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Muscarine, imidazole, oxazole, thiazole, Amaryllidaceae and 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: jinzhong2000@263.net; Fax: 86-22-23503438 Received (in Cambridge, UK) 26th March 2002 First 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, and synthetic highlights of complex natural products including muscarine, imidazole, oxazole, thiazole, Amaryllidaceae and Sceletium alkaloids. Covering: July 2000June 2001. Previous review: Nat. Prod. Rep. 2001, 18, 95. 1 2 3 4 5 1 Introduction Muscarine alkaloids Imidazole, oxazole and thiazole alkaloids Amaryllidaceae and Sceletium alkaloids References Introduction 2 Muscarine alkaloids Two reviews on the synthesis of naturally occurring muscarine alkaloids have appeared. Alkoxyl radical cyclizations have been applied in the stereoselective construction of the central ring of muscarine alkaloids 1, 2.2 Another review surveys the stereoselective synthesis of the precursors of muscarines by hydrolases and oxidoreductases.3 A novel, stereospecic total synthesis of ( )-muscarine 3 and ( )-epi-muscarine 4 has been achieved by utilizing -glucose as a chiral precursor.4 The key steps in the synthesis of both ments are made on the basis of synthetic undertakings. Undoubtedly, the isolation of new natural products will continue to provide leads for pharmaceutical chemists and also present new methodological challenges for synthetic chemists. This review covers the literatures from July 2000 to June 2001, following closely on from a previous review 1 in the series.

As the cradle of mankind, nature not only supports peoples needs, but also provides many novelties for phytochemists. Every year, many alkaloid structures from nature are reported. Some belong to known frameworks but others are completely new. These natural products have been extensively investigated because of their varying biological activities, many of which have lured chemists into their total synthesis and the evaluation of their potential as chemotherapeutic agents. Even now, with the ready availability of advanced analytical and spectroscopic techniques, structural revisions or assign-

Zhong Jin was born in Nanjin, P. R. China in 1973 and started to study chemistry at Nankai University in 1991. After graduation from Nankai University, he joined Professor Runqiu Huangs group in 2000. His research interests include the discovery of new bioactive substances, the development of selective and ecient synthetic methods, and the total synthesis of natural products.

Zaiguo Li was born in 1970. After he received his Bachelor and Master degrees in Chemical Engineering from Dalian University of Science and Technology, he became a PhD candidate in Nankai University under the supervision of Professor Runqiu Huang in 1995. He joined the faculty of Nankai University in 1998 and was entitled Associate Professor in 2000. His main research interests include the synthesis of new biologically active substances, such as 1-aminoalkylphosphonate and phenanthroindolizidine alkaloids. In 2001, he went to the University of Denver in USA as a visiting scholar.

Professor Runqiu Huang was born in 1939. he studied chemistry in Peking University, where he received his BSc in 1962. He joined the Institute of Elemento-Organic Chemistry in Nankai University after his graduation and became a professor in 1990. His research interests focus on the synthesis of new biologically active substances, including the discovery and total synthesis of natural products.

Zhong Jin

Zaiguo Li

Runqiu Huang

454

Nat. Prod. Rep., 2002, 19, 454476 This journal is The Royal Society of Chemistry 2002

DOI: 10.1039/b108923b

targets 3 and 4 were: (i) the formation of the 2,5-anhydro-idose ethylene acetal derivatives 8 and 9 (Scheme 1) by an intramolecular SN2 process which occurred during an acid catalyzed alcoholysis of the protected furanoses 6 and 7; and (ii) a stereoselective catalytic reduction of the conformationally constrained dihydrofurans 12 which were available from the completely protected 2,5-anhydro--idose derivatives 10 and 11. Finally, the intermediate 13 was prepared by an one-pot procedure which included a catalytic hydrogenation of the double bond, and a hydrogenolytic removal of the benzylidene protection over 10% Pd/C. Thereafter, monotosylation of the diol 13 at 28 C produced 6-O-tosyl derivative 14 which was subsequently treated with lithium aluminium hydride in boiling tetrahydrofuran, to give the key chiral intermediate 15. After another six-step synthetic sequence, compound 15 yielded ( )-muscarine iodide 3 stereospecically. Conversion of the intermediate 15 into ( )-epi-muscarine iodide 4 was similar as outlined in Scheme 2. 3 Imidazole, oxazole and thiazole alkaloids

A wide variety of secondary metabolites have been produced by marine organisms.5 They continue to excite the interest of marine natural product chemists because of their structural diversity and interesting biological activities. Reinvestigation of the extract of the ascidian Didemnum granulatum collected on the Brazilian coastline led to the isolation of two minor compounds, granulatimide 26 and 6-bromogranulatimide 27, which corroborated previous assumptions about the occurrence of granulatimide as a natural product.6 The relatively abundant Caribbean soft coral Erythropodium caribaeorum is a good source of eleutherobin 28 and a number of analogues including sarcodictyin A 29, caribaeoside 30, Z-eleutherobin, desmethyleleutherobin 31, isoeleutherobin A 32, and desacetyleleutherobin 33.7,8 Two new antimitotic diterpenoids, caribaeorane 34 and 15-hydroxycaribaeorane 35, have been identied in Erythropodium caribaeorum extracts by isolation of their C4 methylketals.9 When fresh specimens were extracted with EtOH instead of MeOH, eleutherobin 28 was demonstrated to be an isolated artifact formed from the corresponding hemiketal natural product. A new chitinase inhibitor, namely argadin 36, has been isolated from the cultured broth of Clonostachys sp. FO-7314.10 It is a cyclic pentapeptide structurally elucidated as cyclo(N -acetyl--arginyl--prolyl-homoseryl-bis-tidyl--2-aminoadipyl) in which homoseryl -methylene is bonded to an histidyl -amino residue. From a culture of Bacillus thuringiensis subsp. kustaki HD-1, a novel class of lipopeptides, 37, 38, 39 and 40, has been isolated.11 The lipopeptides have the same amino acid sequence,

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, reux, 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, reux, 4 h, 90%; i) DEAD, PhCO2H, Ph3P, THF, 0 Crt, 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, reux, 3 h, 84%; m) K2CO3, MeOH, THF, rt, 1.5 h, 83%; n) Me3N, EtOH, 80 C, 3 h, 93%.

