Quinoline Quinazoline and Acridone Alkaloids J. P. Michael Department of Chemistry University of the Witwatersrand Wits 2050 South Africa ~~~ ~ Reviewing the literature published mainly between July 1988 and June 1989 (Continuing the coverage of literature in Natural Product Reports 1990 Vol. 7 p. 131) 1 Quinoline Alkaloids 1.1 Occurrence and Detection 1.2 Non- terpenoid Quinolines and Quinolinones 1.3 Prenylquinolinones and Hemiterpenoid Tricyclic Alkaloids 1.4 Sesquiterpenoid Quinoline Alkaloids 1.5 Furoquinoline Alkaloids 1.6 Dimeric Quinolinone Alkaloids 2 Quinazoline Alkaloids 3 Acridone Alkaloids 3.1 General 3.2 Occurrence and Structural Studies 3.3 Synthesis 4 References A proposal for radical revision of the taxonomy of the Rutaceae is based on careful appraisal of the wealth of published phytochemical data for numerous genera belonging to this family as well as on morphological characters.' The proponents of this revision recognize an evolutionary trend in which species containing alkaloids derived from anthranilic acid occupy an intermediate stage between those containing benzylisoquinoline alkaloids and those containing coumarins or limonoids.A significant recommendation is that the subfamily Toddalioideae be entirely dispensed with and its members relocated to the Rutoideae. A separate study of the chemical systematics of the African Toddalioideae has revealed a striking uniformity in alkaloid profiles which may in consequence offer less useful insights into phylogenetic relation- ships than limonoids do.2 1 Quinoline Alkaloids A recent supplement to Rodd's 'Chemistry of Carbon Compounds ' contains a short review of developments per- taining to the quinoline alkaloid^.^ 1.1 Occurrence and Detection Table 1 includes new quinoline and quinolinone alkaloids that have been reported during the period of coverage of this review together with known alkaloids isolated from new sources.2 4-30 Quinoline alkaloids have been reported for the first time from the genus Dictyoloma,* a discovery of taxonomic significance since there has been some doubt of the location of this genus in the Rutaceae. The most noteworthy new compound is OMe A3 haplodimerine (95),13 a dimeric quinoline alkaloid with a unique skeleton incorporating a cyclobutane ring.Synchronous fluorescence spectrometry has been used for the first time in identifying the components of a mixture of dihydrofuro- and pyrano-quinolinium alkaloids from in vitro cultures of Ruta gra~eolens.~' A further report on the variability of production of dihydrofuroquinolinium alkaloids (mainly platydesminium and balfourodinium) from tissue cultures of Choisya ternuta has been published.32 1.2 Non-terpenoid Quinolines and Quinolinones Although the widely-distributed hydroxyquinolinecarboxylic acids of the animal kingdom (kynurenic and xanthurenic acids) have generally not been included in past reports in this series a recent systematic investigation of 29 species of the fly Drosophila is worthy of mention here.All but two species contained xanthurenic acid (2a) in the head parts ;additionally ten species all of them eye-colour mutants accumulated xanthurenic acid 8-O-P-~-glucoside (2b) a side metabolite of the tryptophan-xanthommatin pathway in the eyes.33 Several simple quinolines are among the alkaloids reported in the review period from organisms other than higher plants. The presence of the zoochrome uranidine (3) was confirmed in the sponge Aplysina ~erophoba.~ The first natural source of 2- aminoquinoline (4) at impressive concentrations of about 2g per kg of fresh weight is a North American woodland mushroom Leucopaxillus albissimus var. paradoxus form a1biformis.l8 The compound has a wide spectrum of biological activity and may be responsible for the resistance of the fungus to bacterial decay.Another fungus Penicillium verrucosum var. cyclopium contains a tryptophan-derived diketopiperazine two benzodiazepinediones and the known fungal metabolite 3- O-methylviridicatin (5).'l The culture filtrate of Streptomyces OR H OH H (2a) R = H Uranidine (3) (2b) R = P-D-gtu Ph H O-Methylviridicatin (5) 53 NATURAL PRODUCT REPORTS 1991 Table 1 Isolation and detection of quinoline alkaloids Species Alkaloid (Structure) Ref. Acronychia pedunculata Dictamnine (1 R' = R2 = R3 = H) 4 Skimmianine (1 R' = H R2 = R3 = OMe) Aplysia aerophoba Araliopsis tabouensis (A. soyauxii) Uranidine (3) N-Methylpreskimmianine (13 R' = Me R2 = CH,CH=CMe, R3= OMe) Vepridimerine A (91) 5 6 Vepridimerine B (92) Vepridimerine C (93) Vepridimerine D (94) Veprisine (29) Clausena anisata *N-Methylswietinidine-B (12 R' = Me R2 = OMe) 7 Dictyoloma vandellianum Casimiroine (1 4) 4,7,8-Trimethoxy-l-methylquinolin-2-one(13 R' = R2 = H R3 = OMe) 8 Evodia gracilis (-)-Edulinine (12 R' = Me R2 = CH,CH(OH)C(OH)Me,) 9 (+)-Isoplatydesmine (36) Evodia lepta (-)-Ribahnine (37) Kokusaginine (1 R' = R2 = OMe R3 = H) 9 Skimmianine Evodia rutaecarpa *1-Methyl-2-[(Z)-6-pentadecenyl]quinolin-4-one(7)*1-Methyl-2-[(Z)-IO-pentadecenyl]quinolin-4-one(8)*1-Methyl-2-[(6Z,9Z)-6,9-pentadecadienyl]quinolin-4-one(9)*1-Methyl-2-[(4Z77Z)-4,7-tridecadienyl]quinolin-4-one (10)* l-Methyl-2-[(Z)-6-undecenyl]quinolin-4-one(1 1) 10 Glycosma pentaphylla Haplophyllum bungei *Alkaloid (30) (glycolone) Folimine (13 R' = Me.R2 = R3 = H) *Haplobunghe (13 R' = R2 = H. R3 = OMe) 11 12 4-Methoxy-2-quinolinone (12 R' = R2 = H) Haplophyllum foliosum Haplophyllum perforatum Haplophyllum ramosissimum *Haplodimerine (95) *Haplosidine (69) *Haploshine (70) Evodine (I R' = H R2 = OCH,CH(OH)C(Me)=CH, R3= OMe) Haplopine (67) Methylevoxine (1 R1= H. R2 = OCH,CH(OH)C(OMe)Me, R3 = OMe) 13 14 15 16 Robustine (1 R' = R2 = H R3 = OH) Haplophyllum tuberculatum Leucopaxillus albissimus var. Dihydroperfamine (73) *2-Aminoquinoline (4) 17 18 paradoxus form alblformus Melicope t riphy lla Kokusaginine Skimmianine 19 Murraya paniculata Penicillium verrucosum Ptelea trifoliata Edulitine (13 R' = R2= R3= H) 3-Methoxyviridicatine (5) *Ptelefolidonium (35) 20 21 22 Ruta chalepensis var.latlfolia Dictamnine Graveoline (I 5) 23 Graveolinine (1 6) Kokusaginine Sarcomelicope pembaiensis Stigmatella aurantiaca *5-Methoxydictamnine (7 1) Acronydine (74) *Aurachin E (59) 24 25 *Aurachin F (60) *Aurachin G (61) *Aurachin H (62) Streptomyces griseofulvus Teclea grandifo lia *Aurachin I(63) *3-Hydroxyquinoline-2-carboxylic acid (4) calcium salt Flindersiamine (75 R1 = H