Quinoline quinazoline and acridone alkaloids Joseph P. Michael Centre for Molecular Design Department of Chemistry University of the Witwatersrand Wits 2050 South Africa Covering July 1994 to June 1995 Previous review 1995 12 465 1 Quinoline alkaloids 1.1 Occurrence 1.2 Non-terpenoid quinoline and quinolinone alkaloids 1.3 Prenylquinolines and hemiterpenoid tricyclic alkaloids 1.4 Monoterpenoid and sesquiterpenoid quinoline alka- loids 1.5 Furoquinoline alkaloids 1.6 Dimeric quinolinone alkaloids 1.7 Decahydroquinoline alkaloids 2 Quinazoline alkaloids 2.1 Isolation 2.2 Structural and synthetic studies 3 Acridone alkaloids 3.1 Occurrence and structural studies 3.2 Synthesis and biological studies 4 References 1 Quinoline alkaloids 1.1 Occurrence Five new quinoline alkaloids were reported during the period covered by this review.Table 1 lists these alkaloids together with known alkaloids isolated from new sources.'-16 In a study of the alkaloidal content of about thirty Penicillium species isolated from food sources the occurrence of viridicatin 1 was confirmed in only two organisms P. palitans and P. viridicaturn.' 1.2 Non-terpenoid quinoline and quinolinone alkaloids A new quinolin-2-one alkaloid 3,4,8-trimethoxyquinolin-2-one 4 has been isolated from the aerial parts of the Australian shrub Eriostemon gardneri.' The compound which was fully characterized with the aid of IR UV 'H NMR and I3CNMR spectroscopies is unique amongst the trimethoxyquinolin-2- ones in having an oxygen substituent at C-3 a position that is normally either unsu bsti tuted or prenylated.Ph 0 H 1 viridicatin 2 R=H; n=14 5 R=OMe; n=6 6 R=OMe; n=5 7 R=OMe; n=4 8 R=OMe; n=12 3 4 9 toddaquinoline The three homologous 2-alkylquinolin-4( 1H)-ones 5-7,iso-lated from the trunk bark of the Amazonian plant Esenbeckia almawillia,' were fully characterized with the aid of standard spectroscopic techniques. The only other 2-alkylquinolin-4-one alkaloid known to possess an 8-methoxy substituent is 1-methyl-2-tridecyl-8-methoxyquinolin-4( 1H)-one 8 reported in 1990 from another Esenbeckia species E. leiocarpa. Several new syntheses of 2-arylquinolin-4( 1 H)-one alkaloids are summarized in Scheme 1.The carbonylation of the 2-nitrochalcone 10 catalysed by triruthenium dodecacarbonyl and the new bis(imine) ligand 11 gave mixtures of 2-arylquinolin-4-ones and their 2,3-dihydro analogues 12.l9 The twelve examples reported include two alkaloids Table 1 Isolation and detection of quinoline alkaloids" Species Alkaloid Ref. Aralia biuinnata Dictamnine 51 1 Skimmianine 52 Boronia algida 1-Methyl-2- pentadecylquinolin-4-one 2 Boronia coerulescens spp. Dictamnine 51 spinescens Boronia inornata Dictamnine 51 Evolitrine 53 Isodictamnine 54 Citrus macroptera Isoplatydesmine 40 5 ( f)-Ribalinine 41 Dictamnus dasycarpus 7,8-Dimethoxymyrtopsine 6 42 7,8-Dimethoxyplatydesmine 43 y-Fagarine 55 Platydesmine 44 Ephedra spp.' 6-Hydroxykynurenic acid 3 7 Eriostemon gardneri 3,4,8-Trimethoxyquinolin- 8 2-one' 4 Esenbeckia almawillia 2-Heptyl-8-methoxy-1- 9 methylquinolin-4-one" 5 2-Hexyl-8-methoxy- 1 - methylquinolin-4-one" 6 8-Methoxy-1-methyl-2- pentylquinolin-4-one' 7 Evodia fatraina Evolitrine 53 10 Evodia rutaecarpa Atanine 45 11 Fagara zanthoxyloides y-Fagarine 55 12 (cell cultures) Skimmianine 52 Sarcomelicope megistophylla Acronycidine 56 13 Acronydine 57 ( -)-Sarcomegistine' 58 Vepris heterophylla Evolatine 60 14 Kokusaginine 61 Tecleaverdoornine 62 Zanthoxylum simulans Toddaquinoline 9 15 Zanthoxylum usambarense (+)-N-Methylplatydesmine 16 46 "Only new alkaloids and new records for a given species are listed.'Ephedra altissima E. distachya E. foeminea E. foliata and E. fragilis. 