imidazole, oxazole and thiazole alkaloids

REVIEW www.rsc.org/npr | Natural Product Reports

Imidazole, oxazole and thiazole alkaloids

Zhong Jin*

Received (in Cambridge, UK) 1st November 2005First published as an Advance Article on the web 28th March 2006DOI: 10.1039/b502166a

Covering: July 2004 to June 2005. Previous review: Nat. Prod. Rep., 2005, 22, 196–229

Terrestrial and marine microorganisms as well as marine invertebrates, particularly sponges andascidians, are well known for their production of structurally diverse imidazole-, oxazole-, andthiazole-containing natural products, many of which show extensive biological potential includingantibacterial, antifungal, antiparasitic, antiviral, and antitumor activities. This review, with 186references cited, gives an account of the chemistry and biology of these biologically significantsecondary metabolites.

1 Introduction2 Imidazole alkaloids2.1 Alkaloids from marine sponges2.1.1 Bromopyrrole-imidazole alkaloids2.1.2 Bisindole alkaloids2.1.3 Other alkaloids from sponges2.2 Alkaloids from soft corals2.3 Alkaloids from bryozoans2.4 Alkaloids from marine tunicates2.5 Alkaloids from microorganisms2.6 Alkaloids from plants2.7 Miscellaneous3 Oxazole alkaloids

Institute of Elemento-Organic Chemistry, State Key Laboratory ofElemento-Organic Chemistry, Nankai University, Tianjin, 300071,P. R. China. E-mail: [email protected]

Born in Nanjin, P. R. China in 1973, Zhong Jin started to studychemistry at Nankai University in 1991. After obtaining his BSc,MSc and PhD degrees in organic chemistry from Nankai University,he joined the faculty of Nankai University in 2002. His researchinterests focus on the discovery of novel natural and unnaturalbiological molecules, the development of new selective and efficientsynthetic methods, and the total syntheses of natural products,especially alkaloids.

Zhong Jin

3.1 Alkaloids from marine sponges3.1.1 Macrolides3.1.2 Isoxazoline and isoxazolidine alkaloids3.1.3 Other alkaloids from sponges3.2 Alkaloids from marine tunicates (ascidians)3.2.1 Diazonamides3.2.2 Other alkaloids from marine tunicates3.3 Alkaloids from microorganisms3.3.1 Macrolides3.3.2 Cyclopeptides3.3.3 Ergot alkaloids3.3.4 Other alkaloids from microorganisms4 Thiazole alkaloids4.1 Epothilones4.2 Thiopeptides4.3 Thiazolyl cyclic peptides4.4 Other thiazole alkaloids from microorganisms4.5 Alkaloids from marine invertebrates5 References

1 Introduction

Until the early 20th century, natural products, especially plant ex-tracts, served mankind as the most significant source of medicinesand many of them are still used today for the treatment ofvarious diseases in China, the Middle East, Africa, South America,Mexico and Europe.1,2 Nowadays, although suffering drasticcompetition from other drug discovery methods such as combina-torial chemistry,3,4 rational drug design5,6 and computer-assisteddesign technology, natural product chemistry still represents animportant and efficient approach for drug development.7–13 From2000 to 2003 alone, a total of 15 new natural products and naturalproduct-derived drugs have been launched in the United States,Europe, and Japan.7

The tremendous advances in modern structural analysismethods, such as multidimensional NMR spectroscopy,14 high-resolution mass spectrometry, X-ray crystallography,15,16 andcomputer technology17 have made the identification and structureelucidation of new natural products more convenient, expeditiousand efficient. However, structure misassignments of architecturallycomplex natural products, especially in their stereochemistry, seem

464 | Nat. Prod. Rep., 2006, 23, 464–496 This journal is © The Royal Society of Chemistry 2006

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to be inevitable.18 Chemical total synthesis, meanwhile, providesa powerful vehicle for confirmation of the structure of naturalproducts and has also paved a way to their close structuralanalogues for further biological investigation.

Natural products containing imidazole-, oxazole- and thiazole-subunit(s), which show diverse significant biological activities, arewidely distributed throughout nature including marine organismsand microorganisms. In particular, marine invertebrate animals,belonging to the classes of Porifera, Mollusca, Cnidaria, Antho-zoa, Echinodermata, and Bryozoa (sponges, molluscs, coelenter-ates, tunicates, echinoderms, etc.) have proven to be rich sourcesof such secondary metabolites during the last two decades. Thepresent review, like the previous one of this series,19 summarizes theisolation, identification, biological activities and total syntheses ofthese natural products covering the literature from July 2004 toJune 2005.

2 Imidazole alkaloids

2.1 Alkaloids from marine sponges

Marine sponges continue to be the single richest source ofstructurally diverse secondary metabolites.20 To date, more than3300 natural products have been produced from this type of marineinvertebrate.21 Bromopyrrole-imidazole alkaloids are known to beone of the most common metabolites contained in marine sponges.In addition, bisindole alkaloids are also recognized as a rapidlygrowing class of metabolites of marine sponges. Very recently,a comprehensive review reported research progress on naturalantitumor agents, including pyrrole, pyrazine, imidazole, andother structural families, isolated from various marine sponges,and emphasized again the role of marine sponge alkaloids as animportant source of leads for drug discovery.22

2.1.1 Bromopyrrole-imidazole alkaloids. Simple bromopyr-role-imidazole alkaloids as well as more complex cyclized ones(such as the phakellin family of alkaloids) and dimerizedbromopyrrole-imidazole alkaloids all appear to be derived fromthe non-cyclized precursor oroidin 1 or a close analogue. Themonomeric oroidin-type alkaloids are characterized by the bro-mopyrrole carboxamide and aminoimidazole moieties linkedthrough a propenyl chain. To explore various C–C bond couplingprocesses, oxidative cyclization of oroidin-type alkaloids, oroidin1 and sventrin 2, in DMSO–TFA (1 : 1) has been investigated andthe double bond in the benzylic position of the imidazole ringwas ascertained to be readily oxidized.23 A known oroidin-typealkaloid, keramadine 3, has been isolated from marine spongeEurypon laughlini collected in the Caribbean along with a newcyclic peptide and a new bromopyrrole-guanidine alkaloid.24

A possible biogenetic sequence relating proline–guanidine tooroidin-type alkaloid dispacamide A 4 has been described by

Travert and Al-Mourabit involving proline-based peptide synthe-sis (step 1), oxidation of a proline residue to a pyrrole (step 2) andoxidative rearrangement of a proline–guanidine moiety to the 2-aminoimidazolinone (step 3) (Scheme 1).25 To adduce the criticalbiotransformation process, a biomimetic conversion of proline to2-aminoimidazolinone derivatives involving an aerial oxidationand an intramolecular transamination reaction as the key stepwas accomplished (Scheme 2).

Scheme 1

Scheme 2 Reagents and conditions: a) EDCI, DMAP, CH2Cl2; b) Boc-guanidine, air, THF, reflux; c) AcOH, Br2; d) TFA, CH2Cl2; e) CH3SO3H,80 ◦C. EDCI = 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochlo-ride; DMAP = 4-(dimethylamino)pyridine; TFA = trifluoroacetic acid.

This journal is © The Royal Society of Chemistry 2006 Nat. Prod. Rep., 2006, 23, 464–496 | 465

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Two new cyclized phakellin family alkaloids, namely (−)-7-N-methyldibromophakellin 10 and (−)-7-N-methylmonobromopha-kellin 11, have been isolated from marine sponge of the genusAgelas (order Agelasida, family Agelasidae) collected near thecoast of Wewak, Papua New Guinea.26 Their structures wereascertained by a combination of spectroscopic data analysis andcomparison to the properties of known phakellin alkaloids.

Hypervalent iodine reagents have proven to be efficient elec-trophilic activators in carbon–carbon and carbon–heteroatombond coupling processes and have been extensively applied inthe total syntheses of alkaloids.27 A convergent total synthesis of(±)-dibromophakellstatin 12, originally isolated from the spongePhakellia mauritiana, has been accomplished by Feldman andSkoumbourdis utilizing a hypervalent iodine-mediated Pummerer-type reaction as a key step to construct key N1–C12 and N7–C11 bonds.28 Treatment of the polyfunctional dihydrooroidinderivative 13 with Stang’s reagent, PhI(CN)OTf, in the presence ofdiisopropylethylamine directly delivered the tetracyclic intermedi-ate 14 by an oxidative cyclization sequence. Finally, oxidative hy-drolysis of the thioimidate 14 afforded alkaloid 12 (Scheme 3). Byapplication of hypervalent iodine-mediated vicinal syn diazidationreaction, the cyclic urea skeleton of (±)-dibromophakellstatin 12has been installed and the total synthesis was ultimately completedafter subsequent synthesis steps (Scheme 4).29 N-Acylprolinol15 was transformed into the key dihydrodipyrrolopyrazinone 16in two simple steps. Treatment of pyrazinone 16 with solution-phase hypervalent iodine, TMSN3 and I−, via in situ formation of

Scheme 3 Reagents and conditions: a) PhI(CN)OTf, i-Pr2NEt; b) CAN,CH3CN, H2O. CAN = ceric ammonium nitrate.

Scheme 4 Reagents and conditions: a) PhI(OAc)2, TMSN3, −30 ◦C;b) Et4NI, −30 ◦C to rt.

−I(N3)2, provided syn-diazide 17 as the major diastereomer andthe anti-diazide as a minor diastereomer. Hydrogenation of thesyn-diazide, followed by cyclization to form the urea moiety andbromination of the pyrrole ring completed the total synthesis ofalkaloid 12.

An efficient five-step total synthesis of (±)-dibromopha-kellstatin 12 in 8% overall yield starting from L-prolinol has beenpublished by Lindel and co-workers.30 The key step in the synthesiswas the direct assembly of the urea ring from the readily availableintermediate 18 by reaction with ethoxycarbonylnitrene generatedin situ, which was followed by deprotection of both nitrogen atomswith SmI2 (Scheme 5).