R2 = OMe) Kokusaginine Maculosidine (1 R' = R3= OMe R2 = H) 26 27 Montrifoline (1 R' = OCH,CH(OH)C(OH)Me, R2 = OMe R3 = H) Tecleamine (75 R' = H. R2 = OCH,CH=CMe,) Tecleaverdoornine (75 R' = CH2CH=CMe2 R2 = OH) Vepris dainelli Tecleine (75 R' = H R2 = OH) Kokusaginine Skimmianine 2 Vepris glomerata Ko kusaginine Skimmianine 2 Zanthoxylum austrosinense Zanthoxylum coreanum Zan t hoxy lum sarasin ii Dictamnine Skimmianine Skimmianine 28 29 30 * New alkaloids NATURAL PRODUCT REPORTS 1991-5.P. MICHAEL Me OMe OMe (13) OMe I (14) OMe griseofavus subsp. (GO 3592) was found to contain a new natural product the calcium salt of 3-hydroxyquinoline-2- carboxylic acid (6) the structure of which was deduced from its spectra and confirmed by synthesis from 3-hydroxy-2-methyl- quinoline-4-carboxylic acid.26 A reinvestigation of Evodia rutaecarpa long known as a source of 2-alkyl-4-quinolinones cf. ref. 34(a) has confirmed the presence of four known alkaloids of this type (evocarpine dihydroevocarpine 1-methyl-2-undecyl-4-quinolinoneand 1 -methyl-2-pentadecyl-4-quinolinone), and led to the isolation of five new alkaloids (7)+11) bearing unsaturated side chains.'O The structures were supported by both spectroscopic techniques and chemical degradation.The degree of unsaturation in the side chains was substantiated by catalytic hydrogenation to known compounds; while the positions of the double bonds were determined by Lemieux-Johnson oxidation with osmium tetroxide-sodium periodate and detection of the resulting aldehydes as the 2,4-dinitrophenylhydrazonederivatives. The Z geometry was deduced from the 13C NMR shifts of the allylic carbon atoms (8 25.5-27.4). Compounds (7) and (8) were inseparable and the assumed ratio of 2 3 is based on the ratio of pentanal and nonanal produced in the Lemieux-Johnson oxidation.Only carbazole alkaloids have previously been isolated from the genus Clausena but C. anisata has now been shown to produce a new quinolinone alkaloid N-methylswietinidine-B (12 R1 = Me R2 = OMe).' The UV spectrum in neutral and acidic solution a carbonyl stretch at 1630 cm-l in the infrared spectrum and a resonance at 161.2 ppm in the 13C NMR spectrum indicated the quinolin-2-one structure. The lH and 13C NMR spectra could be fully assigned. The similarity of the former to that of swietinidine-B which lacks the methyl resonance at 6 3.70 clinched the structural assignment. 4-Methoxyquinolin-2-one (12 R1 = R2 = H) has been detected for the first time in the genus Hapfophyllum.12The new alkaloid haplobungine (13 R' = R2 = H R3 = OMe) isolated from Haplophyllum bungei was shown to have the spectroscopic characteristics of other alkaloids of the 4-methoxyquinolin-2- one series.12 The substitution pattern was confirmed by comparing spectroscopic and physical properties of its N-methyl derivative with those reported in the literature.12 The isolation of the structurally similar alkaloid edulitine (robust- inine 13 R' = R2 = R3 = H) along with methyl N-methyl- anthranilate from Indonesian samples of Murraya panicufata is of chemotaxonomic interest since these and other con-stituents are absent in prenylindole-containing samples of the plant collected in Taiwan.20 The finding is perhaps indicative of two distinct chemotypes of the species.NATURAL PRODUCT REPORTS 1991 (17) VI vii b; R = CSHll 32% 1a 70% Q y H2 aR ~ bii% R a VIII 70-80% I H (20) (19) (18) Reagents i NCS cat. pyridine CHCl,,.reflux; ii phenylacetylene or 1-heptyne NEt, CHCl, reflux; iii H, Raney Ni AcOH 20 h; iv NaNO, H,SO, 0 "C to 5 "C; v H, Raney NI 45 min; vi AcC1 NEt, CHCI,; vii cat. boric acid Raney Ni MeOH-H,O; viii cat. conc. HC1 EtOH reflux; ix NaOMe MeOH reflux Scheme 1 C02Et C02Et I II Ill IV NHCOCH3 NCOCH3 I OH OR Me OR Me (23) Daurine (21) R = CH2CH=CMe2 Folidine (22) R = CHzCOCHMe2 Reagents Daurine series i prenyl bromide K,CO, acetone reflux; ii 18-crown-6 t-BuOK Mel Et,O reflux; iii t-BuOK Et,O reflux; iv CH,N, Et,&MeOH r.t.Folidine series i l-bromo-3-methylbutan-2-one, K,CO, acetone reflux then (CH,OH), Me,SiCl r.t. ;ii iii as for daurine; iv CH,N, Et,O-MeOH r.t. then conc. H,SO, acetone reflux Scheme 2 /t\ OH Fabianine (25) Reagents i pyrrolidine p-TsOH C,H, reflux; ii methyl vinyl ketone C,H, reflux; iii NH,OH-HCl EtOH 150 "C (autoclave); iv 80% H,SO, 75 "C Scheme 3 NATURAL PRODUCT REPORTS 1991-5. P. MICHAEL Kametani’s synthesis of quinolines by [4 +21 cycloaddition and the application of this approach to the synthesis of some simple 2-substituted quinoline alkaloids has been reviewed.35 A synthetic approach to 2-substituted 4-quinolinones exploits the dipolar cycloaddition of o-nitrobenzonitrile oxide to appropriately substituted terminal alkynes (Scheme l).36 Cata- lytic reduction of the adducts (17) was initially at the nitro group after which the isoxazole ring was cleaved by hydro- genolysis.The intermediate vinylogous amides (18 X = H) isolable as the acetanilides (18 X = COCH,) underwent cyclization to 4-aminoquinolines (19) faster than they under- went hydrolysis necessitating the completion of the syntheses of the alkaloids (20 R = Ph and pentyl) by diazotization of (19). The acetanilides (18 X = COCH,) were also fortuitously found to undergo acid-or base-induced cyclization and deacylation to give 2,4-dimethylquinazoline an alkaloid of Pseudomonas species. The structures of the alkaloids daurine (21) and folidine (22) previously inferred from spectroscopic data cf.refs. 37(a) (b) have now been confirmed by synthesis from ethyl 3-hydroxy- anthranilate (23) (Scheme 2).38 The 8-alkoxy groups that distinguish the two alkaloids were introduced comparatively early in the synthesis. In the case of daurine base-promoted N-methylation of the prenyl ether of (23) followed by base- induced cyclization and O-methylation with diazomethane gave the alkaloid (21) in 18% overall yield from 3-hydroxy- anthranilic acid. For folidine additional protection and deprotection steps were necessary for the ketonic group in the side chain and an overall yield of 10% was obtained. (+)-Pulegone (24) was the starting material for a short synthesis of fabianine (25) the principal alkaloid of Fabiana imbricata (Scheme 3).39 The pyrrolidine-derived enamine of pulegone underwent conjugate addition with methyl vinyl ketone after which the crude adduct (26) was heated in an autoclave at 150 “C with ethanol and hydroxylamine hydro- chloride to form the pyridine ring of (27).Hydration with sulphuric acid afforded an inseparable mixture (1 :1) of the cis and trans compounds (25) in modest yield. The alkaloid itself is apparently an isomeric mixture in which the cis isomer is dominant. 