摘要:

Hot oV the press H O O H H O H O 2 OH CHO O OMe HO 4 O O 6 1117). The gum mastic resin from Pistacia lentiscus has been shown to contain cis-1,4-poly-‚-myrcene 5 (K. J. van den Berg et al. Tetrahedron Lett. 1998 39 2645). This is the first report of a naturally occurring polymer of a monoterpene. Neodenudatenone A 6 from Odontoschisma denudatum has a novel diterpenoid skeleton (Y. Asakawa and co-workers Tetrahedron Lett. 1998 39 3791) and metabolite YW3699 7 from Codinaea simplex has a new sesterpenoid skeleton (Y. Wang et al. Tetrahedron 1998 54 6415). The first Robert A. Hilla and Andrew R. Pittb aDepartment of Chemistry Glasgow University Glasgow UK G12 8QQ. E-mail bobh@chem.gla.ac.uk bDepartment of Pure and Applied Chemistry Strathclyde University Thomas Graham Building 295 Cathedral Street Glasgow UK G1 1XL.E-mail a.r.pitt@strath.ac.uk Several diterpenoids with novel carbon skeletons including 1 and 2 have been isolated from the Japanese liverwort Pallavicinia subciliata (Y. Asakawa and co-workers Chem. Pharm. Bull. 1998 46 178). The authors propose that they arise biosynthetically from labdane precursors. Obtunone 3 from Chamaecyparis obtusa var. formosana is probably derived by a Diels–Alder cyclisation of two monoterpenoids (Y.-H. Kuo et al. Chem. Pharm. Bull. 1998 46 181). The first labdane linked to a chalcone 4 has been isolated from Alpinia katsumadai (K.-S. Hgo and G. D. Brown Phytochemistry 1998 47 O O H O H H O 1 O 3 O OH n 5 Hill and Pitt Hot oV the press O H OH O H H H OH HO O 7 O CHO O 23 O OH O O O 8 9 OH O O OHC N Me HO H O O N H 10 H 11 N N N N HO N H 12 example of a scalarane derivative with methylation at C-23 8 has been isolated from Cacospongia scalaris (S.De Rosa et al. Tetrahedron 1998 54 6185). Psorothamnone A 9 from Psorothamnus junceus has an intriguing carbon skeleton (C. Chang and co-workers Tetrahedron Lett. 1998 39 3417) and cladobotryal 10 a metabolite of Cladobotryum varium contains a novel furo[2,3-b]pyridone ring system (J. Breinholt et al. Acta Chem. Scand. 1998 52 631). Equisetin 11 from Fusarium heterosporum is an inhibitor of HIV-1 integrase (S.B. Singh Tetrahedron Lett. 1998 39 2243). Three new metabolites including asmarine A 12 with a novel heterocyclic ring structure have been isolated from the Red Sea sponge Raspailia sp. (Y. Kashman and co-workers Tetrahedron Lett. 1998 39 3323). Two terpenoids cladocoran A 13 and B 14 with novel skeletons have been isolated from the Anthozoan Cladocora cespitosa (A. Fontana et al. J. Org. Chem. 1998 63 2845). In a comprehensive review A. G. Medentsev and V. K. Akimenko discuss the structures spectroscopic and biological properties and biosynthesis of 100 naphthoquinone metabolites from filamentous fungi (Phytochemistry 1998 47 935). L. Krenn iii OR H OMe OH OH O CO2H 16 13 sugar 15 18 OH OH * O H2N * * O HO2C * 13 R = Ac 14 R = H and B.Kopp have catologued 267 naturally occurring bufadienolides (Phytochemistry 1998 48 1). The structure of ferrugin from Aglaia ferruginaea has been revised to be the same as rocaglaol 15 from Aglaia odorata (D. A. Mulholland and N. Naidoo Phytochemistry 1998 47 1163). Maracin 16 and maracen 17 are two new metabolites from Sorengium * O * * O O MeO O * H3C CO2H OMe O * O * O * O * CO2H OH * * Cl * HO * O * * * O [CH3]Methionine OH * * * O * * O * * * 19 17 cellulosum containing the unusual acetylenic and unique chlorovinyl ethers respectively (M. Herrmann et al. Angew. Chem. Int. Ed. Engl. 1998 37 1253). The compounds are active against Mycobacterium tuberculosis and appear from C-labelling studies to be biosynthesised from acetate.Labelling studies indicate that the starter unit for the polyketide vicenistatin 18 from a Streptomyces species appears to be 3-amino-2-methylpropanoate formed from glutamate via the glutamate mutase reaction. (K. Kakinuma and co-workers Tetrahedron Lett. 1998 39 3185). The biosynthetic origins of H N iv Natural Product Reports 1998 the carbons in goniodomin A 19 from Alexandrium hiranoi have been investigated using feedings of labelled acetate and methionine (M. Murakami et al. Phytochemistry 1998 48 85). The results are consistent with either TCA intermediates being involved or single carbon depletion processes occurring in a normal polyketide.The pathways of the degradation of quinoline derivatives in bacteria (Scheme 1) have been reviewed giving an indication of N HN HN OH O O HN O Scheme 1 CO2H the diversity of the processes involved in bacterial degradation of small organic molecules (S. Fetzner et al. Angew. Chem. Int. Ed. Engl. 1998 37 576). Desulfovibrio vulgaris a eubacterium representing a primitive stage of development has been shown to have a primitive biosynthetic pathway to porphyrins (T. Ishida et al. Proc. Natl. Acad. Sci. USA 1998 95 4853). Extensive labelling studies have been used to investigate the biosynthesis of salinamide A 20 in Streptomyces sp. CNB-091 HO O O N O a b HN N H O Me N O O O H O O O O HO N N O N H H O H 20 (B.S. Moore and D. Seng Tetrahedron Lett. 1998 39 3915). Both seven carbon non-amino acid residues are formed by a single chain extension of a carboxylic acid derived from an amino acid. The results are consistent with fragment a being derived from valine via isobutyrate with a methylmalonate chain extension whereas fragment b is from isoleucine via tiglate with a malonyl chain extension. The biosynthesis of 1,7-dioxaspiro[5,5]undecane 21 the sex pheromone of the olive fruit-fly Bactrocera oleae has been investigated using deuterium labelled precursors (W. Kitching and co-workers Chem. Commun. 1998 863). The authors O O O OH 21 22 propose that the biosynthesis involves ¢�-hydroxylation of 1-hydroxynonan-5-one 22 or its chemical equivalent.In an issue of Heterocycles in honour of Koji Nakanishi¡�s 75th birthday A. I. Scott has reviewed the anaerobic biosynthetic pathway to vitamin B12 as compared to the aerobic pathway (Heterocycles 1998 47 1051) T. Hashimoto and Y. Asakawa have reviewed the biologically active constituents of Japanese inedible mushrooms (Heterocycles 1998 47 1067) and J. Kobayashi and H. Shigemori have reviewed Taxol= biosynthesis and the bioactive taxoids in Taxus cuspidata (Heterocycles 1998 47 1111). [1-13C]Glucose feeding studies have been used to demonstrate that the isoprenoid part of novobiocin 23 from Streptomyces spheroides is from the non-mevalonate pathway i.e. from pyruvate and glyceraldehyde via 1-deoxy-D-xylulose-5- phosphate (L.Heide and co-workers Tetrahedron Lett. 1998 39 2717). However the monoterpenoid part of shikonin 24 OH H OH N O sugar O O O 23 OH O OH O OH 24 from Lithospermum erythrorhizon has been shown to be formed from the mevalonate pathway phosphate (L. Heide and co-workers Tetrahedron Lett. 1998 39 2721). The pattern emerging is that plant mono- di- and tetra-terpenoids are formed in the plastids by the non-mevalonate pathway whereas sesqui- and tri-terpenoids are formed in the cytosol via the mevalonate pathway. Interestingly the results for shikonin are consistent with shikonin being formed from the cytosolic pool of isopentenyl diphosphate. Biosynthetic studies on the origin of the phytyl side-chain of chlorophyll a indicate that either carbon of acetate is incorporated into all carbons of the phytyl side chain (K.Nabeta et al. Chem. Commun. 1998 671). This is suggested to arise by degradation of the acetate to carbon dioxide and reutilisation via the pentose phosphate cycle followed by the glycolic pathway. In addition labelling studies indicate that both the mevalonate and non-mevalonate pathway are operating simultaneously in liverwort chloroplasts. A review of the current knowledge of mono- sesquiand di-terpene cyclases of plant origin has been published by R. Croteau and co-workers (J. Bohlmann et al. Proc. Natl. Acad. Sci. USA 1998 95 4126). It covers the enzymology and mechanisms of the enzymes and considers possible bionological uses.The mechanism of tyrosine hydroxylase (Scheme 2) has been investigated by studying the kinetic isotope eVect of incubation with 18O2 (W. A. Fransisco et al. J. Am. Chem. Soc. 1998 120 4057). Using both fully coupled and fully uncoupled substrates the same oxygen isotope eVect was observed confirming that oxygen activation was the rate determining step. Oxygen activation is probably via one electron transfer from the tetrahydropterin cofactor to generate the superoxide anion. A review of the current knowledge of ribulose-1,5- bisphosphate carboxylase (Rubisco) a key enzyme involved in Hill and Pitt Hot oV the press HO CO2 CO2 HO HO O2 + NH3 + NH3 H H NH N N N N NH2 NH NH R N R N O H O H O tyrosine hydroxylase Scheme 2 H photosynthesis has appeared (W.W. Cleland et al. Chem. Rev. 1998 98 549). The review concentrates mainly on mechanistic aspects of the enzyme. The precise role of Bro¡§nsted catalysis by amino acids at enzyme active sites is diYcult to determine experimentally and the rate increase due to Bro¡§nsted buVer catalysis in solution is often small. A summary of the evidence for Bro¡§nsted catalysis at enzyme active sites has recently been published (J. P. Richard Biochemistry 1998 37 4305). J. Stubbe and W. A. van der Donk have reviewed the role of protein radicals in enzyme catalysis (Chem. Rev. 1998 98 705). The review is broad ranging (and extensive) covering more than ten enzymes including some that have not yet been extensively studied and includes much mechanistic and structural information.Ab initio calculations carried out on the mechanism of carbonic anhydrase agree well with the experimentally determined energies for the dehydration reaction whereas the energy barrier for proton transfer in the hydration direction appears to be sensitive to a number of factors (D. Lu and G. A. Voth J. Am. Chem. Soc. 1998 120 4006). The involvement of the zinc histidine ligand and the role of hydrogen bonded water in the active site are discussed. The crystal structure of bovine pancreatic cholesterol esterase at 1.6 A reveals that the enzyme is significantly diVerent at the active site from other lipases with the lid being truncated and the C-terminus being buried in the active site (J.C.-H. Chen et al. Biochemistry 1998 37 5107). The results suggest that this may be a member of a new family of lipases. Cyclohexane monooxygenase from Acinetobacter sp. NCIB 9871 has been cloned and expressed to a high level in Saccharomyces cerevisiae generating a useful catalyst for the Baeyer¡© Villiger reaction that has the high activity of the isolated enzyme and the added advantages of using whole cells including no requirement to artificially regenerate cofactors (J. D. Stewart et al. J. Am. Chem. Soc. 1998 120 3541). The system also carries out the reaction with a high degree of stereoselectivity on substituted cyclohexanones. The potential synthetic uses of catalytic antibodies has again been demonstrated by the group of Lerner (T.HoVmann et al. J. Am. Chem. Soc. 1998 120 2768). They have generated a catalytic antibody that catalyses the aldol reaction of a wide range of aldehyde and ketone substrates via the type I aldolase eneamine mechanism with eYciencies that are up to 108 fold better then a simple amine catalyst. They also obtain good enantiomeric excesses of 90¡©95% in many of the chiral products. The first report of the application of surface plasmon resonance to the study of the conformational changes of proteins immobilised on surfaces has appeared (H. Sota et al. Anal. Chem. 1998 70 2019). It was possible to see acid induced conformational changes probably due to protein unfolding of an engineered dihydrofolate reductase attached to the surface via the terminal amino acid.Two consecutive issues of Biol. Chem. have been devoted to areas of general interest. Issue 3 (Biol. Chem. 1998 379 233¡©367) covers protein folding and organisation mainly concentrating on the action of chaperones. Issue 4/5 (Biol. Chem. 1998 379 375¡©625) concentrates on the mechanisms v roles and recognition of the methylation of DNA. The exquisite sensitivity of enzyme function to structure has been shown again with the report that a single amino acid side chain Glu 710 is responsible for the selection of 2-deoxynucleotides rather than ribonucleotides by Escherichia coli Klenow fragment of DNA polymerase I (M. Astatke et al. Proc. Natl. Acad. Sci. USA 1998 95 3402). A Glu to Ala mutation allows the DNA polymerase to synthesise RNA albeit with limited eYciency.The trapping by physical chemical and crystallographic means of a catalytically competent intermediate has given an insight into the mechanism of self-cleavage of hammerhead ribozymes (J. B. Murray et al. Cell 1998 92 665). A large conformational change is required to arrange the catalytic machinery. Issue 3 of Chem. Rev. in 1998 is devoted to a series of articles on RNA and DNA cleavage looking at both enzymatic and chemical cleavage (Chem. Rev. 1998 98 937– 1221). Dervan’s group have reported the sequence selective binding of a combined pyrrole and imidazole polyamide to a vi Natural Product Reports 1998 16 base pair sequence of DNA (J. W. Trauger et al. J. Am. Chem. Soc. 1998 120 3534). The molecule forms a noncovalent dimer and although it has only limited selectivity it has high aYnity and will be an important lead in the field. A review of the interaction of selectins with carbohydrates a key feature of cell recognition has appeared recently (E. E. Simanek et al. Chem. Rev. 1998 98 833). It contains a good review of the role of the selectins followed by structure– activity relation studies and the design of inhibitors of cell recognition. It is complemented by a feature article in Chem. Commun. that covers some of the synthetic aspects of inhibitors in the field (P. Sears and C.-H. Wong Chem. Commun. 1998 1161). An overview of the power of tandem Fourier transform mass spectrometry (also known as ion cyclotron resonance mass spectrometry FTMS or FTICR-MS) for the study of large biomolecules has been published (E. R. Williams Anal. Chem. 1998 70 179A). It discusses the uses of the technique especially the advantages of the incredible resolution that can be achieved.

ISSN:0265-0568    

DOI:10.1039/a804hopy

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Recent progress in the chemistry of non-monoterpenoid indole alkaloids Masahiro Toyota and Masataka Ihara Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan Covering: July 1996 to June 1997 Previous review: 1996, 14 1 Introduction 2 Simple alkaloids 2.1 Non-tryptamines 2.2 Non-isoprenoid tryptamines 3 Ergot alkaloids 4 Bisindole alkaloids 5 References 1 Introduction This section covers the literature on non-monoterpenoid indole alkaloids and their analogs since the last review in this journal, which included the literature from July 1995 to June 1996. 2 Simple alkaloids 2.1 Non-tryptamines The simple disubstituted indole, 5,6-dihydroxyindole, 1a, has been isolated from Rhaphidophora korthalsii. In spite of its simple structure, the ED50 of 1a against p 388 cells was 3.5 Ïg ml"1, and its structure was elucidated spectroscopically after transformation of 1a into the corresponding stable diacetate 1b. The structure was further confirmed by total synthesis.1 (&)-Convolutamydine A 2, a metabolite isolated from the marine Bryozoan Amathia convoluta, has been prepared by a concise synthesis from 3,5-dibromoaniline using modified Sandmeyer methodology.2 Phytoalexins are anti-microbial low-molecular weight secondary metabolites, and produced by plants after exposure to biological, chemical or physical stress.Camalexin 6, a phytoalexin produced in the leaves of Camelina sative in response to infection by the fungus Alternara brassicae, was synthesised from 3 employing palladium-catalysed arylation (4]5) as the key step (Scheme 1).3 Cancer chemopreventive phytoalexins, brassinin 7 and cyclobrassinin 8, have been biomimetically prepared by way of the isothiocyanate 9 as a common synthetic intermediate.4 Biosynthetic studies on the sulfur-containing indole phytoalexins have been examined by a trapping experiment with aniline for a biosynthetic intermediate.5 Three new indoline alkaloids with neuronal cell protecting activity, benzastatins E 10a, F 10b and G 10c, were isolated from Streptomyces nitrosporeus 30643.6 Their structures were established on the basis of spectral data.Spider toxin was the first blocker found from natural sources and it has recently attracted great interest because the glutamate receptors play the most important role in brain function. In order to confirm the aromatic subunit of nephilatoxins (NPTX-1–6), the hydrolysis product of 11, both 4- and 6-hydroxyindole-3-acetic acid were prepared.As a result, the substitution pattern of the oxygen function of NPTX-1–6 has been revised as shown in 12 through 1H NMR studies of the authentic 4- and 6-hydroxyindole-3-acetic acids.7 Chuangxinmycin 16, isolated from Actinoplanes tsinanensis, exhibits an antibacterial spectrum (in vitro) that includes a number of Gram-positive and Gram-negative bacteria. NH RO RO NH O O Br Br OH 1a 5,6-Dihydroxyindole R = H 1b R = Ac 2 Convolutamydine A N SO2Ph I N SO2Ph ZnI N S I N SO2Ph S N NH S N 5 3 4 active Zn Pd(PPh3)4 NaOMe 6 Camalexin Scheme 1 NH NH SMe S NH S N SMe N Boc N C S 7 Brassinin 8 Cyclobrassinin 9 NH H2NOC R2 H R1 OH NH HO NHR O NH NHR O OH 10a 10b 10c Benzastatin E R1 = CH2OMe, R2 = Me F R1 = Me, R2 = Me G R1 = Me, R2 = H Benzastatin 11 NPTX-1–6 (proposed) R = polyamine side chain Benzastatin 12 NPTX-1–6 (revised) Toyota and Ihara: Recent progress in the chemistry of non-monoterpenoid indole alkaloids 327Regio-selective alkylation of the indole 13 with (&)-trans-2,3- epoxy butanoate in the presence of SnCl4 aVorded (&)-4*- iodoindolmycenate 14, which was stereoselectively converted to the thiol 15 via a double SN2 reaction.Palladium-catalysed cyclisation of 15 provided (&)-chuangxinmycin 16 after hydrolysis (Scheme 2).8 Two new diprenylated indoles, 2*,3*-epoxyasteranthine 17 and 2*,3*-dihydroxyasteranthine 18, were isolated from the stem bark and the root bark of Asteranthe asterias.Their structures were elucidated by spectroscopic methods. Each of the two compounds was obtained in an enantiomeric ratio of 3:1 and showed antimycotic activity against Saprolegnia and Rhizoctonia species.9 Five new carbazole alkaloids, clausines B 19, E 20, H 21, I 22 and K 23 were isolated from the stem bark of Clausena excavata. The structures were established from spectral data and chemical transformation, and these carbazoles exhibited significant inhibition of rabbit platelet aggregation and caused vasocontraction.10 Carbazomycin D 31, isolated from Streptoverticillium ehimense, was synthesised by means of iron-mediated consecutive C–C and C–N bond formation (Scheme 3).11a This transition metal promoted cyclisation method for the construction of the carbazole framework (24]30) was further applied to more functionalised carbazole syntheses by the same group.11 Carazostatin 35, a free radical scavenger, has been isolated from Streptomyces chromofuscus.Total synthesis of 35 was achieved employing an allene-mediated electrocyclic reaction (32]33]34) as the pivotal step (Scheme 4).12a Hyellazole,12a carbazoquinocins B–F,12a antiostatins A1–A4,12b antiostatins B2–B5 12b and carbazoquinocin A12b were prepared by the same protocol. Four new carbazole alkaloids, clausines A 36, C 37, G 38 and J 39 have also been found in C. excavata.13 Two pyranocarbazole alkaloids, clausine-W 40 and -T 41, furoclausine-A 42 and -B 43, clausenamine-A 44 (binary carbazole dimer) and carbazomarin-A 45 (carbazole-pyranocoumarin dimer) were also isolated from C.excavata by the same authors and their structures were elucidated using spectroscopic analses.14 The extracts of the leaves and bark of the plant further gave seven new carbazole alkaloids, named clauszoline-A 46, -B 47, -C 48, NH I CO2Me O NH I CO2Me OH NH I CO2Me SH S NH CO2H 13 SnCl4 15 1. Pd(PPh3)4, Et3N 2.NaOH 16 Chuangxinmycin 14 Scheme 2 NH O O H NH O OH OH 17 2',3'-Epoxyasteranthine 18 2',3'-Dihydroxyasteranthine NH R2 R3 R6 R5 R4 R1 Clausine B Clausine E Clausine H Clausine I Clausine K R1 R2 R3 R4 R6 H OH H OH H OH CHO OMe OMe H OMe H CO2Me CO2Me CO2H CHO H OMe H H 19 20 21 22 23 OMe H OMe H H H H R5 H OMe H MeO (CO)3Fe BF4 – OMe OMe Me Me H2N OMe OMe Me Me H2N MeO (CO)3Fe OMe O Me Me HN MeO (CO)3Fe (CO)3Fe N OMe O Me Me (CO)3Fe MnO2 N OMe O Me Me 27 + 25 24 31 Carbazomycin D MeO 26 30 active MnO2 + NH MeO Me OMe OH Me NH MeO Me OMe OMe Me MeI K2CO3 DMSO MeO 28 29 CF3CO2H Me3N O + Scheme 3 N MOM OEt OMOM N MOM OEt OMOM N MOM OEt Me OMOM NH OH Me nC7H15 34 35 Carazostatin KOBut 32 33 Scheme 4 328 Natural Product Reports, 1998-D 49, -F 50, -E 51 and -G 52.15 Four new carbazoles, murrayamine-F 53, -G 54, -H 55 and euchrestifoline 56 have been isolated from the leaves of Murraya euchrestifolia.In addition, the variation of 26 carbazole alkaloids in the leaves with the seasons was also examined.16 Carbazoquinocins A 61a and D 61b, potent lipid peroxidation inhibitors isolated from Streptomyces violaceus, have been prepared for the first time chirally.Thermal condensation (58]59]60) of the enamines 58, synthesised from the (R)- glycidol 57, yielded the carbazoles 60, which were converted to carbazoquinocins A 61a and D 61b (Scheme 5).17 Indolmycin 65, produced by Streptomyces griseus, exhibits an antibacterial spectrum that includes the pathogenic species Pasteurella, Haemophilus and Mycoplasma, which are responsible for many of the respiratory diseases in farm animals.A practical and short synthesis of (&)-65 has been achieved. Alkylation of 3-[1-(N,N-dimethylamino)ethyl]indole 62 with 5-benzyloxycarbonyl oxazolinone 63 proceeded smoothly to give rise to the coupled products 64, which were transformed into (&)-indolmycin 65 and (&)-isoindolmycin (Scheme 6).18 Alboinon 66, an oxadiazinone alkaloid from the ascidian Dendrodoa grossularia, was isolated and its structure was confirmed by synthesis.19 In the course of screening for inhibitors of protein farnesyltransferase, kurasoin B 67 has been isolated from a fermentation broth of Paecilomyces species.The IC50 value of 67 against protein farnesyltransferase is 58.0 ÏM.20 The absolute configuration of 67 was decided via its enantioselective synthesis.20 The structures of novel tumor cell NH O OH CHO HO N H O CHO HO NH R Me O N H Me MeO O NH Me O O 51 Clauszoline E 52 Clauszoline G 53 Murrayamine-F R = OMe 54 Murrayamine-G R = H 55 Murrayamine-H 56 Euchrestifoline BnO O H NH NH CO2Et NH NAc CO2Et H O NH CO2Et NH O O 57 n 58 Ac2O AcOH reflux n 59 60 n n 61a Carbazoquinocin A n = 1 61b Carbazoquinocin D n = 2 Scheme 5 Toyota and Ihara: Recent progress in the chemistry of non-monoterpenoid indole alkaloids 329growth inhibitory glycosides, secalosides A 68 and B 69, have been elucidated through NMR spectroscopy.21 Mescengricin 70, an ·-carboline structure substituted by glycerol-ester and dihydropyrone residues, was isolated from Streptomyces griseoflavus as a neuronal cell protecting substance.22 The clinical significance and unique structures of mitomycins have prompted a number of model studies directed toward their synthesis, however, there still remains major interest in the synthesis and biological evaluation of structural analogs which possess strong activity against tumor cells and reveal lower associated toxicity towards healthy cells.Commencing from the easily obtainable 2,3,5,6,7,8-hexahydro-8- oxo-1H-pyrrolo[1,2-a]indole 71, an eYcient 12-step route to the fully functionalised aziridinomitosene analog 81 has been developed. After DDQ oxidation, the resulting vinyl acetate 72 was subjected to palladium-catalysed methoxycarbonylation to aVord the unsaturated ester 73, which was converted to the carboxylic acid 74.When 74 was treated with aqueous bromine, the corresponding bromohydrin was produced in good yield. This compound was treated with sodium azide to furnish the azido alcohol 75 as the major isomer. After mesylation of 75, DDQ-mediated dehydrogenation was conducted to give the 2,3-dihydro-1H-pyrrolo[1,2-a]indole 76. Solvolytic bromination followed by reaction with sodium azide provided the 1,7-diazidoquinone 77. Finally, exposure of 77 to sodium dithionite gave rise to the corresponding azidohydroquinone intermediate, which was subjected to subsequent thermal reaction to produce 78 (Scheme 7).23 In addition to the NH NMe2 O N O BnO2C NMe2 NH O N CO2Bn O NMe2 NH O N H O NHMe 62 + PBun 3 D 63 64 65 (±)-Indolmycin Scheme 6 NH N N O NMe2 O NH OH O 66 Alboinon 67 Kurasoin B NH O O O O HO O HO OH O O OH OMe O O OH HO O O OH OH OH HO O HO NH N O OH O O HO O OH HO 69 Secaloside B [epimers at C-3 of (2-oxoindol-3-yl)acetic acid moiety] 70 Mescengricin 68 Secaloside A 3 N O OAc N O OAc OMe N O CO2Me OMe N O CO2H N O CO2H N3 OH N OH CO2Et N3 OMs N O CO2Et N3 OMs N3 O N O CO2Et H2N O NH 71 72 DDQ MeOH 1.MeLi; PhNTf2 2. Pd(OAc)2, CO, Et3N MeOH, DMSO TMSCl LiBr D 73 74 1. Br2, THF–H2O 2. NaN3 75 1. MsCl, Et3N; EtOH 2. DDQ 76 1. Br2 2. NaN3 77 78 1. Na2S2O4 2. PPh3, Et3N Scheme 7 NH NH H N NH2 O CO2 H NH NH NH R O Br CO2H NH NH NH H NH NH2 NH N NH 80 79 81 82 R = , , 330 Natural Product Reports, 1998above synthetic study, a cellular resistance mechanism to mytomycin is also reported.24 Simple peptides 79–82 were isolated from Leptoclinides dubius and their structures were elucidated by spectroscopic analyses and degradation experiments.25 2.2 Non-isoprenoid tryptamines An historical development of the chemistry of the cyclic tautomer of tryptophan has been reviewed.26 Leaf extracts, from Sri Lankan Clausena indica of diVerent provenances gave four new tryptamine derived amides, madugin 83, methylmadugin 84, prebalamide 85 and balasubramide 86.27 Five new alkaloids 87–91 were obtained from biotransformations using Streptomyces staurosporeus.28 Four novel indole alkaloids, moschamine 92, cis-moschamine 93, moschamindole 94 and moschamindolol 95, have been isolated from the seeds of Centaurea moschata.The structures of these compounds were determined primarily on the basis of NMR NH RN O NH HN O O NH NMe OH O R = Me 83 Madugin R = H 84 Methylmadugin 85 Prebalamide 86 Balasubramide NH R1 R3 NHAc R2 87 88 89 90 91 R1 R2 R3 H F H O-b-D-quinovose O-a-L-rhamnose OH OH OH H H H H F H H NH HO HN R O OMe OH O OMe OH HN NH O HO MeO O HN NH O HO HO OH MeO 92 Moschamine 93 cis-Moschamine 94 Moschamindole 95 Moschamindolol R = R = N Me NH Me N CO2 H O O Me MeNH NH HN O N Me H NAc O 96 Hemiasterlin 97 Terpeptin N Boc Br MeO N N EtO OEt N Boc MeO N N OEt OEt N Boc MeO NH2 CO2Et H Troc N Cl O H N Bo c MeO HN CO2Et H Troc N O H NH MeO HN H N O O H BunLi 99 98 100 Et3N 101 102 Tryprostatin A Scheme 8 Toyota and Ihara: Recent progress in the chemistry of non-monoterpenoid indole alkaloids 331experiments.29 An improved degradation procedure for determination of the absolute configuration in chiral ‚-carboline derivatives has been reported.30 Hemiasterlin 96 is an antibiotic agent which inhibits tubulin polymerisation by binding NH NPhth CO2Me H N NPhth CO2Me H Cl Me BCl2 Me N Cl B Me Me Cl Cl NH NPhth CO2Me H NH HN N O O H H 104 ButOCl 103 105 106 107 108 Tryprostatin B – + Scheme 9 NH N NH NH2 OAc H H AcO OAc CHO NH NH OAc H OAc H OAc NH N OH H OH H OH O 109 Vulcanine Tryptamine + CF3CO2H 110 111 112 Scheme 10 NH R N O NH N O MeN N 113 Eudistomin S R = Br 114 Eudistomin T R = H 115 Xestomanzamine A NH N H OAc OR OH NH N Me CO2Me N O O NH2 116 Pyridiondolol K1 117 Pyridiondolol K2 118 Lavendamycin methyl ester R = Ac R = H N N Me Br NH N Ac H OH 120 Flustramine C 119 NH N NH O N NH H O NH2 O NH NH O HO2C NH HN NH O HO O O HN H2N NH NH O O O O 121 Oscillatorin NH HN N R2 N O O R1 NH N N MeO O O O H H H NH N N O O O H H 122a 122b 122c 122d Didemnimide A Didemnimide B Didemnimide C Didemnimide D R1 R2 H Br H Br H H 123 Spirotryprostatin A 124 Spirotryprostatin B Me Me 332 Natural Product Reports, 1998N N O R H OH O N N O AcO O H R = H 125 27- epi-Nortryptoquivaline 126 27- epi-Tryptoquivaline R = Me NH NH2 CO2Me H CHO NH N CO2Me H Fmoc N Cl O H NH N CO2Me H H O NFmoc H NH N N O O H H 127 128 HC(OMe)3 Py 129 130 131 Demethoxyfumitremorgin C 1.separation 2. 20% piperidine Scheme 11 NH N N OH O O OR H MeO NH N N OH O O OH H NH N N OH O O O H O NH N O H HO H HN O O 132 Cyclotryprostatin A 133 Cyclotryprostatin B R = H R = Me 134 Cyclotryprostatin C 135 Cyclotryprostatin D 136 Sclerotiamide O O NH NMe N O O O O NH NMe N O O O O NH NMe N O O HO 137 Marcfortine A 6 steps G 138 Paraherquamide B 139 Paraherquamide A 7 steps Scheme 12 N SiPri 3 NMe2 CHO N SiPri 3 NMe2 OH N SiPri 3 NMe2 OH NH OH H NBoc CO2Et CO2Et NH HN H H CO2H NH HN H H CO2H H BocN CO2Et CO2Et 140 ButLi; 141 Bun 4NF 142 143 144 cis-Clavicipitic acid 145 trans-Clavicipitic acid MeI; Scheme 13 Toyota and Ihara: Recent progress in the chemistry of non-monoterpenoid indole alkaloids 333to the Vinca alkaloid site.A general synthetic route to this family of peptides has been accomplished.31 A novel mammalian cell cycle inhibitor, terpeptin 97, has been isolated from the cultured broth of Aspergillus terreus and its structure was elucidated by spectral analyses.32 Tryprostatins A 102 and B 108 are cell cycle progression inhibitors of tsFT210 cells in the G2/M phase: 102 and 108 have been prepared independently by two diVerent groups.When the bromide 98 was alkylated with the Schöllkopf chiral auxiliary, only one diastereomer 99 was obtained. A series of functional group modifications in 99 led to the tryptophan ethyl ester 100.After amidation, the proline substituted intermediate 101 was converted to 102 (Scheme 8).33 3-Chloroindolenine 104, synthesised from N-phthaloyl-Ltryptophan methyl ester 103 with tert-butyl hypochlorite, was treated with the allyl borane derivative 105 to aVord the desired prenylated 107 by way of the ‘ate’-like intermediate 106. Functional group manipulations of 107 led to (")- tryprostatin B 108 (Scheme 9).34 Simple ‚-carboline alkaloid, vulcanine 109, has been isolated from Haplophyllum vulcanicum and its structure was established by X-ray analysis.35 The structure of new ‚-carboline triol 112, isolated from cultured hybrid cells of two Apocynaceae plants Rauwolfia serpentina and Rhazya stricta, was confirmed by its total synthesis.The aldehyde 110, prepared from D-glucose, was condensed with tryptamine in the presence of CF3CO2H to yield the tetrahydro-‚-carboline 111, which was transformed into 112 by several steps (Scheme 10).36 Antimicrobial active eudistomins S 113, T 114 and xestomanzamine A 115, which display cytotoxic activity, have been synthesised employing a tandem aza Wittig–electrocyclic ring closure process.37 Pyridiondolols K1 116 and K2 117 were isolated from the culture broth of Streptomyces species.In particular, 117 inhibits the adhesion of HL-60 cells to LPS-activated HUVEC MeN NR O O HN NMe O O Cl N NMe O H2N Cl N NMe O NH Br Br O N NH O RN H R = Me R = H 146 Damirone A 147 Damirone B R = H 148 Batzelline C 149 Isobatzelline C 150 Discorhabdin C 5 4 3 151a Makuluvamine A 151b Makuluvamine B 151d Makuluvamine D R = 4-HOC6H4(CH2)2 151c Makuluvamine C 3,4-dihydro- N+5-Me N NH O O O HN NH O H2N OH 152 Haematopodin 153 Veiutamine + HN NR O NH HO HN NH O NH Br Br R1 R2 Br 154b R = H 154a R = Me 155 14-Bromodiscorhabdin C R1 + R2 = O 156 14-bromodihydrodiscorhabdin C R1 = OH, R2 = H Tsitsikammarine B Tsitsikammarine A + + N N NH N O OH N N NH NH OH O N N NH N OH O N N NH N 157 6-Deoxymanzamine X OH 158 Manzamine J N-oxide O 159 3,4-Dihydromanzamine A N-oxide 160 Manzamine A N-oxide N Ts NBoc CO2Me Br N Ts Br MeO2C H MeNBoc MeO2C NTs H NH H H HO MeNBoc HNMe 161 162 PdCl2–BPPP Ag3PO4, CaCO3 D 163 164 Chanoclavine-I H Scheme 14 334 Natural Product Reports, 1998monolayer (IC50=75 Ïg ml"1).38 A practical preparation of the potent antitumor agent lavendamycin methyl ester 118 has been achieved.39 A new tryptamine metabolite, 119, was isolated from Streptomyces staurosporeus.40 The first total synthesis of flustramine C 120 was accomplished employing a tandem olefination-Claisen rearrangement process as the key step.41 Oscillatorin 121, a chymotrypsin inhibitor, was isolated from freshwater toxic cyanobacterium Oscillatoria agardii, and its structure was elucidated by chemical degradation and NMR analyses.42 Four new alkaloids, didemnimides A–D (122a–d), possessing a unique indole–maleimide–imidazole carbon skeleton, have been obtained from the Caribbean mangrove ascidian Didemnum conchyliatum.43 Two novel diketopiperazine alkaloids, spirotryprostatin A 123 and B 124, were isolated as new inhibitors of the mammalian cell cycle from the secondary metabolites of Aspergillus fumigatus through a separation procedure guided by cell cycle inhibitory activity.44 From NH N HN R 165a 19-Bromoisoeudistomin U 165b Isoeudistomin U R = H R = Br N HN CHO 166 Homofascaplysin C NH H N R2 R1 O O HO OH 167a Semicochliodinol A 167b Semicochliodinol B R1 = ; R2 = H R1 = H; R2 = NH R3 O R1 R2 HO O OH HN R4 R5 R6 168a Asterriquinone CT1 168b Asterriquinone CT2 168c Asterriquinone CT3 168d Asterriquinone CT4 168e Asterriquinone CT5 R1 R2 R3 R4 R5 R6 H H H H H H H H H H H H H H H H H H H H NH N HN NH Y X O NH R1 N HN NH R2 169a Deoxytopsentin 169b Topsentin 169c Bromotopsentin X Y H OH OH H H Br NH NH N O NH N NH2 Me NH Br Br 170a Nortopsentin A 170b Nortopsentin B 170c Nortopsentin C R1 R2 Br Br H Br H Br 171 Nortopsentin D Toyota and Ihara: Recent progress in the chemistry of non-monoterpenoid indole alkaloids 335Corynascus setosus, two new 27-epi-isomers of tryptoquivalines 125 and 126 have been obtained.45 Cell cycle inhibitor, demethoxyfumitremorgin C 131, was synthesised via acyliminium Pictet–Spengler condensation.After conversion of L-tryptophan methyl ester 127 to the imine 128, the pivotal acyliminium Pictet–Spengler condensation of 128 was performed by treatment with the acid chloride 129 to furnish the tetrahydro-‚-carboline 130.Separation followed by deprotection gave rise to 131 (Scheme 11).46 Four new natural diketopiperazine derivatives, cyclotryprostatins A 132, B 133, C 134 and D 135, were isolated as new inhibitors of the mammaliam cell cycle from the secondary metabolites of Aspergllus fumigatus. The structures of these natural products were determined by detailed analyses of their 1H and 13C NMR spectra.47 A new member of the paraherquamide class with potent insecticide activity, sclerotiamide 136, has been isolated from the sclerotia of Aspergillus sclerotiorum. 48 The paraherquamides and marcfortines are a novel class of anthelmintics. Only one structural diVerence between paraherquamide A 139 and marcfortine A 137 occurs in ring G. Beginning with marcfortine A 137, the first formal synthesis of paraherquamide A 139 has been achieved via paraherquamide B 138 in 13 steps (Scheme 12).49 A concise total synthesis of (&)-clavicipitic acids 144 and 145 was accomplished by combinational use of 4-selective lithiation of 140 and a fluoride ion-induced elimination– addition reaction of 142 with an aminomalonate derivative as the key step (Scheme 13).50 Several marine alkaloids such as damirone A 146 and B 147, batzelline C 148, isobatzelline C 149, discorhabdin C 150 and makuluvamine A 151a, B 151b, C 151c and D 151d were synthesised utilising quinoline derivatives as the synthetic intermediate.51 A mushroom pigment, haematopodin 152, has been prepared from 6,7-bis(benzyloxy)indole.52 Veiutamine 153, a new pyrroloiminoquinone derivative, was isolated from the Fijian sponge Zyzzya fuliginosa: 153 is the first pyrroloiminoquinone alkaloid bearing a C-6 p-benzyloxy substituent. 53 New bis-pyrroloiminoquinone alkaloids, tsitsikammarine A 154a and B 154b, and novel pyrroloiminoquinones, 14-bromodiscorhabdin C 155 and 14-bromodihydrodiscorhabdin C 156, have been isolated from a South African latrunculid sponge, and all these natural products show antimicrobial activity.54 Analysis of the Phillippine marine sponge Xestospongia ashmorica aVorded four novel manzamine congeners 157–160.These structures were unambiguously established on the basis of spectroscopic data. 3,4-Dihydromanzamine A N-oxide 159 and manzamine A N-oxide 160 exhibit cytotoxicity against L1578y mouse lymphoma cells.55 Several synthetic studies toward the unusual skeleton have been reported.56,57 3 Ergot alkaloids A diastereoselective total synthesis of (–)-chanoclavine-I 164, an ergot alkaloid, has been accomplished.Intramolecular N SEM N SEM Br MeN HN OH O SnBu3 N SEM N SEM MeN HN OH O NH NH MeN HN OH O OH OH 172 + 173 Bun 4NI 174 D Pd(PPh3)4 1. OsO4 2. Bu n 4NF 175 Cytoblastin Scheme 15 N MeO2C MeO N N MeO2C MeO N O O O O NR R1 N R1 N O O O O R2 R2 NR R3 R3 176 Tenuisine A 177b Tenuisine C R R1 R2 R3 CO2Me OMe OMe H2 CO2Me OMe H O 177a Tenuisine B NH N NH NH O N N HN H HO O O NH H H H O HN O O NH2 HN NH O O HN O HN NH2 O O O O H2N CO2H HO O 178 Kawaguchipeptin A 336 Natural Product Reports, 1998Heck reaction of the conjugate ester 162 yielded the expected tricyclic ester 163, which was transformed into (")-164 by several steps (Scheme 14).58 4 Bisindole alkaloids 19-Bromoisoeudistomin U 165a and isoeudistomin U 165b, two new dihydro-‚-carbolines, have been isolated from an undescribed Western Australian ascidian of the genus Eudistoma. 59 A short and eYcient synthesis of homofascaplysin C 166, the first natural 12H-pyrido[1,2-a:3,4-b*]diindole, was achieved.60 Semicochliodinols A 167a and B 167b have been isolated as inhibitors of HIV-1 protease from the culture broth of the fungus Chrysosporium merdarium P-5656. The structures were elucidated by spectroscopic methods. The metabolites inhibit HIV-1 protease with an IC50 value as low as 0.17 ÏM and epidermal growth factor receptor protein tyrosine kinase at 15–60 ÏM.61 Five new quinone pigments asterriquinones CT 1–5 168a–e have been discovered from the fermentation broth of Aspergillus, Humicola and Botryotrichum species isolated N N O O NH HN O N NH O N HN O O N H NH2 O O OH N N O O NH HN O N NH O N HN O O N H NH O O OH H N N O O NH HN O N NH O N HN O O N H 179 Kapakahine A NH O O OH H 180 Kapakahine C 181 Kapakahine D OH OH N Boc Me N O O NH R N O O NH Br NH Br + 182 183 Pd(OAc)2 185 Arcyriacyanin A R = H Ph3P, Et3N 184 R = Me Scheme 16 DMB N N N O Me OHC OH O DMB N N N O Me O O HO HN N N O Me O OH MeO HN N N O Me O OH MeO HN N N O Me O MeO OH HNMe 186 BF3·Et2O 187 188 (+)-RK-286c 189 (+)-MLR-52 190 (+)-Staurosporine Scheme 17 Toyota and Ihara: Recent progress in the chemistry of non-monoterpenoid indole alkaloids 337from diVerent soil samples. These natural products show serine proteases of the coagulation pathway.62 Total syntheses of three marine bisindole alkaloids, deoxytopsentin 169a, topsentin 169b and bromotopsentin 169c, have been reported.63 Cytotoxic and antifungal constituents of a marine sponge, Spongosorites ruetzleri, nortopsentins A 170a, B 170b and C 170c have been prepared through a palladium-catalysed cross-coupling reaction as the key step.64 Nortopsentin D 171, a bisindole alkaloid, was isolated from the deep-water axinellid sponge Dragmacidon species: 171 possesses a 2-amino-5-methylimidazole appendage at the central 4,5-dihydro-1H-imidazol-5-one nucleus.65 The first total synthesis and stereochemical elucidation of cytoblastin 175, a low molecular weight immunomodulator produced by Streptoverticillium eurocidium, has been reported.Palladium-mediated coupling reaction of 7-bromoindolactam V 172 with the allylstannane 173 provided 174, which was subjected to osmylation to aVord the desired triol as the major product. After removal of the protecting groups, cytoblastin 175 was obtained.The success of the above total synthesis rests on high regio- and stereo-selectivities observed through the overall sequence (Scheme 15). Synthetic 175 matched the naturally occurring cytoblastin in all analyses performed. After re-investigation on the biological activity of 175, it was found that cytoblastin 175 exhibited an activity toward PKC that is roughly equivalent to that of (")-indolactam V.66 Three novel dimeric indoles, tenuisines A 176, B 177a and C 177b, were isolated from Kopsia tenuis.These natural products possess a unique carbon framework with a C2 axis and their structures were elucidated by spectral analysis.67 Kawaguchipeptin A 178, a novel cyclic undecapeptide, has been obtained from cyanobacterium Microcystis aeruginosa. The absolute stereochemistry of 178 was deduced by a combination of spectral and chemical studies.68 The marine sponge Cribrochalina olemda gave three cyclic peptides, kapakahines A 179, C 180 and D 181, and their structures including complete stereochemistry were elucidated by spectral analysis and chemical elucidation.The three octapeptides have identical eastern amino acid patterns.69 Arcyriacyanin A 185, a modified bisindolylmaleimide alkaloid isolated from yellowish sporangia of the slime mold Arcyria obvelata, has been prepared by three diVerent methods. The most sophisticated route is shown in Scheme 16. Namely, a domino Heck reaction between bromo(indolyl)- maleimide 182 and 4-bromoindole 183 was conducted to give rise to the hexacyclic compound 184, which was converted to 185.70 NH N NH Me O O OMe N O NH OMe OH N NH2 O OH 191 CC-1065 NH N NH OMe OMe OMe O O Me MeO2C O NH N NH OMe OMe OMe O MeO2C O NH N NH OMe OMe OMe O O Me MeO2C HO X NH N NH OMe OMe OMe O O Me MeO2C HO X 192a Duocarmycin A 192b Duocarmycin SA 193a Duocarmycin B2 X = Br 193b Duocarmycin C2 194b Duocarmycin C1 X = Br X = Cl 194a Duocarmycin B1 X = Cl N Bz Me NSO2Ph OH OBn OAc N Bz Me NSO2Ph OAc OBn N Bz Me NSO2Ph OH OBn HO OH NO2 OBn OAc OAc NO2 OBn OAc Lipase PS 195 + 196 197 78% ee (41%) AcO OH NO2 OBn Ac2O Py 74% ee (53%) HO OAc NO2 OBn PPL 199 198 PPL EtOH–Pri 2O 200 (92% ee) N Boc O 202 (92% ee) 201 Scheme 18 338 Natural Product Reports, 1998Many compounds containing an indolopyrrolocarbazole ring system have recently been reported to inhibit protein kinase C or topoisomerases. In order to develop an eVective synthetic route to the target molecules, a unified strategy via the common intermediate has recently been reported.71 Interestingly, ring expansion of the hydroxy aldehyde 186 proceeded stereo- and regio-selectively to 187, which was in turn transformed into (+)-RK-286c 188, (+)-MLR-52 189 and (+)-staurosporine 190 (Scheme 17).Reviews about CC-1065 191 and duocarmycins 192–194, which show strong cytotoxic activity, have been published.72 Enzymatic preparations of optically active precursors (196, 197, 200 and 202) of CPI unit and the common pharmacophore of CC-1065 and duocarmycins have been reported independently by two groups (Scheme 18).73 Details concerning the syntheses, chemical properties and evaluation of CC- 1065 191 and duocarmycins 192–194 have been published.74 Following the isolation of the dodecacyclic polyindole alkaloid, psycholeine 203, and the demonstration of its potential pharmacological uses, a number of chemists pursued its total synthesis.Recently, a stereocontrolled total synthesis of meso-chimonanthine 213 and meso-calycanthine 214 has been published as the initial step in the development of a strategy for the total synthesis of psycholeine 203.75 The key conversion of 204 to 206 was accomplished by a samariumpromoted reductive dialkylation via the chelation transition state 205. After Red-Al> reduction of 206, the structure of the resulting hexacyclic compound 207 was elucidated by X-ray analysis. Further transformation led to the exclusive formation of the meso-chimonanthine 213, whose structure was also confirmed by X-ray crystallography.Finally, 213 was converted to the meso-calycanthine 214 (Scheme 19). 5 References 1 K. T. Wong, B. K. H. Tan, K. Y. Sim and S. H. Goh, Nat. Prod. Lett., 1996, 9, 137. 2 S. J. Garden, J. C. Torres, A. A. Ferreira, R. B. Silva and A. C. Pinto, Tetrahedron Lett., 1997, 38, 1501. 3 T. Sakamoto, Y.Kondo, N. Takazawa and H. Yamanaka, J. Chem. Soc., Perkin Trans. 1, 1996, 1927. 4 P. Kutschy, I. Achbergerova, M. Dzurilla and M. Takasugi, Synlett, 1997, 289. 5 K. Monde, A. Tanaka and M. Takasugi, J. Org. Chem., 1996, 61, 9053. 6 W.-G. Kim, J.-P. Kim, H. Koshino, K. Shin-Ya, H. Seto and I.-D. Yoo, Tetrahedron, 1997, 53, 4309. 7 T. Shinada, M. Miyachi, Y. Itagaki, H. Naoki, K. Yoshihara and T. Nakajima, Tetrahedron Lett., 1996, 37, 7099. 8 K. Kato, M. Ono and H. Akita, Tetrahedron Lett., 1997, 38, 1805. 9 M. H. H. Nkunya, S. A. Jonker, L. K. Mdee, R. Waibel and H. Ackenbach, Nat. Prod. Lett., 1996, 9, 71. 10 T.-S.Wu, S.-C. Huang, P.-L.Wu and C.-M. Teng, Phytochemistry, 1996, 43, 133. 11 (a) H.-J. Knölker and G. Schlechtingen, J. Chem. Soc., Perkin Trans. 1, 1997, 349; (b) H.-J. Knölker and W. Fröhner, Tetrahedron Lett., 1997, 38, 1535; (c) 1997, 38, 4051; (d) 1997, 38, 533; (e) 1996, 37, 9183; (f) 1996, 37, 7947; (g) H.-J. Knölker, H. Goesmann and C.Hofmann, Synlett, 1996, 737. 12 (a) T. Choshi, T. Sada, H. Fujimoto, C. Nagayama, E. Sugino and S. Hibino, J. Org. Chem., 1997, 62, 2535; (b) T. Choshi, H. Fujimoto, E. Sugino and S. Hibino, Heterocycles, 1996, 43, 1847. 13 T.-S. Wu, S.-C. Huang and P.-L. Wu, Phytochemistry, 1996, 43, 1427. 14 (a) T.-S. Wu, S.-C. Huang and P.-L. Wu, Heterocycles, 1997, 45, 969; (b) Tetrahedron Lett., 1996, 37, 7819. 15 C. Ito, H. Ohta, H. T.-W. Tan and H. Furukawa, Chem. Pharm. Bull., 1996, 44, 2231. 16 T.-S. Wu, M.-L. Wang and P.-L. Wu, Phytochemistry, 1996, 43, 785. 17 K. Shin and K. Ogasawara, Synlett, 1996, 922. 18 Y.-K. Shue, Tetrahedron Lett., 1996, 37, 6447. 19 T. Bergmann, D. Schories and B. SteVan, Tetrahedron, 1997, 53, 2055. 20 (a) R. Uchida, K. Shiomi, T. Sunazuka, J. Inokoshi, A. Nishizawa, T. Hirose, H. Tanaka, Y. Iwai and S. Omura, J. Antibiot., 1996, 49, 886; (b) T. Sunazuka, T. Hirose, T. Zhi-Ming, R. Uchida, K. Shiomi, Y. Harigaya and S. Omura, ibid., 1997, 50, 453. 21 (a) J.-C. Jaton, K. Roulin, K. Rose, F. M. Sirotnak, A. Lewenstein, G. Brunner, C. P. Fankhauser and U. Burger, J. Nat. Prod., 1997, 60, 356; (b) B. Jaun, B. Martinoni, F. Marazza and M. Bertolin, ibid., 1997, 60, 361. 22 J.-S. Kim, K. Shin-ya, K. Furihata, Y. Hayakawa and H. Seto, Tetrahedron Lett., 1997, 38, 3431. 23 E. D. Edstrom and T. Yu, Tetrahedron, 1997, 53, 4549. 24 D. A. Johnson, P. R. August, C. Shackleton, H.-W. Liu and D. H. Sherman, J. Am. Chem. Soc., 1997, 119, 2576. 25 A. Garcia, M. J. Vazquez, E. Quinoa, R. Riguera and C. Debitus, J. Nat. Prod., 1996, 59, 782. 26 T. Hino, Yakugaku Zasshi, 1996, 116, 566. 27 B. Riemer, O. Hofer and H. Greger, Phytochemistry, 1997, 45, 337. NH N Me HN Me N HN MeN NMe NH H H 203 Psycholeine BnN O NBn O Cl Cl BnN O NBn O M Cl NBn BnN O O O N Bn N Bn Me3Al R2 = Bn 211 R1 = H, O N Bn N Bn 204 SmI2, LiCl X X 205 206 Red-Al® 207 OsO4, NMO; Pb(OAc)4; NaBH4 208 X = OH NR 1 NR 2 H R1 N R2 N H 209 X = N3 210 X = NH2 HN3, Ph3P, MeO2CN=NCO2Me Ph3P, H2O 212 R1 = Me, 213 R1 = Me, R2 = Bn R2 = H HN MeN NMe NH Na, liq.NH3 AcOH H2O 214 CH2O, NaBCNH3 Scheme 19 Toyota and Ihara: Recent progress in the chemistry of non-monoterpenoid indole alkaloids 33928 S.-W. Yang and G. A. Cordell, J. Nat. Prod., 1997, 60, 230. 29 S. D. Sarker, T. Savchenko, P. Whiting, V. Sik and L. N. Dinan, Nat. Prod. Lett., 1997, 9, 189. 30 G. Bringmann, R. God and M. SchäVer, Phytochemistry, 1996, 43, 1393. 31 R. J. Andersen, J. E. Coleman, E. Piers and D. J. Wallace, Tetrahedron Lett., 1997, 38, 317. 32 T. Kagamizono, N. Sakai, K. Arai, K. Kobinata and H. Osada, Tetrahedron Lett., 1997, 38, 1223. 33 T. Gan and J. M. Cook, Tetrahedron Lett., 1997, 38, 1301. 34 K. M. Depew, S. J. Danishefsky, N. Rosen and L. Sepp-Lorenzino, J. Am. Chem. Soc., 1996, 118, 12 463. 35 T. Gözler, B. Gözler, A. Linden and M. Hesse, Phytochemistry, 1996, 43, 1425. 36 M. Kitajima, S. Shirakawa, S. G. A. Abdel-Moty, H.Takayama, S. Sakai, N. Aimi and J. Stöckigt, Chem. Pharm. Bull., 1996, 44, 2195. 37 P. Molina, P. M. Fresneda and S. Garcia-Zafra, Tetrahedron Lett., 1996, 37, 9353. 38 Y.-P. Kim, S. Takamatsu, M. Hayashi, K. Komiyama and S. Omura, J. Antibiot., 1997, 50, 189. 39 M. Behforouz, J. Haddad, W. Cai, M. B. Arnold, F. Mohammadi, A. C. Sousa and M. A. Horn, J. Org. Chem., 1996, 61, 6552. 40 S.-W. Yang and G. A. Cordell, J. Nat. Prod., 1997, 60, 44. 41 T. Kawasaki, R. Terashima, K.Sakaguchi, H. Sekiguchi and M. Sakamoto, Tetrahedron Lett., 1996, 37, 7525. 42 T. Sano and K. Kaya, Tetrahedron Lett., 1996, 37, 6873. 43 H. C. Vervoort, S. E. Richard-Gross, W. Fenical, A. Y. Lee and J. Clardy, J. Org. Chem., 1997, 62, 1486. 44 (a) C.-B. Cui, H. Kakeya and H. Osada, Tetrahedron, 1996, 52, 12 651; (b) J. Antibiot., 1996, 49, 832. 45 H. Fujimoto, E. Negishi, K. Yamaguchi, N. Nishi and M. Yamazaki, Chem. Pharm. Bull., 1996, 44, 1843. 46 H. Wang and A. Ganesan, Tetrahedron Lett., 1997, 38, 4327. 47 C.-B. Cui, H. Kakeya and H. Osada, Tetrahedron, 1997, 53, 59. 48 A. C. Whyte and J. B. Gloer, J. Nat. Prod., 1996, 59, 1093. 49 B. H. Lee and M. F. Clothier, J. Org. Chem., 1997, 62, 1795. 50 M. Iwao and F. Ishibashi, Tetrahedron, 1997, 53, 51. 51 D. Roberts, J. A. Joule, M. A. Bros andM. Alvarez, J. Org. Chem., 1997, 62, 568. 52 C. Hopmann and W. Steglich, Liebigs Ann. Chem., 1996, 1117. 53 D. A. Venables, L. R. Barrows, P. Lassota and C. M.Ireland, Tetrahedron Lett., 1997, 38, 721. 54 G. J. Hooper, M. T. Davies-Coleman, M. Kelly-Borges and P. S. Coetzee, Tetrahedron Lett., 1996, 37, 7135. 55 R. A. Edrada, P. Proksch, V. Wray, L. Witte, W. E. G. Müller and R. W. M. Van Soest, J. Nat. Prod., 1996, 59, 1056. 56 Y. Torisawa, T. Hosaka, K. Tanabe, N. Suzuki, Y. Motohashi, T. Hino and M. Nakagawa, Tetrahedron, 1996, 52, 10 597. 57 S. Li, S. Ohba, S. Kosemura and S. Yamamura, Tetrahedron Lett., 1996, 37, 7365. 58 Y.Yokoyama, K. Kondo, M. Mitsuhashi and Y. Murakami, Tetrahedron Lett., 1996, 37, 9309. 59 H. Kang and W. Fenical, Nat. Prod. Lett., 1996, 9, 7. 60 S. V. Dubovitskii, Tetrahedron Lett., 1996, 37, 5207. 61 A. Fredenhagen, F. Petersen, M. Tintelnot-Blomley, J. Rösel, H. Mett and P. Hug, J. Antibiot., 1997, 50, 395. 62 U. Mocek, L. Schultz, T. Buchan, C. Baek, L. Fretto, J. Nzerem, L. Sehl and U. Sinha, J. Antibiot., 1996, 49, 854. 63 S. Achab, Tetrahedron Lett., 1996, 37, 5503. 64 I. Kawasaki, M. Yamashita and S. Ohta, Chem. Pharm. Bull., 1996, 44, 1831. 65 I. Mancini, G. Guella, C. Debitus, J. Waikedre and F. Pietra, Helv. Chem. Acta, 1996, 79, 2075. 66 O. A. Moreno and Y. Kishi, J. Am. Chem. Soc., 1996, 118, 8180. 67 T.-S. Kam, K. Yoganathan and H.-Y. Li, Tetrahedron Lett., 1996, 37, 8811. 68 K. Ishida, H. Matsuda, M. Murakami and K. Yamaguchi, Tetrahedron, 1996, 52, 9025. 69 B. K. S. Yeung, Y. Nakao, R. B. Kinnel, J. R. Carney, W. Y. Yoshida, P. J. Scheuer and M. Kelly-Borges, J. Org. Chem., 1996, 61, 7168. 70 M. Brenner, G. Mayer, A. Terpin and W. Steglich, Chem. Eur. J., 1997, 3, 70. 71 (a) J. L. Wood, B. M. Stoltz and S. N. Goodman, J. Am. Chem. Soc., 1996, 118, 10 656; (b) J. L. Wood, B. M. Stoltz, K. Onwueme and S. N. Goodman, Tetrahedron Lett., 1996, 37, 7335. 72 (a) D. L. Boger and D. S. Johnson, Angew. Chem., Int. Ed. Engl., 1996, 35, 1439; (b) D. L. Boger, C. W. Boyce, R. M. Garbaccio and J. A. Goldberg, Chem. Rev., 1997, 97, 787. 73 (a) L. Ling and J. W. Lown, Chem. Commun., 1996, 1559; (b) R. Chênevert and G. Courchesne, Chem. Lett., 1997, 11. 74 (a) H. Muratake, M. Tonegawa and M. Natsume, Chem. Pharm. Bull., 1996, 44, 1631; (b) S. Nagamura, A. Asai, Y. Kanda, E. Kobayashi, K. Gomi and H. Saito, Chem. Pharm. Bull., 1996, 44, 1723; (c) D. L. Boger, N. Han, C. M. Tarby, C. W. Boyce, H. Cai, Q. Jin and P. A. Kitos, J. Org. Chem., 1996, 61, 4894; (d) D. L. Boger, J. A. McKie, T. Nishi and T. Ogiku, J. Am. Chem. Soc., 1997, 119, 311; (e) D. L. Boger, D. L. Hertzog, B. Bollinger, D. S. Johnson, H. Cai, J. Goldberg and P. Turnbull, J. Am. Chem. Soc., 1997, 119, 4977; (f) D. L. Boger, B. Bollinger, D. L. Hertzog, D. S. Johnson, H. Cai, P. Mésini, R. M. Garbaccio, Q. Jin and P. A. Kitos, J. Am. Chem. Soc., 1997, 119, 4987. 75 J. T. Link and L. E. Overman, J. Am. Chem. Soc., 1996, 118, 8166. 340 Natural Product Reports, 1998