Scheme 5 Reagents and conditions: a) TsONHCO2Et, CaO, CH2Cl2;b) SmI2, THF; then MeOH.

An alternative strategy towards the ABC tricyclic cores 16and 18 of the phakellin family of alkaloids has been describedinvolving regioselective intramolecular cyclizations of a pyrrole-proline precursor.31

In order to evaluate its antitumor and toxicological effects, anenantiospecific total synthesis of (−)-agelastatin A 20, first isolatedfrom the axinellid sponge Agelas dendromorpha, has been com-pleted by Hale and co-workers from the chiral oxazolidinone (−)-21.32–34 Using a combination of n-BuLi and DABCO as the base,oxazolidinone 21 was readily transformed into the N-carbamoyloxazolidinone 22. Thereafter, a second N-acylation with a pyrroleacid chloride afforded the desired pyrrolocarboxamide 23. The b-trimethylsilylethanesulfonyl (SES) group of 23 was removed withBu3SnH and AIBN in PhMe. This is the first time that an SESgroup has been reductively removed from an amide nitrogen byBu3SnH under free radical conditions. The oxazolidinone ring of


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Scheme 6 Reagents and conditions: a) n-BuLi, THF, −78 ◦C, then ClCON(Me)Bn, warm to rt, then DABCO; b) TEA, DMAP; c) Bu3SnH, AIBN,PhMe; d) LiOH, THF–H2O (9 : 1); e) PDC, DMF; f) NBS, THF, 0 ◦C, then i-Pr2NEt, rt; g) H2, Pd/C, MeOH, NaOAc; h) H2, Pd(OH)2, THF; i) NBS,THF, 0 ◦C to r.t. DABCO = 1,4-diazabicyclo[2,2,2]octane; TEA = triethylamine.

24 was successfully hydrolyzed, leaving the urethane unit intact,with aqueous LiOH in THF. After oxidation by pyridiniumdichromate in DMF, enone 26 was obtained in acceptable yield.Direct base-mediated cyclization of 26 to 28 was ineffectivebut after bromination of the pyrrole base-catalysed cyclisationwas successful and the bromine atoms were then removed bycatalytic hydrogenation., Ketone 28 was finally converted to thetarget alkaloid 20 by N-debenzylation and monobromination ofthe pyrrole ring (Scheme 6).

Very recently, Davis and Deng also achieved an asymmetrictotal synthesis of (−)-agelastatin A from the key intermediate4,5-diaminocyclopenten-2-enone (−)-30, which was efficientlyprepared from the sulfinimine-derived a,b-diamino ester 31 usinga ring-closing metathesis methodology.35

The sponge alkaloids Palau’amines 32 and styloguanidines33 belong to polycyclic bisguanidine members of bromopyrrole-imidazole alkaloid family, which are probably produced viaan oroidin-based dimerization–cyclization biosynthetic pathway.Their significantly biological potential and challenging structureshave attracted the attention of a number of synthetic groups overthe last few years.

During synthetic studies towards the Palau’amines 32, anelectronically adjustable protecting group on one of the amidenitrogen atoms, namely the tosylvinyl group (Tsv), was introducedinto the diene substrate 34 in order to improve the regioselectivityof the key Diels–Alder process. Subsequently, for the sake ofavoiding aromatization of adduct 36 in the chlorination process,the electron-deficient p-tosylvinyl group (Tsv) was readily con-verted to the electron-rich p-tosylethyl group (Tse) under catalytichydrogenation conditions (Scheme 7).36

In addition, a DBU-mediated spirocycloisomerization strategyof alkylidene-tethered glycocyamidines has been developed byHarran’s group during synthetic efforts towards the core linkageof the Palau’amines family of alkaloids.37 Lovely and co-workershave also devised a concise approach towards the spiro-fusedDEF-rings in Palau’amine alkaloids. The strategy featured anintramolecular Diels–Alder reaction of elaborated vinylimidazole38 and subsequent oxidative rearrangement provided rapid accessto polycyclic framework of the target natural products.38


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Scheme 7 Reagents and conditions: a) 2,6-lutidine, 95 ◦C, sealed tube,96 h; b) TBDPSCl, TEA, DMAP, CH2Cl2; c) Pd(OH)2/C, H2, EtOAc.TBDPSCl = tert-butyldiphenylsilyl chloride.

From the marine sponge Agelas sp. collected off Sera-gaki, Okinawa, eight new dimeric bromopyrrole-imidazole al-kaloids nagelamides A–H 39–46 and a monomeric one, 9,10-dihydrokeramadine 47 have been isolated by Kobayashi’s group,together with known related alkaloids ageliferin 48, bromoagelif-erin 49, dibromoageliferin 50, mauritiamine 51, keramadine 3,oroidin 1, stevensine 52, tauroacidin A 53, taurodispacamide A54, cyclooroidin 55, and manzacidin A.39 Based on 1H, 13C NMR,2D NMR and ROESY correlation analysis, nagelamides E–G43–45 were concluded to be the 10-epi isomers of ageliferin 48,bromoageliferin 49, and dibromoageliferin 50, respectively.

Taking advantage of the known photocycloaddition reactionof maleic anhydride to trans-1,4-dichloro-2-butene, the centralcyclobutane skeleton of the dimeric bromopyrrole-imidazole alka-loids sceptrin 56 and dibromosceptrin 57 was efficiently assembledby Birman and Jiang, leading to their total syntheses.40 Intramolec-ular Diels–Alder cycloaddition reactions of 4-vinylimidazolederivatives have been extensively investigated by Lovely’s groupand application of this methodology to the total synthesis ofthe dimeric bromopyrrole-imidazole alkaloids, ageliferin 48 andnagelamide E 43, has also been presented.41,42

2.1.2 Bisindole alkaloids. Over the last decade, an ever-increasing number of novel bisindole alkaloids have been isolatedfrom marine organisms especially from deep-water sponges. Thesenatural products typically have a skeleton in which the two indolerings are linked with a central heterocyclic unit such as imidazole,pyrazine, etc. More recently, a review focusing on the isolation,structure determination, and total synthesis of these bioactivemarine alkaloids has been published by Jiang and co-workers.43

Bioactivity-guided fractionation from the MeOH extract ofa marine sponge Spongosorites sp., collected off the coast ofJeju Island, Korea, has led to the isolation of a new bisindolealkaloid of the topsentin class, namely dibromodeoxytopsentin58, and three new bisindole alkaloids of the hamacanthin classalong with other known bisindole alkaloids including topsentin59, bromotopsentin 60, deoxytopsentin 61, bromodeoxytopsentin62, isobromodeoxytopsentin 63, trans-3,4-dihydrohamacanthin Aand cis-3,4-dihydrohamacanthin B.44

The bisindole alkaloids of the dragmacidin class, such asdragmacidins D 64, E 65, and F 66 belong to the structurallycomplex pyrazinone-containing members. After initially beingreported as a communication,45 the first enantiospecific totalsynthesis of (+)- and (−)-dragmacidin F 66 has been presented indetail by Stoltz and co-workers, featuring a palladium-mediatedintramolecular oxidative carbocyclization, a halogen-selectiveSuzuki cross-croupling reaction, and a high-yielding late-stageNeber rearrangement (Scheme 8).46 The synthesis commencedwith bicyclic lactone 67 prepared from (−)-quinic acid by a knowntwo-step procedure. Oxidation of 67 followed by Wittig olefinationof the resultant ketone produced exo-methylene lactone 68. Afterreductive isomerization to carboxylic acid 69, a Weinreb amidationprocedure followed by the addition of protected 2-lithiopyrroleprovided the key oxidative cyclization substrate 71. SubsequentPd-mediated oxidative pyrrole–olefin carbocyclization success-fully afforded the desired pyrrole-fused bicycle 72, which wasconverted into methyl ether 73 via catalytic hydrogenation of theolefin followed by methylation. After regioselective bromination–metalation of the pyrrole ring to produce boronic ester 74, thecritical halogen-selective Suzuki coupling reaction between 74and 75 smoothly delivered the dragmacidin F framework 76.The ketone 77 was obtained via selective deprotection of the silylether and Dess–Martin oxidation. Conversion of ketone 77 totosyloxime 78, followed by a Neber rearrangement successfullyinstalled an amino group in the a-position of the ketone. Finally,removal of bis-methyl ether in 79 and cyclization with cyanamideproduced (+)-dragmacidin F.

Homocarbonyltopsentin 80, a bisindole alkaloid of thetopsentin class, exhibits potent anti-inflammatory activity invivo. In order to investigate the role of the heterocycles in themodulation of their activity, several analogues 81 have beensynthesized in which one of the indoles has been replaced eitherby a substituted indole or a heterocycle such as pyrrolo[2,3-b]pyridine, benzo[b]thiophene or pyridine.47

2.1.3 Other alkaloids from sponges. From the EtOH extractof a southern Australian marine sponge of the genus Echinodic-tyum, a novel imidazole betaine (+)-echinobetaine B 82 has beenisolated by Gill and co-workers.48 A preliminary SAR relationshiphas been summarized from analysis of related synthetic interme-diates and the known marine metabolites zooanemonin 83, nor-zooanemonin 84, and the new sponge metabolite norzooanemoninmethyl ester 85, the isolation of which was reported for the firsttime from a selection of Australian sponges, including an Axinyssasp., a Niphates sp., an Axinella sp. and a Ptilocaulis sp. It isworthwhile noting that naturally occurring (+)-echinobetaine B82 displayed potent nematocidal activity with a LD99 value of8.3 lg mL−1, comparable to that of the two commercial syntheticanthelmintics closantel and levamisole (LD99 5–10 lg mL−1).


