The leaves of Alseodaphne perakensis contain one major and a complex mixture of minor alkaloids. The

major component was identified as N-methyl-2,3, 6-trimethoxymorphinandien-7-one by spectroscopic analyses

of the parent compound, its methiodide salt and sodium borohydride reduction products

Din, Laily

Lajis, Md Nordin

Mahmud, Zurina

Toia, Robert F.

Universiti Putra Malaysia Institutional Repository

Pertanika 12(3), 421-424 (1989)COMMUNICATION IChemotaxonomy of the Lauraceae: N-Methyl-2,3,6-trimethoxymor-phinandien-7-one, the Major Alkaloid from Alseodaphne perakens'isABSTRAKDaun pokok Alseodaphne perakensis mengandungi satu alkaloid utama dan campuran kompleks alkaloidsampingan. Komponen utama telah dikenal pasti sebagai N-metil-2,3, 6-trimetoksimorfinandien-7-on melaluianalisis spektroslwpi sebatian induk, garam metiodida dan hasil penurunan natrium borohidrida.ABSTRACTThe leaves ofAlseodaphne perakensis contain one major and a complex mixture of minor alkaloids. Themajor component was identified as N -methyl-2,3, 6-trimethoxymorphinandien-7-one by spectroscopic analysesof the parent compound, its methiodide salt and sodium borohydride reduction products.INTRODUCTIONDuring a phytochemical survey in the Lancangarea of West Malaysia, a specimen identified asAlseodaphne perakensis was selected for chemicalinvestigation because of its high alkaloid con-tent as indicated by the Culvenor-Fitzgerald fieldtest method (Lajis et al. 1985). A. perakensis isa moderate sized tree growing in the lowermoun tain forest in the western part ofPeninsular Malaysia and has been reported toprovide a durable timber useful for housebuilding. In addition, the aborigines of the Sakaitribe claimed that the fruit from this plant ispoisonous (Burkill, 1936). It is also of interestto note that this species was formerly classifiedas Dehaasia microcarpa. A literature surveyindicated that chemical investigation of a re-lated species, A. semicarpifolia resulted in theisolation of a hydroxyaporphine alkaloid(Smolnycki et al. 1978) but that no work hadbeen reported on A. perakensis. We now reportthe, esults from our work on the isolation andstruc.tural assignment of the major alkaloid fromthis latter species.MATERIALS AND METHODSGeneralThe leaves and bark of this plant were collectedfrom the vicinity of the Wild Life TrainingCenter, Lancang, Pahang and the voucherspecimen was deposited at the herbarium ofthe University Pertanian Malaysia.Melting points were determined on aKofler hot stage and are uncorrected. Infraredand ultraviolet spectra were recorded on HitachiEPI-62 and Perkin Elmer 124 spectrophoto-meters respectively. Rotations were measuredon Bendix NPL Automatic Polarimeter 143C atroom temperature (23-25°C). IH nmr spectrawere measured at 300 MHz on a Bruker CPX300 instrument, and 13C nmr spectra were takenon a Bruker WP80. Mass spectra were recordedon a MS 12 instrument at 70eV. Spectral datafor known compounds are quoted only whenthe literature is incomplete. Column and thinlayer chromatography utilized Merck 7734 and7730 silica gel, respectively. Solvents were dis-tilled before use.Extraction of Plant MaterialThe leaves (1.8Kg) were air dried, ground in ahammer mill to give a powder which was steepedin methanol for 48 hrs. The methanol wasremoved by filtration and fresh methanol addedto the plant material. This process was repeateduntil the re'sidue gave a negative test for alka-loids (Meyers reagent). The methanol extractswere combined and evaporated under reducedpressure to give a green gum. The gum wastaken up in chloroform and extractedrepeatedly with 