ThrGlyAlaSerHisGlnGln, but dierent fatty acids. The fatty acyl chain is linked to the N-terminal amino acid residue via an amide bond. Each lipopeptide has a lactone linkage between the carboxy terminal amino acid and the hydroxy group in the serine residue. Marine sponges have produced extensive secondary metabolites containing an imidazole group. Two new bis(dihydroxystyryl)imidazole alkaloids, wondonins A 41 and B 42, have been isolated from an association of the sponges Poecillastra wondoensis and Jaspis sp. from Keomun Island, Korea.12 A guanidine containing alkaloid, naamine D 43 was isolated from the Egyptian Red Sea sponge Leucetta cf chagosensis along with four known alkaloids, naamidine A 44, B 45, D 46 and G 47.13 The rst total syntheses of naamidine A 44 and naamine A 48 have been achieved through thirteen and twelve Nat. Prod. Rep., 2002, 19, 454476 455

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, reux, 3 h, 90%; e) K2CO3, MeOH, THF, rt, 1.5 h, 65%; f ) Me3N, EtOH, 80 C, 3 h, 95%.

steps of reactions, respectively, starting from 1-methyl-2phenylthio-1H-imidazole 49.14 Cyclooroidin 50 and taurodispacamide A 51 are two novel pyrrole-imidazole alkaloids from the Mediterranean sponge Agelas oroides.15 Although both alkaloids may be conceived of as derivatives of the C11N5 skeleton of the known oroidin 52, remarkably cyclooroidin 50 possesses the unprecedented N1C9 connection. Biosynthetically, this class of C11N5 pyrroleimidazole alkaloids such as the palauamines 53, the styloguanidines 54 and the axinellamines 55 were thought to be derived from a common precursor, oroidin.16 A synthetic approach to this class of bisguanidine marine alkaloids has been described.17 This strategy provides a rapid entry into the complex spirocycle core of these compounds. A convenient total synthesis of midpacamide 56 and dispacamide 57 which belong to this oroidin group of natural products has been developed.18 Three imidazole alkaloids have been isolated from an Australian non-verongid sponge, Oceanapia sp.19 Of these alkaloids, compound 58 is new, the others 59, 60 have been reported previously. These natural marine products showed strong activity against mycothiol S-conjugate amidase (MCA), a novel mycobacterial enzyme.20 Archerine 61 is a novel anti-histaminic bromotyrosinederived alkaloid from the Caribbean marine sponge Aplysina archeri.21 The structure of archerine is suggestive of its biogenetic origin from a [1 1] intermolecular oxidative coupling of two molecules of aerophobin-2 62, which was initially isolated from the butanolic extract of Verongia aerophoba. Microcyclamide 63, isolated from the cultured cyanobacterium Microcystis aeruginosa is a cytotoxic cyclic hexapeptide alkaloid containing an imidazole ring system.22 It 456 Nat. Prod. Rep., 2002, 19, 454476

showed moderate cytotoxicity against P388 murine leukemia cells. The total synthesis of the closely related phenylahistin 64 and aurantiamine 65, which were isolated from Aspergillus ustus NSC-F038 and Penicillium aurantiagriseum, has been achieved.23 Ethyl isobutyrate was converted into the alcohol 66, followed by tosylation to yield 67, which was subsequently converted into olen 68. Saponication with sodium hydroxide aorded 2,2-dimethylbut-3-enoic acid 69. The acid chloride of 69 reacted with the dilithio dianion of monoethylmalonate to give -ketoester 70. Chlorination with sulfuryl chloride yielded 71, which was reuxed with formamide in the presence of water to give 72. After reduction with DIBALH and oxidation with MnO2, aldehyde 74 was obtained. Condensation with the

diacetyldiketopiperazine derivatives 75 gave both natural alkaloids 64 and 65 (Scheme 3). A short synthesis of the cytotoxic alkaloids, slagenins A 76, B 77, and C 78, recently isolated from the sponge Agelas nakamurai has been described.24 The synthetic route features the preparation of -hydroxyimidazolone 79 from ornithine and its subsequent oxidative cyclization to the slagenin core. An expeditious synthesis of pentosidine 80, one of the advanced glycation end products (AGEs), has been achieved via an asymmetric alkylation of a chiral Schi base, a mercury salt mediated intramolecular guanylation, and the regioselective alkylation of imidazo[4,5-b]pyridine ring.25 This ecient synthesis promises the availability of pentosidine in quantities for biochemical investigation. Certain marine-derived imidazole and indole compounds including topsentins and nortopsentins have been found to inhibit the activity of brain nitric oxide synthase (bNOS).26 The

ability to inhibit bNOS is useful in therapeutic applications including the treatment of neurodegenerative diseases such as Alzheimers, Parkinsons and Huntingtons. A short synthesis of topsentin A 81 and nortopsentins B 82 and D 83 has been accomplished from readily available starting materials.27 The synthesis was highly symmetrical in nature, and to date, represents the most ecient entry into this bioactive class of bis(indolyl)imidazole metabolites. Nortopsentin D has also been regioselectively synthesized by utilizing a microwaveassisted methodology.28 Chartellines A 84, B 85, C 86 and chartellamides A 87 and B 88 are members of a small group of highly halogenated indoleimidazole alkaloids produced by the marine bryozoan Chartella Nat. Prod. Rep., 2002, 19, 454476 457

Scheme 3 Reagents and conditions: a) TosCl, Py, rt, 88%; b) DBU, reux, 140 C, 96%; c) 4 M NaOH, EtOH, rt, 99%; d) i: SOCl2, reux, ii: EtOCOCH2COOH, BuLi, THF, 70 10 C, 85%; e) SO2Cl2, CHCl3, reux, 77%; f ) formamide, H2O, reux, 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.

papyracea from the North Sea. A model study towards total synthesis of chartelline alkaloids containing a spirocyclic lactam moiety and ,-unsaturated imine has been constructed from isatin using a Staudinger imine-ketene cycloaddition and an addition to an N-activated -lactam as key steps.29 458 Nat. Prod. Rep., 2002, 19, 454476

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

synthesis of aromatic xestomanzamine A was conveniently achieved by way of a Grignard reaction in dichloromethane between 1-cyano--carboline 91 and Grignard reagent 92, whilst xestomanzamine B 90, an oxidation-sensitive dihydro-carboline, was prepared by PictetSpengler condensation of tryptamine 93 with a vicinal tricarbonyl substituted imidazole 94 (Scheme 4).