ISSN:0265-0568    

DOI:10.1039/a815327y

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

‚-Phenylethylamines and the isoquinoline alkaloids Kenneth W. Bentley Marrview, Tillybirloch, Midmar, Aberdeenshire, UK AB51 7PS Covering: July 1996 to June 1997 Previous review: 1997, 14, 387 1 ‚-Phenylethylamines 2 Isoquinolines 3 Naphthylisoquinolines 4 Benzylisoquinolines 5 Bisbenzylisoquinolines 6 Cularines 7 Pavines and isopavines 8 Berberines and tetrahydroberberines 9 Secoberberines 10 Protopines 11 Phthalide-isoquinolines 12 Spirobenzylisoquinolines 13 Indanobenzazepines 14 Rhoeadines 15 Other modified berberines 16 Emetine and related alkaloids 17 Benzophenanthridines 18 Aporphinoid alkaloids 18.1 Proaporphines 18.2 Aporphines 18.3 Dimeric aporphines 18.4 Benzylisoquinoline–aporphine dimers 18.5 Phenanthrenes 18.6 Oxoaporphines 18.7 Dioxoaporphines 18.8 Aristolochic acids and aristolactams 19 Alkaloids of the morphine group 20 Phenethylisoquinolines 21 Colchicine 22 Erythrina alkaloids 22.1 Erythrina alkaloids 22.2 Cephalotaxine and related alkaloids 23 Other isoquinolines 24 References 1 ‚-Phenylethylamines trans-N-Feruloyltyramine has been isolated from Stephania cepharantha.1 The yields of ephedrine and dihydropseudoephedrine from plants derived from axillary buds of Ephedra gerardiana and from the parent plants have been compared.2 Ephedrine and pseudoephedrine have been condensed with paraformaldehyde to give the oxazolines 1a and 1b, respectively, 3 and the oxazolines 2a, 2b and 2c have been prepared from pseudoephedrine.4 N-Cyanomethylephedrine and N-cyanomethylpseudoephedrine have been prepared.5 Complexes of ephedrine and of norephedrine with copper, nickel and cobalt salts have been prepared, the copper derivatives being much the most stable.6 Highly diastereoselective additions of lithium alkyls to the (2S)-aziridine aldehyde 3 have been achieved, as a result of chelation-controlled carbon–carbon bond formation, to give the alcohols 4, which have been catalytically reduced selectively to 5, relatives of ephedrine and pseudoephedrine.Similar reactions have been accomplished with the R isomer of 3.7 The pharmacological and physiological eVects of ephedrine, 8,9,10 of methylephedrine10 and of pseudoephedrine11 have been studied. 2 Isoquinolines The new alkaloids stephaoxocanine 6 and stephaoxocanidine 7 have been isolated from Stephania cepharantha.1,12 These are analogues of excentricine, reported in the previous review, and a comparison of the spectra of these three alkaloids has suggested12 a reversal of the absolute stereochemistry of excentricine from that given in the previous review to 8a.Methylexcentricine, 8b on this basis, has been isolated as a new alkaloid from Stephania excentrica.13 7-ODemethylisosalsolidine 9 has been isolated as a new alkaloid from Hernandia nymphaeifolia.14 N-Cyanomethylsalsoline has been prepared.5 A convenient process for the synthesis of (&)-carnegine from N-methylhomoveratrylamine and acetic acid, by Bischler–Napieralsky cyclisation with polyphosphoric acid and subsequent reduction with sodium borohydride, has been described.15 A stereospecific synthesis of (R)-salsolidine 10 has N Me O CH2 R1 Me N Me O R Ph Me R2 1a R1 = Ph; R2 = H 1b R1 = H; R2 = Ph 2a R = CHMe2 2b R = Ph 2c R = p-Anisyl N N HN R R C Ph Me H C Ph Me H C Ph Me H Me H CHO H H H H OH OH 3 4 5 N O N OH MeO MeO Me MeO HO H NH O OH MeO MeO H NR O OH MeO MeO H H H OH 6 7 9 8a R = H 8b R = Me Bentley: ‚-Phenylethylamines and the isoquinoline alkaloids 341been achieved by the catalytic reduction of 1-methyl-6,7- dimethoxy-3,4-dihydroisoquinoline using the chiral zinc complex 11 as catalyst.16 The benzophenone amide 12 has been cyclised to the 4-aryltetrahydroisoquinolone 13 by potassium hexamethyldisilazide, and the product has been reduced with lithium aluminium hydride to (&)-O-methylcherylline.17 3 Naphthylisoquinolines Five new naphthylisoquinoline alkaloids have been isolated from the following plant species: Ancistrocladus tectorius18 6-O-methyl-8-O-demethylancistrocladinine 14a, 6-O - methyl-4*-O-demethylancistrocladinine 14b and 6-Omethyl- 8,4*-O-demethylancistrocladinine 14c Ancistrocladus korupensis19 yaoudamine A 16 and its 6-rhamnoside (yaoudamine B).Spectroscopic studies suggest that the free bases 14a and 14c exist in the tautomeric keto forms 15a and 15b. The absolute stereochemistry of these alkaloids at C-3 has been deduced from their CD spectra and confirmed by the oxidation of 14c to (3S)-aminobutyric acid.18 The Grignard reagent 18 has been condensed with the dihydrooxazole 17 and the product has been hydrolysed to the amide 19a, which was separated into its atropomers in the ratio 6:1, the major component of which was converted into O-methylancistocladine 19b.20 The boronic acid derivative 20a has been condensed with the iodides 21a and 21b to give, after reduction and removal of the benzyl groups from oxygen and nitrogen, ancistrobrevine B and korupensamine C.21 In a similar manner korupensamine D has been prepared from 20b and 22.22 The bromo compound 23 has been coupled with the organotin derivative 24 to give O-benzylkorupensamines A and B, which have been oxidised by silver oxide and debenzylated to give a mixture of michellamines A, B and C.23 Palladium-catalysed cross coupling of tetrabenzylkorupensamine A 6*-boronic acid with 6*-bromotetrabenzylkorupensamine B, followed by removal of the benzyl groups, has aVorded michellamine B only.24 A patent has been published covering previously described syntheses of the michellamines, directly and from the korupensamines.25 Interest in the antiviral properties of the michellamines has led to the synthesis of analogues of these alkaloids. 4,4*- Didemethoxy-2,2*-didemethylmichellamine B 25, synthesised by processes analogous to the previously reported direct synthesis of michellamine, inhibits recombinant HIV reverse transcriptase at 60 Ïg ml"1.26 The naphthyltin derivative 24 has been converted into 26a, and oxidation of the related phenol 26b gave a dimeric quinone, which was reduced to S Zn N NH MeO MeO Me Me MeO MeO OMe O N O Me Ph2P O Et Me Ph Me MeO MeO NMe O OMe 10 11 12 13 N MeO OR2 Me Me OMe OR HO MeO Me NH OMe Me OR1 O Me MeO N Me OMe HO Me Me Me 14a R1 = Me; R2 = H 14b R1 = H; R2 = Me 14c R1 = R2 = H 15a R = Me 15b R = H 16 NH OMe OMe OMe MgBr MeO OMe OMe OMe R N O N Me MeO OMe Me Pri Me Me 17 18 19a R = CONH2 19b R = Me N N Me OMe OR B(OH)2 O I OR Ph Ph O Ph I O Ph Ph N O Ph Br O Ph Ph Me Me Me Me Me Me Me OMe OPri SnBu3 22 23 20a R = Me 20b R = H 21a R = Me 21b R = CH2Ph 24 342 Natural Product Reports, 1998pindikamine A 27, with an unnatural ‘skew’ structure.This shows no antiviral activity, but is active against Plasmodium falciparum at 1.23 Ïg ml"1, compared with 3.49 Ïg ml"1 for the monomer 26b.27 Dioncophylline A 28a has been brominated to 28b, the benzyl ether of which was dimerised by tert-butyllithium at low temperature to a single rotamer of jozimine A 29, which equilibrated to a mixture at room temperature.This was found to be active at 0.75 Ïg ml"1 against the asexual erythrocytic stage of Plasmodium falciparum; the monomer 28a is active against the same organism at 1.44 Ïg ml"1.28 Antimalarial activity has also been found in 7-epidioncophylline A, 5*-O-demethyl-6-Omethyl- 7-epidioncophylline A, dioncolactone A and dioncophylline C, the last being the most active of the whole group with IC50=0.014 Ïg ml"1.29 Dioncophylline A and some of its 8-ethers, especially the 8-O-benzyl and 8-O-(4-bromobenzyl) derivatives, show growth retardant activity against larvae of Spodoptera littoralis; studies of other derivatives shows that a free NH group is essential for this activity.30 4 Benzylisoquinolines Benzylisoquinoline alkaloids have been isolated from the following plant species, the six marked with asterisks being new alkaloids: Berber turcomanica31,32 papaverine and turcomanine* 30 Papaver setigerum33 laudanosine, papaverine, setigerine* 31a and setigeridine* 31b Polyalthia insignis34 polysignine* 32a and methoxypolysignine* 32b Stephania cepharantha1,35 coclaurine, N-methylcoclaurine, juziphine, norjuziphine, laudanidine, protosinomenine and reticuline Stephania excentrica36 coclaurine and N-methylcoclaurine Zanthoxylum nitidum37 isotembetarine chloride* 33.The crystal structure of papaverine38 and the 15N NMR spectrum of armepavine39 have been studied. N-Chloroacetylnorlaudanosine methine 34, on photolysis in the presence of oxygen, has given the cyclised lactams 35 and 36.40 The condensation of L-gluconolactone with homoveratrylamine has yielded the amide 37, which was cyclised, N-methylated and reduced to 38a. Oxidation of this to the aldehyde 38b, followed by treatment with 3,4- dimethoxyphenyllithium, aVorded hydroxy-(R)-laudanosine 39a, which was hydrogenolysed to give (R)-(")-laudanosine 39b.41 (S)-(")-Norlaudanosine has been synthesised in good enantiomeric yield by the hydrogenation of 1-(3,4- dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline in the presence of chiral iridium complexes,42 and stereoselective reduction of the corresponding 1-(3-hydroxybenzyl) compound has given (R)-noranicanine.43Bischler–Napieralsky cyclisation of the amide 40, followed by reduction of the resulting chiral iminium salt and N-methylation, has aVorded the benzylisoquinoline 41,44 which diVers from the alkaloid fumarizine, to which this structure has been assigned.45 The Reissert compound 42 on treatment with 2-benzyloxy- 3,4-methylenedioxybenzaldehyde has given 43, which was HN HN OH OR OMe Me OMe N OH MeO Ph OH OMe Me OMe Me OH OH NH NH Me Me Me Me Me Me Me Me Me Me OH HO MeO OH 25 27 26a R = Pri 26b R = H MeO MeO Me NH R OH Me Me HN NH OH OMe OMe Me OH MeO MeO Me Me Me Me Me 28a R = H 28b R = Br 29 N MeO OH MeO MeO NMe2 MeO MeO +NMe2 OR2 OR1 OMe OH OMe R N MeO HO OH OH MeO H Cl– 30 33 31a R1 = R2 = Me 31a R1R2 = CH2 32a R = H 32b R = OMe Bentley: ‚-Phenylethylamines and the isoquinoline alkaloids 343converted by conventional methods into 44, found to be identical with the alkaloid sauvagnine,46 to which a cularinelike structure has been assigned. The physiological eVects of papaverine47 and of atracurium48,49 have been studied. 5 Bisbenzylisoquinolines Bisbenzylisoquinoline alkaloids have been isolated from the following plant species, the six marked with asterisks being new alkaloids: Berberis crataegina50 aromoline, berbamine, isotetrandrine and oxyacanthine Berberis turcomanica32 aromaline and oxyacanthine Dehaasia triandra51 homoaromoline and thalrugosinone Hernandia nymphaeifolia14 vatteamine 2*‚-N-oxide* 45 Isopyrum thalictroides52 fangchinoline, isopyruthaline* 46 and isopythaline* 47 Mahonia aquifolium53 aquifoline, aromoline, baluchistanamine, berbamine, obamegine and oxyacanthine Pachygone dasycarpa54 angchibangkine* 48, atherospermoline, cosculine, 2*-norcosculine, daphnoline, fangchinoline, isoboldine, 7-O-demethyl-N-methylpeinamine, penduline, tetrandrine, tricordatine and 12-O-methyltricordatine* 49 Stephania cepharantha1 berbamine, 2-norberbamine, cepharanthine, 2-norcepharanthine, cepharanoline, 2-norcepharanoline, cycleanine, 3,4-dehydrocycleanine* 50, homoaromoline, isotetrandrine, 2-norisotetrandrine, obaberine, obamegine, secocepharanthine, stephababerine, 3,4-dehydrostephasuberine and thalugosinone.Angchibangkine 48 represents a new type of bisbenzylisoquinoline alkaloid, having a skeleton isomeric with that of all of the alkaloids of the trilobine group, which have the arrangement of three diphenyl ether linkages shown in 49. Both angchibangkine and 12-O-methylisocordatine show appreciable activity against Plasmodium falciparum.The physiological eVects of aquifoline,53 of aromoline,53 of baluchistanamine,53 of berbamine,53 of fangchinoline,55 of hernandezine,56 of obamegine,53 of oxyacanthine53 and of tetrandrine56–75 have been studied. 6 Cularines Cularine cis-N-oxide 51a and sarcocapnine cis-N-oxide 51b have been isolated from Ceratocapnos heterocarpa, the relative stereochemistry being deduced from studies of the spectra of cularine cis- and trans-N-oxides prepared from the free base.76 Clavizepine 5b has been synthesised from the thioketal 52, prepared by an internal Ullmann reaction. An elimination reaction converted this into 53a, which was desulfurised to 53b, and oxidation of this with osmium tetroxide aVorded the diol 54.Rearrangement of this by sodium hydride gave the aldehyde 55a, which was converted through the alcohol 55b and its ester 55c into the amino acetal 55d, and this was cyclised and reduced to clavizepine 56.77 Following a successful synthesis of dioxoaporphine (Section 18.7), the diphenyl ether 57 was condensed with oxalyl chloride and stannic chloride with simultaneous Bishler–Napieralsky cyclisation of the intermediate 58 to give a mixture of dioxocularine 59, the ring-contracted 60 (which is an isomer of aristoyagonine) and the dibenzopyran 61.78 Following the identification of sauvagnine as the benzylisoquinoline 4446 and of linaresine as rugosinone,79 the NMR spectra of these alkaloids have been reinterpreted.46 OMe OMe MeO MeO MeO MeO N COCH2Cl Me NMe NMe O O MeO O MeO OMe OMe OMe H HO 34 35 36 NMe NMe MeO MeO NH O MeO MeO MeO MeO R OH HO OH OH OH R OMe OMe H H 37 38a R = [CH(OH)]4CH2OH 38b R = CHO 39a R = OH 39b R = H O O N O O N O O O O NMe O O O O NCOPh CN O O O O NCOPh O O O MeO CH MeO O Ph O OH NC Ph H Me OH 40 41 42 43 44 344 Natural Product Reports, 19987 Pavines and isopavines Amurensinine has been isolated from Papaver caucasicum (P.fugax)80 and N-methylamurensinine chloride has been isolated as a new alkaloid, together with the free base, from Meconopsis robusta.81 The N-alkylpavines 62a–62e have been prepared by the selective N-demethylation of the related N-alkyl-N-methylpavine quaternary salts by heating in refluxing 2-aminoethanol. 82Photolysis of N-chloroacetylpavine 62f has aVorded 63.83 Homoveratric aldehyde has been condensed with N,N-bis-di (trimethylsilyl)formamide to give 64, which has been cyclised to N-formylpavine 62g and this has been hydrolysed to pavine 62h and reduced to argemonine 62i.84 The keto acid 65 has been condensed with (S)-phenylglycinol to give the oxazoline 66, which was reduced by red aluminium at low temperature to the lactam 67a, which was converted through 67b into 67c. Reduction of this gave the hydroxy amide 68, which was cyclised via the iminium ion 69 to pavine 62h, which was converted through 62g into (+)-argemonine 62i.85 The antiviral activity of thalimonine has been studied.86 8 Berberines and tetrahydroberberines Alkaloids of this group have been isolated from the following plant species, the four marked with asterisks being new alkaloids: +N MeO HO MeO H Me O– MeN OMe OH OMe H OH NMe MeO H MeN OMe OMe OMe H O OMe MeO OMe O O NMe MeO H MeN OMe OMe OMe H O OMe O O O O N Me MeN O OH H O O N Me MeN O OMe H H OMe OH H NMe MeO MeO MeN O O OMe OMe H H 48 49 50 45 O 46 47 +N O R1 MeO R2 MeO O– H Me 51a R1 = H; R2 = OMe 51b R1 = OMe; R2 = H O O O O MeO S S MeO OMe MeO OMe R MeO MeO OH OH MeO OMe OMe OMe R MeO O NMe OMe OMe MeO 52 53a R = S(CH2)3SH 53b R = H 54 55a R = CHO 55b R = CH2OH 55c R = CH2OTos 55d R = NMeCH2CH(OMe)2 56 NMe O MeO OMe MeO NMe O O OMe OMe MeO MeO MeO OMe O MeO OMe O MeO OMe NHMe O NMe O Cl O O O O O Cl H 57 58 59 60 61 MeO MeO Bentley: ‚-Phenylethylamines and the isoquinoline alkaloids 345Berberis crataegina50 berberine, columbamine, jatrorrhizine and palmatine Berberis ilicifolia87 ilicifoline* 70 Berberis turcomanica31,32 berberine Corydalis racemosa88 tetrahydropalmatine Eschscholtzia californica89 berberine Fumaria densiflora90 coptisine, scoulerine, sinactine, stylopine and N-methylstylopine chloride Fumaria indica91 8-hydroxystylopine glucoside* 71 Hernandia nymphaeifolia92 N-methylcoralydine chloride Meconopsis cambrica81 mecambridine and N-methylmecambridine chloride Meconopsis robusta81 coptisine and corysamine Papaver setigerum33 coptisine, scoulerine and stylopine Polyalthia cerasoides93 cerasodine* 72a and cerasonine* 72b Stephania cepharantha1 scoulerine Zanthoxylum nitidum37 cis-N-methylcanadine chloride.Ilicifoline is the first dimeric berberine of its type to be discovered. Berberine and its analogues have been shown to react with methanol to give 8-hydroxymethyl compounds such as 73a and 73b, and the latter has been further converted in the presence of oxygen into solidaline 74.94 The amide 75 has been cyclised by phosphorus pentachloride via 76 to the iminium salt 77, reduction of which gave coralydine.95 N-Acetyl- and N-ethoxy-carbonylhomoveratrylamine and homoveratric acid have been converted, via the amides 78a and 78b, into 79a and 79b, and reduction of these with sodium borohydride, followed by further cyclisation, aVorded 77 and 80a, which were converted into coralydine 80b and xylopinine 80c.15 The chiral benzylic lactam 66 has been reduced to (S)-(")-norlaudanosine, which gave (S)-(")- xylopinine 80c on condensation with formaldehyde.85 The physiological eVects of berberine,96–100 of tetrahydroberberine, 101,102 of N-(4-chlorobenzyl)tetrahydroberberine chloride,103 of coralyne,104 of govadine,105 of 12-chloroscoulerine, 106 of stepholidine,102,107–111 of tetrahydropalmatine88,102,112,113 and of N-benzyltetrahydropalmatine chloride114 have been studied.MeO MeO OMe OMe NR MeO MeO OMe OMe NR MeO MeO OMe OMe NCHO OH Me3SiO OSiMe3 63 R = COCH2Cl 64 62a R = Et 62b R = Pr n 62c R = Bu n 62d R = CH2CH=CH2 62e R = CH2Ph 62f R = COCH2Cl 62g R = CHO 62h R = H 62i R = Me NR MeO MeO MeO MeO CO2H O MeO MeO N O O OMe OMe O OMe OMe OMe OMe Ph H H 65 66 67a R = CH(Ph)CH2OH 67b R = H 67c R = CO2But NBoc MeO MeO OH OMe OMe NH MeO MeO OMe OMe H H + 68 69 N MeO MeO OMe OMe N N MeO HO OMe OR O O O O N OMe OMe OMe MeO O O O OC6H11O5 70 71 72a R = H 72b R = Me N MeO MeO OMe N MeO MeO OMe R OH Me O OMe OMe 74 73a R = H 73b R = Me 346 Natural Product Reports, 19989 Secoberberines Two new secoberberine alkaloids, fumaflorine 81a and its methyl ester 81b, have been isolated from Fumaria densiflora.90 10 Protopines Alkaloids of the protopine group have been isolated from the following plant species: Eschscholtzia californica89 hunnemanine Fumaria densiflora90 cryptopine and protopine Fumaria indica91 pseudoprotopine Meconopsis cambrica81 allocryptopine and protopine Meconopsis robusta81 allocryptopine, cryptopine and protopine 11 Phthalide-isoquinolines Adlumine and bicuculline have been isolated from Fumaria densiflora.90 The secoberberine fumaflorine 81a, isolated from the same plant, may also be assigned to this group.Treatment of the tetrahydroisoquinoline 82a with methyllithium aVords the C-1 anion and this reacts with magnesium bromide to give the C-1 Grignard reagent. This in turn reacts stereoselectively with piperonal to give the erythro compound 83 and these processes show more regio- and stereo-selectivity than similar reactions previously reported with simpler analogues of 82.The alcohol 83 has been converted as previously reported into the alkaloids egenine and bicuculline, and the dimethoxy compound 82b has been similarly converted into corlumine.115 The physiological eVects of adlumine,116 of bicuculline,117 of norbicuculline116 and of hydrastine118,119 have been studied. 12 Spirobenzylisoquinolines Fumaricine, fumariline, fumarophycine and parfumine have been isolated from Fumaria densiflora.90 13 Indanobenzazepines Fumaritridine, fumaritine and fumarofine have been isolated from Fumaria densiflora.90 14 Rhoeadines Alkaloids of the rhoeadine group have been isolated from the following plant species: Meconopsis cambrica81 papaverrubine C and papaverrubine D Meconopsis robusta81 rhoeadine Papaver setigerum33 papaverrubines A, B, C, D and E. 15 Other modified berberines A ring-C homoberberine of a new type, hediamine 84, has been isolated from Berberis actinacantha.120 Although this has the NHCOMe MeO MeO O OMe OMe SiPh2 But N MeO MeO Cl OMe OMe +N MeO MeO OMe OMe Me Me 75 Cl– 76 77 NHCOR MeO MeO OMe OMe NCOR MeO MeO OMe OMe N MeO MeO O OMe OMe X H 79a R = Me 79b R = OEt 80a X = O 80b X = H,Me 80c X = H,H 78a R = Me 78b R = OEt N MeO MeO CO2R O O O 81a R = H 81b R = Me N R1O R2O N O O N O N O Me Me O O HO H 82a R1R2 = CH2 82b R1 = R2 = Me 83 Bentley: ‚-Phenylethylamines and the isoquinoline alkaloids 347same carbon–nitrogen skeleton as puntarenine 85a and saulatine 85b, the arrangement of substituents show that these two alkaloids are ring-B homoberberines. Puntarenine and saulatine are regarded as artefacts rather than natural alkaloids, puntarenine arising from berberine-chloroform 86 (produced from berberine during extraction of plant material with chloroform and ammonia) via the intermediates 87–90,121 and it may be noted that reductive opening of the aziridine ring of 87 and hydrolysis of the gem-dichloride would aVord hediamine 84. The tetrahydroisoquinoline 91a has been reduced to 91b, which was cyclised by phosphorus trichloride to the amine 92, the N-oxide of which suVered Polonovski rearrangement to give the isoxazolidine 93.Reduction of this gave the alcohol 94a, which was converted through the ketone 94b into the unsaturated ketone 95. This could not be acylated, but 94a was N-acylated and oxidised to 96a, which was converted through 96b into 97a.Conversion of this into the palladium derivative 97b enabled cyclisation to be eVected to give 98, from which the palladium was eliminated to give magallanesine 99.122 16 Emetine and related alkaloids The likely biological conversion of alangiside into azaberberine alkaloids has been reproduced in the laboratory. Alangiside 100a has been hydrolysed in a phosphate/citric acid buVer to the aglycone 100b, which may be assumed to be in equilibrium with 101, and this, when treated with ammonia and trifluoroacetic acid, was converted into (+)-alagimaridine 102a.In a similar manner, dihydroalangiside has been converted into (+)-dihydroalangimaridine 102b.123 17 Benzophenanthridines Alkaloids of the benzophenanthridine group have been isolated from the following plant species: Eschscholtzia californica89 sanguinarine Zanthoxylum nitidum37 chelerythrine and nitidine. The 15N NMR spectra of chelerythrine and sanguilutine have been studied.124 Fagaridine 103a has been oxidised to the quinone 104, reduction of which has aVorded 8,10-Odemethylsanguilutine 103b.125 O-Demethylation of oxofagaridine 105a has given 105b, partial benzylation of which gave 105c, and reduction of this with lithium aluminium hydride N OMe OMe O N OR2 O O MeO OMe O O R1O A B C D A B C D 85a R1R2 = CH2 85b R1 = R2 = Me 84 N O O C OMe OMe Cl Cl Cl +N O O OMe OMe Cl Cl O N O O OMe OMe Cl Cl O O O N MeO OMe O O +N O O OMe OMe Cl Cl H H : 86 – OH– HO– 89 88 87 90 O O NH O O N O O N R O 91a R = CO2Me 91b R = CH2OH 92 93 O O NH O O NH R1 R2 O 94a R1 = H; R2 = OH 94b R1R2 = O 95 O O N O O R OMe OMe O O N O O OMe OMe R 96a R = H 96b R = SPh 97a R = H 97b R = PdBr O O N O PdBr OMe OMe O O N O OMe OMe O 98 99 348 Natural Product Reports, 1998yielded 106a.O-Methylation of this aVorded 106b, which was debenzylated to dihydroisofagaridine 106c, and this was oxidised to isofagaridine, isomeric with 103a, confirming the structure of this alkaloid.126 Oxochelerythrine 105d has been synthesised by the palladium-assisted internal biaryl coupling of the amides 107a and 107b.127 The keto ester 108, on treatment with benzylamine, acetyl chloride and titanium tetrachloride, gave a mixture of the enamide 109 and the naphthyl amide derivative 110, and the latter was cyclised by phosphorus oxychloride (but not by phosphorus pentachloride) to 11-acetoxy-Nbenzylnornitidine 111.95 A review of methods of synthesis of benzophenanthridine alkaloids has been published.128 The physiological eVects of chelerythrine129–132 and of sanguinarine132–135 have been studied. 18 Aporphinoid alkaloids 18.1 Proaporphines Proaporphine alkaloids have been isolated from the following plant species: Croton ruizianus136 crotsparine and jacularine N O MeO HO H O N CHO CHO MeO HO H O N N MeO HO H O R H H H H OR 100a R = Glucose 100b R = H 101 102a R = CH=CH2 102b R = Et +NMe O O MeO OH +NMe O O MeO O NMe O O R1O OR2 NMe O O R1O OR2 O O R OH– OH– 103a R = H 103b R = OH 104 105a R1 = Me; R2 = H 105b R1 = R2 = H 105c R1 = CH2Ph; R2 = H 105d R1 = R2 = Me 106a R1 = CH2Ph; R2 = H 106b R1 = CH2Ph; R2 = Me 106c R1 = H; R2 = Me R MeO OMe NMe O O O 107a R = Br 107b R = I MeO MeO O MeO MeO +N O O MeO MeO N O O MeO MeO N O O MeO2C MeO2C CO CH2 Me Ph CO CH2 Me Ph AcO Me CH2Ph AcO OMe OMe 108 109 110 111 NMe NH O O NH O O MeO MeO O O NR MeO MeO O O OH MeO MeO MeO HO CHO 112 113 114a R = Me 114b R = H 115 +NMe2 MeO MeO MeO MeO OH NMe NMe2 CHO MeO MeO MeO MeO MeO MeO OH NMe MeO MeO OH H Cl– 116 117 118 119 Bentley: ‚-Phenylethylamines and the isoquinoline alkaloids 349Meconopsis cambrica81 mecambrine Papaver caucasicum80 mecambrine Stephania cepharantha1,35 N-methylcrotsparine and stepharine. 18.2 Aporphines Aporphine alkaloids have been isolated from the following plant species, the eleven marked with asterisks being new alkaloids: Berberis crataegina50 magnoflorine Berberis turcomanica32 glaucine, isocorydine and thalicmidine NCO2Me NMe MeO O MeO MeO O O CH2OR OMe MeO H H 121a R = H 121b R = Me 120 NMe MeO MeO HO MeO H NMe MeO MeO MeO H NAc MeO NAc MeO N MeO N MeO OMe OMe O OMe OMe Me OH OMe OMe OMe OMe OMe Br 122 124 125 123 126 127 NMe MeO MeO HO MeO NH MeO MeO HN OMe OMe R1 R2 MeN OMe OMe OH OMe H H NMe MeO MeO MeO HO NMe MeO MeO MeO O NMe MeO MeO MeO HO NMe MeO MeO MeO H H H H 129 128a R1 = R2 = H 128b R1 = R2 = OMe 128c R1 = H; R2 = OMe O 130 131 NMe N O O CO H R1O R2O N O O H OR1 OR2 N CO H HO MeO N H OH OMe MeO MeO OMe OMe MeO MeO 132 134 133a R1 = R2 = CH2 133b R1 = Me; R2 = H CHO O MeO CHO MeO OMe 135 NMe2 NMe2 N MeO MeO MeO OH OMe MeO MeO MeO HO Me CO2R O O O 138 139 136 137a R = H 137b R = OH N MeO MeO Me R O O 350 Natural Product Reports, 1998Cissampelos glaberrima137 cissaglaberrimine* 112 Dehaasia triandra51,138 dehydroisocorydione* 113, isocorydione* 114a, norisocorydione* 114b, isoboldine, norisocorydine, Nmethyllaurotetanine, N-methyllindcarpine and nantenine Fumaria densiflora90 corytuberine Hernandia nymphaeifolia14,92 hernandaline, 7-formyldehydrohernangine* 115 and N-methylovigerine Magnolia sieboldii139 magnoporphine* 116 Meconopsis cambrica81 corytuberine, magnoflorine, mecambroline, roemerine and roemeroline Meconopsis robusta81 corytuberine and magnoflorine Ocotea benesii140 3-hydroxynuciferine* 118, 3-hydroxydehydronuciferine* 119 and isocorydine Ocotea holdrigeana141 corytuberine, isocorydine and norisocorydine Papaver caucasicum80 nuciferine, nornuciferine and roemerine N MeO MeO R O CHO OMe OMe 140a R = H 140b R = OMe NMe MeO MeO OMe O O OMe NH MeO MeO OMe O O OMe O O 141 142 OMe OMe O O CO2H MeO MeO MeO MeO R O N CO CO 143 144 145 146a R = OH 146b R = Cl 146c R = CN 146d R = CO2H 146e R = MeO MeO MeO MeO R NMe O Cl O N NMe MeO MeO NMe MeO MeO O O O 148 147a R = 149 147b R = OH 147c R = NHMe 150 HO MeO N O OMe 151 NMe O HO NMe O HO NMe R1 CH2N R1 R2 CH2Ph N O R2 HO MeO H H HO 152a R1 = R2 = Me 152b R1 = Me; R2 = Et 152c R1 = R2 = Et 153 154a R1 = R2 = H 154b R1 = Cl; R2 = H 154c R1 = Br; R2 = H 154d R1 = H; R2 = Cl NMe O MeO NMe O MeO MeO C HO R2 R1 COR MeO 155a R1 = H; R2 = Ph 155b R1 = Ph; R2 = H 155c R1 = Me; R2 = Ph 155d R1 = Ph; R2 = Me 156a R = Ph 156b R = H 156c R = Me Bentley: ‚-Phenylethylamines and the isoquinoline alkaloids 351Papaver setigerum33 corytuberine, isoboldine and magnoflorine Polyalthia insignis34 assimilobine Rollinia mucosa142 anonaine, glaucine, purpureine and romucosine* 120 Stephania cepharantha1,35 anonaine, corydine, isoboldine, isocorydine, isocorytuberine, litsiferine and N-methyllaurotetanine Stephania excentrica13 isoboldine and roemerine Thalictrum fauriei143 faurine* 121a and O-methylfaurine* 121b Thalictrum simplex144 ocoteine, preocoteine, preocoteine N-oxide, thalicmidine, thalicmidine N-oxide and thalicsimidine Thalictrum thalictroides145 magnoflorine Xylopia papua146 anonaine and xylopine Zanthoxylum nitidum37 magnoflorine and menispermine.Of the new alkaloids the structure of dehydroisocorydione was confirmed by its preparation from (S)-(+)-isocorydine 122 by oxidation with Fremy’s salt,138 and that of romucosine by its preparation from the related secondary base, anonaine, by treatment with methyl chloroformate and trimethylamine.142 Only an abstract of the paper in which the structure 116 is assigned to magnoporphine is readily available, but the amine salt would be expected to lose a proton to give the aldehydo base 117; structures analogous to 116 have not previously been assigned to the salts of pseudo bases in the isoquinoline alkaloid series.The alkaloid faurine is probably the product of oxidation of a benzylisoquinoline–aporphine dimer. The 13C and 15N NMR spectra of roemeridine have been studied.124 (R)-(")-Laudanosine, prepared from L-gluconolactone (Section 4) has been oxidised by chromium trioxide to (R)-(")-glaucine 123.41 Photocyclisation of the 6*-bromobenzylidenetetrahydroisoquinoline 124 has given the N O O HO R OH Cl F N O HO HO X H R N O HO HO X H N O OH OH X H 157a R = Ph 157b R = 157c R = 157d R = a-Naphthyl 157e R = 9-Anthracenyl 157f R = 3-Pyridyl 157g R = 4-Pyridyl 158a X = O; R = CO2H 158b X = H,H; R = CH2OH 159a X = O 159b X = H,H NR O O HO O NMe O HO OH Cl O CH2 NR O O HO NH Cl O CH2 HN Me Et2NOC CH2 CH2 N O HO OH X Me2NOC NMe O HO OH N NMe O O HO N O O 160a R = Me 160b R = 161a R = Me 161b R = 162 163a X = NH 163b X = O 164 165 MeO O MeO H O MeO MeO Cl Cl 166 167 N O AcS AcO H N O N3 HO H O 168 169 N N MeO MeO OMe OMe OMe OMe MeO MeO 170 171 352 Natural Product Reports, 1998dehydroaporphine 125 and oxidation of this with Fremy’s salt aVorded the oxoaporphine 126, which reacted with methylmagnesium bromide to give (&)-sinomendine 127.147 The physiological eVects of boldine148 and of apomorphine149 –157 and the eVects of a series of 11-substituted- (R)-aporphines on the dopamine-2A and 5-hydroxytryptamine- 1A receptors158 have been studied.A method for the estimation of apomorphine has been published.159 18.3 Dimeric aporphines Urabaine 128a and the new 7,7*-dimers 7,7*-bis(dehydro-Omethylisopiline) 128b and 7-dehydronuciferyl-7*-dehydro- O-methylisopiline 128c have been isolated from Polyalthia bullata.160 The first carbon–carbon and carbon–oxygen– carbon coupled aporphines that are direct analogues of the bisbenzylisoquinolines and the benzylisoquinoline–aporphine dimers have been identified in the 8,8*-linked bis-(S)- isocorydine 129 and its R isomer, the 8,9*-linked dehatriphine 130138 and the 8,11*-oxygen-linked O-bisisocorydine 131,51 all isolated from Dehaasia triandra.The structure of 8,8*- bis-(S)-isocorydine was confirmed by its preparation from (S)-isocorydine by oxidation with manganese trisacetylacetonate. 51 Dehatriphine is formulated as a dimer of isocorydine and N-methyllaurotetanine, but an attempt to confirm this by fission of the alkaloid with sodium and liquid ammonia yielded the aporphine 132 as the only identifiable product.138 The new carbamides ovigeridimerine 133a, ovihernangerine 133b and oviisocorydine 134, isolated from Hernandia nymphaeifolia14,92 can be formally regarded as aporphine dimers, but are more logically seen as derivatives of simple aporphines. 18.4 Benzylisoquinoline–aporphine dimers Thalicarpine has been isolated from Hernandia nymphaeifolia.92 Faurine (Section 18.2), oxohernandaline and 4-methoxyoxohernandaline (Section 18.6) are presumably products of oxidation of bases of this group, as may also be the diphenyl ether dialdehyde hernandial 135, isolated with 4-methoxyoxohernandaline from Hernandia nymphaeifolia.14 18.5 Phenanthrenes Secoaporphines, which are derivatives of phenanthrene, have been isolated from the following plant species, the four marked with asterisks being new alkaloids: Dehaasia triandra51 secoxanthoplanine* 136 Thalictrum simplex144 northalicthuberine* 137a, N-hydroxynorthalicthuberine* 137b thalihazine and thalihazine N-oxide* 138.The structures of the new alkaloids have been confirmed by the preparation of secoxanthoplanine by the Hofmann degradation of xanthoplanine and by the reduction of thalihazine N-oxide to thalihazine. Apocodeine has been converted into a series of alkyloxycarbonylnorapocodeines 139 by treatment with alkyl chloroformates.161 The physiological eVects of N-allylnorsecoboldine have been studied.162 18.6 Oxoaporphines Oxoaporphine alkaloids have been isolated from the following plant species, the two marked with asterisks being new alkaloids: Artabotrys zeylanicus163 atherospermidine, lanuginosine, liriodenine, oxobuxifoline and oxocrebanine Hernandia nymphaeifolia14,92 oxohernandaline* 140a and 4-methoxyoxohernandaline* 140b MeO MeO MeO O OMe NH MeO MeO MeO O R NHAc MeO MeO MeO R O NHAc MeO MeO MeO O NHAc R1O R1O MeO O R2 NHCOR3 MeO MeO MeO O OMe R2 R R1 O O CHCH2O(CH2)5 (CH2)5Me 2 O n 172a n = 0 172b n = 1 172c n = 2 172d n = 3 173a R = NH2 173b R = NH((CH2)2CO2H 173c R = NH(CH2)3NH(CH2)2CO2H 174a R = OMe 174b R = SMe 174c R = SPh 175a R = SMe 175b R = SPh 176 R1 = H, Glucose, Me; R2 = OMe, SMe; R3 = C1–C6 Haloalkyl 177a R1 = H; R2 = OAc 177b R1 = H; R2 = OCOCF3 177c R1 = H; R2 = OCOPr n 177d R1 = H; R2 = COPh 177e R1R2 = O N O MeO MeO HO N O MeO MeO RO N O MeO MeO MeO N MeO MeO MeO O OH OH 178 179a R = H 179b R = Me 180 181 Bentley: ‚-Phenylethylamines and the isoquinoline alkaloids 353Papaver caucasicum80 liriodenine and lysicamine Polyalthia insignis34 liriodenine, O-methylmoschatoline and oxostephanine Xylopia championi163 O-methylmoschatoline. 18.7 Dioxoaporphines Dioxoaporphine alkaloids have been isolated from the following plant species, the two marked with asterisks being new alkaloids: Artabotrys zeylanicus163 ouregidione and 8-methoxyouregidione* 141 Xylopia championi163 dicentrinone* 142. The fluoren-9-one 143 has been oxidised by the Baeyer– Villiger process to the benzocoumarin 144, which was hydrolysed and methylated to the diphenyl carboxylic acid 145.Reduction of this with lithium aluminium hydride gave the alcohol 146a, which was converted through 146b and 146c into the acid 146d and this was further converted through the acid chloride into the amide 146e.Bischler–Napieralsky cyclisation of this yielded the phenanthrene 147a, which was converted through 147b into 147c. The N-chloroacetyl derivative 148 of this was subjected to Friedel–Crafts cyclisation to give deoxycepharadione B 149, which was oxidised to cepharadione B 150.164 18.8 Aristolochic acids and aristolactams Aristolochic acids B-II and D-II have been isolated from Aristolochia manchuriensis165 and the new alkaloid piperlactam 151 has been isolated from Piper puberullum.166 19 Alkaloids of the morphine group Alkaloids of the morphine–hasubanonine group have been isolated from the following plant species: Meconopsis cambrica81 flavinantine Papaver caucasicum80 salutaridine Papaver setigerum33 codeine, morphine, thebaine and N-methylthebaine iodide Stephania cepharantha1,35 aknadicine, aknadinine, aknadilactam, cephakacine, cephamuline, cepharamine, cephasamine, cephatonine, sinoacutine, sinomenine, 14-episinomenine, stephodeline, tannagine and alkaloid FK 3000 Stephania excentrica13,36 aknadinine, cephamorphimine and sinococculine.The 1H and 13C NMR spectra of codeine167 and of the N-oxides of thebaine168 and of 14-hydroxycodeinone168 have been studied, the spectra of the N-oxides permitting distinctions to be made between the cis and trans forms. Morphine has been shown to undergo the Mannich reaction with formaldehyde and secondary amines to give the 2-aminomethyl compounds 152a, 152b and 152c; with primary amines the product undergoes further condensation with formaldehyde to give oxazines such as 153.169 Codeine and both 6- and 7-halogenated 6-demethoxythebaine have been rearranged to apocodeine 154a and the halogenated derivatives 154b, 154c and 154d, respectively, in good yield by heating with methanesulfonic acid and methionine.170 Calculations of the fully optimised transition states for Diels–Alder additions to thebaine have been made.171 The 20S and 20R alcohols 155a and 155b have been prepared by the reduction of the ketone 156a and the reaction of the aldehyde 156b with phenylmagnesium bromide respectively.172 Similarly the alcohols 155c and 155d have been obtained from the ketones 156c and 156d by treatment with phenylmagnesium bromide and with methylmagnesium iodide, respectively.173 The condensation of naltrexone with the appropriate aldehydes in the presence of piperidine has given the (E)- arylidene derivatives 157a–157g, some of which have been converted by ultraviolet light into their Z isomers.174,175 Reaction of normorphine with cubane 1,4-dicarboxylic acid has given the amides 158a and 159a, which have been reduced by lithium aluminium hydride to the amines 158b and 159b.Of these 159b does not bind to any of the three opioid receptors and 158b binds only weakly to the Ï and ‰ receptors, but not to the Í receptor.176 MeO MeO N MeO MeO N MeO MeO S S N O O MeO MeO N O R HO R O Me3Si SPh R O – Li+ 182 183 184 185 186 O O N OMe O MeO CO (CH2) n Me Me O HO H R OH CO OH Me Me HO O HO CO OH O HO H OH CO OH Me Me O MeO H R1 CO OH R2 RO H Me Me HO 187a R = 188a 187b R = 188b 187c R = 188c 187d R = 189a 187e R = 189b 187f R = 190 187g R = 191 187h R = 192a 187i R = 192b 187j R = 192c 188a n = 1 188b n = 3 188c n = 4 188d n = 2 189a R = H 189b R = OH 190 191 192a R1 = H; R2 = Ph 192b R1 = H; R2 = CH2Ph 192c R1 = OH; R2 = Ph 192d R1 = H; R2 = CH2CMe2OH 354 Natural Product Reports, 1998Details of the preparation of the following have been published: 3-esters of morphine,177,178 14-hydroxydihydrocodeinone and 14-hydroxy-5-methyldihydrocodeinone,179 2-chloroacrylyl esters of 14-hydroxydihydromorphinone 160a and its N-cyclopropylmethyl analogue 160b and the related acylated 14-aminodihydromorphinones 161a and 161b,180 the heterocyclic compounds 162, 163a, 163b, 164 and related compounds,181–183 and fluorescent derivatives of N-benzylnaltrindole, 184 ·, ‚ and „-isomorphine169 and buprenorphine. 185 The lactam 165 has been isolated as a metabolite of pholcodine in humans.186 Methods for the estimation of morphine,187 morphine 3- and 6-glucuronides,188 heroin,187 codeine,187 naloxone,189 naltrexone, 190 ‚-naltrexol,190 nalbuphine,191 buprenorphine192 and dihydroetorphine193 have been described. Michael addition of methyl vinyl ketone to 5-chloro-7,8- dimethoxy-1-tetralone, followed by internal aldol condensation and dehydration, has given the unsaturated ketone 166.Reaction of this with lithium vinylcuprate aVorded the B/C cis-13-vinylphenanthrene derivative 167, an intermediate in an earlier synthesis of morphine, thus constituting a formal synthesis of the alkaloid.194 Methods of synthesis of morphine have been reviewed.195,196 The analgesic properties,197–230 pharmacokinetics231–234 and metabolism235–237 of morphine have been studied, as have the eVects of the alkaloid on behaviour,210,238–250 on immune responses,251–262 on the brain,263–265 on the brain stem,266 on the hypothalamus,267–269 on spinal receptors,270 on neurones,271–273 on locomotor activity,274 on somatosympathetic reflexes,275 on the heart,276,277 on coronary bypass grafts,278 on opioid,279 monoaminergic280 and adreno281 receptors, on respiration,282 on the gastrointestinal tract,283,285 on body weight,286 on tolerance of cold,287 on the consumption of alcohol,288 on taste preferences,215 on the utilisation of glucose,289 on the inflammatory process,290,291 on shock,292 on lymphocytes,293 on cerebral activity in neonates,294 on postherpetic neuralgia,295 and on levels of acetyl choline,296,297 of cyclic AMP,298 of adrenocorticotropic hormone,299 of amylase,300 of cortisol,299 of dopamine,301 of „-aminobutyric acid,302,303 of nitric oxide,304 of proteoglycan305 and of substance P.306 The morphine antagonist properties307–309 and the paradoxical analgesic eVect310 of N-allyl-14-hydroxydihydromorphinone (naloxone) have been studied as have the eVects of this compound on behaviour,311–314 on the brain,315 on the cardiovascular system,316–318 on the eye,319 on the baroreflex, 320 on the intake of sugar,321 on levels of cortisol,322 of dopamine,323–327 of endorphins,322 of testosterone328 and of thyrotropin,329 and on the eVects of cocaine,330 of paracetamol331 and of non-steroidal anti-inflammatory agents.332 The pharmacological and/or physiological eVects of the following have also been studied: morphine 3-glucoside,333–337 morphine 6-glucoside,335–339 heroin,340,341 codeine,342–346 3-Oethylmorphine, 347 normorphine,339 naloxonazine,348 naltrexone, 349–356 methylnaltrexone,357,358 nalbuphine,351,359–365 nalmefene,366,367 funaltrexamine,352,368,369 the acetylthio compound 168,370 the azide 169,371 naltrindole,369 oripavine,372 etorphine,373 dihydroetorphine,374–376 buprenorphine377–394 and norbuprenorphine.394 20 Phenethylisoquinolines Catalytic reduction of the dihydroisoquinolines 170 and 171 with chiral iridium complexes has aVorded (S)- norhomolaudanone.42 21 Colchicine N-Deacetylcolchicine has been converted into the lipid derivatives 172a–172d395 and colchicine has been converted into the amines 173a–173c.396 Isocolchicine 174a in methanol or dimethyl sulfoxide undergoes ipso-substitution with thiols and their sodium salts to give 174b and 174c, which are prone to tele-substitution in situ to give 175a and 175b.397 Patents for the preparation of compounds of general formulae 176 have been published.398,399 Derivatives of deacetamidocolchicine of structures 177a–177e have been synthesised and evaluated as antitubulin agents.400 O O N OMe R3O H R1 R2 O O N OMe R3O O O N OMe RO H H O O O N MeO OR H O 193a R1 = H; R2 = OH; R3 = 188d 193b R1 = H; R2 = OH; R3 = 188b 193c R1 = OH; R2 = H; R3 = 188b 194 R = 187d 195 R = 191d O O O O O O O O O O OR O O O O O OSO2Me R Bu tSiMe2 R 196a R = I 196b R = CHO 197 198a R = H 198b R = SO2Me 199a R = CHO 199b R = CH2NHCH2Ph O O N O R O O N O CO2But OH O O N O R O O O N O O 202a R = CO2CH2Ph 202b R = H 201 200a R = CH2Ph 200b R = CO2But 200c R = H 203 Bentley: ‚-Phenylethylamines and the isoquinoline alkaloids 355The physiological eVects of colchicine,401–407 of colchiceine, 408 of ‚-lumicolchicine408 and of thiocolchicoside409 have been studied. 