Zhong Jin, Zaiguo Li and Runqiu Huang- Muscarine, imidazole, oxazole, thiazole, Amaryllidaceae and Sceletium alkaloids

Muscarine, imidazole, oxazole, thiazole, Amaryllidaceaeand Sceletium alkaloids

Zhong Jin,* Zaiguo Li and Runqiu Huang

Institute and State Key Laboratory of Elemento-organic Chemistry, Nankai University,Tianjin 300071, P. R. China. E-mail: [email protected]; Fax: 86-22-23503438

Received (in Cambridge, UK) 26th March 2002First published as an Advance Article on the web 7th May 2002

A review with 136 references covers the literature from July 2000 to June 2001 on the isolation, bioactivities, andsynthetic highlights of complex natural products including muscarine, imidazole, oxazole, thiazole, Amaryllidaceaeand Sceletium alkaloids.

Covering: July 2000–June 2001. Previous review: Nat. Prod. Rep. 2001, 18, 95.

1 Introduction2 Muscarine alkaloids3 Imidazole, oxazole and thiazole alkaloids4 Amaryllidaceae and Sceletium alkaloids5 References

1 Introduction

As the cradle of mankind, nature not only supports people’sneeds, but also provides many novelties for phytochemists.Every year, many alkaloid structures from nature are reported.Some belong to known frameworks but others are completelynew. These natural products have been extensively investigatedbecause of their varying biological activities, many of whichhave lured chemists into their total synthesis and the evaluationof their potential as chemotherapeutic agents.

Even now, with the ready availability of advanced analyticaland spectroscopic techniques, structural revisions or assign-

ments are made on the basis of synthetic undertakings.Undoubtedly, the isolation of new natural products will con-tinue to provide leads for pharmaceutical chemists and alsopresent new methodological challenges for synthetic chemists.

This review covers the literatures from July 2000 to June2001, following closely on from a previous review 1 in the series.

2 Muscarine alkaloids

Two reviews on the synthesis of naturally occurring muscarinealkaloids have appeared. Alkoxyl radical cyclizations havebeen applied in the stereoselective construction of the centralring of muscarine alkaloids 1, 2.2 Another review surveys thestereoselective synthesis of the precursors of muscarines byhydrolases and oxidoreductases.3

A novel, stereospecific total synthesis of (�)-muscarine 3 and(�)-epi-muscarine 4 has been achieved by utilizing -glucoseas a chiral precursor.4 The key steps in the synthesis of both

Zhong Jin was born in Nanjin, P. R.China in 1973 and started to studychemistry at Nankai University in1991. After graduation from NankaiUniversity, he joined Professor RunqiuHuang’s group in 2000. His researchinterests include the discovery of newbioactive substances, the developmentof selective and efficient syntheticmethods, and the total synthesis ofnatural products.

Zaiguo Li was born in 1970. After he receivedhis Bachelor and Master degrees in ChemicalEngineering from Dalian University of Science andTechnology, he became a PhD candidate in NankaiUniversity under the supervision of Professor RunqiuHuang in 1995. He joined the faculty of NankaiUniversity in 1998 and was entitled AssociateProfessor in 2000. His main research interests includethe synthesis of new biologically active substances,such as 1-aminoalkylphosphonate and phenanthro-indolizidine alkaloids. In 2001, he went to theUniversity of Denver in USA as a visiting scholar.

Professor Runqiu Huang was born in1939. he studied chemistry in PekingUniversity, where he received hisBSc in 1962. He joined the Instituteof Elemento-Organic Chemistry inNankai University after his gradu-ation and became a professor in 1990.His research interests focus on thesynthesis of new biologically activesubstances, including the discoveryand total synthesis of naturalproducts.

Zhong Jin Zaiguo Li Runqiu Huang

454 Nat. Prod. Rep., 2002, 19, 454–476 DOI: 10.1039/b108923b

This journal is © The Royal Society of Chemistry 2002

targets 3 and 4 were: (i) the formation of the 2,5-anhydro--idose ethylene acetal derivatives 8 and 9 (Scheme 1) by anintramolecular SN2 process which occurred during an acidcatalyzed alcoholysis of the protected furanoses 6 and 7; and(ii) a stereoselective catalytic reduction of the conformationallyconstrained dihydrofurans 12 which were available from thecompletely protected 2,5-anhydro--idose derivatives 10 and11. Finally, the intermediate 13 was prepared by an one-potprocedure which included a catalytic hydrogenation of thedouble bond, and a hydrogenolytic removal of the benzylideneprotection over 10% Pd/C. Thereafter, monotosylation of thediol 13 at �28 �C produced 6-O-tosyl derivative 14 which wassubsequently treated with lithium aluminium hydride in boilingtetrahydrofuran, to give the key chiral intermediate 15. Afteranother six-step synthetic sequence, compound 15 yielded(�)-muscarine iodide 3 stereospecifically. Conversion of theintermediate 15 into (�)-epi-muscarine iodide 4 was similar asoutlined in Scheme 2.

3 Imidazole, oxazole and thiazole alkaloids

A wide variety of secondary metabolites have been producedby marine organisms.5 They continue to excite the interest ofmarine natural product chemists because of their structuraldiversity and interesting biological activities.

Reinvestigation of the extract of the ascidian Didemnumgranulatum collected on the Brazilian coastline led to theisolation of two minor compounds, granulatimide 26 and6-bromogranulatimide 27, which corroborated previousassumptions about the occurrence of granulatimide as a naturalproduct.6

The relatively abundant Caribbean soft coral Erythropodiumcaribaeorum is a good source of eleutherobin 28 and a numberof analogues including sarcodictyin A 29, caribaeoside 30,Z-eleutherobin, desmethyleleutherobin 31, isoeleutherobin A32, and desacetyleleutherobin 33.7,8 Two new antimitoticditerpenoids, caribaeorane 34 and 15-hydroxycaribaeorane 35,have been identified in Erythropodium caribaeorum extracts byisolation of their C4 methylketals.9 When fresh specimens wereextracted with EtOH instead of MeOH, eleutherobin 28 wasdemonstrated to be an isolated artifact formed from the corre-sponding hemiketal natural product.

A new chitinase inhibitor, namely argadin 36, has beenisolated from the cultured broth of Clonostachys sp. FO-7314.10

It is a cyclic pentapeptide structurally elucidated as cyclo-(N ω-acetyl--arginyl--prolyl-homoseryl-bis-tidyl--2-amino-adipyl) in which homoseryl γ-methylene is bonded to an histidylα-amino residue.

From a culture of Bacillus thuringiensis subsp. kustaki HD-1,a novel class of lipopeptides, 37, 38, 39 and 40, has been isol-ated.11 The lipopeptides have the same amino acid sequence,

Thr–Gly–Ala–Ser–His–Gln–Gln, but different fatty acids. Thefatty acyl chain is linked to the N-terminal amino acid residuevia an amide bond. Each lipopeptide has a lactone linkagebetween the carboxy terminal amino acid and the hydroxygroup in the serine residue.