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%.

namely ianthesines A 102, B 103, C 104, and D 105, which showed potent Na, K-ATPase inhibitory activity.32 Most of these dibromotyrosine-derived metabolites are the terminal amine-type, to the best of our knowledge, whereas, ianthesines AD are the rst examples of the amino acid-type among this class of metabolites.

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

The syntheses of some tyrosine-derived secondary metabolites isolated from marine sponges of the order Verongida have been reported.31 Synthesis of the known metabolite verongamine 95 was achieved by oxidation of O-methyl bromotyrosine methyl ester 96 and amidation of the resulting oxime ester 97 with histamine. WadsworthEmmons olenation of the dibromobenzaldehyde 98 with a phosphonate gave the pyruvate silylenolether 99. Deprotection and in situ oxime formation gave the oxime ester 100. Amidation with histamine, followed by deprotection of the MOM ether gave the rst synthesis of purealidin N 101 (Scheme 5). The EtOAc extract portion of the marine sponge of the genus lanthella sp. collected at the Great Barrier Reef in Australia supplied four novel dibromotyrosine-derived metabolites,

A strain designated as Streptomyces sp. KSM-2690 has been found to produce a new complex of triene--lactone antibiotics in the culture ltrate.33 Among them, the new antibiotics 106 and 107 were identied as additional members of this group. Nat. Prod. Rep., 2002, 19, 454476 459

Two new classes of inhibitors of lipoprotein-associated phospholipase A2 (LpPLA2) have been identied in the culture broths of Pseudomonas uorescens strain DSM11579.34,35 SB-253514 108 represents the major component of this metabolite family. Single crystal X-ray studies of non-glycosylated analogue SB-311009 109, the biotransformation product derived from SB-253514, was presented to support the elucidated structure of the parent metabolite. Aclidinomycins A 110 and B 111 are two novel naphthyridinomycin-type antibiotics from Streptomyces halstedi KB012 isolated from a sea sand sample collected from Yasuura seashore (Hiroshima, Japan).36 They exhibited antimicrobial activity against the Gram-positive bacteria, B. subtilis, B. dereus and Micrococcus luteus, but were inactive against the Gramnegative bacteria, Candida albicans and Aspergillus fumigates. A previous undescribed compound, all-cis 7,1120:2 (dihomotaxoleic acid, DHT) 112, has been characterized by gas chromatography-mass spectrometry as being present in seed oils of two Taxaceae containing high levels of taxoleic acid (all-cis 5,918:2). This compound was absent from oils of 10 other conifer genera, as well as from one member of Taxaceae containing very low amounts of taxoleic acid, suggesting that DHT is a taxoleic acid elongation product.37 Variation of the culture conditions of Streptomyces sp. strain Al, which produced streptazolin 113, resulted in the isolation of four new co-metabolites: 5-O- (--xylopyranosyl)streptazolin 114, 9-hydroxystreptazolin 115, 13-hydroxystreptazolin 116, and a streptenol E.38 460 Nat. Prod. Rep., 2002, 19, 454476

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 to spiramine S 118 only with a dierent pattern of substituents. The stereochemistry of spiramide was determined on the basis of the absolute structure of spiramine A.

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

A catecholate siderophore, anachelin 122, which was the rst genuine siderophore of a cyanobacterium, has been isolated from the cyanobacterium Anabaena cylindrica CCAP 1403/ 2A.42 The central part of the siderophore is a tripeptide consisting of -Thr, -Ser, and -Ser. The ecient total syntheses of pyrinodemins A 123 and B 124 have been developed in 2630% overall yield.43 Based on analysis of the spectral data, the position of the double bond in pyrinodemin A was assigned between carbons 15 and 16 as in 123, not between carbons 16 and 17 as in the previously proposed structure. The rst total synthesis of racemic phthoxazolin A 125 has been concluded involving a convergent series of palladiumcatalysed cross-coupling reactions of stereoselectively constructing the Z, Z, E-trienyl unit.44 An asymmetric total synthesis of rhizoxin D 126 has been described utilizing catalytic asymmetric allylation as a key strategic element.45 Comparison with previous syntheses of rhizoxin D, this strategy provided inherent exibility in the timing of the necessary operations and also allowed for other ring closure options to be investigated using the same basic subunits.

The complete structure and stereochemistry of mycobactin J 121, a commercially available siderophore isolated from Mycobacterium avium subsp. paratuberculosis, have been reported along with methodology to enable the determination of the absolute conguration of other mycobactins on a small scale.41

An ecient and convergent synthetic pathway provided the C1 C11 side chain of the antifungal antitumour agent leucascandrolide A 127, isolated from a calcareous sponge Leucascandra caveolata from the east coast of New Caledonia, in nine steps and in 3.2% overall yield for the longest linear sequence.46 Highlights of the synthetic strategy were the preparation of the oxazole moiety by a mild three-stage process involving oxidationcyclodehydrationdehydrohalogenation of the unstable alcohol 128 and the semihydrogenation of the alkyne moiety at the stage of the relatively stable oxazole 129 to give the novel cis-alkenyl oxazole derivative that is a unique structural feature of leucascandrolide A. The rst total synthesis of ( )-tetrazomine 130 has been reported and its relative and absolute stereochemistry has been determined.47 A key step of the synthetic sequence involved a 1,3-dipolar cycloaddition to an azomethine ylide of tricycle core ultimately derived from the ortho-anisaldehyde.