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By contrast, the synthetic racemate (±)-echinobetaine Bwas considerably less active (LD99 65 lg mL−1).

Along with the known compounds N,N-dimethylnaamidine D86 and isonaamine B 87, a fused 2-aminoimidazole oxalane ringnatural product (−)-spiroleucettadine 88 has been isolated fromthe sponge Leucetta sp. collected from Viti Levu, Fiji.49 It showedgood antibacterial activity against Enterococcus durans with anMIC value of <6.25 lg mL−1 compared with that of vancomycin(<0.625 lg mL−1) and penicillin (12.5 lg mL−1).

Chemical investigation of the hitherto undescribed spongeDragmacidon sp. from the Andaman Sea has lead to the isolationof two new b-carboline alkaloids, named dragmacidonaminesA 89 and B 90, which were the first b-carboline-3-carboxylatealkaloids isolated from the phylum Porifera.50 A known metabolitediscorhabdin H 91 has been obtained by Davies-Coleman andhis colleagues from a new species of dark green, encrustingLatrunculia sponge, L. bellae, and the stereochemistry of the L-histidine residue in this compound has been confirmed by chiralGC-MS analysis.51


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Five asmarine alkaloids, including two known asmarines A92, F 93, and three new ones, I 94, J 95, K 96 as well as fourditerpenes have been identified by Kashman and co-workers from

the Indian Ocean sponge Raspailia sp. collected from Nosy Be,Madagascar.52 Their structures were assigned by combinationof HREIMS and NMR data. Shortly after, during syntheticstudies toward the total synthesis of asmarines, three cyclizationstrategies, namely aminomercurization, iodocyclization, and acid-catalyzed cyclization have been developed by the same groupfor construction of the unique 9,9-disubstituted 10-hydroxy-tetrahydro[1,4]diazepino[1,2,3-gh]purine ring system.53

The first synthesis of cribrostatin 6 97, originally obtained fromMaldives marine sponge Cribrochalina sp., has been achievedby Nakahara and Kubo in ten linear steps from 2,4-diethoxy-3-methylphenol.54 Girolline 98 is a metabolite, originally isolatedfrom the New Caledonian sponge Cymbastela cantharella, withpromising antitumor activity. However, undesirable side-effects onthe cardiovascular system, including severe hypotension, emergedduring phase I clinical trials. With the aim of improving itstherapeutic index, an aminothiazole analogue 99 of girollinehas been designed and synthesized starting from a chiral poolcompound and utilizing the Hantzsch reaction to form theaminothiazole ring.55 Unfortunately 99 showed no antitumoractivity.

Scheme 8 Reagents and conditions: a) PDC, Celite, MS 4 A, CH3CN; then MePPh3Br, t-BuOK, THF; b) H2, 10% Pd/C, MeOH; c) CDI,NH(OMe)Me·HCl, CH2Cl2; d) THF, −78 to 0 ◦C; e) Pd(OAc)2, DMSO, HOtBu, AcOH; f) 10% Pd/C, H2, EtOAc; then NaH, MeI, THF; g) NBS, THF,0 ◦C to rt; then n-BuLi, THF, −78 ◦C, i-PrOB(OCMe2CMe2O); h) Pd(PPh3)4, Na2CO3, H2O, MeOH, PhH; i) LiBF4, CH3CN, H2O; then Dess–Martinreagent, CH2Cl2; j) NH2OH·HCl, NaOAc, MeOH, H2O; then TsCl, Bu4NBr, KOH, H2O, PhMe, 0 ◦C; k) KOH, H2O, EtOH, 0 ◦C; 6 M HCl, 60 ◦C; thenK2CO3, THF, H2O; l) TMSI, CH3CN; then H2NCN, NaOH, H2O.


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2.2 Alkaloids from soft corals

Sarcodictyins A 100, B 101, and eleutherobin 102, belonging tothe eleutheside family of natural products isolated from marinesoft corals, own a common tricyclic diterpene core. They showedan antitumor profile different from that of Taxol and holdpotential as second-generation microtubule-stabilizing anticanceragents.

A formal total synthesis of eleutherobin 102 has been ac-complished recently by Gennari and co-workers featuring aring-closing metathesis (RCM) reaction catalyzed by a second-generation Grubbs catalyst.56 The RCM precursor diene 109was synthesized from protected dialdehyde 103 by two stereos-elective Hafner–Duthaler oxyallylations. The first oxyallylationproceeded in the presence of the chiral titanium complex [(S,S)-(taddol)(Cp)TiCl] with complete stereocontrol to give the de-sired stereoisomer 104. After protection of the alcohol as themethoxymethyl ether, cleavage of the dimethylacetal group and re-duction with NaBH4 gave alcohol 106, followed by conversion intohomologated aldehyde 107. The second oxyallylation procedure inthe presence of the [(R,R)-(taddol)(Cp)TiCl] gave the desired dienealcohol 108 which was transformed into its pivalate ester 109.Treatment of the diene with Grubbs catalyst 110 afforded E RCMproduct 111. After sequential removal of two p-methoxyphenyl(PMP) groups and Dess–Martin oxidation, the E-enedione 112was obtained, which isomerized to the more stable Z-isomer113 spontaneously at room temperature. The MOM protectinggroup was removed to give tricyclic 114, which finally deliveredtarget natural product 102 according to Danishefsky’s method(Scheme 9).

Shortly after this, using the same synthetic strategy, Gennari andco-workers also prepared a number of novel, simplified, C7 sub-stituted eleutheside analogues, with the aim of discovering potentmicrotubule-stabilizing agents.57 In addition, a fully functionalizedC-ring equivalent 115 of eleutherobin has been synthesized byan Indian group for more comprehensive understanding of itsSAR.58


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Scheme 9 Reagents and conditions: a) s-BuLi, PMPOAllyl, [(S,S)-taddolCpTiCl], THF–Et2O, −78 ◦C to 0 ◦C; b) iPr2NEt, TBAI, MOMCl, CH2Cl2; c)LiBF4, CH3CN–H2O; then NaBH4, EtOH; d) MsCl, TEA, CH2Cl2; KCN, [18]crown-6, CH3CN; then DIBAL-H, toluene–hexane, −78 ◦C; e) s-BuLi,PMPOAllyl, [(R,R)-taddolCpTiCl], THF–Et2O, −78 ◦C to rt; f) PivCl, DMAP, iPr2NEt, CH2Cl2, rt; g) toluene, 110 ◦C; h) CAN, CH3CN–H2O, 0 ◦C;Dess–Martin Periodinane; CH2Cl2, rt; i) CDCl3, 25 ◦C; j) BF3·Et2O, Me2S, CH2Cl2, −78 ◦C to −20 ◦C.

2.3 Alkaloids from bryozoans

The securines A 116, B 117, securamines A 118, B 119,chartellines A 120, B 121, C 122, and chartellamides A 123, B124 are an unique class of naturally occurring alkaloids, firstidentified by Christophersen and co-workers from the marinebryozoa Chartella papyracea and Securiflustra securifrons. Dueto the highly dense assembly of several sensitive functionalities

including spiro-b-lactam, indolenine, chloroenamide, and 2-bromoimidazole, no total synthesis of any of these marinealkaloids has been reported to date.

Recently, Baran and co-workers have described an efficientsynthetic strategy to the unsaturated 10-membered ring frame-work 125, containing the fused indolenine, spiro-b-lactam andimidazole units of the chartelline-type alkaloids.59 Sonogashiracoupling of 2-bromoindole 126 and alkyne 127, followed byhydrogenation, removal of the TBS protecting group, and MnO2-mediated oxidation of the resulting alcohol afforded the alde-hyde 129. Formation of 130 followed by macrocyclization via aHorner–Wadsworth–Emmons reaction gave the precursor 131.Thermolytic removal of the Boc protecting group followed bytreatment with NBS resulted in the critical cyclisation to the spiro-b-lactam skeleton 125 (Scheme 10).

Another access to the macrocyclic core of securine alkaloids hasbeen introduced by Wood and his colleagues based on a Cacchiindole synthesis method.60 Sonagashira coupling between alkyne132 and iodoaniline afforded 133, which was converted to indole134 in the presence of palladium(0) catalyst. Functionalization atthe 3-position of the indole ring followed by protection of NHand OH group lead to 136. Subsequent treatment with iodinemonochloride–sodium acetate followed by sodium azide affordedazido acetate 137. Saponification and cyclization resulted in theefficient construction of key lactone 139, which ultimately under-went tandem azide reduction–ring expansion to the macrolactam141 (Scheme 11).

Additionally, the bromoindolenine spiro-b-lactam moiety 143of the chartelline alkaloids has been prepared by nucleophilicsubstitution at the nitrogen atom of O-sulfonylated hydrox-amic acid 142 in a study towards the total synthesis of thesealkaloids.61


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Scheme 10 Reagents and conditions: a) Pd(PPh3)4, CuI; b) Pd/C, H2; TBAF; then MnO2; c) LiOH; then BOPCl; d) i-Pr2NEt, LiCl, MeCN, 70 ◦C; e)180 ◦C; then NBS. BOPCl = N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride, TBAF = tetrabutylammonium fluoride.

Scheme 11 Reagents and conditions: a) PdCl2(PPh3)2, CuI, TEA–PhH; b) Pd(PPh3)4, Et2NH; c) n-BuLi, ICH2CO2n-Bu; d) TBSCl, Imid.; then Boc2O,TEA, 60 ◦C; e) ICI, MeCN, NaOAc; NaN3, DMF, 100 ◦C; f) LiOH, THF–H2O, 80 ◦C, 72 h; g) TEA, THF, DMAP; h) TBAF–AcOH; i) Bu3SnH, PhH,AIBN, 80 ◦C. TBSCl = t-butyldimethylsilyl chloride, Imid. = imidazole.