Marine sponges have produced extensive secondarymetabolites containing an imidazole group. Two new bis-(dihydroxystyryl)imidazole alkaloids, wondonins A 41 and B42, have been isolated from an association of the spongesPoecillastra wondoensis and Jaspis sp. from Keomun Island,Korea.12

A guanidine containing alkaloid, naamine D 43 was isolatedfrom the Egyptian Red Sea sponge Leucetta cf chagosensisalong with four known alkaloids, naamidine A 44, B 45, D 46and G 47.13 The first total syntheses of naamidine A 44 andnaamine A 48 have been achieved through thirteen and twelve

Scheme 1 Reagents and conditions: a) TrCl, Py, rt, 3 days, then MsCl,�4 �C, 24 h, 100%; b) TrCl, Py, rt, 3 days, then TsCl, �4 �C, 24 h, 100%;c) ethylene glycol, TsOH, 80 �C, 5 h, 53%; d) PhCH(OMe)2, TsOH,DMF, 70 �C, 20 h, 86%; e) Bu4NF, MeCN, N2, reflux, 48 h, 86%; f ) H2,10% Pd/C, EtOH, AcOH, rt, 16 h, 83%; g) TsCl, Py, �28 �C, 6 days,80%; h) LiAlH4, THF, N2, reflux, 4 h, 90%; i) DEAD, PhCO2H, Ph3P,THF, 0 �C–rt, 20 h; j) TFA, 6 M HCl, �4 �C, 24 h; k) NaBH4, MeOH,rt, 2 h, 27% from 15; l) imidazole, Ph3P, I2, toluene, N2, reflux, 3 h, 84%;m) K2CO3, MeOH, THF, rt, 1.5 h, 83%; n) Me3N, EtOH, 80 �C, 3 h,93%.

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steps of reactions, respectively, starting from 1-methyl-2-phenylthio-1H-imidazole 49.14

Cyclooroidin 50 and taurodispacamide A 51 are two novelpyrrole-imidazole alkaloids from the Mediterranean spongeAgelas oroides.15 Although both alkaloids may be conceived ofas derivatives of the C11N5 skeleton of the known oroidin 52,remarkably cyclooroidin 50 possesses the unprecedented N1–C9

connection. Biosynthetically, this class of C11N5 pyrrole-imidazole alkaloids such as the palau’amines 53, the stylo-guanidines 54 and the axinellamines 55 were thought to bederived from a common precursor, oroidin.16 A syntheticapproach to this class of bisguanidine marine alkaloids hasbeen described.17 This strategy provides a rapid entry into thecomplex spirocycle core of these compounds. A convenienttotal synthesis of midpacamide 56 and dispacamide 57 whichbelong to this ‘oroidin group’ of natural products has beendeveloped.18

Three imidazole alkaloids have been isolated from anAustralian non-verongid sponge, Oceanapia sp.19 Of thesealkaloids, compound 58 is new, the others 59, 60 have beenreported previously. These natural marine products showedstrong activity against mycothiol S-conjugate amidase (MCA),a novel mycobacterial enzyme.20

Archerine 61 is a novel anti-histaminic bromotyrosine-derived alkaloid from the Caribbean marine sponge Aplysinaarcheri.21 The structure of archerine is suggestive of itsbiogenetic origin from a [1�1] intermolecular oxidativecoupling of two molecules of aerophobin-2 62, which wasinitially isolated from the butanolic extract of Verongiaaerophoba.

Microcyclamide 63, isolated from the cultured cyano-bacterium Microcystis aeruginosa is a cytotoxic cyclichexapeptide alkaloid containing an imidazole ring system.22 It

Scheme 2 Reagents and conditions: a) BzCl, Py, rt, 24 h, 86%; b) TFA,6 M HCl, �4 �C, 24 h; c) NaBH4, MeOH, rt, 2 h, 59% from 21; d)imidazole, Ph3P, I2, toluene, N2, reflux, 3 h, 90%; e) K2CO3, MeOH,THF, rt, 1.5 h, 65%; f ) Me3N, EtOH, 80 �C, 3 h, 95%.

showed moderate cytotoxicity against P388 murine leukemiacells.

The total synthesis of the closely related phenylahistin 64 andaurantiamine 65, which were isolated from Aspergillus ustusNSC-F038 and Penicillium aurantiagriseum, has beenachieved.23 Ethyl isobutyrate was converted into the alcohol 66,followed by tosylation to yield 67, which was subsequentlyconverted into olefin 68. Saponification with sodium hydroxideafforded 2,2-dimethylbut-3-enoic acid 69. The acid chloride of69 reacted with the dilithio dianion of monoethylmalonate togive β-ketoester 70. Chlorination with sulfuryl chloride yielded71, which was refluxed with formamide in the presence of waterto give 72. After reduction with DIBALH and oxidation withMnO2, aldehyde 74 was obtained. Condensation with the

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diacetyldiketopiperazine derivatives 75 gave both natural alkal-oids 64 and 65 (Scheme 3).

A short synthesis of the cytotoxic alkaloids, slageninsA 76, B 77, and C 78, recently isolated from the spongeAgelas nakamurai has been described.24 The synthetic routefeatures the preparation of β-hydroxyimidazolone 79 fromornithine and its subsequent oxidative cyclization to theslagenin core.

An expeditious synthesis of pentosidine 80, one of theadvanced glycation end products (AGEs), has been achieved viaan asymmetric alkylation of a chiral Schiff base, a mercury saltmediated intramolecular guanylation, and the regioselectivealkylation of imidazo[4,5-b]pyridine ring.25 This efficientsynthesis promises the availability of pentosidine in quantitiesfor biochemical investigation.

Certain marine-derived imidazole and indole compoundsincluding topsentins and nortopsentins have been found toinhibit the activity of brain nitric oxide synthase (bNOS).26 The

ability to inhibit bNOS is useful in therapeutic applicationsincluding the treatment of neurodegenerative diseases such asAlzheimer’s, Parkinson’s and Huntington’s. A short synthesisof topsentin A 81 and nortopsentins B 82 and D 83 hasbeen accomplished from readily available starting materials.27

The synthesis was highly symmetrical in nature, and to date,represents the most efficient entry into this bioactive class ofbis(indolyl)imidazole metabolites. Nortopsentin D has alsobeen regioselectively synthesized by utilizing a microwave-assisted methodology.28

Chartellines A 84, B 85, C 86 and chartellamides A 87 and B88 are members of a small group of highly halogenated indole-imidazole alkaloids produced by the marine bryozoan Chartella

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papyracea from the North Sea. A model study towards totalsynthesis of chartelline alkaloids containing a spirocyclic β-lactam moiety and α,β-unsaturated imine has been constructedfrom isatin using a Staudinger imine-ketene cycloaddition andan addition to an N-activated γ-lactam as key steps.29

Several synthetic pathways have been developed for thesynthesis of the alkaloids xestomanzamine A 89 and B 90, isol-ated from the Okinawan marine sponge Xestospongia sp.30 The

Scheme 3 Reagents and conditions: a) Tos–Cl, Py, rt, 88%; b) DBU,reflux, 140 �C, 96%; c) 4 M NaOH, EtOH, rt, 99%; d) i: SOCl2, reflux,ii: EtOCOCH2COOH, BuLi, THF, �70∼�10 �C, 85%; e) SO2Cl2,CHCl3, reflux, 77%; f ) formamide, H2O, reflux, 145 �C, 48%; g)DIBALH, toluene, �30 �C, 50%; h) MnO2, acetone, rt, 95%; i) t-BuOK,n-BuOK, DMF, rt, 28% NH4OH, rt, chiral HPLC.