Nat. Prod. Rep., 2002, 19, 454476

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An asymmetric aldol-olen ring closing metathesis approach has been applied to the total synthesis of the carbocyclic sugar trehazolin 131 isolated from a culture broth of Micromonospora strain SANK 62390.48 The synthesis was completed in 18 steps from the N-acyloxazolidinethione 132. An alternative strategy to aminocyclopentital core 133 of tehazolin has been devised using an intermediate polyhydroxylated cyclopentene 134 which derived from the cyclizations of diene 135 by ring closing metathesis (RCM).49

After a range of methods for the synthesis of mono-, bis-, and tris-2,4-disubstituted oxazoles were evaluated, a total synthesis of the unique tris-oxazole macrolide ulapualide A 136, from the marine nudibranch Hexabranchus sanguineus, whose relative stereochemistry was assigned on the basis of an earlier molecular mechanics study, has been described.50,51 The double functionalised tris-oxazole phosphonium salt 137 was coupled with the protected polyol aldehyde 138 to yield the alkene 139. Attachment of the -carboxy substituted keto-phosphonate residue 140 produced 141, and macrocyclisation via an intramolecular WadsworthEmmons olenation lead to 142. Sequential functional group manipulation, 462 Nat. Prod. Rep., 2002, 19, 454476

including introduction of the C9 methyl group, and nally the terminal N-methyl N-alkenyl formamide residue gave the natural ulapualide A (Scheme 6). A highly convergent asymmetric total synthesis of the actin-depolymerizing agent ( )-mycalolide A 143, structurally closely related to ulapualide A, has been achieved through the assembly and union of the C1C19 trisoxazole fragment 144 and the C20C35 aliphatic fragment 145, respectively.52 The marine natural product ( )-hennoxazole A 146 has been synthesized by a convergent approach that combined a tetrahydropyran segment 147 and a triene unit 148 via Wipfs oxidationcyclodehydration process.53 Diazonamide A 149, a secondary metabolite isolated from the colonial ascidian Ciazona chinensis, exemplies an unprecedented molecular architecture encompassing a cyclic polypeptide backbone as well as an admirably complex and strained halogenated heterocyclic core trapped as a single atropisomer harbouring a quaternary center at the epicentre. Model studies towards the synthesis of diazonamide A have been taken up by several groups of researchers. Synthesis of the heterocyclic core 150 was achieved by utilizing the Suzuki and HornerWadsworthEmmons reactions.54 The benzofuranone 151, as a potential intermediate in the synthesis of diazonamide A, has been synthesized in eight steps from an N-protected tyrosine ester.55 The indole bis-oxazole fragment 152 of diazonamide A has been synthesized utilizing rhodium catalyzed carbenoid NH insertion reactions as a key step.56 Another related indole-bisoxazole fragment 153 has been prepared by a Chan-type rearrangement of a tertiary amide.57 The highly substituted 4-aryltryptamine 154 bearing the CDFG ring system of the natural product has been synthesized via a palladium catalyzed intermolecular coupling reaction.58 Based on a modied Vilsmeier procedure for the synthesis of 3-(2-Nphthaloylacyl)indole derivatives, the GCDEF fragment 155 of diazonamide A has been prepared by a convenient route in multigram quantities.59 All these approaches represent remarkable strategies for the synthesis of natural polyoxazole alkaloids. The structural variety of the natural cyclic oxazole- and thiazole-containing secondary metabolites and their biological activities has attracted strong synthetic interest. Phorboxazoles A 156 and B 157 are two isomeric oxazole-containing macrolides isolated from the marine sponge Phorbas sp. endemic to the western coast of Australia. The total synthesis of phorboxazole B has been accomplished in 27 linear steps and an overall yield of 12.6%.60 The absolute stereochemistry found in C4C12, C33C38, and C13C19 fragments was established utilizing catalytic asymmetric aldol methodology, while the absolute stereochemistry of the C20C32 fragment was derived from an auxiliary-based asymmetric aldol reaction. All remaining chirality was incorporated through internal asymmetric induction, with the exception of the C43 stereocentre which was derived from (R)-trityl glycidol. After the C1C19, C20C38, and C39C46 subunits were accomplished, these fragments have been successfully assembled into natural phorboxazole B in 27 linear steps and 12.6% overall yield.61,62

Scheme 6 Reagents and conditions: a) n-BuLi, THF, toluene, 33%.

78 C, 70%; b) 2,4,6-trichlorobenzoyl chloride, Et3N, rt, 3h, 42%; c) K2CO3, 18-crown-6,

Shortly thereafter, a highly convergent, stereocontrolled total synthesis of ( )-phorboxazole A has been achieved in 27 steps, with an overall yield of 3%.63 Highlights of the synthetic venture include the use of modied PetasisFerrier rearrangements for the eective assembly of both the C11C15 and C22C26 cis-tetrahydropyan rings; the design, synthesis, and application of a novel bifunctional oxazole linchpin; and the preparation and Stille coupling of a C28 trimethylstannane. The rst total synthesis of the marine natural product phorboxazole C 158 occurring in the sea sponge Phorbas a. clathrata has been reported.64 The key steps of the convergent approach involved the 3,4-dichloro-5-ethoxycarbonylpyrrole2-carboxylic acid 159 conversion to an amide 161 with protected 4-(2-amino-1-hydroxyethyl)phenol 160, and the central oxazole was established by cyclodehydration of the acylaminoketone 162 (Scheme 7). Lissoclinum cyclopeptide alkaloids, e.g. westiellamide 164, have been successfully synthesized by cyclooligomerization of dipeptidyl oxazolines.65 Cyclodehydration of Cbz-valylthreonine methyl esters 165 with Burgess reagent allows access to cis- and trans-oxazoline segments 166, which proved to be an ecient entry to natural cyclopeptide alkaloids of the Lissoclinum class of marine natural products.

