Amaryllidaceae Alkaloids M.F.Grundon Department of Applied Physical Sciences The University of Ulster at Coleraine Coleraine Co. Londonderry Northern Ireland BT52 ISA ~ Reviewing the literature published between July 1985 and June 1987 (Continuing the coverage of literature in Natural Product Reports 1987 Vol. 4 p. 89) 1 Occurrence and Structural Studies 2 Synthesis 3 References A review of the alkaloids occurring in Crinum species has been published by Ghosal et al.l 1 Occurrence and Structural Studies During the period covered in this review twenty-six new alkaloids have been isolated and are included in Table l2-I6 with known alkaloids that have been obtained from new sources. Oxocrinine (1) was formed previously by oxidation of crinine (2) but its isolation from Crinum americanum is the first time that it has been recognized as a natural product.2 Ghosal et isolated crinafoline (3) from Crinum latifofium; it was shown to be a hydroxy-derivative of ambelline (4) by the lH n.m.r.spectrum and by partial hydrolysis of the diacetate (5) to a monoacetate which on reaction with thionyl chloride followed by treatment of the product with lithium aluminium hydride was converted into ambelline (4). Crinafolidine which is another new constituent of C. latifolium was shown to be the Oxocrinine (1) R’ R~ = o Crinofoline Crinine (2) R’= OH,~2= Ambelline H amino-aldehyde (6) by spectroscopy and by its formation from the methiodide of crinafoline (3) on reaction with sodium hydroxide.The structures of 6a-hydroxy-3-0-methylepimari-tidine (7) and the 6P-isomer (8) which were obtained as an inseparable mixture from Narcissus tazetta var. chinensis were determined by spectroscopic studies.l3 Frahm and co-workers’’ have reported the 13C n.m.r. spectra of fifteen alkaloids with the crinane skeleton and shown how the data can be used to establish the oxygenation pattern and stereo-chemistry of these compounds. Lutessine (1 1) and deacetyl-lutessine (12) which are new alkaloids from Sternbergia lutea are the first alkaloids of the lycorine type to be shown to contain a substituent in ring D.’~ The ‘H n.m.r. spectrum of lutessine was similar to that of 1-0-acetyl-lycorine (1 3) except for the presence of resonances at S 3.73 (IH dd H-4) and at 3.45 (3H s OMe); in the 13C n.m.r.spectra the change in the resonances for C-4 at 6 28.5 (triplet) in 1-0-acetyl-lycorine to 78.8 (doublet) in lutessine showed that the methoxy-group in the latter compound was at C-4. Deacetyl- lutessine (12) was obtained from lutessine by its reaction with potassium hydroxide; since the hydrolysis did not occur under the conditions of the isolation procedure deacetyl-lutessine is not an artefact. A number of new lycorine derivatives have been identified. Thus Crinum asiaticum was shown to contain the palmitoyl derivatives palmilycorine (15) and lycoriside H R’ (3) R1 = OH I R2 = H Crinafolid ine (6) (4)R’ = R2 = H (5) R’ = OAC R2 = AC 6a-Hydroxy-3-0-methylepimaritidine (7) R’ = R3 = HI R2 = OMe R4 = OH 6P-Hydroxy-3-0-methylepimaritidine (8) R’ = R4 = HI R2 = OMe R3 = OH Maritidine (9)R’ = OH R2= R3 = R4 = H 3-0-Methylmaritidine (10) R’ = OMe R2= R3= RL = H 4 79 NPR 6 NATURAL PRODUCT REPORTS 1989 Table 1 The isolation of Amaryllidaceae alkaloids Species Alkaloid (structure) Ref.Crinum americanum 0-Acet ylcrinine Crinine (2) Flexinine Hippadine (59) Lycorine (14) *Oxocrinine (1) Pratorimine (4 1) Pratorinine (40) Pratosine Trisphaeridine Ungeremine (32) Crinum asiaticum *Criasbetaine (33) *Lycoriside (1 6) *Palmilycorine (1 5) Ungeremine (32) Crinum augustum *Craugsodine (44) Crinum giganteum Crinidine Galanthamine (28) Hippeastrine 6 Lycorine (14) Tazettine Crinum latifolium *Crinafolidine (6) 7 *Crinafoline (3) Haemanthus kalbreyeri Haemanthamine Hippadine (59) *Kalbreclasine (36) 8 *Kalbretorine (38) Narciclasine (37) Pratorimine (41) Leucojum aestivum *(-)-3-O-Acetylungiminorine (26) ( +)-9-O-Demethylhomolycorine 9 (-)-Ungiminorine (27) Narcissus assoanus Assoanine (43) 10 *Oxoassoanine (42) Narcissus confusus 9-O-Demethylhomol ycorine *N-Formylgalanthamine (29) Galanthamine (28) 11 Haemanthamine Homo1 ycorine Pre taze ttine Narcissus reguienii * 1 -0-Acetylpseudolycorine (24) *2-0-Acetylpseudolycorine (25) 12 1 Pseudolycorine (23) Narcissus tazetta var.chinensis Epigalanthamine *6a- and 6P-Hydroxy-3-0-methyl- epimaritidine [(7) and (S)] 13 Lycoramine (58) Maritidine (9) 3-0-Methylmaritidine (1 0) Sternbergia lutea *Deacetyl-lutessine (12) 11-Hydroxyvittatine 14 *Lutesine (1 1) Zephyranthes fZava *Alkaloids (17)-(22) 15 Criasbetaine (33) Haemanthidine (45) Kalbreclasine (36) Lycorine (14) Lycorine 1-0-P-D-glucoside Methy Ipseudol ycorine Narciclasine (37) 16 Pratorimine (41) 1 Pretazettine Pseudolycorine (23) Pseudolycorine 1-0-P-D-glucoside Ungeremine (32) *Zefbetaine (34) *Zeflabetaine (3 5) * New alkaloids NATURAL PRODUCT REPORTS 1989-M.F. GRUNDON H OH OH Lutessine (11 1 R’ = Ac R2 = OMe Palmilycorine (15) R = palmitoyl Deacetyl- lutessine 1-0-Acetyl-lycorine (12) R’ = H I R2= OMe (13) R1 = Ac R2 = H Lycoriside (16) R CH20palmitoyl = ‘lo*& Lycor ine (14) R’ = R2 = H HO 0 OR2 II I CH 2CH-C H20R’ 0 II OpalmitoylI (17) R’ = R2 = H R3 R4 = CH2 (18) R’ = palmitoyl R2 = stearoyl ,R3 R4 = H2 (19) R’ = palmitoy1 ,~2 = oleoyl R3 ~4 = CH R (22) R = Me (a-and p-) (20) R’ = palmitoy1 ,R~ = stearoyl R3 = Me ~4 H= (21) R1 = palmitoy1,R~= oleoyl R3 = Me ~4 H= H OR2 Pseudolycorine (23) R’ = R2 = H 3-0-Acetylungiminorine (26) R = AC 1-0-Acetylpseudolycorine (24) R’ = Ac R2 = H Ungiminorine (27) R = H 2-0-Acetylpseudolycorine (25) R1 = H I R2 = Ac 0- R2 Galanthamine (28) R’ = H R2 = R3 = Me Ungeremine (32) R’ R2 = CH, R3 = H N -Formylgalantham ine (2 9) R’ = HI 7)= 3 * CHO IR3= Me Criasbetaine (33) R’ = R2 = Me R3 = H Leucotamine (30) R1 = t(O)CH2CH(Me)OH I R2 = Me R3 = H Zefbetaine (34) R’ = Me R2 = R3 = H 1’ 2’ 3’ 0-Methyl-leucotamine (31) R1 = C(O)CH,CH(Me)OH ,R2 = R3 = Me Zeflabetaine (35) R’ R2 = CH R3 = OMe I OR OH OH NH HO 0 0 Kalbreclasine (36) R = p-D-glUCOSyl Kalbretorine (38) R = H Narciclasine (37) R = H (39) R = Me NATURAL PRODUCT REPORTS 1989 Pratorinine (40) R1 = H R2 = Me Pratorimine (41) R' = Me ,R2= H Reagents i ClC(O)C(O)Cl PhH reflux; ii indoline Et,O; iii H, Pd/C EtOH; iv NaNO, H,SO, AcOH