1M H 2S04 until the organicNORDIN H. LAJIS, ZURlNA MAHMUD, lAILY BIN DIN AND ROBERT F. TOlAPERTANIKA VOL. 12 NO.3, 1989layer gave a negative test for alkaloids. The acidextracts were then combined, basified witha2C03and exhaustively extracted with chloro-form. The chloroform extracts were combined,dried and the solvent removed to give the crudealkaloids as a dark brown amorphous solid (18g, 1%).Isolation of N -methyl-2,3, 6-trimethoxymorphinandien-7-oneA portion of the crude alkaloids (3.8 g) wasfractionated using centrifugal tic. The majorcomponent was eluted at a solvent compositionof CHCI3:MeOH (9:1) and obtained, after eva-poration of the solvent, as a brown gum. Thismaterial was further purified by tic after whichcrystallization froin benzene yielded yellowishcubes (2.1 g). The UV, IR, lH and 13C NMR andMS were consistent with literature (Roblot etal. 1984); m.p.: 127.5-128°c, (lit. m.p. 124-125°C, Lu et al. 1985); [a]o = 11.7°, MeOH(lit. [a]o = 16.9°, MeOH; Bhakuni et al. 1980).Quartemization of N-methyl-2,3, 6-trimethoxymorphinandien-7-oneN-Methyl-2,3,6-trimethoxymorphinandien-7-one(149 mg) was dissolved in dry acetone contain-ing excess methyl iodide. The reaction mixturewas allowed to stand overnight at room temper-ture after which a crystalline solid formed. Thematerial was recovered by filtration and sub-sequently recrystallized from methanol to giveN-methy1-2,3,6-trimethoxymorphinandien-7-onemethiodide (200 mg, 94%) as yellow cubes m.p.:257-8°C. (lit. m.p.: 252-4°C, EtOH; Sivakumaranand Gopinath 1976).Reduction of N-methyl-2,3, 6-trimethoxymorphinan-dien-7-oneThe title compound (154 mg) was dissolved inethanol (10 ml) and the flask cooled in an icebath. Sodium borohydride (1.2 g) was addedand the reaction mixture stirred for one hourafter which water (2 ml) was added. The solu-tion was concentrated and the remaining aque-ous mixture extracted with chloroform. Thecrude product (177 mg) was fractionated bypreparative tlc on silica gel using benzene:ethylacetate:diethylamine (7:2:1 v/v/v) as eluant togive dienol 1 (46 mg) (Rf. 0.33) and dienol II(50 mg) (Rf. 0.19).422Dienol I[a]o = + 22.7° (MeOH)UV Am•xnm (log £) MeOH:225 (sh) (4.08), 287(3.65)IR Dm•xcm- I (CHCI3 film):3200-3600 (OH hydrogen bonded), 1656 (C =C), 1610 (w, aromatic), 1510 (s,aromatic).IH NMR (500 MHz, CDCI3):6.73 (s, IH), 6.53 (s, IH), 5.73 (d,] = 4 Hz, IH,H-8), 5.27 (s, IH, H-5), 4.64 (d,] = 4Hz, H-7),3.83 (s, 3H, Ar-OCH3), 3.81 (s, IH, Ar-OCH3),3.69 (s, 3H, C6 - OCH3), 3.45 (d, ]=6Hz, IH,H-9), 3.19 (d,] = 17.8 Hz, IH, H-I0), 2.87 (dd,] = 6, 17.7 Hz, IH, H-I0), 2.80 (s, br, OH), 2.40-2.48 (m, 2H, H-16), 1.82 (ddd,] = 5.0, 12.7,12.7 Hz, IH, H-15), 1.54(ddd,] = 2.6,2.6,12.7Hz, H-15).13C NMR (125.7 MHz, CDCI3; DEPT-experi-ment)154.49 (C-2 or C-3), 148.02 (C-2 or C-3) , 142.10(C-6), 134.0 (C-11 or C-12),129.16 (C-11 or C-12), 118.25 (CH,G8),110.82(CH, C-l or C-4)108.87 (CH, C-l or C-4) , 101.76 (CH, C-5) ,64.76 (CH, G7), 61.31 (CH, G9), 56.58 (OCH ),356.32 (OCH3), 54.88 (OCH3), 46.94 (CR." C-16),42.34 (G15 and -CH3) , 39.96 (GI3), 3-1,34(CH2, C-lO).Ms mle (%):344 (M + 1, 11.2), 343 (M+, 44.8), 342 (17.6),328 (33.6), 326 (46.4), 325 (100), 310 (40),269(36.8), 267 (46.4), 256 (20).Dienol II[a]D = + 17.3° (MeOH)UV Am., nm (log £) MeOH255 (sh) (4.00), 288 (3.55)IR Um•xcm·l (CHCI3 film)3200-3600 (OH bonded), 1660 (C = C), 1615(w, aromatic), 1520 (s, aromatic).lH NMR (500 MHz, CDCI3):6.74 (s,lH), 6.57 (s, IH), 5.74 (d,] = 3.3 Hz,IH, H-8) , 5.26 (s, IH, H-5) , 4.52 (d,] = 3.3 Hz,H-7), 3.85 (s, 3H, Ar-OCH3), 3.82 (s, 3H, Ar-OCH3), 3.71 (s, 3H, C6 - OCH3), 3.54 (d,] =5.9 Hz, IH, H-9) , 