Since 1986, a large number of cyclic oxazole- and thiazolecontaining secondary metabolites have been isolated from cyanobacteria, sponges, ascidians, and other, predominantly, marine sources.66 Cyanophyceae, or blue-green algae, have proved to be a rich source of novel biologically active secondary metabolites. In particular, the genus Lyngbya has yielded an impressive array of structurally diverse compounds. Lyngbyabellin B 168, an analogue of the potent microlament-disrupter lyngbyabellin A 167, has been isolated as a minor metabolite from the marine cyanobacterium Lyngbya majuscula collected at Apra Harbor, Guam.67 It possesses slightly weaker cytotoxicity than 167. Lyngbyabellin B has also been isolated from cyanobacterium Lyngbya majuscula collected near the Dry Tortugas National Park, Florida.68 The rst total synthesis of lyngbyabellin A has been described involving the oxidative form of functionalized thiazole carboxylic acid units with CMD (chemical manganese dioxide) from the corresponding thiazolidines.69 Use of the functionalized thiazole 169 was initiated by removal of the Boc group with hydrogen chloride followed by coupling with Bocglycine using diethyl phosphorocyanidate (DEPC) to give the dipeptide 170. Ester saponication followed by condensation Nat. Prod. Rep., 2002, 19, 454476 463

with the -hydroxy acid fragment 171 using DCC in the presence of N,N-(dimethylamino)pyridine (DMAP) produced the depsipeptide 172. After cleavage of the allyl ester with Pd(Ph3P)4 in the presence of morpholine, coupling of the resulting carboxylic acid with the ,-dihydroxy thiazole fragment 173 produced the linear precursor 174. Finally, after removal of the TMSe group at the C- terminus by tetrabutylammonium uoride (TBAF) and then deprotection of the Boc group at the N-terminus with toluene-p-sulfonic acid (TsOH), the macrolactamization was eciently achieved using diphenyl phosphorazidate (DPPA, (PhO)2P(O)N3) to provide lyngbyabellin A (Scheme 8). Seven new metabolites, namely apramides AG 175181, have been isolated from a lyngbyastatin 2-producing strain of the marine cyanobacterium Lyngbya majuscula collected at Apra Harbor, Guam.70 The structures of these linear lipopeptides have been elucidated based on spectroscopic techniques and chiral chromatography of hydrolysis products. 464 Nat. Prod. Rep., 2002, 19, 454476

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%.

Marine organisms are prolic sources of halogenated secondary metabolites.5 As part of ongoing eorts to discover new anticancer compounds from marine sources, the lipophilic extract of a Panamanian variety of the cyanobacterium Lyngbya majuscula led to identify two new polychlorinated metabolites, pseudodysidenin 183, dysidenamide 184.71 Both compounds are closely related to dysidenin 182 isolated from the Australian specimens of Dysidea herbacea. ( )-Neodysidenin 185 was isolated from the marine sponge Dysidea herbacea (Keller 1889) collected on the Great Barrier Reef.72

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%.

It is noteworthy that neodysidenin is an epimer of pseudodysidenin 183 diering only at the C13 chiral center. Barbamide 186 is another example of polyhalogenated metabolites from the marine cyanobacterium Lyngbya majuscula. Recently, a new barbamide derivative, dechloroNat. Prod. Rep., 2002, 19, 454476 465

majuscula Harvey ex Gomont from Fingers Reef, Apra Harbor, Guam.75 This cyclodepsipeptide of mixed peptidepolyketide biogenesis bears a thiazoline ring anked by polyketide portions, one of which possesses an unusual methylation pattern. It is a remarkable cytotoxin in vitro as well as in vivo; however, the lack of selectivity limits its potential as an antitumour agent.

barbamide 187 was isolated from the original collection of L. majuscula.73 Subsequently bioassay-guided fractionation using a primary cell culture of rat neurons in a microphysiometer of inhibition of IL-1 stimulation of sPLA2 in hepatocarcinoma cells led to re-isolation of kalkitoxin 188, a novel neurotoxic lipopeptide, in small yield from various Caribbean collections of the marine cyanobacterium Lyngbya majuscula.74 Based on syntheses of kalkitoxins having all possible congurations, the absolute stereochemistry of natural kalkitoxin has been determined and assigned 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 466 Nat. Prod. Rep., 2002, 19, 454476

During the investigation of nostocyclamide from the freshwater cyanobacterium Nostoc 31, a new cyclic peptide, namely nostocyclamide M 190, was obtained.76 Mass spectrometric, chemical, and NMR studies showed that this compound has the same basic structure as the one for nostocyclamide, but the valine moiety is replaced by methionine. The total synthesis of dendroamide A 191, isolated from the cyanobacterium Stigonema dendroideum fremy, has been accomplished by modifying several peptide synthesis protocols and by using molecular modelling to select the precursor for the nal cyclization reaction.77 On the basis of the total synthesis of these cyclic peptide alkaloids, their biological activities appear to be highly dependent on the substitution pattern present at the side-chains of the initial amino acids. A wide ranging screen resulted in the isolation of a potent specic telomerase inhibitor designated as telomestatin 192 from Streptomyces anulatus 3533-SV4.78 Although telomerase consists of several components with DNA polymerase or reverse transcriptase activity in addition to its intrinsic telomerase component, telomestatin specically inhibited telomerase without aecting DNA polymerase and HIV-RT. Recent investigations of the sponge Haliclona nigra from Papua New Guinea have led to the isolation of two new cyclic hexapeptides, haligramides A 193 and B 194, in addition to the known peptide, waiakeamide 195.79 The structures of peptides 193 and 194 were elucidated by extensive NMR analyses and by comparison of their spectral data with those of 195. The identity of 193 was conrmed by its oxidative conversion into 195. A concise and convergent total synthesis of the polyene thiazole-containing 19-membered bis-lactone, ( )-pateamine 196, from the marine sponge Mycale sp., has been described.80 The synthesis features both the intra- and intermolecular Stille sp2sp2 coupling reactions to elaborate the E,Z-diene macrolide core and the side-chain all-E polyene portion, and highlights the scope for enantiopure sulnimine intermediates in the synthesis of chiral -amino ester moieties in complex structures. The rst asymmetric total synthesis of ( )-mycothiazole 197, a polyketide thiazole from the marine sponge Spongia

A total synthesis of the prenylated cyclopeptide trunkamide A 202 produced by ascidians of the genus Lissoclinum, and also its C45 epimer, has been described.83 The macrocycle in the natural product was elaborated to the trunkamide structure following Wipfs method and the thiazoline ring was produced in the nal step from the thioamide cyclic peptide.