1.3 Prenylquinolinones and Hemiterpenoid Tricyclic Alkaloids Debate on the presence or absence of monomeric and dimeric quinolin-2-ones in Araliopsis tabouensis6 appears to have stemmed from confusion in the use of the species names Araliopsis soyauxii and A. tabouensis and the conspecificity or otherwise of these species.4o If as seems likely the species are conspecific then A.soyauxii is the correct name to use. Differences in alkaloidal composition probably arise as a result of local adaptations since Ghanaian populations of the plant were studied in the earlier work cf. ref. 34(b),(c) and Cameroonian populations in the later cJ ref. 37(c). Further information on the new alkaloid (+)-araliopsinine (28) from the Cameroonian population discussed in last year’s review in this serie~,~’‘~) has now become available and its spectra have been reported.6 The structure was confirmed by synthesis from veprisine (29) in two ways by treatment with m-chloro-peroxybenzoic acid followed by hydrolysis of the resulting epoxide and by oxidation with chromic oxide in acetic acid followed by basic hydrolysis.It is unfortunate that the new alkaloid (30) isolated from Glycosmis pentaphyllall has been given the name glycolone since this name has previously been assigned to 4,8-dimethoxy- 3-prenyl-2-quinolinone isolated from the same species cf. ref. 37(d). The new alkaloid has unusual features it is one of a mere handful of naturally occurring 4-ethoxyquinolinones cf. ref. 37(e) and the but-2-en- 1-yl substituent is unprecedented among the anthranilate-derived quinoline alkaloids. The compound is in fact the butenyl analogue of the 3-prenylquinolinone alkaloid homoglycosolone (3 1) cf. ref. 370 also from Glycosmis pentaphylla. The presence of the 2- OMe he OMe Me Araliopsinine (28) Veprisine (29) OEt F! I OH Me OH he (30)R = H (32) (31) R = Me I1 OMe OMe Me Ptelefolidonium (33) Ptelefolid ine (34) R1-R2 = OCH20 Ptel ecu Itiniu m ( 35) R’ = H; R2= OMe 0 II 8 I Me Me lsoplatydesmine (36) Ribalinine (37) quinolinone unit in (30) was supported by UV data and by an infrared carbonyl absorption at 1640 cm-l but the location of the phenolic OH group was tentatively assigned from biogenetic considerations only.Heating with 6N hydrochloric acid converted the alkaloid to the furo[3,2-~]quinolinone (32) in 47 YOyield a somewhat unusual result in view of the tendency of 3-allylquinolin-2-ones to cyclize to pyranoquinolines under similar conditions. That lavish source of natural products Ptelea trifoliata has been shown to produce yet another hitherto unknown dihydrofuroquinolinium alkaloid ptelefolidonium (33).28 It had previously been surmized that (33) might be a natural product cf.ref. 34(d) since base-promoted cleavage of a mixed fraction of quaternary alkaloids from Ptelea trifoliata had produced amongst others the alkaloid ptelefolidine (34). The alkaloid ptelecultinium (35),41 introduced in last year’s review as a metabolite from cell cultures of the same plant was suspected to be an intermediate for more complex alkaloids possessing a higher degree of oxygenation and perhaps therefore unlikely to be present in sufficiently large amounts for detection in intact plants. However it has now been isolated from the roots of P.trifoliata.22 58 NATURAL PRODUCT REPORTS 1991 I Me Almeine (38) \ NI R ___) O \ NI R O R I R I R (39) Scheme 4 (41) R = Me (43) (44) R' = R3 = R4 = H; R2 = OMe (42) R = H (45) R' = Me; R2 = R3 = R4 = H (46) R' = Me; R2 = OMe; R3 = R4 = H (47) R' = Me; R2 = R4 = H; R3 = OMe (48) R' = Me; R2 = H; R3 = R4 = OMe Reagents i HCO,H CHCl, reflux; ii Hg(OAc), THF r.t.then NaC1 H,O; iii NaBH, 3M aq. NaOH CH,Cl, 0 "C; iv DDQ C,H, reflux Scheme 5 II II R' H R' H (56) R' = R2= R3 = H (52) R' = R2 = R3 = H (57) R' = OMe; R2 = R3 = H (53) R' = OMe; R2 = R3 = H (58) R' = R2 = H; R3 = OMe (54) R' = R3 = H; R2 = OMe (55) R' = R2 = H; R3 = OMe Reagents i prenyl bromide NaOH H,O 50 "C; ii Te NaBH, AcOH pH 7.5 -20 "C to reflux; iii CH,N, Et,O-EtOH 0 "C; iv DDQ C,H, reflux Scheme 6 59 NATURAL PRODUCT REPORTS 1991-5.P. MICHAEL Reisch and Iding have synthesized almeine (38) very simply in 28 Yo yield merely by heating 4- hydroxy-N-methylquinolin-2-one with dibromoisoprene (1,4-dibrom0-2-methyl-2-butene) sodium iodide and sodium hydrogen carbonate in acetone." The previously discussed approach of Reisch cf. ref. 37(g) to the synthesis of pyrano[3,2-~]quinolinonealkaloids based on the reaction of 4-hydroxyquinolin-2-ones with 3-chloro-3-H/'Ao methyl- I-propyne has now been extended.43 Model studies with a variety of substrates support the hypothesis that a 4- Aurachin E (59) propargyl ether (39) is formed initially and that this undergoes Claisen rearrangement prior to a series of prototropic shifts and eventual cyclization (Scheme 4).A versatile new synthesis of pyranoquinolinones permits the formation of either angular or fused tricyclic products regioselectively from the same substrates the isopentenyl- quinolinones (40) simply by changing reaction conditions (Scheme 5).44 Heating (40) with formic acid in chloroform brought about cyclization to dihydropyrano[2,3-b]quin-olinones and in this way the alkaloids N-methylkhaplofoline (41) and khaplofoline (42) were obtained in 88% and 59% 0-yields respectively together with 612 YOof the angular isomers. Aurachin F (60) Alternatively treatment of (40) with mercuric acetate followed by reductive demercuration afforded dihydropyrano[3,2-c]-quinolinones (43) as the only detectable products.These could be dehydrogenated with 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) in boiling benzene to produce the angularly fused alkaloids N-desmethylzanthobungeanine(44) N-methylflindersine (49 zanthobungeanine (46) 8-methoxy- xkyY N-methylflindersine (47) and oricine (48). The overall yields (y$ for the three-step process were in the range 32-39 YO. R In view of the manifold difficulties that normally accompany the direct 3-prenylation of quinoline-2,4-diones and related methyl ethers a new procedure devised by Shanmugam and co- I workers is of considerable interest (Scheme 6).45 The strategy 0-involved bisprenylating the 4-hydroxyquinolin-2-ones(49) after which the products (50) were partially deprenylated to Aurachin G (61) R = H; XY = HC=CH (51) with sodium hydrogen telluride in 5&92% yields arguably by an electron-transfer pathway.Treatment of the Aurachin H (62) R = H; XY = CH2CH2 products (51) with diazomethane gave the alkaloids atanine Aurachin I (63)R = OMe; XY = CHzCH2 (52) and glycolone (53) and the alkaloid analogues (54) and (55) in 8(1-90% yields. Alternatively heating (51) with DDQ in boiling benzene produced the pyrano[3,2-~]quinolinone alkaloids flindersine (56) 8-methoxyflindersine (sic; more correctly 7-methoxyflindersine 57) and haplamine (58) in yields of 68-80 YO. OMe OMe 1.4 Sesquiterpenoid Quinoline Alkaloids Aurachins A-D unique sesquiterpenoid quinoline alkaloids from the myxobacterium Stigmatella aurantiaca were described in last year's review cf.ref. 37(h). Structural work on these compounds has still to be published but in the meanwhile another five aurachins (59)-(63) have been described in the R patent literat~re.~~ These compounds were produced when the Anhydroperfori ne (66) organism was cultured in the presence of added anthranilic Haplophyllidine (64) acid. Full reports on these fascinating metabolites are awaited R = CH=CMe2 with interest. Perforine (65) R = CH2C(OH)Me2 1.5 Furoquinoline Alkaloids The 13CNMR spectra of the rare 5,6,7,8-tetrahydrofur0[2,3-6]-quinoline alkaloids haplophyllidine (64) perforine (65) and OMe anhydroperforine (66) have been assigned c~mpletely.~~ When one considers the large number of quinoline alkaloids bearing free phenolic groups it is surprising how few glycosides of these compounds have been isolated.In fact the only confirmed aglycone alkaloid to date has been haplopine (67) whose a-L-rhamnoside and P-D-glucoside (glycoperine (68) and glycohaplopine) occur naturally. The recent literature has OH OH revealed that the aerial parts of HaplophyIIurn perforaturn OMe contain two more glycosides of haplopine which are in fact the first known biosides of the quinoline alkaloids. These com- Haplopine (67) Glycoperine (68) NATURAL PRODUCT REPORTS 1991 HOCH2 I 0 OR How OH Haplosidine (69) R = COCH3 5-Methoxydictamnine (71) R' = OMe; R2 = H Haplosinine (70) R = H y-Fagarine (72) R' = H; R2 = OMe OMe Dihydroperfarnine (73) Acronydine (74) (75) lsomaculosidine (76) Dictarnnine (81) R = H H Evolitrine (82) R = OMe (80) (79) (83) R = Me Reagents i SOCl, C6H6 reflux; ii NH, CHCl, 0 "C; iii POCI, reflux; iv NaOH 30% H,O, MeOH 40 "C to 60 "C; v NaOBr H,O 0 "C to 70 "C; vi conc.HCl NaNO, H20 10 "C then CuCl conc. HCl 5 "C to r.t.; vii 5% HCl-EtOH reflux; viii PPA 120 "C; ix NaOMe MeOH reflux; x DDQ dioxan reflux Scheme 7 pounds are haplosidine (69),14 which is haplopine 7-0-[p- Few recent syntheses of furoquinoline alkaloids have been ; D-glucopyranosyl( 1 +3)]-a-~-(2'-O-acetyI)-rhamnopyranoside published. Haplopine (67) and skimmianine (1 R' = H and haplosinine (70),15 the corresponding 7-0-[p-~-R2= R3= OMe) have been converted to kokusagine (1 glucopyranosyl(I -,3)]-a-~-rhamnopyranoside.Acid hydro-lysis of both gave haplopine and the constituent sugars. Both compounds yielded the same hexaacetate on peracetylation and haplosidine could be saponified under alkaline conditions to give haplosinine. The terminal sugar in the bioside unit was established after enzymatic hydrolysis of haplosinine to D-glucose and glycoperine (68). The sites of linkage and the position of the acetate in (69) were deduced from the 'H and 13C NMR spectra. A new alkaloid with the rather rare 5-methoxyfuroquinoline structure has been isolated from Ruta chalepensis var. latifolia along with several more common alkaloid^.,^ The alkaloid 5- methoxydictamnine (71) was characterized spectroscopically the substitution pattern being inferred from the presence of three adjacent aromatic proton signals and mass spectrometric and TLC comparisons with the 8-methoxy isomer y-fagarine (72).R' = H R2R3 = OCH,O) in about 30% yield by demethyl- ation with boron tribromide followed by methylenation with bromochloromethane and anhydrous potassium carbonate in dry a~etone.~' Kokusaginine (1 R1 = R2= OMe R3 = H) was converted to maculine (1 R' R2 = OCH,O R3 = H) in 23 YO yield by a similar procedure. A preparation of isomaculosidine (76) in 25% yield by a fairly standard approach the modified Tuppy-Bohm method beginning with the condensation of 2,4-dimethoxyaniline chloroacetyl chloride and diethyl sodio-malonate is virtually identical to previously published syntheses in which anilines with other substitution patterns have been used as substrates cf.ref. (37i).48 A novel approach to the synthesis of furoquinoline~~~ is based on transformations of 3-vinyl-2-quinolinones (77) themselves available from N-(but-3-enoyl)isatins (78) (Scheme 7). A sequence of functional group interconversions was used to prepare the key intermediates (79) which cyclized to NATURAL PRODUCT REPORTS 1991-J. P. MICHAEL r 1 IR2 I Me (84a) R' = R2 = OMe (85) (86) (84b) R' = OMe; R2 = H (84c) R' = R2 = H OMe OMe OMe Me Skimm iani ne lsoskimmianine (87) Reagents i conc. H2S0,; ii MeI reflux 24 h; iii 2M NaOH-MeOH r.t.; iv MeI reflux 6 h; v MeI sealed tube 80 "C,5 h Scheme 8 dihydrofuro[2,3-b]quinolines (80) on heating with poly-phosphoric acid.The required oxidation level was introduced by DDQ dehydrogenation and in this way syntheses of dictamnine (81) and evolitrine (82) as well as the unnatural derivative 6-methyldictamnine (83) were completed in approxi- mately 28% overall yield based on (77). In a model study aimed at the synthesis of 3-(3-methyl-2- oxobutyl)quinoline-2-one alkaloids Gaston and Grundon showed that the furo[2,3-b]quinolin-4-ones (84a4) formed pseudobase hydroiodide salts (85) on prolonged refluxing with methyl iodide (Scheme 8).50 The bridgehead methoxy group probably arises from gradual hydrolysis of methyl iodide by adventitious moisture. The salts were cleaved on treatment with sodium hydroxide to give the desired ketones (86) in 60-81 % yields.Under similar conditions skimmianine could be converted by way of the corresponding pseudobase salt to isoskimmianine (87) in 62% yield a conversion that has mechanistic implications for the well-studied 'is0 rearrange- ment ' of 4-methoxyfuro[2,3-b]quinoline alkaloids. The hydroxylated linear dihydrofuro[2,3-b]quinolin-4-ones (88a-c) were shown to undergo acid-catalysed conversion to a mixture of (84) and the angularly fused furo[3,2-~]quinolinones (89) the proportion of the latter increasing with time. The suggested pathway involves dehydration of (88) to (84) protonation of the enol ether moiety followed by cleavage to ketones (90) and recyclization to the observed products. In support of this proposal (84a) was found to convert partially into a 2 1 mixture of (84a) and (89 R1= R2 = OMe) on treatment with concentrated sulphuric acid for two hours.The mutagenicity of furoquinoline alkaloids continues to be of interest. Structure-mutagenicity relationships of the alkaloids anhydroevoxine evolitrine flindersine maculine maculo-sidine and tecleaverdoornine have been st~died,~' as has the modification of the mutagenicity of dictamnine y-fagarine and skimmianine by enzyme inducers and inhibitor^.