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synthesis of aromatic xestomanzamine A was convenientlyachieved by way of a Grignard reaction in dichloromethanebetween 1-cyano-β-carboline 91 and Grignard reagent 92,whilst xestomanzamine B 90, an oxidation-sensitive dihydro-β-carboline, was prepared by Pictet–Spengler condensation oftryptamine 93 with a vicinal tricarbonyl substituted imidazole94 (Scheme 4).

The syntheses of some tyrosine-derived secondary metab-olites isolated from marine sponges of the order Verongidahave been reported.31 Synthesis of the known metaboliteverongamine 95 was achieved by oxidation of O-methyl bromo-tyrosine methyl ester 96 and amidation of the resulting oximeester 97 with histamine. Wadsworth–Emmons olefination of thedibromobenzaldehyde 98 with a phosphonate gave the pyruvatesilylenolether 99. Deprotection and in situ oxime formationgave the oxime ester 100. Amidation with histamine, followedby deprotection of the MOM ether gave the first synthesis ofpurealidin N 101 (Scheme 5).

The EtOAc extract portion of the marine sponge of thegenus lanthella sp. collected at the Great Barrier Reef in Aus-tralia supplied four novel dibromotyrosine-derived metabolites,

Scheme 4 Reagents and conditions: a) CH2Cl2, 55%; b) TFA, CH2Cl2;c) air, several days.

namely ianthesines A 102, B 103, C 104, and D 105, whichshowed potent Na, K-ATPase inhibitory activity.32 Most ofthese dibromotyrosine-derived metabolites are the terminalamine-type, to the best of our knowledge, whereas, ianthesinesA–D are the first examples of the amino acid-type among thisclass of metabolites.

A strain designated as Streptomyces sp. KSM-2690 hasbeen found to produce a new complex of triene-β-lactoneantibiotics in the culture filtrate.33 Among them, the newantibiotics 106 and 107 were identified as additional membersof this group.

Scheme 5 Reagents and conditions: a) TFA, CH2Cl2, Na2WO4, 30%H2O2, EtOH, H2O, 65%; b) histamine, MeOH, 60 �C, 72 h, 98%; c)LDA, THF; d) HF�Et3N, MeOH, NH2OH�HCl; e) histamine, 60 �C,MeOH, 96%.

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Two new classes of inhibitors of lipoprotein-associatedphospholipase A2 (LpPLA2) have been identified in the culturebroths of Pseudomonas fluorescens strain DSM11579.34,35

SB-253514 108 represents the major component of this metab-olite family. Single crystal X-ray studies of non-glycosylatedanalogue SB-311009 109, the biotransformation productderived from SB-253514, was presented to support theelucidated structure of the parent metabolite.

Aclidinomycins A 110 and B 111 are two novel naph-thyridinomycin-type antibiotics from Streptomyces halstediKB012 isolated from a sea sand sample collected from Yasuuraseashore (Hiroshima, Japan).36 They exhibited antimicrobialactivity against the Gram-positive bacteria, B. subtilis, B. dereusand Micrococcus luteus, but were inactive against the Gram-negative bacteria, Candida albicans and Aspergillus fumigates.

A previous undescribed compound, all-cis 7,11–20:2 (di-homotaxoleic acid, DHT) 112, has been characterized by gaschromatography-mass spectrometry as being present in seedoils of two Taxaceae containing high levels of taxoleic acid(all-cis 5,9–18:2). This compound was absent from oils of 10other conifer genera, as well as from one member of Taxaceaecontaining very low amounts of taxoleic acid, suggesting thatDHT is a taxoleic acid elongation product.37

Variation of the culture conditions of Streptomyces sp. strainAl, which produced streptazolin 113, resulted in the isolation offour new co-metabolites: 5-O- (β--xylopyranosyl)streptazolin114, 9-hydroxystreptazolin 115, 13-hydroxystreptazolin 116,and a streptenol E.38

New atisine-type diterpene alkaloid, named spiramide 117,has been isolated from the roots of Spiraea japonica var.acuta.39 The structure of spiramide is related closely tospiramine S 118 only with a different pattern of substituents.The stereochemistry of spiramide was determined on the basisof the absolute structure of spiramine A.

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Amamistatins A 119 and B 120 have been isolated fromNocardia asteroides SCRC-A2359, which was isolated from asoil sample collected at Amami Island in the Kagoshima Pre-fecture, Japan.40 Amamistatin A appears to be useful in inhibit-ing the growth of human tumour cell lines such as MCF-7breast, A549 lung, and MKN45 stomach cancer cell lines.

The complete structure and stereochemistry of mycobactin J121, a commercially available siderophore isolated from Myco-bacterium avium subsp. paratuberculosis, have been reportedalong with methodology to enable the determination of theabsolute configuration of other mycobactins on a small scale.41

A catecholate siderophore, anachelin 122, which was the firstgenuine siderophore of a cyanobacterium, has been isolatedfrom the cyanobacterium Anabaena cylindrica CCAP 1403/2A.42 The central part of the siderophore is a tripeptide consist-ing of -Thr, -Ser, and -Ser.

The efficient total syntheses of pyrinodemins A 123 and B124 have been developed in 26–30% overall yield.43 Based onanalysis of the spectral data, the position of the double bondin pyrinodemin A was assigned between carbons 15� and 16� asin 123, not between carbons 16� and 17� as in the previouslyproposed structure.

The first total synthesis of racemic phthoxazolin A 125 hasbeen concluded involving a convergent series of palladium-catalysed cross-coupling reactions of stereoselectively con-structing the Z, Z, E-trienyl unit.44

An asymmetric total synthesis of rhizoxin D 126 hasbeen described utilizing catalytic asymmetric allylation as a keystrategic element.45 Comparison with previous syntheses ofrhizoxin D, this strategy provided inherent flexibility in thetiming of the necessary operations and also allowed for otherring closure options to be investigated using the same basicsubunits.

An efficient and convergent synthetic pathway providedthe C1�–C11� side chain of the antifungal antitumour agentleucascandrolide A 127, isolated from a calcareous spongeLeucascandra caveolata from the east coast of New Caledonia,in nine steps and in 3.2% overall yield for the longest linearsequence.46 Highlights of the synthetic strategy were thepreparation of the oxazole moiety by a mild three-stage processinvolving oxidation–cyclodehydration–dehydrohalogenation ofthe unstable alcohol 128 and the semihydrogenation of thealkyne moiety at the stage of the relatively stable oxazole 129 togive the novel cis-alkenyl oxazole derivative that is a uniquestructural feature of leucascandrolide A.

