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Amaryllidaceae, Sceletium , imidazole, oxazole, thiazole, peptide

and miscellaneous alkaloids

John R. Lewis

Department of Chemistry, University of Aberdeen, Meston Walk, Old Aberdeen,

UK AB24 3UE

Received (in Cambridge, UK) 10th October 2001

First published as an Advance Article on the web 4th February 2002

Covering: July 1999–June 2000. Previous review: 2001, 18 , 95.

This review covers alkaloids classified in the plant families Amaryallidaceae and Sceletium. In addition alkaloids possessing imidazole, oxazole and thiazole structures are listed followed by alkaloids possessing peptide linkages. Finally miscellaneous alkaloids include those compounds found naturally which cannot be classified into known groups; a relative Pandora’s box. A total of 620 structures has been reviewed from 218 references found in the literature for the period July 1999 to June 2000.

1 Introduction 2 Amaryllidaceae alkaloids 3 Imidazole, oxazole and thiazole alkaloids 4 Peptide alkaloids 5 Miscellaneous alkaloids 6 References

1 Introduction Nature offers phytochemists a cornucopia of delights, every year new alkaloid structures are reported, some are extensions of existing frameworks but others are completely new. Existing frameworks are often targeted because of pharmaceutical activ- ity. The diversity of sources for alkaloids is immense, some are new, others are being reinvestigated, thus allowing the newer analytical and pharmacological techniques to be used to the fullest extent. Even well established sources of alkaloids may demand reinvestigation as smaller quantities of alkaloid are now required for structure elucidation. This chapter contains a number of new structures to further the encyclopedia of organic substances. Note in particular tuber- culosis is increasingly becoming virulent again especially since the bacteria are developing resistance to normal treatment. A review article outlines the role that marine natural products play in producing metabolites with antituberculosis activity. 1

2 Amaryllidaceae alkaloids Eighteen new alkaloids have been reported during the 1999– 2000 period. Most belong to established groups but two have a new lactone structure (see 22 , 23 ).

Dr Lewis graduated at Uni- versity College, Swansea; was Fulbright Fellow in 1958 at University of Iowa, Ames, later becoming Senior Lec- turer in Organic Chemistry at Aberdeen University. He is now retired.

John R. Lewis

Gas chromatography using capillary columns has been shown to be a quick, twenty-five minute, procedure for deter- mining the Amaryllidaceae alkaloids present in Crinum lati- folium. Fifteen and thirty metre DB-5 columns were used and only small quantities of dried plant material were needed for this procedure. 2 This technique could well be used in a much broader coverage using other plant extracts not only of the Amaryllidaceae family. In reviewing the alkaloids found in the Amaryllidacea genera Boophane, Brunsvigia and Crinum an appraisal and retesting of these alkaloids for antimalarial and cytotoxic activity has led to a broad generalisation; namely that the 5,10b-ethanophen- anthridine structure is useful for activity. Crinamine 1 , which has an α-configuration, is the most active. 3

Sixteen alkaloids have been isolated from the fresh bulbs of Ammocharis tinneana. 4 Seven of these contain the 1,2β-epoxide grouping. Of these seven two, 6α-hydroxycrinamidine 2 and 6 α-hydroxyundulatine 3 are new, the others are 1,2β-epoxy- ambiline 4 , 11- O -acetyl-1,2β-epoxyambiline 5 , 3,4-flexinine 6 , crinamidine 7 and undulatine 8. Other alkaloidal constituents were lycorine 9 , sternbergine 10 , 9- O -demethylpluviine 11 , ambelline 12 , 11- O -acetylambelline 13 , crinine 14 , powelline 15 , buphanidrine 16 and buphanisine 17. The bulbs of Brunsvigia radulosa contain eight alkaloids namely 1-epidiacetylbowdensine 18 , crinamine 1 , crinine 14 , hamayne 19 , lycorine 9 , anhydrolycorin-6-one 20 , sternbergine 10 , and the new alkaloid 1- O -acetylnorpluviine 21 which inci- dentally showed good cytotoxic activity towards BL6 mouse melanoma cells. 5 Two new masanane type alkaloids both containing a lactone ring have been found in a fresh whole plant extract of Clivia nobilis. 6 Nobilistine A is 22 and nobilistine B is 23 , both being

DOI: 10/b007741k Nat. Prod. Rep. , 2002, 19 , 223–258 223 This journal is © The Royal Society of Chemistry 2002

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identified by spectroscopic analysis. The interesting features are that they are epimeric at C-3a, 5a and llc, the normal mansonine structure is that associated with 3β, 5α, 11β. The ester functionality of 23 i. the 3-hydroxybutoxy grouping is unusual. Structure determination of 22 and hence 23 was helped by producing acetate 24.

