halipeptin C 219.106 By comparing the spectraldata of the natural products with an appropriate syntheticmodel, the heterocyclic structure of the halipeptins, previ-ously incorrectly assigned as an oxazetidine ring, has beenrevised as a thiazoline unit. Theoretical calculations of 13CNMR chemical shifts for oxazetidine and thiazoline modelcompounds have provided additional evidence for the revisedstructure.

The DNA-damaging natural product leinamycin 220 pos-sesses a unique chemical structure and acts on DNA by acompletely novel sequence of reactions. DNA damage byleinamycin is triggered by attack of thiols on the 1,2-dithiolan-3-one 1-oxide heterocycle of the antibiotic. A theoretical studyindicated that the most reasonable mechanism for thiol-mediated activation of leinamycin involved initial attack ofthiolate at the S2�-position of the antibiotic’s 1,2-dithiolan-3-one 1-oxide heterocycle, followed by conversion to the1,2-oxathiolan-5-one intermediate.107

During the screening of myxobacteria as a potential sourceof new antibiotics, a group of cyclic peptides were isolated fromthe Archangium gephyra strain and named argyrins A–H 221–228.108 By established biological assays using both murineand human B-cell, argyrin B 222 was shown to be immuno-suppressive and a potent inhibitor of T-cell independent anti-body formation. Owing to its interesting biological activities,a total synthesis of argyrin B has been accomplished usingmodifications of known synthetic methods.109,110

Cystothiazoles A–F 229–234, previously isolated from themyxobacterium culture broth of Cystobacter fuscus, displaypotent antifungal activity and inhibit the growth of the phyto-pathogenic fungus Phytophthora capsici. Total syntheses ofcystothiazoles A, C, and E have been achieved by severalgroups.111–113

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Epothilones are antifungal and cytotoxic secondary metabol-ites originally isolated from the Gram-negative myxobacteriumSorangium cellulosum. A recent study on the early enzymes ofthe epothilone biosynthesis cluster has suggested that combin-atorial biosynthesis may be a viable means for producing avariety of epothilone analogues that incorporate diversity intothe heterocycle starter unit.114 Thirty six natural epothilonevariants 235–270 and six epothilone fragments 271–276 havebeen isolated from the culture broth of a 700 L fermentation ofSorangium cellulosum, strain So. ce90/B2 and So. ce90/D13.115

Of them, only the 12,13-desoxyepothilones, epothilone C 248and D 249 were produced in significant amounts (3–6 mg/L),and most of the other epothilone variants were producedonly in 1–100 µg/L. Further, epothilones 244–247 containing an

oxazole moiety in the side chain instead of a thiazole as wellas ring-expanded 18-membered macrolides, epothilones I 264–269, and a ring contracted 14-membered macrolide, epothiloneK 270, were found as very minor metabolites. The biological

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activities of the epothilones A–K and the epothilone fragmentshave been determined by growth inhibition of the mouse fibro-blast cell line L929. Several new natural epothilones showedactivity comparable to epothilone A 235 and B 236, but in nocase exceeded that of epothilone B 236.

A new epothilone, 10,11-didehydroepothilone D 277, hasbeen isolated from a strain of the heterologous host Myxococ-cus 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 ontubulin polymerization were comparable to epothilone D 249.The introduction of the epothilone polyketide synthase (PKS)into Myxococcus xanthus has resulted in the heterologous pro-duction of epothilone D 249 on a large scale.117 An economical,scalable, and high-yielding purification process has beendeveloped in order to isolate this valuable product from thefermentation medium.

The unique structure of epothilones, as well as their potentantitumor activities closely related to that of paclitaxel(Taxol®), have evoked a great deal of interest from chemistsand biologists. A review highlighting recent advances in thetotal synthesis, chemical biology and medicine of the epothi-lones over the last five years has been published.118

A convergent total synthesis of epothilone A 235 has beencompleted involving diastereoselective aldol condensation toform the C6–C7 bond, macrolactonization and Wadsworth–Emmons reaction of methyl ketone with a phosphonatereagent as key steps.119 Total synthesis of epothilone A hasalso been accomplished through sterospecific epoxidation ofthe p-methoxybenzyl ether of epothilone C 248.120 In addi-tion, the asymmetric synthesis of two important syntheticprecursors of epothilone A, the C1–C6 and C7–C15 fragments,has been achieved from commercially available startingmaterials.121

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

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to the development of new reaction methodologies and servedas the proving ground for asymmetric carbon–carbon bondformation. A ring-closing alkyne metathesis reaction (RCM)catalyzed by a molybdenum complex, followed by a Lindlarreduction of the resulting cycloalkyne product, opened an effi-cient and stereoselective entry into epothilones A and C.123

A highly diastereoselective addition reaction of a titaniumenolate offered an efficient entry to the total synthesis of theepothilone family such as epothilone B.124 Based on the sub-sequent Normant reaction, Wadsworth–Emmons reaction,diastereoselective aldol condensation and macrolactonization,a convergent and stereoselective total synthesis of epothiloneB has been achieved.125 The selectively terminal epoxidationof 12,13-desoxyepothilone B (epothilone D 249) to epothiloneB 236, using 2,2�-dimethyldioxirane (DMDO), has beeninvestigated.126 The diastereoselectivity of the epoxidation hasshown to be highly temperature dependent and the diastereo-selectivity increases to > 20 : 1 when the reaction is performedat �78 �C.