^^ 1.6 Dimeric Quinolinone Alkaloids The occurrence structures characterization synthesis and reactions of these alkaloids have recently been Haplodimerine (99 isolated from the fruits of Hapfophyflum fofios~m,~~ possesses a new and most unusual skeleton. Its structure has been established by spectroscopic methods and more securely X-ray crystallographic analysis.This alkaloid is effectively derived from an angular pyranoquinolinone (flindersine 56) and a furo[2,3-b]quinoline (skimmianine 1, R'= H R2= R3 = OMe) the latter of which (but not apparently the former) has previously been isolated from this species. The involvement of a furo[2,3-b]quinoline in dimer formation is novel all known dimeric quinolinone alkaloids hitherto isolated have been derived from hemiterpenoid quinolinones or their tricyclic derivatives. The most striking structural feature is of course the all-cis-substituted cyclo- butane ring formally derived from [2 +21 cycloaddition of the constituent halves. Could this imply a photochemical origin for the dimer ? There are intriguing synthetic possibilities implicit in such a suggestion.Investigations of the dimerization of N-methylflindersine (45) under thermal conditions have resulted in the synthesis of known and novel paraen~idimerines.~~ There is a striking NATURAL PRODUCT REPORTS 1991 Me R Vepridimerine A (91) (Y-Hd.a-He;R = OMe Vepridimerine B (92)a-Hd,fl-H,; R = OMe ParaensidimerineA (96) (Y-Hd,(Y-t-i,; R = H ParaensidimerineC (97) a-Hd,fl-He; R = H Vepridimerine C (93)a-H,,a-H,; R = OMe Vepridimerine D (94) a-Hd,O-He; R = OMe ParaensidimerineA' (100) &Hd,(Y-H& R = H ParaensidimerineC' (101) a-Hd,p-He; R = H ParaensidimerineF (99) O-Hd,a-tie; R = H Paraensidirnerine F' (102) P-Hd,a-H,; R = H H Me I H I OMe Me0 MeO OMe I H Haplodimerine (95) ParaensidimerineD (98) (703) OH OH II OH ( 104) (105) Vasicinone ( 106) X = 0 temperature dependence on the outcome of the reaction.At 105"C low yields of paraensidimerines A (96,6%),C (97,3%) and D (98,3%) were isolated together with unconverted N-methylflindersine (88YO).At 150 "C the hetero Diels-Alder adduct paraensidimerine D was not formed. Starting material was recovered (16YO),together with paraensidimerines A (1 5 YO),C (6YO),and F (99,5 YO).In addition three new mixed quinolin-2-one/quinolin-4-one dimers were formed. These were named paraensidimerines A' (100 3 %) C' (101,7 %) and F' (102 6%) and their structures were elucidated on the basis of spectroscopic data. Paraensidimerine F' is the bis(N-methyl) derivative of the alkaloid geijedimerine cf.ref. 37(g) from which it had previously been prepared. Thermal dimerization of N-methylflindersine at 210 "C yielded only paraensidimerines A (18%) C (18 YO),and F (44%). In a separate study dimerization of haplamine (58) at 220-230 "C was shown to give in 42% yield a product (103)of the same skeletal type and stereochemical series as paraensidimerine F.55 2 Quinazoline Alkaloids Alkaloids have been isolated for the first time from Galium aparine (Rubiaceae) aerial parts of which apparently contain the quinazoline alkaloids (-)-8-hydroxy-2,3-dehydrodeoxy-Vasicine (107) X = 2H peganine (1 04) (-)-1-hydroxydeoxypeganine (105) and ( )-vasicinone (106)as minor constituent~.~~ All three were claimed as new alkaloids the last-named on the grounds that it has never before been obtained from natural sources in racemic form.The unusual geminal amino-alcohol structures for (104) and (105)were deduced from UV IR 'H NMR and high resolution mass spectral data. In particular detailed spin decoupling studies were used to establish the bonding sequences in the non-aromatic parts of both alkaloids. ( +)-Vasicinone has been isolated from Adhatoda vasica well known as a prolific producer of quinazoline a1kaloids.j' This appears to be the first reported isolation of the (+)-enantiomer of the alkaloid though the (-)-and (+)-forms are both known as natural products. The plant displays a marked seasonal variation in the production of its major alkaloid vasicine (107),which occurs in highest concentrations in the inflorescence^.^^ Two distinct morphological types of the plant showed quite different seasonal fluctuations of alkaloids though alkaloidal composition was qualitatively the same in both.59 In view of the suspected occurrence of glucosides of vasicine and vasicinone in Adhatoda vasica materials for comparison have been prepared by converting both alkaloids to their P-D-glucopyranosides.'' The bridgehead-hydroxy structure (108) formerly assigned NATURAL PRODUCT REPORTS 1991-5. P. MICHAEL (108) Vasicol (109a) X = H (110) (109b) X= Br 0 'N 7% LOAc LO" Reagents i HOCH,CH,NH, K,CO, Cu NaI DMF 70 "C; ii Ac,O pyridine r.t.; iii CH(OEt), Ac,O reflux; iv NaOMe MeOH r.t.Scheme 9 r 1 (1 13) Deoxyvasicinone (1 12) Reagents i triphenylphosphine xylene 140 "C 5 h; or tributylphosphine r.t. 2 h Scheme 10 Glycosminine (114) to the alkaloid vasicol cf-ref. 34(e) is wrong.61 The lactam structure (109a) has been proposed instead on the basis of spectroscopic evidence an X-ray crystallographic study of the p-bromo derivative (109b) and a variety of chemical trans- formations. The structure (1 10) for echinozolinone an alkaloid isolated from Echinops echinatus cf. ref. 37(j) has been called into question.62 An unambiguous synthesis of compound (1 10) from 4(3H)-quinazolinone and 2-chloroethanol gave a product whose spectroscopic characteristics were quite different from those reported for the alkaloid.A possible alternative structure (1 1 l) was dismissed after spectra of synthetic material prepared as shown in Scheme 9 also failed to correspond with those of the