Extracts of dried whole plant material obtained from Crinum bulbispermum has produced six alkaloids. 7 Three are new, namely 8α-ethoxyprecriwelline 25 , N -desmethyl-8α-ethoxy- pretazettine 26 and N -desmethyl-8β-ethoxypretazettine 27. The other alkaloids identified in the extract were crinamine 1 , bulbi- spermine 28 3- O -acetylhamayne 29 and 6-hydroxycrinamine 30.

Two novel dinitrogenous alkaloids have been isolated from whole, dried plant material obtained from Galanthus plicatus. 8 They possess the basic tazettine ring system but the oxygen atom at position 7 has been replaced by nitrogen. The alkaloids have been named ()-plicamine 31 and ()-secoplicamine 32.

Three new tazettine type alkaloids have been isolated from two Turkish Galanthus plants. ()-Isotazettinol 33 and ()-3- O -demethyl-3-epimacronine 34 were found in Galanthus graci- lis , while ()-3- O -demethyl-3-epimacronine 34 was also found in Galanthus plicatus subspecies byzantinus. The known base, trispheridine 35 , was also found, for the first time in a Galanthus genus. 9

Hippeastrum equestre bulbs have, upon extraction, yielded two new alkaloids. 10 They are 3- O -demethyltazettine 36 and ergonine 37 also present with tazettine 38 and tazettadiol 39.

A separation of the quaternary benzo[ c ]phenanthridine alkaloids found in Macleaya cordata has identified sanguin- arine 40 , chelerythrine 41 and 8- O -demethylchelerythrine 42. 11 Two phenanthridine alkaloids have been obtained from the dried stem bark of Zanthoxylum myricanthum. 12 They are N - nornitidine 43 and its new 7,9-dimethoxy-regioisomer, alkaloid

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The total synthesis of ()-haemanthidine 83 , ()-pret- azettine 84 and ()-tazettine 38 , as optically pure enantiomers, has been reported. 21 Starting with -mannose the critical relative stereochemical relationships were established with an intramolecular nitrone-alkene cycloaddition reaction. Bromo- diol 85 (prepared in 55% yield from -mannose) was converted to hexene 86 which enabled the methylene dioxybenzene group-

Scheme 1 i. E. coli JM109 (pDTG601A), 4 g l 1 ; ii. DMP, acetone, TsOH, rt then ONHCO 2 Me, NaCO 4 , rt; iii. 62 , Pd(PPh 3 ) 4 , aq. Na 2 CO 3 , PhH, reflux; iv. MO(CO) 6 , MeCN, H 2 O, reflux; v. NaBH 4 , CeCl 3 , MeOH, 0 C; vi. BzOH, Bu 3 P, DEAD, THF, rt; vii. Dowex 50X8–100, MeOH, rt then Ac 2 O, py., DMAP, rt; viii. Tf 2 O, DMAP, CH 2 Cl 2 , 0 C; ix. Amberlyst A21, MeOH, rt then LiCl, DMF, 120 C. ing (Ar) to be added giving 87. At this stage incorporation of ( S )-α-methylbenzylhydroxylamine oxalate created adduct 88 which was converted into 90 via 89. Reduction and methylation produced 91 which could thus be converted into the three alkaloids by established methods.

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(±)-Cherylline 93 and (±)-latifine 94 are representatives of the rare phenolic alkaloids found in the Amaryllidaceae plant family Crinum. The isoquinoline nucleus of these alkaloids has been neatly synthesised by Fries rearrangement of ester 95 which in turn is prepared from syringaldehyde and 4-hydroxy- benzoic acid. 22 The rearrangement of 95 was promoted by butyllithium at 78 to 50 C, the resulting benzophenone alcohol 96 was oxidised to its aldehyde and then to acid 97. Phosphorylated amine 98 was added to create amide 99 which cyclised to 4-arylisoquinolone 100 through treatment with butyllithium. Removal of the protecting groups gave either 93 or 94.