The first total synthesis of (�)-tetrazomine 130 has beenreported and its relative and absolute stereochemistry has beendetermined.47 A key step of the synthetic sequence involved a1,3-dipolar cycloaddition to an azomethine ylide of tricyclecore ultimately derived from the ortho-anisaldehyde.

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An asymmetric aldol-olefin ring closing metathesis approachhas been applied to the total synthesis of the carbocyclic sugartrehazolin 131 isolated from a culture broth of Micromonosporastrain SANK 62390.48 The synthesis was completed in 18 stepsfrom the N-acyloxazolidinethione 132. An alternative strategyto aminocyclopentital core 133 of tehazolin has been devisedusing an intermediate polyhydroxylated cyclopentene 134which derived from the cyclizations of diene 135 by ring closingmetathesis (RCM).49

After a range of methods for the synthesis of mono-, bis-,and tris-2,4-disubstituted oxazoles were evaluated, a totalsynthesis of the unique tris-oxazole macrolide ulapualide A136, from the marine nudibranch Hexabranchus sanguineus,whose relative stereochemistry was assigned on the basis ofan earlier molecular mechanics study, has been described.50,51

The double functionalised tris-oxazole phosphonium salt 137was coupled with the protected polyol aldehyde 138 to yieldthe alkene 139. Attachment of the ω-carboxy substitutedketo-phosphonate residue 140 produced 141, and macrocyclis-ation via an intramolecular Wadsworth–Emmons olefinationlead to 142. Sequential functional group manipulation,

including introduction of the C9 methyl group, and finallythe terminal N-methyl N-alkenyl formamide residue gavethe natural ulapualide A (Scheme 6). A highly convergentasymmetric total synthesis of the actin-depolymerizing agent(�)-mycalolide A 143, structurally closely related to ulapualideA, has been achieved through the assembly and union of theC1–C19 trisoxazole fragment 144 and the C20–C35 aliphaticfragment 145, respectively.52

The marine natural product (�)-hennoxazole A 146 hasbeen synthesized by a convergent approach that combined atetrahydropyran segment 147 and a triene unit 148 via Wipf’soxidation–cyclodehydration process.53

Diazonamide A 149, a secondary metabolite isolated fromthe colonial ascidian Ciazona chinensis, exemplifies anunprecedented molecular architecture encompassing a cyclicpolypeptide backbone as well as an admirably complex andstrained halogenated heterocyclic core trapped as a singleatropisomer harbouring a quaternary center at the epicentre.Model studies towards the synthesis of diazonamide A havebeen taken up by several groups of researchers. Synthesis of theheterocyclic core 150 was achieved by utilizing the Suzuki andHorner–Wadsworth–Emmons reactions.54

The benzofuranone 151, as a potential intermediate in thesynthesis of diazonamide A, has been synthesized in eight stepsfrom an N-protected tyrosine ester.55 The indole bis-oxazolefragment 152 of diazonamide A has been synthesized utilizingrhodium catalyzed carbenoid N–H insertion reactions as a keystep.56 Another related indole-bisoxazole fragment 153 has beenprepared by a Chan-type rearrangement of a tertiary amide.57

The highly substituted 4-aryltryptamine 154 bearing the CDFGring system of the natural product has been synthesized via apalladium catalyzed intermolecular coupling reaction.58 Basedon a modified Vilsmeier procedure for the synthesis of 3-(2-N-phthaloylacyl)indole derivatives, the GCDEF fragment 155 ofdiazonamide A has been prepared by a convenient route inmultigram quantities.59 All these approaches represent remark-able strategies for the synthesis of natural polyoxazolealkaloids.

The structural variety of the natural cyclic oxazole- andthiazole-containing secondary metabolites and their biologicalactivities has attracted strong synthetic interest. PhorboxazolesA 156 and B 157 are two isomeric oxazole-containingmacrolides isolated from the marine sponge Phorbas sp.endemic to the western coast of Australia. The total synthesisof phorboxazole B has been accomplished in 27 linear stepsand an overall yield of 12.6%.60 The absolute stereochemistryfound in C4–C12, C33–C38, and C13–C19 fragments was estab-lished utilizing catalytic asymmetric aldol methodology, whilethe absolute stereochemistry of the C20–C32 fragment wasderived from an auxiliary-based asymmetric aldol reaction. Allremaining chirality was incorporated through internal asym-metric induction, with the exception of the C43 stereocentrewhich was derived from (R)-trityl glycidol.

After the C1–C19, C20–C38, and C39–C46 subunits were accom-plished, these fragments have been successfully assembled intonatural phorboxazole B in 27 linear steps and 12.6% overallyield.61,62

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Scheme 6 Reagents and conditions: a) n-BuLi, THF, �78 �C, 70%; b) 2,4,6-trichlorobenzoyl chloride, Et3N, rt, 3h, 42%; c) K2CO3, 18-crown-6,toluene, 33%.

Shortly thereafter, a highly convergent, stereocontrolled totalsynthesis of (�)-phorboxazole A has been achieved in 27 steps,with an overall yield of 3%.63 Highlights of the syntheticventure include the use of modified Petasis–Ferrierrearrangements for the effective assembly of both the C11–C15

and C22–C26 cis-tetrahydropyan rings; the design, synthesis, andapplication of a novel bifunctional oxazole linchpin; and thepreparation and Stille coupling of a C28 trimethylstannane.

The first total synthesis of the marine natural productphorboxazole C 158 occurring in the sea sponge Phorbas aff.clathrata has been reported.64 The key steps of the convergentapproach involved the 3,4-dichloro-5-ethoxycarbonylpyrrole-2-carboxylic acid 159 conversion to an amide 161 withprotected 4-(2-amino-1-hydroxyethyl)phenol 160, and thecentral oxazole was established by cyclodehydration of theacylaminoketone 162 (Scheme 7).

Lissoclinum cyclopeptide alkaloids, e.g. westiellamide 164,have been successfully synthesized by cyclooligomerizationof dipeptidyl oxazolines.65 Cyclodehydration of Cbz-valyl-threonine methyl esters 165 with Burgess reagent allows accessto cis- and trans-oxazoline segments 166, which proved tobe an efficient entry to natural cyclopeptide alkaloids of theLissoclinum class of marine natural products.

Since 1986, a large number of cyclic oxazole- and thiazole-containing secondary metabolites have been isolated fromcyanobacteria, sponges, ascidians, and other, predominantly,marine sources.66

Cyanophyceae, or blue-green algae, have proved to be a richsource of novel biologically active secondary metabolites. Inparticular, the genus Lyngbya has yielded an impressive array ofstructurally diverse compounds.