mycojiensis, has been achieved.81 Key steps involved CMD oxidation for the conversion of a thiazolidine to thiazole and the Nagao acetate aldol reaction of 198 with aldehyde 199. The skipping diene was constructed by the standard Stille coupling reaction, and the conjugated diene was synthesized by lithium()- and copper()-mediated Stille coupling reaction. Study of the ascidian Lissoclinum patella (Order Enterogona, Family Didemnidae) has yielded two new closely related cyclic peptide alkaloids namely lissoclinamide 9 200 and lissoclinamide 10 201.82 Their structures were determined by a combination of 2D NMR, selective 1D TOCSY, MS and series-wound ESI-MS (MSn) techniques and the assignment of absolute stereochemistry was achieved by the hydrolysis of lissoclinamides followed by chiral TLC. In the case of lissoclinamide 9, NOE restrained molecular dynamic studies were also performed conrming the proposed stereochemistry.

The epothilones exhibit outstanding microtubule binding anities and cytotoxicity against tumour cells and multiple drug resistant tumour cell lines. The role of epothilones as potential paclitaxel successors has initiated intense interest in its synthesis, resulting in a number of total syntheses of epothilones and numerous derivatives thereof.84 Nat. Prod. Rep., 2002, 19, 454476 467

A highly convergent total synthesis of epothilone A 203 has been achieved, which utilized chiral silane-based bond construction methodology to introduce the key C6 and C7 stereocenters.85,86 A completely stereocontrolled total synthesis of epothilones A and B 204 has been reported in 21 steps and 18 steps, respectively.87 An alternative and concise total synthesis of epothilone A and C 207 involved a ring closing alkyne metathesis reaction catalyzed by a molybdenum complex followed by a Lindlar reduction of the resulting cycloalkyne product.88 Epothilone B and its (12R,13R) acetonide 210 have been prepared in a novel highly stereoselective total synthesis in which key intermediates have been constructed via Sharpless AD-reaction and DavisEvans-hydroxylation.89 Another total synthesis of epothilones B has been carried out, essentially based on well established methodology which starts from inexpensive materials.90

A total synthesis of epothilone B 204 and D 208 has been described in 18(17) steps for the longest linear sequence and with about 8% overall yield.91 The synthesis is highly convergent through coupling of the three fragments C1C6 211, C7 C10 212, and C11C21 213. After a series of synthetic eorts toward the epothilones, epothilone B, epothilone D, and cisand trans-9,10-dehydroepothilone D 214 have been fully stereoselectively synthesized.92 The macrolactonization-based strategy for the total synthesis of epothilones has been streamlined and improved to a high level of eciency and stereoselectivity. This strategy has been applied to the construction of a vinyl iodide which served as a common intermediate for the synthesis of a series of natural and designed epothilones including epothilone B10 205, epothilone F 206, 16-desmethylepothilone B 215, and related side chain modied epothilone B analogues.93 A practical, total synthesis of desoxyepothilone F 209 has been accomplished.94 In the approach, two consecutive aldol 468 Nat. Prod. Rep., 2002, 19, 454476

reactions were used to fashion the acyl sector 217. After this fragment had been prepared, the Suzuki coupling reaction with fragment 216 was conducted to give precursor 218, whereafter, sequential reactions gave the targeted product as outlined in Scheme 9. In order to gain further insight into the biological activities of the epothilones, the total syntheses of 12,13,15-desoxy15(S )-azaepothilone B and 12,13,15-desoxy-15(R)-azaepothilone B 221 have been accomplished utilizing a highly convergent strategy.95 Using fully synthetically derived lactams, in vitro and in vivo studies were conducted in comparison with the advanced clinical candidates, 12,13-desoxyepothilone B and 12,13-desoxyepothilone F. Four new cytostatic compounds, tubulysins A 222, B 223, D 224, and E 225, have been isolated from the culture broth of strains of the myxobacteria Archangium gephyra and Angiococcus disciformis.96 The tubulysins were not active against bacteria and only a little against fungi, but showed high cytostatic activity against mammalian cell lines with IC50 values in the picomolar range. Two new triene-ansamycins designated thiazinotrienomycins F (TTF) 226 and G (TTG) 227 and a new deene-ansamycin, benzoxazomycin, have been isolated from a culture broth of Streptomyces sp. MJ672-m3 and their structures have been elucidated through spectroscopic analyses.97 The tumour growth inhibitory activities of TTG appear almost as strong as TTB, in respect of GI50 and TGI against several human cancer cell lines. Steroidal compounds in the roots of Asclepias tuberosa have been investigated and ve doubly-linked cardenolide glycosides were isolated.98 Two of them were identied as 3 -spiro-linked thiazolidinone 228 and S-oxythiazolidinone derivatives 229 of 5-calotropin. Although thiazoline or thiazolidine derivatives

of doubly-linked cardenolide glycosides are known in A. fruticosa, 228 and 229 are the rst thiazolidinone derivatives.

Synthesis of the cruciferous phytoalexins, spirobrassinin 230 from the Japanese radish, has been enantioresolved by utilizing a chiral auxiliary method.99,100 The absolute conguration was unambiguously determined by X-ray crystallography of a (1 S,4 R)-camphanoyl derivative of ( )-230. Consequently, natural ( )-230 was ascertained to be of S-conguration.
Scheme 9 Reagents and conditions: a) i. 9-BBNH, THF, ii. PdCl2(dppf ), AsPh3, DMFTHfH2O, rt, 8h, 89%; b) i. TESOTf, 2,6lutidine, CH2Cl2, 78 Crt, 8h, ii. HClMeOH, 0 C, 78%; c) 2,4,6trichlorobenzoyl chloride, Et3N, then 4-DMAP, toluene, slow addition 3 h, 70%.