()-Mesembrine 101 has been synthesised by a procedure involving a transition metal promotion of carbon to carbon bond formation. Thus cyclisation of cyclobenzylamine 102 was achieved using a large protecting group on nitrogen which when treated with a zirconium (Cp 2 ZrBu 2 ) followed by methyl- magnesium bromide and then oxygen, all in a one pot pro- cedure, generated 103. The yield for 103 was 63%. Modifi- cation of the functionalities of 103 resulted in the formation of ()-mesembrine 101 or ()-mesembrane 104. 23

3 Imidazole, oxazole and thiazole alkaloids A new natural product isolated from Cistanche deserticola is claimed to be (2,5-dioxoimidazolidin-4-yl)carbamic acid 105. Confirmation of its structure was obtained by single crystal X-ray diffraction. 24 The synthesis of leucettamine B 106 has been achieved by two procedures. 25 The first involved an oxazolone intermediate whereby glycine was converted into the target compound 106 in three steps. Its reaction with S -ethyl- N - methylisothiouronium bromide 107 in ethanolic solution containing triethylamine produced 108. Addition of piperonal resulted in a mixture of Z – E isomers of 106 the natural product predominating by 9 to 0. The second route involved thiohydantoin 109 which readily condensed with piperonal to give stereochemically pure ( Z )-4-(3,4-methylenedioxyphenyl)- methylene-2-thiohydantoin 110 which upon S -methylation and then treatment with ammonia produced 106. The yield was 92%.

A red ascidian identified as Botryllus leachi has been found to contain two novel pyrazine alkaloids namely botryllazine A 111 and botryllazine B 112. The other alkaloid present was also new and is 2-( p -hydroxybenzoyl)-4-( p -hydroxyphenyl)imidazole 113. 26 Chrysophysarin A 114 is a yellow, optically active, pig- ment isolated from the microplasmodia of the slime mould Physarum polycephalum. 27 The pigment’s structure was deter- mined by NMR studies and its absolute configuration, that of S , was established by comparison of the CD spectra of the natural product with that of ( R )- and ( S )- N -(3,3-dimethyl- acryloyl)leucine methyl esters. The biosynthesis of this alkaloid has been shown to be from four intact acetate units one of which is incorporated by condensation with valine to give leucine. A fragmented acetate accounts for C-21. Histidine is also implicated, clearly.

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The Verongia aerophobia sponge is well known for its produc- tion of fistularin-3. A recent re-examination 33 of extracts of fresh and dried samples of this sponge has shown a stereo- isomer of fistularin-3 namely 134. Also identified in the extract was the new diene 135.

The total synthesis of racemic phthoxazoline A 136 has been achieved by a convergent series of palladium catalysed cross coupling reactions to construct the Z , Z , E trienyl unit found in the natural product. 34 Oxazole unit 138 was prepared from stannane alcohol 137 using tosylmethylisocyanide. When it was condensed with iododiene 139 , through the Stille coupling procedure, it gave 136 in racemic form. Synthesis of the iodo- diene 139 was elegantly achieved through coupling of the iodo- amide 140 with vinylboronate pinacol ester thus giving 141 , deprotection allowed iodine to be introduced, through iodine monochloride, at the diene terminus and thence to racemic phthoxazolin A 136 via 138.

After many dead ends the total synthesis of rhizoxin D 142 has been accomplished through the following. 35 First aldehyde 143 was condensed with boronate 144 to give 145 , Dess–Martin oxidation gave the ketone which with β-ketophosphonate pro- duced 146. Addition of aldehyde 147 thus gave triene 148 and hence 149. Triol 150 was manipulated to produce sulfonate 151 thus allowing condensation with 149 to give 152 , conversion to phosphonate 153 and Dess–Martin oxidation gave aldehyde 154 which under Horner–Emmons conditions cyclised to macrocycle 155. Removal of the protecting groups and oxid- ation produced rhizoxin D 142.

The calyculins have a variety of physiological properties thus the interest in synthetic approaches to the series. Two publi- cations give in detail an attempt to synthesis ()-calyculin A 156 and ()-calyculin B 157. It resulted in the creation of their antipodes. The papers are worth reading purely for the breadth of synthetic diversity that the project demanded. 36,37 It is unusual for a patent to be taken out on a synthesis of a natural product which involves something like twelve steps. Never- theless that has happened 38 with exochelin 786SM(R) 158. Of seventeen metabolites isolated from an undescribed marine sponge of the genus Pachastrissa five are bengamide and eleven are bengazol related. Only bengazoles 159 to 169 possess anti- fungal properties. 39 The bengamides isolated were A 170 , B 171 , E 172 , F 173 and a new one L 174. A first total synthesis of bengazole A 175 was designed upon a selective electrophilic addition to the serine nucleus. 40 In the first reaction oxazole was lithiated at the 2-position 176 and then reacted with aldehyde 177 to give a separable diastereo- meric mixture 178. Conversion of the wrong epimer to its ketone and sodium borohydride reduction gave again a mix- ture which as before was separated by HPLC. Application of the Mitsunobu inversion procedure to the ‘wrong’ isomer gave better yields of the required synthon 178 6 β. Oxazole 5-aldehyde 179 was ultimately condensed with 177 by first

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reacting it with fresh borane–THF complex at 25 C followed by butyllithium at 78 C to give 180. This mixture of enantiomeric alcohols could not be separated and was acylated with myristoyl chloride to give epimeric bengazole A 175.