22 Erythrina alkaloids Reviews of the chemistry of the Erythrina alkaloids have been published.410,411 22.1 Erythrina alkaloids (&)-Demethylerysotramidine 178, previously prepared by synthesis, has been epoxidised to 179a, which was O-methylated to 179b.Reduction of this with stannous iodide has yielded 180, which on further reduction with lithium aluminium hydride aVorded (&)-erythratidine 181.412 Treatment of the N-substituted maleimide/cyclopentadiene adduct 182 with alkyllithiums aVords the hydroxy amides 183, which can be cyclised to 184, and retro-Diels–Alder decomposition of these leads to compounds of general structures 185; the use of the lithium derivative 186 in this process leads to intermediates useful in the synthesis of alkaloids of this group.413 22.2 Cephalotaxine and related alkaloids The following new esters of cephalotaxine have been isolated from Cephalotaxus harringtonia: nordeoxyharringtonine 187a,414 homodeoxyharringtonine 187b,414 bishomodeoxyharringtonine 187c,414 5*-O-demethylharringtonine 187d,415 (3S)- hydroxy-5*-O-demethylharringtonine 187e,415 5*-O-demethylhomoharringtonine 187f,415 5*-O-demethylisoharringtonine 187g,415 neoharringtonine 187h,416 homoneoharringtonine 187i416 and (3S)-hydroxyneoharringtonine 187j.416 In addition the new alkaloids 11-hydroxydeoxyharringtonine 193a, 11-hydroxyhomodeoxyharringtonine 193b and 11-hydroxyhomodeoxyharringtonine 193c,417 the drupacine ester drupangtonine 194418 and the bimolecular alkaloid cephalotaxidine 195419 have also been isolated from Cephalotaxus harringtonia, together with the known alkaloids cephalotaxine, harringtonine, isoharringtonine, deoxyharringtonine and homoharingtonine.415 Drupangtonine is a powerful inhibitor of P388 leukaemic cells,418 as are 11-hydroxydeoxyharringtonine and 11- hydroxyhomodeoxyharringtonine.All of these alkaloids are less generally cytotoxic than deoxyharringtonine.417 The antitumour eVects of harringtonine have also been studied.420 A new synthesis of (&)-cephalotaxinone, and therefore of (&)-cephalotaxine, has been reported.Treatment of the aryl iodide 196a with butyllithium and N-formylpiperidine aVorded the aldehyde 196b, which, with 1,2-bis(trimethylsilyloxy)- cyclobutadiene, yielded the enol ether 197. This, on treatment with the appropriate Grignard reagent, yielded the acetal 198a, the methylsulfonyl ester of which 198b was hydrolysed to the aldehyde 199a, and then reductively aminated to give 199b.This was hydrolysed and cyclised to 200a, which was converted by tert-butyl carbonate into 200b. Oxidation of this to 201 followed by further oxidation gave 202a, and removal of the protecting group from the nitrogen of this resulted in Michael addition of the resulting secondary base to the enone to give (&)-cephalotaxinone 203.421 When 200b was hydrolysed to 200c it was found that the equilibrium greatly favoured the uncyclised base rather than the tetracyclic base analogous to 203. 23 Other isoquinolines A synthesis of optically pure ecteinascidin-743 has been achieved from the unsaturated ester 204a. This was converted into the unsaturated carbamate 204b, which was reduced over a chiral rhodium catalyst to the chiral carbamate 205. This O O Me O O OMe OMe O O Me OR1 TBSO OMe OTBS Ph O O Me O O OMe OMe Ph CHO HN OC O NR2 O O H H H R O H HN CO2CH2Ph 206a R1 = CH2Ph; R2 = CO2CH2Ph 206b R1 = R2 = H 205 207 204a R = CO2CH2CH=CH2 204b R = NHCO2CH2Ph O N O O Me O H N O O Me O OH OMe HO OH CN H O O H HN CO2 TBSO OMe OTBS CN N O O Me OH Me OMe O OTDPS CN H NMe N CO2 MeO N O O Me O Me OMe O CN H NMe MeO 209 208 H OH H 210 211 356 Natural Product Reports, 1998acetal was then cyclised by boron trifluoride to the lactone 206a, which was converted into 206b.Reaction of this with the aldehyde 207 in the presence of potassium cyanide, followed by allyl bromide, yielded 208, which was cyclised by methanesulfonic acid to 209.This was converted by conventional processes into 210, which was oxidised to the hydroxy dienone 211. Conversion of this into the cysteine derivative 212 was followed by cyclisation and further transformation into 213, which was oxidised to the keto lactone 214. Pictet– Spengler condensation of this with homovanillylamine yielded ecteinascidin-770 215a, which was converted into ecteinascidin-743 215b by aqueous silver nitrate.422 The lactam 216 has been synthesised in an approach to the ecteinascidins.423 24 References 1 N.Kashiwaba, S. Morooka, M. Kimura, Y. Murakoshi, M. Ono, J. Toda, H. Suzuki and T. Sano, Chem. Pharm. Bull., 1997, 45, 470. 2 T. Watanabe, K. Kawaguchi, T. Yoshikawa, A. Takano, H. Khoda and K. J. Malla, Shokubutsu Soshiki Baiyo, 1996, 13, 203. 3 A. M. Gazaliev, A. O. Nurenkov, B. Z. Kokzhalova and V. K. Byistro, Zh. Obshch. Khim., 1996, 66, 1057. 4 S. D. Fazylov, A.M. Gazaliev, L. M. Vlasova and M. Zh. Zhurinov, Zh. Obshch. Khim., 1996, 66, 696. 5 O. A. Nurenkov, A. M. Gazaliev, A. V. Kanakhin, S. K. Kabieva and M. Zh. Zhurinov, Zh. Obshch. Khim., 1996, 66, 349. 6 R. A. Abdel, R. H. Abu-Eittah and L. T. Kamel, Egypt. J. Chem., 1996, 39, 395. 7 G. I. Hwang, J. H. Lee and K. Won, J. Org. Chem., 1996, 61, 6183. 8 N. Oksbjerg and M. T. Soerensen, Acta Agric. Scand., Sect. A, 1996, 46, 125. 9 J. Noerregaard, S. Joergensen, K. L. Mikkelse, P.Toennesen, A. Iversen, T. Soerensen, B. Soeberg and H. B. Jakobsen, Clin. Pharmacol. Ther. (St. Louis), 1996, 60, 679. 10 K. Koike, T. Kawasuji, M. Matsumoto, N. Yasuda, S. I. Niizawa and I. Takanayagi, Pharmacology, 1996, 53, 289. 11 C. C. Lyon and J. H. Turney, Br. J. Clin. Pract., 1996, 50, 396. 12 N. Kashiwaba, S. Morooka, M. Kimura and M. Ono, J. Nat. Prod., 1996, 59, 803. 13 J. Dang and S. K. Zhao, J. Nat. Prod., 1997, 60, 294. 14 J. J. Chen, I. L. Tsai, T. Ishikawa, C.J. Wang and I. S. Chen, Phytochemistry, 1996, 42, 1479. 15 A. P. Venkov and I. I. Ivanov, Tetrahedron, 1996, 53, 12 299. 16 J. Kang, J. B. Kim, K. H. Cho and B. T. Cho, Tetrahedron: Asymmetry, 1996, 8, 657. 17 A. Couturre, E. Deniau, P. Woisel, P. Grandclaudon and J. F. Carpentier, Tetrahedron Lett., 1996, 37, 2697. 18 K. P. Manfredi, M. Britton, V. Vissieche and I. K. Parnell, J. Nat. Prod., 1996, 59, 854. 19 G. Bringmann, M. Stahl and K. P. Gulden, Tetrahedron, 1997, 53, 2817. 20 P. Chan, I. R. Czuba, M. A. Rizzacasa and G. Bringmann, J. Org. Chem., 1996, 61, 7101. 21 T. R. Hoye and L. Mi, Tetrahedron Lett., 1996, 37, 3097. 22 T. R. Hoye and M. Chen, Tetrahedron Lett., 1996, 37, 3099. 23 G. Bringmann, R. Götz, S. Harmsen, J. Holenz and R. Walter, Liebigs Ann., 1996, 2045. 24 P. D. Hobbs, V. Upender, J. Liu, D. J. Pollart, D. W. Thomas and M. I. Dawson, Chem. Commun., 1996, 923. 25 G. Bringmann and S. Harmsen, PCT Int. Appl., WO/03382/1996 (Chem. Abstr., 1996, 125, 33 933). 26 V. Upender, D. J. Pollart, J. Liu, P. D. Hobbs, C. Olsen, W. Chao, B. Bowden, J. L. Crase and D. W. Thomas, J. Heterocycl. Chem., 1996, 33, 1371. 27 G. Bringmann, R. Götz and G. Francois, Tetrahedron, 1996, 52, 13 419. 28 G. Bringmann, W. Saeb, D. Koppler and G. Francois, Tetrahedron, 1996, 52, 13 409. 29 G. Francois, G. Timperman, J. Holenz, L. Assi, G. T. Ake, L. Maes, J. Dubois, M. Hanocq and G. Bringmann, Ann. Trop.Med. Parasitol., 1996, 90, 115. 30 G.Bringmann, J. Holenz, B. Wiesen, B. W. Nugrobo and P. Proksch, J. Nat. Prod., 1997, 60, 342. 31 I. Khamidov, A. K. Karimvo, M. V. Telezhenetskaya and B. Tashkhodzhaev, Khim. Prir. Soedin., 1996, 107. 32 I. Khamidov, M. Faskhutdinov, M. V. Telezhenetskaya, A. K. Kamirov, M. G. Levkovich, N. D. Abdulaev and K. Sh. Shakirov, Khim. Prir. Soedin., 1996, 74. 33 L. Slavikova, Coll. Czech. Chem. Commun., 1996, 61, 1047. 34 K. H. Lee, C. H. Chuah and S. H. Goh, Tetrahedron Lett., 1997, 38, 1253. 35 H. Kashiwaba, S. Morooka, M. Ono, T. Toda, H. Suzuki and T. Sano, Chem. Pharm. Bull., 1997, 43, 545. 36 G. Zhang, J. Deng, S. Zhao and H. Yang, Zhongcaoyao, 1996, 27, 586. 37 M. Moriyasu, M. Ichimaru, Y. Nishiyama, A. Kato, J. W. Wang, H. Zong and G. B. Lu, J. Nat. Prod., 1997, 60, 299. 38 R. Marek, J. Dostal and J. Slavik, Z. Kristallogr., 1996, 211, 651. 39 R. Marek, J. Dostal, J. Slavik and V. Sklenar, Molecules, 1996, 1, 166. 40 I. M. Sudarma and J. B. Bremner, ACGC Chem.Res. Commun., 1995, 3, 45 (Chem. Abstr., 1997, 126, 238 527). 41 Z. Czarnocki, J. B. Mieczkowski and M. Ziolowski, Tetrahedron: Asymmetry, 1996, 7, 2711. 42 T. Morimoto, N. Suzuki and K. Achiwa, Heterocycles, 1996, 43, 2557. 43 K. Komori, T. Takaba and J. Kunimoto, Heterocycles, 1996, 43, 1681. 44 K. Takaba, K. Komori and J. Kunimoto, Heterocycles, 1996, 43, 1777. 45 Atta-ur-Rahman, S. S. Ali, M. M. Qureshi, S. Hassan and K. Bhatti, Fitoterapia, 1989, 60, 552. 46 A. Garcia, L.Castedo and D. Dominguez, J. Nat. Prod., 1996, 59, 806. 47 H. Ma, X. Li and W. Wang, Beijing Yike Daxue Xuebao, 1995, 27, 465 (Chem. Abstr., 1996, 125, 905). O O N Me O Me OMe O MeO NMe O O N Me OAc Me OMe O MeO NMe H S O O O N Me OAc Me OMe HO NMe H S O O HN Me OMe Me OMe MeO NMe H O HN O OH CN CN R O O N Me OAc Me OMe O MeO NMe H S O O O CN H O O S HN O O H O O NH MeO HO O O 213 212 214 216 215a R = CN 215b R = OH Bentley: ‚-Phenylethylamines and the isoquinoline alkaloids 35748 E.A. Martinez, K. L. Mealey, A. A. Woodbridge and D. A. Mercer, Am. J. Vet. Res., 1996, 57, 1623. 49 H. Mellinghof, L. Radbruch, C. Diefenbach and W. Buzello, Anesth. Analg. (Baltimore), 1996, 83, 1072. 50 M. V. Telezhenetskaya, I. Khamidov and K. H. C. Basel, Khim. Prir. Soedin., 1996, 106. 51 S. S. Lee, C. K. Chen and C. H. Chen, Tetrahedron, 1996, 52, 6561. 52 A. A. Philipov and R. S. Istatkova, Phytochemistry, 1997, 44, 1591. 53 L. Bezakova, V. Misik, L.Malekova, E. Svajdlenka and D. Kostalova, Pharmazie, 1996, 51, 758. 54 H. Guinaudeau, M. Böhlke, L. Z. Lin, C. Angerhofer, G. A. Cordell and N. Ruangrungsi, J. Nat. Prod., 1997, 60, 258. 55 F. Frappier, A. Jossang, J. Soudon, F. Calvo, P. Rasonaivo, S. Ratsimamanga-Urverg, J. Saez, J. Schrevel and P. Grellier, Antimicrob. Agents Chemother., 1996, 40, 1476. 56 A. M. Low, M. Berdik, H. Schlicht and A. Ziegler, J. Pharm. Sci., 1996, 85, 690. 57 Q. Sun, W. Ma and J. Wang, Zhongguo Yaoxue Zazhi, 1996, 31, 80. 58 S. Zhang, F. Li, S. Lei, J. Zhang, Y. Tang, L. Chen, P. Li, B. Sun and W. Chen, Juaxi Yike Daxue Xuebao, 1996, 27, 59. 59 D. Zhang, L. Peng, Q. Quan and Y. Wang, Zhongcaoyao, 1996, 27, 93. 60 X. Chen, Y. M. Hu and Y. Q. Liao, Zhongguo Yaoli Xuebao, 1996, 17, 348. 61 B. Xuan, F. Liu, M. Y. Zhang and J. C. Xiao, J. Ocul. Pharmacol. Ther., 1996, 12, 331. 62 H. Takemura, K. Imoto, H. Oshikawa and C. Y. Kwan, Clin. Exp. Pharmacol. Physiol., 1996, 23, 751. 63 Y. M. Leung, M. Berdik, C. Y. Kwan and T. T. Loh, Clin. Exp. Pharmacol. Physiol., 1996, 23, 653. 64 Y. He, K. Xu, Q. Zhang, W. Dai, Z. Xu and B. Liu, Zhongguo Zhongyao Zazhi, 1996, 21, 177. 65 Y. Feng, K. Huang, Y. Zhang and M. Wang, J. Tonji Med. Univ., 1996, 16, 103. 66 Q. Y. He, H. Q. Zhang, D. B. Pang, X. S. Chi and S. B. Xue, Zhongguo Yaoli Xuebao, 1996, 17, 545. 67 J. Chen, S. Chen, J. Zhong, G. Zhang, X. Gong and Z. Wu, Zhongguo Yaolixue Tongbao, 1996, 12, 226. 68 Q. Wang, H.Wang, J. Kang and R. Ding, Zhongguo Yike Daxue Xuebao, 1996, 25, 260. 69 C. Cai, X. Zhou, D. Xiu and R. Lai, Guangdong Yixue, 1996, 17, 629. 70 J. Che, J. Zhang and Z. Qu, Yaoxue Xuebao, 1996, 31, 161. 71 M. Tang, F. Gu, X. Tang, K. Shen, Q. Liu and X. Hu, Tongi Yike Daxue Xuebao, 1996, 25, 260. 72 H. X. Wang, C. Y. Kwan and J. M. Wong, Eur. J. Pharmacol., 1997, 319, 115. 73 F. Chen, S. Sun, D. C. Kuh, Y. Lu, L. J. Gaydos, X. Shi and L. M. Demers, Biochem. Biophys. Res.Commun., 1997, 231, 99. 74 H. L. Wang, X. H. Zhang, Y. Hong, X. Jin, H. Y. Jin, X. J. Lue and D. R. Zhang, Drug Dev. Res., 1996, 39, 158. 75 Z. F. Cao, Planta Med., 1996, 62, 413. 76 R. Suau, R. Garcia-Segura, M. V. Silva and M. Valpuesta, Phytochemistry, 1996, 43, 1389. 77 M. C. de la Fuente, L. Castedo and D. Dominguez, J. Org. Chem., 1996, 61, 5818. 78 R. Suau, J. M. Lopez-Romero and P. Rico, Tetrahedron Lett., 1996, 37, 9557. 79 A. Garcia, L. Castedo and D. Dominguez, Tetrahedron, 1996, 52, 5929. 80 A. Shafiee and R. Vafadar, J. Sci. Islamic Repub. Iran, 1996, 7, 263. 81 J. Slavik and L. Slavikova, Coll. Czech. Chem. Commun., 1996, 61, 185. 82 S. S. Lee and K. T. Tung, Heterocycles, 1996, 43, 1403. 83 I. M. Sudarma and J. B. Bremner, ACGC Chem. Res. Commun., 1996, 4, 30. 84 A. P. Johnson, R. W. A. Luke, G. Singh and A. N. Boa, J. Chem. Soc., Perkin Trans. 1, 1996, 907. 85 M. J. Munchof and A. I. Meyers, J. Org. Chem., 1996, 61, 4607. 86 T. L. Varadinova, S.A. Shishkov, N. D. Ivanovska and M. P. Velcheva, Phytother. Res., 1996, 10, 414. 87 V. Fajardo, C. Carcano and B. Moreno, Heterocycles, 1996, 43, 949. 88 L. N. Chu, F. L. Hsu, F. Y. Chieh and J. T. Cheng, J. Chin. Chem. Soc. (Taipei), 1996, 43, 489. 89 L. Jain, M. Tripathy and V. B. Pandey, Planta Med., 1996, 62, 188. 90 E. Taborska, H. Bochorakova, J. Sousek, P. Sedmera, C. Vavrickova and V. Simanek, Coll. Czech. Chem. Commun., 1996, 61, 1064. 91 S. A. Khan and V.K. Sharma, J. Indian Chem. Soc., 1997, 74, 63. 92 J. J. Chen, T. Ishikawa, C. Y. Duh, I. L. Tsai and I. S. Chen, Planta Med., 1996, 62, 528. 93 M. C. Gonzalez, M. C. Zafra-Polo, M. A. Blazquez, A. Serrano and D. Cortes, J. Nat. Prod., 1997, 60, 108. 94 R. Suau, F. Najera and R. Rico, Tetrahedron Lett., 1996, 37, 3575. 95 N. Sotomayor, E. Dominguez and E. Leete, J. Org. Chem., 1996, 61, 4062. 96 E. Reinelt-Wasilewski, R. Lemmens-Gruber, H. Marei and P. Heistracher, Potassium Channels Norm.Pathol. Conf. 95, ed. J. Vereecke, P. P. Van Bogaert and F. Verdonek, Leuven Univ. Press, Louvain, 1996, p. 388. 97 M. K. Lee and Y. H. Zhang, Med. Sci. Res., 1996, 24, 561. 98 Y. X. Wang, Y. M. Zhang and X. B. Zhou, Eur. J. Pharmacol., 1996, 316, 307. 99 M. Watari and T. Matsubara, Toyama-ken Yokuji Kenkusho Nenpo, 1995, 23, 58. 100 Z. Pang, B. Wang and J. Hongtao, Fenxi Kexue Xuebao, 1997, 13, 51. 101 J. Wu and G. Z. Jin, Neurosci. Lett., 1997, 222, 115. 102 C.Han, Z. Lu, X. Wei and G. Z. Jin, Drug Dev. Res., 1996, 39, 191. 103 Y. Yang, D. Dai, J. Zhao, W. Huang and S. Peng, Zhongguo Yaoli Yu Dulixue Zazhi, 1996, 10, 31. 104 B. Gatto, M. H. Sanders, C. Yu, H. Y. Wu, D. Makhey, E. J. La Voie and L. F. Liu, Cancer Res., 1996, 56, 2795. 105 F. N. Ko, Y. L. Chang, C. M. Chen and C. M. Teng, J. Pharm. Pharmacol., 1996, 48, 629. 106 L. J. Chen, X. X. Zhang and X. Guo, Zhongguo Yaoli Xuebao, 1996, 17, 477. 107 L. L. Zhou, Y. Chen, Y. Y. Song and G.Z. Jin, Zhongguo Yaoli Xuebao, 1996, 17, 311. 108 C. L. You, Z. F. Han, Y. S. Qu, Y. M. Wang, L. J. Chen and G. Z. Jin, Zhongguo Yaoli Xuebao, 1996, 17, 382. 109 B. C. Sun, X. X. Zhang and G. Z. Jin, Life Sci., 1996, 59, 299. 110 L. L. Zou, S. T. Cai and G. S. Jin, Zhongguo Yaoli Xuebao, 1996, 17, 485. 111 L. Shi, X. Wang and A. Xue, Yaoxue Xuebao, 1996, 31, 492. 112 M. T. Hsieh and L. Y. Wu, J. Pharm. Pharmacol., 1996, 48, 959. 113 C. Xu, M. Z. Sun, Y. R. Li, B. F.Wang, L. J. Wang and J. M. Li, Zhongguo Yaoli Xuebao, 1996, 17, 329. 114 S. Dai, W. Yao, G. Zia, M. Jiang, X. Niu, T. Zeng and H. Kang, Zhongguo Yaolixue Yu Dulixue Xuebao, 1996, 10, 71. 115 R. E. Gawley and I. Zhang, J. Org. Chem., 1996, 61, 8103. 116 J. Cardos, T. B. Luyen, N. D. Luyen, E. Dörnyei, E. Gacs-Baitz, M. Simonyi, D. J. Cash, G. Blasko and C. Czantay , Eur. J. Med. Chem., 1996, 31, 761. 117 B. Ferry and G. Di Scala, Neurobiol. Learn. Mem., 1997, 67, 80. 118 M. Palmery, M.F. Cometa and M. G. Leone, Phytother. Res., 1996, 110 (suppl. I), 47. 119 M. F. Cometa, C. GaleY and M. Palmery, Phytother. Res., 1996, 110 (suppl. I), 56. 120 M. Rahimizadeh, J. Sci. Islamic Repub. Iran, 1996, 7, 172. 121 M. Shamma and M. Rahimizadeh, J. Nat. Prod., 1986, 49, 398. 122 R. Yoneda, Y. Sakamoto, Y. Oketo, S. Harusawa and T. Kurihara, Tetrahedron, 1996, 52, 14 563. 123 A. Itoh, T. Tanahashi and N. Nakagura, J. Nat. Prod., 1996, 59, 535. 124 R. Marek, D.Dostal, J. Slavik and V. Sklenar, Molecules, 1996, 1, 166. 125 W. J. Cho, S. J. Yoo, B. H. Chung, B. G. Choi, S. H. Chen, S. H. Whang, S. K. Kim, B. H. Kang and C. O. Lee, Arch. Pharmacal. Res., 1996, 19, 321. 126 W. J. Cho andM. Hanaoka, Arch. Pharmacal. Res., 1996, 19, 240. 127 T. Harayama, T. Akiyama and K. Kawano, Chem. Pharm. Bull., 1996, 44, 1634. 128 S. P. Mackay, O. Meth-Cohn and R. D.Waigh, Adv. Heterocyclic Chem., 1996, 67, 345. 129 J. E. Lombardini, Biochem. Pharmacol., 1996, 52, 253. 130 B. H. Shah, G. Shamin, S. Khan and S. A. Saeed, Biochem. Mol. Biol. Int., 1996, 38, 1135. 131 A. E. Eckly-Michel, A. Le Bec and C. Lugnier, Eur. J. Pharmacol., 1997, 324, 85. 358 Natural Product Reports, 1998132 C. Vavreckova, I. Gawlick and K. Mueller, Planta Med., 1996, 62, 397. 133 H. Babisch, H. L. Zuckerbraun, I. B. Barber, S. B. Babisch and E. Borenfreund, Pharmacol. Toxicol. (Copenhagen), 1996, 76, 397. 134 M. Netopilova, J. Drsata and T. Ulichova, Pharmazie, 1996, 51, 589. 135 A. M. Polson, S. Garrett, N. H. Stoller, C. L. Bandt, P. J. Hanes, W. J. Killoy, G. L. Sothard, S. P. Duke and G. C. Boyle, J. Periodontol., 1997, 68, 119. 136 H. C. Del Castillo Cotillo, F. De Simone and V. De Fero, Biochem. Syst. Ecol., 1996, 24, 463. 137 J. M. Barbos-Fillio, E. V. L. Da-Cunha, M. Lopez-Cornelio, C. Da Silva and A. I. Gray, Phytochemistry, 1997, 44, 959. 138 S. S. Lee, C. K. Chen, I. S. Chen and C. H. Chen, J. Nat. Prod., 1996, 59, 55. 139 H. J. Park, Saengyak Hakhoechi, 1996, 27, 123. 140 J. A. Lopez, W. Barillos, J. Gomez-Laurito, F. T. Liu, A. J. Al-Rehaily, M. H. M. Sharaf and P. L. SchiV, Int. J. Pharmacogn., 1996, 34, 145. 141 L. Varga, M. Barrios, J. M. Cabezas and O. Castro, Fitoterapia, 1996, 67, 188. 142 Y. Y. Chen, F. R. Chang and Y. C. Wu, J. Nat. Prod., 1996, 59, 904. 143 S. S. Lee and R. W. Doskotch, J. Nat. Prod., 1996, 59, 738. 144 M. P. Velcheva, R. R. Petrova, Z. Samdanghiin, S. Samdanghiin, Z.Yansanghiin and H. Budzekiewicz, Phytochemistry, 1996, 42, 435. 145 M. S. Hoard and S. D. Elakovich, Phytochemistry, 1996, 43, 1129. 146 A. Bermejo, P. Protais, M. A. Blasquez, K. S. Rao, M. C. Zafra-Polo and D. Cortes, Nat. Prod. Lett., 1995, 6, 57 (Chem. Abstr., 1996, 125, 215 247). 147 D. M. Zhou, B. Z. Yue, J. Q. Cai and L. H. Zhang, Heterocycles, 1997, 45, 439. 148 S. Chulia, J. Moreau, E. Naline, M. A. Noguera, M. D. Ivorra, M. P. D’Ocon and C. Advenir, Br. J. Pharmacol., 1996, 119, 1305. 149 A. P. Wickens and E. W. Thornton, Exp. Brain Res., 1996, 109, 17. 150 R. B. Dewey, D. Maragonore, J. E. Ahlskog and J. Y. Matsumoto, Clin. Neuropharmacol., 1996, 19, 193. 151 M. Gassen, Y. Glinka, B. Pinchasi and M. B. H. Youdini, Eur. J. Pharmacol., 1996, 308, 219. 152 S. Gancher, A. Mayer and S. Youngman, Brain Res., 1996, 729, 190. 153 C. M. Knapp and C. Kornetsky, Pharmacol. Biochem. Behav., 1996, 55, 87. 154 J. V. Corwin, K. J. Burcham and G. I. Hix, Behav.Brain Res., 1996, 79, 41. 155 P. C. Fletcher, C. D. Firth, P. M. Grasby, K. J. Friston and R. J. Dolan, J. Neurosci., 1996, 16, 7055. 156 M. Glasgow and J. P. Evert, Neurosci. Lett., 1996, 220, 215. 157 L. V. Metman, E. R. Locatelli, D. Brevi, M. M. Mouradian and T. N. Chen, Neurology, 1997, 48, 369. 158 M. H. Hedberg, T. Linnanen, J. M. Jansen, G. Norvall, S. Hjorth, L. Unelius and A. M. Johansson, J. Med. Chem., 1996, 39, 3503. 159 M. J. Prioton and G. J. Sewell, J. Chromatogr.B, 1996, 681, 161. 160 J. D. Connolly, E. Haque and K. A. A. Kadir, Phytochemistry, 1996, 43, 295. 161 S. Hosztafi and S. Makleit, ACH-Models Chem., 1996, 133, 401. 162 C. M. Teng, G. Hsiao, K. N. Ko, D. T. Lin and S. S. Lee, Eur. J. Pharmacol., 1996, 303, 129. 163 E. M. K. Wijeratne, Y. Hartanaka, T. Kikuchi, Y. Tezuka and A. A. L. Gunatilaka, Phytochemistry, 1996, 42, 170. 164 R. Suau, J. M. Lopez-Romero, R. Rico, F. J. Alonso and C. Lobo, Tetrahedron, 1996, 52, 11 307. 165 V. P. Bulgakov, Yu. N. Zhuravlev, S. V. Radchenko, S. A. Fedoreyev, V. A. Denisenko, M. Veselova, N. I. Kulesh and E. K. Alshevskya, Fitoterapia, 1996, 67, 238. 166 Q. L. Wu, S. P. Wang, G. Z. Tu, Y. X. Feng and J. S. Yang, Phytochemistry, 1997, 44, 727. 167 M. M. Nair, G. E. Jackson and W. E. Campbell, Spectrosc. Lett., 1997, 30, 497. 168 G. W. Caldwell, A. D. Gauthire and J. E. Mills, Magn. Reson. Chem., 1996, 34, 505. 169 K. Goerlitzer, I. M. Weltrowski and K. T. Wanner, Sci.Pharm., 1996, 64, 651. 170 C. Csutoras, S. Berenyi and S. Makleit, Synth. Commun., 1996, 26, 2251. 171 J. M. A. Baas, R. H. Woudenberg and L. Maat, Liebigs Ann., 1997, 13. 172 J. Marton, Z. Szabo, C. Simon, S. Hoszatfi and S. Makleit, Liebigs Ann., 1996, 1653. 173 J. Marton, C. Simon, S. Hosztafi, Z. Szabo, A. Marki, A. Borodi and S. Makleit, Bioorg. Med. Chem., 1997, 5, 369. 174 Y. Nan, S. P. Upadhayaya, W. Xu, K. E. Hughes, W. J. Dunn, L. Bauer and H. N. Bhargava, J.Heterocycl. Chem., 1996, 32, 399. 175 R. B. Palmer, A. L. Upthagrove andW. I. Nelson, J. Med. Chem., 1996, 40, 749. 176 C. Y. Chen, L. W. Hsiu and P. L. Tao, Clin. Pharm. J. (Taipei), 1996, 48, 139. 177 C. Mignaf, D. Heber and A. Ziegler, Ger. OVen., DE 19 508664 (Chem. Abstr., 1996, 125, 276 275). 178 C. Mignaf, D. Heber, H. Schlicht and A. Ziegler, J. Pharm. Sci., 1996, 85, 690. 179 R. Krassnig, C. Hederer and H. Schmidhammer, Arch. Pharm. (Weinheim), 1996, 329, 325. 180 I.Hutchinson, S. Archer, K. P. Hill and J. M. Bidlack, Bioorg. Med. Chem. Lett., 1996, 6, 1563. 181 G. Dondino and S. Ronzoni, PCT Int. Appl., WO/02545/1996 (Chem. Abstr., 1996, 125, 11 196). 182 P. S. Portoghese and F. S. Faroux-Grant, PCT Int. Appl., WO/23793/1996 (Chem. Abstr., 1996, 125, 248 211). 183 H. Nagase, K. Kawai, T. Endo, S. Ueno, M. Maeda and S. Sakami, PCT Int. Appl., WO/11948/1997 (Chem. Abstr., 1997, 126, 277 642). 184 V. Korlipara, J. Ells, J. Wang, S. Tani, R.Elde and P. S. Portoghese, Eur. J. Med. Chem., 1997, 32, 171. 185 P. Stelmach, E. Bobrowska and K. Falek, Pol. Pat., POL 166095 (Chem. Abstr., 1996, 125, 301 302). 186 J. Gore, B. Kasum, M. A. Holman, I. M. Scharfbillig and A. D. Ward, Aust. J. Chem., 1996, 49, 1235. 187 T. Hyoetylaeinen, H. Siren and M. L. Riekkola, J. Chromatogr., 1996, 735, 439. 188 N. Tyrefora, B. Hylbrandt, L. Ekman, M. Johanson and B. Langstroem, J. Chromatogr., 1996, 729, 279. 189 F. Franklin and J. Odontiadis, J.Chromatogr. B, 1996, 678, 289. 190 A. F. Davidson, T. A. Emm and H. J. Pieniaszek, J. Pharm. Biomed. Anal., 1996, 14, 1717. 191 S. T. Ho, J. J. Wang, O. Y. P. Hu, P. S. Chiang and S. S. Lee, J. Chromatogr. B, 1996, 678, 289. 192 G. Alemany, C. Rossello and M. Nicolaus, Biomed. Chromatogr., 1996, 10, 146. 193 F. Li, Y. Luo, J. L. Feng and X. Y. Hu, J. Chromatogr. B, 1996, 679, 113. 194 J. Mulzer, G. Dürner and D. Trauner, Angew. Chem., Int. Ed. Engl., 1996, 35, 2830. 195 T. Hudlicky, G. Butora, S. P. Fearnly, A. P. Gum and M. R. Stable, Stud. Nat. Prod. Chem., 1996, 18, 43. 196 M. Maier, Organic Synthesis Highlights, ed. H. Waldman, VHC Weinheim, 1995, vol. 2, 357. 197 P. E. Macintyre and D. A. Jarvis, Pain, 1996, 64, 357. 198 M. Spinella, M. L. Cooper and R. J. Bodnar, Pain, 1996, 64, 545. 199 T. W. Vanderah, R. N. Bernstein, H. I. Yamamura, V. J. Hruby and F. Porreca, J. Pharm. Exp. Ther., 1996, 278, 212. 200 M. Bianchi, R. Maggi, A. E. Panerai and L.Martini, Pharmacology, 1996, 52, 387. 201 F. V. Abbott, Y. Hong and K. B. J. Franklin, Pain, 1996, 65, 17. 202 T. Kim, S. Murande, A. Gruber and S. Kim, Anesthesiology, 1996, 85, 331. 203 Z. Y. Wei, F. Karim and S. C. Roerig, J. Pharmacol. Exp. Ther., 1996, 278, 1392. 204 J. D. Swenson, M. Wisniewski, S. McJames, M. A. Ashburn and N. L. Pace, Anesth. Analg. (Baltimore), 1996, 83, 523. 205 U. Hodoglugil, H. Z. Guney, B. Savran, C. Gzey, C. Z. Gorgun and H. Zengil, Chronobiol.Int., 1996, 13, 227. 206 O. Christensen, P. Christensen, C. Sonnenschein, P. R. Nielsen and S. Jacobson, Acta Anaesthesiol. Scand., 1996, 40, 842. 207 M. A. Plone, D. F. Emerich and M. D. Lindner, Pain, 1996, 66, 265. 208 R. M. Allen, K. R. Powell and L. A. Dykstra, Analgesia (Elmsford, N.Y.), 1996, 2, 145. 209 J. M. Chung and H. S. Na, Analgesia (Elmsford, N.Y.), 1996, 2, 151. 210 H. W. D. Matthes, R. Maldonada, F. Simonin, O. Valverde, S. Sloowe, I. Kitchen, K.Belfort, A. Dierich and M. La Meur, Nature, 1996, 383, 819. 211 B. H. Manning, J. Mao, H. Frenk, D. D. Price and D. J. Mayer, Pain, 1996, 67, 79. 212 B. Ben-David, R. A. Moscona and S. Stahl, Acta Anaesthesiol. Scand., 1996, 40, 892. Bentley: ‚-Phenylethylamines and the isoquinoline alkaloids 359213 C. Olofson, A. Ekblom, G. Ekman-Ordeberg, A. Hjelm and L. Irestedt, Br. J. Obstet. Gynaecol., 1996, 103, 968. 214 A. A. Bagal, L. B. Hough, J. W. Nalwalk and S. D. Glick, Brain Res., 1996, 741, 258. 215 R. Gagin, E. Cohen and Y. Shavit, Pharmacol. Biochem. Behav., 1996, 55, 629. 216 Y. Kolesnikov, S. Jain, R. Wilson and G. W. Pasternak, J. Pharmacol. Exp. Ther., 1996, 279, 502. 217 T. J. Cicero, B. Nock and E. R. Meyer, J. Pharmacol. Exp. Ther., 1996, 279, 767. 218 D. R. Jasinski, Acta Anaesthesiol. Scand., 1997, 41, 184. 219 M. Eriksson-Mjaeberg, J. O. Svensson, O. Almqvist, A. Oelund and L. L. Gustafsson, Br. J. Anaesth., 1997, 78, 10. 220 M. A. Chaney, K.R. Smith, J. C. Barclay and S. SlogoV, Anesth. Analg. (Baltimore), 1996, 83, 215. 221 A. R. Claxon, G. Meguire, F. Chung and C. Cruix, Anesth. Analg. (Baltimore), 1997, 84, 509. 222 H. Choe, Y. S. Choi, Y. H. Kim, S. H. Ko, H. G. Choi, Y. S. Han and H. S. Sun, Anesth. Analg. (Baltimore), 1997, 84, 560. 223 J. W. Duckett, T. Cangiano, M. Cubina, C. Howe and D. Cohen, J. Urol. (Baltimore), 1997, 157, 1407. 224 J. H. Chung, R. S. Sinatra, F. B. Sevarino and L. Fermo, Reg. Anesth., 1997, 22, 119. 225 S. Sigga, K. Metcalf and C. Eintrei, Reg. Anesth., 1997, 22, 131. 226 M. Kanbak, N. Akpolat, T. Ocal, M. N. Doral, M. Ercand and K. Erdem, Eur. J. Anaesthesiol., 1997, 14, 153. 227 J. L. Plummer, H. Owen and D. Flanagan, Anesth. Analg. (Baltimore), 1997, 84, 794. 228 G. C. Rossi, L. Leventhal, Y. X. Pan, J. Cole, W. Su, R. J. Bodnar and G. W. Pasternak, J. Pharmacol. Exp. Ther., 1997, 281, 109. 229 W. Yu, J. X. Hong, X. S. Xu and Z. Wiesenfeld-Hallin, Brain Res., 1997, 756, 141. 230 R. F. Mucha, H. Kalant and N. Birbaumer, Psychopharmacology (Berlin), 1996, 124, 365. 231 J. Drake, C. T. Kirkpatrick, C. A. Aliyar, E. Crawford, P. Gibson and C. E. Horth, Br. J. Clin. Pharmacol., 1996, 41, 420. 232 L. Loetsch, A. Stackmann, G. Kibal, K. Brune, R. Waibel, N. Schmidt and G. Geisslinger, Clin. Pharmacol. Ther. (St. Louis), 1996, 60, 316. 233 I. Kaetsu, K. Uchida, S. Ueta, K. Sutani and T. Okuda, Drug Delivery Syst., 1996, 11, 399. 234 Y. Deng, K.Wang, J. Liu, Y. Lou and Z. Cai, Zhongguo Linchuang Yaolixue Zazhi, 1996, 12, 160. 235 T. WolV, H. Samuelson and T. Hedner, Pain, 1996, 68, 209. 236 J. A. O’Brien, A. M. Evans and R. L. Nation, Clim. Exp. Pharmacol. Physiol., 1997, 24, 143. 237 L. L. Christrup, Acta Anaesthesiol. Scand., 1997, 41, 116. 238 A. Poling, M. L. David, D. Roe and D. Schaefer, Pharmacol. Biochem. Behav., 1996, 54, 485. 239 A. Cepeda-Benio and S. T. TiVany, Pharmacol. Biochem. Behav., 1996, 54, 575. 240 T. Krivastik, K. Vuorikallas, T. P. Piepponen, A. Zharkovsky and L. Ahtee, Pharmacol. Biochem. Behav., 1996, 54, 371. 241 Y. Uchihashi, H. Kurihara, T. Morita, Y. Kitani, F. Karasawa and T. Sato, Pharmacol. Toxicol. (Copenhagen), 1996, 78, 322. 242 T. Suzuki, M. Tsuji, T. Moro, M. Misawa, T. Endoh and H. Nagase, J. Pharmacol. Exp. Ther., 1996, 279, 172. 243 T. Hol, S. Ruven, J.M. Van Ree and B. M. Spruijt, Neuropeptides (Edinburgh), 1996, 30, 283. 244 H. Kuribara, Psychopharmacology (Berlin), 1996, 125, 129. 245 E. Del Pozo, M. Barrios and J. M. Baeyens, Psychopharmacology (Berlin), 1996, 125, 209. 246 A. M. Young, W. J. Mullen, M. M. Makhyay and P. J. Goushaw, Psychopharmacology (Berlin), 1996, 125, 230. 247 S. A. Vanecek and A. M. Young, Exp. Clin. Psychopharmacol., 1996, 4, 251. 248 S. M. Hoelter, T. M. Tzschentke and W. J. Schmidt, Behav. Brain Res., 1996, 81, 53. 249 A. N. N. SchoVelmeer, P. Voorn, A. J. Jonker, G. Wardeh, P. Nestby, L. J. M. J.Vanderschuren, T. J. De Vries, A. H. Mulder and G. H. K. Tjon, Neurochem. Res., 1996, 21, 1417. 250 T. Ho, M. Niesink, J. M. Van Ree and B. M. Spruijt, Pharmacol. Biochem. Behav., 1996, 55, 515. 251 H. I. Magazine, Y. Lin, T. V. Bilfinger, G. Fricchione and G. B. Stefano, J. Immunol., 1998, 156, 4845. 252 P. Honore, V. Chapman, J. Buritova and J. M. Besson, Anesthesiology, 1996, 85, 150. 253 K. R. Gogas, H. J. Cho, C. I. Botchkina, J. D. Levine and A. I. Basbaum, Pain, 1996, 65, 9. 254 L. L. Lockwood, L. H. Silbert, M. R. Fleshner, C. McNeal, L. R. Watkins, M. L. Landenslager, K. C. Rice, R. J. Wiber and S. F. Maier, J. Pharmacol. Exp. Ther., 1996, 278, 689. 255 P. C. Singhal, Z. Shan, P. Garg, K. Sharma, I. Sharma and N. Gibbons, Nephron, 1996, 73, 526. 256 M. M. Garcia, J. Glister and R. E. Harlan, Brain Res., 1996, 734, 123. 257 S. L. Chang, R. L. Modlow, S. D. House and J. E. Zadina, Adv. Exp. Med. Biol., 1996, 402, 35. 258 J. T. Martin, S. L. Nehlsen-Cannarella, G.M. Gugelchuk and O. Fagoaga, Adv. Exp. Med. Biol., 1996, 402, 402. 259 P. C. Singhal, C. Q. Pan, S. Sagar, E. Valderama and R. K. Stahl, Nephron, 1996, 74, 197. 260 A. Bencsics, I. J. Elenkov and E. S. Vizi, J. Neuroimmunol., 1997, 73, 1. 261 E. Z. Tomei and F. L. Renaud, J. Neuroimmunol., 1997, 74, 111. 262 M. G. Segeeva, Z. V. Grishina and S. D. Varfolomeev, Immunolgiya (Moscow), 1995, 35 (Chem. Abstr., 1997, 126, 312 077). 263 A. Gorio, L. Vergani, M. L. Malosio, E.Lesma and A. M. Di Guilio, J. Pharmacol., 1996, 303, 21. 264 J. D. Alvaro, J. B. Tatro, J. M. Quillan, M. Fogliano, M. Eisenhard, M. R. Lerner, E. J. Nestler and R. S. Duman, Mol. Pharmacol., 1996, 50, 583. 265 D. A. Bereiter, Neuroscience (Oxford), 1997, 77, 863. 266 C. J. Malanga, J. Meng, W. W. Fleming and D. A. Taylor, J. Pharmacol. Exp. Ther., 1997, 280, 16. 267 J. Lesage, F. Bernet, V. Montel and J. P. Dupouy, Neurochem. Res., 1996, 21, 723. 268 L. Wardlaw, J.Kim and S. Sobieszczyk, Mol. Brain Res., 1996, 41, 140. 269 O. K. Ronnekliev, M. A. Bosch, M. J. Cunningham, E. J. Wagner, D. K. Grandy and M. J. Kelly, Neurosci. Lett., 1996, 216, 129. 270 P. L. Tao, C. S. Wong and M. C. Lin, Naunyn-Schmiedebergs Arch. Pharmacol., 1996, 354, 187. 271 R. Dallel, P. Luccarini, J. L. Molat and A. Woda, Eur. J. Pharmacol., 1996, 314, 19. 272 P. I. Johnson and T. C. Napier, Neuroscience (Oxford), 1997, 77, 187. 273 J. Meng, C. J. Malannga, J. Q.Kang, D. A. Taylor and W. W. Fleming, J. Pharmacol. Exp. Ther., 1997, 281, 41. 274 J. Kamei and A. Santoh, Neurosci. Lett., 1996, 210, 57. 275 L. W. Min, A. Sato, Y. Sato and R. F. Schmidt, Neurosci. Lett., 1996, 221, 53. 276 J. V. Rabadan, M. V. Milanes and M. L. Laorden, J. Pharmacol. Exp. Ther., 1996, 280, 32. 277 C. Ela, J. Barg, Z. Vogel, Y. Hasin and Y. Eilam, J. Mol. Cell Cardiol., 1997, 29, 711. 278 M. A. Chaney, P. Furry, E. M. Fluder and S. SlogoV, Anesth. Analg. (Baltimore), 1997, 84, 241. 279 G. Patrini, P. Massi, G. Ricevuti, A. Mazzone, G. Fossati, I. Mazzucchelli, E. Gori and D. Parolaro, J. Pharmacol. Exp. Ther., 1996, 279, 172. 280 M. S. Desole, E. Esposito, G. Fresu, R. Migheli, P. Enrico, M. A. Mura, G. De Natale, G. Miele and M. Miele, Brain Res., 1996, 723, 154. 281 H. Ammer and R. Schultz, J. Pharmacol. Exp. Ther., 1997, 280, 512. 282 M. Grossman, A. Abiose, O. Tangphao, T. F. Blaschke and B. B. HoVman, Clin. Pharmacol. Ther. (St. Louis), 1996, 60, 554. 283 L. Singh, R. J. Oles, M. J. Field, P. Atwal, G. N. WoodruV and J. C. Hunter, Br. J. Pharmacol., 1996, 118, 1317. 284 M. M. Puig, O. Pol and W. Warner, Anesthesiology, 1996, 85, 1403. 285 C. L. Williams, C. C. Bihm, G. C. Rosenfeld and T. F. Burks, J. Pharmacol. Exp. Ther., 1997, 280, 656. 286 R. Espert, J. F. Navarro, A. Salvador and V. M. Simon, Med. Sci. Res., 1996, 24, 385. 287 C. S. Cleeland, Y. Nakamura, E. Howland, N. R. Morgan, K. R. Edwards and M. Backonja, Neuropsychopharmacology, 1996, 15, 252. 288 L. A. Grupp, G. Hsu, N. Ng and S. Harding, Alcohol (N.Y.), 1997, 14, 71. 289 F. Oriz, F. Pascarelli, M. La Riccia, R. Di Grezia and F. E. Pontieri, Eur. J. Pharmacol., 1996, 302, 49. 290 P. Gruca, A. Jozkowicz, M. Chadzinska, J. Mika, S. Jozefowski, B. Przewlocki, R. Przewlocki, B. Plytycz and R. Seljelid, Modulators Immune Response Conf. Papers, 1995, 291. 291 O. Pol, E. Planas and M. M. Puig, Pharmacology, 1996, 53, 180. 360 Natural Product Reports, 1998292 P.P. Golikov, V. I. Udovichenko, V. N. Kalinin, L. M. Kozhevnikova, N. Yu. Nikolayeva, V. V. Marchenko and S. K. Moiseyev, Patol. Fiziol. Eksp. Ter., 1996, 9. 293 J. G. Hanna and T. L. Yaksh, Anesthesiology, 1996, 85, 355. 294 A. M. E. Bye, D. Lee, D. Naidoo and D. Flanagan, J. Clin. Neurosci., 1997, 4, 173. 295 J. W. G. Watt, J. R. Wiley and D. R. Bowsher, Anaesthesia, 1996, 51, 647. 296 A. Limperato, M. C. Obinu, M. A. Casu, M. S. Mascia, G.L. Carta and G. L. Gessa, Eur. J. Pharmacol., 1996, 302, 21. 297 K. Z. Ahmed and J. Crossland, Pak. J. Pharmacol., 1996, 13, 19. 298 T. Ichida and K. Kuriyama, Life Sci., 1996, 59, 2173. 299 C. C. Taylor, Y. Soong, D. Wu, J. S. Yee and H. H. Szeto, Pediatr. Res., 1997, 41, 411. 300 Y. Miwa, M. Saeki, A. Yamaji, Maeda and K. Saito, Life Sci., 1996, 59, 1809. 301 M. Pearl, I. M. Maisonneuve and S. D. Glick, Neuropharmacology, 1996, 35, 1779. 302 C. O. Stillar, J. Bergquist, O.Beck, R. Ekman and E. Brodin, Neurosci. Lett., 1996, 209, 165. 303 A. Bonci and J. T. Williams, J. Neurosci., 1997, 17, 796. 304 Y. Liu, D. Shenouda, T. V. Bilfinger, M. L. Stefano, H. I. Magazine and G. B. Stefano, Brain Res., 1996, 722, 125. 305 R. M. Tulamo, M. Raekullio, P. Taylor, C. B. Johnson and M. Salonen, J. Vet. Med. Ser. A, 1996, 43, 147. 306 P. A. Cantarella and L. A. Chahl, Behav. Pharmacol., 1996, 7, 470. 307 S. L. Cruz, J. E. Villareal and N. D. Volkow, Life Sci., 1996, 58, PL381. 308 F. Benedetti, Pain, 1996, 64, 535. 309 K. A. Lemke, W. J. Tranquilli, J. C. Thurman, G. J. Benson and W. A. Olson, J. Am. Vet. Assoc.., 1996, 209, 776. 310 G. R. Rossi, L. Leventhal and G. W. Pasternak, Eur. J. Pharmacol., 1996, 311, 7. 311 J. Philopena, D. Greenberg and G. P. Smith, Pharmacol. Biochem. Behav., 1996, 54, 333. 312 M.Weinstock, T. Poltyrev, G. I. Keshet and R.Malool, Proc. Int. Sympos. Catecholamines Neurotransm., 1996, 2, 933. 313 A. V. Kuzmin, M.A. F. M. Gerritis, J. M. van Ree and E. E. Zvartu, Life Sci., 1997, 60, PL257. 314 E. O’Hare, J. Cleary, P. J. Bartz, D. T. Whelan and C. J. Billington, Psychopharmacology (Berlin), 1997, 129, 289. 315 V. Tortorici, E. Vasquez and H. Vanegas, Brain Res., 1996, 725, 106. 316 E. V. Shlyakhto, A. A. Zaitsev, A. V. Panov, A. V. Ardashev, E. M. Nifontov, E. A. Kashina, V. V. Kazarin and V. V. Ivanov, Eksp. Klin. Farmakol., 1996, 59, 34. 317 G. L. Chien and D. M. Van Winkle, J. Mol.Cell Cardiol., 1996, 28, 1895. 318 S. Y. Sun, Z. Liu, P. Li and A. J. Ingenito, Gen. Pharmacol., 1996, 27, 1187. 319 M. B. Dutia, D. B. Gilchrist, A. J. Sansom, P. F. Smith and C. L. Darlington, Exp. Neurol., 1996, 141, 141. 320 D. Zheng, Y. Wu, S. Zhang, C. Wang and B. Ling, Zhongguo Yaolixue Tongbao, 1996, 12, 174. 321 D. T. Weldon, E. O’Harre, B. J. Cleary, C. J. Billington and A. Levine, Am. J. Physiol., 1996, 270, R1183. 322 H. Okur, A. Bozkurt, M. Kucukaydin and S.Muhtarogh, Res. Exp. Med., 1996, 196, 247. 323 S. Tokoyama, H. Wakabayashi and B. Hoskins, Pharmacol. Biochem. Behav., 1996, 54, 461. 324 J. J. Feigenbaum and S. G. Howard, Life Sci., 1996, 59, 2009. 325 J. J. Feigenbaum and S. G. Howard, Neurosci. Lett., 1996, 218, 5. 326 J. J. Feigenbaum and S. G. Howard, Neurosci. Lett., 1997, 224, 71. 327 J. J. Feigenbaum and S. G. Howard, Life Sci., 1997, 60, 1659. 328 N. Pedron, D. Pedroza, L. Calzada, L. Salazar and V. Fuentes, Arch.Androl., 1996, 37, 15. 329 J. Gumprecht, M. Zembala, E. Zukowska-Szczechowska, W. Grzeszck, Z. Religa, D. Moczulski and J. Wojarski, Transplant Proc., 1996, 28, 3450. 330 H. S. Kim, W. K. Park, C. G. Jang, K. W. Oh, J. Y. Kong, S. Oh, H. M. Rheu, D. H. Cho and S. Y. Kang, Behav. Brain Res., 1997, 85, 37. 331 L. A. Pini, G. Vitale, A. Ottani and M. Sandrins, J. Pharmacol. Exp. Ther., 1997, 280, 934. 332 J. F. Herrero and P. M. Headley, Br. J. Pharmacol., 1996, 118, 968. 333 C.C. Faura, M. J. Olaso, C. C. Cabanes and S. Horga, Pain, 1996, 65, 25. 334 J. T. Bian and H. N. Bhargava, Peptides (N.Y.), 1996, 17, 1415. 335 U. Bickel, O. P. Schumacher, Y. S. Kang and K. Voigt, J. Pharmacol. Exp. Ther., 1996, 278, 107. 336 D. A. Barret, D. P. Barker, N. Rutter, M. Pawula and P. N. Shaw, Br. J. Clin. Pharmacol., 1996, 41, 531. 337 S. V. Loeser, J. Meyer, S. Freundedthaler, M. Sattler, C. Desel, I. Meineke and U. Gundert-Remy, Naunyn-Schmiedeberg’s Arch.Pharmacol., 1996, 354, 197. 338 I. Jurna and J. Baldauf, Brain Res., 1996, 722, 132. 339 J. Haselstroem, J. O. Svensson, J. Saewe, Z. Wiesenfeld-Hallin, Q. T. Yue and X. J. Xu, Pharmacol. Toxicol. (Copenhagen), 1996, 79, 40. 340 G. C. Ross, G. P. Brown, L. Leventhal, K. Yang and G. W. Pasternak, Neurosci. Lett., 1996, 216, 1. 341 G. Kunst, S. Chubrasik, A. M. S. Black, J. Chubrasik, J. Schulte-Moenting and J. I. Alexander, Eur. J. Anaesthesiol., 1996, 13, 117. 342 K. Bjune, A.Stubhaug, M. S. Dodgson and H. Breink, Acta Anaesthesiol. Scand., 1996, 40, 399. 343 Y. Caraco, T. Tateishi, F. Guengerich and A. J. J. Wood, Drug Metab. Dispos., 1996, 24, 761. 344 D. E. Rollins, D. G. Wilkins and G. G. Krueger, Eur. J. Clin. Pharmacol., 1996, 50, 391. 345 Y. Caraco, J. Sheller and A. J. J. Wood, J. Pharmacol. Exp. Ther., 1996, 278, 1165. 346 L. Poulsen, K. Broesen, L. Arendt-Nielsen, L. F. Grain, K. Elbaek and S.M. Sindrup, Eur. J. Clin. Pharmacol., 1996, 51, 289. 347 B.Q. Xu, T. A. Aasmundstad, B. Lillekjendlie, A. Bjoernbee and A. S. Christophersen, Pharmacol. Toxicol. (Copenhagen), 1997, 80, 171. 348 M. B. Gatch, A. Liguori, S. S. Negus, N. K. Mello and J. Bergman, Eur. J. Pharmacol., 1996, 312, 389. 349 B. J. Rounsavillie, NIDA Res. Monogr., 1995, 150 (Chem. Abstr., 1996, 125, 25 431). 350 A. L. Muntoni, M. Diana and G. L. Gessa, Eur. J. Pharmacol., 1996, 301, R9. 351 E. A. Walker, T. M. Richardson and A. M. Young, Psychopharmacology (Berlin), 1996, 125, 113. 352 A. E. Kelly, E. F. Bless and C. J. Swanson, J. Pharmacol. Exp. Ther., 1996, 278, 1499. 353 A. S. Roth, R. B. OstroV and R. E. HoVman, J. Clin. Psychiatry, 1996, 57, 233. 354 L. D. Reid, L. R. Gardell, S. Chattopadhyay and C. L. Hubbell, Alcohol: Clin. Exp. Res., 1996, B20B, 1329. 355 S. L. Walsh, J. T. Sullivan, K. L. Preston, J. E. Garner and G. E. Bigelow, J. Pharmacol. Exp. Ther., 1996, 279, 524. 356 A. C. King, J. R. Volpicelli, A. Frazer and C.P. O’Brien, Psychopharmacology (Berlin), 1997, 129, 15. 357 C. S. Yuan, J. F. Foss, M. F. O’Connor, A. Toledano, M. F. Roizen and J. Moss, Clin. Pharmacol. Ther. (St. Louis), 1996, 59, 469. 358 J. F. Foss, M. F. O’Connor, C. S. Yuan, M. Murphy, J. Moss and M. F. Roizen, J. Clin. Pharmacol., 1997, 37, 25. 359 E. Nicolle, F. Deviller, B. Delaney, C. Durand and G. Bessard, Eur. J. Clin. Pharmacol., 1996, 49, 485. 360 J. J. Wang, S. T. Ho and Y. P. Hu, Reg. Anesth., 1996, 21, 214. 361 R. W. Gear, C. Miaskowski, N. C. Gordon, M. Paul, P. H. Heller and J. D. Levine, Nat. Med. (N.Y.), 1996, 2, 1248. 362 H. F. Miranda, F. Sierralta, L. Volosky and G. Pinardi, Analgesia (Elmsford, N.Y.), 1996, 2, 193. 363 A. Dervisogullari, A. Abram, J. P. Kamfire and L. F. Tseng, Analgesia (Elmsford, N.Y.), 1996, 2, 219. 364 J. P. Zacny, K. Conley and S. Marks, J. Pharmacol. Exp. Ther., 1997, 280, 1159. 365 R. W. Gearm, C. Mioskowski, N. C. Gordon, S. M. Paul, P. H. Heller and J.D. Levine, Nat. Med. (N.Y.), 1996, 2, 1248. 366 S. S. Murthy, C. Mathur, L. T. Kvalo, R. A. Lessor and J. A. Wilhelm, Xenobiotica, 1996, 26, 779. 367 R. F. Frye, G. R. Matzke, N. S. Jallad, J. A. Wilhelm and G. B. Bikhazi, Br. J. Pharmacol., 1996, 42, 301. 368 C. Chen, J. Yin, J. K. de Riel, R. I. Des-Jarlais, L. F. Raveglia, J. Zhu and L. Y. Liu-Chen, J. Biol. Chem., 1996, 27, 21 422. 369 Z. W. Pavlovic, M. L. Cooper and R. J. Bodnar, Brain Res., 1996, 741, 13. 370 R.Hoscki, S. Niizawa, K. Koike, T. Sagara, K. Kanematsu and I. Takayanagi, Arch. Int. Pharmacodyn. Ther., 1996, 331, 136. 371 J. Dallo and L. Koles, Neurobiology (Budapest), 1996, 4, 257. 372 P. Gomez-Serranillos, T. Ortega, M. E. Carretero and A. M. Villar, Phytother. Res., 1996, 10 (Suppl. 1), 116. 373 S. M. Crain and K. F. Shen, Brain Res., 1996, 741, 275. Bentley: ‚-Phenylethylamines and the isoquinoline alkaloids 361374 D. X. Wang and B. T. Qu, Zhongguo Yaoli Xuebao, 1996, 17, 281. 375 J. Kamei, T. Suzuki and H. Nagase, Neurosci. Lett., 1996, 215, 87. 376 A. Wang, Q. Zhang, C. Huang and Z. Wang, Junshi Yixue Kexueyuan Yuankan, 1996, 20, 113. 377 S. Kagaya, Jikeikai Med. J., 1996, 43, 57. 378 T. J. Hall, B. Jagher, M. Schaeublin and I. Weisenberg, Inflammation Res., 1996, 45, 299. 379 C. Grant, R. N. Upton and T. R. Kuchel, Austral. Vet. J., 1996, 73, 129. 380 Y. K. Batru, P. K. Gill, S. Vaidyanathan and A. Aggarwal, Int. J. Clin. Pharmacol.Ther., 1996, 34, 309. 381 T. Hayase, Y. Yamamoto and K. Yamamoto, J. Toxicol. Sci., 1996, 21, 143. 382 K. J. Schuh, S. L. Walsh, G. E. Bigelow, K. L. Preston and M. J. Stitzer, J. Pharmacol. Exp. Ther., 1996, 278, 836. 383 S. D. Comer, S. T. Lac, C. L. Wyvell and M. E. Carroll, Psychopharmacology (Berlin), 1996, 125, 355. 384 J. L. Kuhlman, S. Lalani, J. Magluilo, B. Levine and W. D. Darwin, J. Anal. Toxicol., 1996, 20, 369. 385 Y. Inagaki, T. Mashimo and I. Yoshida, Anesth. Analg.(Baltimore), 1996, 83, 530. 386 R. W. Foltin and M. W. Fischman, J. Pharmacol. Exp. Ther., 1996, 278, 1153. 387 A. L. Stinchcomb, A. Paliwal, R. Dua, H. Imoto, R. W. Woodard and G. I. Flynn, Pharm. Res., 1996, 13, 1519. 388 E. Kouri, S. E. Lukas and J. H. Mendelson, Biol. Psychiatry, 1996, 40, 617. 389 C. Lejus, Y. Blanoeil, T. Francois, S. Testa, P. Michel and B. Dixeneuf, Eur. J. Anaesthesiol., 1996, 13, 57. 390 F. A. Khan and R. S. Kamal, Anaesthesia, 1996, 51, 274. 391 J. S. Walker, A. K. Chandler, J. L. Wilson, W. Binder and R. O. Day, Inflammation Res., 1996, 45, 557. 392 N. Nishimi, Keio J. Med., 1996, 45, 324. 393 E. C. Strain, S. L. Walsh, K. L. Preston, I. R. Liebson and G. E. Bigelow, Psychopharmacology (Berlin), 1997, 129, 329. 394 M. Ohtain, H. Kotaki, K. Nishitateno, Y. Sawada and T. Iga, J. Pharmacol. Exp. Ther., 1997, 281, 428. 395 P. Ducray, L. Lebeau and C. Mioskowski, Helv. Chim. Acta, 1996, 79, 2346. 396 N. A. Aiktozhina, E. O. Esbolaev, T. A. Zubenko, K. A. Toibaeva and L. A. Aleksandrova, Bioorg. Khim., 1996, 22, 383. 397 M. Cavazza and F. Pietra, Z. Naturforsch. B: Chem. Sci., 1996, 51, 1347. 398 E. Bombardelli and B. Gabetta, PCT Int. Appl., WO/11184/1996 (Chem. Abstr., 1996, 125, 58 833). 399 E. Bombardelli and B. Gabetta, PCT Int. Appl., WO/01570/1997 (Chem. Abstr., 1997, 126, 186 239). 400 Q. Shi, P. Verdier-Pinard, A. Brossin, E. Hamel, A. T. McPhail and K. H. Lee, J. Med. Chem., 1997, 40, 961. 401 R. Ferrat, L. Sebbag, R. Ferrera, G. Hadow, E. Canet, A. Tabib and M. de Lorgeil, J. Cardiovasc. Pharmacol., 1996, 27, 876. 402 C. A. Palmerini, C. Saccardi, A. Floridi and G. Arienti, Clin. Chem. Acta, 1996, 254, 149. 403 A. Cedillo, M. Mourella and P. Muriel, Pharmacol. Toxicol. (Copenhagen), 1996, 79, 241. 404 T. Tateishi, P. Soueck, Y. Caraco, F. P. Guengerich and A. J. J. Woods, Biochem. Pharmacol., 1996, 53, 111. 405 K. Kitaura, H. Takikawa, N. Sano, Y. Takamori, S. Fukumura, T. Ichihara, M. Aiso, S. Uegaki, K. Tadokoro, A. Sato and M. Yamanaka, Yakuri to Chiro, 1996, 24 (suppl.), 2131. 406 N. Itoh, M. Kasamatsu, S. Onoosaka, N. Muto and K. Tanaka, Toxicology, 1997, 116, 201. 407 Z. Z. Altindag, G. Werner-Felmayer, G. Salim, H. Wachter and D. Fuchs, Clin. Exp. Immunol., 1997, 107, 574. 408 A. A. Nava-Ocampo, S. Suster and P. Muriel, Eur. J. Clin. Invest., 1997, 27, 77. 409 M. Cimino, P. Marini and F. Cattabeni, Eur. J. Pharmacol., 1996, 318, 201. 410 Y. Tsuda and T. Sano, Alkaloids (Academic Press), 1996, 48, 249. 411 A. S. Chawla and V. K. Kapoor, Handbook of Plant Fungal Toxicants, ed. J. P. F. D’Mello, CRC Press, Boca Raton, FL, 1997, 37. 412 S. Hosoi, M. Sato, M. Nagao and Y. Tsuda, Chem. Pharm. Bull., 1996, 44, 2342. 413 I. Manteca, N. Sotomayor, M. J. Villa and E. Leete, Tetrahedron Lett., 1996, 37, 7841. 414 I. Takano, I. Yasuda, M. Nishijima, Y. Hitotsuyanagi, K. Takeya and H. Itokawa, J. Nat. Prod., 1996, 59, 965. 415 I. Takano, I. Yasuda,M. Nishijima, Y. Hitotsuyanagi, K. Takeda and H. Itokawa, Phytochemistry, 1996, 43, 299. 416 I. Takano, I. Yasuda, M. Nishijima, Y. Yanagi, K. Takeya and H. Itokawa, Phytochemistry, 1997, 44, 735. 417 I. Takano, I. Yasuda, M. Nishijima, Y. Hitotsuyanagi, K. Takeya and H. Itokawa, J. Nat. Prod., 1996, 59, 1192. 418 I. Takano, I. Yasuda, M. Nishijima, Y. Hitotsuyanagi, K. Takeya and H. Itokawa, Bioorg. Med. Chem. Lett., 1996, 6, 1689. 419 I. Takano, I. Yasuda, M. Nishijima, Y. Hitotsuyanagi, K. Takeya and H. Itokawa, Tetrahedron Lett., 1996, 37, 7053. 420 M. Y. Zhu, W. B. Jin and N. C. Zhao, Zhongguo Yaoli Xuebao, 1997, 18, 90. 421 X. Linn, R. W. Kavash and P. S. Mariano, J. Org. Chem., 1996, 61, 7335. 422 E. J. Corey, D. Y. Gin and R. S. Kama, J. Amer. Chem. Soc., 1996, 118, 9202. 423 N. Saito, K. Toshiro, Y. Maru, K. Yamaguchi and A. Kubo, J. Chem. Soc., Perkin Trans. 1, 1997, 53. 362 Natural Product Reports, 1998