Lyngbyabellin B 168, an analogue of the potentmicrofilament-disrupter lyngbyabellin A 167, has been isolatedas a minor metabolite from the marine cyanobacterium Lyngbyamajuscula collected at Apra Harbor, Guam.67 It possessesslightly weaker cytotoxicity than 167. Lyngbyabellin B hasalso been isolated from cyanobacterium Lyngbya majusculacollected near the Dry Tortugas National Park, Florida.68

The first total synthesis of lyngbyabellin A has beendescribed involving the oxidative form of functionalized thi-azole carboxylic acid units with CMD (chemical manganesedioxide) from the corresponding thiazolidines.69 Use of thefunctionalized thiazole 169 was initiated by removal of the Bocgroup with hydrogen chloride followed by coupling with Boc-glycine using diethyl phosphorocyanidate (DEPC) to give thedipeptide 170. Ester saponification followed by condensation

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with the β-hydroxy acid fragment 171 using DCC in thepresence of N,N-(dimethylamino)pyridine (DMAP) producedthe depsipeptide 172. After cleavage of the allyl ester withPd(Ph3P)4 in the presence of morpholine, coupling of the result-ing carboxylic acid with the α,β-dihydroxy thiazole fragment173 produced the linear precursor 174. Finally, after removal ofthe TMSe group at the C- terminus by tetrabutylammoniumfluoride (TBAF) and then deprotection of the Boc group at theN-terminus with toluene-p-sulfonic acid (TsOH), the macro-lactamization was efficiently achieved using diphenyl phos-phorazidate (DPPA, (PhO)2P(O)N3) to provide lyngbyabellinA (Scheme 8).

Seven new metabolites, namely apramides A–G 175–181,have been isolated from a lyngbyastatin 2-producing strain ofthe marine cyanobacterium Lyngbya majuscula collected atApra Harbor, Guam.70 The structures of these linear lipo-peptides have been elucidated based on spectroscopictechniques and chiral chromatography of hydrolysis products.

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Marine organisms are prolific sources of halogenatedsecondary metabolites.5 As part of ongoing efforts to discovernew anticancer compounds from marine sources, the lipophilicextract of a Panamanian variety of the cyanobacteriumLyngbya majuscula led to identify two new polychlorinatedmetabolites, pseudodysidenin 183, dysidenamide 184.71 Bothcompounds are closely related to dysidenin 182 isolatedfrom the Australian specimens of Dysidea herbacea. (�)-Neo-dysidenin 185 was isolated from the marine sponge Dysideaherbacea (Keller 1889) collected on the Great Barrier Reef.72

Scheme 7 Reagents and conditions: a) DCC, HOBt, EtNiPr2, CH2Cl2,rt, 65%; b) DMP, CH2Cl2, rt, 98%; c) PPh3, C2Cl6, NEt3, CH2Cl2, rt,87%; d) H2NC2H4OH, 170 �C, 85%.

It is noteworthy that neodysidenin is an epimer of pseudo-dysidenin 183 differing only at the C13 chiral center.

Barbamide 186 is another example of polyhalogenatedmetabolites from the marine cyanobacterium Lyngbyamajuscula. Recently, a new barbamide derivative, dechloro-

Scheme 8 Reagents and conditions: a) HCl, dioxane, DEPC, Et3N,DMF, 65%; b) aq. LiOH, THF, DCC, DMAP, toluene, 90%; c)Pd(Ph3P)4, morpholine, DCC, DMAP, CSA, toluene, 64%; d) TBAF,THF, TSOH, CH2Cl2, DPPA, NaHCO3, DMF, 4 �C, 58%.

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barbamide 187 was isolated from the original collection ofL. majuscula.73

Subsequently bioassay-guided fractionation using a primarycell culture of rat neurons in a microphysiometer of inhibitionof IL-1β stimulation of sPLA2 in hepatocarcinoma cells led tore-isolation of kalkitoxin 188, a novel neurotoxic lipopeptide, insmall yield from various Caribbean collections of the marinecyanobacterium Lyngbya majuscula.74 Based on syntheses ofkalkitoxins having all possible configurations, the absolutestereochemistry of natural kalkitoxin has been determined andassigned to be the (3R,7R,8S,10S,2�R)-isomer.

A potent cytotoxin with a novel skeleton, apratoxin A 189,has been obtained from the marine cyanobacterium Lyngbya

majuscula Harvey ex Gomont from Finger’s Reef, ApraHarbor, Guam.75 This cyclodepsipeptide of mixed peptide-polyketide biogenesis bears a thiazoline ring flanked bypolyketide portions, one of which possesses an unusual methyl-ation pattern. It is a remarkable cytotoxin in vitro as well as invivo; however, the lack of selectivity limits its potential as anantitumour agent.

During the investigation of nostocyclamide from the fresh-water cyanobacterium Nostoc 31, a new cyclic peptide, namelynostocyclamide M 190, was obtained.76 Mass spectrometric,chemical, and NMR studies showed that this compound hasthe same basic structure as the one for nostocyclamide, but thevaline moiety is replaced by methionine.

The total synthesis of dendroamide A 191, isolated from thecyanobacterium Stigonema dendroideum fremy, has beenaccomplished by modifying several peptide synthesis protocolsand by using molecular modelling to select the precursor for thefinal cyclization reaction.77 On the basis of the total synthesis ofthese cyclic peptide alkaloids, their biological activities appearto be highly dependent on the substitution pattern present atthe side-chains of the initial amino acids.

A wide ranging screen resulted in the isolation of a potentspecific telomerase inhibitor designated as telomestatin 192from Streptomyces anulatus 3533-SV4.78 Although telomeraseconsists of several components with DNA polymerase orreverse transcriptase activity in addition to its intrinsic telomer-ase component, telomestatin specifically inhibited telomerasewithout affecting DNA polymerase and HIV-RT.

Recent investigations of the sponge Haliclona nigra fromPapua New Guinea have led to the isolation of two newcyclic hexapeptides, haligramides A 193 and B 194, inaddition to the known peptide, waiakeamide 195.79 Thestructures of peptides 193 and 194 were elucidated by extensiveNMR analyses and by comparison of their spectral datawith those of 195. The identity of 193 was confirmed by itsoxidative conversion into 195.

A concise and convergent total synthesis of the polyenethiazole-containing 19-membered bis-lactone, (�)-pateamine196, from the marine sponge Mycale sp., has been described.80

The synthesis features both the intra- and intermolecular Stillesp2–sp2 coupling reactions to elaborate the E,Z-diene macrolidecore and the side-chain all-E polyene portion, and highlightsthe scope for enantiopure sulfinimine intermediates in the syn-thesis of chiral β-amino ester moieties in complex structures.

The first asymmetric total synthesis of (�)-mycothiazole197, a polyketide thiazole from the marine sponge Spongia

466 Nat. Prod. Rep., 2002, 19, 454–476

mycofijiensis, has been achieved.81 Key steps involved CMDoxidation for the conversion of a thiazolidine to thiazoleand the Nagao acetate aldol reaction of 198 with aldehyde 199.The skipping diene was constructed by the standard Stillecoupling reaction, and the conjugated diene was synthesized bylithium()- and copper()-mediated Stille coupling reaction.