Antitumour BE-70016 is produced by an Actinoplanes bac- terium in shake culture. Compound 181 appears to be useful in the control of human and mouse tumours. 41 A total synthesis of ()-hennoxazole A 182 has been reported utilising the cyclis- ation of a serine intermediate 183 to oxazoline 184 with diethylaminosulfur trifluoride and then its oxidation with DBU in bromotrichloromethane to oxazole 185. Addition of a second serine unit followed by a similar conversion procedure gave dioxazole 186. Stannane 187 was trans metallated with 188 which upon addition of the acid counterpart of 186 gave 189. Conversion of the alkene to β-methoxy was followed by mild acid treatment which resulted in the formation of a single tetrahydropyran isomer 190. Synthesis of the terminus grouping 191 and its activation through sulfone 193 thus allowed condensation with aldehyde 191 derived from 190 to give hennoxazole A 182. 42 The stereochemistry of the mycalolides has been estab- lished through a comparison of the NMR spectra of three related metabolites isolated from the marine sponge Mycale

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into its α-enantiomer. Conversion to diene 215 allowed acid 216 to be added to give diene ester 217. Metathesis of 217 with Grubb’s catalyst created macrocycle 218 which by further established procedures led to epothilone E 219. 49 Intended to be a total synthesis of the macrolide thiazole 220 keramide J or what was thought to be keramide J has resulted in a different compound and there is thus a need for a reexamin- ation of what the structure is for this metabolite. 50 It probably is a configurational isomer at C13. Cystothiazole analogues can be produced by culturing the slime-forming bacterium Cystobacter fucus (FERMP-15997).

A patent 51 describing these fungal agents designates them as C 221 , D 222 , E 223 and F 224. Agrochelin is a new cytotoxic alkaloid obtained from a marine bacterium of the Agrobacterium family. Metabolite, 225 , chelates zinc() ions and it was obtained by extraction of the mycelium of this microorganism. 52 Melithiazoles A to N are antifungal metabolites found when the gliding bacteria Melithangium lichenicola, Archangium gephyra and Micrococcus stipitatus are cultured. 53 The structures of these thiazoles are based on a triazole-thiazoline structure e. A is 226 and D, K

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and L are related. Melithiazole B is 227 and E, F, G, H, I and M are related to it, but melithiazole C has only one thiazole ring 228 and is the first representative of its class. The total synthesis of thiangazole 229 which is a tris- thiazoline-oxazole alkaloid, was achieved by producing the linear peptide 230 by conventional means and upon treatment with titanium tetrachloride simultaneous dehydration of the three deprotected cysteine residues resulted in trithiazoline formation. Dess–Martin oxidation produced ketone 231 which with toluene- p -sulfonic acid gave oxazoline 232 , DDQ oxid- ation gave thiangazole 229. 54 The total synthesis of microcidin 233 was successfully con- cluded by assembling thiazole 234 with cysteine derivative 235 whereby cyclisation with trifluoric acid produced thiazoline

236. Oxazole ring opening and condensation with 237 produced 238 which upon hydrolysis and treatment with zinc chloride solution produced complex 239. In this process the complex caused isomerization of the C-10 configuration resulting in a 3 : 1 ratio of 9 R : 9 S at C-10. Hydrolysis and purification by HPLC of the product gave microcidin 233. 55 The first total syn- thesis of micrococcin P 24056 resulted by constructing the cen- tral 2,3,6-tristhiazolyl-substituted pyridine skeleton followed by condensation with protected ethyl threonylaminoprop-2-enyl- thiazole-4-carboxylate and protected threonylaminopropanol to give a protected fragment 241. BOP mediated cyclisation of compound 241 , upon removal of the protecting groups, gave the natural product 240.