3.24 (d,] =17.7 Hz, IH, H-10),3.18 (s, br, OH), 2.92 (dd,] = 6.1,17.9 Hz,CHEMOTAXONOMY OF THE LAURACEAEIH, H-I0), 2.45-2.57 (m, 2H, H-16), 2.45 (s, 3H,N-CH3) ,1.97 Hz (ddd,j = 4.8,12.5,12.5 Hz, IH,H-15), 1.59 (ddd, j = 2.75, 2.75, 12.6 Hz, IH,H-15).J3C NMR (125.7 MHz, CDCI3; DEPT-experi-ment)154.47 (C-20rC-3), 148.11 (C-20rC-3), 140.24(C-6), 133.99 (C-ll or C-12), 128.92 (C-ll orC-12), 119.11 (CH, C-8), 110.90 (CH, C-l or C-4),108.43 (CH C-l or C-4), 101.09 (CH, C-5),64.31 (CH, C-7), 61.20 (CH, C-9), 56.35 (2 xOCH3), 54.99 (OCH3), 46.97 (CH2, C-i6),42.118 (N-CH3), 41.55 (CH 3 , C-15), 39.95(C-13), 31.98 (CH2, C-I0).MS mle (%)344 (M+l, 12.8),343 (M+57.6), 342 (22.4),328(40),326 (48),325 (100),310 (36.8),269 (27.2),267 (25.6), 256 (19.2).RESULTS AND DISCUSSIONAlseodaphne perakensis is a rich source of alka-loids, with crude bases being isolated from theleaves in 1% yield. This mixture was complex,but with one major component, 1, isolated byvarious chromatographic methods and purifiedby multiple recrystallisation.The mass spectrum of 1 showed a molecu-lar ion of m/e 341 corresponding to a molecu-lar formula of C20 H 23 N04 . The UV spectrumdisplayed strong absorption bands at Amax280and 238 nm (log £ = 3.94 and 4.20 respectively)and the IR spectrum indicated the presence ofan a-~ unsaturated carbonyl functionality (umax1662, 1641, 1620 cml).The IH and l5C NMR data suggested amorphinandienone skeleton and scrutiny ofthe literature indicated the known N-methyl-2,3, 6-trirnethoxymorphinandien-7-one as theprobable structure (Roblot et al. 1984). Sup-port for the structural assignment was forth-coming by the sodium borohydride reduction(Battersby et al. 1981). Thus, reduction of theparent alkaloid gave a pair of diastereomericalcohols, designated as I and II in a 1: 1 ratio,in quantitative yield. These were readily sepa-rated using preparative thin layer chro-mato-graphic techniques. The lH nmr spectra ofthesecompounds were consistent with the proposedstructures, and the absence of vicinal couplingto H-7 supported the placement of one of themethoxy groups in the parent ketone at C-6. Inaddition, signals at 8 6.35 and 8 6.32 on theparent ketone can be assigned as the cyclohex-adienyl protons since they shift upfield onreduction of the carbonyl group.Further examination of the literaturerevealed that the parent alkaloid occurs underthree names, either O-methylflavinantine(Gerard et al. 1986), O-methylpallidine(Kametani et al. 1969) or sebiferine (Bhakuniand Singh 1979) depending on its configura-tion. In the present work, the optical rotationof the compound indicated that the alkaloidfrom A. perakensis is identical with sebiferine(Bhakuni and Singh 1979).Sebiferine and its (-) isomer have beenisolated from several other plants includingCocculus laurifolius (Menispermaceae) (Bhakuniand Jain 1980), Rhigiocarya racemifera (Menis-~--'-,16oCHiJOHDienol IandDienol II(1) (2)PERTANIKA VOL. 12 NO.3, 1989 423NORDIN H. LAJIS, ZURINA MAHMUD, LAlLY BIN DIN AND ROBERT F. TalApermaceae) (Tackie et al. 1974) and Litseasebifera (Lauraceae) (Sivakumaran andGopinath 1974).Pharmacological studies have been re-ported on O-methylflavinantine and it has beenshown to depress the response of the isolatedguinea pig ileum to coaxial electrical stimula-tion (Naomesi 1980). In addition, biologicalscreening has shown it to have uterine stimu-lating properties; it is also hypotensive, an anal-gesic agent and results in reduction of motoractivity (Kanjanapothi 1987). This range ofact-ivity is of interest and warrants similar investiga-tion for other compounds in this general