'New alkaloids. Michael Quinoline quinazoline and acridone alkaloids 2-phenylquinolin-4-one 13 and norgraveoline 14. Both 13 and 14 were amongst five 2-arylquinolin-4-ones prepared by a high-yielding oxidation of the 2,3-dihydro analogues 12 with iodobenzene diacetate.20 The cyclization of 0x0-amide 15 with a low-valent titanium reagent generated in situ from titanium trichloride and zinc afforded 2-phenylquinolin-4-one 13 in 56% yield probably via a titanium enolate." The hydrochloride salt of the same alkaloid was produced in two steps by hydrog- enolysis of the isoxazole 16 over Raney nickel followed by heating of the resulting vinylogous amide 17 in acidic ethanol- water solution.22 Vinylogous urethanes 18 underwent thermal cyclization at 300 "C to yield analogues of 13 bearing methoxy substituents in ring B.23 0 10 0 OCOMe R=H 57:43 R,R=OCH20 40:60 11 / 13 R=H 12 14 R,R=OCH20 It 85% for 13 78% for 14 v 65% for 13.HCI c- \ \NHCOMe 89% \ NHCOMe 17 16 EtOZC 11 ArNH% 18 Scheme 1 Reagents i CO (30atm) Ru~(CO),~ (l%) 11 (3%) EtOH-H,O 170°C; ii PhI(OAc), KOH MeOH 60°C; iii TiCl, Zn THF reflux; iv Raney Ni H3BO3 dioxane; v 1 M HCl in EtOH-H2O (1 :2) 90 "C Two short routes to the anti-leishmania1 quinoline alkaloid chimanine D 19 are illustrated in Scheme 2.24 Since direct epoxidation of 2-(prop- 1-enyl)quinoline 20 was complicated by formation of the heterocyclic N-oxide an indirect method for epoxidation was investigated.Treatment of 20 with N-bromosuccinimide (NBS) and water produced a bromo-hydrin which underwent cyclization to chimanine D 19 in 44% yield upon reaction with sodium hydroxide in propan-2-01. The dibromide 21 was formed as a by-product (22%). In an alternative synthesis of the alkaloid the reaction between quinoline-2-carbaldehyde 22 and the sulfonium ylide derived from triethylsulfonium tetrafluoroborate yielded a mixture of chimanine D (51%) and its cis isomer 23 (42%). New synthetic 12 Natural Product Reports 20 I i ii 44% + 22% 1 19 chimanine D Br 21 aCHO 22 I iii 51% + 42% 1 19 23 24 R=CeHs 25 R=CO*Et 26 R = COzCHzC02Et Scheme 2 Reagents i NBS dioxane-H,O room temp.; ii Pr'OH NaOH (1 M); iii Et3S' BF,- KOH MeCN-H,O 60 "C then 22 MeCN 60 "C analogues of chimanine D include the phenyl compound 24 obtained in 45% yield by the bromohydrin route and the two esters 25 and 26 prepared in 32.5% and 14% yields respect- ively by Darzens condensation between aldehyde 22 and ethyl chl~roacetate.~~ 1.3 Prenylquinolines and hemiterpenoid tricyclic alkaloids In last year's review an important new approach to the enantioselective synthesis of hemiterpenoid quinoline alkaloids involving the resolution of bromohydrins via their correspond- ing (+)-methoxy(trifluoromethy1)phenylacetyl esters (MTPA or Mosher's esters) was described.'*' Boyd and co-workers have now applied this resolution procedure to bromohydrins derived from 3-prenylquinolines 27 (Scheme 3)." Bromohy-drins 28 were made by opening the corresponding racemic epoxide derivatives of 27 with gaseous hydrogen bromide.Compounds 29 and 30 the diastereomeric Mosher's esters of 28 were then separated by multiple elution preparative thin- layer chromatography. The 2'R absolute stereostructure of the crystalline isomer (+)-29 was determined crystallographically. Compound 29 was converted in four steps into (+)-(2'R)- lunacridine 31 thereby confirming a tentative assignment of the alkaloid's absolute configuration made over 20 years ago.26 The non-crystalline Mosher's ester 30 was converted in analo- gous fashion into ( -)-lunacridine ent-31.When the pre- nylated quinoline 32 was subjected to the above procedure the outcome was more complex. The 2-benzyloxy group of the initally formed racemic epoxide was also cleaved on treatment with hydrogen bromide giving the racemic quinolin-2-one bromohydrin 33. Mosher esterification of this product yielded not only the expected diastereomers (+)-(R)-34 and ( -)-(9-35 but also the tricyclic derivatives (+)-(S)-36 and ( -)-(R)-37. Transformations of some of these products into (R)-8-methoxyplatydesmine 38 (3-8-methoxyplatydesmineent-38 and (+)-(S)-9-methoxygeibalansine 39 are illustrated in Scheme 3. OMe OMe OMe OMe OMe OMe OMe OMe 27 28 29 30 v-viii 16% v-viii 15% 1 1 