ISSN:0265-0568    

DOI:10.1039/a815341y

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Pyrrolizidine alkaloids James Richard Liddell 12 Merryweather Estate, Ringwood, Hampshire, UK BH24 1UL Covering: July 1996 to June 1997 Previous review: 1997, 14, 653 1 The synthesis of necines 2 The synthesis of necic acids 3 Alkaloids of the Asteraceae (Compositae) 4 Alkaloids of the Boraginaceae 5 Alkaloids of the Apocynaceae 6 Alkaloids from animals 7 General studies 8 Pharmacological and biological studies 9 References 1 The synthesis of necines The synthesis of both the pyrrolizidine and indolizidine skeletons via a nickel-catalysed stereoselective cyclisation reaction has been demonstrated by Sato et al.1 For the pyrrolizidine synthesis the key intermediate 2 was prepared from 1 by N-alkylation, deprotection and oxidation with Dess–Martin reagent (Scheme 1).Exposure of 2 to bis(cycloocta-1,5-dienyl)nickel and triphenylphosphine in the presence of triethylsilane gave 3 and 4 in a 3.3:1 ratio, 64% yield and high enantiomeric excess. Changing the silane to triphenylsilane accelerated the reaction and improved the ratio of 3 to 4 to 9.1:1.An enantioselective route to (")-platynecine 18 and (")- hadinecine 19 via the common intermediate 17 has been reported by Kang et al. (Scheme 2).2 A 7:1 mixture of benzylidenes 5 and 6, obtained from D-malic acid, was subjected to Swern oxidation and then reacted with phosphonate 7 to provide lactones 8–10. Reduction of the mixed lactones followed by acetylation and removal of the benzylidene protecting groups gave a mixture of 1,2-diols (which were removed by treatment with sodium periodate) and the 1,3-diols 11 and 12.The monosilyl ethers 13 and 14, obtained by regioselective silylation of 11 and 12, were converted into a 1:1 mixture of the trans-oxazolines† 15 by reaction with trichloroacetonitrile in diazabicyclo[5.4.0]undecene (DBU) followed by iodine in potassium carbonate. Chromatographic separation of 13 and 14 prior to formation of 15 did not aVect the 1:1 ratio.Introduction of the double bond and reduction of the trichloromethyl group in a single step provided 16 from which 17 was obtained after deprotection and double cyclisation of the resultant amino diol. Finally, basic hydroboration of 17 and subsequent acid treatment gave (")-platynecine 18, while dihydroxylation using catalytic amounts of osmium tetroxide and N-methylmorpholine N-oxide gave (")- hadinecine 19. Another approach to (")-platynecine 18 has been reported by Denmark et al.(Scheme 3).3 Tricyclic lactam (+)-20, available from earlier work,4 was converted into thionocarbonate (+)-21 in high yield and excellent enantiomeric purity. The thionocarbonate moiety was then removed using AIBN and tributyltin hydride to give lactam (+)-22. This, on deprotection, aVorded a 10:1 mixture of anomeric lactols 23 which on reduction provided (")-platynecine 18. Using their tandem [4+2]/[3+2] cycloaddition of nitro alkene methodology, Denmark and Thorarensen have also synthesised (+)-crotanecine 32.5 After exploring various approaches, the final route utilised the cycloaddition of nitro alkene 24 to silyl vinyl ether 25 which generated lactone (+)-26 in 73% optimised yield (Scheme 4).The required silyl vinyl ether 25 was synthesised from acetylenic ether 27 by silylcupration. Reduction of the lactone moiety of 26 followed by hydrogenolysis gave the tricyclic lactam (+)-28 which has the correct relative and absolute stereochemistry required for crotanecine.Next, the methyl ether was formed, and the secondary alcohol then mesylated to provide (+)-29. Removal of the silyl group to give 30 and reveal the eventual C-6 hydroxy of crotanecine was accomplished using Fleming’s bromination–desilylation–hydroxylation procedure. The authors stress the importance of thoroughly quenching any residual peracid prior to purification by silica gel chromatography. Failure to do so results in a very exothermic reaction on the silica gel.Finally, removal of the methyl ether to reveal the primary alcohol group followed by borane reduction of both the lactol and lactam generated adduct 31, which on heating with triethylamine gave crotanecine (+)-32. The same group have also published full details of their synthesis of (")-rosmarinecine 33, reviewed previously.6,7 The 1,3-dipolar cycloaddition of nitrones has been used to synthesise pyrrolizidines 40 and 47.8 The required nitrone 36 for the synthesis of 40 was obtained as a single epimer in three steps from protected ribofuranose 34 by aWittig type reaction, oxidation to provide the unstable aldehyde 35, and reaction with hydroxylamine (Scheme 5).Cycloaddition of 36 with allyl tert-butyldiphenylsilyl ether gave 37 as the major isomer. Conversion of 37 to 38 followed by hydrogenolysis of the N–O bond and accompanying cyclisation provided 39. This on reduction and hydrolysis gave the desired compound 40 as its trifluoroacetate salt.In a related approach the protected erythrose 41, available from D-arabinose, was converted via 42 into a 1:1 mixture of nitrones 43 and 44 (Scheme 6). Cycloaddition of 43 and the allyl silyl ether used previously provided 45 as the major †IUPAC name: 4,5-dihydrooxazole. N O OEE N O OH N O CHO N O H OSiR3 N O H OSiR3 H + iii 2 1 i, ii 3 R = Et or Ph 4 R = Et or Ph iv Scheme 1 Reagents: i, NaH, 1-bromopenta-2,4-diene, DMF; ii, p-TsOH, MeOH; iii, Dess–Martin periodinane, CH2Cl2; iv, 20 mol% Ni(cod)2, 40mol% Ph3P, R3SiH (5 equiv., R=Et, Ph) Liddell: Pyrrolizidine alkaloids 363product, which after desilylation, mesylation, and reduction in a hydrogen atmosphere gave pyrrolizidine 46.This on hydrolysis aVorded 47 as the trifluoroacetate salt. A second and concise synthesis of pyrrolam A has been reported.9,10 (R)-Prolinol 48 was protected and then subjected to Mitsunobu dehydrative alkylation to provide triester 49 ( )m ( ) n ( )m ( ) n 5 6 7 8 9 Z-isomer 10 E-isomer 11 m = 2; n = 1 12 m = 1; n = 2 13 m = 2; n = 1 14 m = 1; n = 2 15 16 18 17 19 D-Malic acid i, ii iii, iv v–viii x, xi xiii, xiv xvii xv, xvi + + ix xii O O O O O O O OH HO P(OEt)2 O O O TBDMSO OAc OAc OH Ph O O O Ph O Ph Ph O N O TBDMSO OAc CCl3 N HO H N HO H OH N HO H OH OH N O TBDMSO OAc I OAc HO OAc OAc OH Scheme 2 Reagents: i, BH3 ·SMe2, B(OMe)3, THF, 0220 )C; ii, PhCHO, p-TsOH, toluene, Dean–Stark trap, 140 )C; iii, Swern oxidation; iv, 7, DBU, LiCl, MeCN, 0 )C ; v, DIBAL, CH2Cl2, "78 )C, then MeOH, NaBH4, 0 )C; vi, Ac2O, DMAP, NEt3, CH2Cl2, 0 )C; vii, AcOH–H2O (4:1), 20 )C; viii, NaIO4, MeOH–H2O (4:1), 20 )C; ix, TBDMSCl, imidazole, DMF, "40 )C; x, Cl3CCN, DBU, MeCN, 0 )C; xi, I2, K2CO3, MeCN, 0220 )C; xii, Zn, NH4Cl, ButOH–H2O (4:1), 0220 )C; xiii, 6 M HCl–MeOH (1:5), 20 )C; xiv, CCl4, Ph3 P, NEt3, DMF, 20 )C; xv, BH3·THF, THF–CH2Cl2 (2:1), 0 )C, then basic H2O2, EtOH, 50 )C; xvi, 6 M HCl–MeOH (1:1), 50 )C; xvii, OsO4, NMO, acetone–H2O (4:1), 0 )C N HO OH H N O O OH H N O O OMe H N O O O OMe H OPh S N O OH O OMe H i (+)-21 (+)-22 23 (–)-18 iv ii iii (+)-20 Scheme 3 Reagents: i, Phenyl chlorothionoformate, DMAP, CH3CN; ii, Bu3SnH, AIBN, benzene, reflux; iii, 90% aq.TFA, rt, 4 h; iv, Red-Al, THF, reflux (+)-28 27 (–)-25 i 24 ii (+)-26 iii, iv v, vi (+)-29 vii (+)-30 (+)-31 (+)-32 viii, ix x N HO H HO OH N OMs HO H HO OH BH3 N O O OMs HO OMe H H H N O O OMs PhMe2Si OMe H H H N O O OH PhMe2Si OH H H H O O N O O H H H OG* H SiMe2Ph O NO2 O OPri O O Ph SiMe2Ph O Ph PriO2C Scheme 4 Reagents: i, PhMe2SiLi (2 equiv.), CuCN, THF, 0 )C; ii, methylaluminium (2,6-diphenylphenoxide) (5 equiv.), toluene, "14 )C; iii, L-Selectride, CH2Cl2, "78 )C; iv, Raney Ni, H2 (200 psi), EtOH; v, TsOH, MeOH, CH(OMe)3; vi, MeSO2Cl, NEt3; vii, KBr, AcOOH, AcOH, NaOAc; viii, 90% TFA, 60 )C, 24 h; ix, BH3 (40 equiv.), THF, reflux; x, NEt3, MeOH (2:1), 120–130 )C N H OH HO OH 33 364 Natural Product Reports, 1998(Scheme 7).In a one-pot process, without isolation of intermediates, 49 was deprotected, hydrolysed and decarboxylated to 50, and then cyclised to the dihydropyrrolam 51. Dehydration of 51 by formation of the phenylselenide and in situ oxidation with peroxide aVorded the desired pyrrolam A 52. A concise route to the 1-aminonecine framework which occurs in the loline alkaloids lolidine and absouline has been developed.11 The [2+2] cycloaddition of prolinal imine 53 with benzyloxyketene provided ‚-lactam 54 as a single diastereomer and in high yield (Scheme 8).Rearrangement of 54 to „-lactam 55 followed by reduction provided 56, or alternatively, 54 was debenzyloxylated to 57 which on rearrangement provided pyrrolizidinone 58. Using a radical cyclisation methodology, heliotridane 62 and (6S,7S)-dihydroxyheliotridane 67 have been synthesised by Robertson et al. (Scheme 9).12 Alcohol 59 was converted into tosylate 60 and then reacted with either pyrrolidine or the protected pyrrolidine diol 64 to aVord the required key precursors 61 and 65.These underwent radical formation and cyclisation on treatment with tributyltin hydride and AIBN, and on completion of the reaction tin salts were removed by complexation with thiophenol to provide a 13:1 mixture of heliotridane 62 and pseudoheliotridane 63 from 61, or 66 from 65. Finally, removal of the protecting groups from 66 provided the dihydroxyheliotridane 67.Pseudoheliotridane 63 has also been synthesised enantiospecifically by Coldham et al.13 Starting from the available stannane 68, removal of the Boc group and replacement by the but-3-enoyl side chain gave amide 69 which was then reduced to amine 70 (Scheme 10). Transmetallation of 70 with n-butyllithium generated an ·-aminoorganolithium which, on trapping with methanol, gave (+)-pseudoheliotridane 63 as N HO HO OH H HO N O O OH H EtO2C N O O O H OMs EtO2C N O O O H OSiPh2But EtO2C O O N+ O– EtO2C O OH OH O O CHO O O EtO2C CH2OSiPh2But i, ii iii 36 37 38 39 40 toluene, reflux iv, v vi vii, viii 34 35 Scheme 5 Reagents: i, Ph3P=CHCO2Et, CH2Cl2, 18 h; ii, NaIO4, aq.MeOH; iii, NH2OH, NaOAc, H2O–EtOH, rt, 18 h; iv, TBAF, THF, rt, 1 h; v,MsCl, NEt3; vi, H2, Pd/C, EtOH; vii, LiAlH4; viii, TFA, H2O O O PhSe N+ O– N HO HO OH H N O O OH H N O O O H PhSe OSiPh2But O O PhSe N+ O– CH2OH O O O OH O O viii 42 i ii–iv 43 45 46 47 41 44 toluene, reflux, 2 h CH2OSiPh2But + v–vii Scheme 6 Reagents: i, Ph3 P=CH2; ii, (COCl)2, DMSO, CH2Cl2, "60 )C, then NEt3; iii, NH2OH; iv, PhSeBr, CH2Cl2; v, TBAF, THF, rt, 1 h; vi, MsCl, NEt3; vii, Raney Ni, H2, EtOH; viii, TFA, H2O N H O N H O NH H OH N H C(CO2Et)3 Boc NH H CO2H 48 49 i, ii iii, iv 50 v vi 51 52 Scheme 7 Reagents: i, Boc-ON, CH2Cl2, rt; ii, CH(CO2Et)3, Ph3 P, DEAD, Et2O, rt; iii, TFA, CH2Cl2, rt; iv, 12 M HCl, reflux; v, HMDS, TMSCl (cat.), MeCN, reflux; vi, LDA, THF, "78 )C, then PhSeCl, then H2O2, THF, 0 )C vii 53 54 ii iii 55 56 iv–vi 57 58 N H NHBn O N Boc N Bn O H N H NHBn OBn N O BnO NHBn N Boc N Bn O BnO H H N Boc N Bn i Scheme 8 Reagents: i, PhCH2OCH2COCl, NEt3, CH2Cl2, "78 )C, rt, 20–24 h; ii, TFA, CH2Cl2, then 12 M HCl, EtOH, reflux; iii, BH3·SMe2, THF, reflux, 2 h; iv, NaOAc–MeOH, 5 min, then I2, CH2 Cl2; v, NH4HCO2, Pd/C, acetone, reflux; vi, NaH, CS2, THF–HMPA, MeI, rt, 30 min; vii, Bun 3SnH, AIBN, toluene, reflux, 1 h; 12 M HCl, EtOH, reflux, 24 h Liddell: Pyrrolizidine alkaloids 365a single diastereomer.Replacement of methanol by other electrophiles (benzophenone, benzaldehyde or trimethylsilyl chloride) gave the related pyrrolizidines 71–73 respectively. An enantioselective route to pyrrolizidines from pyrroloimidazoles has been developed.14 Pyrroloimidazole 74 was converted into pyrrolidine 75 by aminal reduction and hydrogenolysis using Pearlman’s catalyst (Scheme 11).Protection of the nitrogen and transformation of the tert-butyl ester to an aldehyde gave 76, which on chain extension and then cyclisation provided pyrrolizidine 77. Barluenga et al. have synthesised a number of N-fused pyrroles, including the two dihydropyrrolizines 80 and 81, via a propargylation–cycloamination process.15 For the synthesis of 80 the key azadiene intermediate 79 was generated from pyrroline 78 by metalation, addition of benzonitrile, and trapping of the resulting carbanion with prop-2-ynyl bromide (Scheme 12). On heating, 79 underwent pyrrole annulation and hydrolysis of the imine group to yield 80.Dihydropyrrolizine 81 was obtained in a similar manner using cyclohexanecarbonitrile in place of benzonitrile. A new and facile route to the optically pure Geissman– Waiss lactone 87, an important intermediate in many syntheses of necines, has been reported by Kunieda’s group.16 In the presence of boron trifluoride–diethyl ether, the available oxazolidinone (+)-82 was treated with the lithium enolate of tert-butyl acetate and converted into a 1:5 mixture of trans- and cis-oxazolidinones 83 (Scheme 13).tert- Butoxycarbonylation of 83 followed by ring opening with caesium carbonate gave lactones 84 and 85, from which the major isomer, 84, was isolated by a single recrystallisation. Ozonolysis of 84 and reaction with dimethyl sulfide gave 59 ii 60 61 , iii 65 v iv 62 63 66 67 vi + 64 i N H HO HO N H TBDMSO TBDMSO N H N H Br N OTBDMS OTBDMS Br N Br OTs Br OH NH OTBDMS TBDMSO Scheme 9 Reagents: i, TsCl, pyridine, rt; ii, pyrrolidine, benzene, reflux; iii, NEt3, CH3CN, reflux; iv, Bu3SnH, AIBN, benzene, reflux, 3 h, then PhSH, rt; v, Bu3SnH, AIBN, benzene, reflux, 14 h, then PhSH, rt; vi, H2SiF6 (2 equiv.), aq.CH3CN, 80 )C, 16 h i ii 70 iii 63 68 69 N H N SnBu3 N SnBu3 O N Boc SnBu3 Scheme 10 Reagents: i, B-Bromocatechol borane, CH2Cl2, then but-3- enoyl chloride; ii, AlH3, diethyl ether, 0 )C; iii, BunLi (2 equiv.), hexane–diethyl ether (10:1), "78 )C to rt, 1 h then "78 )C, MeOH N H SiMe3 N H Ph H OH N H Ph Ph OH 71 72 73 i, ii 75 76 iii–vi vii viii, ix 77 N O CO2Me N CO2Me Z EtO2C N OHC CO2Me Z HN ButO2C CO2Me N N Ph Ph H H CO2Me CO2But 74 Scheme 11 Reagents: i, NaBH3 CN, 2 M HCl, THF; ii, Pd(OH)2, H2 (60 psi), MeOH, TFA (1 mol equiv.); iii, PhCH2OCOCl, NEt3, DCM; iv, TFA; v, DCCI, HOSu, THF, then NaBH4; vi, TPAP, NMO, DCM, 4 Å sieves; vii, (EtO)2POCH2CO2Et, NaH, THF; viii, Pd/C, H2 (60 psi), MeOH; ix, xylene, reflux N Ph O NH HN Ph N NH Ph N N Ph Li N Li+ – i, ii iii iv 78 79 80 Scheme 12 Reagents: i, LDA, THF, "78 )C, 1 h; ii, benzonitrile, THF, "78 )C, 1 h; iii, prop-2-ynyl bromide, THF, "78 )C, 1 h; iv, EtOH– NEt3 (1:1), 100 )C sealed tube, 6 h N O 81 366 Natural Product Reports, 1998compound 86, but similar treatment of pure 85 failed to produce any bicyclic materials.Finally, demethoxylation of 86 and removal of the Boc protecting group gave the desired Geissman–Waiss lactone (+)-87.In a like manner, the enantiomeric lactone (")-87 was synthesised from (")-82. A detailed review of hydroxylated necine synthesis, covering the period 1989–1995, has been published by Casiraghi et al.17 Indolizidine analogues of the polyhydroxylated pyrrolizidine alkaloids alexine 88 and australine 89 have been synthesised by Pearson and Hembre, and the analogues tested for biological activity.18 The approach used may have application in pyrrolizidine syntheses. 2 The synthesis of necic acids A synthesis of 93, the immediate precursor to senecivernic acid 94, using a retro-Diels–Alder reaction has been outlined by Liu et al. (Scheme 14).19 1,4-Addition of dimethyllithiumcuprate to tricyclic ketone 90 followed by methoxycarbonylation produced 91. This on methylation and retro-Diels–Alder thermolysis gave cyclopentenone 92. Further reaction with dimethyllithiumcuprate followed by Baeyer–Villiger oxidation and finally an aldol condensation with formaldehyde aVorded the lactone 93.Sharpless asymmetric dihydroxylation has been used to synthesise (+)- and (")-trachelanthic acid and then indicine 98 and intermedine 100.20 Ethyl acetoacetate was alkylated, reduced to an 11:1 mixture of syn- and anti-‚-hydroxy esters, and the major diastereomer then dehydrated to provide the key alkenoate 95 (Scheme 15). Sharpless asymmetric dihydroxylation of 95 with AD-mix-· aVorded dihydroxy ester (+)-96 in high yield and 90% enantiomeric excess, which on hydrolysis with barium hydroxide gave the desired (")- trachelanthic acid 97.The alkaloid indicine 98 was obtained from 97 by first protecting the diol as the acetonide, coupling the acid to (+)-retronecine with the aid of acylating agents, and finally removing the acetonide protecting group. In a similar manner, reaction of alkenoate 95 with AD-mix-‚ and NH O OMe O O NH 2 O O NH O Boc NH O O CO2But NH O OMe O O NH 2 O O N Boc O OMe O NH O Boc + Cl– + Cl– ii, iii 85 iv (+)-87 v, vi (–)-82 i 83 cis:trans = 5:1 84 + 86 (–)-87 (+)-82 Scheme 13 Reagents: i, tert-butyl acetate, BusLi, BF3·OEt2; ii, (Boc)2O, NEt3, DMAP; iii, Cs2CO3, MeOH, then NaH, THF; iv, O3, MeOH, Me2S; v, Et3SiH, BF3·OEt2; vi, HCl, Et2O N H OH HO HO HO N H OH HO HO HO 88 89 i, ii iii, iv 90 91 92 93 v–vii O CO2Me O O CO2Me O CO2Me O Scheme 14 Reagents: i, Me2CuLi; ii, methoxycarbonylation; iii, methylation; iv, thermolysis; v, Me2CuLi; vi, Baeyer–Villiger oxidation; vii, LDA, HCHO HO2C CO2H OH 94 (+)-98 vi–viii (–)-97 (+)-99 v (+)-96 iv ix, v i–iii 95 vi–viii (+)-100 CO2Et O CO2Et CO2Et OH OH CO2H OH OH CO2H OH OH O O HO OH OH H O O HO OH OH H Scheme 15 Reagents: i, NaOEt, Pri Br, EtOH, reflux, 18 h; ii, Zn(BH4)2, diethyl ether, "50 )C, 6 h; iii, POCl3, py, 25 )C for 12 h, then 100 )C for 1 h; iv, AD-mix-·, MeSO2NH2, But OH–H2O (1:1), 0 )C, 42 h, 81%, 90% ee; v, Ba(OH)2·8H2O, H2O, heat, 0.5 h; vi, Me2C(OMe)2, HCl (cat.), 25 )C, 2 h; vii, DCC, DMAP, camphorsulfonic acid (cat.), toluene, then (+)-retronecine, 25 )C, 6 d; viii, 1 M HCl, 25 )C, 8 h; ix, AD-mix-‚, MeSO2NH2, But OH–H2O (1:1), 0 )C, 42 h, 83%, 85% ee Liddell: Pyrrolizidine alkaloids 367subsequent hydrolysis provided (+)-trachelanthic acid 99 and, following coupling to (+)-retronecine, intermedine 100. 3 Alkaloids of the Asteraceae (Compositae) Five groups have reported isolating pyrrolizidine alkaloids from species in the Asteraceae (Table 1).21–25 The only new alkaloid is 18-hydroxyjaconine 101, which was isolated from the Brazilian species Senecio selloi.21 The toxic alkaloids integerrimine and usaramine have been found in Gynura divaricata, a constituent of the Chinese medication ‘Bai Bei San Qi’.24 A review (in Serbo-Croatian) of physiologically active pyrrolizidines and other compounds from plants of the family Asteraceae has been published.26 4 Alkaloids of the Boraginaceae A number of new alkaloids have been identified in the complex mixtures present in four species within the Boraginaceae.These alkaloids, along with those isolated from less complex mixtures present in other species are listed in Table 2.27–33 New alkaloids are indicated by an asterisk. Thirteen alkaloids were found in Egyptian Echium setosum and eighteen in E. vulgare from Germany. In both species echimidine was the major component with the tigloyl (2-methylbut-2-enoyl) isomer of echimidine (i.e.hydroxymyoscorpine 102) as a minor component along with trace amounts of a number of known alkaloids not previously reported in Echium species.27 Of the new alkaloids, the most abundant was 3*-acetylechimidine 103, while alkaloids 104–109 were tentatively identified from mass spectral data. Two further alkaloids, present in both species, were incompletely indentified and have been omitted from Table 2. A GC–MS study of Cynoglossum oYcinale and Table 1 Pyrrolizidine alkaloids in the Asteraceae Species Pyrrolizidine alkaloids Ref.Senecio oxiphyllus Retrorsine, riddelline, usaramine, seneciphylline 21 S. brasiliensis Senecionine, integerrimine, retrorsine, usaramine 21 S. cisplatinus Retrorsine, usaramine, riddelline (trace) 21 S. heterotrichus Senecionine, integerrimine, retrorsine 21 S. leptolobus Senecionine, integerrimine, retrorsine (trace), usaramine, senecivernine, neosenkirkine, senkirkine, otosenine, florosenine, doronine 21 S.selloi Senecionine, retrorsine, usaramine, senecivernine, *18-hydroxyjaconine 101 21 S. inornatus 7-Angeloylretronecine 22 S. ambraceus Senecionine, integerrimine, retrorsine, seneciphylline, senkirkine 23 Gynura divaricata Integerrimine, usaramine 24 Petasites hybridus Senecionine, seneciphylline, senkirkine, tussilagine 25 *New alkaloid. N O O O O H OH Cl HO OH 101 Table 2 Pyrrolizidine alkaloids in the Boraginaceae Species Pyrrolizidine alkaloids Ref.Echium setosum Echimidine, hydroxymyoscorpine 102, 7-angeloylretronecine, 9-angeloylretronecine, 7-tigloylretronecine (trace), 9-tigloylretronecine (trace), uplandicine, *7-angeloyl-9-(2-methylbutyryl)retronecine 106, *7-tigloyl-9-(2-methylbutyryl)retronecine 107, *7-angeloyl-9-(2,3-dimethylbutyryl)retronecine 108 (trace), *7-angeloyl-9-(2,3-dihydroxybutyryl)retronecine 109 27 E. vulgare Echimidine, hydroxymyoscorpine 102, *3* -acetylechimidine 103, retronecine (trace), 7-angeloylretronecine, 9-angeloylretronecine, 7-tigloylretronecine, 9-tigloylretronecine, 9-senecioylretronecine (trace), uplandicine, ecihumiline (trace), *7-(2-methylbutyryl)retronecine 104 (trace), *9-(2-methylbutyryl)-retronecine 105 (trace), *7-angeloyl-9-(2-methylbutyryl)retronecine 106, *7-tigloyl-9-(2-methylbutyryl)retronecine 107, *7-angeloyl-9-(2,3-dihydroxybutyryl)retronecine 109 (trace) 27 Cynoglossum oYcinale Heliosupine, heliosupine N-oxide, 3*-acetylheliosupine, viridiflorine, 7-angeloylheliotridine, 7-tigloylheliotridine, rinderine, 7-angeloylrinderine, echinatine, 7-angeloylechinatine, *7-angeloyl-1-formyl-6,7-dihydro-5H-pyrrolizine 110, *7-angeloyl-9-(2-methylbutyryl)heliotridine 111, *7-angeloyl-9-(2,3-dihydroxybutyryl)heliotridine 112 28 C.amabile Amabiline, supinine, rinderine, echinatine, 7-acetylechinatine (trace) 28 Arnebia decumbens 7-Angeloylretronecine, 9-angeloylretronecine, 7-tigloylretronecine, 9-tigloylretronecine, europine, heliotrine, lycopsamine, rinderine, supinine 29 Messerschmidia argentea Indicine, indicine-N-oxide, 3*-acetylindicine, *3*-acetylindicine-N-oxide 113 30 Heliotropium bacciferum Europine, heleurine, heliotrine, supinine 31 H.indicum Heliotrine, lasiocarpine 32 H. esfandiarii Europine, europine-N-oxide 33 *New alkaloids. 368 Natural Product Reports, 1998C. amabile, revealed fourteen and five alkaloids respectively.28 Among the alkaloids identified in C. oYcinale were structures 110–112, all of which appear to be new.A similar study of Arnebia decumbens revealed three known tetrahydroisoquinoline alkaloids in addition to eleven pyrrolizidine alkaloids, nine of which were identified.29 Also new is 3*-acetylindicine N-oxide 113, isolated from Messerschmidia argentea.30 Alkaloid levels in samples of Heliotropium curassavicum, a medicinal plant sold in Cordoba, Argentina, have been found to be far in excess of recommended limits.Concerns for the eVects on the local population, and the need for adequate controls were expressed.34 The variability of alkaloid content in Symphytum oYcinale has been reviewed, and the influence of ecotype, harvest, and detection method discussed.35 5 Alkaloids of the Apocynaceae Parsonsia straminea, the larval food plant of Tellervo zoilus and other butterfly species, has been found to contain lycopsamine N-oxide and lesser amounts of intermedine N-oxide.36 6 Alkaloids from animals Larvae of the butterfly Tellervo zoilus have been found to sequester lycopsamine and intermedine, obtained from food plants, and the alkaloids used to provide protection against predation by the orb weaving spider, Nephila maculata.36 The sequestration and use of tropane and pyrrolizidine alkaloids at diVerent stages in the life cycles of Placidula euryanassa and Miraleria cymothoe butterflies has been investigated.37 Studies of the mitochondrial 16S rDNA gene of a number of Arctiidae and Nymphalidae indicate that sequestration of pyrrolizidine alkaloids (and of cardiac glycosides) appears to have evolved independently and convergently.38 Tracer studies have revealed that pyrrolizidine N-oxides fed to three species of insect are reduced to the free alkaloids.The enzyme involved has been isolated and characterised, and shown to be highly specific for pyrrolizidine alkaloids containing structural elements essential for hepatotoxic and genotoxic activity.39 The sequestration of secondary plant compounds by butterflies and moths has been reviewed.40 7 General studies Using 2D NMR techniques, Krebs and Carl have confirmed the correct assignments of the 13C chemical shifts for retrorsine, for which there had previously been some uncertainty. 41 A Korean group has developed an expert system which uses mass spectra to determine molecular weights and structural types of alkaloids, including pyrrolizidines.42 The optimum conditions for the biosynthesis of radio-labelled monocrotaline have been studied, and the most eYcient and cost eVective method was noted as being the utilisation of 14CO2.43 A quantitative photometric determination of otonecine-based pyrrolizidines, based on a colour reaction, has been developed and used for the determination of senkirkine in Farfarae folium at the 1 ppm level.44 The same group has developed a new HPLC method for the simultaneous quantitative determination of pyrrolizidines and their N-oxides in extracts of plant material.45 A sensitive competitive enzyme immunoassay which is specific for senecionine type alkaloids has been developed.Retrorsine N-oxide, monocrotaline and senkirkine do not respond to the test.46 An ELISA test for retrorsine, its N-oxide, senecionine and monocrotaline with detection limits in the parts per billion level has been developed. The structurally similar swainsonine and lupinine alkaloids do not respond to the test.47 8 Pharmacological and biological studies Analysis of commercially available comfrey tablets and of comfrey roots and leaves has indicated that the tablets were derived from root material rather than leaves. Bioassays of the principal isolated alkaloids, their N-oxides, and of the whole comfrey extract showed that only the whole extract had any mutagenic eVect upon the p53 gene within the cell line used for the assay.48 Integerrimine, obtained from Senecio braziliensis, has been shown to be recombinagenic when tested for genotoxicity using the wing somatic mutation and recombination test and fruit fly of the Drosophila melanogaster species.49 Thirteen pyrrolizidines, including some N-oxides, have been analysed for interactions with acetylcholine-related enzymes and their receptors.Most of the alkaloids tested did not aVect the enzymes, but all showed significant binding to the receptors. The eVect of this on chemical defense in plants and animals against herbivores and predators was discussed.50 Retrorsine present in the milk of lactating rats has been shown to aVect the handling of copper in the liver of newborn pups.This may explain the synergistic hepatotoxicity of copper and retrorsine, and be of importance in Indian Childhood Cirrhosis.51 Moncrotaline has induced right ventricular hypertrophy in neonatal guinea pigs, and this may serve as a model for human congenital heart disease associated with pulmonary hypertension.52 Further work on the metabolic processes of pyrrolizidine alkaloid toxicity has been carried out.An in vivo study of the eVect of retrorsine on biliary sulfur metabolism in rats has shown that levels of glutathione and its precursors are markedly increased following retrorsine administration.53 Perfusion of isolated rat liver with monocrotaline leads to a decrease in taurine levels and an increase in methionine and N O O O O H OH HO H O O N O OH O H N O H HO O N O H O O R2 R1 O N O O O O H OH HO H OH N O H O R2 R1 O O N O CHO O N O H O O O N O H O OH OH O O N+ HO O O H OH H O O O– 113 112 111 110 108 R1 = R2 = Me 109 R1 = R2 = OH 103 106 R1 = Me; R2 = H 107 R1 = H; R2 = Me 105 104 102 Liddell: Pyrrolizidine alkaloids 369glutathione and its precursors in the perfusate. Within the liver, glutathione levels were increased, while taurine and methionine levels decreased.54 In a related study, supplementary feeding of taurine to rats both prior and subsequent to monocrotaline administration significantly reduced some of the eVects of monocrotaline poisoning.55 A comparison of the cytotoxicity of monocrotaline and its metabolites, monocrotaline pyrrole and glutathione-conjugated dihydropyrrolizine, on cultured bovine pulmonary artery endothelial cells showed that only monocrotaline pyrrole had any eVects on the cell metabolism as judged by a variety of markers.56 Using radioactive labelling, monocrotaline pyrrole has been shown to bind tightly to rat red blood cells, with the majority of the radioactive label associated with the globin ‚-chains.57 Incubation of two alkaloids and one N-oxide with microsomal preparations from humans, rat and avocado has shown that the human and rat microsomes convert the alkaloids and the N-oxide into dehydroretronecine, a known toxic metabolite.The implications are that N-oxides may be more toxic than previously believed.58 The oral LD50 value of monocrotaline in Wistar rats has been determined.59 The available data for the in vitro rat hepatocyte micronucleus assay has been reviewed, and the sensitivity of the assay in identifying mutagens and genotoxic liver carcinogens assessed.For retrorsine, monocrotaline and particularly isatidine long exposure times were shown to be essential to detect mutagenic potential.60 A major review and assessment of fourteen classes of naturally occurring orally active carcinogens, one of which is the pyrrolizidine alkaloids, has been published by Scimeca.61 The sequence selectivity of DNA-DNA crosslinking by pyrrole-derived bifunctional alkylating agents, including pyrrolizidines, has also been reviewed.62 Acknowledgements.The use of the University of Southampton Libraries is gratefully acknowledged. 9 References 1 Y. Sato, N. Saito and M. Mori, Tetrahedron Lett., 1997, 38, 3931. 2 S. H. Kang, G. T. Kim and Y. S. Yoo, Tetrahedron Lett., 1997, 38, 603. 3 S. E. Denmark, D. L. Parker, Jr. and J. A. Dixon, J. Org. Chem., 1997, 62, 435. 4 S. E. Denmark, A. Thorarensen and D. S. Middleton, J. Org. Chem., 1995, 60, 3574. 5 S. E. Denmark and A. Thorarensen, J. Am. Chem. Soc., 1997, 119, 125. 6 S. E. Denmark, A. Thorarensen and D. S. Middleton, J. Am. Chem. Soc., 1996, 118, 8266. 7 J. R. Liddell, Nat. Prod. Rep., 1996, 13, 187 and ref. 2 therein. 8 A. Hall, K. P. Meldrum, P. R. Therond and R. H. Wightman, Synlett, 1997, 123. 9 J. R. Liddell, Nat. Prod. Rep., 1997, 14, 653 and ref. 3 therein. 10 G. B. Giovenzana, M. Sisti and G. Palmisano, Tetrahedron: Asymmetry, 1997, 8, 515. 11 C. Palomo, J. M. Aizpurua, C. Cuevas, P. Román, A. Luque and M. Martínez-Ripoll, An. Quím. Int. Ed., 1996, 92, 134. 12 J. Robertson, M. A. Peplow and J. Pillai, Tetrahedron Lett., 1996, 37, 5825. 13 I. Coldham, R. Hufton and D. J. Snowden, J. Am. Chem. Soc., 1996, 118, 5322. 14 R. C. F. Jones, K. J. Howard and J. S. Snaith, Tetrahedron Lett., 1996, 37, 1711. 15 J. Barluenga,M. Tomás, V. Kouznetsov, A. Suárez-Sobrino and E. Rubio, J. Org. Chem., 1996, 61, 2185. 16 T. Kouyama, H. Matsunaga, T. Ishizuka and T. Kunieda, Heterocycles, 1997, 44, 479. 17 G. Casiraghi, F. Zanardi, G. Rassu and L. Pinna, Org. Prep. Proced. Int., 1996, 28, 641. 18 W. H. Pearson and E. J. Hembre, J. Org. Chem., 1996, 61, 5546. 19 Z.-Y. Liu, X.-J. Chu, L. He, Y.-N. Xie and L.-Y. Zhao, Youji Huaxue, 1997, 17, 62. 20 M. Nambu and J. D.White, Chem. Commun., 1996, 1619. 21 H. C. Krebs, T. Carl and G. G. Habermehl, Phytochemistry, 1996, 43, 1227. 22 H. Wiedenfeld, E. Roeder and W. Luck, Planta Med., 1996, 62, 483. 23 K. Liu and E. Roeder, Zhongcaoyao, 1996, 27, 203. 24 E. Roeder, A. Eckert and H. Wiedenfeld, Planta Med., 1996, 62, 386. 25 B. Sqener and F. Ergun, J. Fac. Pharm. Gazi Univ., 1997, 13, 171. 26 N. Kovacevic, Arh. Farm., 1995, 45, 183 (Chem. Abstr., 1996, 124, 140 884v). 27 A. El-Shazly, T. Sarg, A.Ateya, A. Abdel Aziz, S. El-Dahmy, L. Witte and M. Wink, J. Nat. Prod., 1996, 59, 310. 28 A. El-Shazly, T. Sarg, A. Ateya, E. Abdel Aziz, L. Witte and M. Wink, Biochem. Syst. Ecol., 1996, 24, 415. 29 S. El-Dahmy and A. A. Ghani, Al-Azhar J. Pharm. Sci., 1995, 15, 24. 30 K. Ogihara, Y. Miyagi, M. Higa and S. Yogi, Phytochemistry, 1997, 44, 545. 31 N. M. Farrag, E. M. Abdel-Aziz, A. M. El-Shafae, A. M. Ateya and M. M. El Domiaty, Int. J. Pharmacogn., 1996, 34, 374. 32 D. Pandey, J.P. Singh, R. Roy, V. P. Singh and V. B. Pandey, Orient. J. Chem., 1996, 12, 321. 33 N. Yassa, H. Farsam, A. Shafiee and A. Rustaiyan, Planta Med., 1996, 62, 583. 34 M. Agnese, S. Mellina and J. L. Cabrera, Acta Farm. Bonaerense, 1995, 14, 273. 35 B. Michler and C. G. Arnold, Dtsch. Apoth. Ztg., 1996, 136, 15. 36 A. G. Orr, J. R. Trigo, L. Witte and T. Hartmann, Chemoecology, 1996, 7, 68. 37 A. V. L. Freitas, J. R. Trigo, K. S. Brown, L. Witte, T. Hartmann and L. E. S. Barata, Chemoecology, 1996, 7, 61. 38 M. Wink and E. Von Nickisch-Rosenegk, J. Chem. Ecol., 1997, 23, 1549. 39 R. Lindigkeit, A. Biller, M. Buch, H.-M. Schiebel, M. Boppré and T. Hartmann, Eur. J. Biochem., 1997, 245, 626. 40 R. Nishida, Chemoecology, 1994–1995, 5/6, 127. 41 H. C. Krebs and T. Carl, Magn. Reson. Chem., 1996, 34, 1046. 42 M. H. Kim, H. H. Kim and H. H. Pak, Chosen Minjujuui Inmin Konghwaguk Kwahagwon Tongbo, 1995, 4, 41 (Chem. Abstr., 1996, 124, 117 662n). 43 M. W. Lame, D. Morin, D. W. Wilson and H. J. Segall, J. Labelled Compd. Radiopharm., 1996, 38, 1053. 44 J.-P. B. Bartkowski, H. Wiedenfeld and E. Roeder, Phytochem. Anal., 1997, 8, 1. 45 G. Hoesch, H. Wiedenfeld, Th. Dingermann and E. Roeder, Phytochem. Anal., 1996, 7, 284. 46 T. Langer, E. Möstl, R. Chizzola and R. Gutleb, Planta Med., 1996, 62, 267. 47 D. M. Roseman, X. Wu and M. J. Kurth, Bioconjugate Chem., 1996, 7, 187. 48 C. E. Couet, C. Crews and A. B. Hanley, Nat. Toxins, 1996, 4, 163. 49 V. R. Campesato, U. Graf, M. L. Reguly and H. H. R. De Andrade, Environ. Mol. Mutagen., 1997, 29, 91. 50 T. Schmeller, A. El-Shazly and M. Wink, J. Chem. Ecol., 1997, 23, 399. 51 N. Aston, P. Morris and S. Tanner, J. Hepatol., 1996, 25, 748. 52 S. Tabete, H. Miyamura, M. Sugawara, H. Watanabe and S. Eguchi, Jpn. Circ. J., 1996, 60, 604. 53 C. C. Yan and R. J. Huxtable, Proc. West. Pharmacol. Soc., 1996, 39, 19. 54 C. C. Yan and R. J. Huxtable, in Taurine 2: Basic and Clinical Aspects, ed. R. J. Huxtable, J. Azuma, M. Nakagawa, K. Kuriyama and A. Baba, Plenum, New York, 1996, pp. 135. 55 C. C. Yan and R. J. Huxtable, in Taurine 2: Basic and Clinical Aspects, ed. R. J. Huxtable, J. Azuma, M. Nakagawa, K. Kuriyama and A. Baba, Plenum, New York, 1996, pp. 33. 56 D. W. Taylor, D. W. Wilson, M. W. Lame, S. D. Dunston, A. D. Jones and H. J. Segall, Toxicol. Appl. Pharmacol., 1997, 143, 196. 57 M. W. Lame, A. D. Jones, D. Morin, D. W. Wilson and H. J. Segall, Chem. Res. Toxicol., 1997, 10, 694. 58 C. E. Couet, J. Hopley and A. B. Hanley, Toxicon, 1996, 34, 1058. 59 T. Marar and C. S. S. Devi, J. Environ. Biol., 1996, 17, 125. 60 K. Müller-TegethoV, B. Kersten, P. Kasper and L. Müller, Mutat. Res., 1997, 392, 125. 61 J. A. Scimeca, in Handbook of Human Toxicology, ed. E. J. Massaro, CRC Press, Boca Raton, Florida, 1997, pp. 409. 62 P. B. Hopkins, Adv. DNA Sequence Specific Agents, 1996, 2, 217. 370 Natural Product Reports, 1998