at 0 "C then at 100 "C; v 5 YoKOH in MeOH.at 50 "C Scheme 1 MHO \eoqy R H Oxoassoanine (42)R = 0 Craugsodine (44) Assoanine (43) R =H2 Ar Ar /Ph & 0 U (481 1:; Ar Ph (491 (R = HI.. (50) X = OH I Y = H VIII-x m viii xi =H,Y= OH xiii -(52) X = OMe Y =H RO HH xi xii RO MeO" r 1 Crinine (46) R = H Haemanthidine (45 Buphanisine (47)R = Me Reagents :i PhCH=NCH(Li)P(O)(OEt), THF at -78 "C then reflux then Bu"Li at -78 "C ;ii BrCH,CH,N(CO,CH,CH=CH,)CH,Ph,then H,O+; iii pyrrolidine-33 YOaq.AcOH-MeOH (1 :3 30); iv PhNMe,Br, EtOAc catalytic H,SO,; v 1,8-diazabicyclo[5.4.0]undec-7-ene, PhH reflux; vi Pd(Ph,P), Ph,P Bu(Et)CHCO,H CH,CI,; vii AlH, THF; viii Ms,O Et,N CH,CI,; ix CsOAc DMF; x MeOH K,CO,; xi MeOH then MeCH(Cl)OC(O)CI ClCH,CH,Cl Proton Sponge@ [1,8-bis(dimethylamino)naphthalene],reflux xii MeOH reflux ;xiii HCHO MeOH then 6M HCl Scheme 2 NATURAL PRODUCT REPORTS 1989-M. F. GRUNDON NPht 1.; X' (53) .1'. OAc Reagents i potassium phthalimide DMF; ii Fe(CO), xylenes heat; iii OsO, N-methylmorpholine N-oxide Me,CO H,O then NaIO ; iv MeO,CCH,CO,H piperidine PhNH, pyrjdine heat; v H,NNH, H,O MeOH heat; vi HCIO, EtOH CH,Cl, then the salt added to (59 KCN CaCI, THF; vii AgBF, DME; viii LiBr MeCN; ix 1,8-diazabicyclo[5.4.0]undec-7-ene, CH,CI, at 0 "C; x PhMe heat Scheme 3 (1 6)3 and phospholipids of the flowers of Zephyranthes Java consist of compound (1 7) mixtures of the fatty acid derivatives (18) and (19) and (20) and (21) and the quaternary ammonium salts (22).15 The alkaloids of Narcissus requienii were studied for the first time; pseudolycorine (23) was identified and the structures of two new alkaloids 1 -0-acetylpseudolycorine (24) and 2-0-acetylpseudolycorine (25) were determined mainly by 'H and I3Cn.m.r.chemical-shift-correlation experiments.12 The structure of the new alkaloid 3-0-acetylungiminorine (26) which was isolated from Leucojum aestivum was established by spectroscopy and by its acetylation to the diacetate of ungiminorine (27).' The bulbs of Narcissus confusus are rich in galanthamine (28) and also contain a new alkaloid that was given the name N-formylgalanthamine (29) ;ll its structure was apparent from the amide carbonyl absorption at 1650 cm-' and from the 'H n.m.r. spectrum which showed resonances for methylene groups at C-6 and at C-12 and singlets at 8 8.02 and 8.07 due to rotamers arising from hindered rotation of the N-CHO group. A full account has now been given of the isolation and structure determination of leucotamine (30) and O-methyl- leucotamine (3 1) from Leucojum aestiuumg (cf ref.18). Optically impure 3'-methyl-leucotamine acetate [cf. (3 l)] was prepared from the reaction of galanthamine (28) with 3-acetoxybutyryl chloride in the presence of boron trifluoride etherate. Ungere- mine (32) which was obtained previously from Ungernia minor and is formed by oxidation of lycorine with selenium dioxide has now been isolated from Crinum a~iaticum.