e,::!l-..i,i1dr-\ @w \ 51% OH \ OH \ OH OBn I I I OMe OMe H OMe Me OMe Me 32 33 31 (+)-(2'R)hnacridine ent-31 (-)-(2's)-lunacridine I iii iv ix 42% 21Yo ,-I-? r--l \ \ @r+ OMTPA e\ r OMTPA + q\ y y P A + @JyyA I I OMe H OMe H OMe OMe 34 35 36 37 v iv 31% v iv 34% 1 1 OMe OMe OMe OMe OMe OMe 38 enf-38 39 Scheme 3 Reagents i MCPBA CH2Cl, sodium hydrogen phosphate buffer (1 M pH 8) 0 "C to room temp.; ii HBr (g) Et20 0 "C; iii (+)-MTPA-chloride DMAP (cat.) pyridine room temp.; iv multiple elution preparative TLC; v KOBut THF reflux; vi BH,.THF LiBH, 0 "C then H,SO,-THF room temp.; vii HCl (g) Et,O room temp.; viii MeI K,CO, Me,CO reflux; ix semi-preparative HPLC (Zorbax sil); x KOH MeOH room temp.The known alkaloid atanine 45 has been isolated for the first time from Evodia rutaecarpa a plant used in the traditional Chinese medicine 'wuzhuyu'.' The alkaloid was located by activity-guided fractionation against the sheep nematode Ostertagia circumcincta; the purified alkaloid was also shown Me to be active against larvae of the human parasite Schistosoma H 46 mansoni and against the soil nematode Caenorhabditis elegans.45 atanine These are the first reports of atanine's antiparasitic and anthelmin tic activity . 1.4 Monoterpenoid and sesquiterpenoid quinoline alkaloids The cytotoxicity of the new monoterpenoid quinolinone alka- loids zanthosimuline 47 and huajiaosimuline 48 which were described in last year's review,'" has been in~estigated.'~ Zanthosimuline elicited a general cytotoxic response when evaluated with a variety of cultured human cancer cell lines and cultured P-388 cells.Huajiaosimuline produced a Me Me more selective profile of cytotoxic activity and was especially 40 isoplatydesmine 41 ribalinine R' @-OH R' 42 R1 =OMe; R2=OH 43 R1 = OMe; R2 = H Me Me 44 platydesmine R1 = R2 = H 47 zanthosimuline 48 huajiaosimuline Michael Quin0 line qu inazoline and acr idone alkaloids effective with the estrogen receptor-positive breast cancer cells ZR-75-1. Both compounds were able to induce the expression of cellular markers associated with cell differentia- tion in cultured HL-60 cells but only huajiaosimuline showed significant antiplatelet aggregation activity. Cytochromes bo and bd two terminal respiratory oxidases found in Escherichia coli and many other bacteria catalyse the oxidation of ubiquinol by molecular oxygen.It has recently been shown that the sesquiterpenoid quinolinone alkaloid aurachin C 49 is an extremely potent inhibitor of the quinol oxidation sites of both enzymes; binding appears to be far tighter than that of any previously described inhibitors known to affect the quinone binding Aurachin D 50 is also a highly effective inhibitor of cytochrome bd. I R 49 aurachinC R=OH 50 aurachin D R = H 1.5 Furoquinoline alkaloids ( -)-Sarcomegistine 58 occurs with several known furoquino- line and acridone alkaloids in the aerial parts of the New Caledonian tree Surcomelicope megistophyllu. ' The structure of this new alkaloid was established with the aid of spectro- scopic data that included COSY DEPT heteronuclear multi- ple quantum correlation (HMQC) and heteronuclear multiple bond correlation (HMBC) NMR experiments and by corre- lating the chemical shifts of I3C NMR signals with those of related dihydrofuroquinoline alkaloids such as perfamine 59.The presence of a free hydroxy group was confirmed by the formation of a monoacetate derivative on treatment with acetic anhydride in pyridine. The absolute configuration was not determined. The isolation of sarcomegistine is inter- esting from a chemotaxonomic viewpoint because the only other known alkaloids possessing the rare ring B oxidized furo[2,3-b]quinoline system occur in the genus Huplophyllum. In vitro cell culture of Fugaru zunthoxyloides a West African tree used in traditional medicine has been reported for the first time.Both benzophenanthridine and furoquinoline alkaloids were isolated from cultures the levels of the latter