ISSN:0265-0568    

DOI:10.1039/a815363y

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Muscarine, imidazole, oxazole, thiazole and peptide alkaloids, and other miscellaneous alkaloids John R. Lewis Department of Chemistry, University of Aberdeen, Meston Walk, Old Aberdeen, UK AB24 3UE Covering: July 1994 to June 1995 Previous review: 1996, 13, 435 1 Muscarine, imidazole, oxazole and thiazole alkaloids 2 Peptide alkaloids 3 Miscellaneous alkaloids 4 References 1 Muscarine, imidazole, oxazole and thiazole alkaloids An asymmetric synthesis of (+)-muscarine iodide 7 which is also suitable for producing 5-substituted analogues, has been developed starting with butyrolactone 1 (Scheme 1).The (S)-epoxy ester 2 was prepared in four steps from (S)-malic acid via butyrolactone 1 and could be regioselectively used to alkylate lithiopropyne to generate the (R)-hydroxy ester 3. Lindlar reduction provided mostly the alkenyl hydroxy ester 4 which was cyclised to the hydroxyfuran (5, R1=H, R2=Me). A one carbon degradation was achieved using the Barton– Hundsdieker procedure on the protected furan carboxylic acid [5; R1=TIPS (triisopropylsilyl), R2=H].The more reactive iodide 6 could be produced in this degradation when CHI3 was used in the final reaction sequence. Thereafter trimethylamine gave (+)-muscarine iodide 7; identical (except for rotation) with naturally occurring muscarine iodide. The use of (R)- malic acid would have given the natural product.1 Ovothiol A 15 is a metabolite present in the unfertilised eggs of the sea urchin Paracentrus lividus and it is also accompanied by its disulfide.Ovothiol C 16 and its disulfide is also widely distributed in the reproductive system of several marine invertebrate animals. A synthesis2 of these imidazoles has now been reported starting from 4/5-bromoimidazole 8 (Scheme 2). Firstly, compound 8 was N-dimethylated to give 9 which upon heating in vacuo lost methyl iodide to give the isomeric 4/5-bromo-N-methylimidazoles which were separated by flash chromatography to realise the major 4-bromo isomer 10.Hydroxymethylation occurred at C-5 to aVord 11 which upon MnO2 oxidation gave aldehyde 12. Reaction of 12 with 4-methoxy-·-toluenethiol gave sulfide 13 which could be reduced to the hydroxymethyl sulfide 14. As this sulfide has already been converted into ovothiol A 15 and ovothiol C 16, a new route to these and other histidine natural products thus becomes available. The major metabolite of the sponge of the Oceanapia family is oceanapamine.It has antimicrobial properties and contains a terpenoid and imidazole structural arrangement 17, the latter being derived from amino acid precursors.3 A new approach to the synthesis of nortopsentins 22 has been achieved through a diarylation of 1H-imidazole at its 2/4 and 2/5 position. Thus tribromoimidazole 18 could be coupled with various metal aryl reagents at position 2 to give 19 when an equimolecular amount of arylboric acid was used in the presence of catalytic amounts of Pd0(PPh3)4 and sodium carbonate.4 A second aryl group could be added successively to give 20 in a ‘one pot’ procedure.Removal of the remaining bromine substituent could be achieved by lithiation followed by water quenching to give 21. Deprotection gave the natural product 22 (Scheme 3). A new examination of the mycelial products of Penicillium verrucosum has resulted in the identification of Nformylroquefortine 23 as well as roquefortine; both are mycotoxins5 isolated from cassava by cultivation of the fungus on a liquid medium for two weeks.O O O H O CO2Me O CO2Me R CO2 R2 CO2Me HO H HO R1O H H HO HO 1 2 3 4 5 6 R = I 7 R = NMe3I– + i, ii iii iv v, vi vii–x Scheme 1 Reagents: i, Me3 SiI, MeOH, argon, 12 h, rt; ii, Ag2O, diglyme, 80 )C, 8 h; iii, Li, propyne, THF, "78 )C, 10 min then BF3OEt2 then 2, "78 )C; iv, H2/5% PdCl2–BaSO4, quinoline, EtOAc, 20 )C, 0.75 h; v, I2 (3 equiv.), NaHCO3, MeCN, 0 )C, 72 h; vi, triisopropylsilyl trifluoromethanesulfonate, Pri 2NEt, CH2Cl2, 0 )C, 3 h; vii, KOH, wet MeOH, 20 )C, 16 h; viii, (COCl)2, benzene, DMF (cat.), py, 20 )C, 1 h, N-hydroxypyridine-2-thione Na salt, CHI3, cyclohexene, reflux 16 h; ix, TBAF, THF, 20 )C, 40 h; x, Me3N, EtOH, reflux, 4 h HN N Br Me N N Me Br Me N N Br Me N N SH Me N N SCH2C6H4OMe Me N N Br CO2H NR2 R R H + 5 8 9 10 11 R = CH2OH 12 R = CHO 13 R = CHO 14 R = CH2OH 15 R = H 16 R = Me i ii iii v several steps iv vi I– Scheme 2 Reagents: i, MeI, NaOH, EtOH, 65 )C, 10 h; ii, pyrolysis, 235–245 )C, N2, 28 mmHg; iii, CH2O, AcOH, AcONa, H2O, reflux, 24 h; iv, active „-MnO2, CHCl3, reflux, 1 h; v, MeOC6H4CH2SH, DMF, NaH, N2, 120 )C, 3 h; vi, NaBH4, MeOH, rt, 30 min H2N N HN 17 Lewis: Muscarine, imidazole, oxazole, thiazole and peptide alkaloids, and other miscellaneous alkaloids 371Penicillium glandicola var glandicola when grown as a surface culture produced two metabolites called glandicolin A (24; R=H) and glandicolin B (24; R=OH).Both of these alkaloids are related to meleagrin (24; R=OMe) and a biosynthetic relationship has been discussed.6 A synthesis of leucettamine B 30, the guanidine metabolite of the sponge Leucetta microraphis has been achieved by creating the 3-aminoimidazole ring using a tandem aza-Wittig procedure7 (Scheme 4). Thus, aldehyde 25 was converted into the azide 26 which under Staudinger reaction conditions with triphenylphosphine provided the iminophosphorane 27 in 92% yield.An aza-Wittig type reaction of this phosphorane with methyl isocyanate at room temperature produced carbodiimide 28 which could be converted in situ into the natural product 30 by treatment with ammonia in toluene at 43 )C. The guanidine intermediate 29 undergoes regioselective imidazole formation involving the ester and methylamino functionalities. This four step synthesis makes available gram quantities of this metabolite. A total synthesis of hymenialdisine 40 and its debromo derivative 41, metabolites having the novel pyrrolo–azepine– pyrazole ring system, has been reported.8 Pyrrole-2-carboxylic acid 31 was reacted with ‚-alanine methyl ester (through its acid chloride) to give ester 32.At this stage bromine could be introduced as a means for producing hymenialdisine 40 whereby the ester 33 cyclised to give a mixture of 2- and 3-bromoaldisin (34; X=Br or Y=Br). Separation of these isomers allowed 2-bromoaldisin (34; X=Br) to be protected by the 2-(trimethylsilyl)ethoxymethyl (SEM) grouping 35.A Horner–Emmons reaction with ethyl diethylphosphonoacetate gave the ·,‚- and ‚,„-unsaturated esters 36 which upon deprotonation with KHMDS allowed quenching with 2-phenylsulfonyl-3-phenyloxaziridine to give the ·-hydroxy- ‚,„-unsaturated ester 37. Mesylation to 38 then allowed guanidine to be incorporated with double bond migration N N Br Br CH2OMe Br N N Br Br CH2OMe Ar N N Br Ar CH2OMe Ar NH N N N R R i ii i 18 19 20 21 R = TBDMS 22 R = H iii Scheme 3 Reagents: i, Ar2 B(OH)2·Pd0, Na2 CO3; ii, ButLi then H2O; iii, Bun 4NF N N NH NH N CHO O O N N OH O R HN O N NH 23 24 O O CHO O O O O CO2Et X N NMe O NH2 O O CO2Et N C NH2 NHMe i 26 X = N3 27 X = NPPh3 ii 25 30 29 28 iii iv O O CO2Et N C NMe Scheme 4 Reagents: i, N3CH2CO2Et, NaOEt, "15 )C; ii, Ph3P, CH2Cl2, rt; iii, MeN=C=O, toluene, rt; iv, NH3, toluene, sealed tube, 43 )C NH NH CO2H X HN O CO2Me N NR Y X O R O NSEM N SEM Br O CO2Et RO NSEM N SEM Br O CO2Et NR NR Br O N HN H2N O NH NH O N HN H2N O v viii i 31 41 36 32 X = H 33 X = Br ii 34 R = H; X or Y = Br 35 R = SEM; X = Br; Y = H iv 37 R = H 38 R = Ms vii 39 R = SEM 40 R = H ix iii vi Scheme 5 Reagents: i, SOCl2, cat.DMF, toluene, 60 )C, 1 h then H2NCH2CH2CO2Me, Et3N, CH2Cl2, rt, 3 h; ii, NBS, THF, rt, 2 h; iii, 10% aq. NaOH·MeOH (2:1), rt, 5 h then PPA, P2O5, 100 )C, 1 h; iv, NaH (2 equiv.), 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) (2 equiv.), DMF, rt, 2 h; v, (EtO)2POCH2CO2Et, NaH, DME, 50 )C, 24 h; vi, KHMDS, THF, "67 )C, 2 h then PhSO2NOCHPh; vii, MsCl, Et3N, CH2Cl2, 0 )C; viii, guanidine, DMF, 50 )C, 5 h; ix, 5% aq.HCl–MeOH (1:1), 80 )C, 2 h 372 Natural Product Reports, 1998giving 39 which upon deprotection gave the natural product 40. Debromohymenialdisine 41 was synthesised by omitting the bromination step ii in Scheme 5. Zyzzin 42, isolated from freeze dried extracts of the sponge Zyzza massalis, underwent transformation when being chromatographed, the first step being replacement of the sulfur of the thioketonic group by oxygen which could be followed by the addition of either water or methanol to the N3–C4 double bond.9 The synthesis of pimprinine 43 (R=Me) requires the creation of an oxazolyl grouping at the 3-position of indole.This has been achieved10 by reaction of N-Boc protected-3- acetylindole through its lithium enolate, with trifluoroethyl trifluoroacetate followed by reaction with methanesulfonyl azide.The resulting diazo ketone 44 upon treatment with methyl cyanide followed by deprotection gave pimprinine (43; R=Me), while ethyl cyanide gave pemprinethine (43; R=Et). Almazole A (45; R=H) and almazole B (45; R=CHO) are two unusual oxazole alkaloids isolated from an unidentified red coloured seaweed found oV the coast of Senegal. This plant, belonging to the family Delesseriaceae, is the first seaweed to produce an oxazole although these metabolites are common to tunicates, sponges and nudibranches.11 BE 32030 46 is an antitumouric mixture of compounds manufactured by a shake culture of Norcardia species A 32030; R1 can be H or OH and R2 can be (CH2)10CH3 etc.12 Four new chlorinated 5-phenyl-2-pyrrolyl oxazoles have been isolated from the Indo-Pacific sponge Phorbas aV.clathrata. They represent a new class of marine alkaloids embodying an unprecedented chlorinated pyrrole system.13 After the structure of the first member of this series phorbazole A (47; R1=R2=H, R3=R4=Cl) was determined by X-ray analysis the rest were identified by NMR measurements, including phorbazole B (47; R1=R4=H, R2=R3=Cl), phorbazole C (47; R1=R2=R4=H, R3=Cl) and phorbazole D (47; R1=R2=R3=R4=H). Cultivation of species KO-7888 of Streptomyces has produced oxazole 48 which has herbicidal activity.It is particularly useful in weed control for diakon and sorghum cultivation.14 The absolute configuration of hennoxazole A 49 has been deduced by synthesis of its enantiomer.15 Acinetobactin 50 was isolated from the microorganism Acinetobacter baumannii species ATCC 19606 when it was cultured on a low iron containing medium.16 The structure of this catechol–oxazoline–hydroxamic acid containing metabolite was determined by FAB-MS, 1H and 13C NMR spectroscopy.A related siderophore is anguibactin17 which has a thiazole ring instead of oxazoline. The marine sponge Jaspis digonexea continues to be a rich source of diverse structures.18 Peptides bengamide A and B19 have been reisolated together with digonazole 51 which is a bis-oxazole containing metabolite.Twenty-nine disorazoles have been isolated from the bacterium Sorangium cellulosum,20 which are all highly cytotoxic to fungi and were separated by a combination of solvent partition and chromatography. Disorazole B1 52 contains two epoxide functionalities 3 4 42 43 44 45 NH N NH NH O N N Boc N2 O N S O R O NHR O CH(NMe2)CH2Ph NH CO2 CH NH N N O R1 OH O (CH2)4 Me O O HO OH NCOR2 OH CONH2 N O R1 N Cl R3 R2 R4 N O OH OH 46 47 48 O HO OH O N O N N N O NH N O OH OMe H OH OMe 49 50 N O O N O O N O O OH O N O R2 R1 CO2(CH2)18Me OR H H OR RO H OH R3 R4 OMe 52 51 R = H or Ac Lewis: Muscarine, imidazole, oxazole, thiazole and peptide alkaloids, and other miscellaneous alkaloids 373(R1+R2=R3+R4=epoxide) while variation in the oxygenation pattern essentially gives rise to the other members of this group of alkaloids.Disorazole A 53 has also been reported as a constituent of the same bacterium. It has an eYcient inhibitor property against eukaryotic organisms.21 Two more theonezolides have been obtained from extracts of the marine sponge Theonella.22 The species collected oV Okinawa was previously reported to contain theonezolide A (54; n=3),23 now B (54; n=2) and C (54; n=4) have been isolated and characterised. All possess cytotoxic activity against murine and epidermoid cancer cells. A total synthesis of (")-bistatramide C 65 as a result of an amide bond disconnection approach (Scheme 6) has been published.24 First the valine–serine derived depeptide 55 cyclised to the oxazoline 56 by treatment with the Burgess reagent which upon oxidation and deprotection gave oxazole 58.Thiazole 61 was prepared from thioamide 59 by an improved Hantzsch procedure and coupled to 58 using a mixed anhydride methodology.The resulting protected amine ester 62 was deprotected thus allowing a second thiazole to be added to give 64. This amide 64 upon hydrolysis could then be cyclised intramolecularly to give the natural product 65. A Streptomyces mycelial cake when extracted with acetone produced two metabolites possessing tip A promoter-inducing activity. Thioxmycin had already been reported but the second thioactin 66 is new.25 Another, similar oxazole–thiazole containing metatolite, thiotipin 67, has also been found, this time in Streptomyces mycelium.26 Promothiocins A and B 68 are thiopeptides obtained from a Streptomyces strain sp SF 2741.27 They diVer in structure by the length of the side chain n being 1 and 3, respectively.Pateamine 69 obtained from the sponge Mycale has antitumour, antiviral and immunosuppressive activity; as such it has been patented.28 A synthesis of isodolastin (70; 6R) has enabled X-ray crystallographic measurements to be made so that its molecular conformation could be compared with that of dolastin (70; 6S).29 Interestingly, both enantiomers exhibited the same extraordinary antitumour properties.A revised structure for mirabazole C 71 has been suggested based on the synthesis of the trithiazole system with an R configuration at the ring A stereocentre.30 Using the same synthetic strategy 31 mirabazole B has also been synthesised starting from ·-methylcysteine.32 A new total synthesis of didehydromirabazole A 72 has indicated that a revision of its original stereochemistry is necessary. Rather than a ‚-orientation33 to the methyl group an ·-configuration is suggested.34 A total synthesis of thiangazole 87, the novel inhibitor of HIV-1 rather than HIV-2, isolated from gliding bacteria Me HO O N O O MeO OH O O O N O MeO OH OH OH HO3SO NH O O HO O N HO HO O HO OH O N S NH2 OH OH OH OH n 53 54 NH N OH NH NHBoct O CO2Me O S N O HN O S N NH O NH N O S N O CO2Me S N NH O NH2HCl O N NHBoct O N NHBoct CO2Me NH N O S N O CO2Me HN O N NH2HCl CO2Me S N NHBoct CO2H S N NHBoct CO2Et S NH2 NHBoct CO2Me R 65 55 56 57 58 59 60 61 64 62 R = Boc t 63 R = H i iv v vi vii viii ii, iii vii ix or x then xi Scheme 6 Reagents: i, Et3NSO2NCO2Me; ii, NiO2, benzene, heat; iii, MnO2, benzene, heat; iv, MeOH, AcCl; v, KHCO3, DME, rt then BrCH2COCO2Et, then TFAA, py, DME, 0 )C to rt; vi, LiOH, MeOH; vii, ClCO2But, N-methylmorpholine, THF; viii, CH3COCl, MeOH; ix, toluene, heat; x, 2 M NaOH, MeOH; xi, diphenylphosphoryl azide, DMF 374 Natural Product Reports, 1998confirms its absolute stereochemistry.35 Thus condensation of cinnamylnitrile 73 with (2R)-methylcysteine methyl ester 74 gave thiazoline ester 75 which through its amide 76 gave nitrile 77 which allowed condensation of the methyl cysteine 74 to introduce the second thiazoline ring.This could be condensed with oxazole 85, prepared from theronine methyl ester 81 through conventional procedures.Condensation of 80 and 85 followed by conversion of ester 86 to the amide gave the natural product 87 (Scheme 7). Another synthesis of thiangazole36 produced its (")-isomer (87; R2=‚). Basically, a previously synthesised tripeptide 8837 was deprotected to give 89 and then condensed with dihydrocinnamoyl chloride to give amide 90. Hydrolysis of the terminal ester group in 91 allowed condensation with O-benzylthreonine-N-methylamide 92 and the resulting tetrapeptide was reductively deprotected to enable cyclisation to create the trithiazoline 93.Deprotection to give 94 allowed oxidation with the Dess–Martin reagent to give ketone 95 which cyclised to oxazoline 96 by treatment with p-TsOH in boiling benzene. Finally dehydrogenation of the phenylethyl side chain gave the natural (")-enantiomer of thiangazole (87; R2=‚; Scheme 8). Patellamide A 97 is a cytotoxic metabolite obtained from the ascidian Lissoclinum patella.38 Upon crystallisation from aqueous methanol a solvate was obtained which upon X-ray analysis showed the molecule to be cup shaped with the solvent molecules inside.38 A total synthesis of lissoclinamide 5, the cytotoxic cyclic peptide produced by the tunicate Lissoclinum patella,39 has made structural revision necessary.40 The new structure diVers from the previous formulation in that the substituents at C-21 and C-31 are reversed and are now as indicated in 98.The fermentation broth of a ‘Sebekia’ species (LL-14E605) contains a novel antibiotic.It is called glycothiohexide-· 99 and is closely related to nosiheptide and antibiotic S-54832 A.41 An antibiotic 100 from Pseudomonas aeruginosa 3120 has the ability to coordinate copper. It is composed of two N-methyl-N-thioformylhydroxylamine molecules coupled to copper. Interestingly this antibiotic MRL 3120 was produced only if soybean was present in the medium. If soytone was used, the addition of CuSO4 was necessary to create 100.Addition of ETDA completely removed activity.42 An extract of the blue-green algae Aulosira fertillissima43 contains a cytotoxin with antitumour activity in the Corbett assay, using a bioassay-guided fractionation, the active component of which, aulosirazol, was characterised as the juglone isothiazole 101. 2 Peptide alkaloids Two amino acid amides have been extracted from the bulbs of Hemerocallis longituba.44 These furan containing metabolites were named longitubamine A (102; R=Ph) and longitubamine B (103; R=H).Clathrynamide 103 has been isolated from a sponge of the Clathria family. This polyenyne has useful antitumour properties.45 Halicylindrosides are antifungal and cytotoxic cerebrosides found in the marine sponge Halichondria cylindrata.46 Ten new ones, namely A1–A4 and B1–B6, have the basic skeletal arrangement 104 where R=H or OH and m and n equal 16–18 and 8–11, respectively. AM4299A and B are two novel thiol protease inhibitors isolated from Chromelosporium fulvum47 N CONHCCONH2 CH2 S N N O NH HN O O N S HN S N O HN O N O HN SMe HO NH O O HN N O HN NH N O N HN O O O O HO NH O N O HN OH O N S HNCO)4 HO2C(C CH2 O O N S H2N O NMe2 O N N S N O NH O N S N O HN NH O O CO HN O CH2 NHC C NH O O N Me HN OMe O N HN O Ph N S Me2N O OMe H S N S N S N S N O N CONHMe S N S N S N S N n 66 67 68 69 70 6 71 72 A a Lewis: Muscarine, imidazole, oxazole, thiazole and peptide alkaloids, and other miscellaneous alkaloids 375which both contain the interesting oxirane-2,3-dicarboxylic acid-derived moiety 105 terminating with R=CH2OH or CH(NH2)CO2H, respectively.A similar terminus has been found in two metabolites isolated from the bacterium SCRS0OB16 found in a sponge, called cathestatin A (106; R=H) and B (106; R=OH). Both metabolites are reported to be useful in the treatment of bone disorders.48 Antibiotic Tu 1718B has been synthesised and confirmation of its revised structure as L-valyl-3,5-dihydroxylysine 107 has been substantiated.49 Two novel hypotensive agents have been isolated from a fresh leaf extract of Moringa oleifera.Niazimin A (108; NH=Z) and its tautomer niazimin B (108; NH=E) are the first carbamates to be found naturally occurring. Also present in this extract were glycosides having a thiocarbamate side chain.50 The culture broth of Bacillus laterosporus has produced three metabolites, namely bacithrocin A (109; R=But), bacithrocin B (109; R=Pri) and bacithrocin C (109; R=Et), all of which show thrombin inhibitor activity.51 The sponge Spongia oceania found oV Hawaii contains a phosphate ester grouping, linking 5-methylhexanol with homoserine to which in turn is coupled a C8 carboxylic acid with a terminating furan unit 110.This metabolite called pokepola ester possesses mild anti-HIV activity.52 Vibrioferrin 111 is a new siderophore isolated from Vibrio parahaemolyticus. It exists as an equilibrium mixture involving the amidic nitrogen of the alanine component and the keto group of the 20-ketoglutanic acid side chain.53 Sponge Psammaphysilla purpurea found in the Bay of Bengal54 contains two bromotyrosine derivatives (112; R1=R2=H and R1=H, R2=Br).Axiceramide A and B are two new tri-·-glycosyl type ceramides found in an Axinella sponge species.55 Both contain various fatty acid residues attached at R1 with either ·-galactopyranose or ·-glucopyranose as indicated in structure 113.Longiside 114 is a digalactosylceramide isolated from the Caribbean sponge Agelas longissima;56 in this instance ·-galactopyranose was coupled to ·-galactofuranose. Another cerebroside, this time only containing one sugar unit where a ‚-glucoside and a single fatty acid, 2-hydroxypalmitic acid, comprise the metabolite was obtained from Candida deformaus57 and is called diformis 115. Four new cerebrosides, also containing one ·-glucose unit, have been obtained from the latex of Euphorbia biglandulosa58 with 116 being typical of this group.A thiol isolated from Leishmania donovni is the same as one isolated from Crithrida fasciculata namely ovothiol A.37 From the bacterial pathogen Mycobacterium tuberculosis and Micobacterium bovis a related thiol, mycothiol 117, has been identified.59 Three more manumycins designated E, F and G 118 have been isolated from a Streptomyces species strain WB-8376.60 A related manumycin like polyene 119 has been produced by cultivation of Streptomyces parvullus TA-8564.Its antibacterial activity and ease of production prompted it being patented.61 Nisamycin 120 is another new manumycin type peptide alkaloid isolated from a Streptomyces strain designated K106.62 Psammaplysins are a series of bromotyrosine derivatives produced by sponges of the order Verongida. Two new ones CN HS S N Ph N S S N Ph R H2N CO2Me R BocS BocHN CO2Me BocS BocHN NH O OH CO2Me BocHN BocS N O CO2Me ClH3N HS N O CO2Me BocHN BocS N O CO2Me N S Ph S N N S O N R2 COR1 ·HCl + – 75 R = CO2Me 76 R = CONH2 77 R = CN 85 83 81 84 82 74 78 R = CO2Me 79 R = CONH2 80 R = CN 73 ii iii ii vii vi iv i v i + i iii 86 R1 = OMe; R2 = a-Me 87 R1 = NHMe; R2 = a-Me viii Scheme 7 Reagents: i, MeOH, Et3N, reflux, 48 h; ii, EtOH, aq.NH3, 25 )C, 24 h; iii, Ph3P=CCl4, 50 )C, 2 h; iv, PyBOP, Et3N, CH2Cl2 then 74, Et3 N, 25 )C; v, Burgess reagent, THF; vi, ButOCO2Ph, CuI(Br), benzene, heat; vii, HCl, Et2O; viii, MeNH2, EtOH, 4 h 88 R1 = Cbz; R2 = Me 89 R1 = H; R2 = Me 90 R1 = CO(CH2)2Ph; R2 = Me 91 R1 = CO(CH2)2Ph; R2 = H 95 96 vii Cl– + 92 93 R = Bn 94 R = H v R1 HN NH H N CO2 R2 O NHMe H3N OBn O SBn O SBn SBn 87 R1 = NHMe; R2 = b-Me NH N S N S N S Ph O MeHN O O N S N S N S Ph N O MeHN O ii i iii iv vi viii NH N S N S N S Ph O O MeHN OR Scheme 8 Reagents: i, HBr, AcOH, thioanisole, CH2Cl2, rt; ii, Ph(CH)2)2COCl, DMAP, Pri 2EtN, "78 )C; iii, NaOH, DMF, rt; iv, PyBOP, DMAP, Hunig’s base, CH2Cl2, rt; v, Na, NH3, THF, "78 )C, then NH4Cl then TiCl4, CH2 Cl2; vi, Dess–Martin reagent, CH2Cl2, rt; vii, pTsOH, benzene, reflux, 4 Å sieves; viii, DDQ, benzene, reflux 376 Natural Product Reports, 1998have been identified as constituents of an Aplysinella sponge,63 designated D and E 121.Two total syntheses of (")-balanol 137, the unusual metabolite found in the fungus Verticillium balanoides, have been reported.64,65 Basically the benzophenone unit is created and coupled to the azepane subunit (Scheme 9).The bromobenzyl alcohol 122 coupled with acid 123 via its acid chloride gave ester 124 which underwent an intramolecular anionic homo-Fries rearrangement to give benzophenone 125 under the influence of BunLi at "78 )C. Oxidation of this alcohol 125 with pyridinium dichromate in DMF gave a stable benzaldehyde 126 which could be further oxidised to the acid 127 with tetrabutylammonium permanganate and thence to its benzyl ester 128 which upon thermolysis gave the benzophenone acid 129.The azepane unit was synthesised from HN S O N N NH HN O N NH S N O O O HN S N HN O N NH S N O Ph O O N O N S N S S N S HN NH HN N CONH2 O HO O OMe S N NH O HN O O O O S N O O NMe2 HO O 97 21 98 99 31 MeN O Cu S O NMe S N S OH O O OMe 100 101 O HN CO2H Me Br OH CONH2 O R NH2 OH 102 103 O O HO2C N H O NH HO HO OH NHCOMe O (CH2) nCHMe2 CH(CH2)mMe R NHCO OH OH O HO2C N H O Bui HN (CH2)4R O O NH2 R 104 105 106 108 107 N OEt O H O O OH HO AcO H2N OH HO2C NH O HO NH2 R HN NH (CH2)3NHCNH2 NH O NH OP(OH)O(CH2)4CHMe2 O O Ph O O N O HO2C OH CONH2 O CO2H CO2H OH O R2 MeO Br NH O NH2 NOH O R1 Br 109 110 111 112 Lewis: Muscarine, imidazole, oxazole, thiazole and peptide alkaloids, and other miscellaneous alkaloids 377powdered 3-hydroxylysine 131 by adding its solution in hexamethyldisilylazane and xylene to propanol whence lactam 132 was formed with little epimerisation.Reduction with borane gave the azepane 133, N-protection to give 134 allowed condensation with protected benzoyl chloride 135, to give the desired azepane 136.Coupling of the benzophenone acid 129 via its acid chloride 130 with azepane 136 gave protected (")-balanol, which upon deprotection gave the natural product 137. Four new dimeric peptide alkaloids have been isolated from the Mediterranean sponge Anchinoe tenacior.66 Three have been named anchinopeptolide B, C and D as they are congeners of A isolated previously.All have either H or Me groups distributed as depicted in 138. The fourth is cycloanchinopeptolide 139 which is thought to be derived by a head to head intramolecular [2+2] cycloaddition reaction of two ‘mono’ peptolides. Spider toxins nephilatoxin-9 and -11 have been synthesised by a novel solid-phase strategy.67 Previously these toxins were only available after a diYcult conventional synthesis. The new procedure employs coupling orthogonally N-protected N·-(m- ·-L-Asp)-NÂ-(Dde-cadaverine) to a solid support which, after removal of the Dde protecting group (2% hydrazine in DMF) allows continuous flow solid-phase methodology to proceed67 to give 140 i.e.nephilatoxin-9. Two reports on the synthesis of (+)-jaspamide 141 [(+)- jasplakinolide] have been reported.68,69 Both methods use conventional peptide techniques to couple a tetrapropionate to the tyrosylindolyl moiety. Cyclamenol 142 is a fermentation product of Streptomyces strain MHW 846 and because of its inflammation inhibitor activity it has been patented.70 A synthesis of eurystatin A 151 has been achieved71 by first condensing (2S)-alaninal 143 with methyl (2S)-isocyano-4- methylpentanoate 144 under Passerini conditions, to give a diastereomeric mixture of ‚-amino-·-hydroxybutyric ester 145.Saponification and replacement of the benzoyloxycarbonyl group (Z) by a tert-butyloxycarbonyl (Boc) protecting group gave carboxylic acid 146.Coupling with benzoyloxycarbonylornithine methyl ester gave diastereoisomeric methyl ester 147. After HPLC separation the pure isomers were then converted to their pentafluorophenyl esters 148. Removal of the Boc protecting groups (HC1) gave the hydrochloride salt which in the presence of saturated aq. sodium hydrogen carbonate solution and chloroform, in a two phase system gave ring closure to 149. Oxidation with the pyridinium dichromate method gave the ketone 150 which could be N-deprotected to allow condensation with (E)-6-methylhept-2-enoyl chloride thus producing the natural product 151 (Scheme 10).A concise synthesis of the spermidine alkaloid (&)- dihydroperiphylline 152 used an enantioselective aldol-type reaction of an imine with a ketenesilyl acetal promoted by a chiral Brønsted assisted chiral Lewis acid followed by a boron templated cyclisation of triamino esters.72 An Amycolatopsis species TAO234 produces a 19-membered macrolactam 153 which possesses antitumour properties.73 The synthesis of leualacin 155, the calcium blocking agent R1 O OH NH O R1 OH O OH HO O O HO HO NHAc O O HO HO HO HO OH (CH2)11Me O OH NH O (CH2)21Me OH O OH HO O OH OH O OH HO OH OH HO 113 114 (CH2)8Me O (CH2)2 (CH2)6Me OH HN (CH2)13Me OH O O OH OH HO OH OH HN O (CH2)24Me OH O OH HO OH OH 115 116 O OH HO OH NH O OH OH HO OH OH SH NHCOMe O O O HO H N R HN HO O O O O O HO (CH=CH)3CO2H H N (C=CH)2 O Me CH(CH2)3Me O O HO (CH=CH)3CO2H HN O Me 117 119 120 118 E R = CH2CH2CHMe 118 F R = 118 G R = CHMe2 O N O Br MeO Br NH O O Br Br R1 NHR2 HO O CH O 121 Psammaplysin D R1 = OH; R2 = H 121 Psammaplysin E R1 = H; R2 = 378 Natural Product Reports, 1998obtained from Hapsidospora irregularis, has been accomplished74 through coupling of the appropriate valeric acids and phenylalanine thereby producing the linear depsipeptide 154, which produced the best cyclisation results to give 155 using pentafluorophenyl diphenylphosphinate. Cytotoxic cyclodepsipeptide doliculide 156 has been isolated from the sea hare Dolabella amicularia.75 Its stereostructure has been determined and confirmed by its synthesis.76 Related cyclodepsipeptides jaspamide 157 and geodiamolide 158 have also been synthesised with relative eYciency,77 thus making these cytotoxic alkaloids readily available for further testing.A marine bac terium designated SANK 70992 produces two novel cyclic lactam–lactone metabolites.Designated B1371A 159 and B1371B 160 they both possess cysteine protease activity.78 Extraction of the culture broth of a species of Humicola PF1070 produced two antitumour antibiotics designated PF1070A and PF1070B.79 The structure of PF1070A 161 was shown to have a tetrapeptide system coupled to an epoxydecanoic acid. A cyclotetrapeptide 162 containing the epoxide moiety has been obtained from Verticillium coccosporum80 and has been shown to exhibit phytotoxic properties.It bears a close relationship to chlamydocin [162; R=COCH(OH)CH3]. O BnO2C OBn Br OH ButO2C OBn OBn CO2H OBn Br O O OBn BnO CO2But OBn CO2R BnO OBn O R OBn CO2But BnO OBn O OH OH HO2C OH NR H2N CO2 H O O COCl OBn X OH OH NH2 NH2 NR HN CO OBn OH HN CO OH NH 122 123 124 131 135 137 128 R = OBu t 129 R = OH 130 R = Cl 125 R = CH2OH 126 R = CHO 127 R = CO2H 136 R = Boc 132 X = O; R = H 133 X = R = H 134 X = H; R = Boc ii i v + + xi xii vi vii iii iv viii–x xiv xv xiii Scheme 9 Reagents: i, But OK, THF; ii, BunLi, THF, "78 )C; iii, PDC, DMF; iv, Bu4NMnO4, py; v, BnBr, K2CO3; vi, quinoline, 205 )C; vii, SOCl2; viii, (TMS)2NH, xylene, ƒ; ix, propan-2-ol; x, 1 M HCl; xi, BH3·THF, ƒ; xii, (Boc)2O, NaOH; xiii, H2, Pd/C; xiv, 128, NaOH, CH2Cl2; xv, CF3CO2H HO HN O N O (CH2)3 OH NH H2N HN NH NH2 HN HN O R1 NH O H2N HN H HN NH2 NH NH OH O HN O H H H NH H N HO O O R2 OH OH OH 138 A R1 = R2 = Me 138 B R1 = Me; R2 = H 138 C R1 = H; R2 = Me 138 D R1 = R2 = H 139 HN NH NH HN O H2N HN H2N NH O CONH2 O O NH H2N Me N NH CO2H O O OH NH Br NH O OH 140 141(+) = b 141(–) = a 142 Lewis: Muscarine, imidazole, oxazole, thiazole and peptide alkaloids, and other miscellaneous alkaloids 379The roots of Aster tataricus contain a number of cyclic pentapeptides.81 One of these, astin I, has been shown to have structure 163.Fungicidal, antiinflammatory and antineoplastic 2-norrapamycin 164 has been found in the culture broth of Streptomyces hygoscopicus.82 A Flexibacter species produces several cyclic peptides, all of which have inhibitor properties for the esterase of leukocytes.83 Basic skeletal structures for these metabolites include 165, where R1 is benzylcarbonyl or isovaleryl and R2=R3 is H or OH, and 166.A study of fresh water blue-green algae for serine protease activity has established the presence of active compounds. One is nostopeptin 167 which is obtained from Nostoc minutum; another is radiosumin 168 found in Plectonema radioscius.84 Phakellistatin-5 169 is a new cancer growth inhibitor obtained from the marine sponge Phakellia costada.85 Depsipeptide F1022-E 170 is produced by a non-spore forming mold; interestingly it has anthelmintic activity.86 A marine mollusc of the Onchidium family produces a cytotoxic depsipeptide encompassing a new amino acid (3-amino-2-methyloct-7-ynoic acid) as well as having C2 symmetry.87 Onchidin thus only shows MNR signals for a ‘monomer’ structure while it actually is 171.Theonegramide is an antifungal glycopeptide isolated from the sponge Theonella swinhoei.88 Similar to previously isolated theonellamide, it contains however a new 4*-bromo-3- methylphenylalanine component 172. Anthocerodiazonin 173 is an alkaloid obtained from in vitro cultures of the hornwort Anthoceros agrestis.89 A hexapeptide alkaloid with potent estrogen-like activity has been isolated from the seeds of Vaccaria segatalis. Called segatalin A, its structure 174 was determined by extensive NMR and ESI-MS-MS methods.90 Two new cyclopeptide alkaloids have been isolated from the roots of Ziziphus mucronata;91 mucronine D was also present.The new alkaloids were designated P2 175 and P3 176. An N-formyl cyclopeptide alkaloid, from Zigyphus mummularia bark, has been identified by spectroscopic studies;92 and is called mumularine T 178. Scutianine-J is a new 14-membered ring cyclopeptide alkaloid obtained from the powdered bark of Scutia buxifolia.93 From a combination of mass spectroscopy and NMR measurements its structure was determined as 179.A cyclopeptide alkaloid 180 has been obtained from the bark of Zizyphus oenoplia94 its structure was established by spectroscopic methods as having a 13-membered ring. NHZ O NC OMe O O NH OR1 NHR2 O OBz O H N O NH O HN OH NHZ O H N OR NHZ O NH NHBoc O OH O H N O NH O HN O NHZ O H N NH NH NH O O O O 143 144 145 R1 = Me; R2 = Z 146 R1 = Me; R2 = Boc 149 150 151 147 R = Me 148 R = C6F5 + i, ii iii, iv v viii vi, vii x xi, xii ix Scheme 10 Reagents: i, benzoic acid, CH2Cl2, rt, 48 h; ii, MeOH, Cs2CO2, 15 min, rt; iii, MeOH, Boc2O, Pd/C, H2, 2 h; iv, LiOH, H2O–dioxane, rt; v, benzoyloxycarbonylornithine methyl ester, HCl, 2-(1-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), CH2Cl2; vi, LiOH, H2O, dioxane, 0 )C; vii, C6F5OH, N-(3- dimethylaminopropyl)-N*-ethylcarbodiimide hydrochloride (EDC), "15 to 20 )C; viii, 6 mol dm"3 HCl, dioxane, 2 h, 20 )C; ix, CHCl3– NaHCO3, rt, 6 h; x, pyridinium dichromate, DMF, rt, 48 h; xi, MeOH–CH2Cl2, Pd/C, H2, hÌ; xii, DMF–CH2Cl2–(E)-6-methylhept- 2-enoyl chloride, py, rt, 3 h NH Ph NH N Ph O O H N Ph OH O HO MeO O 152 153 O Me N Ph NH O O PhO2C O O O NH2 O Me N NH Ph O O NH O O H O O O 154 155 380 Natural Product Reports, 1998A concise total synthesis of bouvardin 184 O-methylbouvardine 185 and O-methyl-N9-desmethylbouvardin 186 has been developed.95 Based on the synthesis of the protected erythro-N-methyl-‚-hydroxy-L-4*-iodophenylalanine 181 and its coupling with protected N-O4-dimethyl-L-DOPA methyl ester, compound 182 was produced which ‘surprisingly’ underwent Ullmann cyclisation in a macrocyclic process to give the 14-membered subunit 183 and hence 184, 185 and 186.This macrocyclisation procedure has also been used to prepare vancomycin derivatives.96 A nitro group activating fluoride displacement by a ‘phenoxy group’, which was then either reductively removed (187; R=H) or converted into a chlorosubstituent (187; R=Cl), was the key step in this synthetic procedure.The glucocyclohexapeptide obtained from Rubia yunnanensis possesses antitumour properties and is called RY-111 188.97 The remarkable antimitotic activity of the bastatins98 has stimulated continued examination of the sponge Inthella and Dolastin families. Several new bastatins 189 have been isolated from the sponge Inthella basta collected in Indonesia,99 including bastatin 16 (189; R1=R3=H, R3=R4=Br) and 17 (189; R1=OH, R2=Br, R3=R4=H) and another unnumbered example 190 (R1=R3=H, R2=R4=Br).100 Two peptide alkaloids isolated from a Streptomyces sp.have shown inhibitor activity against HIV. They have been called chloropeptin 1 (191; a–b) and 11 (191; a–c).101 Using a bioassay for detecting acyl CoA cholesterol acyltransferase inhibitors, a moderately active one, A1–3, which is a metabolite of a soil Streptomyces sp., was isolated from its culture broth and characterised.102 Its structure 192 was similar to that of the skin tumour promoter olivoretin A.Aselacins are novel compounds which inhibit the binding of endothelin to its receptor. These compounds are cyclic pentapeptides, to which are attached diVerent functionalised fatty acids,103 with a typical one being 193. Crytophycins A to D are potent tumour selective agents obtained from the terrestrial blue-green algae Nostoc sp. GSV 224.Their structures have I HO MeN O NH O OH O O I HO NMe HN R O O O HN O HN Br NMe HN O O OH O NH O O O 156 158 157 HO HN NH HN O O OH OH O Pri O NH O NMe O OH O O HN NH HN NH OH Pri NH HN O OH O Pri O O O HO HO O NMe O O OH Me O HN Ph NH O N HN O O HN HN (CH2)5R O O NH O N O Ph H O O Me COC CH2 O 159 160 161 162 R = H R = COCH(OH)Me O NH HO NH N O NH O O HN O H Et Et Ph OH Cl H O N O O O O O OMe OH O OMe OH HO HO 163 164 Lewis: Muscarine, imidazole, oxazole, thiazole and peptide alkaloids, and other miscellaneous alkaloids 381been previously reported as incorporating L-tyrosine.A convergent synthesis has now indicated that D-tyrosine is the correct component of 194 and indeed the synthetic L-isomer was found to be 100 times less cytotoxic.104 Because herbimycin 195 inhibits melanin formation it is being used as a skin lightening agent,105 along with the catechols.106 By the use of chiral GC and HPLC analyses, the absolute configurations of the unusual tryptophan derived amino acid component of the cyclic peptides konbamide and keramide A 196, produced by the sponge Theonella, have been shown to be normal (i.e.L).107 3 Miscellaneous alkaloids Lactacystin 197 is a metabolite of a Streptomyces sp. and its biosynthesis has now been established by feeding experiments, in which isobutyrate or L-valine, L-leucine and cysteine have been incorporated. The „-lactam skeleton was created from methylmalonic acid semi-aldehyde and the ·-carbon of leucine.108 A novel antifungal agent azoxybacilin 198 has been isolated from Bacillus cereus NR2991.109 It possesses a novel azoxygrouping hitherto unknown in bacterial metabolites.A fluorescent glucoside with the structure 199 is isolated from the protein free extract of human lenses and is thought to be associated with the yellow coloured pigments also found in this extract.110 A hydrophilic extract of the marine sponge Jaspis showed metamorphic activity on the tadpole larvae Halocynthia rorezi.111 Bioassay led to two active compounds being identified as responsible for this activity; they are the geometric isomers of the N,N-dimethylguanidinium sulfate 200.Noesartoria fischeri produces three antifungal isocyanide metabolites, designated as NK 372135A, B and C 201 (R=H, OMe and OH, respectively).112 Isocyanide antibiotics darlucin A 202 and darlucin B 203 are produced by Sphaerellopsis filum.113 They, like the previous metabolites, resemble xanthocillin type antibiotics.Acanthella cavernosa, the marine sponge R1HN NH HN O H N O Ph OH HN CONH2 HN O O O O O O R2 R3 HN O NH HN N Me O NH OSO3H O HN NH O AcHN CH N H CO2H O CH2 NH2 NHAc O O HN O N Me N O N O NHCO(CH2)3H H2NOC O NH HN O OH OH O O 165 166 167 168 NH HN N NH NH HN H2N O O O MeS O O O NH O Ph O O N Me O O O Ph MeN O O O Me N O O O NMe OH O O 169 170 OH HN O O NMe HN O O O O O NH (CH2)3CºCH O NH O O O O O MeN HCºC(CH2)3 O O H N O HN NH O OH NH HN O OH NH O HN O H2NOC NH O H2NOC OH HN O HN O HO HN O Ph O HN OH O CO2 – Br N N O HO HO 172 + 171 382 Natural Product Reports, 1998obtained from the Seychelles, has been shown to contain two alkaloids114 which possess the isocyanide grouping, kelihinene A (204; R1=NC, R2=Me) and B (204; R1=Me, R2=NC).The cyclopropylamino acid (2S,1*S,2*R)-·-[2- (carboxymethyl)cyclopropyl]glycine 211, which is a constituent of the seeds of Blighia unijugata, has been synthesised.115 Starting with oxazolidine aldehyde 205, which was easily prepared in four steps from D-serine, a Wittig reaction with 206 created a mixture of alkenes with the Z isomer 207 predominating.This mixture upon treatment with dibromocarbene gave two dibromocyclopropyl derivatives 208, both of which upon reduction gave the cyclopropyl mixture of 209 and 210. They were easily separated by flash chromatography with 210 thus being converted to the natural product 211 by the Jones reagent (Scheme 11).NH HN HO2C O OH OH NH NH O HN NH HN O H NH N O O O O H H 173 174 CON R1N HN O O HN OR3 O O N HN HN NH N CHO Me O O Ph O MeO O R2 175 R1 = R2 = R3 = Me 176 R1 = R3 = H; R2 = COCH(NMe2)CH2Ph 177 R1 = H; R2 = COCH(NMe2)CH2Ph; R3 = Me 178 O NH O NH Ph OH O HN NMe2 Ph HO O OMe O N N NH HN Me2N O Ph O O O 179 180 CO2H MeO2C Me N NBoc O Me N NH HN Me N O HN NMe O CO2Me Me N NMe O R4 O O O O OMe O I OMe OH O R5 MeNBoc OSiBu tMe2 OSiBu tMe2 OSiBu tMe2 R2 R3 I OR1 Me Boc 9 181 182 183 184 Bouvardin R1 = R4 = R5 = H; R2 = OH; R3 = Me 185 O-Methylbouvardin R1 = R3 = Me; R2 = OH; R4 = R5 = H 186 O-Methyl-N9-desmethylbouvardin R1 = R3 = Me; R2 = OH; R4 = R5 = N9 = H O R NH HO HN O-Sugar O Cl NH HN NH OH O NMeH2 O H2NOC O H O O OH HO NH –O2C O 188 + 187 O-Gluc N Me O HN O NMe O O OMe N Me O NH HN O O Lewis: Muscarine, imidazole, oxazole, thiazole and peptide alkaloids, and other miscellaneous alkaloids 383One of the two antibiotics obtained from the culture of Micromonospora sp.is Y03559J-A 212,116 the other also possesses an oxirane ring but does not contain nitrogen 213. (R)-(")-Dysidazirine 221 is a cytotoxic antibiotic obtained from Dysidea fragilis, 117 while azironomycin 216 is an antibiotic produced by Streptomyces aureus. An asymmetric synthesis of these azirines has been achieved which confirms their absolute stereochemistry. The key step in both these routes118 is the ‚-elimination of an N-sulfinyl group. Thus treatment of racemic N-(p-tolylsulfinyl)-2-methoxycarbonyl-3-phenylaziridine 214 with LDA at "78 )C and quenching with water in the presence of methyl iodide gave a 52% yield of the antibiotic ester 215 (R=Me) which on hydrolysis gave the antibiotic 216 (Scheme 12).Dysidazirine 221 was obtained by first condensing the sulfinamide 217 with the lithium enolate of methyl bromoacetate 218 to give 219 which was decomposed to methyldysidazirine 220 and thence 221.Another diunsaturated polychlorinated diketopiperazine, the sixth, was obtained from the marine sponge, Dysidea fragilis,119 called dysamide E 222. Rhizomes of Pedate pinellia contain three amino acid anhydrides, namely L-propyl-L-alanine anhydride, L-phenylalanyl- L-seryl anhydride and tyrosyl-L-alanine anhydride as well as the alkaloids, pedatisectine D (223; R1=R2=H) and pedatisectine E (223; R1=OH, R2=Me).120 The phenazine ring system has been found in the new alkaloid K3-Ye 224 isolated from the fermentation broth of a genetically engineered Streptomyces K3 bacterium.121 Another indazole alkaloid nigellidine (225; R=4-hydroxyphenyl; R2=O") has been found in the seeds of Nigella sativa. Previously nigellicine 225 (R1=CO2 ", R2=OH) had been isolated from the same source.122 Penazetidine A 226 is an inhibitor of protein kinase C and was isolated from the marine sponge Panares sollasi.123 NH O NOH Br Br Br OH HN Br O OH Br O R4 R1 NOH O R2 NOH NH O HO R3 HO NH O NOH Br Br O 189 190 O N Me HN OH HN NH HN O O O O Cl OH Cl OH Cl Cl NH O O OH Cl Cl O NH HO2C OH Me N HN NH CH2=CH O OMe a b c 191 192 b HN NH O OH O NH HN O O O O HN NHCO Ph O HN O NH O O R OMe O O CH(CH2)CONH2 NHCO(CH2)7CH=CHCH=CH (CH2)4 Me 193 194 A ab sat.R = Cl 194 B ab sat. R = H 194 C ab unsat. R = Cl 194 D ab unat. R = H a NH O O NH O OH H2NOC OMe OMe MeO NH O HN Me N O HN O O NH O HO Cl Ph 195 196 384 Natural Product Reports, 1998Phytosiderophores are iron-chelating agents needed by higher plants to assimilate iron necessary for their photosynthesis. 