Study of the ascidian Lissoclinum patella (Order Enterogona,Family Didemnidae) has yielded two new closely relatedcyclic peptide alkaloids namely lissoclinamide 9 200 and lisso-clinamide 10 201.82 Their structures were determined by acombination of 2D NMR, selective 1D TOCSY, MS andseries-wound ESI-MS (MSn) techniques and the assignment ofabsolute stereochemistry was achieved by the hydrolysis oflissoclinamides followed by chiral TLC. In the case of lisso-clinamide 9, NOE restrained molecular dynamic studies werealso performed confirming the proposed stereochemistry.

A total synthesis of the prenylated cyclopeptide trunkamideA 202 produced by ascidians of the genus Lissoclinum, and alsoits C45 epimer, has been described.83 The macrocycle in thenatural product was elaborated to the trunkamide structurefollowing Wipf’s method and the thiazoline ring was producedin the final step from the thioamide cyclic peptide.

The epothilones exhibit outstanding microtubule bindingaffinities and cytotoxicity against tumour cells and multipledrug resistant tumour cell lines. The role of epothilones aspotential paclitaxel successors has initiated intense interestin its synthesis, resulting in a number of total syntheses ofepothilones and numerous derivatives thereof.84

Nat. Prod. Rep., 2002, 19, 454–476 467

A highly convergent total synthesis of epothilone A 203 hasbeen achieved, which utilized chiral silane-based bond con-struction methodology to introduce the key C6 and C7 stereo-centers.85,86 A completely stereocontrolled total synthesis ofepothilones A and B 204 has been reported in 21 steps and 18steps, respectively.87 An alternative and concise total synthesisof epothilone A and C 207 involved a ring closing alkynemetathesis reaction catalyzed by a molybdenum complexfollowed by a Lindlar reduction of the resulting cycloalkyneproduct.88 Epothilone B and its (12R,13R) acetonide 210 havebeen prepared in a novel highly stereoselective total synthesis inwhich key intermediates have been constructed via SharplessAD-reaction and Davis–Evans-hydroxylation.89 Another totalsynthesis of epothilones B has been carried out, essentiallybased on well established methodology which starts frominexpensive materials.90

A total synthesis of epothilone B 204 and D 208 has beendescribed in 18(17) steps for the longest linear sequence andwith about 8% overall yield.91 The synthesis is highly con-vergent through coupling of the three fragments C1–C6 211, C7–C10 212, and C11–C21 213. After a series of synthetic effortstoward the epothilones, epothilone B, epothilone D, and cis-and trans-9,10-dehydroepothilone D 214 have been fully stereo-selectively synthesized.92

The macrolactonization-based strategy for the total synthesisof epothilones has been streamlined and improved to a highlevel of efficiency and stereoselectivity. This strategy has beenapplied to the construction of a vinyl iodide which served as acommon intermediate for the synthesis of a series of naturaland designed epothilones including epothilone B10 205, epo-thilone F 206, 16-desmethylepothilone B 215, and related sidechain modified epothilone B analogues.93

A practical, total synthesis of desoxyepothilone F 209 hasbeen accomplished.94 In the approach, two consecutive aldol

reactions were used to fashion the acyl sector 217. After thisfragment had been prepared, the Suzuki coupling reaction withfragment 216 was conducted to give precursor 218, whereafter,sequential reactions gave the targeted product as outlined inScheme 9.

In order to gain further insight into the biological activitiesof the epothilones, the total syntheses of 12,13,15-desoxy-15(S )-azaepothilone B and 12,13,15-desoxy-15(R)-azaepo-thilone B 221 have been accomplished utilizing a highlyconvergent strategy.95 Using fully synthetically derived lactams,in vitro and in vivo studies were conducted in comparison withthe advanced clinical candidates, 12,13-desoxyepothilone B and12,13-desoxyepothilone F.

Four new cytostatic compounds, tubulysins A 222, B 223, D224, and E 225, have been isolated from the culture broth ofstrains of the myxobacteria Archangium gephyra and Angio-coccus disciformis.96 The tubulysins were not active againstbacteria and only a little against fungi, but showed high cyto-static activity against mammalian cell lines with IC50 values inthe picomolar range.

Two new triene-ansamycins designated thiazinotrienomycinsF (TT–F) 226 and G (TT–G) 227 and a new deene-ansamycin,benzoxazomycin, have been isolated from a culture broth ofStreptomyces sp. MJ672-m3 and their structures have been elu-cidated through spectroscopic analyses.97 The tumour growthinhibitory activities of TTG appear almost as strong as TT–B,in respect of GI50 and TGI against several human cancer celllines.

Steroidal compounds in the roots of Asclepias tuberosa havebeen investigated and five doubly-linked cardenolide glycosideswere isolated.98 Two of them were identified as 3�-spiro-linkedthiazolidinone 228 and S-oxythiazolidinone derivatives 229 of∆5-calotropin. Although thiazoline or thiazolidine derivatives

468 Nat. Prod. Rep., 2002, 19, 454–476

Scheme 9 Reagents and conditions: a) i. 9-BBN–H, THF, ii.PdCl2(dppf ), AsPh3, DMF–THf–H2O, rt, 8h, 89%; b) i. TESOTf, 2,6-lutidine, CH2Cl2, �78 �C–rt, 8h, ii. HCl–MeOH, 0 �C, 78%; c) 2,4,6-trichlorobenzoyl chloride, Et3N, then 4-DMAP, toluene, slow addition3 h, 70%.

of doubly-linked cardenolide glycosides are known in A. fruti-cosa, 228 and 229 are the first thiazolidinone derivatives.

Synthesis of the cruciferous phytoalexins, spirobrassinin 230from the Japanese radish, has been enantioresolved by utilizinga chiral auxiliary method.99,100 The absolute configuration wasunambiguously determined by X-ray crystallography of a(1�S,4�R)-camphanoyl derivative of (�)-230. Consequently,natural (�)-230 was ascertained to be of S-configuration.

A total synthesis of yersiniabactin 231, a siderophoreproduced by the Gram-negative coccoid bacterium Yersiniaenterocolitica, has been summarized.101 During the cyclizationstep of β-hydroxythioamide to thiazoline, Burgess reagent wasutilized to preserve chirality at the C9 carbon center, which canbe readily made racemic. Based on this synthesis, the absoluteconfiguration of natural yersiniabactin has been determined as9R,10RS,12R,13S,19S.

4 Amaryllidaceae and Sceletium alkaloids

Several reviews on the isolation and total synthesis of Amaryl-lidaceae alkaloids have appeared during the 2000–2001 period.A single report on the occurrence of Amaryllidaceae alkaloids

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in Urginea altissima has been questioned following a reinvesti-gation of this species.102 Four Amaryllidaceae species, includingwild, cultivated and ornamental plants (Sternbergia lutea,Pancratium, Narcissus tazetta and Clivia nobilis) have beeninvestigated for their content of alkaloids.103 In addition, threepublications have outlined synthetic highlights of Amaryl-lidaceae alkaloids for the past year.104,105,106 Over the past year,fourteen new alkaloids have been reported and all of thembelong to established frameworks.