remaining high even after several months of subculture. Levels of y-fagarine 55 which has apparently never been isolated from intact I; zanthoxyloides plants decreased with time as levels of skimmianine 52 increased thus supporting the notion that 55 is a biosynthetic precursor of 52. The production of furoquinoline alkaloids as well as acri- done epoxides can be elicited in in vitro cultures of Rutu graveolens by challenging the cultures with a homogenate of the yeast Rhodotorulu rubra2* Alkaloid promotion seems to occur by stimulation of anthranilate synthase which biases the biotransformation of chorismate towards the branch of the shikimic acid pathway responsible for the production of anthranilic acid-derived metabolites.Oxymercuration of acrophylline 63 with mercuric acetate in water-THF followed by treatment with sodium borohydride yielded acrophyllidine 64 (73%).29 When tested for antiallergic responses both compounds were found to reduce the volume of plasma exudate in mice suffering from oedema of the ear though apparently by different mechanisms. Skimmianine 52 and to a lesser extent kokusaginine 61 and confusameline 65 act as antagonists at the 5-HT2 receptor site for the neurotransmitter 5-hydroxytryptamine (serotonin) in isolated membranes of the rat cerebro~ortex.~' 14 Natural Product Reports OMe I R3 51 dictamnine R1 = R2 = R3 = H 52 skimmianine Ri = H; R2 = R3 = OMe 53 evolitrine R1 = R3 = H; R2 = OMe 55 y-fagarine R1 = R2 = H; R3 = OMe 60 evolatine R1 = OMe; R2 = OCH2CH(OH)C(OH)Me2; R3 = H 61 kokusaginine R1 = R2 = OMe; R3 = H 65 confusameline R1 = R3 = H; R2 = OH 0 OMe OMe \ I I Me OMe MeO-54 isodictamnine 56 acronycidine 57 acronydine R OMe OMe OMe 58 sarcomegistine R = OH 62 tecleaverdoor nine 59 perfamine R=H 0 0 1 OH 63 acrophylline 64 acrophyllidine 1.6 Dimeric quinolinone alkaloids The synthesis of dimeric quinolinones by Diels-Alder cycloaddition of dienes such as 66 was previously described in a comm~nication~~ [cf ref.18(d)]. An amplified report of this work has now been published with full experimental details.32 Palladium-catalysed coupling of iodoquinolin-2-one 67 with 2-methylbut-3-en-2-01 has been improved by strict temperature control to yield diene precursor 68 (73%) rela- tively free of the by-products that were isolated in the earlier work (Scheme 4).Dehydration of 68 with acetic acid con- taining concentrated sulfuric acid for 2 h at room tempera- ture yielded viu the detectable diene 66 a mixture of the Diels-Alder dimer 69 (27%) a previously undescribed dimer 70 (34%) and N-methylflindersine 71 (12%). When the reac- tion time was increased to 48 h 69 was no longer found; instead 70 (34.5%) was accompanied by the dimer 72 (33%). It was shown in a separate experiment that dimer 69 could be converted quantitatively into 72 on leaving it to stand in the acidic medium for one day.The stereochemistry of 72 previously undetermined was elucidated with the aid of X-ray crystallography. Compound 70 underwent base-induced hydrolysis and rearrangement probably via the ring opened intermediate 73 to give 74 (97%) the structure of which was also determined crystallographically. Me Me I I - I I Me Me 67 68 I 66 ii or/iii -Me -\ I IV Me J OAc 0 V I 97% 70 74 Me 71 Scheme 4 Reagents i H,C=CCMe,OH Pd(PPh,),Cl, CuI NEt, DMF 85-90 "C 3 h; ii HOAc H,SO, 2 h; iii HOAc H,SO, 48 h; iv HOAc H,SO, 24 h; v aq. NaOH (1 M) EtOH room temp. 1.7 Decahydroquinoline alkaloids Analysis of 'Bohlmann bands' which occur in the IR region between 2800-2600cm-' has been used to elucidate the relative stereochemistry at three of the four stereogenic centres in several decahydroquinoline alkaloids isolated from the skins of dendrobatid frogs.33 The technique works because 2,6-cis- disubstituted piperidine rings show significant Bohlmann bands whereas the trans isomers do not.The effect depends on the dihedral angle between the nitrogen lone pair and a-CH bonds and on the number of a-hydrogen atoms