A new unnamed antitumour compound has been obtained from a culture of Streptomyces nobilis. 57 Its structure is reported as 242. GM-95 is an antitumour substance obtained from Streptomyces anulatus 58 by shake culture. Its structure has been formulated as 243. Methylsulformycin 1 244 is a new antibiotic containing three oxazole and two thiazole rings in its macrolide ring. It was obtained from the fermentation of Streptomyces species HIL Y-9420704. It appears to have good in vitro activity against a number of virulent organisms. 59

4 Peptide alkaloids A trichloroleucine derivative called herbacic acid 245 has been extracted from the sponge Dysidea herbacea found on the Great Barrier Reef. 60 Recent biosynthetic observations suggest that probably the pro-S -methyl group of leucine is the site of halogenation. Muricatisine 246 is a new alkaloid found in two species of Oxytropis. The epigeal parts of Oxytropis muricata and of Oxytropis puberula both yielded quantities of this alkaloid. 61

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WF14861 261, a new inhibitor to cathepsins B and L, was found in the mycelium of strain No 14861 of a Colletotrichum fungus. 69 An enantiomeric synthesis of ()-LL-C10037α 262 employs enzymes to yield a single stereoisomer. 70 Thus racemic epoxide 263 was resolved by exposure to Candida rugosa in toluene–isopropenyl acetate whereby only ()- 263 was acetylated and therefore easily separated from its enantiomer. ()- 263 was treated with sodium azide to realise 264 which was epoxidised and a second epoxide created by HBr elimination to give 265. Conversion of azide to acetamide 266 and Dess– Martin oxidation of 266 gave the corresponding ketone which spontaneously rearranged to ()-LL-C10037α 262.

A precursor of oudenone 267 has been identified as the α-diketone 268. Through feeding experiments in growing cul- tures of Oudemansiella radicata the deuterated precursor 268 of endonone was obtained labelled at the appropriate carbon atoms as indicated. 71 Stresgenin B 269 is produced by Streptomyces sp. AS-9. It has the ability to protect cells from heat shock. 72 The total synthesis of korormicin 270 leads to the establish- ment of its absolute configuration. 73 Starting with oxirane 271

triflate formation allowed lithium acetylide to make 272 and thence to its bromo-derivative 273 which with palladium catalysed hydrostannation gave E -vinylstannane 274. Addition to iodoester 275 produced diene 276 which upon removal of the ester and protecting group 277 allowed condensation with amine 278 to give korormicin 270.

The structural elucidation of UCK14A, which is a cell cycle inhibitor produced by a Streptomyces species, has indicated a unique combination of the novel amino acid 3-(2-amino- cyclopropyl)alanine and a β-lactone resulting in structure 279. The absolute configuration was also obtained by investigating the component parts e. alanine by chiral GC–MS while the acyl side chain and amino acid were determined by conform- ational and configuration analysis – the Matsumori method as modified by Moscher. Synthesis confirmed the assignments. 74

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A Streptomyces species MER-88 produces the benzopyran amide 280 which has immunosuppressive properties and it is suggested that it might have use in the treatment of asthma and rheumatoid arthritis. 75 Two ten-membered lactones, with cytotoxic activity, have been found in a species of the gliding bacterium Chondromyces. 76 Called epicularen A and B they incorporate a salicylic acid moiety and are 281 and 282 respect- ively. Identifying the bacterium as Chrondromyces robustus allowed these authors to patent these metabolites. 77

A total synthesis of (±)-nisamycin 283 using a convergent approach 78 involves starting with 2,5-dimethoxyaniline which was protected thus allowing hypervalent iodine to oxidise it to dieneone 284. Epoxidation with DBU and TBHP gave chemoselectively 285. Vinyllithium introduced the appropri- ate side chain again stereospecifically to give 286. Thereafter appropriate side chain attachments created racemic 283.

Mukanadins A, B and C are new bromopyrrole amide alkaloids found in the Marine sponge Agelas nakamuri. 79 Structure determination by NMR, UV and MS measurements established their structures as 287 , 288 and 289 respectively. Another species of Agelas namely wiedenmeyeri , also a marine sponge, contains another new bromopyrrole alkaloid 290 also present was 4,5-dibromopyrrole-2-carboxylic acid and oroidin 113 loc cit. 80 Tokaramide A 291 is a new cathepsin B inhibitor isolated from the marine sponge Theonella cf mirabilis. 81 Hemiasterlins are a class of antitumour agents previously and currently found in sponges of the Auletta genus. They have also been present in two collections of Siphonochalina species 82 where they were accompanied by a new hemiasterlin C 292.

The cyanobacterium Microcystis aeruginosa produces a number of protease inhibitors, 83 all are aeruginosin type peptides. A new inhibitor is designated kasumsigamide, which is an anti-green algal peptide with structure 293.