Eleven alkaloids have been isolated from fresh bulbs ofCrinum macowanii.107 Macowine 232, which possessed a β-5,10b-ethano bridge, was reported for the first time along withthe other known crinane-type alkaloids including crinine 233,krepowine 234, powelline 235, buphanidrine 237, lycorine 239,crinamidine 242, undulatine 243, 4a-dehydroxycrinamabine244, 1-epideacetylbowdensine 245, cherylline 246.

Extract of the dried and powdered non flowering wholeplants obtained from Crinum moorei has produced thirteenalkaloids.108 Of these thirteen two are new, designated as 3-[4�-(8�-aminoethyl)phenoxy]bulbispermine 247 and mooreine 248,the other are the known crinine 233, 3-O-acetylcrinine 234,powelline 235, epibuphanisine 238, lycorine 239, 1-O-acetyl-lycorine 240, crinamidine 242, undulatine 243, 1-epideacetyl-bowdensine 245, cherylline 246, and epivittatine 257.

In the course of identifying the phenolic constituents ofCrinum bulbispernum, a new alkaloid has been obtained, desig-nated as hippacine 249.109

The alcoholic extract of the fresh bulbs of Cyrtanthus elatushas yielded two new alkaloids, namely zephyranthine 251 and1,2-O-diacetylzephyranthine 252, together with three otherknown alkaloids galanthamine 253, haemanthamine 254,haemanthidine 255.110

Dry whole plants of Zephyranthes citrina contain eightcrinane and lycorane type alkaloids, namely, lycorine 239,haemanthamine 254, haemanthidine 255, vittatine 256,maritidine 261, galanthine 262, narcissidine 264, and the newalkaloid oxomaritidine 260 which was reported for the first timefrom a natural source.111

Two new benzophenanthridine alkaloids, namely 8-acetonyl-dihydronitidine 265 and 8-acetonyldihydroavicine 266 havebeen isolated from Zanthoxylun trtraspermum stem bark.112

Both of them showed significant antibacterial activity while8-acetonyldihydronitidine was strongly antifungal. A benzo-phenanthridine alkaloid, chelidonine 267, was also isolatedfrom the fructus of Chelidonium majus.113

The bulbs of Ammocharis coranica have yielded eight alkal-oids.114 One is new, namely 1-O-acetyl-9-O-demethylpluviine263. The other alkaloids identified were 6α-hydroxypowelline236, lycorine 239, 1-O-acetyllycorine 240, acetylcaranine 241,hippadine 250, hamayne 258, crinamine 259.

470 Nat. Prod. Rep., 2002, 19, 454–476

(�)-3-epi-3,4-Dihydro-3-hydroxygraciline 268, isolated fromGalanthus gracilis of Turkish origin, is a new member of thegracilines, a recently established subgroup of the Amaryl-lidaceae alkaloids. G. plicatus subsp. byzantinus has producedthree new alkaloids, namely (�)-plicane 269, which is a newplicamine-type alkaloid, along with (�)-3-O-(3-hydroxy-butyryl)tazettinol 270, and N-formylismine 271.115

Enantioselective total syntheses of the antitumour alkaloids,(�)-narciclasine 272 and (�)-pancratistatin 273, have beenachieved from a common phenanthridone intermediate 275starting from commercial cyclohex-3-ene-1-carboxylic acid.116

Treatment of phenanthridone 275 with diphenyldiselenide–NaBH4 and then H2O2 installed the requisite C3–C4

unsaturation, and acylation of the free hydroxy groupsfurnished compound 276. Stereoselective cis-dihydroxylationand protection of the resultant diol gave 277. Selective depro-tection of the hydroxy group at C1 followed by dehydrationafforded compound 278 in good yield. Ultimately, (�)-narciclasine 272 was obtained after a series of deprotectionsteps (Scheme 10). Compound 279 was derived from 275 instraightforward fashion, followed by protection as a benzylether to give compound 281. Treatment with PhSe2, NaBH4,and then H2O2 afforded allylic alcohol 282. Routine cis-dihydroxylation gave 283 in good yield. Exposure of 283to Pd(OH)2–C–H2 in EtOH resulted in the penultimate inter-mediate 284. Finally, the synthesis of (�)-pancratistatin 273was completed by treatment of 284 with LiCl–DMF to removethe C7 methyl group protection (Scheme 11).

A new total synthesis of (�)-7-deoxypancratistatin 274has been accomplished in 19 steps (8% overall yield) from tworeadily available compounds, furan and trans-1,2-bis(phenyl-sulfonyl)ethylene.117 Ring opening of an enantiomerically pure

7-oxanorborenic system and intramolecular lactonization withconcomitant oxirane opening constituted two key steps of thesynthesis.

(�)-Narciclasine, as it is available in practical quantity fromthe bulbs of certain Amaryllidaceae species, has been employedas a precursor for a 10-step synthetic conversion to natural (�)-pancratistatin in 3.6% overall yield.118

A convergent total synthesis of anhydrolycorinone 285,anhydrolycorinium chloride 286, and hippadine 250 have been

Scheme 10 Reagents and conditions: a) (PhSe)2, NaBH4, Ox; b) NaH,AcCl; c) OsO4, TMNO, t-BuOH; d) TsOH, (Me)2C(OMe)2; d) F�,THF; f ) Burgess reagent; g) K2CO3, MeOH; h) n-BuLi, THF, O2; i)TsOH.

Scheme 11 Reagents and conditions: a) NaH, MeI, 98%; b) TBAF,85%; c) Dess–Martin reagents, NaBH4, �20 �C, NaH, BnBr, 73%; d)(PhSe)2, NaBH4, H2O2, reflux, 84%; e) OsO4, t-BuOH, 89%; f )Pd(OH)2, H2, 87%.

Nat. Prod. Rep., 2002, 19, 454–476 471

described enlisting a tetrazine diazine benzene strategyfeaturing a two sequential intramolecular [4�2] cycloadditionreaction of an asymmetrical 6-(acylamino)-1,2,4,5-tetrazine 119

(Scheme 12).

A new strategy for the synthesis of the Amaryllidaceae alka-loid family has been developed based in part on an intra-molecular Diels–Alder reaction of a furanyl carbamate forinitial construction of the hexahydroindolinone core.120 Takingadvantage of an intramolecular Diels–Alder reaction of analkenyl-substituted furanyl carbamate derivative 294, theIMDAF cycloaddition–rearrangement cascade was successfullyused in the total synthesis of (±)-γ-lycorane 292 and also (±)-1-deoxylycorine 293 as outlined in the Scheme 13.

Construction of the ABCD tetracyclic skeleton of theAmaryllidaceae lycorine-type alkaloids has been devised viaan ionic domino reaction involving orthoquinol acetatemoieties.121 Exploitation of the electrophilicity and differen-tially activated double bonds led to the development of a newmethodology aimed at the regiochemical controlled construc-tion of fused heteropolycycles.