2.4 Alkaloids from marine tunicates

In contrast to the well-known class of b-carboline-derived naturalproducts, grossularine-1 144 and N,N-didesmethylgrossularine-1145, originally reported from marine tunicates Dendrodoa grossu-laria and Polycarpa aurata, respectively, were the first examples

of naturally occurring a-carboline metabolites. A remarkablyconcise synthesis of grossularines-1 144 and 145 has been realizedby Horne and co-workers, which also represents a plausible

biosynthetic pathway for members of this a-carboline family.62


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Scheme 12

Oxidative dimerization and subsequent electrocyclic ring closureof 2-amino-4-(3-indolyl)imidazoles 146 gave directly imines 148,which were hydrolyzed to yield grossularines-1 144 and 145(Scheme 12).

2.5 Alkaloids from microorganisms

Microbes are abundant in secondary metabolites, which oftenexhibit either antimicrobial (antibacterial, antifungal, antiproto-zoal), antitumor, antiviral, or other activities.21

From a culture of Metarhizium sp. FKI-1079, a known anti-fungal imidazole derivative fungerin 149, originally produced byFusarium sp., was found and shown to arrest the cell cycle atthe M phase through inhibition of microtubule polymerization.63

Using characteristic morphological changes of cells as an in-dicator to screen microbial products for microtubule-actingagents, Yoshimura and co-workers identified a new microtubulepolymerization-promoter with high water-solubility from Strep-tomyces sp. No. 9885, compound FR182876 150, whose structureincluding absolute configuration was completely elucidated bya combination of modern spectroscopic methods and chemicalcorrelations.64 On the basis of extensive NMR and MS data, anovel cyclic peptide, designated as Sch 486058 151, was isolatedand identified from Actinomycete sp. by Puar et al.65

The mannopeptimycins a–e 152–156, recently isolated fromStreptomyces hygroscopicus, are a class of new glycopeptideantibiotics exhibiting predominant activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant entero-cocci. An efficient method for the hydrolysis of mannopeptimycin-a 152 to mannopeptimycin-b 153, catalyzed by a-mannosidase,has been established by Sutherland and co-workers.66 Eithermannopeptimycin-b or the mono-O-mannosyl intermediate couldbe isolated on a preparative scale depending on the catalyst used.For further structure–activity relationship studies on mannopep-

timycin antibiotics, mannopeptimycin-a cyclic acetal derivativeswere prepared by He and co-workers, who originally isolatedthese antibiotics from Streptomyces sp. The acetal reactions wereidentified as occurring at the 4,6-positions of the terminal mannoseby spectroscopic analyses.67

Over the past decades, freshwater cyanobacteria has proven tobe rich source of a variety of lethal toxins such as cylindrosper-mopsin 157, saxitoxin 158, anatoxin-a(s) 159.68 An asymmetrictotal synthesis of 7-epicylindrospermopsin 160, obtained fromaqueous extracts of a cyanobacterium Cylindrospermopsis raci-borskii, has been recently completed by White and Hansen featur-ing on an intramolecular dipolar [2 + 3] cycloaddition betweena nitrone and an alkene.69 On the basis of this synthesis, theabsolute configuration was assigned as 7S,8R,10S,12S,13R,14S.Both cylindrospermopsin 157 and 7-epicylindrospermopsin 160are potent inhibitors of protein synthesis both in vitro and in vivo.Although the exact mechanism remains unknown, a number ofstudies have shown that these toxins act by inhibiting the transla-tion of mRNA into protein. Studies towards the total synthesis ofthese intriguing natural products and elucidation of their mode ofaction have led to the synthesis of 7-deoxycylindrospermopsin161.70 Contrary to previously reported results, it seemed thatremoval of the oxygenation at C7 did not reduced its inhibitorypotential on protein synthesis.

During the course of chemical screening of microbial metabo-lites, neoxaline 162 and oxaline 163 had been isolated from theculture broth of Aspergillus japonicus Fg-551 by Omura and co-workers. Both secondary metabolites were recently found to inhibitcell proliferation and arrest cell cycle at M phase in Jarkat cells.In studies towards the synthesis of these attractive bioregulatoryproducts, the indoline spiroaminal framework 164 of neoxalineand oxaline has been stereoselectively synthesized by Omura’sgroup.71 The synthetic sequence featured a Lewis acid mediatedring-opening–recyclization of aminal 165 to the diaminal 166 andthe tungstate-catalyzed oxidation of the resulting diaminal to the


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nitrone 167, which smoothly cyclized to the indoline spiroaminalskeleton 168 (Scheme 13).

Polyhydroxylated octahydro-imidazo[1,2-a]pyridine bicyclicderivatives 171, diazasugar analogues of microbial metaboliteskifunensine 169 and nagstatin 170, have been synthesized andevaluated for their glycosidase inhibitory activity.72 More recently,a new method of systematic and automated computer-assistedsearch of full UV spectra in a large number of data files fornew natural products has been introduced by Larsen and hiscolleagues based on the new mathematical algorithm X-hitting.As a result, application of X-hitting has led to the identificationof two novel spiro-quinazoline metabolites, lapatins A 172 and B,from Penicillium lapatayae.73

2.6 Alkaloids from plants

From the CHCl3–MeOH (1 : 1) extract of the roots of the IndianJatropha curcas L. (Euphorbiaceae), a new antibacterial alkaloid

173, 4-butyl-2-chloro-5-formyl-1H-imidazole, has been isolatedand characterized.74

The plant family of Pilocarpus sp. is the only source of theimidazole alkaloid pilocarpine 174, which has traditionally beenused in glaucoma treatment. An extensive survey on the chemicalconstituents and their biological activities from Pilocarpus specieshas been recently published.75 In an investigation of muscarinicacetylcholine receptor agonists for the treatment of Alzheimer’sdisease, a highly convergent and efficient synthetic methodologyfor alkaloid isopilocarpine 175, often co-occurring with pilo-carpine, has been developed by Braun and co-workers using aone-pot Michael-addition–alkylation protocol.76


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Moroidin 176 and celogentin A 177, cyclic peptides of the mo-roidin family, were first isolated from the leaves of the AustralianLaportea moroides and the seeds of Celosia argentea, respectively.Despite their fascinating structures, these cyclic peptides havereceived little attention from synthetic community. Recently, thecentral tryptophan residue 179 of stephanotic acid 178, thesimplest member of this family of cyclic peptides isolated fromStephanotis floribunda, has been stereoselectively synthesized byBentley and Moody.77

2.7 Miscellaneous

Thiols, such as coenzyme M, trypanothione, mycothiol, ergoth-ioneine 180, and the ovothiols 181, in living systems play acritical role for the maintenance of cellular redox potentialsand protein thiol–disulfide ratios, as well as for the protectionof cells from reactive oxygen species. A recent review provideda survey of the chemistry and biochemistry of these criticallyimportant intracellular thiols isolated from both microbial and

marine origin.78 A minireview by Daly discussed the biosyntheticpathways of a few classes of guanidinium toxins, includingtetrodotoxin, chiriquitoxin, and zetekitoxin, found in both marineand nonmarine organisms.79 The structure of zetekitoxin AB 182,

Scheme 13


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a saxitoxin analogue from the amphibian Panamanian goldenfrog Atelopus zeteki, has been elucidated by Daly’s group.80 Theproposed structure is characterized by a richness of heteroatomsand a unique 1,2-isoxazolidine ring-fused lactam, a sulfate ester,and an N-hydroxycarbamate moiety. Zetekitoxin AB was shownto be an extremely potent blocker of voltage-dependent sodiumchannels expressed in Xenopus oocytes with an IC50 value of 280pM for human heart channels, 6.1 pM for rat brain IIa channels,and 65 pM for rat skeletal muscle channels.

(+)-Biotin (vitamin H) 183, an important coenzyme involvedin metabolic processes, plays a crucial role in human nutritionand animal health. Because of the vast amount required andthe small amount produced by fermentation, it has receivedintense interest from synthetic chemists. A short and efficientsynthesis of (+)-biotin has been achieved from L-cysteine byChavan and co-workers in 10 steps with 20% overall yieldutilizing amidoalkylation of 1,2-bis(trimethylsilyloxy)cyclohexeneby hydroxyimidazothiazolone 184 via an acyliminium ion in-termediate to furnish C7-substituted imidazothiazolone 185 asthe key step.81,82 Based on a diastereoselective Strecker reactionon a-amino aldehyde 186 derived from L-cysteine, Seki andhis colleagues have developed a practical synthetic pathway to(+)-biotin.83,84 S,N-carbonyl migration of the Strecker reactionproduct 187 followed by lactonisation led to the key intermediatethiolactone 188. Finally, Fukuyama coupling with a zinc reagentand diastereoselective hydrogenation achieved 183.

3 Oxazole alkaloids

Over the past two decades, a number of unprecedented oxazole-containing natural products have been isolated from marine andnon-marine organisms. The structure elucidation and fascinatingbiological activities, as well as total synthesis, of these naturallyoccurring oxazoles have attracted much attention from bothindustrial and academic communities. Recently a review by Yeh,covering literature up to the end of 2003, summarized recentadvances in the total syntheses of oxazole-containing natural


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products including mono-oxazole, bisoxazole, and trisoxazolederivatives.85

3.1 Alkaloids from marine sponges

3.1.1 Macrolides. Since the late 1980s, many trisoxazole-containing macrolides have been isolated from the sponges ofthe genera Halichondria, Jaspis, and Mycale, the nudibranch eggmasses of Hexabranchus sanguineus, and unrelated stony coral ofthe genus Tubastrea. A known trisoxazole macrolide kabiramideC 189, which functions as an unregulated biomimetic of actin fila-ment (+)-end-capping proteins, has been isolated from the IndianOcean sponge Pachastrissa nux collected from Sichang Island,Thailand. As an optical and chemical probe, 7-(4-aminomethyl-1H-1,2,3-triazol-1-yl) analogue 190 of kabiramide C was synthe-sized and characterized for further understanding of actin functionin cells.86 From the marine sponge Chondrosia corticata Thiel

collected from reef slopes on the south side of Cocos Lagoon,Guam, three new oxazole-containing secondary metabolites,designated as neohalichondramide 191, (19Z)-halichondramide192, and secohalichondramide 193, have been isolated along withfour known analogues of the same structural class includinghalichondramide 194, dihydrohalichondramide 195, jaspisamideA 196, and halishigamide D 197.87 On the basis of combinedspectroscopic analyses, 192 was identified to be 19Z-isomer ofpreviously reported halichondramide, while 193 was structurallydefined to be a seco-oxazole derivative of halichondramide. Allthese compounds exhibited significant cytotoxicity and antifungalactivity toward the human leukemia cell-line K562 and Candidaalbicans, respectively.