Slagenins A, B and C have also been obtained from the marine sponge Agelas nakamurai. They possess 84 a unique tetrahydrofuro[2,3- d ]imidazolidin-2-one moiety as indicated in formula 294 , 295 and 296. Of the three only B and C show cytotoxic activity. Antifungal dilactone UK-2A which was found in the mycelial cake of Streptomyces species 51502 contains a nine- membered lactone ring attached to a picolinic acid moiety 297. It has been synthesised using the Evans aldol reaction to create stereospecific carboxylic acids which were lactonised prior to combination with the required picolinic acid. 85 Mycalamide D 298 is a new cytotoxic amide obtained from a New Zealand sponge of the Mycale family. 86 It is the C 13 - O - methyl derivative of mycalamide A 299.

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the antifungal activity claimed for compounds PF1163B and PF1163A, both of which are produced by the fungus Peni- cillium PF1163 (FERMP-15473), a patent protecting their commercial development has been taken out. 94

Antitumour substance BE-67251 320 is produced by culti- vation of Streptomyces species A67251 under shake culture conditions. A mutant strain of this micro-organism also pro- duced this P-388 leukemia inhibitor. 95 Madangolide 321 and laingolide A 322 are novel macrolides produced by the blue green coloured alga Lyngbya bouillonii. 96 A South China sea alga Sargassum vachellianum has been found to contain an alkaloid with a high nitrogen content. A

trilactam structure 323 has been proposed for this unnamed metabolite. 97 Two bioactive metabolites isolated from the marine sponge of the Stelletta family 98 have been called bistellettadine A 324 and bistellettadine B 325. Their name implies that they are dimers of stellettadine A 326. Anchinopeptolide D 327 is also a dimeric alkaloid which is presumed to be formed from tri- peptide 328. Its synthesis, by a biomimetic procedure, 99 involved aldol dimerization of 329 , a protected modified 328 , the reaction taking place in alkaline methanol at 0 C in twenty minutes. Removal of the protecting groups gave 327 in 45% overall yield. The first total synthesis of (±)-colobomycin D 320 proceeded by coupling bromotriene 331 with stannane 332. This procedure which had been developed for synthesis in the alisamycin and manumycin group of alkaloids also worked in this case. 100

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Two new macrocyclic spermine alkaloids of the ()- aphelandrine type have been obtained from the extracts of roots of Aphelandra fuscopunctata. 101 They are ()- N (6)- hydroxyaphelandrine 333 and ()- N (6)-acetoxyaphelandrine 334. Cyclopeptides glabrin C 335 and glabrin B 336 have been found in the seeds of Annona glabra. 102 By conventional peptide analyses their structures have been determined as [cyclo(prolyl-

glycyl-tyrosyl-valyl-leucyl-alanyl-leucyl-valyl)] and [cyclo(prop- yl-prolyl-valyl-tyrosyl-glycyl-prolyl-glutamyl)] respectively. The Ecuadorian medicinal plant Heisteria nitida contains two cyclopeptide alkaloids, 103 one is integerrenine 337 and it is accompanied by the new alkaloid anorldanine 27- N -oxide 338. Two cyclopeptide alkaloids found in the bark of both Scutia buxifolia and Discaria febrifuga 104 are waltherine A 339 and waltherine B 340. Related waltherine C 341 has been isolated from the bark of Waltheria douradinha. 105

RA-VII is a bicyclic hexapeptide 342 its potent antitumour activity operating by inhibiting protein synthesis through eukaryotic ribosomal binding. Its synthesis is reported 106

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Four papers 107–110 describe the events leading to the total synthesis of vancomycin 351 , the first discusses the design and development of the methodology, the second and third the actual synthesis of the aglycone of vancomycin while the fourth paper describes the attachment of the sugar moieties. On the basis of synthetic studies, 111 a revised structure for the red arcidian chromophore has been proposed. It is 352 and differs from the previously proposed structure where the naphthoamide was attached β-at site b. Amathaspiramides A to F were obtained from the marine bryozoan Amathia wilsoni. 112 An X-ray crystallographic anal- ysis on amathaspiramide F indicated structure 358 the others were assigned as A 353 , B 354 , C 355 , D 356 and E 357. The successful realisation of the total synthesis of cyto- chalasin D 359 meant that the method could be adapted for the synthesis of cytochalasin O thus confirming its structure as 360. This synthetic scheme 113 made use of the Diels–Alder reaction whereby diene and dienophile were incorporated into one molecule 361 whereupon heating in toluene to 80 C caused 362 to be formed. Further adjustments resulted in the natural products being produced.