that are trans-antiparallel to the lone pair. Using cis-fused alkaloid 195A 75 -also known as pumiliotoxin C -and three of its synthetic epimers as reference compounds the authors were able to assign the stereochemistry of a new alkaloid extracted from the skin of the Peruvian frog Epipedobates bassleri as trans-195A 76.The relative stereochemistry at C-5 remains unknown. The relative stereochemistries of five other recently isolated34 decahydroquinoline alkaloids from amphibian skin were similarly determined. A new synthesis of ( f)-pumiliotoxin C rac-75 by Mehta and Praveen makes use of regioselective Haller-Bauer cleav-age of the readily available Diels-Alder dimer 77 with sodium hydroxide solution (Scheme 5).35 Esterification of the cleaved products afforded a 3:7 mixture of the epimers 78 and 79 without competitive isomerization of the double bond into conjugation. After a sequence of standard functional group transformations on 79 Beckmann rearrangement of the oxime derived from ketone 80 gave the bicyclic lactam 81 containing three of the four stereogenic centres of the target alkaloid.The remaining stereogenic centre was introduced by treatment of imino ether 82 with propylmagnesium bromide followed by a facially selective reduction with diisobutyl- aluminium hydride. The final product was characterized as its hydrochloride salt. Michael Quinoline quinazoline and acridone alkaloids The synthesis of ( -)-pumiliotoxin C 75 by Kibayashi and co-~orkers~~ took advantage of an intramolecular Diels-Alder cycloaddition that occurred spontaneously when the chiral hydroxamic acid 83 was oxidized with periodate (Scheme 6). In non-aqueous medium the acylnitroso inter- mediate 84 was converted into a mixture of two adducts 85 and 86 with relatively poor diastereoselectivity (1:1.4).How- ever the ratio of the latter product was increased substan- tially (1:4.5) in aqueous medium. After catalytic hydrogena- tion of 86 the propyl side chain adjacent to nitrogen was introduced completely stereoselectively by addition of propyl- magnesium bromide followed by reduction with sodium cyanoborohydride. The oxazine ring of 87 was cleaved by hydrogenolysis to give the 2,6-cis-dialkylpiperidine 88 after which functional group interconversions and aldol condensa- tion afforded the enone 89. Catalytic hydrogenation of 89 occurred exclusively from the less hindered p face to establish the cis-fused decahydroquinoline ring system in 90. Unfortu-nately the C-5 methyl substituent emerged with the incorrect configuration.On the basis of finely argued conformational arguments the N-benzoyl protecting group was reduced to the corresponding N-benzyl equivalent before base-induced epimerization was attempted. The best ratio of the ensuing products 91 and 92 was 1.2:l. Prolonged heating with zinc trifluoromethanesulfonate followed by ethanedithiol induced further epimerization and a single thioacetal 93 was isolated in 66% yield. The synthesis of (-)-pumiliotoxin C 75 was completed as illustrated. The first asymmetric synthesis of a trans-decahydroquinoline alkaloid (+)-2 19A 94 has been reported by Comins and Dehghani (Scheme 7).37In this new variation of the well-known Comins methodology for alkaloid syn- thesis the chiral N-acylpyridinium salt 95 was converted in five steps into the 2,6-cis-disubstituted piperidinone 96.The trL HI H 76 trans-1 95A 0 65% (3:7) 0 77 78 79 iii-viii 24% J xi- ix x - 65% HI H 82 81 80 xii xiiil45% HI H rac-75 pumiliotoxin C Scheme 5 Reagents i NaOH (aq. l%) (36 room temp.; ii CH,N, Et,O 0 "C; iii HOCH,CH,OH p-TsOH C,H, Dean-Stark appara- tus then chromatography on SiO,; iv LiAlH, THF reflux; v CBr, PPh, CH,Cl, 0 "C to room temp.; vi H (1 atm) 10% Pd-C EtOAc room temp.; vii NaBH,CN HMPA 80 "C; viii aq. HCl; ix NH,OH.HCl NaOAc MeOH room temp.; x p-TsC1 NaOH H,O- dioxane 5 "C to room temp.; xi Me,O' BF,- Et,NPr' CH,Cl, 10 "C; xii PrMgBr C6H6 reflux; xiii DIBAL CH,Cl, -78 "C bicyclic nucleus