Phorboxazoles A 198 and B 199 were first isolated fromthe Indian Ocean sponge Phorbas sp. by Searle and Molinskiin 1995. Both of them were reported to exhibit exceptionalcytostatic activity (198 shows a mean GI50 value of 1.58 nM


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against the US National Cancer Institute panel of 60 humancancer cell lines). Due to their intriguing structures and promisingbiological activity, much interest has been focused on the totalsynthesis of naturally occurring macrolides and total syntheseshave been achieved by several synthetic groups. Additionally,during numerous synthetic efforts towards their total synthesis,various disconnected segments have been completed by othersynthetic groups.88–93

Novel [4 + 2] annulation reactions between chiral allylsilanesand functionalized aldehydes have proven to be efficient meth-ods for smooth construction of cis- and trans-2,6-disubstitutedtetrahydropyran rings. As a consequence, utilizing the newlyintroduced methodology as the key steps, Panek and co-workershave accomplished the enantioselective total syntheses of naturallyoccurring callipeltoside A 200 and (+)-leucascandrolide A 201,94,95

which were originally isolated from the New Caledonia spongeCallipelta sp. and Leucascandra caveolata, respectively.

3.1.2 Isoxazoline and isoxazolidine alkaloids. The membersof a marine sponge family of the order Verongida are characterizedas the main source of naturally occurring brominated tyrosinederivatives. Seven new dibromotyrosine alkaloids purpurealidin

A 202, B 203, C 204, D 205, F, G, H have been isolated fromthe Verongida sponge Psammaplysilla purpurea collected fromMandapam, Tamil Nadu, India., together with known compoundspurealidin Q 206, purpurealidin E, and purpuramine I.96 To inves-tigate structural activity relationship of zebra mussel (Dreissenapolymorpha) antifouling and antimicrobial agents, the knowndibromotyrosine alkaloids from the marine Verongid sponge,including psammaplysin A 207, ceratinamide A 208, ceratinamideB 209, fistularin-3 210, hemifistularin-3 211, aerophobin-2 212,etc., have been selected for evaluation in the zebra musselreattachment assay.97 Some of them showed significant selectivityagainst macrofouling organisms such as zebra mussels suggestingthe potential utility of this class of alkaloids as a naturallyderived antifoulant lead. On the basis of microscale LC-MSMarfey’s derivatiation analysis, the C11 configuration of fistularin-3 210, isolated from a Brazilian specimen of the sponge Aplysinacauliformis, was confirmed to be opposite of that of 11-epi-fistularin-3 213, obtained from an Australian specimen of thesponge Agelas oroides. The absolute configurations at C11 for210 and 213 are assigned to be 11S and 11R, respectively.98 Theoriginally proposed structure of calafianin 214, isolated from thesponge Aplysina gerardogreeni n. sp., has been revised by successfulchemical synthesis and the trans-relationship between the epoxygroup and the oxygen atom in the spiroisoxazoline ring wasascertained.99

The pyrinodemins A 215, B 216, C 217, and D 218, belonging toa new family of marine natural products isolated from the spongeAmphimedon sp. by Kobayashi and co-workers, are characterized


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by a cis-cyclopent[c]isoxazolidine core connected by two fattychains terminated with two 3-pyridine rings. They differ by thenature of the side chain on the nitrogen atom of isoxazolidinering. The accurate position of the cis double bond as well asthe absolute configuration had been recently determined by totalsynthesis. However, the exact structure of pyrinodemin A 215still remains arguable. The double bond isomers (+)-219 and (+)-220 of the originally proposed structure for pyrinodemin A 215have been stereoselectively synthesized by Kobayashi’s group.100 Bycomparison of C18 and chiral HPLC analysis of naturally occurringpyrinodemin A and the synthetic samples as well as ESIMS data ofoxidative degradation products of the double bond, pyrinodeminA was assigned to be a 1 : 1 racemic mixture of 219, with theolefin between C15′ and C16′. In contrast, Baldwin and co-workerssuggested that the C14′–C15′ isomer 220 was the best candidatefor the structure of pyrinodemin A based on comparisons of the

1H and 13C NMR data of the synthetic derivatives with those ofthe natural product.101 Additionally, a stereoselective approach tothe bicyclic isoxazolidine core 221 of the pyrinodemin alkaloidshas been developed by Kouklovsky and co-workers, featuringan asymmetric intramolecular [2 + 3] cycloaddition of a chiralphenylglycinol-derived oxazoline N-oxide 222.102

3.1.3 Other alkaloids from sponges. Calyculins such as caly-culins A 223 and C 224, which exhibit strong serine–threonineprotein phosphatase inhibitory activity, are a class of marinesecondary metabolites originally isolated from the sponge Dis-codermia calyx by Fusetani and co-workers. A protected C9–C19 fragment of calyculin C, lactone 225, has been highlydiastereoselective synthesized by Karisalmi and Koskinen via two


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sequential intermolecular asymmetric crotylation reactions be-tween a chiral aldehyde and in one case a crotyl borane reagentand in the other case a crotyl trifluorosilane reagent.103,104

3.2 Alkaloids from marine tunicates (ascidians)

3.2.1 Diazonamides. Marine secondary metabolite diazon-amide A 226 was first isolated from the colonial ascidian Diazonaangulata by Clardy and co-workers. In 2001, the structure orig-inally proposed by them, 226a, was proved to be incorrect andwas revised to 226b on the basis of a total synthesis completed byHarran’s group. As a result of the unprecedented and challengingmolecular architecture of diazonamide A, including the strainedhalogenated bisindole bisoxazole macrocyclic core, the quaternarycenter at the epicenter of its two major macrocyclic subunitsand the cyclic polypeptide moiety, and its promising in vitrocytotoxic activity, it has received extensive interest from thesynthetic community. After solving a number of key syntheticchallenges posed by the diazonamide framework, the Nicolaougroup completed the first total synthesis of diazonamide A 226band confirmed the revised structure. As part of this synthesis, theyintroduced several new synthetic methods and tactics such as a 5-exo-tet cyclization to establish the C10 quaternary center, a Suzukibiaryl coupling to generate the bisindole skeleton, and an Horner–Wadsworth–Emmons approach to complete the synthesis of theheterocyclic macrocycle, A few months thereafter, they reported asecond total synthesis of this intriguing natural product throughan entirely different synthetic approach involving a SmI2-mediatedhetero-pinacol macrocyclization cascade for the construction ofthe bisindole bisoxazole framework as key step. Recently, they havedetailed total syntheses of the original structure 226a as well as therevised structure 226b of diazonamide A, concurrently exploringthis natural product’s intriguing structure–activity relationshipusing the developed sequences.105–108

3.2.2 Other alkaloids from marine tunicates. Ongoing effortsin search of new antifungal agents from marine organisms have ledto isolation of a known bis-oxazolidinone 227 from the ascidianClavelina oblonga.109 Because this characteristic bromotyrosine-derived metabolite has previously been associated only withVerongid sponges (phylum Porifera), the finding of 227 withinan ascidian (phylum Chordata) is noteworthy, although otherbromotyrosine derivatives have been isolated from ascidiansbelonging to the genus Botryllus.

3.3 Alkaloids from microorganisms

3.3.1 Macrolides. The leupyrrin family of myxobacterialsecondary metabolites shows an unusual structural assembly,including a substituted c-butyrolactone fragment, a central pyrrolering, a substituted dihydrooxazole unit, and a dehydrofuranring, which cannot be explained by typical polyketide synthase(PKS) and nonribosomal peptide synthetase (NRPS) biosynthesismechanisms. The biosynthesis of leupyrrin A1 228, the maincomponent of the leupyrrin family from the myxobacteriumSorangium cellulosum So ce690, has been fruitfully investigatedby labeling studies.110

The disorazole family from the fermentation broth of themyxobacterium Sorangium cellulosum possess significant cyto-toxic and promising antitubulin activities. Due to their pseudo-dimer structures as well as their macrocyclic-heterocyclic skeletonand labile polyene segments, the definitive structural assignment


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and the relative and absolute configuration of these macrolideshave remained unresolved. Wipf and Graham have recently ac-complished a highly convergent and stereoselective total synthesisof (−)-disorazole C1 229 in a linear 20 steps with an overallyield of 1.5% and established the correct relative and absoluteconfiguration of the disorazoles (Scheme 14).111 Sonogashiracross-coupling between alkyne 230 and iodide 231 afforded themasked monomer 232, which was acylated with an excess of 233to provide iodide 234. A second Sonogashira coupling between234 and alkyne 230 yielded seco-disorazole C1 235. Selectivemonosaponification of the methyl ester followed by a Yamaguchilactonization gave macrocycle 236. Finally, removal of the PMBgroup with DDQ and catalytic reduction of the two alkynes gave(−)-disorazole C1 229.