A total synthesis of yersiniabactin 231, a siderophore produced by the Gram-negative coccoid bacterium Yersinia enterocolitica, has been summarized.101 During the cyclization step of -hydroxythioamide to thiazoline, Burgess reagent was utilized to preserve chirality at the C9 carbon center, which can be readily made racemic. Based on this synthesis, the absolute conguration of natural yersiniabactin has been determined as 9R,10RS,12R,13S,19S. 4 Amaryllidaceae and Sceletium alkaloids

Several reviews on the isolation and total synthesis of Amaryllidaceae alkaloids have appeared during the 20002001 period. A single report on the occurrence of Amaryllidaceae alkaloids Nat. Prod. Rep., 2002, 19, 454476 469

in Urginea altissima has been questioned following a reinvestigation of this species.102 Four Amaryllidaceae species, including wild, cultivated and ornamental plants (Sternbergia lutea, Pancratium, Narcissus tazetta and Clivia nobilis) have been investigated for their content of alkaloids.103 In addition, three publications have outlined synthetic highlights of Amaryllidaceae alkaloids for the past year.104,105,106 Over the past year, fourteen new alkaloids have been reported and all of them belong to established frameworks. Eleven alkaloids have been isolated from fresh bulbs of Crinum macowanii.107 Macowine 232, which possessed a 5,10b-ethano bridge, was reported for the rst time along with the other known crinane-type alkaloids including crinine 233, krepowine 234, powelline 235, buphanidrine 237, lycorine 239, crinamidine 242, undulatine 243, 4a-dehydroxycrinamabine 244, 1-epideacetylbowdensine 245, cherylline 246.

Extract of the dried and powdered non owering whole plants obtained from Crinum moorei has produced thirteen alkaloids.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-acetyllycorine 240, crinamidine 242, undulatine 243, 1-epideacetylbowdensine 245, cherylline 246, and epivittatine 257. In the course of identifying the phenolic constituents of Crinum bulbispernum, a new alkaloid has been obtained, designated as hippacine 249.109 The alcoholic extract of the fresh bulbs of Cyrtanthus elatus has yielded two new alkaloids, namely zephyranthine 251 and 1,2-O-diacetylzephyranthine 252, together with three other known alkaloids galanthamine 253, haemanthamine 254, haemanthidine 255.110 Dry whole plants of Zephyranthes citrina contain eight crinane and lycorane type alkaloids, namely, lycorine 239, haemanthamine 254, haemanthidine 255, vittatine 256, maritidine 261, galanthine 262, narcissidine 264, and the new alkaloid oxomaritidine 260 which was reported for the rst time from a natural source.111 Two new benzophenanthridine alkaloids, namely 8-acetonyldihydronitidine 265 and 8-acetonyldihydroavicine 266 have been isolated from Zanthoxylun trtraspermum stem bark.112 Both of them showed signicant antibacterial activity while 8-acetonyldihydronitidine was strongly antifungal. A benzophenanthridine alkaloid, chelidonine 267, was also isolated from the fructus of Chelidonium majus.113 470 Nat. Prod. Rep., 2002, 19, 454476

The bulbs of Ammocharis coranica have yielded eight alkaloids.114 One is new, namely 1-O-acetyl-9-O-demethylpluviine 263. The other alkaloids identied were 6-hydroxypowelline 236, lycorine 239, 1-O-acetyllycorine 240, acetylcaranine 241, hippadine 250, hamayne 258, crinamine 259.

( )-3-epi-3,4-Dihydro-3-hydroxygraciline 268, isolated from Galanthus gracilis of Turkish origin, is a new member of the gracilines, a recently established subgroup of the Amaryllidaceae alkaloids. G. plicatus subsp. byzantinus has produced three new alkaloids, namely ( )-plicane 269, which is a new plicamine-type alkaloid, along with ( )-3-O-(3-hydroxybutyryl)tazettinol 270, and N-formylismine 271.115

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.

Enantioselective total syntheses of the antitumour alkaloids, ( )-narciclasine 272 and ( )-pancratistatin 273, have been achieved from a common phenanthridone intermediate 275 starting from commercial cyclohex-3-ene-1-carboxylic acid.116 Treatment of phenanthridone 275 with diphenyldiselenide NaBH4 and then H2O2 installed the requisite C3C4 unsaturation, and acylation of the free hydroxy groups furnished compound 276. Stereoselective cis-dihydroxylation and protection of the resultant diol gave 277. Selective deprotection of the hydroxy group at C1 followed by dehydration aorded compound 278 in good yield. Ultimately, ( )narciclasine 272 was obtained after a series of deprotection steps (Scheme 10). Compound 279 was derived from 275 in straightforward fashion, followed by protection as a benzyl ether to give compound 281. Treatment with PhSe2, NaBH4, and then H2O2 aorded allylic alcohol 282. Routine cisdihydroxylation gave 283 in good yield. Exposure of 283 to Pd(OH)2CH2 in EtOH resulted in the penultimate intermediate 284. Finally, the synthesis of ( )-pancratistatin 273 was completed by treatment of 284 with LiClDMF to remove the C7 methyl group protection (Scheme 11). A new total synthesis of ( )-7-deoxypancratistatin 274 has been accomplished in 19 steps (8% overall yield) from two readily available compounds, furan and trans-1,2-bis(phenylsulfonyl)ethylene.117 Ring opening of an enantiomerically pure

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

7-oxanorborenic system and intramolecular lactonization with concomitant oxirane opening constituted two key steps of the synthesis. ( )-Narciclasine, as it is available in practical quantity from the bulbs of certain Amaryllidaceae species, has been employed as 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 Nat. Prod. Rep., 2002, 19, 454476 471

described enlisting a tetrazine diazine benzene strategy featuring a two sequential intramolecular [4 2] cycloaddition reaction of an asymmetrical 6-(acylamino)-1,2,4,5-tetrazine 119 (Scheme 12).

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 ) RaNi, 97%; g) DDQ, 65%; h) RedAl, O2, 82%.