2-Deoxymugineic acid (243; R=OH) and nicotianamine (243; R=NH2) are two such agents which have been recently synthesised stereoselectively124 (Scheme 13). Starting from ethyl p-methoxycinnamate 227 dihydroxylation, using the Sharpless reagent AD-mix-‚, gave diol 228 with more than 99% ee. Removal of the 2-hydroxy group (three steps through its p-nitrobenzenesulfonyl ester, chlorination and transfer hydrogenation) preceded protection of the 3‚-hydroxy group thus allowing DIBAL reduction of this ester 229 to give aldehyde 230.The tyrosine derivative 236 was synthesised from the methyl ester of protected p-methoxyphenylglycine 231 via the alcohol 232, methanesulfonate 233, cyanide to acid 234 and then to ester 235, from which after deprotection the synthon amine 236 became available. Reductive condensation of 230 with 236 gave 237 which after ester reduction and suitable protecting group manipulation gave the di-pmethoxyphenyl (MP) acetate 238.Ruthenium catalysed oxidation of the MP groups gave dicarboxylic acid 239 which was esterified and the terminal hydroxy functionality converted HN HO HO OSO3 – NMe2 H2N H2N OGluc NH2 O CO2H OH O COSCH2 OH CHNHCOMe CO2H MeN NCH2CH2 O CHCO2H NH2 E/Z + 197 198 199 200 R MeO +NºC– +NºC– OMe +NºC– MeO +NºC– OH HO 204 203 +NºC– MeO +NºC– OH O O H H R1 R2 CNMe2C 201 202 Br CO2H H H2N CO2 H H H O Boc N O O CHO O O O Boc N O O O Boc N Br O O O Boc N O O O Boc N Ph3P Br– + 209 205 206 207 210 208 a and b 211 + i ii + iii Scheme 11 Reagents: i, 95% NaH, THF, argon, rt, 2 h; ii, CHBr3, KOH, TEBA, <30 )C, 18 h; iii, Bun 3 SnH, hexane, argon, reflux, 24 h; iv, CrO3, H2SO4, acetone H2O, 3 h then Dowex 5 W (H+ form) O (CH2)11CO2H O (CH2)11CO2H O OH CN 212 213 N N N N Ph H CO2Me H Ph H CO2R SO SO H H CO2Me C12H25 p -Tolyl p-Tolyl S N C12H25 O C12H25 CO2R H OMe OLi Br p -Tolyl : 217 219 214 i ii 220 R = Me 221 R = H 215 R = Me 216 R = H ii – 78 °C 218 i Scheme 12 Reagents: i, LDA, THF, MeI, "78 )C, 20 min, then H2O; ii, KOH, H2O, MeOH, reflux, 1 h N Me Me N N N Cl3C O O CCl3 R2 R2 R1 OH OH OH N N N N NH OH OH (CH2)9 OCH2CO2Me R1 R2 223 222 + 225 226 224 Lewis: Muscarine, imidazole, oxazole, thiazole and peptide alkaloids, and other miscellaneous alkaloids 385into aldehyde 240.Condensation of this aldehyde 240 with tert-butyl azetidine-2-carboxylate 241 gave 2*-deoxymugineic acid derivative 242 which upon deprotection gave the natural product (243; R=OH). Utilising the 3-amino synthon 244 [OHCCH2CH(MP)NHBoc] instead of 230, nicotianamine (243; R=NH2) was also synthesised.The complete absolute stereochemistry of aplyronine A, the potent antitumour substance obtained from the sea hare Aplysia kurodai, has been established as 245.125 Its total synthesis has also been reported by the same research group.126 Lepadiformine is a new marine cytoxic alkaloid found in the ascidian Clavelina lepadiformis.127 Interestingly it possesses a unique zwitterion-like moiety 246.Rice culturing of Fusarium equiseti produces two mycotoxins both of which contain the 5-aminochroman-4-one ring system 247 (ab sat. or unsat.).128 A short synthesis of tortuosamine 253 involving four steps has been achieved.129 The key ring closure was an intramolecular SRN1 reaction between ketone enolate 248 and 2-bromo-3- bromomethylpyridine 249 to give 250 which upon irradiation gave 251.Deoxygenation through trifluoromethanesulfonate 252 and reduction gave 253 (Scheme 14). A new axinohydantoin isolated from a sponge of the Monanchora family is the debrominated analogue (254; R=H) of axinohydantoin (254; EtO2C MP EtO2C OH MP OH EtO2C OTBS MP OHC OTBS MP MeO2C NH2 MP MeO2C NHBoc MP OHC NHBoc MP R NHBoc MP MeO2C NH MP OTBS MP NH MP OTBS MP TrocO NH CO2H OAc CO2H TrocO NH CO2H R CO2H N CO2H N Boc CO2But OAc CO2But N CO2But OHC N Boc CO2But OAc CO2But NH CO2But 236 237 238 239 240 xv–xvii 243 R = OH 242 232 R = OH 233 R = Ms 234 R = CO2H 235 R = CO2Me i ii–iv v xi xii, xiii x viii ix vi xiv 241 xviii deprotection vii 227 228 229 230 231 244 OMe MP = Scheme 13 Reagents: i, AD-mix-‚, CH3SO2NH2, But OH, 4 )C, 11 h to rt; ii, nitrobenzenesulfonyl chloride, py, 4 )C, 18 h; iii, LiCl, DMF, 85 )C, 14 h; iv, 5% Pd/C, HCO2NH4, MeOH, 0 )C, 2 h; v, DIBAL, CH2Cl2, "78 )C, 15 min; vi, LiCl, NaBH4, THF, EtOH, rt, 16 h; vii, MsCl, py, 0 )C, 2 h; viii, KCN, 18-crown-6, DMSO, 50 )C, 3 h then conc.HCl, THF, 100 )C, 12 h; ix, MeI, K2CO3, DMF, rt 12 h; x, 10% HCl, MeOH, rt, 1 h; xi, 1 M NaBH3CN, THF, AcOH, MeOH, 0 to 10 )C, 10 h; xii, Boc2O, Et3N (cat.), dioxane, 50 )C, 14 h, then Troc Cl, DMAP, py, rt, 20 h; xiii, Ac2O, TBAF, THF, rt, 3 h, "50 )C, 4 h rflux then Ac2O, py, rt, 18 h; xiv, RuCl3, NaIO4, EtOAc, CH3 CN, H2O, rt, 5 h; xv, O-tert-butyl-N,N*- diisopropylisourea, ButOH, CH2Cl2, 50 )C, 1 h; xvi, Zn, HOAc, THF, rt, 3 h; xvii, (COCl)2, DMSO, Et3N, CH2Cl2, "78 to 0 )C, 2 h; xviii, 1 M NaBH3, CN, THF, MeOH, 0 to 7 )C, 19 h O MeO OH O OH O O NMe2 OAc N+ HO O O– H O NH2 O N 245 246 247 a b CHO Me NMeBn O NMeBn N Br O OMe OMe OMe OMe NHMe N OMe OMe NMeBn N OMe OMe R N Br Br 249 250 253 251 R = OH 252 R = OTf PhN(Tf)2 248 ii i iii Scheme 14 Reagents: i, LDA, THF, "78 )C; ii, LDA (2–5 equiv.), THF, hÌ; iii, H2, Pd/C, LiCO3, EtOH 386 Natural Product Reports, 1998R=Br).130 The phenanthrene alkaloid obtained from the leaves of Thalictrum simplex northalicthuberine 255 was accompanied by thalicthuberine and its N-oxide.131 The new siderophore from Pseudomonas putida called isopyoverdin has the structure 258.This makes it biogenetically interesting132 as the pyoverdin siderophores are based on a tricyclic structural system, e.g. 257, which undergo ring closure through the ·-nitrogen of precursor 256 whereas 258 involves the ‚-nitrogen for coupling.An extract from the aerial parts of Lycopodium casuarinoides possesses anticholinesterase activity, so using a bioassaydirected fractionation of its extract,133 an active compound was found to be N-demethylhuperzinine 259. A short synthesis of the dynemicin core has been achieved starting from quinoline 260 which upon reaction with protected magnesioacetylide 261 in the presence of 1-adamantyl chloroformate gave a completely regiospecific addition product 262.Removal of the THP protecting group and stabilising of the yne groups with cobalt carbonyl allowed cyclisation to the enediyne chromophore 263 (Scheme 15). The five steps have a 15% yield so the method134 has been exploited to synthesise analogues which show diVerent rates of cycloaromatisation. 135 Interestingly, synthetic dynemicin analogues 264 (where R1 and R2 are OH or H) have the ability to function as DNA cleaving agents136 and also cycloaromatise upon irradiation.Maduropeptin is a complex composed of an acidic water soluble carrier protein and an enediyne chromophore. To separate this 1:1 complex a series of chromatographic studies were carried out whence it was found that the holo-antibiotic could be bound to DEAE-cellulose. Elution with methanol released the bioactive chromophore as a methoxy adduct (265; X=OMe), while ethanol elution gave an ethoxy analogue (X=OEt) and chloride inpurities in the resin gave a chloro product (X=Cl), all of which were bioactive.137 A convergent, total synthesis of calicheamicin-„ 266 has been reported through the assembly of the enediyne alcohol with the carbohydrate moiety.Both components were highly protected prior to the coupling process.138 Coupling was achieved by the diyne alcohol displacing the glycosidic trichloroacetimidate group mediated by silver triflate in the presence of a molecular sieve.A blood anticoagulating agent P1-334 267 was produced when the culture Ramichloridium schulzeri var. schulzeri was grown in a shake culture.139 The water soluble portion of an aqueous methanol extract of the sponge Stylotella aurantium showed inhibitory properties towards chitinase.140 Three compounds were isolated from this extract and were identified as the guanidines styloguanidine (268; R1=R2=H), 3-bromostyloguanidine (268; R1=Br, R2=H) and 2,3-dibromostyloguanidine (268; R1=R2=Br) all of which showed antichitinase activity and could become potentially useful as antifouling agents.Nerve growth factors can be assessed by their ability to extend neuroaxons of cultured PC-12 cells. One such factor 269 has been obtained from the culture broth of Stachybotrys parvispora141 and shown to enhance growth by a factor of five. Pamamycin 721 270, isolated from the mycelium of Streptomyces aurantiacus IMET213917, has been shown to be a new macrolide antibiotic.142 A simple synthesis of staurosporine aglycone 279 has been achieved143 in an overall yield of 25% starting with dibromomaleic acid 271 and benzylamine 272 which in the presence of DCC and a trace of DMAP gave the 3,4-dibromo-2,5- dioxopyrrole 273.Condensation with indolylmagnesium bromide 274 gave the imide 275 which when converted to its O O OMe OMe NHMe NH HN NH NH O O O R 254 255 N HO HO HO HO NH HN N NH2 NH2 N HO HO N NH–Glu CO2R RO2C NH Ser CO CH NH Asp Ala Asp CO N HO O Ac(HO)N(CH2)3 HN H NH Me H O 256 257 258 259 a b N N OTBS OMe OTHP H OTBS OTHP Mg AdO2C OMe N H AdO2C OMe + i 260 261 262 263 ii–v Scheme 15 Reagents: i, 1-adamantyl chloroformate 261; ii, pyridinium tosylate, EtOH; iii, Co(CO)6, THF; iv, Tf2O, 2-nitropropyl-2,6-di-tertbutyl- 4-methylpyridine, "10 )C, 30 min; v, Ce(NH4)2(NO2)6, acetone N R1 R2 O O O NO2 MeO MeO 264 Lewis: Muscarine, imidazole, oxazole, thiazole and peptide alkaloids, and other miscellaneous alkaloids 387anhydride 276 allowed ring closure to take place through photocyclisation to give 277.Reconversion to the imide 278 enabled reduction by a Clemmensen method to give staurosporine 279 (Scheme 16). A second synthesis of a precursor to staurosporine 279 was developed so that a monosubstituted aglycone was produced so as to diVerentiate the two indole nitrogen groupings. Thus N-substituted indoleacetic acid 280 was condensed with indole amine 281 to give amide 282 which was protected as 283 prior to reduction to give 284.Deprotection 285 allowed oxidative photocyclisation to provide the N-substituted aglycone 286 which thus makes available the aglycone 279144 (Scheme 17). It is possible to obtain indolopyrrolocarbazoles by a fermentation process using microorganisms selected from Microtetraspora and Saccharothrix species. The patent145 vaguely describes a variety of compounds 287 with an extensive range of substitution at R, X and Y.The kinase C activity of these alkaloids is also accompanied by an immunosuppressive activity. MLR 52 288 is another new metabolite this time obtained from Streptomyces sp. AB1869R-359.146 A total synthesis of the antipode of papuamine 298 has also established the natural product’s absolute stereochemistry.147 Essentially amine 289 was condensed with 1,3-dibromopropane 290 to give the bis-benzyl ether 291, which upon deprotection 292 and Swern oxidation gave dialdehyde 293.Direct conversion to the bis-vinyl iodide 294 or to its stannane 295 gave potentially two precursors suitable for ring closure. All attempts to ring close either diiodide 294 or distannane 295 failed. However formation of the iodo stanane 296 enabled cyclisation to take place with Pd(PPh3)4 in toluene at 100)C to Me OH Me CO HN O HO OH O X NH O HO Cl O MeO OH 266 R OH ONHCCl3 Sugar 265 + BF3·OEt2, Et2O, CH2Cl2, – 78 °C a–15% b-45% anomeric mixture 266 O OH HO MeO O I Me OMe OMe S O O O NH O OH O O O OMe NHEt + O SSSMe HO OH N N O NH N N HN HN N O N OH O OH HO O O O O O O O NMe2 OH OH SMe O OCOCH(Me)CH(OH)CH(Me)COC(Me)=CHMe HS O R2 R1 O H H2N H NH2 Cl H2N HO H 267 268 269 270 Br CO2H Br CO2H H2N Ph N Br Br O O Ph NH Br Mg NH NH O O O NH NH N O O NR NH HN O O NH NH O O O NR NH HN O Ph 271 ii 272 273 274 275 276 277 278 279 R = H iv v + i + iii vi Scheme 16 Reagents: i, DDC, DMAP, THF, rt, 2 h; ii, THF, toluene, reflux; iii, 5 M KOH, EtOH, reflux, 1 h, iv, hÌ, I2, CH3CN; v, NH4OAc, 150 )C, overnight; vi, Zn(Hg), HCl, EtOH, toluene reflux, 1.5 h 388 Natural Product Reports, 1998give protected papuamine 297, which upon deprotection gave antipodal papuamine 298 (Scheme 18).Almost simultaneously a second synthesis was reported148 which utilised an allene aldehyde 299 whereby condensation with diaminopropane 300 gave diamine 301. Conversion to the stannyl derivative 302 allowed cyclisation to proceed, using a PdII catalyst, to give papuamine 298 itself (Scheme 19). Halicyclamine A is a diamine alkaloid isolated from a marine sponge of the Haliclona family.149 From its structure 303, its biogenetic origin was suggested to involve precursors similar to those associated with the manzamines, saraines, petrosins and the xestospongines.Keramaphidin B 304 is a cytotoxic alkaloid isolated from a marine sponge of the Amphimedon group.150 It is also thought to be biogenetically related to the manzamine alkaloids by being a possible precursor.Ingamines A and B are also cytotoxic alkaloids isolated from a marine sponge, this time Xestospongia ingeus.151 By extensive spectroscopic analysis the structures for A (305; R=OH) and B (305; R=H) were proposed. Madangamine A 306 is another cytotoxic alkaloid isolated from the same sponge.152 Rigidin 314 was isolated and characterised in 1990 as a pyrrolopyrimidine alkaloid obtained from the marine tunicate Eudistoma rigida.Its novel structure has been synthesised quite simply153 from 2,4-dimethoxypyrrolo[2,3-d]pyrimidine 307. After protection 308, lithiation in the 6-position enabled attachment of the aryl moiety to give 309 which upon DDQ oxidation gave the aroyl group 310. Deprotection resulted in 311 and iodination gave the 5-iodo product 312 which reacted with 2-(4-methoxyphenyl)-1,3,2-dioxaborinane in DMF with a N NH N N R2 HN O N N R HN O NR NH HN O CO2H H2N O O O R1 O O O O vi 280 281 282 R1 = O; R2 = H 283 R1 = O; R2 = SEM 284 R = SEM 285 R = H 286 R = CH2–CH(O2CH2CH2O) 279 R = H i, ii iii, iv v vii Scheme 17 Reagents: i, N,N*-carbonyldiimidazole, CH2Cl; ii, N-ethyldiisopropylamine, THF, rt, 18.5 h; iii, KN(SiMe3)2, THF, 0 )C, 2 h; iv, SEM-Cl, rt, 1 h; v, KOBu, ButOH, reflux, 18 min; vi, mol.sieves, DMF, 80 )C, TBAF, ethylenediamine, 2 h; vii, hÌ, aceone, O2, 40 min RN O O HN O O N NH O OH OH OH OH O HO OH OMe N N H H X Y 287 288 ii iii iv v 297 R = Tf 298 R = H viii Br(CH2)3Br + i vi vii H RN RN H H H H H CH2OBn H H R H H Tf N Tf N R H H H Tf Tf N HN SnMe3 I NHTf 289 290 291 R = CH2OBn 292 R = CH2OH 293 R = CHO 294 R = CH=CHI 295 R = CH=CHSnMe3 296 Scheme 18 Reagents: i, K2CO3, KI(cat.), MeCN, heat; ii, H2, Pd/C, EtOH; iii, Swern oxidation; iv, CHI3, CrCl2, dioxane, THF; v, Me6Sn2, LiCO3, PdCl2(PPh3)2, THF, 60 )C; vi, I2 (1 equiv.), Et2O; vii, Pd(PPh3)4, toluene, 100 )C; viii, LiAlH4, Et2O, heat CHO C SiMe3Ph HN HN H H H H H H SiMe3Ph SiMe3Ph HN HN H H H H H H SnBu3 SnBu3 H H 299 300 301 298 302 H2N(CH2)3NH2 + i ii, iii iv Scheme 19 Reagents: i, toluene, reflux, 16 h; ii, TBAF, THF; iii, Bu3SnH, THF, reflux, AIBN; iv, Pd/Cl2(PPh3)2, DMF, rt Lewis: Muscarine, imidazole, oxazole, thiazole and peptide alkaloids, and other miscellaneous alkaloids 389Pd0 catalyst to give O-methylorigidin 313.Demethylation with BBr3 gave the natural product 314 (Scheme 20). From the leaves of Adhotoda vasica three known pyrroloquinazoline alkaloids were isolated together with a new one, vasnetine 315.Comprehensive NMR data for all these alkaloids is discussed and complete assignments established.154 3·-Methylaraguspongine 316 is a bis-1-oxaquinolizidine alkaloid obtained from the sponge Haliclona exigua.155 Previously, four alkaloids with the same skeletal arrangement had been found which all possess vascodilatory properties. Woody parts of Psychotria camponutans contains the pharmacologically active benz[g]isoquinoline alkaloid 317.It aVects KB cells, chloroquine resistant mosquitoes and brine shrimps.156 A series of polyketide antibiotics with the general structure 318 has been isolated from Streptomyces venezuelae,157 in which the substituents R1 and R2=H or lower alkyl groups, e.g. jadomycine B has R1=Bui, R2=Me. A synthesis of the naphthyridine alkaloid neozeylanicine 324 starts from 3-bromo-4-picoline 319 which with LDA and dimethyl carbonate gave ester 320.Palladium catalysed cross coupling with trimethyl(1-ethoxyvinyl)stannane gave ethoxyvinyl pyridine 321 which was then converted to the methyl N N H H H N H N N N H 303 304 305 306 N N R N N N N N NR CHO OMe OMe MeO MeO OMe OH OMe N N N MeO OMe O OMe N N N H MeO OMe O OMe N N N H MeO OMe O N N N H RO OR O OR SO2Ph SO2Ph OR OMe I 309 310 311 312 307 R = H 308 R = SO2Ph 313 R = Me 314 R = H i ii then iii iv i vi v Scheme 20 Reagents: i, NaH, THF, PhSO2Cl; ButLi, THF, 4-methoxybenzaldehyde; iii, DDQ, dioxane; iv, KOH, MeOH; v, I2, KOH, DMF; vi, Pd(PP3)4, 2-(4-methoxyphenyl)-1,3,2-dioxaborane; vii, BBr3, (CH2Cl)2 N N N O O O O N NH O O N O O O O R2 OH HO R1 HO R1 CO2Me N O H HO OH 315 316 317 318 N Br N Br CO2Me N CO2Me OEt N N N N CO2Me O O CO2Me NMe2 CO2Me 319 320 321 322 323 324 i ii iii iv v Scheme 21 Reagents: i, LDA, CO(OMe)2, THF, 50 )C, then rt, 24 h; ii, trimethyl(1-ethoxyvinyl)stannane, PdCl2 (Ph3P)2, toluene, reflux N2, 4 h; iii, HCl(c), MeOH (1:1), rt, 2 h; iv, dimethylformamide diethyl acetal, toluene, reflux, N2, 15 h; iv, EtOH, NH4Cl, reflux 2 h 390 Natural Product Reports, 1998ketone 322 by acid treatment.Reaction with dimethylformamide diethyl acetal gave amine 323 which cyclised in refluxing ethanol containing NH4Cl to give neozeylanicine 324 (Scheme 21).158 A benzophenanthridine alkaloid, namely ailanthoxidine 325, with a pendant cyanopyridine has been identified as a constituent of the bark of Xanthoxylum allanthoides.Ailanthoxidine 325 shows a blue fluorescence which turns to yellow on prolonged exposure to air and light.159 Two new phenanthroindolizidine N-oxide alkaloids have been isolated from the stem and root bark of Vincetoxicum hirundinaria.160 They diVer in the orientation of the N-oxide functionality, thus one is 10‚-(")-antofine N-oxide 326 (·-O) and the other is the ‚-isomer. A new synthesis of (R)-(")-cryptopleurine 331 employs a cyclic N-acyliminium intermediate with a chiral appendage to direct asymmetric addition of a carbon nucleophile.The key steps161 are addition of 327 to enol ether 328 to give 329 which after removal of the pyrrolidine group could be condensed with 4-methoxyphenylacetyl chloride to give 330 which could be photocyclised to (")-cryptopleurine 331 (Scheme 22). A UV mutant strain of Streptomyces murayamaensis has produced a new metabolite called murayaanthraquinone 332.162 Makaluvimines A to G all have the basic pyrroloquinolinone ring system (333; ab sat.or unsat.). Two synthetic schemes163,164 have produced this tricyclic arrangement starting from either a dimethoxy-4-aminoindole 334 or from a trimethoxyindole 335. In the latter case oxidative demethylation gave a quinone which ring closed to the quinolinone. Another synthetic route,165 of five steps, started with a dibenzyloxyindolylglyoxylic acid 336 which was converted to its amide 337 and thence to amine which upon deprotection produced the unstable dihydroxyindole 338.This underwent oxidative cyclisation readily in methanol with triethylamine and air to give the pyrroloquinolinedione 339 which with the appropriate base (RNH2) gave the natural products 340 (Scheme 23). NMe O O MeO MeO H R1 H N N MeO MeO OMe H O CN 325 326 N N N N N O N O O H O OH O BnO OMe OSiMe3 Br OMe OMe BnO Br OMe OMe OMe MeO MeO OMe OMe OMe Br 327 i 328 329 331 + iv–vii ii, iii 330 Scheme 22 Reagents: i, BF3 , Et2 O, CH2Cl2, rt; ii, BH3, THF, reflux, then 10% NaOH, reflux; iii, 4-methoxyphenylacetyl chloride, 5% NaOH, CH2Cl2, 0 )C to rt; iv, PDC, CH2Cl2, 4 Å mol.sieves, rt; v, KOH, EtOH, reflux; vi, hÌ (high pressure), Et3N, dioxane or Bu3SnH, AIBN, benzene, reflux; vii, LiAlH4, THF, reflux O O N O OH O CONH2 332 N Me NMe N OMe MeO TocNH O H2N NMe OMe MeO OMe MeO2C TocN H 333 334 335 a b NH OBz BzO COCO2H NH OBz BzO COCONH2 NH OH HO N O RHN N NH O O HN H3N 336 337 338 339 340 i, ii RNH2 iii, iv v vi Scheme 23 Reagents: i, SOCl2, benzene reflux, 1 h; ii, NH3, Et2O, rt; iii, LiAlH4, THF, reflux; iv, H2, Pd, BaSO4; v, Et3 N, MeOH, air; vi, RNH2, KOH, MeOH Lewis: Muscarine, imidazole, oxazole, thiazole and peptide alkaloids, and other miscellaneous alkaloids 391A condensation between cyclohexanediones and kynuramine, kyrunenine or diaminobenzophenone leads to various heterocycles related to marine alkaloids such as eilatin 341 and axididemin 342.Thus cyclohexanedione 343 and kynuramine 344 reacted in boiling acetic acid containing HCl to give 345. This synthetic procedure was described by the authors166 as being ‘biomimetic’! The first total synthesis of the biologically active pyridoacridine alkaloid diplamine 348 has been accomplished in 21 steps.167 Key components in this synthesis were the ‚-keto amide 346 which could be converted into chloroquinolinedione 347 and thence into 348. Crytodamine is a pentacyclic cytotoxic aromatic alkaloid isolated from the Mediterranean ascidian Cystodytes delle chiajei.It has an interesting triplet in the NMR spectrum due to an 1H–14N coupling (J=52 Hz) which can be associated with structure 349, presumably because the measurements were made in [2H6]DMSO containing a trace of acetic acid.168 Meridine 350 is a pentacyclic aza-aromatic alkaloid which has been synthesised from quinolinedione 351 and nitrocinnamaldehyde dimethylhydrazone 352 in four steps.169 Five new alkaloids have been isolated from the tropical ascidian belonging to the Lissoclinum family170 which include lissalin A 353 (R=CH2CHMe2), lissoclin B 353 [R=(E)= CMe=CHMe], lissoclin C 354, lissoclin D 355 and lissoclin E 356.The high cytotoxic activity (IC50 209 Ïg ml"1) of an alkaloid extracted from Biemna has prompted it being patented. 171 Its structure 357 puts it into the ascididemin group of alkaloids. The first total synthesis of the marine antitumour alkaloid grossularine-2 358 has been achieved172 in a nine step sequence via a cross coupling of the trifluoromethanesulfonate 359 with 4-(MeOCH2O)C6H4B(OH)2.Pinnatoxin A is a toxic amphoteric macrocycle 360 obtained from the bivalve Pinna muricata.173 Leptosins I 361; R1=Cl, R2=Ac) and J (361; R1=Cl, R2=H) are cytotoxic diketopiperazines isolated from a fungus of the Leptosphaeria family which was found attached to the marine alga Sargassum tortile.174 N N N N N N N N O O O H2N O H2N N 341 342 343 344 345 + N N O NH OH N N N O NH NHAc O2N O OMe O O O2N Cl O SMe NH2 O + 346 347 348 349 N N N N OMe O O OH O NO2 N (Me)2N 350 351 352 4 steps N N N N NH NH S S S S NH O MeS NHCOR Br OH MeO MeS SMe NH2 HO OMe NH2 O O NH N OMe OH NH2 353 354 355 356 357 N NH N Me3Si(CH2)2OCH2N NMe2 OTf NH N O OH N N NMe2 358 359 392 Natural Product Reports, 1998Okaramine D, E and F are congeners isolated from okara fermented by Penicillium simplicissimum strain ATCC90288 with a proposed structure of 362.175 4 References 1 D.W. Knight, D. Shaw and G. Fenton, Synlett, 1994, 295. 2 M. Ohta, T. Mukaihira and T. Fuji, Chem. Pharm. Bull., 1994, 42, 1784. 3 G. Boyd, M. K. Harper and D. J. Faulkner, J. Nat. Prod., 1995, 58, 302. 4 I. Kaswasaki, M. Yamashita and S. Ohta, J. Chem. Soc., Chem. Commun., 1994, 2085. 5 A. Musuku, M. I. Selala, T. de Bruyne, M. Claegs, P. J. C. Schepens, A. Tsatrsakis and M. I. Shtilman, J. Nat. Prod., 1994, 57, 983. 6 A. G. Kozlovsky, N. G. Vinokurova, T. A. Reshetilova, V. G. Sakharovsky, B. P. Baskunov and S. G. Seleznyov, Prikl. Biochim. Mikrobiol., 1994, 30, 410 (Chem. Abstr., 1994, 121, 225 944). 7 P. Molina, P. Almendros and P. M. Fresneda, Tetrahedron Lett., 1994, 35, 2235. 8 H. Annoura and T. Tatsuoka, Tetrahedron Lett., 1995, 36, 413. 9 I. Mancini, G. Guella, C. Debitus, D. Duhet and F. Pietra, Helv. Chim. Acta, 1994, 77, 1886. 10 K. J. Doyle and C. J. Moody, Synthesis, 1994, 1021. 11 I. N’Diaye, G. Guella, G. Chiasera, I. Mancini and F. Pietra, Tetrahedron Lett., 1994, 35, 4827. 12 K. Ojiri, M. Tsukamoto, S. Nakajima, H. Suzuki and H. Suda, Jpn. Tokkyo Koho, JP 06306074 (Chem. Abstr., 1995, 122, 185 519). 13 A. Rudi, Z. Stein, S. Green, I. Goldberg, Y. Kashman, Y. Benayahu and M. Schleyer, Tetrahedron Lett., 1994, 35, 2589. 14 S. Oomura, K. Shiomi, Y. Tanaka and H. Yoshida, Jpn. Kokai Tokkyo Koho, JP 06 256 324 (Chem. Abstr., 1995, 122, 158 765). 15 P.Wilf and S. Lim, J. Am. Chem. Soc., 1995, 117, 558. 16 S. Yamamoto, N. Okujo and Y. Sakakibara, Arch. Microbiol., 1994, 162, 249 (Chem. Abstr., 1995, 122, 76 143). 17 J. R. Lewis, Nat. Prod. Rep., 1991, 8, 171. 18 A. Rudi, Y. Kashman, Y. Benayahu and M. Schleyer, J. Nat. Prod., 1994, 57, 829. 19 J. R. Lewis, Nat. Prod. Rep., 1989, 6, 503. 20 R. Jansen, M. Irschik, H. Reichenbach, V. Wray and G. Hofle, Liebigs Ann. Chem., 1994, 759. 21 H. Irschik, R. Javasen, K. Gerth, G. Hoefle and H.Reichenbach, J. Antibiot., 1995, 48, 31 (Chem. Abstr., 1995, 122, 128 225). 22 K. Kondo, M. Ishbashi and J. Kobayashi, Tetrahedron, 1994, 50, 8355. 23 J. Kobayashi, K. Konda, M. Ishibashi, M. R. Walchli and T. Nakamura, J. Am. Chem. Soc., 1993, 115, 6661. 24 E. Aguillar and A. I. Meyers, Tetrahedron Lett., 1994, 35, 2477. 25 B.-S. Yun, T. Hidaka, K. Furihata and H. Seto, J. Antibiot., 1994, 47, 1541 (Chem. Abstr., 1995, 122, 182 845). 26 B.-S. Yun, T. Hidaka, K. Furihata and H.Seto, Tetrahedron, 1994, 50, 11 659. 27 B.-S. Yun, T. Hidaka, K. Furihata and H. Seto, J. Antibiot., 1994, 47, 510 (Chem. Abstr., 1994, 121, 103 694). 28 P. T. Northcote, M. H. G. Munro, J. W. Blunt and D. G. Gravalos, Eur. Pat. Appl., EP 647 645 (Chem. Abstr., 1995, 122, 287 299). 29 G. R. Pettit, J. K. Sriangam, D. L. Herald and E. Hamel, J. Org. Chem., 1994, 59, 6127. 30 R. L. Parsons Jr. and C. H. Heathcock, Tetrahedron Lett., 1994, 35, 1379. 31 J. R. Lewis, Nat.Prod. Rep., 1994, 11, 395. 32 R. L. Parsons Jr. and C. H. Heathcock, Tetrahedron Lett., 1994, 35, 1383. 33 R. J. Boyce and G. Pattenden, Synlett, 1994, 587 (Chem. Abstr., 1994, 121, 231 130). 34 G. Pattenden and S. M. Thom, J. Chem. Soc., Perkin Trans., 1993, 1, 1629. 35 R. J. Boyce, G. C. Mulqueen and G. Pattenden, Tetrahedron Lett., 1994, 35, 5705. 36 R. L. Parsons Jr, and C. H. Heathcock, J. Org. Chem., 1994, 59, 4733. 37 J. R. Lewis, Nat. Prod. Rep., 1995, 12, 135. 38 Y.In, M. Doi, M. Inoue and T. Ishida, Acta Crystallogr., Sect., C, 1994, 50, 432. 39 J. R. Lewis, Nat. Prod. Rep., 1992, 9, 81. 40 C. Boden and G. Pattenden, Tetrahedron Lett., 1994, 35, 8271. 41 P. T. Northcote, M. Siegel, D. B. Borders and M. D. Lee, J. Antibiot., 1994, 47, 901 (Chem. Abstr., 1995, 122, 106 474). 42 H.-R. Ko, H.-K. Chun, Y.-H. Kho and N.-K. Sung, Haviguk Norighwa Hakhoechi, 1993, 36, 428 (Chem. Abstr., 1994, 121, 152 876). 43 K. Stratmann, J. Belli, C. M.Jensen, R. E. Moore and G. M. L. Patterson, J. Org. Chem., 1994, 59, 6279. 44 K. Yoshikawa, M. Nagai and S. Arihara, Phytochemistry, 1994, 35, 1057. 45 S. Oota and S. Ikegami, Jpn. Kokai Tokkyo Koho, JP 06 256 279 (Chem. Abstr., 1995, 122, 114 903). 46 Hung-yu Li, S. Matsunaga and N. Fusetani, Tetrahedron, 1995, 51, 2273. 47 A. Morishta, S. Ishikawa, Y. Ito, K. Ogawa, M. Takeda, S. Yaginuna and S. Yamamoto, J. Antibiot., 1994, 47, 1065 (Chem. Abstr., 1995, 122, 101 224). 48 T.Seitai, T. Tsuji and S. Kondo, Jpn. Kokai Tokkyo Koho, JP 07 70 098 (Chem. Abstr., 1995, 122, 289 054). 49 H.-T. Postels and W. A. Konig, Tetrahedron Lett., 1994, 35, 4535. 50 S. Faizi, B. S. Siddiqui, R. Saleem, S. Siddiqui, K. Aftab and A. ul. H. Gilani, J. Chem. Soc., Perkin Trans., 1994, 1, 3035. 51 T. Kamiyama, T. Umino, T. Satoh and K. Yokose, J. Antibiot., 1994, 47, 959 (Chem. Abstr., 1995, 122, 76 128). 52 R. S. Kalidindi, W. Y. Yoshida, J. A. Palermo and P. J. Scheuer, Tetrahedron Lett., 1994, 35, 5579. 53 S.Yamamoto, N. Okujo, T. Yoshida, S. Matsuura and S. Shinoda, J. Biochem. (Tokyo), 1994, 115, 868 (Chem. Abstr., 1994, 121, 296 702). 54 S. C. Pakrashi, B. Achari, P. K. Dutta, A. K. Chakrabarti, C. Giri, S. Saha and S. C. Basa, Tetrahedron, 1994, 50, 12 009. 55 V. Costantino, E. Fattorusso, A. Mangoni, M. Aknin and E. M. Gaydon, Liebigs Ann. Chem., 1994, 1181. 56 F. Cafieri, E. Fattorusso, Y. Mahajnah and A. Mangoni, Liebigs Ann. Chem., 1994, 1187. 57 S. Mineki,M. Iida and T. Tsutsumi, J. Ferment. Bioeng., 1994, 78, 327 (Chem. Abstr., 1995, 122, 5082). 58 G. Falsone, F. Cateniz, G. Visuntin, V. Lucchini, H. Wagner and O. Seligmann, Farmaco, 1994, 49, 167 (Chem. Abstr., 1994, 121, 175 122). 59 H. S. C. Spies and D. J. Steenkamp, Eur. J. Biochem., 1994, 224, 203 (Chem. Abstr., 1994, 121, 250 761). 60 Y. Z. Shu, S. Huang, R. R. Wang, K. S. Kam, S. E. Klohr, K. J. Volk, D. M. Pirnik, J. S. Wells, P. B. Fernandes and P. S.Patel, J. Antibiot., 1994, 47, 324 (Chem. Abstr., 1994, 121, 77 894). 61 I. Takagi, S. Akashi, K. Mizogami, K. Hanada and M. Yamagishi, Jpn. Kokai Tokkyo Koho, JP 06239848 (Chem. Abstr., 1995, 122, 29 878). O HN O O CO2 – O O O OH OH H N N NMe O O NH N NMe O O S4 O R2 R1 OH N N N HN O O MeO OH HO OH 360 361 362 + Lewis: Muscarine, imidazole, oxazole, thiazole and peptide alkaloids, and other miscellaneous alkaloids 39362 M. Nakagawa and M. Nakayama, J. Antibiot., 1994, 47, 1104 (Chem.Abstr., 1995, 122, 5080). 63 T. Ichiba, P. J. Scheuer and M. Kelly-Borges, J. Org. Chem., 1993, 58, 4149. 64 J. W. Lampe, P. F. Hughes, C. K. Biggers, S. H. Smith and H. Hu, J. Org. Chem., 1994, 59, 5147. 65 K. C. Nicolaou, M. E. Bunnage and K. Koide, J. Am. Chem. Soc., 1994, 116, 8402. 66 A. Casapullo, L. Minale, F. Zollo and J. Lavayre, J. Nat. Prod., 1994, 57, 1227. 67 B. W. Bycroft, W. C. Chan, D. N. Hone, S. Millington and I. A. Nash, J. Am. Chem. Soc., 1994, 116, 7415. 68 Y. Hirai, K. Yokota and T. Momose, Heterocycles, 1994, 39, 604 (Chem. Abstr., 1995, 122, 214 492). 69 P. Ashworth, B. Broadbelt, P. Jankowski, P. Kocienski, A. Pimm and R. Bell, Synthesis, 1995, 199 (Chem. Abstr., 1995, 122, 214 506). 70 H. Bueller, E. BischoV, B. Voklker, K. Weber, B. Fugmann and B. Rosen, Ger. OVen., DE 4 231 289 (Chem. Abstr., 1994, 121, 7441). 71 U. Schmidt and S. Weinbrenner, J. Chem. Soc., Chem. Commun., 1994, 1003. 72 K. Ishihara, Y. Kuroki and H.Yamamoto, Synlett, 1995, 41 (Chem. Abstr., 1995, 122, 291 252). 73 M. Shimura, S. Akashi, K. Mizogami, T. Nagate and K. Hanada, Jpn. Kokai Tokkyo Koho, JP 06 178 693 (Chem. Abstr., 1995, 122, 131 134). 74 H. Schmidt and J. Langner, J. Chem. Soc., Chem. Commun., 1994, 2381. 75 H. Ishiwata, T. Nemoto, M. Ojika and K. Yamada, J. Org. Chem., 1994, 59, 4710. 76 H. Ishiwata, H. Sone, H. Kgoshi and K. Yamada, Tetrahedron, 1994, 50, 12 853. 77 T. Imaeda, Y. Hamada and T.Shioiri, Tetrahedron Lett., 1994, 35, 591. 78 I. Kaneko, H. Minekura, Y. Takeuchi, K. Kodama, T. Nakamura, H. Haruyama and Y. Sakaida, PCT Int. Appl., WO 94 19 481 (Chem. Abstr., 1994, 121, 279 063). 79 S. Yoshida, M. Yoshioko, T. Yaguchi, M. Nagasawa and M. Koyama, Meiji Seika Kenkyu Nenpo, 1993, 32, 58 (Chem. Abstr., 1995, 122, 288 946). 80 S. Gupta, G. Peiser, T. Nakajima and Y.-S. Hwang, Tetrahedron Lett., 1994, 35, 6009. 81 H. Morita, S. Nagashima, K. Takeya and H. Itokawa, Chem. Lett., 1994, 2009 (Chem.Abstr., 1995, 122, 235 210). 82 R. J. Russo, S. R. Howell and S. Nath, Eur. Pat. Appl., EP 589 703 (Chem. Abstr., 1994, 121, 82 874). 83 K. Yasumuro, Y. Suzuki, M. Shibazaki, K. Abe, Y. Imai and K. Suzuki, Jpn. Kokai Tokkyo Koho, JP 06 172 385 (Chem. Abstr., 1995, 122, 131 132). 84 H. Matsuda, T. Okino, R. Haraguchi, M. Murakami and K. Yamuguchi, Tennen Yuki Kagobutsu Koen Yoshishu, 1993, 35, 654 (Chem. Abstr., 1994, 121, 200 486). 85 G. R. Pettit, J.Xu, Z. A. Cichacz, M. R. Boyd and R. L. Cerny, Bioorg. Med. Chem. Lett., 1994, 4, 2091 (Chem. Abstr., 1995, 122, 51 698). 86 M. Ooyama, Y. Okada, K. Nakagawa, M. Takagi, T. Okada, Y. Murai, T. Yoneda and K. Iinuma, Jpn. Kokai Tokkyo Koho, JP 06 184 126 (Chem. Abstr., 1995, 122, 104 043). 87 J. Rodriguez, R. Fernandez, E. Quinoa, R. Riguera, C. Debitus and P. Bouchet, Tetrahedron Lett., 1994, 35, 9239. 88 C. A. Bewley and D. J. Faulkner, J. Org. Chem., 1994, 59, 4849. 89 F. Trennheuser, G. Burkhard and H. Becker, Phytochemistry, 1994, 37, 899. 90 H. Morita, Y. S. Yun, K. Takeya and H. Itokawa, Tetrahedron Lett., 1994, 35, 9593. 91 L. Barboni, P. Gariboldi, E. Torregiani and L. Verotta, Phytochemistry, 1994, 35, 1579. 92 B. Singh and V. B. Pandey, Phytochemistry, 1995, 38, 271. 93 A. S. Menezes, M. A. Mostardeiro, N. Zanaha and A. F. Morel, Phytochemistry, 1995, 38, 783. 94 I. Khokhar and A. Ahmad, Pak. J. Sci., 1993, 45, 54 (Chem. Abstr., 1995, 122, 5434). 95 D. L. Boger, M. A. Patane and J. Zhou, J. Am. Chem. Soc., 1994, 116, 8544. 96 R. Beugelmans, G. P. Singh, M. Bois-Choussy, J. Chastanet and J. Zhu, J. Org. Chem., 1994, 59, 5535. 97 M. He, C. Zou, Z.-J. Hao and J. Zhou, Chin. Chem. Lett., 1993, 4, 1065 (Chem. Abstr., 1994, 121, 31 180). 98 J. R. Lewis, Nat. Prod. Rep., 1996, 13, 435. 99 S. K. Park, J. Jurek, J. R. Carney and P. J. Scheuer, J. Nat. Prod., 1995, 57, 407. 100 S. K. Park, H. Park and P. J. Scheuer, Bull. Korean Chem.Soc., 1994, 15, 534 (Chem. Abstr., 1994, 121, 175 553). 101 K. Matsuzaki, H. Ikeda, T. Ogino, A. Matsumoto, B. H. WoodruV, H. Tanaka and S. Omura, J. Antibiot., 1994, 47, 1173 (Chem. Abstr., 1995, 122, 76 133). 102 T.-S. Jeong, S.-U. Kim, H.-W. Lee, K.-H. Son, Y.-K. Kwon, M.-U. Choi and S.-H. Bok, Sanop Misaengmul Hakhoechi., 1993, 21, 600 (Chem. Abstr., 1994, 121, 152 873). 103 J. E. Hochlowski, P. Hull, D. N. Whittern, M. H. Scherr, R. R. Rasmussin, S. A. Dorwin and J.R. McAlpine, J. Antibiot., 1994, 47, 528 (Chem. Abstr., 1994, 121, 103 715). 104 R. A. Barrow, T. Hemscheidt, J. Liang, S. Paik, R. E. Moore and M. A. Tius, J. Am. Chem. Soc., 1995, 117, 2479. 105 Y. Yada, M. Kimura, N. Morizaki and G. Imokawa, Jpn. Kokai Tokkyo Koho, JP 06 321 751 (Chem. Abstr., 1995, 122, 142 050). 106 Y. Yada, M. Kimura, N. Morizaki and G. Imokawa, Jpn. Kokai Tokkyo Koho, JP 06 321 750 (Chem. Abstr., 1995, 122, 142 049). 107 M. Isbibashi, Y. Li, M. Sato and J.Kobayashi, Nat. Prod. Lett., 1994, 4, 293 (Chem. Abstr., 1995, 122, 56 448). 108 A. Nakagawa, H. Kainosho and S. Omura, Pure Appl. Chem., 1994, 66, 2411 (Chem. Abstr., 1994, 121, 296 845). 109 M. Fujiu, S. Sawairi, H. Shimada, H. Takaya, Y. Aoki, T. Okuda and K. Yokose, J. Antibiot., 1994, 47, 833 (Chem. Abstr., 1994, 121, 200 527). 110 A. Inone and K. Salch, Bioorg. Med. Chem. Lett., 1994, 4, 2303 (Chem. Abstr., 1995, 122, 56 327). 111 S. Tsukamoto, H. Kato, H. Hirota and N.Fusetani, Tetrahedron Lett., 1994, 35, 5873. 112 T. Morino, M. Nishimoto, N. Itou and T. Nishikiori, J. Antibiot., 1994, 47, 1546 (Chem. Abstr., 1995, 122, 128 216). 113 S. Zapf, M. Hossfeld, H. Anke, R. Velten and W. Steglich, J. Antibiot., 1995, 48, 36 (Chem. Abstr., 1995, 122, 234 928). 114 J. C. Braekman, D. Daloze, F. Gregoire, S. Popov and R. Van Soest, Bull. Soc. Chim. Belg., 1994, 103, 187 (Chem. Abstr., 1994, 121, 297 429). 115 C. Alcaraz and M. Bernabe, Tetrahedron: Asymmetry, 1994, 5, 1221 (Chem.Abstr., 1994, 121, 301 254). 116 T. Sugawara, M. Shibazaki, Y. Shimizu, T. Sasaki and Y. Imai, Jpn. Kokai Tokkyo Koho, JP 07 02 821 (Chem. Abstr., 1995, 122, 263 680). 117 J. R. Lewis, Nat. Prod. Rep., 1990, 7, 365. 118 F. A. Davis, V. Reddy and H. Liu, J. Am. Chem. Soc., 1995, 117, 3651. 119 J.-U. Su, Y.-L. Zhong, Y. Lu, Z.-Y. Tian and Q. T. Zheng, Huaxue Xuebao, 1995, 53, 90 (Chem. Abstr., 1995, 122, 183 509). 120 W. Qin, L. Ma, Y.Wen, L. Yang and L. Ma, Zhongcaoyao, 1995, 26, 3 (Chem. Abstr., 1995, 122, 298 789). 121 W. P. Chen and J. B. Wu, Zaoxue Xuebao, 1994, 29, 585 (Chem. Abstr., 1994, 121, 299 169). 122 Atta-ur-Rahman, S. Malik, S. S. Hasan, M. I. Choudhary, C. Z. Ni and J. Clardy, Tetrahedron Lett., 1995, 36, 1993. 123 K. A. Alvi, M. Jaspars and P. Crews, Bioorg. Med. Chem. Lett., 1994, 4, 2447 (Chem. Abstr., 1995, 122, 51 392). 124 F. Matsuura, Y. Hamada and T. Shioiri, Tetrahedron, 1994, 50, 9457. 125 M. Ojika, H. Kigoshi, T. Ishigaki, I. Tsukada, T. Tsuboi, T. Ogawa and K. Yamada, J. Am. Chem. Soc., 1994, 116, 7441. 126 K. Kigoshi, M. Ojika, T. Ishigaki, K. Suenaga, T. Mutou, A. Sakakura, T. Ogawa and K. Yamada, J. Am. Chem. Soc., 1994, 116, 7443. 127 J. F. Biard, S. Guyot, C. Roussakis, J. F. Verbist, J. Vercauteren, J. F. Weber and K. Bouket, Tetrahedron Lett., 1994, 35, 2691. 128 W. Xie, C. J. Mirocha and Y. Wen, J. Nat. Prod., 1995, 58, 124. 129 E. R. Goehring, Tetrahedron Lett., 1994, 35, 8145. 130 G. Groszek, D. Kantoci and G. R. Pettit, Liebigs Ann., 1995, 715 (Chem. Abstr., 1995, 122, 235 585). 131 M. P. Velcheva, R. R. Petrova, S. Daughaogtiin and Z. Yansanghisin, Planta Medica, 1994, 60, 485 (Chem. Abstr., 1995, 122, 101 593). 132 P. Jacques, I. Gwose, D. Seinache, K. Taras, H. Budzikiewicz, H. Schroeder, H. Ongena and P. Thonart, Nat. Prod. Lett., 1993, 3, 213 (Chem. Abstr., 1995, 122, 5030). 133 Ya-Ching Shen, J. Nat. Prod., 1995, 57, 824. 134 P. Magnus, D. Parry, T. Lliadis, S. A. Eistenbeis and R. H. Fairhurst, J. Chem. Soc., Chem. Commun., 1994, 1543. 135 P. Magnus and R. A. Fairhurst, J. Chem. Soc., Chem. Commun., 1994, 1541. 394 Natural Product Reports, 1998136 P. A. Wender, S. Beckham and J. G. O’Leary, Synthesis, 1994, 1278 (Chem. Abstr., 1995, 122, 132 830). 137 D. R. Schroeder, K. L. Colson, S. E. Klohr, N. Zein, D. R. Langley, M. S. Lee, J. A. Matson and T. W. Doyle, J. Am. Chem. Soc., 1994, 116, 9351. 138 S. A. Hilchcock, S. H. Boyer, M. Y. Chu-Moyer, S. H. Olson and S. J. Danishefsky, Angew. Chem., Int. Ed. Engl., 1994, 33, 858 (Chem. Abstr., 1994, 121, 281 023). 139 S. Chin, H. Ka, M. Kishimoto, T. Kagamizoni, A. Kawashima and K. Hanada, Jpn. Kokai Tokkyo, JP 07 25 878 (Chem. Abstr., 1995, 122, 289 044). 140 T. Kato, Y. Shizuri, M. Izumida, A. Yokoyama and M. Endo, Tetrahedron Lett., 1995, 36, 2133. 141 Y. Orii, Y. Kawamura, F. Mizobe, N. Saki and J. Hanada, Jpn. Kokai Tokkyo Koho, JP 06 256 350 (Chem. Abstr., 1995, 122, 29 880). 142 U. Graefe, R. Schlogel, K. Dornberger, W. Ihn, M. Kitzau, C. Stengel, M. Beran and W. Guenther, Nat. Prod. Lett., 1993, 3, 265 (Chem. Abstr., 1994, 121, 250 741). 143 G. Xie and J. W. Lown, Tetrahedron Lett., 1994, 35, 5555. 144 J. Bruning, T. Hache and E. Winterfeld, Synthesis, 1994, 25. 145 H. Suzuki, H. Kondo and H. Suda, Eur. Pat. Appl., EP 602 597 (Chem. Abstr., 1994, 121, 229 009). 146 J. B. McAlpine, J. P. Karwowski, M. Jackson, M. M. Mullally, J. E. Hochlowski, U. Premachandran and S. N. Burres, J. Antibiot., 1994, 47, 281 (Chem. Abstr., 1994, 121, 271). 147 A. G. M. Barrett, M. L. Boys and T. L. Bochm, J. Chem. Soc., Chem. Commun., 1994, 1881. 148 X. Lin, R. W. Kavash and P. S. Mariano, J. Am. Chem. Soc., 1994, 116, 9789. 149 M. Jaspars, V. Pasupathy and P. Crews, J. Org. Chem., 1994, 59, 3253. 150 J. Kobayashi, M. Tsuda, N. Kawasaki, K. Matsumoto and T. Adachi, Tetrahedron Lett., 1994, 35, 4383. 151 F. Kong, R. J. Andersen and T. M. Allen, Tetrahedron, 1994, 50, 6137. 152 F. Kong, R. J. Andersen and T. M. Allen, J. Am. Chem. Soc., 1994, 116, 6007. 153 T. Sakamoto, Y. Kondo, S. Sato and H. Yamanaka, Tetrahedron Lett., 1994, 35, 2919. 154 B. S. Joshi, Y. Bai, M. S. Puar, K. K. Dubose and S. W. Pelletier, J. Nat. Prod., 1994, 57, 953. 155 Y. Venkateswarlu, M. V. R. Reddy and J. V. Rao, J. Nat. Prod., 1994, 57, 1283. 156 P. N. Solis, C. Langat, M. P. Gupta, G. C. Kirby, D. C. Warhurst and J. D. Phillipson, Planta Medica, 1995, 61, 62 (Chem. Abstr., 1995, 122, 209 749). 157 S. W. Ayer, P. Thiboult, J. L. Doull and G. L. Mcinnes, PCT Int. Appl., WO 94 20 061 (Chem. Abstr., 1994, 121, 299 301). 158 F. Bracher and K. Mink, Liebigs Ann., 1995, 645 (Chem. Abstr., 1995, 122, 265 726). 159 H. Ishii, T. Ishikawa, S. Takeda, M. Mihara, K. Koyama, K. Ogata and T. Harayama, Chem. Pharm. Bull., 1991, 39, 1340. 160 L. Lavault, P. Richomme and J. Bruneton, Pharm. Acta. Helv., 1994, 68, 225 (Chem. Abstr., 1994, 121, 17 809). 161 H. Suzuki, S. Aoyagi and C. Kibayashi, Tetrahedron Lett., 1995, 36, 935. 162 A. M. Hassan, C. M. Cone, C. R. Melville and S. J. Gould, Bioorg. Med. Chem. Lett., 1995, 5, 191 (Chem. Abstr., 1995, 122, 234 933). 163 T. Izawa, S. Nishiyama and S. Yamamura, Tetrahedron, 1994, 50, 13 593. 164 E. V. Sadanandan, S. K. Pillai, M. V. Lakshmikantham, A. D. Billimoria, J. S. Culpepper and M. P. Cava, J. Org. Chem., 1995, 60, 1800. 165 H. Wang, A. H. Al-Said and J.W. Lown, Tetrahedron Lett., 1994, 35, 4085. 166 G. Gellerman, A. Rudi and Y. Kashman, Tetrahedron, 1994, 50, 12 959. 167 B. G. Szczepankiewicz and C. H. Heathcock, J. Org. Chem., 1994, 59, 3512. 168 N. Bontemps, I. Bonnard, B. Banaigs, G. Combaut and C. Francisco, Tetrahedron Lett., 1994, 35, 7023. 169 Y. Kitahara, F. Tamura and A. Kubo, Chem. Pharm. Bull., 1994, 42, 1363. 170 P. A. Searle and T. F. Molinski, J. Org. Chem., 1994, 59, 6600. 171 J. Kobayashi, S. Nakaike and T. Adachi, Jpn. Kokai Tokkyo Koho, JP 07 25 875 (Chem. Abstr., 1995, 122, 274 042). 172 T. Choshi, S. Yamada, E. Sugino, T. Kuwada and S. Hibino, Synlett, 1995, 147 (Chem. Abstr., 1995, 122, 265 140). 173 D. Uemura, T. Chou, J. Haino, A. Nagatsu, S. Eukuzawa, S. Z. Zheng and H. S. Chen, J. Am. Chem. Soc., 1995, 117, 1155. 174 C. Takahashi, A. Numata, L. Matsumura, K. Minoura, H. Eto, T. Shingu, T. Ito and T. Hasegawa, J. Antibiot., 1994, 47, 1242 (Chem. Abstr., 1995, 122, 101 236). 175 H. Hayashi, Y. Asabu, S. Murao and M. Arai, Biosci., Biotechnol., Biochem., 1995, 59, 246 (Chem. Abstr., 1995, 122, 234 943). Lewis: Muscarine, imidazole, oxazole, thiazole and peptide alkaloids, and other miscellaneous alkaloids 395