alkaloid. The authors doubt that the reported NMR spectra indicate either a quinazoline structure or the presence of a hydroxymethyl terminus. For the moment the problem remains unresolved. A quantitative HPLC procedure has been devised to cast light on the course of an old synthesis of deoxyvasicinone (I 12) from anthranilic acid and pyrrolidin-2-one cf. ref. 34(fJfi3 A short new synthesis of deoxyvasicinone makes interesting use of an intramolecular aza-Wittig reaction (Scheme The key step in the synthesis involved Staudinger reaction of the azide (1 13) with a phosphine the resulting iminophosphorane condensing with the lactam carbonyl group to form the alkaloid.With triphenylphosphine the reaction required heating in xylene under reflux to produce the desired alkaloid in 99.5 % yield whereas the reaction with tributylphosphine proceeded at room temperature in 99 O/O yield. The method has also been applied to the cyclization of succinimide-and glutarimide-based a~ides.~~ A one-pot preparation of glycos- minine (1 14) in 40 % yield from N-(o-bromopheny1)-phenylacetamide carbon monoxide the titanium isocyanate reagent [3THF * Mg,CI,O. TiNCO] and tetrakis(tripheny1-phosphine)palladium(O) as catalystfi6 is the only other note- worthy synthesis of a quinazoline alkaloid in the period under review. 3 Acridone Alkaloids 3.1 General An important new review deals with the isolation of new acridone alkaloids since 1970 and with their 13C NMR spectra biosynthesis and biological activity.67 Advances in the field have also been summarized in Rodd's Chemistry of Carbon Compounds.68 The elegant work of Funayama and Cordell on the synthesis and structure of polymers of acronycine and related compounds presented in several past reports in this journal has now been consolidated in the form of a review.69 Recent biological studies on acridone alkaloids include the testing of rutacridone and rutacridone epoxide for muta-genicity ;70 investigations of the anti-herpes virus activity of citrusinine I ;71 the antitumour activity of acronycine in mice;72 and the testing of thirty acridone alkaloids both in vitro and in vivo against rodent mala~ia.'~ In the latter study atalaphyllinine completely suppressed the formation of malaria parasites without obvious acute toxic effects when injected intra-peritoneally into mice infected with Plasmodium berghei or P.vinckei. NPR 8 64 NATURAL PRODUCT REPORTS 1991 Table 2 Isolation and detection of acridone alkaloids Species Alkaloid (Structure) Ref. Araliopsis tabouensis Arborinine (1 15 R = Me) 6 (A. soyauxii) A talan t ia buxifolia *Atalafoline-B (1 17) 74 Citrus funadoka *( -)-Acrimarine-A (1 2 I) 75 *(-)-Acrimarine-B (122) *(-)-Acrimarine-C (123) Grandisine-I1 (125) Natsucitrine-I1 (126) Citrus grandis *Buntanhe (1 18) 76 Citrus nobilis Citracridone-I (128 R1 = OMe R2 = OH) 77 Citropone-A (1 29) Citrusinine-I (1 30 R' = R3 = OH R2 = H) 11-Hydroxynoracronycine (128 R1 = OH R2 = H) Ruta chalepensis var.latifolia 1-Hydroxy-N-methylacridone(13 1) 23 1-Hydroxy-N-methylfuracridone (1 32) 78 Surcomelicope argyrophylla *( +)-Acronycine epoxide (1 20) 79 Sarcomelicope pembaiensis Acronycine (1 19) 24 Melicopicine (130 R1 = R2 = OMe R3= H) Sarcomelicope simplicifolia *( +)-Acronycine epoxide 79 subsp. neo-scotica Saussureu nepalensis Arborinine 80 Teclea borenensis Arborinine 2 Vepris duinelli Xanthoxoline (1 15 R = H) 2 * New alkaloids &OMe O.+LO I OMe 1340 OR2 R (1 15) (116) R' = OMe; R2 = H; R3 = R4 = Me Atalafoline B (1 17) (118) R' = CH2CH=CMe2; R2 = R4 = H; R3 = Me (125) R' = R2 = H; R3 = R4 = Me (126) R' = R3 = H; R2 = R4 = Me (127) R' = R3 = R4 = H; R2 = Me o.'-H\ HO OMe O M e r n o Me I OMe t R' Me0 Acronycine epoxide (120) Acrimarine A (1211 R' = Me; R2 = OH Acrimarine C (123) Acrimarine B (122) R' = H; R2 = OMe 3.2 Occurrence and Structural Studies Six new acridone alkaloids have been reported during the period covered by this report.These compounds together with known alkaloids isolated from new sources are listed in Table 2.2.6,23.24.74-80 At alantia buxifolia shown previously to contain the alkaloid atalafoline (1 16) cf. ref. 37(k) has now yielded atalafoline-B (1 17) which was characterized by standard Me0mo spectroscopic method^.'^ This is the first 1,3,4,5,6-penta-oxygenated acridone to be isolated from a natural source and Suberosin ( 124) it brings to six the number of simple pentaoxygenated acridone alkaloids.Buntanine (1 1S) a new prenylacridone from the root NATURAL PRODUCT REPORTS 1991-5. P. MICHAEL Citropone A (129) ( 133) bark of Citrus grandis was also characterized spectro-s~opically.~~ In this case AB signals in the 'H NMR spectrum at S 6.92 and 8.05 served to identify the ortho-coupled H-7 and H-8 respectively while NOE experiments on the 3,6-bis-(methoxymethyl) ether of (1 18) were performed to establish the relative positions of methoxy and hydroxy groups. Reinvestigation of the bark of Sarcomelicope (= Bauerella) simplicifolia subsp. neoscotica led to the isolation of an optically active minor alkaloid whose spectroscopic properties were in the main similar to those of acronycine (119) though its molecular ion was 16 mass units higher.79 Signals in the 'H NMR spectrum typical of a 3,4-epoxydimethylchroman system supported the proposal that the compound was acronycine epoxide (120).The compound proved to be identical to an unstable minor metabolite previously isolated from S. argyro-phylla. The compound is biogenetically interesting as the probable intermediate between acronycine and the acronycine diols described in an earlier report cf. ref. 37(k). In view of the biological activity of certain epoxides it is also possible that (120) may be the active form of acronycine in vivo. The most notable new acridone alkaloids are the three optically active compounds (12 1)-(123) isolated from the roots of Citrus funadoka seedlings.75 The acrimarines as they have been called are novel dimeric compounds in which an acridone unit has been coupled to a coumarin.The monomeric precursors are well known as constituents of Citrus species but their union as dimers is unprecedented. In all cases the mass spectra showed molecular ions for the dimers as well as prominent ions for the acridone and coumarin fragments. The latter was the same in all three cases (m/z 242; C,,H,,O,). NMR characteristics typical of 1-hydroxy-9-acridones and a (130) (132) (134) common coumarin nucleus