was created by oxidative cleavage of the alkenyl group of 96 followed by intramolecular aldol con-densation to yield 97.The stereogenic centre at C-5 was introduced by stereoselective conjugate addition of a higher- order cuprate followed by trapping of the resulting enolate as the vinyl trifluoromethanesulfonate 98. The alkene 99 derived from 98 by palladium-induced hydrogenolysis followed by deacylation underwent stereoselective hydrogenation to give a mixture of trans-and cis-fused quinolines 100. Separation of the isomers was left until after replacement of the OH groups by phenylseleno substituents the major product being the trans compound 101 (87:13). From this isomer the synthesis of (+)-trans-219A 94 was completed as illustrated.2 Quinazoline alkaloids Developments in the chemistry of quinazoline alkaloids over the period 1986 to July 1993 have been reviewed by Johne in a recent supplementary volume to Rodd's Chemistry of Carbon Compounds.38The same supplement includes a review of recent syntheses and reactions of pyrimidines and quina~olines.~~ 2.1 Isolation 2-Acetylquinazolin-4(3H)-one102 has been isolated from a culture broth of the mycoparasitic fungus CZadobotryum varium together with several a-pyrone and amino acid derivative^.^' 83 84 85 + 96% \ \ 87 86 I Me ,..A I HI OH COPh COPh 88 89 71% xi xii 4 73% (1.2:l)'&..,A HI COPh 91 90 + n CH2Ph ' ' CH2Ph 92 93 xiv vil 63% Me IH m.-.-HI H 75 (-)-pumiliotoxin C Scheme 6 Reagents i Pr,NIO, H,O-MeOH (6:1) 0 "C; ii H, 10% Pd-C THF room temp.; iii PrMgBr THF O"C then NaBH,CN AcOH THF 0°C; iv Zn AcOH (aq.85%) 60°C; v PhCOC1 CH,CI, K2C03 (aq. lo%) then KOH; vi H, 10% Pd-C MeOH room temp.; vii PCC CH,Cl, room temp.; viii KOH MeOH 0 "C; ix KHSO, MeOH room temp.; x H, 10% Pd-C 1 M HC1 room temp.; xi LiAlH, THF reflux; xii (COCI), DMSO CH,CI, -90 'C then NEt, room temp.; xiii Zn(OTf), CH,Cl, reflux 4d then (CH,SH), reflux 4 d; xiv Raney Ni dioxane reflux A new investigation on a well-studied Indian medicinal plant Adhatoda vasica has yielded four known alkaloids ( -)-vasicine 103 ( -)-vasicinone 104 ( -)-vasicol 105 and anisotine 106 as well as two new natural prod-ucts 3-hydroxyanisotine 107 and vasnetine 108.4' 3-Hydroxyanisotine was previously known as a synthetic com- pound prepared by oxidation of anisotine with potassium permanganatee4* All the compounds isolated in this study were characterized with the aid of an unusually comprehensive range of 'H and I3C NMR experiments.In fact this publica- tion indubitably contains the definitive NMR data (S and J values) for pyrrolo[2,1 -b]quinazoline alkaloids. The authors 16 Natural Product Reports 9 X C02R C02R C02Ph 95 R = (+)-frans-2-102 103 (-)-vasicine R = OH X = H,H I (a-cumyl)cyclo hexyl V 79% 104 (-)-vasicinone R = OH; X = 0 111 deoxyvasicine R = H; X = H,H 113 peganol R = H; X = H,OH 114 deoxypeganidine R = H; X = H,CH2COMe I I C02Ph C02Ph 97 96 viii ix 182% C02Ph H 98 99 I 'H ArAe W S e A r xiii-xv 63% (+ 10% cis) HI HI C02Bn H 101 100 xvi xvii 187% HI H 94 (+)-219A Scheme 7 Reagents i H2C=CH(CH,),MgBr toluene-THF -78 OC then radial PLC; ii NaOMe MeOH then aq.HCl (10%); iii BuLi; iv PhOCOCl; v BnO(CH,),MgBr CuBr BF,-OEt, -78 "C; vi OsO (cat.) NaIO,; vii p-TsOH C,H, 52 "C;viii [BnO(CH,),],CuCNLi,; ix N-(5-chloro-2-pyridyl)triflimide; x HCO,H Bu,N (Ph,P),Pd(OAc),; xi KOH Pr'OH reflux; xii H, 5% Pt-C Pd(OH), EtOH; xiii BnOCOCI NaOH; xiv K,CO, MeOH; xv o-NO,PhSeCN Bu,P CH,Cl,; xvi H,O (30%) THF; xvii Na NH, THF ascribed the variability in published optical rotations for ( -)-vasicine to oxidative conversion into vasicinone.Investigation of the epigeal parts of Nitraria komarovii has yielded two new pyrrolo[2,1 -b]quinazoline alkaloids deoxy- peganine N-oxide 10943 and peganine N-oxide l10.44 In addition to the customary spectroscopic characterization chemical confirmation of the structure of 109 was provided by reduction with zinc and hydrochloric acid which afforded a compound identical in all respects to authentic deoxypeganine (=deoxyvasicine) 111. Similarly reduction of 110 yielded peganine (=vasicine) 103 and a small quantity of deoxypega- nine. Other quinazoline N-oxides from the same plant were described in last year's review.I8" A new quinazolinocarboline alkaloid (+)-7-hydroxy-rutaecarpine 112 has been isolated from the heartwood ,of Tetradium glabrifolium (=Evodia meliaefolia) and the fruit of T.r~ticarpum.