ISSN:0265-0568    

DOI:10.1039/a815371y

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Bufadienolides of plant and animal origin Pieter S. Steyn*,a and Fanie R. van Heerdenb aSASOL Centre for Chemistry, Potchefstroom University for CHE, Private Bag X6001, Potchefstroom, 2520, South Africa bDepartment of Chemistry and Biochemistry, Rand Afrikaans University, P.O. Box 524, Auckland Park 2006, South Africa Covering: January 1977 to December 1997 1 Introduction 2 Plant sources of bufadienolides 2.1 Crassulaceae 2.2 Hyacinthaceae 2.3 Iridaceae 2.4 Melianthaceae 2.5 Ranunculaceae 2.6 Santalaceae 3 Animal sources of bufadienolides 3.1 Bufo (toad) 3.2 Photinus (fireflies) 3.3 Rhabdophis (snake) 3.4 Mammalian bufadienolides/cardenolides 4 Structure determination 4.1 Nuclear magnetic resonance spectroscopy 4.2 Mass spectrometry 4.3 UV and circular dichroism 4.4 X-Ray crystallography 5 Analysis 6 Reactions and syntheses 7 Biosynthesis 8 Structure–activity relationships among cardiac glucosides 9 References 1 Introduction Bufadienolides and cardenolides are described as cardiac glycosides owing to the similarity in their biological activity, viz.the increase in the contractile force of the heart by inhibiting the enzyme Na+, K+-ATPase. The enzyme is the only receptor for the cardiac glycosides and is responsible for the active extrusion of intercellular Na+ in exchange for extracellular K+. Cardiac glycosides contain a perhydrophenanthrene nucleus substituted at C-17 with a pentadienolide and butenolide for the bufadienolides (e.g.bufalin 1) and cardenolides (e.g. digitoxigenin 2), respectively. Most of the clinical attention was directed to the cardenolides owing to their therapeutic use. Digoxin 3 and digitoxin 4 are the two most widely used digitalis inotropes; there are an estimated two million patients receiving these cardenolides in the USA.1 In review articles2 on cardiac glycosides, bufadienolides are normally grouped with the cardenolides, and only occupy a small subsection. However, drugs prepared from bufadienolidecontaining plants and toads are widely used in traditional medicine, whilst, on the other hand, bufadienolide-containing plants create a problem in agriculture in South Africa3 and Australia4 due to their toxicity to livestock. According to Kellerman and co-workers3,5 bufadienolide glycosides represent the most important cause of mortality due to plant poisoning among cattle in South Africa and it is estimated that 33% of plant-related mortality may be attributed to bufadienolides; the 12 000 heads of cattle that are killed annually by cardiac glycoside poisoning exert a negative impact on the agricultural economy of the region.5 The antineoplastic and cell growth inhibitory properties6,7 as well as the eVect on the central nervous system8,9 of several bufadienolides are also well documented.A review article on the chemistry of the bufadienolides is long overdue considering the progress made on the structural chemistry and the biological importance of these compounds.This review comprises the chemical findings for the period 1977–1997; brief reference will be made to the bufadienolides reported prior to this period since no comprehensive review on bufadienolides is available. The article will focus on bufadienolides from plants, toads, fireflies and snakes. Mammalian bufadienolides will be briefly mentioned. 2 Plant sources of bufadienolides 2.1 Crassulaceae Certain species of the Cotyledon, Tylecodon and Kalanchoe cause acute and subacute intoxication in sheep and cattle, and are of considerable economic importance in South Africa and Australia.Kalanchoe (syn. Bryophyllum) species are used in traditional medicine for the treatment of several ailments, e.g. infections, rheumatism and inflammation, and extracts of Kalanchoe have immunosuppressive eVects.10 Several of the bufadienolides isolated from the Crassulaceae also have unique biological activities.Not only do they induce the typical symptoms of cardiac poisoning, but repeated small HO H OH O O 1 1 2 3 4 5 7 10 11 9 13 8 6 12 14 15 20 21 19 16 17 18 23 24 22 R2O H OH O O 2 R1 = R2 = H 3 R1 = OH; R2 = b-D-digitoxopyranosyl-(1®4)-b-D-digitoxopyranosyl- (1®4)-b-D-digitoxopyranosyl 4 R1 = H; R2 = b-D-digitoxopyranosyl-(1®4)-b-D-digitoxopyranosyl- (1®4)-b-D-digitoxopyranosyl R1 Steyn and van Heerden: Bufadienolides of plant and animal origin 397doses also cause cotyledonosis,8,11 an intoxication aVecting the nervous and muscular systems of small animals, particularly sheep, in the Karoo area of South Africa.Five bufadienolides have been isolated from Kalanchoe daigremontiana,9 viz. daigremontianin 5, bersaldegenin 1,3,5- orthoacetate 6,12 3-O-acetyldaigredorigenin 7, 1-O -acetylbersaldegenin 8 and 3-O-acetylbersaldegenin 9.12 Compounds 5 and 6 not only exhibited the expected strong positive inotropic eVect, but also had a sedative eVect after small doses and an eVect on the central nervous system at higher doses.The induced paralysis and muscle contractions are similar to those reported for cotyledonosis. The toxic principles of Kalanchoe lanceolata have been ascribed to derivatives of hellebrigenin 10 and the structures were assigned as 3-Oacetyl- hellebrigenin, the rhamnoic acid ester of 5-O-acetylhellebrigenin (lanceotoxin A, 11) and 5-O-acetyl-3-O-·-Lrhamnosylhellebrigenin (lanceotoxin B, 12).13 Acyclic sugar derivatives are rare in nature and this is the only example of a bufadienolide glyconate. A cytotoxic compound, kalanchoside 13, was isolated from K.tomentosa, an ornamental plant from Madagascar.14 The structure of kalanchoside was assigned as 2‚-acetoxy- 3‚-(4,6-dideoxy-‚-mannopyranosyloxy)-5‚,14‚-dihydroxy-19- oxobufa-20,22-dienolide 13; the absolute configuration of the carbohydrate is arbitrarily portrayed as the D-configuration. Several Kalanchoe (syn. Bryophyllum) species were introduced into Australia and are responsible for significant cattle losses.4,15 The active principles of K.tubiflorum were isolated and characterised as bryotoxin A 14,16 bryotoxin B 1517 and bryotoxin C 16.17 Owing to problems with the separation of the compounds, bryotoxins B and C were characterised as the acetate derivatives. The aglycone of bryotoxin A 14 was identified as the 11·-hydroxy-12-keto derivative of hellebrigenin 10, and the sugar was assigned as a 3-O-acetyl-4,6- dideoxy-‚-altroside, arbitrarily portrayed as the D-con- figuration in 14.The glycoside moiety is analogous to that of kalanchoside 13. However, the structures of the carbohydrate moieties of both kalanchoside 13 and bryotoxin A 14 cannot be accepted unconditionally. Although diVerent relative stereochemistries have been assigned to these compounds, a comparison of the 1H NMR data of the carbohydrate moieties of 2*-O-acetylbryotoxin A16 and 2*,3*-di-O-acetylkalanchoside14 suggests that these two sugars may have the same relative stereochemistry.The assignments of both structures are, in part, based on a prediction of the most stable chair conformation, but do not take into account that, due to the anomeric eVect, the conformation with an axial ether substituent on C-1 is more stable than that with an equatorial substituent on C-1. Furthermore, the coupling constants observed between 1-H, 2-H and 3-H of the sugar moiety in these two compounds are closely related to those which were observed for a synthetic 6-deoxyallopyranoside derivative.18 Bryotoxin C was also isolated as a cytotoxic component from K.pinnatum and the structure confirmed by single crystal X-ray analysis.6 A second cytotoxic compound from K. pinnatum was identified as bryophyllin B19 17. Tylecodon wallichii, a succulent, is one of the major plant species associated with cotyledonosis in South Africa. The active principle was identified as cotyledoside 18,20 a glycoside in which the aglycone was doubly linked to the tetrahydropyran moiety via acetal bonds involving the C-1 and C-3 hydroxy groups of the carbohydrate. Related structures were O CHO OH O O R3O OH R1 OH O O R2O O O Me R2 R1 7 R1 = Me; R2 = H; R3 = Ac 8 R1 = CHO; R2 = Ac; R3 = H 9 R1 = CHO; R2 = H; R3 = Ac 5 R1 = O; R2 = OH 6 R1 = H2; R2 = H R2O OR1 OHC OH O O Me O O HO Me HO OH OH OH OH OH 12 R1 = Ac; R2 = 11 R1 = Ac; R2 = 10 R1 = R2 = H O OH OHC OH O O O OH OAc Me O HO 13 14 O OH OHC OH O O O OH HO Me AcO O R1 OH O O O O Me HO R2 HO OH OH O O AcO O HO 15 R1 = CH2OH; R2 = O 16 R1 = CHO; R2 = H2 17 398 Natural Product Reports, 1998assigned to tyledosides A 19, B 20, D 21, F 22 and G 23, metabolites isolated from Tylecodon grandiflorus.21 The structures of cotyledoside and the tyledosides are unique among natural compounds.The structure of tyledoside A 19 was confirmed by X-ray crystallography.22 A sixth active compound of T.grandiflorus, tyledoside C, was assigned structure 24. In contrast to the other tyledosides that are derived from 3-oxo carbohydrates, tyledoside C is derived from a 2-oxo sugar. The carbohydrate–aglycone linkage of tyledoside C is unique as far as bufadienolides are considered, but is related to that of a number of cardenolide glycosides, e.g. gomphoside23 25. It is of interest to note that the 1,3-linked glycosides 18–23 are derived from L-sugars, whereas the carbohydrate moiety of tyledoside C 24, in common with related cardenolide glycosides, has a D-configuration.Orbicuside A 26, orbicuside B 27 and orbicuside C 28, the active principles of Cotyledon orbiculata, 24 feature another interesting arrangement of the steroid– carbohydrate linkage. In this case the compounds originated from a 4,6-dideoxy carbohydrate and a 3-hydroxy-2- oxobufadienolide. 2.2 Hyacinthaceae Two genera of this family are known to produce bufadienolides, i.e.Urginea and Bowiea. A large proportion of the known bufadienolides have been isolated from Urginea species, and during the past decade many new compounds were isolated from this genus. The botanical classification of this genus is complex, and the diVerentiation between Urginea and Scilla is not always clear. Urginea maritima, commonly known as squill, is ubiquitous on the Mediterranean coast. The plant has been used in medicine since early times because of its powerful digitalis-like eVect.According to morphological, karyological and chemical investigations, U. maritima is an aggregate of at least six species, inter alia U. maritima, U. aphylla, U. hesperia, U. pancration and U. numidica. All the bufadienolides isolated from Urginea are collated in Table 1. The bufadienolides in Table 1 are mostly glycosides and are derived from scillarenin 29, proscillaridin A 30, scillaren A 31, scillicyanoside 32, scilliglaucogenin 33, scilliglaucoside 34, scilliglaucosidin 35, scilliphaeosidin 36, scilliphaeoside 37, scillirosidin 38, scilliroside 39, scillirubrosidin 40 and scillirubroside 41.The toxic principles of U. physodes were identified as two hellebrigenin derivatives, i.e. physodine A 42 and physodine B 43.25 Two nontoxic bufadienolides, physodine C 44 and physodine D 45, were also isolated from U. physodes,25 and are, apart from two epoxy derivatives from Melianthus comosus (see section 2.4), the only known plant-derived 14-deoxy bufadienolides.The lack of toxicity is clearly associated with the absence of the 14‚-hydroxy group. In the structure of rubellin 46, the toxic principle of U. rubella,26 the carbohydrate moiety is linked by two bonds to the aglycone, resulting in a structure closely related to that of cotyledoside 18. 6¢ O H OH O O O O O OMe HO Me OH O H OH O O O O O OMe Me R1 R3 R2 18 19 R1 = R2 = O; R3 = OH 20 R1 = O; R2 = H2; R3 = OH 21 R1 = b-OH,H; R2 = O; R3 = OH 22 R1 = b-OH,H; R2 = H2; R3 = OH 23 R1 = R2 = b-OH,H; R3 = H 1¢ 2¢ 3¢ 4¢ 5¢ O H OH O O O O HO O O OH Me O H OH O O OH Me AcO HO H O O 24 25 O H OH O O O O R1 O O R2 Me HO 26 R1 = O; R2 = H 27 R1 = b-OH,H; R2 = H 28 R1 = O; R2 = OH OH O O OR1 OHC OH O O RO R2 32 R1 = b-D-glucopyranosyl; R2 = OAc 33 R1 = R2 = H 34 R1 = b-D-glucopyranosyl; R2 = H 29 R = H 30 R = a-L-rhamnopyranosyl 31 R = b-D-glucopyranosyl- (1®4)-a-L-rhamnopyranosyl Steyn and van Heerden: Bufadienolides of plant and animal origin 399Table 1 Bufadienolides isolated from Urginea species Bufadienolide Urginea species 16‚-Acetoxygamabufotalin 3-O-·-L-rhamnoside30 U.aphylla,30 U. maritima31 16‚-Acetoxyglucoscillaren A32 U. maritima32 16‚-Acetoxyproscillaridin A32 U. maritima32 16‚-Acetoxyscillarenin 3-O-‚-D-glucoside32 U. maritima32 16‚-Acetoxyscillarenin 3-O-[‚-D-glucosyl-(1]4)-‚-D-glucoside]32 U. maritima32 16‚-Acetoxyscillarenin 3-O-[‚-D-glucosyl-(1]4)-‚-D-glucosyl-(1]4)-·-L-glucomethyloside]32 U.maritima32 16‚-Acetoxyscillirubroside32 U. maritima32 11-O-Acetylgamabufotalin 3-O-[‚-D-glucosyl-(1]4)-·-L-rhamnoside]33 U. maritima33 Anhydroscilliphaeosidin34 U. indica35 Arenobufagin 3-O-[‚-D-glucosyl-(1]4)-·-L-rhamnoside]36 U. pancration36 Arenobufagin 3-O-·-L-rhamnoside37 U. altissima37 10-Carboxy-5‚,14‚-dihydroxybufa-3,20,22-trienolide 5-O-‚-D-glucoside38 U. numidica38 6-Desacetoxyscillirosidin39 U. indica39 6-Desacetyl-12‚-hydroxyscilliroside32 U.maritima32 6-Desacetyl-12‚-hydroxyscillirosidin40 U. sanguinea40 6-Desacetylscilliroside33 U. maritima,32 U. numidica,41 U. pancration41 6-Desacetylscillirosidin42 U. sanguinea40 5·-4,5-Dihydro-16‚-acetoxyscillirosidin 3-O-[‚-D-glucosyl-(1]4)-·-L-thevetoside]32 U. maritima32 5·-4,5-Dihydroglucoscillaren A31 U. maritima31 5·-4,5-Dihydro-12‚-hydroxyscillirosidin40 U. sanguinea40 5·-4,5-Dihydro-12‚-hydroxyscillirosidin 3-O-[‚-D-glucosyl-(1]4)-·-L-thevetoside]43 U. maritima,32 U.pancration36 5·-4,5-Dihydro-12‚-hydroxyscillirosidin 3-O-·-L-thevetoside32 U. maritima32 5·-4,5-Dihydro-16‚-hydroxyscillirosidin 3-O-·-L-thevetoside32 U. maritima32 5·-4,5-Dihydro-19-oxoproscillaridin A31 U. maritima31 5·-4,5-Dihydroproscillaridin A31 U. maritima31 5·-4,5-Dihydroscillaren A44 U. maritima,33 U. sanguinea44 5·-4,5-Dihydroscillirosidin 3-O-·-L-glucomethyloside32 U. maritima32 5·-4,5-Dihydroscillirosidin 3-O-‚-D-glucoside32 U. maritima32 5·-4,5-Dihydroscillirosidin 3-O-[‚-D-glucosyl-(1]4)-·-L-glucomethyloside]32 U.maritima32 5·-4,5-Dihydroscillirosidin 3-O-[‚-D-glucosyl-(1]4)-‚-D-glucosyl-(1]4)-·-L-glucomethyloside]32 U. maritima32 5·-4,5-Dihydroscillirosidin 3-O-[‚-D-glucosyl-(1]4)-‚-D-glucosyl-(1]4)-·-L-rhamnoside]32 U. maritima32 5·-4,5-Dihydroscillirosidin 3-O-[‚-D-glucosyl-(1]4)-‚-D-glucosyl-(1]4)-·-L-thevetoside]30 U. maritima,32 U. aphylla30 5·-4,5-Dihydroscillirosidin 3-O-[‚-D-glucosyl-(1]4)-·-L-rhamnoside]32 U. maritima32 5·-4,5-Dihydroscillirosidin 3-O-[‚-D-glucosyl-(1]4)-·-L-thevetoside]36 U.maritima,32 U. pancration36 5·-4,5-Dihydroscillirosidin 3-O-·-L-thevetoside32 U. maritima32 12-Epiglucoscilliphaeoside38 U. numidica41 12-Episcilliphaeoside38,41 U. numidica,41 U. maritima31 12-Episcilliphaeosidin 3-O-‚-D-glucoside38 U. numidica33 12-Episcilliphaeosidin 3-O-[·-L-rhamnosyl-(1]4)-·-L-rhamnoside]38 U. numidica38 Gamabufotalin 3-O-[‚-D-glucosyl-(1]4)-·-L-rhamnoside]31 U. aphylla,30 U. maritima33 Gamabufotalin 3-O-·-L-rhamnoside45 U.aphylla,30 U. hesperia,45 U. maritima,31 U. altissima37 Glucoscillaren A45 U. maritima,32 U. pancration33 Glucoscilliphaeoside34 U. maritima,33 U. numidica33 Glucoscilliroside32 U. maritima32 Hellebrigenin46 10 U. altissima47 Hellebrigenin 3-O-‚-D-glucoside47 U. altissima47 16‚-Hydroxyglucoscillaren A32 U. maritima32 16‚-Hydroxyproscillaridin A32 U. maritima32 400 Natural Product Reports, 1998Table 1 Continued. Bufadienolide Urginea species 16‚-Hydroxyscillarenin 3-O-‚-D-glucoside32 U.maritima32 11·-Hydroxyscilliglaucoside38 U. maritima33 12‚-Hydroxyscilliglaucosidin 3-O-‚-D-glucoside38 U. numidica33 11·-Hydroxyscilliglaucosidin 3-O-·-L-rhamnoside45 U. hesperia,45 U. maritima32 9-Hydroxyscilliphaeoside48 U. maritima48 12‚-Hydroxyscilliroside30 U. aphylla,30 U. maritima,32 U. numidica,33U. sanguinea40 12‚-Hydroxyscillirosidin40 U. maritima,32 U. sanguinea40 12‚-Hydroxyscillirosidin-3-one40 U. sanguinea40 12‚-Hydroxyscillirubrosidin 3-O-·-L-rhamnoside32 U.maritima32 12‚-Hydroxyscillirubrosidin-3-one40 U. sanguinea40 Physodine A25 42 U. physodes25 Physodine B25 43 U. physodes25 Physodine C25 44 U. physodes25 Physodine D25 45 U. physodes25 Proscillaridin A50 30 U. aphylla,30 U. hesperia,45 U. indica49 U. maritima32 Rubellin26 46 U. rubella26 Scillaren A50 31 U. indica,49 U. maritima,32 U. numidica,41 U. pancration,41 U. sanguinea44 Scillarenin50 29 U. hesperia,45 U. indica49 Scillarenin 3-O-‚-D-glucoside33 U.aphylla,30 U. maritima,41 U. numidica,41 U. pancration41 Scillarenin 3-O-[‚-D-glucosyl-(1]4)-·-L-2,3-di-O-acetylrhamnoside]45 U. hesperia45 Scillarenin 3-O-[‚-D-glucosyl-(1]4)-‚-D-glucoside]32 U. maritima32 Scillarenin 3-O-[‚-D-glucosyl-(1]3)-‚-D-glucosyl-(1]4)-·-L-2,3-di-O-acetylrhamnoside]45 U. hesperia45 Scillarenin 3-O-[‚-D-glucosyl-(1]4)-‚-D-glucosyl-(1]4)-·-L-2,3-di-O-acetylrhamnoside]45 U. hesperia45 Scillarenin 3-O-[‚-D-glucosyl-(1]3)-‚-D-glucosyl-(1]4)-·-L-rhamnoside]45 U.hesperia45 Scillicyanoside51 32 U. aphylla,30 U. maritima31 Scilliglaucogenin38 33 U. numidica38 Scilliglaucoside (scillaren F)52 34 U. aphylla,30 U. maritima,31 U. numidica,41 U. pancration36 Scilliglaucosidin53 35 U. altissima47 Scilliglaucosidin-3-one47 U. altissima47 Scilliglaucosidin 3-O-‚-D-glucoside54 (Altoside) U. indica,49 U. altissima47 Scilliglaucosidin 3-O-·-L-rhamnoside47 U. altissima,47 U. indica,49 U. maritima41 Scilliphaeoside34 37 U.aphylla,30 U. hesperia,45 U. indica,49 U. maritima,32 U. numidica,41 U. pancration41 Scilliphaeosidin34 36 U. hesperia45 Scilliphaeosidin 3-O-‚-D-glucoside30 U. aphylla,30 U. maritima,32 U. numidica41 Scilliphaeosidin 3-O-[‚-D-glucosyl-(1]3)-‚-D-glucosyl-(1]4)-·-L-rhamnoside]45 U. hesperia45 Scilliphaeosidin 3-O-[‚-D-glucosyl-(1]4)-‚-D-glucosyl-(1]4)-·-L-rhamnoside]45 U. hesperia45 Scilliroside55 39 U. numidica,41 U. pancration36 Scillirosidin55 38 U. maritima,55 U.sanguinea40 Scillirubroside56 41 U. pancration,36 U. maritima56 Scillirubrosidin56 42 Scillirubrosidin 3-O-[‚-D-glucosyl-(1]4)-‚-D-glucoside]32 U. maritima32 Scillirubrosidin 3-O-[‚-D-glucosyl-(1]4)-‚-D-glucosyl-·-L-rhamnoside]32 U. maritima32 Steyn and van Heerden: Bufadienolides of plant and animal origin 401No new information has been published during this period on the bufadienolide contents of Bowiea. The known compounds from Bowiea volubilis are bovoside A27 (a 6-deoxy-3-O-methylglucoside derivative of bovogenin A 47), glucobovoside A,28 and bovoruboside (16-oxo-3-O-·-Lthevetosylhellebrigenin). 29 2.3 Iridaceae Bufadienolides were isolated from two genera of this family, i.e.Homeria and Moraea. These plants are associated with ‘tulip poisoning’ of livestock in South Africa. The active principles were identified as 1·,2·-epoxyscillirosidine57 and 1·,2·-epoxy-12‚-hydroxyscillirosidine58 from Homeria glauca, and 16‚-formyloxybovogenin A,59 16‚-hydroxybovogenin A59 and 3-dehydro-16‚-hydroxybovogenin A60 from both Moraea polystachya and Moraea graminicola. No new information on the bufadienolide content of plants of this family has been published during the period of review. 2.4 Melianthaceae Bufadienolides have been isolated from two genera of this family, i.e. Bersama and Melianthus. The investigation of the East African medicinal plant Bersama abyssinica was stimulated by the reported antitumour and insect antifeedant activity of the root bark.A number of structurally diVerent bufadienolides were isolated from this species. However, the botanical classification of this genus is complex and diYcult,61 and the plants used in the diVerent investigations might have been derived from diVerent subspecies. The metabolites reported before 1976 were mainly derivatives of hellebrigenin 10, bersaldegenin (1‚,3‚,5‚,14‚-tetrahydroxy-19-oxobufa- 20,22-dienolide) and beramagenin (1‚,3‚,5‚,14‚-tetrahydroxybufa- 20,22-dienolide).7,12,62 Bowen et al.61 could not detect these compounds in the bark of B.abyssinica subs. abyssinica and subs. paullinioides, but were able to isolate two new compounds, i.e. 3-O-acetylbufalin and 3‚,6-diacetoxy-5‚,14‚- dihydroxy-6,20,22-bufatrienolide. By using antifeedant assays, Kubo and Matsumoto63,64 were able to isolate four bufadienolides, abyssinin 48,63 abyssinol A 4964, abyssinol B 5064 and abyssinol C 5164 from B. abyssinica. These four compounds not only exhibited a strong antifeedant eVect on the cotton OHC OH O O HO OH O O RO OH 35 36 R = H 37 R = a-L-rhamnopyranosyl OH O O R1O OH R2 38 R1 = H; R2 = OAc 39 R1 = b-D-glucopyranosyl; R2 = OAc 40 R1 = R2 = H 41 R1 = b-D-glucopyranosyl; R2 = H OHC OH O O R2O OH R1 O Me HO MeO OH O HOCH2 HO O HO HO O OAc OMe Me 42 R1 = H; R2 = 43 R1 = OAc; R2 = H O O RO AcO H O HO O HO HO OH HO O HOCH2 HO O HO HO O HO Me 44 R = AcO 45 R = O Me 46 O OH O O O O OMe HO OH H OH OH O HO OHC OH O O HO H 47 402 Natural Product Reports, 1998pest insect Heliothis zea, but also showed antibacterial activity against Bacillus subtilis.65 No new information has been published on the bufadienolide contents of the Melianthus genus.The known compounds from Melianthus comosus are melianthugenin66 (syn. bersaldegenin 1,3,5-orthoacetate, 6), melianthusigenin66 (19-acetoxy derivative of melianthugenin), 6‚-acetoxymelianthugenin,67 14-deoxy-15‚,16‚-epoxymelianthugenin68 and 6‚-acetoxy-14- deoxy-15‚,16‚-epoxymelianthugenin.68 2.5 Ranunculaceae The bufadienolides of Helleborus, the only genus of this family known to contain these metabolites, are all derivatives of hellebrigenin 10, viz.hellebrin46 {3-O-[‚-D-glucopyranosyl- (1]4)-·-L-rhamnopyranosyl]hellebrigenin}, desglucohellebrin46 and 11·-hydroxydesglucohellebrin.69 The position and stereochemistry of the glycosidic bonds of hellebrin were confirmed by NMR studies.70 2.6 Santalaceae Thesium lineatum, in common with other members of the family Santalaceae, is a root parasite.This plant is responsible for sheep losses in the arid parts of South Africa, and the toxin has been identified as thesiuside (5-O-acetyl-3-O-‚-Dglucopyranosylhellebrigenin, 52).71 3 Animal sources of bufadienolides 3.1 Bufo (toad) Bufadienolides and the more polar conjugates, the bufotoxins, are present in the bodies of toads of the genus Bufo. The toad bufadienolides occur not only in the unconjugated form, but several C-3 conjugates are also known: sulfates, dicarboxylic esters and amino acid – dicarboxylic acid esters.The arginine– suberoyl esters, e.g. bufalitoxin 57, are known as the bufotoxins. There are several variations of these compounds where the suberyl ester has been replaced by succinyl 53, glutaryl 54, adipyl 55, or pimelyl 56 residues and the amino acid arginine by glutamine, histidine, 1-methylhistidine or 3-methylhistidine. The major toad bufadienolides are derivatives of the steroids 58–73.A 14-deoxy derivative 74 found in the bile of B. marinus is 1160 times less toxic than marinobufagin 66.72 14·-Artebufogenin 75 and 14‚- artebufogenin were isolated from Ch’an Su, but are considered as artefacts originated from resibufogenin 69.73,74 It has been suggested that, by virtue of their potency as digitalislike inhibitors of Na+,K+-ATPase and therefore active monovalent cation transport, bufadienolides and their derivatives may be important in sodium homeostasis in toads that migrate between fresh and salt water environments.75 The bufadienolides isolated from Bufo species are listed in Table 2. 3.2 Photinus (fireflies) An investigation into the defensive mechanisms of the fireflies Photinus pyralis, P. ignitus and P. marginellus (Coleoptera: R2 O O OR1 CHO O O AcO OH O AcO O R3 O OMe 51 48 R1 = Ac; R2 = CHO; R3 = OMe 49 R1 = R3 = H; R2 = CHO 50 R1 = H; R2 = CH2OH; R3 = OMe O OAc OHC OH O O HO O HO HOCH2 HO 52 O H OH O O (CH2) n NH HN H2N NH O O HOOC 53 n = 2 54 n = 3 55 n = 4 56 n = 5 57 n = 6 R1 H OH O O R2 HO 58 R1 = b-OH,H; R2 = O 59 R1 = b-OH,H; R2 = H,H 60 R1 = O; R2 = H,H 61 R1 = b-OH,H; R2 = O, 9,11-dehydro R2 R1 O O O R3 HO 62 R1 = CHO; R2 = OH; R3 = H 63 R1 = Me; R2 = H; R3 = OAc 64 R1 = CH2OH; R2 = H; R3 = OAc 65 R1 = Me; R2 = OH; R3 = OAc 66 R1 = Me; R2 = OH; R3 = H 67 R1 = CHO; R2 = R3 = H 68 R1 = CH2OH; R2 = R3 = H 69 R1 = Me; R2 = R3 = H Steyn and van Heerden: Bufadienolides of plant and animal origin 403Lampyridae) led to the isolation of certain compounds that render the fireflies distasteful to birds.113 Seven steroids were isolated from P.pyralis – five esters of, and the parent 2‚,5‚,11·-trihydroxy-12-oxobufalin (76–81), and the analogous 12-hydroxy-11-oxo derivative 84.114 The major component, which constituted ca. 60% of the steroid mixture, was 2‚-acetoxy-3-O-acetyl-5‚,11·-dihydroxy-12-oxobufalin 78.A bioassay showed that 81 and 84 were responsible for the activity of the extract. However, there is some doubt whether 84 is a natural product or whether it is an artefact that arose from isomerisation during isolation of the compounds. The two species P. ignitus and P. marginellus contain the same four bufadienolides (82, 83, 85, 86).115 They diVer from the compounds isolated from P. pyralis in that the 2-hydroxy function is absent. These steroids, to which the generic name lucibufagins was given, are the only insect-derived bufadienolides known.It is of interest to note that in monarch butter- flies, the compounds that render them distasteful to birds were identified as the closely related cardenolides. It was found that these cardenolides originated from the plants on which the larvae of butterflies fed.116 However, for the fireflies, Table 2 Bufadienolides isolated from Bufo species Arenobufagin76 58 Arenobufagin hemisuberate77 Arenobufagin 3-suberoyl-L-arginine ester77,78 (arenobufotoxin) Arenobufagin 3-sulfate77 Argentinogenin79 61 Bufalin80 1 Bufalin 3-adipoyl-L-arginine ester77,78 55 Bufalin hemisuberate81 Bufalin 3-pimeloyl-L-arginine ester77,78 56 Bufalin 3-suberoyl-L-arginine ester (bufalitoxin)77,78 57 Bufalin 3-succinoyl-L-arginine ester77,82 53 Bufalin 3-sulfate77,83 Bufogenin 3-hemisuberate81 Bufogenin 3-suberoyl-L-arginine ester84 Bufotalin85 70 Bufotalin 3-suberoyl-L-arginine ester77 (vulgarobufotoxin) Bufotalin 3-suberoyl-L-histidine ester86 Bufotalin 3-suberoyl-L-1-methylhistidine ester86 Bufotalin 3-suberoyl-L-3-methylhistidine ester86 Bufotalin 3-sulfate77 Bufotalinin87 62 Bufotalone85 Cinobufagin88 63 Cinobufagin 3-adipoyl-L-arginine ester77,78 Cinobufagin 3-glutaryl-L-arginine ester89 Cinobufagin hemisuberate81 Cinobufagin 3-pimeloyl-L-arginine ester77,78 Cinobufagin 3-suberoyl-L-arginine ester77,78 (cinobufotoxin) Cinobufagin 3-succinoyl-L-arginine ester77,78 Cinobufagin 3-sulfate90 Cinobufaginol91 64 Cinobufotalin92 65 Cinobufotalin 3-suberoyl-L-arginine ester77,78 (cinobufotalitoxin) Desacetylcinobufagin 3-hemisuccinate77 Desacetylcinobufagin 3-succinyl-L-arginine90 16-Desacetylcinobufaginol93 Desacetylcinobufotalin94 16-Desacetyl-19-oxocinobufotalin93 11·,19-Dihydroxytelocinobufagin95 20,21-Epoxyresibufagin96 Gamabufotalin97 59 Gamabufotalin 3-adipoyl-L-arginine ester77,98 Gamabufotalin hemisuberoate77 Gamabufotalin 3-pimeloyl-L-arginine ester77,82 Gamabufotalin 3-suberoyl-L-arginine ester77,99 (gamabufotalitoxin) Gamabufotalin 3-succinoyl-L-arginine ester77,98 Gamabufotalin 3-sulfate77 Gamabufotaliniol100 60 Hellebrigenin46 10 Hellebrigenin 3-suberoyl-L-arginine ester (hellebritoxin)101 4‚-Hydroxybufalin93 15-Hydroxybufalin93 19-Hydroxybufalin93 19-Hydroxybufalin 3-suberoyl-L-histidine ester86 19-Hydroxybufalin 3-suberoyl-L-3-methylhistidine ester86 12‚-Hydroxycinobufagin93 19-Hydroxycinobufotalin93 11·-Hydroxymarinobufagin95 19-Hydroxytelocinobufagin95 11·-Hydroxytelocinobufagin95 12‚-Hydroxytetrahydroresibufogenin 3-sulfate72 74 Marinobufagin102 66 Marinobufagin 3-glutaryl-L-arginine ester103 Marinobufagin 3-pimeloyl-L-arginine ester104 Marinobufagin 3-suberoyl-L-arginine ester104 (marinobufotoxin) Marinobufagin 3-suberoyl-L-glutamine ester105,106 Marinobufagin 3-succinoyl-L-arginine ester103 Marinobufagin 3-sulfate104 Marinoic acid107 72 Marinosin108 73 19-Oxocinobufagin109 19-Oxocinobufotalin109 Resibufagin110 67 Resibufagin 3-sulfate104 Resibufaginol111 68 Resibufogenin74 (bufogenin) 69 Resibufogenin hemisuberate81 Resibufogenin 3-succinoyl-L-arginine ester77 Resibufogenin 3-suberoyl-L-arginine ester112 (resibufotoxin) Telocinobufagin94 71 Telocinobufagin 3-glutaryl-L-arginine ester103 Telocinobufagin 3-suberoyl-L-arginine ester104 (telocinobufotoxin) Telocinobufagin 3-suberoyl-L-glutamine ester106 R1 O O OH R2 HO 70 R1 = H; R2 = OAc 71 R1 = OH; R2 = H OH OH O O O O O MeO HO HO H COOH Me O O 73 72 404 Natural Product Reports, 1998no evidence has yet been published on the origin of the bufadienolides. 3.3 Rhabdophis (snake) Apart from toads and fireflies, bufadienolides were also isolated from snakes.Snakes of the genus Rhabdophis, which are common in Japan and Southern East Asia, have a pair of special glands, known as nuchal glands, along the neck. These glands form part of the defence mechanism of the snake and it was reported that material from these glands causes severe injury when coming into contact with the eyes.Analysis of this glandular material of Rhabdophis tigrinus117 led to the isolation of nine new polyhydroxylated bufadienolides 87–95, as well as the known gamabufotalin 59. The conjugated form of gamabufotalin (the suberoyl arginine derivative) found commonly in toad venom, was not detected in the snake. No bufadienolides could be detected in other snake tissue, and it seems that the bufadienolides only accumulated in the nuchal glands.It is known that bufonid toads contain these steroids in prominent parotoid glands found behind the eyes. 3.4 Mammalian bufadienolide/cardenolides The discovery of the endorphins, endogenous ligands for opiate receptors, stimulated a renewed interest in the search for endogenous digitalis. The belief in endogenous digitalis is supported by the evolutionary conservation of the digitalis binding matrix in the receptor enzyme.Despite the considerable eVorts of a number of laboratories, a consensus on the existence, origin and chemical nature of the putative endogenous digitalis has not yet been reached.118 Several groups reported the isolation of endogenous steroidal inhibitors of Na+,K+-ATPase, and the structures proposed for these compounds are an isomer of ouabain,119 19-norbufalin (C18H32O4)120 and a dihydropyrone-substituted steroid.121 It is proposed that these compounds are, inter alia, associated with hypertension and cataract formation.120,122 4 Structure determination 4.1 Nuclear magnetic resonance spectroscopy NMR remains the single most valuable tool for the structural determination of not only bufadienolides, but steroids overall.H H O O OH OH HSO3O 74 H H O O O HO 75 OH OH O O R1O R2 O HO 76 R1 = COCHMe2; R2 = OCOMe 77 R1 = COCH2Me; R2 = OCOMe 78 R1 = COMe; R2 = OCOMe 79 R1 = COMe; R2 = OH 80 R1 = H; R2 = OCOMe 81 R1 = H; R2 = OH 82 R1 = COMe; R2 = H 83 R1 = R2 = H OH OH O O R1O R2 O OH 84 R1 = H; R2 = OH 85 R1 = COMe; R2 = H 86 R1 = R2 = H OH OH O O R1 R3 R2 R5 R4 OH O O R1 R2 OH O 87 R1 = b-OH; R2 = R4 = H; R3 = H,H; R5 = OH 88 R1 = a-OH; R2 = OH; R3 = H,H; R4 = R5 = H 89 R1 = b-OH; R2 = OH; R3 = H,H; R4 = R5 = H 90 R1 = a-OH; R2 = OH; R3 = O; R4 = R5 = H 91 R1 = b-OH; R2 = OH; R3 = O; R4 = R5 = H 92 R1 = a-OH; R2 = R4 = OH; R3 = H,H; R5 = H 93 R1 = a-OH; R2 = H 94 R1 = b-OH; R2 = H 95 R1 = b-OH; R2 = OH, D14,15 Steyn and van Heerden: Bufadienolides of plant and animal origin 405Bufadienolides are characterised by the signals of the pyrone ring: ‰H([2H6]acetone) 7.85 (dd, J 9.8 and 2.6 Hz, 22-H), 7.40 (dd, J 2.7 and 0.9 Hz, 21-H) and 6.17 (d, J 9.8 and 0.8, 23-H); ‰C([2H6]acetone) 122.1 (C-20), 149.3 (C-21), 147.0 (C-22), 114.3 (C-23) and 161.2 (C-24).20 The 13C chemical shifts of C-19 also give valuable information on the stereochemistry at C-5.In 5‚-steroids, C-19 resonates at ca.‰ 23, whereas C-19 of 5·-steroids resonates at ca. ‰ 12. Most of the publications dealing with the structure of bufadienolides contain detailed discussions of the NMR data, and a few papers deal only with the NMR assignments. The 13C NMR data of 36 bufadienolides have been collated in a review.123 The incorrect 13C NMR assignment of strophanthidin (the cardenolide analogue of hellebrigenin), published by Tori et al.124 and often wrongly used to assign 13C spectra of hellebrigenin and strophanthidin derivatives, have prompted the publication of a revised 13C NMR assignment for hellebrigenin.125 The assignments of acrihellin126 (hellebrigenin ‚-dimethylacrylate), a synthetic bufadienolide with superior pharmacological properties, and of four of the abundant toad bufadienolides (bufalin, marinobufagin, resibufagin and telocinobufagin)127 have been the topic of two papers. 4.2 Mass spectrometry The investigation by Brown et al.128 on the fragmentation of bufadienolides in EI mass spectrometry remains invaluable.Positive ion FAB mass spectra of underivatised bufadienolides and cardenolides contain information of molecular weight, the carbohydrate sequence and structural information of the aglycone. 129 In a glycerol matrix, fragmentation is observed, but the use of triethylamine–1,1,3,3-tetramethylurea as a supporting matrix resulted in the complete disappearance of all sequence ions and aglycone fragment ions.However, the latter method can be useful for purity assessment of plant glycosides. 129 Bufalin 1, resibufogenin 69 and cinobufagin 63 were detected in Ch’an Su by GC/MS (operating in the electron impact mode).130 4.3 UV and circular dichroism The UV spectra of bufadienolides are characterised by a single maximum at 298 nm (Â 5000) and a second band between 220 and 200 nm of similar intensity. Green et al.131 investigated the circular dichroism of 50 bufadienolides.In most of the bufadienolides a distinct Cotton eVect is observed around 300 nm, which corresponds to the �4]�5* transition. A second Cotton eVect, observed only as a shoulder, appears between 270 nm and 250 nm. This second Cotton eVect has been assigned to the n]�5* transition of the ·-pyrone. One or two Cotton eVects can be found at shorter wavelengths (210– 220 nm). For the 14‚-hydroxybufadienolides, both the first and the second Cotton eVects are negative, the third is positive and the fourth, if observed at all, is again negative.The CD spectra of some 22,23-dihydrobufadienolides were also investigated.132 4.4 X-Ray crystallography Table 3 lists the bufadienolides studied by X-ray crystallography during the period of review. Rohrer et al.133 found the steroid backbone of bufalin 1 to be virtually the same as that of digitoxigenin 2.134 The change of a „-lactone (digitoxigenin) to a ‰-lactone (bufalin) as the C(17) ‚-side substituent displaces the relative location of the lactone carbonyl by 1.64 Å.Nassimbeni et al.135,136 determined the structures of three bufadienolides and concluded that the conformation of the lactone ring is mainly a result of intra- and not inter-molecular interaction with packing forces contributing minimally. The crystal structures of helleborogenone 96 were determined by Ribar et al.137 to assess the influence of unsaturation on the conformation of ring A. In helleborogenone the planar ring A is transferred into a 1·,2‚ half-chair conformation of the 4,20,22-trienolide; this half-chair is trans rather than cis with respect to the fused ring B.The partial saturation of ring A is accompanied by a diVerent orientation (nearly 180)) of the lactone ring about the C(17)–C(20) bond. Argay et al.138 investigated the structures of gamabufotalin 59 and arenobufagin 58. The conformation of the 14-isoaetiocholane skeleton of gamabufotalin was found to be almost identical to that of bufalin;133 the orientation of the planar ‰-lactone diVers by 166) in these two structures.Arenobufagin 58, the 12-oxoderivative, and gamabufotalin 59 are quasi-isostructural as revealed by a comparison of their lattice parameters and atomic coordinates. The structures of bufotalin 70, cinobufotalin 65 and cinobufagin 63 were also investigated.139 The addition of a hydroxy group to C-5 in cinobufagin leads to cinobufotalin, both substances contain similar lattice parameters.The presence of the 5-OH has hardly any influence upon the conformation of the steroid and the two compounds form a quasi-isostructural pair. The formation of the 14,15‚-epoxide ring in cinobufagin prevents the development of the hydrogen bonding built up via the 14-OH in bufotalin. 14·-Artebufogenin 75 is structurally unique, the epimerisation at C-14 via the altered shape of ring D (a distorted twisted chair) considerably diplacing the lactone ring.140 Kalman et al.141 defined the ‘main-part’ isostructuralism of several cardenolides and bufadienolides, as shown by similar unit cells and a common space group P212121.It is based on the 14-isoaetiocholane skeleton and possesses a folded globular shape, as shown by the identical conformations of rings B, C and D in uzarigenin (AB-trans), scillarenin (4-dehydro) and bufalin (AB-cis).141 Tyledoside A 19 is representative of the bufadienolide glycosides with 2,4-doublylinked tetrahydropyran structures. The six-membered rings are Table 3 Bufadienolides that have been studied by X-ray crystallography 3‚-Acetoxy-15·-(o-nitrobenzoyloxy)-5‚,14‚-bufa-8,20,22-trienolide135 3‚-Acetoxy-15·-(o-nitrobenzoyloxy)-7-oxo-5‚,14‚-bufa-8,20,22- trienolide136 3-O-Acetyldaigredorigenin11 7 3-O-Acetyl-12-oxo-23-phenylsulfonyl-22,23-dihydrobufalin132 Arenobufagin138 58 14·-Artebufagin140 75 Bryotoxin C18 16 Bufalin133 1 Bufotalin139 70 Cinobufotalin139 65 Daigremontianin11 5 1,2-Dihydrohelleborogenone137 Gamabufotalin138 59 Helleborogenone137 96 3‚-Hydroxy-5‚-bufa-14,20,22-trienolide136 Proscillaridin A142 30 Telocinobufagin140 71 Tyledoside A22 19 OHC O O O OH 96 406 Natural Product Reports, 1998in the chair conformation except for ring B (half-chair) containing the 7,8-epoxide moiety, and the seven-membered ring F which is predominantly in a chair-like conformation.22 5 Analysis High performance liquid chromatography was used for the analysis of bufalin, cinobufagin and resibufogenin143 [the main constituents of Lieu-Shen-Wan (LSW), a proprietary traditional Chinese medicine]; proscillaridin A and scillaren A from extracts of Urginea maritima agg.;144 cinobufagin and its metabolites, viz.deacetylcinobufagin, 3-epideacetylbufagin, 3-deketodeactylcinobufagin, 3-epicinobufagin and 3-ketodeacetylcinobufagin in rat serum and urine;145 marinobufotoxin and cinobufotalitoxin (using „-cyclodextrin in the mobile phase);146 bufotalin and cinobufotalin (using preparative liquid chromatography and two to five recycles);147 eleven glycosides from U. maritima and the glycosides from Bulbus scilla;148 for the qualitative and quantitative determination of bufadienolides from Scilla alba and Scilla rubra.149 The analysis of cardiac glycosides (cardenolides and bufadienolides) in pharmaceuticals from plants by HPLC methods employing a diode array detection system has been described.150 6 Reactions and syntheses In this section, only reactions and partial syntheses directly related to the bufadienolides will be discussed. Other relevant steroid reactions were covered in the series ‘Steroids: Reactions and Partial Synthesis’ in this journal.151 The main diYculty encountered in the synthesis of bufadienolides, as discussed by Sondheimer152 in 1965, was building both an ·-pyrone ring and a labile 14‚-hydroxy (or epoxide) on the D-ring while keeping thermodynamically unstable confions.Thirty years later, this problem has still not been solved satisfactorily. In contrast to the cardenolides, which can be prepared eY- ciently in three steps153 from the readily available 14,15- dehydro-3,21-dihydroxypregnane,154 the synthesis of the bufadienolides still requires a long and cumbersome multi-step reaction sequence. Six approaches to the ·-pyrone ring have been published during this review period. Yoshii et al.155 used 5‚-pregn-14-en-3‚-acetate 97 as the starting material for the synthesis of resibufagin (Scheme 1).Acid-catalysed condensation of the steroid with trimethyl orthoformate, and subsequent treatment of the product with acidic methanol, yielded the ‚-methoxyvinyl ketone. Reaction of the product with dimethylsulfonium methylide, followed by hydrolysis and oxidation yielded the dehydrolactone 98. The more reactive 14,15-double bond was transformed into the epoxide via the bromohydrin. Reaction of the 20,22-enolide with bromine followed by treatment with DBU yielded 3-O-acetylresibufagin 99.In a related approach, Engel and Dionne156 also used a Michael addition to form the pyrone ring. The synthesis by Wiesner and co-workers157 started from a furan-containing intermediate 102, prepared either by the condensation of a testosterone-derived ·,‚-unsaturated ketone 100 with a lithiated derivative 101 followed by several functional group transformations, or directly from digitoxigenin 2 (Scheme 2).The endoperoxide, formed by irradiation of 102 in the presence of 5,10,15,20-tetraphenylporphyrin while O2 was bubbled through the solution, was cleaved with an excess of Me2S and the resultant unsaturated aldehyde was immediately reduced with an excess of NaBH4. Hydrolysis of the acetal gave a lactol that was oxidised to the lactone with silver carbonate. Simple adjustment of the functionalities yielded the required bufalin 1. Welzel and co-workers158 used deoxycholic acid as starting material for the syntheses of bufadienolides and cardenolides.In the key sequence, the 14‚-hydroxy function is introduced by photolytic ·-cleavage to an acyl alkyl biradical which, by hydrogen transfer reactions, forms a ‰,Â-unsaturated aldehyde 103. Reduction of the aldehyde, followed by mesylation and solvolytic ring closure yielded the 14‚-hydroxy steroid. However, this reaction sequence cannot be performed on a substrate with a pyrone ring, because the bufadienolide 2-pyrone has a UV absorption at the same wavelength as a ketone.Therefore, it was necessary to introduce the second double bond of the pyrone ring after the photolysis step (Scheme 3). Two other preparations for 14-deoxybufadienolides were also published. In the procedure of Bauer et al.,159 the key step involved the synthesis of a „-hydroxy-·,‚-unsaturated thiol ester 104 by reaction of the 1-phenylthio-1-trimethylsilylprop- 2-enyl anion with a pregnan-20-one, followed by oxidation O OMe O O O O O O O OMe O MeO O O OMe H 97 99 98 (MeO)3CH MeOH H+ 1.Me2SCH2 2. HCl, MeOH 2. Al2O3 1. BCl3 HClO4 1. NBS, H2O 2. CrO3 1. Br2 2. DBU Scheme 1 H O O O O H O O O O O O H HO O O O O O O O HO O O OH OH HO OH 100 101 102 1 1. H2, Pd/CaCO3 2. Py, SOCl2 1. Ac2O, Py 2. CaCO3 1. hn, O2 2. Me2S 1. HCl 2. Ag2CO3, Celite 3. NaBH4 1. MsCl, NEt3 2. DBU 3. NBS, H2O 4. Raney Ni + – Li+ Scheme 2 Steyn and van Heerden: Bufadienolides of plant and animal origin 407of the trianion (Scheme 4).Kabat et al.160 formed the key intermediate 105 by condensation of ethyl cyanoacetate with a 17-oxoandrostane (Scheme 5). Compound 105 was transformed in several steps into the required 14·-bufadienolide. Pettit et al.161 prepared bufalitoxin and bufotoxin, starting from bufalin. A novel approach to the synthesis of bufadienolides was recently published by Liu and Meinwald.162 It involved the palladium-catalysed coupling of 5-trimethylstannyl- 2H-pyran-2-one 107 (prepared from the readily available 5-bromo-2H-pyran-2-one163) with a 14‚-hydroxy-16- ene-17-ol triflate steroid derivative 106 to yield a bufadienolide analogue (Scheme 6).Although only an estronederived bufadienolide 108 was prepared, this method presents the most eYcient and elegant approach to natural bufadienolides. Several derivatives of bufadienolides were prepared in order to study their biological activity. Stache et al.164 prepared the 14,15‚-epoxy derivatives of scillarenin and proscillaridin A.Pettit et al.165 obtained the 8,14,20,22-tetraenolide by dehydrogenation of 14-dehydrobufalin with selenium dioxide. Albrecht166 treated scillarenin and proscillaridin A with CH2I2–Zn to yield the 4,5-methylene derivatives. Several groups reported the preparation of the pyridone analogues of bufadienolides167,168 Wiesner and co-workers169 reported the synthesis of ·-isobufalin, ‚-isoresibufogenin and „-isobufalin, bufadienolide analogues with diVerent points of attachment of the ·-pyrone ring.Diels–Alder reactions of dienophiles with the pyrone ring of bufadienolides yielded several 1,4- cycloadducts and 17-aryl derivatives.168,170 Tanase et al.171 prepared a number of bufotoxin analogues of the aglycone scillarenin. An interest in the activity of bufadienolides with abormal configuration resulted in the synthesis of 5·-cinobufagin,172 16-deacetylbufagin173 and 14·-hydroxybufotalin. 