Rhizoxins are a class of macrolide originally isolated from theplant pathogenic fungus Rhizopus chinensis. The unique structuresof rhizoxins, including a 16-membered macrocyclic lactone, a d-lactone, and an oxazole-terminated side chain, along with their po-tent in vitro cytotoxicity and in vivo antitumor activity have madethem intriguing targets for the chemical and biological commu-nities. Recently, a review by Hong and White has been publishedfocusing on isolation, structure determination, biological activitiesas well as total synthesis of the members of the rhizoxin family.112

Ardisson and co-workers have achieved a new and convergent totalsynthesis of rhizoxin D 237 very recently, the highlights of which

were an intermolecular Heck reaction to construct C10–C11 bond,an intramolecular Wittig–Wadsworth–Emmons reaction to formthe C2–C3 E-olefin, and a Horner–Wadsworth–Emmons (HWE)reaction to deliver the C20–C21 E-olefin (Scheme 15).113 Cross-coupling reaction of the C11–C20 and C3–C10 segments 238 and239 under Heck–Jeffery conditions provided the expected C3–C20fragment 240, onto which was installed the phosphonoacetateat C15 to give 241. The intramolecular macrocyclisation wasthen effected under Masamune–Roush conditions to deliver themacrolactone core 242 of rhizoxin D. Finally, incorporation of theoxazole-terminated side chain 243 into 242 via a HWE reactionfurnished rhizoxin D 237.

3.3.2 Cyclopeptides. A new cytotoxic depsipeptide, namelymechercharmycin A 244, has been isolated by Kanoh and co-workers from marine-derived Thermoactinomyces sp. YM3-251,collected at Mecherchar in the Republic of Palau, along withits linear congener mechercharmycin B 245.114 Almost concur-rently, Paco et al. have also isolated the same cyclopeptide fromactinomycete strain ES7-008 and designated it as IB-01211.115

Mechercharmycin A 244 exhibited significant cytotoxic activitywith the IC50 values of 40 nM for A549 cells (human lung cancer)and 46 nM for Jurkat cells (human leukemia), respectively, whereasits linear congener 245 did not show any inhibitory activity towardeither cells even at 1 lM.

Scheme 14 Reagents and conditions: a) PdCl2(PPh3)2, CuI, TEA–MeCN; b) 233, DCC, DMAP, CH2Cl2; c) 230, PdCl2(PPh3)2, CuI, TEA–MeCN; d)LiOH, H2O, THF; then 2,4,6-trichlorobenzoyl chloride, TEA, THF, DMAP, toluene; e) DDQ, phosphate buffer, CH2Cl2; then H2, Lindlar catalyst,quinoline, EtOAc, rt.


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Scheme 15 Reagents and conditions: a) Pd(OAc)2, K2CO3, Bu4NCl, PPh3, DMF–H2O; b) Amberlyst 15, MeOH; Me4NBH(OAc)3, HOAc, MeCN;TIPSOTf, 2,6-lutidine, CH2Cl2; then diethylphosphonacetic acid, DCC, DMAP; c) TASF, DMF; IBX, DMSO; iPr2NEt, LiCl, MeCN; d) DDQ, CH2Cl2,H2O; IBX, DMSO; 243 t-BuOK, DME; then HF·pyridine, THF. TASF = [(Et2N)3S+SiMe3F2

−]; IBX = 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide.

The known cyclic peptide, designated YM-216391 246a, hadbeen isolated from the cultured mycelium of Streptomyces nobilisJCM 4274 a few years ago. Recently, fermentation, isolation,biological activities as well as physical and chemical propertiesof YM-216391 have also been published. Bioassay showed thatit inhibited the growth of human cervical cancer HeLa Se cells

in a dose-dependent manner with an IC50 value of 14 nM.116,117

On the basis of a recent total synthesis completed by Deeleyand Pattenden, the stereochemistry of YM-216391 has beenestablished and the L-valine and D-allo-isoleucine residues wererevised to D-valine and L-allo-isoleucine 246b, respectively.118

Virginiamycin M1 (VM1) 247 is a common macrolactone ofstreptogramin antibiotics produced by Streptomyces sp. and alsoappears in the literature as other names, such as pristinamycinIIA, ostreogrycin A, streptogramin A, PA 114 A1, vernamycinA, staphylomycin M1, synergistin A1 and mikamycin A. X-Raycrystallographic studies of VM1 bound to bacterial 50S ribosomeand to a deactivating enzyme showed a different conformation tothat of VM1 in chloroform solution. By analysis of high resolution2D NMR experiments, the conformation of VM1 in DMSO andMeOH was shown to be different from both that in chloroformsolution and in the bound form.119

3.3.3 Ergot alkaloids. The ergot-type alkaloids are a classof indole peptide alkaloids derived from the fungus Clavicepspurpurea, a parasite on many grasses, rye, wheat and other grains.Due to their considerable pharmacological importance, greatefforts have been devoted to chemistry and biochemistry of thesenaturally occurring alkaloids over the past decades. The genomicregion of Claviceps purpurea strain P1 containing the ergotalkaloid gene cluster, as well as additional genes probably involvedin the ergot alkaloid biosynthesis, has been extensively investigatedby Tudzynski’s group.120 By comparison of the cluster sequencesof strain P1 with that of strain ECC93, the nonribosomal peptidesynthetase (NRPS) genes of the ergot alkaloid cluster have evolvedsubstantially whereas the genes in the central part of the clusterhave remained highly conserved.


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In order to facilitate future analyses of grass extracts consideredresponsible for outbreak of related livestock diseases, Lehnerand co-workers have studied fragmentation patterns of the ergotalkaloids, including ergovaline 248, ergotamine 249, ergocornine250, ergocryptine 251, ergocrystine 252, ergonovine, lysergol, andlysergic acid 253, by electrospray ionization tandem quadrupolemass spectrometry.121 Szantay and co-workers have achieved thefirst direct synthesis of (+)-lysergic acid 253, which subsequentlyled to an efficient total synthesis of a-ergocryptine 251 and itsC8-epi isomer a-ergocryptinine 254 by coupling with the peptidedilactam moiety.122,123

3.3.4 Other alkaloids from microorganisms. From the fresh-water bloom of the cyanobacterium Nostoc sp., novel peptidesbanyasides A 255 and B 256 have been identified by Pluotnoand Carmeli and their structures elaborated by homonuclear andinverse-heteronuclear 2D NMR spectra as well as high-resolutionmass spectrometry.124

A new cytotoxic compound, designated brasilibactin A 257,has been isolated from the actinomycete Nocardia brasiliensis andexhibited potent cytotoxicity against murine leukemia L1210 andhuman epidermoid carcinoma KB cells.125

The absolute configurations of antibiotics kigamicins A 258, B259 and C 260, isolated from the culture broth of Amycolatopsissp. not long ago, have been established by a combination of X-raycrystallographic analysis and chemical degradation studies.126

Anachelin 261 and anachelin-2 262 were isolated from the fresh-water cyanobacterium Anabaena cylindrica several years ago. Thestereochemistry of both of them has been ascertained recently.127

Using a Boc-phenylglycine (BPG) method described previously,the absolute configuration at C3 position of the 1,1-dimethyl-3-amino-1,2,3,4-tetrahydro-6,7-dihydroxyquinolinium unit at theright-hand end of the molecules was determined to possessthe S configuration, while the 6-amino-3,5,7-trihydroxyheptanoicacid unit at the left-hand end of the molecules has the 3′R,5′S,6′Sconfiguration, based on Mosher’s method.


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A concise total synthesis of (+)-streptazolin 263 and its dihy-dro derivative 264, first isolated from cultures of Streptomycesviridochromogenes, has been accomplished from readily availableaminocyclopentenol (−)-265, the highlights being a stereoselectiveepoxidation, an intramolecular aldol condensation, and a Wittigreaction.128 Utilizing a palladium-catalyzed reductive cyclizationof a diyne as the key step, Trost’s group has achieved a highlystereocontrolled total synthesis of (+)-streptazolin 263. The diyne266 was subjected to the crucial palladium-catalyzed reductivecyclization reaction to provide the desired 1,3-diene 267, followedby cyclization and removal of TBS group to give naturallyoccurring (+)-streptazolin (Scheme 16).129

Optically active a-hydroxy oxime ethers 269 have been efficientlyprepared via base-catalyzed diastereoselective imino 1,2-Wittigrearrangement of hydroximates 268 (Scheme 17).130 By applicationof the newly developed strategy, Naito and co-workers haveachieved an asymmetric route to (+)-cytoxazone 270 isolated fromStreptomyces sp.

4 Thiazole alkaloids

4.1 Epothilones

Microtubules play a crucial role in the process of separatingduplicated chromosomes before cell division.131,132 It is this rolethat make them an important target for anticancer drugs bystabilizing or destabilizing the microtubules during mitotic spindleformation. Like paclitaxel (Taxol R©), epothilones A 271 and B 272from myxobacteria also bind to microtubules, but with a higheraffinity, at the same site on b-tubulin, or at least largely overlappingsites. They exhibit potent antiproliferative activity against a varietyof human cancer cells in vitro with IC50 values from the sub-nMto low nM concentrations and, in particular, are also active

Scheme 16 Reagents and conditions: a) Pd2(dba)3·CHCl3, HCO2H,Et3SiH, toluene, rt; b) NaH, THF; c) TBAF, THF.

Scheme 17


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against multidrug-resistant (including paclitaxel-resistant) celllines. Additionally, in contrast to paclitaxel, the epothilones canbe obtained from the cultures of the myxobacterium in essentiallyunlimited quantities. Several analogues of epothilones A and Bare currently undergoing clinical trials in humans.