class.ACKNOWLEDGEMENTThe authors wish to thank the InternationalFoundation for Science (IFS) for financingthis work, UNESCO Network for the Chemistryof Natural Products for South East Asia for thetravel grant to UNSW and the network for theChemistry of Biologically Important aturalProducts, (NCBINP) an activity of the Interna-tional Development Program of AustralianUniversities and Colleges for its support. Dr.H.M. Ruth Kiew and Dr. Ab. Latif Mohamedare also thanked for their assistance in identi-fYing the plant specimen.NORDIN H. LAJISZURINA MAHMUDChemistry Depmtment,University Pertanian Malaysia43400 UPM Serdang, Selangor Darul Ehsan,MALAYSIA.LAlLY BIN DINChemistry DepartmentUniversity Kebangsaan Malaysia43600 Bangi, MALAYSIA.ROBERT F.TOIADepartment of Organic ChemistryUniversity of New South WalesKensington, NSW 2033 AUSTRALIA.Present Address: Pesticide Chemistry and ToxicologyLabomtor)',University of California, Berkeley,CA 94720, USA.REFERENCESBAITERSBV A.R., A.K BHATNAGAR, P. HACKEIT , C.W.THOR 'BER, and j.STAUNTON. 1981. Synthesisalong Biosynthetic Pathways. Part 2. Synthesis ofProtostephanone. j. Chern. Soc., Perkin Trans. 1 7:2002-9.BHAKUNI, D.S and S. JAIN. 1980. Alkaloids ofCocculus laurifolius D.C. Tetrahedmn 36: 3107-14.BHAK NI D.S. and A. . SINGH. 1979. Absolute Con-figuration of Sebiferine. Tetrahedmn 35: 2365-7.BURKlLL I.H. 1936. A Dictionary of the EconomicProducts of the Malay Peninsular, 2 vols. CrownAgents for the Colonies, London. (Reprint 1966,Ministry of Agriculture and Cooperative, KualaLumpur).GERARD. R.Y., D.S. MACLEAN and T.M.ANTONIO. 1986. Examination of three Sipal'unaspecies for Alkaloid Contents. Phytochemistry 25:2155-56.KAMETANI, T. T.K FUKUMOTO, A. Kozuka H. YOGI,and M. KOIZUMI. 1969. Syntheses of Hetero-cyclic Compounds CCCI. Biogenetic Syntheses ofthe Morphinandienone-type Compounds, Isosa-lutaridine and Q.methylflavinantine,J. Chern. Soc.C.15:2034-6.KANJANAPOTHI D. 1987. Department of Pharmo-cology, Faculty of Medicine, Chiang-Mai Univer-sity, Thailand. - Pel's. Comm.L\JIS, .H, D. LAlLV, S. MOHO. WAHID, M. ABDL'LLATIFF, R. KIEW, and R.F. TOIA. 1985. Aspectsof Natural Product Chemistry 'The PhytochemicalSurvey". Pmceedings ofa Workshop held 22-24 Fe/mary.1985. Department of Chemistry, Universiti Per-tanian Malaysia, Serdang, Selangor.Lu, S.Y. Wu, and S. LEON. 1985. Alkaloids ofFormosan Fissistigma and Goniothalamus species.Phytochemist1), 24: 1829-34.NAOMESI, B.K and E.A. GVANG. 1980. Effect ofQ.methylflavinantine on the Response of CoaxialStimulation of Guinea-pig Ileum. Planta Medica38: 138-43.ROBLOT, F. R. HOCQUEMILLER and A. CAVE.1984. Study of Morphinandienones: Carbon-13and Proton NMR of Sebiferine and relatedalkaloids. Bull. Soc. Chim. Fr. 3-4 (Pt 2): 139-41.SIVAKUMARAN, M. and KW. GOPINATH. 1976. Sebi-ferine and Litseferine Two New Alkaloids fromLitsea sebifera, IndianJ. Chem. 14B: 150-1.SMOLNVCKl W.D..J.L. MONIOt, D.M. HINDEr\LA'\G, M.A.MlANA, and M. SHAMYIA. 1978. SriLankine: A4-Hydroxylated Aporphine. Tetrahedron Lett. 47:4617-20.TACKlE A.N., D. DWUlvL-\ BADU,j.E. Kl APP, OJ. SL\T-KIN, and P.C. SCHIFF Jr. 1974. O-Methyl-flavinan ti ne from Rhigiocarya racemifera,Phytochemist/)', 13: 2885.(Received 21 JanualJ, 1989)424 PERTANlKA VOL. 12 NO.3, 1989

Chemotaxonomy of the Lauraceae: N-Methyl-2,3,6 trimethoxymorphinandien- 7-one, the Major Alkaloid from Alseodaphne perakens'is

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Chemotaxonomy of the Lauraceae: N-Methyl-2,3,6 trimethoxymorphinandien- 7-one, the Major Alkaloid from Alseodaphne perakens'is

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