~~ The gross structure was elucidated by means of full spectroscopic analysis. The axial orientation of the 7-hydroxy group was inferred from the small coupling con- Michael Quinoline quinazoline and acridone alkaloids dqR OH OH QC02Me KQ NHMe 105 vasicol 106 anisotine R = H 107 3-hydroxyanisotine R = OH q/Q R 0 108 vasnetine 109 R=H 110 R=OH BrqcDQd& HO H -OMe 115 112 stants between H-7 and the adjacent hydrogen atoms on C-8. The absolute configuration of the new alkaloid was not determined. 2.2 Structural and synthetic studies Unambiguous 'H and 13C NMR assignments for a range of quinazolin-4(3H)-ones and their corresponding 4-thiones should be useful in future structural elucidations of quin- azolinone alkaloids of this class.46 X-Ray crystallographic analyses have been reported for dehydroxypeganine and hydrochloride dih~drate~~ the peganine-zinc chloride complex,48 as well as for several tetramethylene and pentam- ethylene analogues and their derivative^.^^ Peganolll3 has been converted into deoxypeganidine 114 in 30% yield upon heating with anhydrous copper sulfate and acetone." In view of the pharmacological potential of vasicine analogues the novel brominated analogue 115 of deoxyvasi-cine was synthesized from 2-amino-5-bromovanillin and 4-aminobutyraldehyde for studies on structure-activity relationships.5' Danishefsky and co-workers have devised a three-step syn- thesis of the reverse-prenylated hexahydropyrroloindole sys- tem 116 from bis(tert-butoxycarbony1)tryptophanmethyl ester 117.52Compound 116 was an intermediate in the synthesis of several alkaloids including the quinazolinones ardeemin 118 and N-acetylardeemin 119 the latter having importance as a potent agent for reversal of multiple drug resistance in human tumour cell lines.The central feature of these syntheses was an efficient (72%) intramolecular variant of the aza-Wittig reac- tion as exemplified by the conversion of 120 into ardeemin 118 (Scheme 8). Boc 117 116 i ii/71yo 120 v 72% 1 118 ardeemin R = H 119 5-Kacetylardeernin R = Ac Scheme 8 Reagents i FCN pyridine CH2CI, -15 “C; ii D-Ala- OMe-HCl NaHCO, H20 CH,C12; iii TMSI MeCN O’C then NH, DMAP MeOH; iv KHMDS o-N,C,H,COCI THF -78 “C; v Bu,P C,H,; vi LDA THF -78 “C to room temp.then AcCI reflux 3 Acridone alkaloids 3.1 Occurrence and structural studies The new alkaloids isolated during the review period (Table 2) include four members of the rapidly growing family of acridonexoumarin dimers. Roots of the Citrus hybrid ‘Yalaha’ (a cross between the Duncan grapefruit C. paradisi and C. tangerina the Dancy tangerine) yielded representative examples of three distinct classes of dimer.53 Acrimarine-N 121 was isolated as an optically inactive oil. Like all the other acrimarines it incorporates the coumarin suberosin linked in this case through C-1’ of its prenyl side chain to C-2 of the known acridone alkaloid citpressine-I1 122.In ( -)-neoacrimarine-E 123 the acridone moiety is natsucitrine-I1 124. The most interesting new compound is (+)-dioxinoacrimarine-A 125 which is the first doubly-bridged acridone-coumarin dimer to have been isolated from a natural source. The 1,4-dioxane ring connecting the acridone and coumarin nuclei has been encounted previously only in the acridone-lignan dimer acrignine-A 126.Isf All the new alka- loids were characterized spectroscopically with HMBC 18 Natural Product Reports Table 2 Isolation and detection of acridone alkaloids“ Species A1 kaloid Ref. Citrus hybrid ‘Yalaha’ Acrimarine-Nb 121 53 (+)-Dioxinoacrimarine-A’ 125 ( -)-Neoacrimarine-E’ 123 Citrus paradisi ( f)-Citbismine-A’”127 54 (+)-trans-Dihydroxycitracridone-55 Ib 129 Furoparadine’” 128 55 Marshdineb 130 56 ( -)-Marshmine’ 131 56 Sarcomelicope Melicopidine 132 13 megistophylla 1,2,3-Trimethoxy-N-methylacridone 133 “Only new alkaloids and new records for a given species are listed.’New alkaloids. 