By a combination of the electron-crystallography and NMRstructure determination, Downing and co-workers have deter-mined the structure of the epothilone A–tubulin complex.133

Knowing the bioactive conformation of epothilone A and itsbinding mode to tubulin will be useful in developing novelepothilones to obtained higher selectivity and lower sensitivitytoward the development of resistance.134

Genetic engineering has proven to be a powerful tool togenerate novel epothilones with greater therapeutic potential. Theepothilone polyketide synthase (PKS) genes responsible for thebiosynthesis of epothilones C 273 and D 274 have been introducedand expressed in Myxococcus xanthus, a myxobacterium which ismore amenable to genetic manipulation than the original host

Sorangium cellulosum.135 By inactivation of the ketoreductase(KR) domain in module 6 of the epo PKS, novel unnaturalnatural products 9-oxoepothilone D 275 and its isomer 8-epi-9-oxoepothilone D 276 were obtained as the major components,while modification of the KR domain in module 4 resultedin the production of the expected derivative 12,13-dihydro-13-oxoepothilone C 277 and the unexpected 11,12-dehydro-12,13-dihydro-13-oxoepothilone D 278.

In the epothilone biosynthetic pathway, a 165 kDa nonri-bosomal peptide synthethase (NRPS) EpoB forms part of anotherwise entirely PKS assembly line. This requires the formationof two hybrid NRPS–PKS interfaces. Walsh and co-workers haveexamined the C- and N-terminal sequences of EpoB to determinethe sequences involved in the formation of these interfaces.136

Apart from genetic engineering, fully chemical syntheticmethodologies are also feasible to provide epothilone analoguesas clinical development candidates.137,138 A full account of thediscovery of the (E)-9,10-dehydro derivatives 279 of 12,13-desoxyepothilone B (dEpoB), which is currently in phase II clinicaltrials, as well as a novel promising clinical development candidate26-trifluoro-(E)-9,10-dehydroepothilone 280 has been publishedby Danishefsky and co-workers recently.139 The conformationallyconstrained C8–C10-furan-bridged analogues 281 and 282 relatedto epothilone C or D,140,141 as well as C10–C12-phenylene-bridgedanalogue 283 of epothilone D,142 have been synthesized for biolog-ical investigation. Unfortunately, all of them showed a decreasedanticancer potential compared to their corresponding parentcompounds. In addition, both C4-aza and C10-oxa analogues284 and 285 of the macrocycle core in the epothilones havebeen synthesized for biological evaluation and conformationalanalysis, respectively.143,144 In search of potent antitumor agents,a 16-membered hybrid macrolide 286 has been designed andsynthesized by replacing macrocycle core of the epothilones with16-membered carbonolide-type lactone framework.145

Utilizing a Normant coupling to establish the desired (Z)-double bond at C12–C13, a Wadsworth–Emmons olefinationto construct trisubstituted double bond at C16–C17, and adiastereoselective aldol condensation to form the C6–C7 bondas the key steps, Avery and co-workers have achieved a convergent


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total synthesis of epothilones B 272 and D 274 last year.146 Shortlyafter, Gaich and Mulzer also devised a concise total synthesis ofepothilones B and D using a ring-closing metathesis reaction ofa disiloxane to form the key northern subunit of the epothilonemacrocycle core.147 Many other synthetic efforts related to the totalsynthesis of epothilones have also been presented.148–150

4.2 Thiopeptides

The thiopeptide antibiotics are a special class of naturally oc-curring sulfur-containing, macrocyclic peptides, featuring highlymodified and dehydro-amino acids. To date, more than sev-enty six structurally distinct thiopeptides belonging to twentynine different families have been identified mostly from variousactinomycetes and Gram-positive bacteria, largely of the genusStreptomyces. These thiopeptide antibiotics can be essentiallycategorized into five distinct classes according to the structuralcomponents of the central heterocyclic domain; they are thepiperidine, dehydropiperidine, imidazopiperidine, pyridine, andhydroxypyridine families. Each class can be further subdividedinto many families based on structural homology or the producingorganism. All the thiopeptide antibiotics exhibit highly inhibitoryactivity against Gram-positive bacteria and, in particular, areeffective against methicillin-resistant Staphylococcus aureus whichis resistant to most conventional treatments.

A comprehensive review by Bagley and colleagues has sum-marized the structural classification of the known membersof the thiopeptide antibiotics, together with their biologicalproperties and the development of their chemical synthesis andmodification.151

Despite the fact that the first thiopeptide antibiotics wereisolated in 1948, the structural identities of the micrococcin familyhave remained in doubt. The chemical structure of micrococcinP1 (MP1) 287 was first proposed by Walker and Lukacs and waslater revised by Bycroft and Gowland on the basis of chemicaland spectroscopic evidence. Recently Bagley and Merritt haveproposed that the stereochemistry of the valine residue in MP1

should be corrected to S-configuration based upon Walker’sdegradation experiment.152

Siomycin A 288 isolated from the culture broth of Actinomycetesbelongs to the 1,2-dehydropiperidine family of the thiopeptideantibiotics. It showed the in vitro immunosuppressive property

against B-cells stimulated with T-cell independent antigen DNP-LPS. Moreover, siomycin also showed inhibitory effect in bothT-cell dependent and independent murine antibody productionmodels and decreased the severity in murine collagen arthritismodel.153

Due to their promising biological properties and complexmolecular architecture, the synthesis of thiopeptide antibioticshas attracted considerable interest in recent years. Bagley and co-workers have achieved a synthesis of the central trisubstitutedpyridine domain, dimethyl sulfomycinamate 292, of the thiopep-tide antibiotics sulfomycin I 289, II 290 and III 291, via a one-potmultistep Bohlmann–Rahtz heteroannulation process.154 Recently,Heckmann and Bach have reported a concise synthetic approachto the 2,3,6-trisubstituted pyridine core 294 of thiopeptide an-tibiotic GE2270A 293 and, as a result, resolved the absoluteconfiguration of the 1,2-amino alcohol moiety.155 They reportedthat the 1H NMR spectrum and specific rotation of the synthetic(R,R)-enantiomer 294 matched perfectly those of the previousdegradation product.

Cyclothiazomycin 295, a thiopeptide antibiotic isolated fromthe fermentation broth of Streptomyces sp. NR0516, has a uniquebismacrocyclic peptide structure. To verify its structure and estab-lish an efficient approach to the pyridine-containing heterocycliccore, Bagley and Xiong have achieved a stereoselective synthesisof c-lactam hydrolysis product 296, utilizing a Bohlmann–Rahtzreaction to assemble the pyridine domain.156 During syntheticstudies toward thiopeptide antibiotic thiocilline I 297 isolated fromthe culture of Bucillus bodius, three disconnected fragments a, cand d were assembled to give the main fragment 298 containing thekey 2,3,6-trithiazolyl-pyridine skeleton.157 Novel thiazolyl peptideantibiotics nocathiacin I 299 and II 300 were recently isolatedfrom Nocardia sp. fermentations by Ueda’s group. They belongto a unique indole-containing family of tricyclic thiazolyl peptideantibiotics. An efficient chemical conversion of nocathiacin I tonocathiacin II has been accomplished by Ueda and co-workersby treatment of nocathiacin I with ethyl bromopyruvate in the


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presence of either Hunig’s base, or a phosphazene base, or caesiumcarbonate in DMF at room temperature.158

After several unsuccessful attempts, Nicolaou’s group hasachieved a highly convergent total synthesis of thiostrepton 301, a1,2-dehydropiperidine thiopeptide antibiotic isolated from variousStreptomyces sp. (Scheme 18).159,160 The central dehydropiperi-dine building block 302, prepared by a hetero-Diels–Alder-typedimerization process, was coupled with azido thiazoline derivative303 to give hexacyclic intermediate 304. Selective hydrolysis ofone of the two methyl esters to give monoacid 305 followed byreduction of the azide and of peptide bond formation affordedmacrolactam 306, which delivered acid 307 after hydrolysis ofthe second methyl ester. The bis(phenylselenyl)-protected tailwas then attached to yield intermediate 308. Subsequent peptidecoupling and lactonisation between deprotected amine 309 andthe entire quinaldic acid building block 310 provided the maskedthiostrepton skeleton 311. t-BuOOH-mediated oxidation of threephenylseleno groups followed by spontaneous syn elimination ofthe resulting selenoxides furnished the corresponding dehydroala-nine subunits. Removal of the TES and TBS protecting groupsby HF·pyridine in THF ultimately produced naturally occurringthiostrepton 301 (Scheme 18).

4.3 Thiazolyl cyclic peptides

A great number of secondary metabolites associated with marineinvertebrates, such as molluscs and tunicates, structurally veryclosely resemble natural products biosynthesized by microbialsymbionts. Although for the most part the origin of marineinvertebrate natural products is still unknown, several strongpieces of evidence support the view that microbial symbionts

do indeed produce marine invertebrate-associated secondarymetabolites. Over the last decades, numerous structural classesof cyclic peptides have been identified from ascidians in the familyDidemnidae, which commonly harbour symbiotic cyanobacteria,Prochloron spp. Genetics-based evidence has been presented bySchmidt and co-workers that Prochloron spp. have the potentialto biosynthesize marine cyclic peptides patellamides A 312 and C313 found in didemnid ascidian extracts.161,162

Bistratamides E–J 314–319, new members of the bistratamidefamily very recently isolated from ascidian Lissoclinum bistratumin the southern Philippines, showed moderate cytotoxic activityagainst a human colon tumor cell line. An efficient total synthesisof bistratamides F–I has been achieved by You and Kelly involvingMnO2-mediated oxidative conversion of a thiazoline, preparedfrom the corresponding dipeptide using Burgess’s reagent, to athiazole substructure as the key step.163 The first total synthesisof didmolamides A 320 and B 321, isolated from the marineascidian Didemnum molle collected in Madagascar, has beenaccomplished by solid- and solution-phase peptide couplingreactions, respectively.164 The solid-phase assembly of heterocyclicamino acids building blocks into thiazole- and oxazole-containingmacrolactams has proved to be a very efficient strategy whichprovides an expeditious route to natural products incorporating(un)natural heterocyclic amino acid subunits. By application ofthis methodology, Kelly and co-workers have completed the totalsynthesis of tenuecyclamides A–D 322–325 originally isolatedfrom the cyanobacterium Nostoc spongiaeforme var. tenue.165 As aresult, the stereochemistry of tenuecyclamides A 323 and B 324,which could not be fully assigned due to racemization duringthe degradation procedure used to assign their structures, wasultimately determined.