A Streptomyces strain (unquoted) is reported 114 to produce a series of physiologically active metabolites again unnamed. Structure 363 is proposed where R is H or lower alkyl and these compounds are said to have a use as antitumour, antiallergy, autoimmune and organ transplant rejection agents!

The total synthesis of five cryptophycins has been reported. 115 These macrocyclic depsipeptides were first reported in blue green alga (cyanobacteria) of the Nostoc family. A typical example is 364 which has been assembled from an

amino acid segment 365 and the substituted dienoic acid 366 both of which required stereochemical control in their syn- thesis. Coupling of 365 and 366 was first through ester form- ation followed by macrocyclic lactamization – the result was cryptophycin 4 364.

Xanthobaccin antibiotics produced by the fungus Xantho- monas species SB-K88 are reported to have excellent antifungal properties. 116 Three compounds are described xanthobaccin A 367 , xanthobaccin B 368 and xanthobaccin C 369. Cyclic peptide YM-175201 370 has TGF-β-like action as well as having antitumour activity. It was obtained from Dihelerispora chlamydosporia by shake culture. 117

FO-6979 is a new substance 371 which is a low toxicity inhibitor for acyl CoA cholesterol transferase. It can be manufactured by culturing a Beauvera fungus. 118

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Rhodopeptins are novel cyclic tetrapeptides possessing anti- fungal activity. These metabolites are produced by the micro- organism Rhodococcus 119 and a synthesis of 372 confirms that rhodopeptin B5 has an R configuration at the valinyl centre. Sansalvamide 373 is a cytotoxic cyclic depsipeptide produced by a marine fungus of the genus Fusarium. This particular fungus was found growing on the surface of seagrass Halodule wrightii. 120

Yanucamide A 374 and yanucamide B 375 are two new depsipeptides obtained from an assemblage of the marine cyanobacterium Lyngba majuscula with a Schizothrix species. 121 Substance FTD-0668 is produced by the filamentous fungus Gliocladium sp. FTD-0668 (FERM P-16626). It, 376 , possesses chitinase inhibitory activity. 122 Montanastatin 377 is a new octapeptide isolated from the terrestrial soil actinomycte Streptomyces analutus found in Montana. It possesses cancer cell growth inhibitor activity. 123 The structure determination of two antifungal cyclodepsipeptides W493 A and B, produced by the fungus Fusarium , has been made and their absolute stereo- chemistry established by synthesis. 124 Thus A is 378 and B is 379. The structure of xanthobaccin A 380 has been elucidated through spectroscopic analysis and by its chemical conversion into a macrocyclic lactam containing a new tetramic acid. 125 Streptomyces sp. strain SB-K88 which produced the metabolite also produced 381 and 382 as their tautomeric sodium salts. Four proteasome inhibitors have been identified as components present in the fermentation broth of Apiospora montagnei. 126 They are designated TMC-95A 383 and its three diastereo- isomers TMC-95B 384 , TMC-95C 385 , and TMC-95D 386. An additional publication has detailed the spectroscopic analysis of these four novel proteasomic inhibitors isolated from Apiospora montagnei. 127 In particular TMC-95D 386 was the role compound used in the analytical measurements. The struc- ture of the bitter taste principle associated with the Korean oyster Crassostrea gigas has been identified 128 as the peptide 386. It has a hydantoin component associated with six amino acids. A total synthesis ()-motuporin 388 is described 129 through the synthesis of peptides such as 389 , 390 followed by their coupling to give 391. Cyclisation occurred, after removal of the terminal protecting groups, using HATU in N -ethyl- morpholine. A 79% yield was obtained.

Anabaenopeptin G 392 and anabaenopeptin H 393 are potent carboxypeptidase inhibitors found in the cyano- bacterium Oscillatoria agardhii. 130 Tamandarin A 394 is a cyclic depsipeptide showing antitumour activity against pancreatic carcinoma. 131 Isolated from an unidentified Brazilian ascidian of the Didemnidae family it is somewhat akin to didemnin B in

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imidazole, oxazole, thiazole, peptide and miscellaneous alkaloids

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Amaryllidaceae, Sceletium, imidazole, oxazole, thiazole, peptide

and miscellaneous alkaloids

John R. Lewis

Department of Chemistry, University of Aberdeen, Meston Walk, Old Aberdeen,

UK AB24 3UE

Received (in Cambridge, UK) 10th October 2001

First published as an Advance Article on the web 4th February 2002

Covering: July 1999–June 2000. Previous review: 2001, 18, 95.