173 The photolysis of proscillaridin A and resibufogenin was investigated.174 7 Biosynthesis The biosynthetic pathway: acetic acid]mevalonic acid] isopentenyl pyrophosphate]squalene]squalene 2,3-oxide] lanosterol]cholesterol]pregnenolone is well established.175 Pregnenolone is the precursor to the cardenolides, e.g. digitoxigenin 2,176 and the plant-derived bufadienolides, e.g. hellebrigenin 10177 (Scheme 7). The conversion of pregnenolone into digitoxigenin requires the inclusion of an acetate group,178 whereas in the biogenesis of scilliroside 39, the ·-pyrone is formed by the condensation of a pregnane derivative with one molecule of oxaloacetic acid (Scheme 8).179 In experiments with toads, [1,2-3H]cholesterol, [21-14C]-5‚-cholestan-3‚-ol and [21-14C]-3‚-hydroxy-5‚-pregnan-20-one were injected into H OHC H OH O OHC H O H O H O OH O H O O O O O O O O CO2H CO2But SMe SMe SMe 5 steps 1. LiAl(OBu t)3 2.MCPBA 3. MeSO2Cl 4. (CO2H)2, H2O hn MeSCH2CO2But NaH TsOH MCPBA 1 103 Scheme 3 H O O H MeO OH SPh O H MeO OH SiMe3 SPh H OMe O SiMe3 SPh HBr sec-butyllithium O2 – 104 Scheme 4 H O O H CHO EtO2C H CH2OTHP EtO2C H OHC CH2OTHP H NC CO2Et H 105 NCCH2CO2Et AcONH4 p-TsOH 2.PCC 2. Dihydropyran, p-TsOH 1. NaBH4 3. DIBAL – 1. p-TsOH (EtO)2POCHCO2Et O Scheme 5 TBDMSO OH O SnMe3 O TBDMSO OTf OH O O + 106 107 108 Pd(PPh3)4, LiCl Scheme 6 408 Natural Product Reports, 1998Bufo arenarum, and only the compounds containing the intact cholesterol side chain were incorporated in the isolated arenobufagin.180 It was also shown that [14C]progesterone was incorporated into bufadienolides with a ƒ3 or ƒ4 double bond.Proscillaridin A was converted to scilliphaeside and scillaren A, but not into scilliglaucosidin-·-L-rhamnosides.181 Miller et al.182 recently proposed that 24-alkyl sterols rather than cholesterol could be the favoured precursors of the cardenolides in Digitalis lanata. It is of interest to note that, whereas all the Bufo steroids have the 5‚ stereochemistry, the plant toxins can be divided into three major groups: the 4,5-dehydro derivatives, the 5‚-hydroxy derivatives and the 5·-bufadienolides.The change in configuration at C-5 in the plant-derived bufadienolides indicates a divergent biosynthesis. In the case of cardenolide biosynthesis, Stuhlemmer and Kreis183 reported that progesterone 5‚-reductase and progesterone 5·-reductase may compete for the same substrate in Digitalis lanata.This finding may shed light on the cis and trans A–B ring junctions observed in certain cardiac glycosides. 8 Structure–activity relationship among cardiac glycosides The structures and conformations of bufadienolide and cardenolide glycosides play an important role in determining their Na+, K+-ATPase inhibitory potency.184,185 Most information is available on the cardenolides, owing to their therapeutic use. Some of the data on the cardenolides are reported to provide a better insight into the mode of the bufadienolide action.Shigei et al.186 studied the influence of substituents at C-14 and C-15 on the structure–activity relationships of cardenolides, e.g. digitoxigenin 2. Digitoxigenin had the highest potency, however, in the 14-deoxy-14‚H-series the activity was similar to that of the 14‚-hydroxy series; the 15·-hydroxy derivatives being inactive; the 14‚-hydroxy group was not indispensable for cardiotonic activity. Rohrer et al.184 reported the structural and biological analysis of ‚-D-digitoxosides, ‚-D-digitoxose acetonides and their genins.The analysis was based on the crystal structure of seven digitalis analogues and on known crystal structures of several other cardenolides. The A, B, and C rings of the steroid backbone remain conformationally invariant (A, B and C rings have the standard chair conformation), regardless of the C-3 substituent. The D rings have a great deal of conformational flexibility; D rings substituted with a planar lactone at C-17 prefer a C-14‚-envelope conformation.184 The planar lactone side chain of digitoxigenin has two low-energy orientations relative to the steroid backbone which are related by a 180) rotation about the C17–C20 bond.The ‘active’ orientation for digitoxigenin has a C13–C17–C20–C22 torsion angle, �, of approximately 76). The conformations for the glycoside crystal structures showed the orientations about the C3–O3 bond (i.e.C2–C3–O3–C1*) of 77.2). The addition of the sugar moiety does not significantly influence the conformation of the steroid or the orientation of the C-17‚-group (butenolide). The cardenolide gomphoside187 25 contains the A–B trans junction and a glycoside moiety rigidly linked to the steroid through oxygen atoms at 2· and 3‚ of the steroid; it was used to determine the influence of conformation in cardiac glycoside activity. The 3*-axial hydroxy of the conformationally rigid sugar residue appears to be the functional group responsible for the potent inotropic activity.The conformational distribution of the glycosidic moiety was postulated to be the major determinant of the biological activity of these cardenolides. The steroid aglycone provides the major part of the binding energy to the receptor, whereas the glycoside portion plays a HO H H H HO H H H O HO H H OH HO H H OH O O O O HO OHC H H OH O O HO OHC H H OH O O H OH H H Cholesterol Pregnenolone 2 Digitoxigenin 1 Bufalin 10 Hellebrigenin 47 Bovogenin Bufa arenarum Digitalis lanata Bowiea volubilis Helleborus atrorubens Scheme 7 Biogenesis of cardenolides and bufadienolides O OH –O2C O CO2 – GluO OAc OH OH O O * * * CO2H CH2COCO2H * 39 * * Scheme 8 Steyn and van Heerden: Bufadienolides of plant and animal origin 409secondary role in stabilising the cardenolide receptor complex. 187 Gomphoside has the same steroid structure as the conventional cardenolides (e.g.digitoxigenin) at the B–C and C–D ring junctions; however, its A–B ring junction is trans. Uzarigenin (5·-H) and digitoxigenin (5‚-H) have very similar inotropic activities, therefore in the inotropic test, the stereochemical diVerence has little eVect on the biological activity.188 Digitoxin, digoxin and most naturally occurring cardiac glycosides contain sugars with a ‚-D stereochemistry, the exception is ouabain, an ·-L-rhamnoside. Rathore et al.189 stereoselectively synthesised digitoxigenin ·-L-, ‚-L-, ·-D- and ‚-D-glucosides; ·-L-, ‚-L-, ·-D- and ‚-D-mannosides; and ·-Land ‚-L-rhamnosides to establish the influence of sugar stereochemistry on Na+,K+-ATPase receptor inhibitory activities.The observed activities revealed that a given sugar substituent may have a role in the binding of some glycoside stereoisomers, e.g. with ·-L- and possibly ‚-L-rhamnosides the 5*-CH3 and the 4*-OH appear to have a predominant role in binding to the Na+,K+-ATPase receptor: In the hog kidney Na+,K+-ATPase inhibition, digitoxigenin, its ·-L-rhamnoside, and ‚-L-rhamnoside had relative activities of 1, 18, and 25, respectively. In a study of 73 digitalis-like acting steroids, Schönfeld et al.190 found that the tridigitoxose side-chain at C-3 can be isoenergetically replaced by e.g.glucose, digitoxose and rhamnose indicating a remarkable degree of conformational adaptibility of the sugar binding site. An extrathermodynamic approach was used to establish the minimal structural requirement for specific and powerful receptor recognition. 5‚,14‚- Androstane-3‚,14-diol is the steroid nucleus of cardiac glycosides of the digitalis type as the minimum structure for specific receptor recognition and the key structure for introducing protein conformational change, and thus Na+,K+-ATPase inhibition.190 It was also described as the structural requirement for maximum contributions of the butenolide at C-17‚ and the sugar substituent at C-3‚-OH to the overall interaction energy.The unsubstituted butenolide, e.g. in digitoxigenin, aVorded the greatest contribution to the overall interaction energy.190 The interaction energy of 14‚-androst-4-ene-3‚,14- diol derivatives was increased through the conversion of the ‚-steroidal butenolide into the ‚-steroidal pentadienolide (ƒG)*= "9.9 kJ mol"1).190 The presence of the rhamnose had little eVect on the "ƒG)*. Schönfeld et al.190 concluded that the receptor binding site of the Na+ ,K+-ATPase for digitalis glycosides appears to be formed by an interlobal cleft, the bottom of which envelopes the butenolide side chain, and the top encompasses the sugar closest to the steroid nucleus.The depth of the cleft amounts to 20 Å calculated from the distance between the butenolide carbonyl oxygen and the C4*-OH of the sugar in the digitoxigenin–monodigitoxoside.190 Shimada et al.191 investigated the structure–activity relationship of 43 diVerent cardiac steroids having a doubly linked sugar, together with some related compounds for the inhibition of Na+,K+-ATPase from guinea pig heart.The doubly linked glycosides showed higher activities than the respective genins. In case of ring C substituted cardiac steroids, e.g. the bufadienolides arenobufagin and ÿ-bufarenogin, the 11-hydroxy 12-oxo groups showed a much higher activity than the 11,12-ketol. L-Rhamnose is known to substantially increase the cardiotonic activity of aglycones, e.g.scilliglaucosidin-·-Lrhamnoside was three times more active than the genin, whereas the corresponding glucoside, scilliglaucosidin-‚-Dglucoside, showed no marked inhibitory eVect.191 34 Bufadienolides and two related cardenolides were evaluated in vitro against a series of rhinoviruses.192 Scillarenin 29 and 3-O-[N-(tert-butoxycarbonyl)hydrazido]succinylbufalin were the most active with chemotherapeutic indices (CI) of 32 and 16, respectively. The 14‚-hydroxybufadienolides e.g.bufalin 1 showed the strongest antiviral activity and were found to be more toxic than the corresponding 14‚,15‚- epoxybufadienolides, e.g. resibufogenin 60.192 Takechi et al.193 compared the antiviral, cytotoxic and anti-ATPase activities of 14 synthetic bufalyl glycosides and found a high degree of correlation among the three activities. Weiland et al.194 determined the association Kon and the dissociation rate constants KoV and the equilibrium dissociation constant KD* of A–B trans cardenolides (uzarigenin and gomphogenin derivatives) and A–B cis cardenolides (digitoxigenin derivatives) with Na+,K+-ATPase isoforms.The conversion of an A–B trans into an A–B cis ring junction considerably increased the inhibitory potcies of the aglycones. In the A–B trans epimer series the rhamnosyl chain eVects only a small increase in potency, whereas the glucosyl chain causes a strong drop of potency. In the A–B cis epimer series both the rhamnosyl and glucosyl chain appear to perfectly circumscribe the sphere of the sugar binding subsite of both isoforms. The interpretation supports earlier findings that the equatorial 4*-OH, and not the 3*-OH is common to all potent cardenolides.195 Acetylation of the 2·-OH group in gomphogenin increased its binding aYnity by 15-fold and the 3-O-acetylation of gomphogenin increased the aYnity twofold.Acetylation of the 4*-OH or 3*,4*-dihydroxy of gomphoside 25, instead reduced the high aYnity of gomphoside towards Na+,K+-ATPase.196 Van der Walt et al.197 investigated the eVects of the cardiotoxic (non-cumulative) bufadienolides (thesiuside 52 and tyledoside C 24) and neurotoxic (cumulative): bufadienolides (lanceotoxin B 12 and tyledoside F 22) on the Na+,K+ pump current (Ip) in cardiac and dorsal root ganglion cells and on Ca2+ currents in cardiomyocytes.The phenomena related to pump inhibition, as hypercontracture and increase in T-type Ca2+ current in cardiomyocytes, were influenced to the same extent.Therefore, the apparent neurotoxicity of lanceotoxin B and of tyledoside F could not be explained by diVerences in the Na+,K+ pump activity. The reported cumulative and noncumulative properties of the bufadienolides are neither evident from an inspection of their structures. The diVerences in their distribution and accumulation in the nervous system may play a role in the cardio- and neuro-toxic properties.In conclusion, the structure requirements for activity of the bufadienolides seem to be very similar to that of the cardenolides, although much less comparative information is available on the biological activity of the bufadienolides. The 5‚,14‚- androstane-3‚,14‚-diol containing the 17‚ lactone (butenolide or ·-pyrone) is the optimal steroid nucleus for both cardenolides and bufadienolides to induce the Na+,K+-ATPase inhibition. 9 References 1 K. R. H. Repke and R.Megges, Expert Opin.Ther. Patents, 1997, 7, 1. 2 D. Deepak, S. Srivastava, N. K. Khare and A. Khare, Fortschr. Chem. Org. Naturst., 1996, 69, 71; R. H. Ode, G. R. Pettit and Y. Kamano, Int. Rev. Sci., Org. Chem. Ser. Two, 1976, 8, 145. 3 T. S. Kellerman, J. A. W. Coetzer and T. W. Naudé, Plant Poisonings and Mycotoxicoses of Livestock in Southern Africa, Oxford University Press, Cape Town, 1988, pp. 99–105. 4 R. A. McKenzie, F. P. Franke and P. J. Dunster, Aust. Vet. J., 1987, 64, 298. 5 T. S. Kellerman, T. W. Naudé and N. Fourie, Onderstepoort J. Vet. Res., 1996, 63, 65, and references cited therein. 6 T. Yamagishi, X.-Z. Yan, R.-Y. Wu, D. R. McPhail, A. T. McPhail and K.-H. Lee, Chem. Pharm. Bull., 1988, 36, 1615. 7 S. M. Kupchan, I. Ognyanov and J. L. Moniot, Bioorg. Chem., 1971, 1, 13. 8 T. W. Naude and R. A. Schultz, Onderstepoort J. Vet. Res., 1982, 49, 247. 9 H. Wagner, M. Fischer and H. Lotter, Z. Naturforsch., Teil B, 1985, 40, 1226; H. Wagner, M.Fischer and H. Lotter, Planta Med., 1985, 169; H. Wagner, H. Lotter and M. Fischer, Helv. Chim. Acta, 1986, 69, 359. 10 S. S. Costa, A. Jossang and B. Bodo, J. Nat. Prod., 1996, 59, 327; B. Rossi-Bergmann, S. S. Costa, M. B. S. Borges, S. A. da Silva, G. R. Noleto, M. L. M. Souza and V. L. G. Moraes, Phytotherapy Res., 1994, 8, 399. 410 Natural Product Reports, 199811 T. W. Naude, J. S. Afr. Biol. Soc., 1977, 18, 7. 12 First isolated from Bersama abyssinica: S. M.Kupchan and I. Ognyanov, Tetrahedron Lett., 1969, 1709. 13 L. A. P. Anderson, P. S. Steyn and F. R. van Heerden, J. Chem. Soc., Perkin Trans. 1, 1984, 1573. 14 P. Rasoanaivo, C. GaleY, G. Multari, M. Nicoletti and L. Capolongo, Gazz. Chim. Ital., 1993, 123, 539. 15 H. Friedrich and E. Krüger, Dtsch. Apoth. Ztg., 1968, 108, 1273; R. A. McKenzie, F. P. Franke and P. J. Dunster, Aust. Vet. J., 1989, 66, 374. 16 R. J. Capon, J. K. MacLeod and P. B. Oelrichs, J. Chem. Res. (S), 1985, 333. 17 R. J. Capon, J. K. MacLeod and P. B. Oelrichs, Aust. J. Chem., 1986, 39, 1711. 18 F. R. van Heerden, J. T. Dixon and C. W. Holzapfel, Synth. Commun., in the press. 19 T. Yamagishi, M. Haruna, X.-Z. Yan, J.-J. Chang and K.-H. Lee, J. Nat. Prod., 1989, 52, 1071. 20 P. S. Steyn, F. R. van Heerden and A. J. van Wyk, J. Chem. Soc., Perkin Trans. 1, 1984, 965. 21 P. S. Steyn, F. R. van Heerden, R. Vleggaar and L. A. P. Anderson, J. Chem. Soc., Perkin Trans. 1, 1986, 429. 22 J.L. M. Dillen, F. R. van Heerden, P. H. van Rooyen and R. Vleggaar, J. Chem. Res. (S), 1993, 74. 23 R. G. Coombe and T. R. Watson, Aust. J. Chem., 1964, 17, 92; H. T. A. Cheung and T. R. Watson, J. Chem. Soc., Perkin Trans. 1, 1980, 2162. 24 P. S. Steyn, F. R. van Heerden, R. Vleggaar and L. A. P. Anderson, J. Chem. Soc., Perkin Trans. 1, 1986, 1633. 25 F. R. van Heerden, R. Vleggaar and L. A. P. Anderson, S. Afr. J. Chem., 1988, 41, 145. 26 P. S. Steyn, F. R. van Heerden and R.Vleggaar, S. Afr. J. Chem., 1986, 39, 143. 27 A. Katz, Helv. Chim. Acta, 1953, 36, 1344. 28 R. Tschesche, S. Goenechea and G. Snatzke, Ann., 1964, 674, 176. 29 R. Tschesche and U. Dölberg, Chem. Ber., 1958, 91, 2512. 30 L. Krenn, B. Kopp, E. Griesmayer-Camus and W. Kubelka, Sci. Pharm., 1992, 60, 65. 31 L. Krenn, R. Ferth, W. Robien and B. Kopp, Planta Med., 1991, 57, 560. 32 B. Kopp, L. Krenn, M. Draxler, A. Hoyer, R. Terkola, P. Vallaster and W. Robien, Phytochemistry, 1996, 42, 513. 33 L. Krenn, B. Kopp, M. Fernandez, A. Macal, U. Macherndl, A. Steinlechner, E. A. Aboutabl and W. Kubelka, Sci. Pharm., 1996, 64, 511. 34 A. von Wartburg, M. Kuhn and K. Huber, Helv. Chim. Acta, 1968, 51 1317. 35 S. Jha and S. Sen, Phytochemistry, 1981, 20, 524. 36 B. Kopp, M. Unterluggauer, W. Robien and W. Kubelka, Planta Med., 1990, 56, 193. 37 E. Dagne, W. Mammo, M. Alemu and I. Casser, Bull. Chem. Soc. Ethiop., 1994, 8, 85. 38 L. Krenn, B. Kopp, A. Deim,W. Robien and W.Kubelka, Planta Med., 1994, 60, 63. 39 V. K. Saxena and P. K. Chaturvedi, J. Inst. Chem. (India) 1992, 64, 35. 40 L. Krenn, B. Kopp, M. Bamberger, E. Brustmann and W. Kubelka, Nat. Prod. Lett., 1993, 3, 139. 41 B. Kopp, Sci. Pharm., 1983, 51, 238. 42 A. J. Verbiscar, J. Patel, T. F. Banigan and R. A. Schatz, J. Agric. Food Chem., 1986, 34, 973. 43 L. Krenn, M. Bamberger and B. Kopp, Planta Med., 1992, 58, 284. 44 R. R. T. Majinda, R. D. Waigh and P. G. Waterman, Planta Med., 1997, 63, 188. 45 L. Krenn, M. Jambrits and B. Kopp, Planta Med., 1988, 227. 46 J. Schmutz, Helv. Chim. Acta, 1949, 32, 1442. 47 K. Shimada, E. Umezawa, T. Nambara and S. M. Kupchan, Chem. Pharm. Bull., 1979, 27, 3111. 48 L. Krenn, B. Kopp, S. Steurer and M. Schubert-Zsilavecz, J. Nat. Prod., 1996, 59, 612. 49 B. Kopp and M. Danner, Sci. Pharm., 1983, 51, 227. 50 A. Stoll, J. Renz and A. Brack, Helv. Chim. Acta, 1952, 35, 1934. 51 H. Lichti, P. Niklaus and A. von Wartburg, Helv.Chim. Acta, 1973, 56, 2088. 52 H. Lichti, P. Niklaus and A. von Wartburg, Helv. Chim. Acta, 1973, 56, 2083. 53 A. Stoll, A. von Wartburg and J. Renz, Helv. Chim. Acta, 1953, 36, 1531. 54 H. Lichti and A. von Wartburg, Helv. Chim. Acta, 1960, 43, 1666. 55 A. von Wartburg and J. Renz, Helv. Chim. Acta, 1959, 42, 1620. 56 A. von Wartburg, Helv. Chim. Acta, 1966, 49, 30. 57 P. R. Enslin, T. W. Naudé, D. J. J. Potgieter and A. J. van Wyk, Tetrahedron, 1966, 22, 3213. 58 A. J.van Wyk and P. R. Enslin, J. S. Afr. Chem. Inst., 1969, 22, 186. 59 A. J. van Wyk and P. R. Enslin, J. S. Afr. Chem. Inst., 1968, 21, 33. 60 A. J. van Wyk, J. S. Afr. Chem. Inst., 1972, 25, 82. 61 I. H. Bowen, B. P. Jackson and H. M. I. Motawe, Planta Med., 1985, 483. 62 S. M. Kupchan, R. J. Hemingway and J. C. Hemingway, Tetrahedron Lett., 1968, 149; S. M. Kupchan, R. J. Hemingway and J. C. Hemingway, J. Org. Chem., 1969, 34, 3894; S. M. Kupchan, J. L. Moniot, C. W. Sigel and R.J. Hemingway, J. Org. Chem., 1971, 36, 2611. 63 I. Kubo and T. Matsumoto, Tetrahedron Lett., 1984, 25, 4601. 64 I. Kubo and T. Matsumoto, ACS Symp. Ser., 1985, 276, 183. 65 M. Taniguchi and I. Kubo, J. Nat. Prod., 1993, 56, 1539. 66 L. A. P. Anderson and J. M. Koekemoer, J. S. Afr. Chem. Inst., 1969, 22, 191. 67 J. M. Koekemoer, L. A. P. Anderson and K. G. R. Pachler, J. S. Afr. Chem. Inst., 1970, 23, 146. 68 J. M. Koekemoer, L. A. P. Anderson and K. G. R. Pachler, J. S. Afr.Chem. Inst., 1971, 24, 75. 69 B. Kissmer and M. Wichtl, Planta Med., 1986, 152. 70 P. Muhr, F. Kerek, D. Dreveny, W. Likussar and M. Schubert- Zsilavecz, Liebigs Ann., 1995, 443. 71 F. R. van Heerden, R. Vleggaar and L. A. P. Anderson, S. Afr. J. Chem., 1988, 41, 39. 72 S.-S. Lee, F. Derguini, R. C. Bruening, K. Nakanishi, E. T. Wallick, T. Akizawa, C. S. Rosenbaum and V. P. Butler, Heterocycles, 1994, 39, 669. 73 Y. Kamano, S. Kumon, T. Arai and M. Komatsu, Chem. Pharm. Bull., 1973, 21, 1960. 74 H. Linde and K. Meyer, Helv. Chim. Acta, 1959, 42, 807. 75 J. Flier, M. W. Edwards, J. W. Daly and C. W. Myers, Science, 1980, 208, 503. 76 P. Hofer, H. Linde and K. Meyer, Helv. Chim. Acta, 1960, 43, 1950. 77 K. Shimada, Y. Fujii, E. Yamashita, Y. Niizaki, Y. Sato and T. Nambara, Chem. Pharm. Bull., 1977, 25, 714. 78 K. Shimada, Y. Sato, Y. Fujii and T. Nambara, Chem. Pharm. Bull., 1976, 24, 1118. 79 R. Rees, O. Schindler, V. Deulofeu and T. Reichstein, Helv.Chim. Acta, 1959, 42, 2400. 80 K. Meyer, Helv. Chim. Acta, 1949, 32, 1238. 81 Y. Kamano, H. Yamamoto, Y. Tanaka and M. Komatsu, Tetrahedron Lett., 1968, 5673. 82 K. Shimada, Y. Fujii, Y. Niizaki and T. Nambara, Tetrahedron Lett., 1975, 653. 83 K. Shimada, Y. Fujii and T. Nambara, Tetrahedron Lett., 1974, 2767. 84 H. O. Linde-Tempel, Helv. Chim. Acta, 1970, 53, 2188. 85 K. Meyer, Helv. Chim. Acta, 1949, 32, 1993. 86 K. Shimada, K. Ohishi and T. Nambara, Chem. Pharm. Bull., 1984, 32, 4396; K.Shimada, K. Ohishi and T. Nambara, Tetrahedron Lett., 1984, 25, 551. 87 E. Iseli, M. Kotake, E. Weiss and T. Reichstein, Helv. Chim. Acta, 1965, 48, 1093. 88 P. Hofer, H. Linde and K. Meyer, Helv. Chim. Acta, 1960, 43, 1955. 89 K. Shimada, J. S. Ro, K. Ohishi and T. Nambara, Chem. Pharm. Bull., 1985, 33, 2767. 90 K. Shimada, J. S. Ro, C. Kanno and T. Nambara, Chem. Pharm. Bull., 1987, 35, 4996. 91 H. Linde, P. Hofer and K. Meyer, Helv. Chim. Acta, 1966, 49, 1243. 92 F. Bernoulli, H. Linde and K. Meyer, Helv. Chim. Acta, 1962, 45, 240. 93 J.-P. Ruckstuhl and K. Meyer, Helv. Chim. Acta, 1957, 40, 1270. 94 N. Höriger, D. Zivanov, H. H. A. Linde and K. Meyer, Helv. Chim. Acta, 1972, 55, 2549. 95 T. Akizawa, T. Mukai, M. Matsukawa, M. Yoshioka, J. F. Morris and V. P. Butler, Chem. Pharm. Bull., 1994, 42, 754. 96 N. Kaneda, T. Kuraishi and K. Yamasaki, Chem. Pharm. Bull., 1981, 29, 257. 97 K. Meyer, Helv. Chim. Acta, 1949, 32, 1599. 98 K. Shimada, Y.Fujii and T. Nambara, Chem. Ind. (London), 1974, 983. Steyn and van Heerden: Bufadienolides of plant and animal origin 41199 K. Shimada, Y. Fujii, E. Mitsuishi and T. Nambara, Chem. Ind. (London), 1974, 342. 100 H. H. A. Linde and F. Löhrer, Pharm. Acta Helv., 1991, 66, 98. 101 K. Shimada, N. Ishii and T. Nambara, Chem. Pharm. Bull., 1986, 34, 3454. 102 H. Schröter, R. Rees and K. Meyer, Helv. Chim. Acta, 1959, 42, 1385. 103 K. Shimada, Y. Sato and T. Nambara, Chem.Pharm. Bull., 1987, 35, 2300. 104 K. Shimada and T. Nambara, Chem. Pharm. Bull., 1979, 27, 1881. 105 K. Shimada and T. Nambara, Tetrahedron Lett., 1979, 163. 106 K. Shimada and T. Nambara, Chem. Pharm. Bull., 1980, 28, 1559. 107 M. Matsukawa, T. Akizawa, J. F. Morris, V. P. Butler and M. Yoshioka, Chem. Pharm. Bull., 1996, 44, 255. 108 M. Matsukawa, T. Akizawa, M. Ohigashi, J. F. Morris, V. P. Butler and M. Yoshioka, Chem. Pharm. Bull., 1997, 45, 249. 109 N. Höriger, H. H.A. Linde and K. Meyer, Helv. Chim. Acta, 1969, 52, 1097. 110 Y. Kamano, K. Hatayama, M. Shinohara and M. Komatsu, Chem. Pharm. Bull., 1971, 19, 2478. 111 H. H. A. Linde and F. Löhrer, Pharm. Acta Helv., 1992, 67, 2. 112 K. Shimada, K. Ohishi and T. Nambara, J. Nat. Prod., 1985, 48, 159. 113 T. Eisner, D. F. Wiemer, L. W. Haynes and J. Meinwald, Proc. Natl. Acad. Sci. USA, 1978, 75, 905. 114 J. Meinwald, D. F. Wiemer and T. Eisner, J. Am. Chem. Soc., 1979, 101, 3055; M. A. Goetz, J. Meinwald and T.Eisner, Experientia, 1981, 37, 679. 115 M. Goetz, D. F. Wiemer, L. W. Haynes, J. Meinwald and T. Eisner, Helv. Chim. Acta, 1979, 62, 1396. 116 F. Eggenberger and M. Rowell-Rahier, J. Insect. Physiol., 1993, 39, 751, and references cited therein. 117 T. Akizawa, T. Yasuhara, R. Kano and T. Nakajima, Biomed. Res., 1985, 6, 437; H. Azuma, S. Sekizaki, T. Akizawa, T. Yasuhara and T. Nakajima, J. Pharm. Pharmacol., 1986, 38, 388. 118 K. R. H. Repke, K. J.Sweadner, J. Weiland, R. Megges and R. Schön, Prog. Drug. Res., 1996, 47, 9 and references therein. 119 A. A. Tymiak, J. A. Norman, M. Bolgar, G. C. DoDonato, H. Lee, W. L. Parker, L.-C. Lo, N. Berova, K. Nakanishi, E. Haber and G. T. Haupert, Proc. Natl. Acad. Sci. USA, 1993, 90, 8189. 120 D. Lichtstein, I. Gati, S. Samuelov, D. Berson, Y. Rozenman, L. Landau and J. Deitsch, Eur. J. Biochem., 1993, 216, 261. 121 P. J. Hilton, R. W. White, G. A. Lord, G. V. Garner, D. B. Gordon, M.J. Hilton, L. G. Forni, W. Mckinnon, F. M. D. Ismail, M. Keenan, K. Jones and W. E. Morden, Lancet, 1996, 348, 303. 122 K. Yamada, A. Goto, C. Hui, N. Yagi, H. Nagoshi, M. Sasabe and T. Sugimoto, Am. J. Physiol., 1994, 266, H1357. 123 W. Robien, B. Kopp, D. Schabl and H. Schwarz, Prog. Nucl. Magn. Reson. Spectrosc., 1987, 19, 131. 124 K. Tori, H. Ishii, Z. W. Wolkowski, C. Chachaty, M. Sangare, F. Piriou and G. Lukacs, Tetrahedron Lett., 1973, 1077. 125 F. R. van Heerden and R.Vleggaar, Magn. Reson. Chem., 1988, 26, 464. 126 A. Müller, G. Nonnenmacher, B. Kutscher and J. Engel, Magn. Reson. Chem., 1991, 29, 18. 127 W. F. Reynolds, A. Maxwell, B. Telang, K. Bedaise and G. Ramcharan, Magn. Reson. Chem., 1995, 33, 412. 128 P. Brown, Y. Kamano and G. R. Pettit, Org. Mass Spectrom., 1972, 6, 47. 129 G. Allmaier and E. R. Schmid, Mikrochim. Acta, 1986, 179. 130 T. L. Barry, G. Petzinger and S. W. Zito, J. Forensic Sci., 1996, 41, 1068. 131 B. Green, F.Snatzke, G. Snatzke, G. R. Pettit, Y. Kamano and M. L. Niven, Croatia Chem. Acta, 1985, 58, 371. 132 U. Werner, H.-W. Hoppe, P. Welzel, G. Schnatzke and R. Boese, Tetrahedron, 1989, 45, 1703. 133 D. C. Rohrer, D. S. Fullerton, E. Kitatsuji, T. Nambara and E. Yoshii, Acta Crystallogr., 1982, B38, 1865. 134 I. L. Karle and J. Karle, Acta Crystallogr., 1969, B25, 434. 135 L. R. Nassimbeni, M. L. Niven, G. R. Pettit, Y. Kamano, M. Inoue and J. J. Einck, Acta Crystallogr., 1982, B38, 2163. 136 L. R. Nassimbeni, M. L. Niven, G. M. Sheldrick, G. R. Pettit, M. Inoue and Y. Kamano, Acta Crystallogr., 1983, C39, 801. 137 B. Ribar, G. Argay, A. Kalman, S. Vladimirov and D. Zivanov- Stakic, J. Chem. Res. (S), 1983, 90. 138 G. Argay, A. Kalman, B. Ribar, S. Vladimirov and D. Zivanov- Stakic, Acta Crystallogr., 1987, C43, 922. 139 A. Kalman, V. Fülöp, G. Argay, B. Ribar, D. Lazar, D. Zivanov- Stakic and S. Vladimirov, Acta Crystallogr., 1988, C44, 1634. 140 G. Argay, A.Kalman, B. Ribar, D. Zivanov-Stakic and S. Vladimirov, Acta Crystallogr., 1992, C48, 1823 and references cited therein. 141 A. Kalman, G. Argay, D. Scharfenberg-PfeiVer, E. Höhne and B. Ribar, Acta Crystallogr., 1991, B47, 68. 142 H. Wiedenfeld, F. Knoch, I. Naidis and B. Kopp, Sci. Pharm., 1987, 55, 167. 143 Z. Hong, K. Chan and H. W. Yeung, J. Pharm. Pharmacol., 1992, 44, 1023; M. Okamoto, Chromatographia, 1988, 26, 145; M. Okamoto, J. Chromatogr., 1991, 552, 381. 144 B. Kopp, L. Krenn and J. Jurenitsch, Dtsch. Apoth. Zeit., 1990, 130, 2175. 145 L. Zhang, K. Aoki, T. Yoshida and Y. Kuroiwa, J. Liq. Chromatogr., 1990, 13, 3515. 146 K. Shimada, Y. Kurata and T. Oe, J. Liq. Chromatogr., 1990, 13, 493. 147 M. Inoue, Y. Kamano, G. R. Pettit and C. R. Smith, J. Liq. Chromatogr., 1987, 10, 2453. 148 H. Kirchner, J. Jurentisch andW. Kubelka, Sci. Pharm., 1981, 49, 281. 149 G. Tittel and H. Wagner, Planta Med., 1980, 39, 125. 150 G. Tittel, Anal. Chem.Symp. Ser., 1985, 23, 485. 151 J. R. Hanson, Nat. Prod. Rep., 1996, 13, 227, and references therein. 152 F. Sondheimer, Chem. Br., 1965, 454. 153 F. Bonadies, A. Cardilli, A. Lattanzi, S. Pesci and A. Scettri, Tetrahedron Lett,, 1995, 36, 2839. 154 L. Simbi and F. R. van Heerden, J. Chem. Soc., Perkin Trans. 1, 1997, 269, and references therein. 155 E. Yoshii, T. Oribe, T. Koizumi, I. Hayashi and K. Tumura, Chem. Pharm. Bull., 1977, 25, 2249. 156 C. R. Engel and G. Dionne, Can.J. Chem., 1978, 56, 424. 157 T. Y. R. Tsai and K. Wiesner, Can. J. Chem., 1982, 60, 2161; A. Sen, F. J. Jäggi, T. Y. R. Tsai and K. Wiesner, J. Chem. Soc., Chem. Commun., 1982, 1213; K. Wiesner, T. Y. R. Tsai, A. Sen, R. Kumar and M. Tsubuki, Helv. Chim. Acta, 1983, 66, 2632. 158 P. Welzel, B. Janssen, H. Stein, T. Milkowa, H.-W. Hoppe, U. Werner, U. Möller, B. Stammen, D. Böttger, A. Ponty, M. Kaiser, P. Wagner and D. Müller, in Trends in Medicinal Chemistry ’90. Proc. Int.Symp. Med. Chem., ed. S. Shalom, R. Mechoulam and I. Agranat, Blackwell, Oxford, 1992, Vol 11, pp. 277; H.-W. Hoppe and P. Welzel, Tetrahedron Lett., 1986, 27, 2459; H.-W. Hoppe, M. Kaiser, D. Müller and P. Welzel, Tetrahedron, 1987, 43, 2045; H.-W. Hoppe, B. Stammen, U. Werner, H. Stein and P. Welzel, Tetrahedron, 1989, 45, 3695. 159 P. E. Bauer, K. S. Kyler and D. S. Watt, J. Org. Chem., 1983, 48, 34. 160 M. M. Kabat, A. Kurek and J. Wicha, J. Org. Chem., 1983, 48, 4248. 161 G.R. Pettit, Y. Kamano, P. Drasar, M. Inoue and J. C. Knight, J. Org. Chem., 1987, 52, 3573. 162 Z. Liu and J. Meinwald, J. Org. Chem., 1996, 61, 6693. 163 G. Posner, K. Afarinkia and H. Dai, Org. Synth., 1994, 73, 231. 164 U. Stache, K. Radscheit, W. Haede and W. Fritsch, Liebigs Ann. Chem., 1982, 342. 165 G. R. Pettit, Y. Kamano, M. Inoue, Y. Komeichi, L. R. Nassimbeni and M. L. Niven, J. Org. Chem., 1982, 47, 1503. 166 H. P. Albrecht, Liebigs Ann. Chem., 1980, 886. 167 M.-J.Shiao, T. Y. R. Tsai and K. Wiesner, Heterocycles, 1981, 16, 1879; J. Wicha and M. Masnyk, Bull. Pol. Acad. Sci.: Chem., 1985, 33, 29. 168 J. Mori, S.-I. Nagai, J. Sakakibara, K. Takeya and Y. Hotta, Chem. Pharm. Bull., 1988, 36, 48. 169 K. Wiesner, T. Y. R. Tsai, F. J. Jäggi, C. S. J. Tsai and G. D. Gray, Helv. Chim. Acta, 1982, 65, 2049; S. Lociuro, T. Y. R. Tsai and K. Wiesner, Tetrahedron, 1988, 44, 35. 170 N. Murakami, T. Tanase, S.-I. Nagai, Y. Sato, T. Ueda, J. Sakakibara, H. Ando, Y. Hotta and K. Takeya, Chem. Pharm. Bull., 1991, 39, 1962; T. Tanase, N. Murakami, S.-I. Nagai, T. Ueda, J. Sakakibara, H. Ando, Y. Hotta and K. Takeya, Chem. Pharm. Bull., 1992, 40, 327. 171 T. Tanase, A. Nagatsu, N. Murakami, S.-I. Nagai, T. Ueda, J. Sakakibara, H. Ando, Y. Hotta, K. Takeya and M. Asano, Chem. Pharm. Bull., 1994, 42, 2256. 172 Y. Kamano, P. Drasar, G. R. Pettit and M. Tozawa, Coll. Czech. Chem. Commun., 1987, 52, 1325. 173 Y. Kamano, G. R. Pettit, M. Inoue, M. Tozawa, C. R. Smith and D. Weisleder, J. Chem. Soc., Perkin Trans. 1, 1988, 2037. 412 Natural Product Reports, 1998174 N. Murakami, T. Tanase, S.-I. Nagai, T. Ueda and J. Sakakibara, Chem. Pharm. Bull., 1991, 39, 1330; T. Tanase, N. Murakami, A. Nagatsu and J. Sakakibara, Heterocycles, 1993, 36, 1411. 175 R. B. Herbert, The Biosynthesis of Secondary Metabolites, Chapman and Hall, London, 1994, pp. 63–95. 176 R. Tschesche and G. Lilienweiss, Z. Naturforsch., Teil B, 1964, 19, 265. 177 R. Tschesche and B. Brassat, Z. Naturforsch., Teil B, 1965, 20, 707. 178 E. Caspi and G. M. Hornby, Phytochemistry, 1968, 7, 423. 179 L. R. Galagovsky, A. M. Porto, G. Burton and E. G. Gros, Z. Naturforsch., Teil C, 1983, 39, 38; L. R. Galagovsky, A. M. Porto, G. Burton, M. S. Maier, A. M. Seldes and E. G. Gros, An. Asoc. Quim. Argent., 1982, 70, 327. 180 H. M. GaraVo, G. Burton, A. M. Porto and E. G. Gros, An. Asoc. Quim. Argent., 1982, 70, 743; H. M. GarraVo and E. G. Gros, Steroids, 1986, 48, 251. 181 B. Kopp and R. Leeb, Sci. Pharm., 1983, 51, 248. 182 F. Miller, E. Reinhard and W. Kreis, Plant Physiol. Biochem., 1997, 35, 111. 183 U. Stuhlemmer and W. Kreis, Plant Physiol. Biochem., 1996, 34, 85. 184 D. C. Rohrer, M. Kihara, T. DeVo, H. Rathore, K. Ahmed, A. H. L. From and D. S. Fullerton, J. Am. Chem. Soc., 1984, 106, 8269. 185 T. W. Günther and H. H. A. Linde, in Cardiac Glycosides, ed. K GreeV, Springer Verlag, New York, 1981, pp. 13–26. 186 T. Shigei, H. Tsuru, Y. Saito and M. Okada, Experientia, 1973, 29, 449. 187 F. C. K. Chiu and T. R. Watson, J. Med. Chem., 1985, 28, 509. 188 T. R. Watson, H. T. A. Cheung and R. E. Thomas, in ‘Natural Products and Drug Development’, Alfred Benzon Symposium 20, Munksgaard, Copenhagen, 1984. 189 H. Rathore, A. H. L. From, K. Ahmed and D. S. Fullerton, J. Med. Chem., 1986, 29, 1945. 190 W. Schönfeld, J. Weiland, C. Lindig, M. Masnyk, M. M. Kabat, A. Kurek, J. Wicha and K. R. H. Repke, Naunyn-Schmiedeberg’s Arch. Pharmacol., 1985, 329, 414. 191 K. Shimada, N. Ishii, K. Ohishi, J. S. Ro and T. Nambara, J. Pharmacobio-Dyn., 1986, 9, 755, and references cited therein. 192 Y. Kamano, N. Satoh, H. Nakayoshi, G. R. Pettit and C. R. Smith, Chem. Pharm. Bull., 1988, 36, 326. 193 M. Takechi, C. Uno and Y. Tanaka, Phytochemistry, 1996, 41, 125. 194 J. Weiland, R. Schön, R. Megges, K. R. H. Repke and T. R. Watson, J. Enzyme Inhib., 1994, 8, 197 and references cited therein. 195 A. H. L. From, D. S. Fullerton and K. Ahmed, Mol. Cell. Biochem., 1990, 94, 157. 196 J. Weiland, M. Ritzau, R. Megges, R. Schön, T. R. Watson and K. R. H. Repke, Eur. J. Med. Chem., 1995, 30, 763. 197 J. J. van der Walt, J. M. van Rooyen, T. S. Kellerman, E. E. Carmeliet and F. Verdonck, Eur. J. Pharmacol., 1997, 329, 201. Steyn and van Heerden: Bufadienolides of plant and animal origin 413

ISSN:0265-0568    

DOI:10.1039/a815397y

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Book review Medicinal natural products: a biosynthetic approach Paul M. Dewick, Wiley, 1997, pp. 466. ISBN 0471 974781 According to the Shennung herbal, said to have been written in 200 BC, liquorice was good for the heart and for treating ulcers, ginseng was able to ‘brighten vision, increase intellect, and prolong life and make one feel young’, garlic was antibacterial, and ma huang (from Ephedra sinaica) was useful for bronchial conditions. A modern pharmacist would find all of these in his pharmacopoeia, and the only major change from the ancient Chinese herbal is the knowledge of the identity of the natural products that are responsible for the pharmacological properties of these plants. Paul Dewick has written his book for undergraduates in Pharmacy, so all of the medicinally important plant extracts are given prominence, but the book deserves to be widely read by chemists as well.The title is a little misleading, because he describes in detail all classes of natural products, not just those of medicinal interest.Purists will claim that he has not provided details of how the various biosynthetic pathways were elucidated. There is very little discussion of labelling experiments or of 13C NMR spectroscopy etc., and the pathways are simply presented as established fact. The coverage is, however, comprehensive. His first chapter provides an extensive introduction to the chemistry of enzyme cofactors, and of the various key processes that underpin secondary metabolism.He then launches into four large chapters on metabolites formed from acetate, mevalonate, shikimate and the alkaloids. Throughout the book, the basic biosynthetic information is complemented by specific information about pharmacologically important compounds. This is usually separated from the main text and placed in boxes. So in Chapter three, he highlights the prostanoids, senna and cascara, khellin and the origins of disodium cromoglycate (Intal), cannabinoids (including the recently discovered endogenous agent anandamide) and the antiemetic drug nabilone, macrocyclic antibiotics, brevetoxins, mevinolin, and rapamycin etc.The only area that is not covered in suYcient depth, is the current exciting work on polyketide synthases and the associated manipulation of the genes coding for these multienzyme complexes. As one would anticipate from his excellent reviews for Natural Product Reports, the chapter on shikimate metabolites is very good.The ‘boxes’ contain interesting information about, inter alia, podophyllotoxin and analogues, warfarin, psoralens, Silybum marianum in traditional medicine (as an antidote to poisoning by Amanita phalloides!), and vitamin E and aging. Paul Dewick also writes a regular review on the C5—C25 isoprenoids for this journal, and his obvious enthusiasm for this class of compounds is in much evidence in the chapter on metabolites formed from mevalonate.The ‘boxes’ contain a wealth of information about herbal extracts from valerian, feverfew, cammomile, Artemisia annua (the antimalarial agent artemisinin), liquorice and ginseng, but also include the more mainstream pharmacological agents like the sex hormones, cardiac glycosides, antiinflammatory steroids, and the clinically useful enzyme inhibitors like formestane (for aromatase) and finasteride (for 5-·-reductase). I would not want to give the impression that the biosynthetic schemes merely complement the ‘boxes’.In all of the chapters, the complex mechanistic schemes are both expertly and accurately depicted, and this feature is especially notable in the chapter on isoprenoids and the one that follows, on the alkaloids. Highlights in this latter chapter include particularly good accounts of the tropane alkaloids, curare, opium alkaloids, physostigmine, ergot alkaloids and purine alkaloids. The book concludes with two more specialised chapters on amino acid derivatives and carbohydrates, respectively.The former includes coverage of peptide hormones (not true secondary metabolites), peptide antibiotics, peptide toxins and a superb account (at this ostensibly undergraduate level) on ‚-lactam antibiotics. The chapter on carbohydrates seems a little out of place, and only provides a very basic coverage of monosaccharides, disaccharides and their polymers, almost as an excuse to discuss the aminoglycoside antibiotics. Finally, there is a useful index, and each chapter has a fairly comprehensive list of key references to the research literature, books and reviews. It must be great to be a student in Paul Dewick’s lectures, because his enthusiasm for natural products and their pharmacology is evident on every page of this book. It would be a shame if it is only purchased by students of Pharmacy, and should be considered for adoption by any department where the teaching of natural products chemistry is important. John Mann University of Reading, UK 415

ISSN:0265-0568    

DOI:10.1039/a815415y

出版商:RSC    

年代:1998

数据来源: RSC