were also apparent. For the latter the diagnostic signals were an AB double doublet (6 ca.6.2 7.6) for the vinylic protons of the pyrone ring; the lactonic carbonyl signal (8 ca. 161.5); and two allylic methyl groups a vinylic proton signal (aI4ca. 5.9) and a vicinal methine proton (6 ca. 5.6) characteristic of a prenyl group linking two aromatic moieties. Nuclear Overhauser effects served to locate the prenyl unit on C-6 of the coumarin and further NOE experiments as well as IH-l3C long-range COSY experiments established not only the remaining connectivities within the coumarin but also the position of linkage of the prenyl side chain to the acridone nucleus. The coumarin turned out to be suberosin (124) which was also isolated from the plants ;and the acridone partners of acrimarines A B and C respectively were grandisine 11 (125) linked at its 2-position natsucitrine I1 (126) linked at its 2-position and natsucitrine I (127) linked at its 4-position.The first two of these were found in the plant alongside the dimers. The absolute configurations of the dimers were not determined but the measured [a] values for acrimarines A B and C were -9.76' (c 0.082 CHCl,) -7.14" (c 0.056 CHCl,) and -6.17" (c 0.081 CHC1,) respectively. The mass spectra of a variety of simple acridones prenyl- acridones linear and angular pyranoacridones and furo-acridones have been examined with a view to elucidating characteristic fragmentation patterns.H' Amongst the most significant fragments are the intense [M-11' peaks from N-methylacridones due to the comparatively stable iminium ions (133); and the [M-151' fragments from pyrano[2,3-c] acridones which are favoured because of the formation of pyrylium ions (134).The fragmentation pathways of 2- and 4- prenylacridones were also elucidated. NATURAL PRODUCT REPORTS 1991 o...H\ o..+ko 0 = iii OH R i OMe I OMe HO,& OMe H Me k (135) (138) R = H (139) R = CHZCH=CMez Reagents i ZnCl, n-BuOH reflux; ii MeI K,CO, acetone reflux; iii CH,N, Et,O-MeOH r.t.; iv Me,C(OH)CH = CH, BF;Et,O dioxan r.t. or reflux Scheme 11 Atalaphylline (137) Reagents i N-methylaniline NEt, 90 "C,then 240 "C; ii PPA heat Scheme 12 3.3 Synthesis A short but conventional synthesis of l-hydroxy-3-methoxy-N- methylacridone (1 35) involves the zinc chloride-induced con- densation of anthranilic acid with phloroglucinol followed by selective methylation of the 3-hydroxy and N-H groups (Scheme 1l).82 1-Hydroxy-3,5-dimethoxy-N-methylacridone (1 36) was prepared similarly during a projected synthesis of the prenylated acridone alkaloid atalaphylline (1 37).83In attempts to prenylate (136) at room temperature with 2-methyl-3-buten- 2-01 and boron trifluoride etherate only the borondifluoro chelate (138) was isolated.At reflux in dioxan prenylation occurred at the 2-position7 but again a boron chelate of the desired product (139) was formed. A new acridone synthesiss4 makes use of chloroalkyl-idenemalonates like (140) readily accessible from acyl-malonates. Reaction of (140) itself with N-methylaniline (Scheme 12) gave the substituted malonate (141) thermolysis of which led to formation of the anthranilate (142) in 56% yield.Cyclization to the alkaloid I -hydroxy-N-methylacridone (131) was effected in 70% yield by heating (142) in poly- phosphoric acid. This method would seem to have potential for the synthesis of other 1-hydroxy-9-acridones. NATURAL PRODUCT REPORTS 1991-5. P. MICHAEL 0 OMe 0 OMe CI H2N / OMe OMe OMe OMe I H H CHO Me CHO 64% iiv COCH3 Hallacridone (143) ( 144) Reagents i Cu K,CO, DMF 80 "C; ii POCl, DMF r.t.; iii MeI Ag,O r.t.; iv BCl, CH,Cl, r.t. 72 h; v ClCH,COCH, K,CO, acetone reflux Scheme 13 0 OMe qMe \ Acronycine (1 19) /70% \ qL&MeH0'. Br Me II ____)35% iv ii 14% (7y$&Me HO ( 145) oy&Me HO" I OH OH (146) Reagents i NBS THF-H,O 1 1,0 "C to 20 "C; ii Bu,SnH AIBN toluene reflux; iii OsO,; iv N,N'-thiocarbonyldiimidazole,2-butanone reflux Scheme 14 Last year's report cf.ref. 37(1) made passing mention of a acronycine (1 19) with N-bromosuccinimide in aqueous medium synthesis carried out to distinguish between possible alternative followed by debromination with tributyltin hydride. The 2-structures for hallacridone (143).s5 The synthesis (Scheme 13) hydroxy isomer (146) was prepared by benzylic reduction of the began with an Ullman coupling of o-chlorobenzoic acid and 1,2-diol formed by reaction of acronycine with osmium 3,5-dimethoxyaniline and exploited a Darzens condensation tetroxide (Scheme 14). on intermediate (144) for the construction of the fused furan ring of the alkaloid.The overall yield was 1.5%. Plausible biosynthetic relationships between hallacridone and other References furoacridones isolated from Ruta gravedens were also presented in this publication. 1 M. F. das G. F. da Silva 0.R. Gottlieb and F. Ehrendorfer Plant Syst. Evol. 1988 161 97. Efforts to Prepare water-so1ub1eacronYcine derivatives that 2 E. Dagne A. Yenesew p. G. Waterman and A. 1. Gray Biochpm. may act as acronycine prodrugs have resulted in the synthesis Syst. Ecol. 1988 16 179. of both hydroxydihydroacronycine regioisomers (1 45) and 3 M. Sainsbury in 'Rodd's Chemistry of Carbon Compounds' ed. (146) from the parent alkaloid.86 The 1-hydroxy compound M. F. Ansell Elsevier Amsterdam 1987 Supplement to the (145) was made in a two-step procedure by treatment of second edition Vol.IV Part G pp. 209-244. 4 V. Kumar V. Karunaratne M. R. Meegalle and K. Sanath Phytochemistry 1989 28 1278. M. Norte M. L. Rodriguez J. J. Fernandez L. Eguren andD. M. Estrada Tetrahedron 1988 44 4973. 6 B. T. Ngadjui J. F. Ayafor and B. L. Sondengam Bull. Chem. SOC. Ethiop. 1988 2 21 (Chem. Abstr. 1989 110 209293). 7 B. T. Ngadjui J. F. Ayafor B. L. Sondengam and J. D. Connolly Phytochemistry 1989 28 1517. 8 P. C. Vieira A. R. Lazaro J. B. Fernandes and M. F. dasG. F. da Silva Biochem. Syst. Ecol. 1988 16 541. 9 Y. Gunawardana G. A. Cordell N. Ruagrungsi S. Chomya and P. Tantivatana J. Sci. Soc. Thailand 1987 13 107 (Chem. Abstr. 1988 109 190621). T.Sugimoto T. Miyase M. Kuroyanagi and A. Ueno Chem. Pharm. Bull. 1988 36 4453. 11 S. K. P. Sinha and P. Kumar Indian J. Chem. Sect. B 1988 27 460. 12 I. A. Bessonova and S. Y. Yunusov Khim. Prir. Soedin. 1989 23 (Chem. Abstr. 1989 111,74797). 13 B. Tashkhodzhaev S. V. Lindeman I. A. Bessonova D. M. Razakova E. N. Tsapkina and Y. T. Struchkov Khim. Prir. Soedin. 1988 838 (Chem. Abstr. 1989 111 4246). 