This review covers alkaloids classified in the plant families Amaryallidaceae and Sceletium. In addition alkaloids

possessing imidazole, oxazole and thiazole structures are listed followed by alkaloids possessing peptide linkages.

Finally miscellaneous alkaloids include those compounds found naturally which cannot be classified into known

groups; a relative Pandora’s box. A total of 620 structures has been reviewed from 218 references found in the

literature for the period July 1999 to June 2000.

1 Introduction

2 Amaryllidaceae alkaloids

3 Imidazole, oxazole and thiazole alkaloids

4 Peptide alkaloids

5 Miscellaneous alkaloids

6 References

1 Introduction

Nature offers phytochemists a cornucopia of delights, every

year new alkaloid structures are reported, some are extensions

of existing frameworks but others are completely new. Existing

frameworks are often targeted because of pharmaceutical activ-

ity. The diversity of sources for alkaloids is immense, some are

new, others are being reinvestigated, thus allowing the newer

analytical and pharmacological techniques to be used to the

fullest extent. Even well established sources of alkaloids may

demand reinvestigation as smaller quantities of alkaloid are

now required for structure elucidation.

This chapter contains a number of new structures to further

the encyclopedia of organic substances. Note in particular tuber-

culosis is increasingly becoming virulent again especially since

the bacteria are developing resistance to normal treatment. A

review article outlines the role that marine natural products

play in producing metabolites with antituberculosis activity.

2 Amaryllidaceae alkaloids

Eighteen new alkaloids have been reported during the 1999–

2000 period. Most belong to established groups but two have a

new lactone structure (see 22, 23).

Dr Lewis graduated at Uni-

versity College, Swansea; was

Fulbright Fellow in 1958 at

University of Iowa, Ames,

later becoming Senior Lec-

turer in Organic Chemistry at

Aberdeen University. He is

now retired.

John R. Lewis

Gas chromatography using capillary columns has been

shown to be a quick, twenty-five minute, procedure for deter-

mining the Amaryllidaceae alkaloids present in Crinum lati-

folium. Fifteen and thirty metre DB-5 columns were used and

only small quantities of dried plant material were needed for

this procedure.

This technique could well be used in a much

broader coverage using other plant extracts not only of the

Amaryllidaceae family.

In reviewing the alkaloids found in the Amaryllidacea genera

Boophane, Brunsvigia and Crinum an appraisal and retesting of

these alkaloids for antimalarial and cytotoxic activity has led to

a broad generalisation; namely that the 5,10b-ethanophen-

anthridine structure is useful for activity. Crinamine 1, which

has an α-configuration, is the most active.

Sixteen alkaloids have been isolated from the fresh bulbs of

Ammocharis tinneana.

Seven of these contain the 1,2β-epoxide

grouping. Of these seven two, 6α-hydroxycrinamidine 2 and

6α-hydroxyundulatine 3 are new, the others are 1,2β-epoxy-

ambiline 4, 11-O-acetyl-1,2β-epoxyambiline 5, 3,4-flexinine 6,

crinamidine 7 and undulatine 8. Other alkaloidal constituents

were lycorine 9, sternbergine 10, 9-O-demethylpluviine 11,

ambelline 12, 11-O-acetylambelline 13, crinine 14, powelline 15,

buphanidrine 16 and buphanisine 17.

The bulbs of Brunsvigia radulosa contain eight alkaloids

namely 1-epidiacetylbowdensine 18, crinamine 1, crinine 14,

hamayne 19, lycorine 9, anhydrolycorin-6-one 20, sternbergine

10, and the new alkaloid 1-O-acetylnorpluviine 21 which inci-

dentally showed good cytotoxic activity towards BL6 mouse

melanoma cells.

Two new masanane type alkaloids both containing a lactone

ring have been found in a fresh whole plant extract of Clivia

nobilis.

Nobilistine A is 22 and nobilistine B is 23, both being

DOI: 10.1039/b007741k Nat. Prod. Rep., 2002, 19, 223–258 223

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Amaryllidaceae, Sceletium , imidazole, oxazole, thiazole, peptide

and miscellaneous alkaloids

John R. Lewis

Department of Chemistry, University of Aberdeen, Meston Walk, Old Aberdeen,

UK AB24 3UE

Received (in Cambridge, UK) 10th October 2001

First published as an Advance Article on the web 4th February 2002

imidazole, oxazole, thiazole, peptide and miscellaneous alkaloids

Course: Material Science

University: University of Malaysia Terengganu

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