Novel radical cyclization reactions, mediated by tributyltinhydride, samarium() iodide or manganese() acetate, havebeen explored to form tri- and tetra-cyclic ring systems relatedto the Amaryllidaceae or Erythrina family of alkaloids.122

Haloethanamide precursor 298, possessing a cyclohexenonering has been shown to form octahydroindolone 299, anderythrinane-type systems could be formed from precursor300 bearing unsaturated side-chains in tandem cyclizations.Oxidative radical cyclization of α-methylthioamide 301 withMn()/Cu() mediation could also be applied to a conciseconstruction of an erythrinane skeleton 302.123

Two conceptually similar routes to the galanthamine ringsystem 253 have been reported, which utilized an intra-molecular Heck reaction to establish the benzofuran ringsystem present in both galanthamine and morphine.124,125 Thetotal synthesis of galanthamine has also been completed,which utilized an intramolecular phenolic reaction usinghypervalent () iodine reagent phenyliodine() bis(trifluoro-acetate) (PIFA).126

The action of phenyliodine() bis(trifluoroaceate) (PIFA)has also been applied to an efficient approach to benzo[c]-

Scheme 12 Reagents and conditions: a) Et3N, MeOH, 51%; b) Boc2O,DMAP, 96%; c) HCl, EtOAc; d) EDCl, HOBt, i-Pr2NEt, 68%; e)265 �C, 100%; f ) Ra–Ni, 97%; g) DDQ, 65%; h) Red–Al, O2, 82%.

phenanthridines 303 and phenanthridinones 304 from properlysubstituted benzylnaphthylamines and naphthylbenzamides,respectively.127 PIFA promoted a non-phenolic oxidative biarylcoupling process, the key step of the synthesis. The total syn-theses of trisphaeridine 305, norchelerythrine 306, chelery-thrine 307 and 12-methyloxydihydrochelerythrine 308, fullyaromatized phenanthridine and benzo[c]phenanthridine alkal-oids, have been accomplished via the intramolecular aryl–arylcoupling reaction.128,129 Norchelerythrine arylhalo amide 309protected by a methoxymethyl group was converted into an N-MOM lactam 310 with the assistance of a Pd reagent, followed

Scheme 13 Reagents and conditions: a) heating; b) HCl, CH2Cl2; c) Py,6-iodobenzo[1,3]dioxole-5-carbonyl chloride; d) Pd(OAc)2, Bu4NCl,KOAc, DMF.

472 Nat. Prod. Rep., 2002, 19, 454–476

by reduction with lithium aluminium hydride and then treat-ment with hydrochloric acid to result in natural product.

A new direct route to benzo[c]phenanthridines has beensystematically studied via a promising C–N bond cleavage.130

Treatment of the readily prepared N-ethoxycarbonylbenzyl-ideneisoquinoline 311 with LDA resulted in cleavage of theC3–N bond, giving the styrylurethane 312. Thermal electro-cyclization of 312 afforded the 2-phenylnaphthalene derivative313, Bischler–Napieralski cyclization of the N-methyl derivativegave the expected benzo[c]phenanthridine 314 (Scheme 14).

Scheme 14 Reagents and conditions: a) LDA, THF, 0 �C, 1 h, 100%; b)10% Pd/C, o-xylene, reflux, 6 days, then NaH, THF, rt, 30 min, MeI, rt,1 h, 75%; c) P2O5, POCl3, reflux, 2.5 h, 66%.

Approaches toward total synthesis of montanine-typeAmaryllidaceae alkaloids using hexahydro-1H-indol-3-one315 as key intermediate have been studied.131 Compound 318,prepared from 316, was treated with n-butyllithium followedby acidic workup to give compound 319. Friedel–Crafts-typecyclization of 319 was effected with trifluoromethanesulfonicacid to afford montanine-type alkaloid skeleton 320 as depictedin Scheme 15.

A formal total synthesis of the montanine-type alkaloid(±)-pancracine 321 has been achieved with full regiocontrol 132

Reaction of a β-nitrostyrene with cyclohexane-1,3-dione inthe presence of DBU afforded the Michael-addition product322, which was readily elaborated, using straightforwardmanipulations, into the 5,11-methanomorphanthridine 323,acquisition of which constituted a formal total synthesis ofthe racemic modification of the montanine alkaloid pancracine321.

A concise total synthesis of cherylline 324, isolated fromCrinum powellii var. alba and other Crinum species, has beendeveloped utilizing the addition of Grignard reagents to nitro-styrene derivatives as the key sep.133 Reaction of a β-nitrostyrenederivative with the Grignard reagent generated from 4-bromo-O-benzylphenol (Scheme 16) furnished nitro compound 325.Reduction of the addition product with LAH gave amine 326.

Scheme 15 Reagents and conditions: a) K2CO3, rt, MeCN, 94%; b)TMSCl, n-BuLi, THF, �78 �C, 1 M HCl, 56%; c) CF3SO3H, rt,CH2Cl2, 63%.

Nat. Prod. Rep., 2002, 19, 454–476 473

The reaction of the amine with formaldehyde and formicacid gave the expected isoquinoline skeleton. The final stepof synthesis was accomplished by hydrogenolytic removalof the benzyl protecting groups to give (±)-cherylline 324(Scheme 16).

The total synthesis of cherylline has also been achievedutilizing an intramolecular cyclization of N-(arylmethyl)-N-methyl-2-aryl-2-(phenylsulfinyl)acetamide 327 underPummerer reaction conditions as a key step.134

The Sceletium alkaloid mesembrine 328 has been totallysynthesized in 13% overall yield by a sequence featuring a[4�1] cycloaddition of a bis(alkylthio)carbene with funtional-ized vinyl isocyanate.135 Thermal decomposition of dithio-oxadiazoline 329 gave the corresponding carbene, whichunderwent cycloaddition with β-aryl-substituted vinyl iso-cyanate 330 to afford hydroindolone 331. Subsequent desul-furization and enamide reduction completed the synthesis ofmesembrine.

The cyclic quaternary centre of (�)-mesembrine has beenenantioselectively constructed via an intramolecular alkylideneC–H insertion reaction.136 Ozonolysis of compound 332,prepared by an intramolecular alkylidene C–H insertionreaction, gave the intermediate keto aldehyde. The intra-molecular aldol reaction and subsequent dehydrationyielded the cyclohexenone 333, then reduced to the alcohol334. Debenzylation produced the primary alcohol 335, whichwas then converted selectively into the mesylate 336. Amin-ation, oxidation, and cyclization then gave (�)-mesembrine(Scheme 17).

Scheme 16 Reagents and conditions: a) THF, �15 �C–rt.; b) LAH,Et2O, rt; c) HCHO, HCOOH, heating; d) 10% Pd/C, CH3CO2C2H5–EtOH (1 : 1 v/v), 1 atm.

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