14 K. A. Rasulova I. A. Bessonova M. R. Yagudaev and S. Y. Yunusov Khim. Prir. Soedin. 1988 94 (Chem. Abstr. 1988 109 5 1 698). K. A. Rasulova I. A. Bessonova M. R. Yagudaev and S. Y. Yunusov Khim. Prir. Soedin. 1987 876 (Chem. Abstr. 1988 109 70 326). 16 I. A. Bessonova D. Kurbanov and S. Y. Yunusov Khim. Prir. Soedin. 1989 46 (Chem.Abstr. 1989 111 54177). 17 M. A. Abd-El-Kawy E. A. El-Kashoury A. M. El-Fishawy A H. Atta and F. M. Soliman Egypt. J. Pharm. Sci. 1989 30 299 (Chem. Abstr. 1990 112 95524). 18 J. R. Pfister J. Nut. Prod. 1988 51 969. 19 T.-T. Jong and T.-S. Wu Phytochemistry 1989 28 245. F. Imai K. Itoh N. Kishibuchi T. Kinoshita and U. Sankawa Chem. Pharm. Bull. 1989 37 119. 21 R. P. Hodge C. M. Harris andT. M. Harris J. Nut. Prod. 1988 51 66. 22 G. Petit-Paly M. Montagu C. Merienne J. D. Ambrose M. Rideau C. Viel and J.-C. Chenieux Planta Med. 1989 55 209. 23 A. Ulubelen H. Guner and M. Cetindag Planta Med. 1988 54 551. 24 S. Mitaku and J. Pusset Plant. Med. Phytother. 1988 22 83. H. Augustiniak K. Gerth G. Hoefle H. Irschik R. Jansen B.Kunze H. Reichenbach H. Steinmetz and W. Trowitzch- Kienast Ger. OfSen. DE 3520229 11 Dec 1986 (Chem. Abstr. 1989 110 73858). 26 S. Breiding-Mack and A. Zeeck J. Antibiot. 1987 40,953. 27 B. T. Ngadjui J. F. Ayafor and L. B. Sondengam Ann. Fac. Sc. Chim. 1988 2 71. 28 Y. Lu S. Jin and Q. Xing Beijing Daxue Xuebao Ziran Kexueban 1988 24 245 (Chem. Abstr. 1988 109 70400). 29 C.S. Yook C. M. Kim and E. T. Shin Saengyak Hakhoechi 1987 18 180 (Chem. Abstr. 1988 108 81927). J. Simeray J. P. Chaumont J. Pusset F. Bevalot and J. Vaquette Planta Med. 1988 54 189. 31 M. Montagu G. Petit-Paly P. Levillain A. Baumert D. Groger J.-C. Chenieux and M. Rideau Pharmazie 1989 44,342. 32 J. Tremouillaux-Guiller H. Kojda F. Andreu J. Creche J.-C.Chenieux and M. Rideau Plant Cell Rep. 1988 7 456. 33 M. D. Real and J. Ferre Insect Biochem. 1989 19 111. 34 M. F. Grundon in ‘The Alkaloids’ ed. M. F. Grundon (Specialist Periodical Reports) The Royal Society of Chemistry London (a) 1977 7 81 ; (b) 1976 6 104; (c) 1978 8 79; (d) 1977 7 88; (e) 1982 12 90; (f)1976 6 108. T. Kametani and H. Kasai in ‘Studies in Natural Products Chemistry’ ed. Atta-ur-Rahman Elsevier Amsterdam 1989 3 pp. 385-398. 36 I. Thomsen and K. B. G. Torssell Actu Chem. Scand. Sect. B 1988 42 309. 37 M. F. Grundon Nut. Prod. Rep. (a) 1984,1 195; (6) 1988,5,295; (c) 1990,7 133; (d) 1987,4,227; (e) 1988,5293;(f)1988,5296; (g) 1988,5,298; (h) 1990,7 134; (i) 1985,2 198; (j)1988,5 300; (k) 1988 5 302; (I) 1990 7 137.38 J. Reisch and G. M. K. B. Gunaherath Monatsh. 1988 119 1169. 39 J. Elguero and B. Shimizu An. Quim. Ser. C 1988 84 198. P. G. Waterman Bull. Chem. Soc. Ethiop. 1988 2 87 (Chem. Abstr. 1989 111 20852). NATURAL PRODUCT REPORTS 1991 41 G. Petit-Paly M. Montagu C. Viel M. Rideau and J.-C. Chhieux Plant Cell Rep. 1987 6 309. 42 J. Reisch and M. Iding Monatsh. 1989 120 363. 43 J. Reisch R. A. Salehi-Artimani A. Bathe and M. Miiller Monatsh. 1988 119 781. 44 P. Bravo G. Resnati F. Viani and G. Cavicchio Gazz. Chim. Ital. 1988 118 507. 45 N. Shobana P. Yeshoda and P. Shanmugam Tetrahedron 1989 45 757. 46 M. P. Yagudaev and I. A. Bessonova Khim. Prir. Soedin. 1989 25 (Chem. Abstr. 1989 111 233302). 47 J. Banerji A. K. Das N.Ghoshal and B. Das Indian J. Chem. Sect. B 1988 27 594. 48 T.-P. Lin B. Shieh and S.-C. Kuo J. Nut. Prod. 1987 50 631. 49 P. Rajamanickam and P. Shanmugam Indian J. Chem. Sect. B 1987 26 910. 50 J. L. Gaston and M. F. Grundon J. Chem. Soc. Perkin Trans. 1 1989 905. 51 H. Paulini R. Waibel and 0.Schimmer Mutat. Res. 1989 227 179. 52 F. Haefele and 0.Schimmer Mutugenesis 1988 3 349. 53 I. A. Bessonova and S. Y. Yunusov Khim. Prir. Soedin. 1989 4 (Chem. Abstr. 1989 110 189344). 54 B. T. Ngadjui J. F. Ayafor S. Mitaku A.-L. Skaltsounis F. Tillequin and M. Koch J. Nut. Prod. 1989 52 300. 55 D. M. Razakova 1. A. Bessonova and S.Y. Yunusov Khim. Prir. Soedin. 1989 51 (Chem. Abstr. 1989 111,233303). 56 B. Sener and F. Ergun Gazi Univ.Eczacilik Fak. Derg. 1988 5 33 (Chem. Abstr. 1989 110 111673). 57 R. Poi and N. Adityachaudhury J. Indian Chem. Soc. 1988 65 814. 58 L. S. R. Arambewela C. K. Ratnayake J. S. Jayasekera and K. T. D. de Silva Fitoterapia 1988 59 151. 59 K. Pundarikakshudu and G. C. Bhavsar Int. J. Crude Drug Res. 1988 26 88. 60 S. M. Jain and C. K. Atal Indian J. Chem. Sect. B 1987,26 585. 61 M. V. Telezhenetskaya B. Tashkhodzhaev M. R. Yagudaev B. T. Ibragimov and S. Y. Yunusov Khim. Prir. Soedin. 1989,18 (Chem. Abstr. 1989 111,233 319). 62 J. Reisch and G. M. K. B. Gunaherath J. Nut. Prod. 1989,52,404. 63 K. R. Nuriddinov K. Sargazakov and S. Abdullaev Khim. Prir. Soedin. 1989 293 (Chem. Abstr. 1990 112 77672). 64 H. Takeuchi and S. Eguchi Tetrahedron Lett.1989 30 3313. 65 S. Eguchi and H. Takeuchi J. Chem. Soc. Chem. Commun. 1989 602. 66 Y. Uozumi N. Kawasaki E. Mori M. Mori and M. Shibasaki J. Am. Chem. Soc. 1989 111 3725. 67 D. Groger Pharmazie 1988 43 815. 68 M. Sainsbury in ‘Rodd’s Chemistry of Carbon Compounds’ ed. M. F. Ansell Elsevier Amsterdam 1987 Supplement to the second edition Vol. TV Part G pp. 245-258. 69 S. Funayama and G. A. Cordell Heterocycles 1989 29 815. 70 H. Paulini and 0.Schimmer Mutagenesis 1989 4 45. 71 N. Yamamoto H. Furukawa Y. Ito S. Yoshida K. Maeno and Y. Nishiyama Antiviral Res. 1989 12 21. 72 R. T. Dorr J. D. Liddil D. D. von Hoff M. Soble and C. K. Osborne Cancer Res. 1989 49 340. 73 H. Fujioka Y. Nishiyama H. Furukawa and N. Kumada Antimicrob.Agents Chemother. 1989 33 6. 74 G. Gu Yaoxue Xuebao 1987 22 886 (Chem. Abstr. 1988 108 183 612). 75 M. Ju-ichi M. Inoue I. Kajiura M. Omura C. Ito and H. Furukawa Chem. Pharm. Bull. 1988 36 3202. 76 T.-S. Wu Phytochemistry 1988 27 3717. 77 T.-S. Wu Phytochemistry 1987 26 3094. 78 A. Ulubelen and H. Guner J. Nut. Prod. 1988 51 1012. 79 M. Brum-Bousquet S. Mitaku A.-L. Skaltsounis F. Tillequin and M. Koch Planta Med. 1988 54 470. 80 S. K. Talapatra B. Karmacharya S. C.De and B. Talapatra Indian J. Chem. Sect. B 1989 28 356. 81 S.-T. Lin and T.-S. Wu J. Chinese Chem. Soc. 1989 36 335. 82 M. H. Bahar and B. K. Sabata Indian J. Chem. Sect. B 1987,26 782. 83 M. H. Bahar and B. K. Sabata Indian J. Chem. Sect. B 1987,26 863.84 0.E. H. Hormi J. Org. Chem. 1988 53 880. 85 J. Reisch and G. M. K. B. Gunaherath J. Chem. Soc. Perkin Trans. 2 1989 1047. 86 S. Mitaku A.-L. Skaltsounis F. Tillequin and M. Koch Planta Med. 1988 54 24.