A total synthesis of epothilones B 236 and D 249 has beenreported in which the trisubstituted 12,13-double bond wasintroduced stereoselectively using the tin() bromide-promotedreaction between an allylstannane and an aldehyde.127 A Bartondeoxygenation reaction and an aldol condensation were alsoapplied to reach the target epothilones. The epothilones Band D have also been enantiospecifically synthesized from-glucose.128

Total synthesis of epothilone 490 277, which is 10,11-didehydroepothilone D, has been accomplished by two routes,one utilizing a vinyl-boronate cross-metathesis followed by aSuzuki macrocyclization 129 and the other using ring-closingmetathesis.130

With the hope of establishing a thorough understanding ofepothilone structure–activity relationships (SAR), numerousepothilone analogues, including: C26-(1,3-dioxolanyl)-12,13-desoxyepothilone B 278,131trans-12,13-cyclopropyl epothiloneB analogues 279,132[17]- and [18]dehydrodesoxyepothilones B280,1339,10-didehydroepothilone D isomers 281 and 282,134and12α,13α-aziridinyl epothilone derivatives 283,135 have beenprepared by total synthesis.

Marine natural product trunkamide A 284 contains a thiazo-line heterocycle and two residues of Ser and Thr with thehydroxy function modified as reverse prenyl (rPr). A total syn-thesis of trunkamide A has been presented, which used solid-phase peptide chain elongation followed by cyclizations insolution.136

Several analogues of the naturally occurring antibioticalthiomycin 285, isolated from Streptomyces althioticus, havebeen synthesized by both total- and semi-synthetic method-ologies.137 The antibacterial activity of these derivatives hasbeen determined in whole cell assays and indicated that thenatural product exhibits a restricted structure–activity relation-ship (SAR).

The thiostrepton family of peptide antibiotics 286–289 wasfirstly isolated from the culture broth of Streptomyces azureus.Because of their complex structural features, synthetic studieson the thiostrepton family of antibiotics have scarcely beenattempted. An enantioselective synthesis of the tetrasubstituteddehydropiperidine and piperidine cores, 290 and 291, of thethiostrepton family of antibiotics has been described.138

Thiazolyl peptide antibiotics nocathiacins I–IV 292–295,recently isolated from fermentation of Nocardia sp., showpotent antimicrobial activity against Gram-positive bacteriain vitro, with promising activity against multi drug-resistantStaphylococcus aureus, Streptococcus pneumoniae, and Entero-coccus faecium. Although nocathiacin IV 295 has been obtainedfrom nocathiacin I 292 enzymatically,139an alternative efficientchemical method for converting nocathiacin I to nocathiacin IVby selective cleavage of the dehydroalanine unit has beendeveloped.140 With the aim of improving the water-solubility of

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nocathiacins, several synthetic analogues have been preparedfrom nocathiacin IV by condensation with glycolaldehydefollowed by tandem reductive amination.141

Marine cyclic peptides, a structurally diverse class of naturalproducts, have shown a broad range of bioactivities such ascytotoxic, antiviral, and anti-inflammatory activities. Their bio-synthesis has been thought to occur primarily through theaction of nonribosomal peptide synthetases.142 Total synthesisof trans,trans- and cis,cis-ceratospongamide, 296a and b, bio-active cyclic heptapeptides recently isolated form a marinealga/sponge symbiont, has been accomplished and theircomformations 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 iso-lated from Streptomyces verticillus. Metabolic inactivation ofthe bleomycins is believed to be mediated exclusively via theaction of bleomycin hydrolase, a cysteine proteinase that iswidely distributed in nature. Total synthesis of deamido bleo-mycin A2 299, the major metabolite of bleomycin A2, has beenreported.145 Synthetic deamido bleomycin A2 has shown to beidentical to the product formed by treatment of bleomycin A2

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with human bleomycin hydrolase and although it retains sig-nificant DNA cleavage activity in DNA plasmid relaxationassays and has the same sequence selectivity of DNA cleavageas bleomycin A2, it has reduced ability to cleave doublestranded DNA. To explore the influence on the sequence select-ivity of DNA cleavage by the carbohydrate moiety of BLMs,BLM A5 298 and three monosaccharide analogues have beensynthesized using a solid-phase synthetic methodology.146

Tallysomycins A 300 and B 301, firstly isolated from fermen-tation broths of Streptoalloteichus hindustanus, are glyco-peptide-derived antitumor antibiotics structurally related to the

bleomycins. A key intermediate toward the total synthesis oftallysomycins that contained the glycosylcarbinolamide moietyhas been synthesized.147

The first racemic syntheses of cruciferous indole phyto-alexins, 1-methoxyspirobrassinin 303, methoxyspirobrassinol304, and 1-methoxyspirobrassinol methyl ether 305, as well as anew synthesis of spirobrassinin 302 have been achieved byspirocyclization of brassinin 306 and its 1-substituted deriv-atives using bromide in dioxane–water or dioxane–methanol.148

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

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