A new strategy for the synthesis of the Amaryllidaceae alkaloid family has been developed based in part on an intramolecular DielsAlder reaction of a furanyl carbamate for initial construction of the hexahydroindolinone core.120 Taking advantage of an intramolecular DielsAlder reaction of an alkenyl-substituted furanyl carbamate derivative 294, the IMDAF cycloadditionrearrangement cascade was successfully used in the total synthesis of ()--lycorane 292 and also ()-1deoxylycorine 293 as outlined in the Scheme 13. Construction of the ABCD tetracyclic skeleton of the Amaryllidaceae lycorine-type alkaloids has been devised via an ionic domino reaction involving orthoquinol acetate moieties.121 Exploitation of the electrophilicity and dierentially activated double bonds led to the development of a new methodology aimed at the regiochemical controlled construction of fused heteropolycycles. Novel radical cyclization reactions, mediated by tributyltin hydride, samarium() iodide or manganese() acetate, have been explored to form tri- and tetra-cyclic ring systems related to the Amaryllidaceae or Erythrina family of alkaloids.122 Haloethanamide precursor 298, possessing a cyclohexenone ring has been shown to form octahydroindolone 299, and erythrinane-type systems could be formed from precursor 300 bearing unsaturated side-chains in tandem cyclizations. Oxidative radical cyclization of -methylthioamide 301 with Mn()/Cu() mediation could also be applied to a concise construction of an erythrinane skeleton 302.123 Two conceptually similar routes to the galanthamine ring system 253 have been reported, which utilized an intramolecular Heck reaction to establish the benzofuran ring system present in both galanthamine and morphine.124,125 The total synthesis of galanthamine has also been completed, which utilized an intramolecular phenolic reaction using hypervalent () iodine reagent phenyliodine() bis(triuoroacetate) (PIFA).126 The action of phenyliodine() bis(triuoroaceate) (PIFA) has also been applied to an ecient approach to benzo[c]472 Nat. Prod. Rep., 2002, 19, 454476

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.

phenanthridines 303 and phenanthridinones 304 from properly substituted benzylnaphthylamines and naphthylbenzamides, respectively.127 PIFA promoted a non-phenolic oxidative biaryl coupling process, the key step of the synthesis. The total syntheses of trisphaeridine 305, norchelerythrine 306, chelerythrine 307 and 12-methyloxydihydrochelerythrine 308, fully aromatized phenanthridine and benzo[c]phenanthridine alkaloids, have been accomplished via the intramolecular arylaryl coupling reaction.128,129 Norchelerythrine arylhalo amide 309 protected by a methoxymethyl group was converted into an NMOM lactam 310 with the assistance of a Pd reagent, followed

Approaches toward total synthesis of montanine-type Amaryllidaceae alkaloids using hexahydro-1H-indol-3-one 315 as key intermediate have been studied.131 Compound 318, prepared from 316, was treated with n-butyllithium followed by acidic workup to give compound 319. FriedelCrafts-type cyclization of 319 was eected with triuoromethanesulfonic acid to aord montanine-type alkaloid skeleton 320 as depicted in Scheme 15.

by reduction with lithium aluminium hydride and then treatment with hydrochloric acid to result in natural product. A new direct route to benzo[c]phenanthridines has been systematically studied via a promising CN bond cleavage.130 Treatment of the readily prepared N-ethoxycarbonylbenzylideneisoquinoline 311 with LDA resulted in cleavage of the C3N bond, giving the styrylurethane 312. Thermal electrocyclization of 312 aorded the 2-phenylnaphthalene derivative 313, BischlerNapieralski cyclization of the N-methyl derivative gave the expected benzo[c]phenanthridine 314 (Scheme 14).

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%.

A formal total synthesis of the montanine-type alkaloid ()-pancracine 321 has been achieved with full regiocontrol 132 Reaction of a -nitrostyrene with cyclohexane-1,3-dione in the presence of DBU aorded the Michael-addition product 322, which was readily elaborated, using straightforward manipulations, into the 5,11-methanomorphanthridine 323, acquisition of which constituted a formal total synthesis of the racemic modication of the montanine alkaloid pancracine 321.

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

A concise total synthesis of cherylline 324, isolated from Crinum powellii var. alba and other Crinum species, has been developed utilizing the addition of Grignard reagents to nitrostyrene derivatives as the key sep.133 Reaction of a -nitrostyrene derivative with the Grignard reagent generated from 4-bromoO-benzylphenol (Scheme 16) furnished nitro compound 325. Reduction of the addition product with LAH gave amine 326. Nat. Prod. Rep., 2002, 19, 454476 473

The reaction of the amine with formaldehyde and formic acid gave the expected isoquinoline skeleton. The nal step of synthesis was accomplished by hydrogenolytic removal of the benzyl protecting groups to give ()-cherylline 324 (Scheme 16).

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

The total synthesis of cherylline has also been achieved utilizing an intramolecular cyclization of N-(arylmethyl)N-methyl-2-aryl-2-(phenylsulnyl)acetamide 327 under Pummerer reaction conditions as a key step.134

Scheme 17 Reagents and conditions: a) O3, Ph3P, TsOH, benzene, Dean stark, 83%; b) LAH, THF, 87%; c) Na, NH3, THF, 78 C, 86%; d) MsCl, Et3N, Et2O, 84%; e) MeNH2, H2O, THF, MnO2, CH2Cl2, 68%.

5
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

References
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The Sceletium alkaloid mesembrine 328 has been totally synthesized in 13% overall yield by a sequence featuring a [4 1] cycloaddition of a bis(alkylthio)carbene with funtionalized vinyl isocyanate.135 Thermal decomposition of dithiooxadiazoline 329 gave the corresponding carbene, which underwent cycloaddition with -aryl-substituted vinyl isocyanate 330 to aord hydroindolone 331. Subsequent desulfurization and enamide reduction completed the synthesis of mesembrine. The cyclic quaternary centre of ( )-mesembrine has been enantioselectively constructed via an intramolecular alkylidene CH insertion reaction.136 Ozonolysis of compound 332, prepared by an intramolecular alkylidene CH insertion reaction, gave the intermediate keto aldehyde. The intramolecular aldol reaction and subsequent dehydration yielded the cyclohexenone 333, then reduced to the alcohol 334. Debenzylation produced the primary alcohol 335, which was then converted selectively into the mesylate 336. Amination, oxidation, and cyclization then gave ( )-mesembrine (Scheme 17). 474 Nat. Prod. Rep., 2002, 19, 454476

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