0 OH A Me0 OMe Me 121 acrirnarine-N OMe k 122 R=Me 124 R=H 0 OH 123 neoacrirnarine-E experiments proving especially valuable in establishing con- nectivities through 2J and 3J correlations. The absolute configurations were not determined. Five new alkaloids have been isolated from the roots of the grapefruit variety Citrus paradisi. Citbismine-A 127 is the first example of a bis(acridone) alkaloid in which the two units are linked by a C-C bond between aromatic and dihydrofuran rings.54 Its gross structure and relative stereochemistry were unequivocally established by X-ray crystallographic analysis after NMR experiments failed to reveal the positions of all substituents.Furoparadine 128 is the first example of an acridone alkaloid possessing the rare furo[2,3-c]acridone nucleus to have been found in the genus Structures for the remaining new alkaloids (+)-trans-dihydroxy-citracridone-I 129,55 marshdine 13056 and ( -)-marshmine 131,56were relatively easily determined by modern spectro- scopic methods. The absolute configurations of 129 and 131 were not established. 0 OH OMe ? %0 Me 125 dioxinoacrimarine-A 0 OH OMe 126 acrignine-A 0 OH OMe H 127 citbismine-A 0 OH 0 OH \ / 0 N OMe Lo he 130 marshdine 131 marshmine 0 OMe Me OMe 132 melicopidine The X-ray crystal structure of the prototypical acridone alkaloid 9( 1OH)-acridone has been determined.57 Intermo- lecular hydrogen bonding between NH and O=C groups and Michael Quinoline quinazoline and acridone alkaloids 7c-7c interactions are the dominant factors controlling the packing of molecules in the crystal lattice.3.2 Synthesis and biological studies Treatment of the acridone alkaloid noracronycine 134 with lithium aluminium hydride or alkyl- and aryl-lithiums in diethyl ether at room temperature or above yielded the 7-substituted o-quinone methides 135 (9-750/0) as blue solids.58 When 1-hydroxy-3-methoxy-N-methylacridone136 was the substrate the analogous purple o-quinone methides 137 were isolated (25-90%).Since neither acronycine 138 nor the dimethoxy compound 139 reacted with alkyllithiums it is likely that lithiated intermediates such as 140 are involved the subsequent reaction presumably then proceeding by addition of the nucleophile to the carbonyl group followed by dehydration. The quinone methide products have potential as alkylating agents for antitumour therapy; their reactivity towards nucleophiles was demonstrated by the formation of 141 (60%) and 142 (74%) when 137 (R=Bu) was treated with methyllithium and lithium aluminium hydride respectively. Thio thioacetyl oxime hydrazone and azine derivatives of acronycine 138 have been prepared from the parent alkaloid and the configurations about the C=N bond in the nitrogen derivatives have been elucidated by NMR spectroscopy.59 Several acronycine analogues obtained by methylation of the corresponding noracronycine precursors with iodomethane- sodium hydride showed weak activity against a variety of tumour cell lines.60 The experimental antitumour activities chemical synthesis and structure-activity relationships of the alkaloids acronycine 138 and glyfoline 143 have been described in a review that highlights their activity against leukaemia and three different murine solid tumours.61 0 OR Me Me 133 R' = R* = OMe 134 noracro nycine R = H 136 R' =OH; R2 = H 138 acronycine R = Me 139 R' = OMe; R2= H RO I II 135 R = H,Me Bu Ph 4-Me2N-C6H4 (CH2)3NMe2 I Me 137 R = Bu 4-Me2N-C6H4 (CH&NMe2 140 Bu R OH 0 OH \ / OMe HO OMe Me Me0 Me OMe 141 R=Me 142 R=H 143 glyfoline 4 References 1 J.-J.Hsaio H.-T. 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