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A new total synthesis of cyclopeptide bistratamide-type den-droamide A 326, isolated from the cyanobacterium Stigonemadendroideum, has been achieved by Shin and his colleagues veryrecently.166

N-Methylated amino acids are often used in the synthesis ofconformationally restrained peptides, for adjusting conforma-tions of peptides, controlling metabolic stability, and preventingunfavourable hydrogen bonding in medicinal chemistry. Variouscyclo-oligomerizations of the N-methyl valine-thiazole amino acid327 to the corresponding cyclic peptides, analogues of naturallyoccurring cyclic peptides, have been extensively investigated byPattenden’s group.167

4.4 Other thiazole alkaloids from microorganisms

Marine cyanobacteria abound in chemically diverse and biolog-ically active metabolites, such as curacins A 328 and D 329,barbamide 330, and kalkitoxin 331. The biosynthetic pathway ofcuracin A 328 isolated from the tropical marine cyanobacteriumLyngbya majuscula has been investigated by combination ofisotope-labelling experiments and gene cluster analysis.168 Twoindependent concise total syntheses of kalkitoxin 331 first iso-lated from the cyanobacterium Lyngbya majuscula have beenaccomplished by White’s and Shioiri’s groups.169,170 On the basisof chemical synthesis, the absolute configuration of naturally


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Scheme 18 Reagents and conditions: a) HATU, HOAt; b) Me3SnOH; c) PMe3–H2O; d) HATU, HOAt; e) Me3SnOH; f) HATU, HOAt;g) Pd(OAc)2, n-Bu3SnH; h) HATU, HOAt; i) Et2NH; j) 2,4,6-trichlorobenzoyl chloride, TEA, DMAP; k) t-BuOOH; l) HF·pyridine. HATU =O-(7-azabenzotriazol-1-yl)-N,N,N ′,N ′-tetramethyluronium hexafluorophosphate; HOAt = 1-hydroxy-7-azabenzotriazole.


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occurring (+)-kalkitoxin was determined to be 3R,7R,8S,10S,2′R.Its cytotoxic activity against the human colon cell line HCT-116was also evaluated.

Treatment of Streptomyces prunicolor 1884-SVT2, which nor-mally produces benthocyanin A, with a mevalonate pathwayinhibitor resulted in the production of a new unrelated secondarymetabolite, designated as mevashuntin 332, containing fusedthiazolone and pyranonaphthoquinone units.171 Several acyclicand cyclic analogs related to leinamycin 333 isolated from aStreptomyces sp. have been synthesized for a study of theirnoncovalent DNA-binding properties and the results demon-strated that the extended p-system of leinamycin was necessaryfor noncovalent association of the natural product with duplexDNA.172 Six novel C-terminus modified analogues (R = aliphaticor aromatic acyl) of bleomycin A6 334 have been synthesized viaselective protection of the primary amine function of bleomycinA6 by means of coordination with CuII ions, amidation withcorresponding aliphatic or aromatic acid, and demetalization.173

Their antitumor activity against HeLa and BGC-823 cells in vitro,their to CT-DNA, and their cleavage potency towards pBR322DNA were also studied.

Tubulysins A–I 335–343, potent tubulin polymerization in-hibitors, are a novel group of tetrapeptide metabolites recentlyisolated from two different species of myxobacteria, Archangiumgephyra and Angiococcus disciformis, by Hofle’s group. Isolation,crystal and solution structure, as well as the biosynthetic pathwayto the tubulysins have been reported very recently.174 In addition,the antiproliferative activity of tubulysins A–I was found to


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correlate perfectly with their lipophilicity as indicated by theirretention time on reversed-phase HPLC. The need for furtherbiological and clinical investigation and the limited availabilityfrom nature has made them attractive goals for synthetic chemists.Application of Mn-mediated asymmetric radical coupling betweenfunctionalized iodides and chiral hydrazones has opened anefficient synthetic entry to the a-hydroxy-c-amino acid and a-methyl-c-amino acid units in the tubuvaline (Tuv) and tubupheny-lalanine (Tup) domains of tubylysins, respectively.175 The Tuv-Tupfragment of tubulysins has also been prepared from protectedchiral valinol and phenylalaninol in a convergent strategy.176

A new convergent enantioselective total synthesis of cystoth-iazoles A 344 and B 345, isolated from a culture broth of themyxobacterium Cystobacter fuscus in 1998, has been recently de-scribed by Shao and Panek.177 First Stille cross-coupling reactionof stannanes 347 with ditriflate 348 achieved the desired bithiazoles349, which was coupled with stannane 350 via a second Stille cross-coupling process directly to give cystothiazole A 344 and protectedcystothiazole B 351, which after a final deprotection step producedtarget cystothiazole B 345 (Scheme 19).

Scheme 19 Reagents and conditions: a) t-BuLi, Et2O, Bu3SnCl;b) Pd(PPh3)4, LiCl; c) Pd(PPh3)4, LiCl; d) TBAF, THF.

Nonribosomal peptide synthetases (NRPS) and polyketidesynthetases (PKS) are responsible for the biogenesis of severalstructurally diverse, medicinally important natural products.Yersiniabactin 352, produced by the bacterium Yersinia pestis,was assembled on a NRPS scaffold including four enzymes:YbtE, HMWP2, HMWP1, and YbtU. Yersiniabactin biosyntheticintermediates have been kinetically, regiospecifically studied usingelectrospray ionization (ESI) combined with quadrupole-Fourier-transform mass spectrometry (ESI-Q-FTMS).178

A new thiazolidine-type zinc-chelating antibiotic, designatedtransvalencin A 353, has been isolated from Nocardia transvalensisIFM 10065, a clinical isolate from a patient with actinomycoticmycetoma.179,180 It showed antimicrobial activity against fungisuch as Trichophyton mentagrophytes and Cryptococcus neofor-mans and was also active against Gram-positive bacteria such asMicrococcus luteus.

To explore further the influence of the C4′, C2′′, and C4′′ asym-metric centers on iron chelation and transport, three analogues355–357 of pyochelin 354, a siderophore produced by the bacteriaPseudomonas aeruginosa and Burkholderia cepacia, have beensynthesized.181


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4.5 Alkaloids from marine invertebrates

A simplified derivative 359 of pateamine A (PatA) 358, a marinemetabolite from the sponge Mycale sp., has been synthesized andwas found to exhibit equal to greater potency in inhibition ofinterleukin-2 (IL-2) production relative to PatA, which verifiedthe presence of distinct binding and scaffolding domains in thePatA structure with respect to interactions with its putative cellularreceptors.182

Potent stimulators of actin assembly hectochlorin 360 anddeacetylhectochlorin 361 have been isolated from the EtOAcextract from the Thai sea hare Bursatella leachii collected fromSichang Island, Thailand.183 The latter showed more potentcytotoxicity than the former against different human carcinomacell lines.

From the Kenyan tunicate Cystodytes cf. violatinctus, a newalkaloid designated violatinctamine 362 has been obtained alongwith four other known metabolites.184 Their structures were eluci-dated on the basis of MS, 1D and 2D NMR spectra, and analysis ofthe spectral information also implied that violatinctamine existedas a mixture of two tautomers – the imino-phenol and the aminoquinone-methide.

Cyclic depsipeptides halipeptins A 363 and B 364, exhibitingpotent anti-inflammatory activity, were isolated from the spongeHaliclona sp. by Gomez-Paloma and co-workers several years ago.Very recently, the first total synthesis of halipeptin A 363 hasbeen reported by Ma and his colleagues and, on this basis, theirstereochemistry was confirmed.185

A concise and efficient total synthesis of latrunculin A 365,isolated from the sponge Negombata magnifica, has been achievedby Furstner and Turet using a ring-closing enyne–yne metathesisreaction as the key step.186 Coupling of the methyl glycoside 367(derived from cysteine) with the enyne 368 (prepared from ethylacetoacetate) resulted in ester 369. After conversion of the PMBinto a Teoc protected group, the crucial enyne–yne metathesisproceeded smoothly under catalysis by [Mo{N(tBu)(Ar)}3] 372 toform the highly strained 16-membered cyclic product 373. Finally,hydrogenation followed by consecutive removal of the Teoc groupand hydrolysis of the methyl glycoside furnished latrunculin A 365(Scheme 20).


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Scheme 20 Reagents and conditions: a) Tf2O, pyridine; b) 15-crown-5, THF; c) CAN, MeCN–H2O; d) Me3SiCH2CH2OH, triphosgene, pyridine, CH2Cl2,DMAP–iPr2NEt; e) 372, 80 ◦C, CH2Cl2–PhMe; f) H2, Lindlar catalyst, quinoline; g) TBAF, THF; h) aq. HOAc, 60 ◦C.

5 References

1 A. D. Buss, B. Cox and R. D. Waigh, in Burger’s Medicinal Chemistryand Drug Discovery, 6th edn, vol. 1, Drug Discovery, ed. D. J. Abraham,Wiley, Hoboken, New Jersey, 2003.

2 H. Madari and R. S. Jacobs, J. Nat. Prod., 2004, 67, 1204–1210.

3 S. S. Young and N. Ge, Curr. Opin. Drug Discovery Dev., 2004, 7,318–324.

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imidazole, oxazole and thiazole alkaloids

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