~ The related new alkaloid (33) is also a constituent of this species4 and of Zephyranthes$avul6 and has been given the name criasbetaine ; it is an oxidation product of methylpseudolycorine. Other new betaines that have been isolated from Z. fraua are the hydroxymethoxy-derivative zefbetaine (34) which is obtained by oxidation of pseudolycorine and the methylenedioxy-methoxy-analogue zeflabetaine (35) ; the structure of the latter alkaloid was indicated by its reaction with sodium in isoamyl alcohol to give ungeremine (32).16 Two new lactam alkaloids have been isolated from Haeman-thus kalbreyeri.* The glycoside kalbreclasine (36) which is also a constituent of Zephyranthes JEava," was hydrolysed by emulsin to narciclasine (37) and D-glucose; kalbretorine (38) reacted with diazomethane to give the known methoxy-derivative (39).Earlier confusion over the structures of pratorinine (40) and pratorimine (41) was settled recently by an X-ray analysis of pratorinine (cf. ref. 19a) and has now been confirmed by the synthesis of pratorimine (Scheme 1).20 Oxoassoanine (42) which was obtained previously as a degradation product has now been isolated from Narcissus assoanus; assoanine (43) is also a constituent of N.assoanus and is converted by aerial oxidation into oxoassoanine. Crinurn augustum contains the Schiff s base craugsodine (44) which was prepared from the reaction of isovanillin and tyramine in methanol and was converted with sodium boro- hydride into 0-methyln~rbelladine.~ 2 Synthesis The synthesis of (+)-haemanthidine (45) by Martin and co- workers involving compounds that contain a quaternary carbon atom (bearing different groups) attached to a carbonyl centre (cf ref. 19b) has been described in The same approach has now been applied to the synthesis of (+)-crinine (46) and (2)-buphanisine (47) (Scheme 2).22The key inter- mediate (49) was prepared from the ketone (48) in 60% yield and then was converted into the indoline derivatives (50) (51) and (52); compounds (50) and (52) gave crinine and buphan- isine respectively.A new approach to the synthesis of the lycorine ring system has been reported by Boeckman et al. (Scheme 3).23 The masked dienamine and cinnamate residues within the spiro- cyclic salt (53) were liberated to give the triene (54); thermolysis then resulted in intramolecular [4 + 21 cycloaddition to provide compound (56) which possesses the skeleton and stereo-chemistry present in lycorine (14). NATURAL PRODUCT REPORTS 1989 0 Me Lycoramine (58) (57) Reagents i Pb(OAc), Hg(OAc),; ii pyridine CHCl, at 60 "C Scheme 4 1 I (60) J 0 Hippadine (59) Reagents i HC-CCO,Me Et,N; ii DMSO H,O (trace) reflux Scheme 5 Ackland and PinheyZ4 have described a new preparation of compound (57) (Scheme 4) which is an intermediate in the Sanchez synthesis of lycoramine (58) (cf.ref. 25). A new synthesis of the lactam alkaloid hippadine (59) that was carried out by Prabhakar and co-workers26 involves 1-aza-1'-oxa-[3,3]sigmatropic rearrangement of the hydroxamic acid derivative (60) (Scheme 5). 3 References 1 S. Ghosal K. S. Saini and S. Razdan Phytochemistry 1985 24 2141. 2 A. A. Ali H. M. El Sayed 0.M. Abdallah and W. Steglich Phytochemistry 1986 25 2399. 3 S. Ghosal A.Shanthy A. Kumar and Y. Kumar Phyto-chemistry 1985 24 2703. 4 S. Ghosal Y. Kumar S. K. Singh and A. Kumar J. Chem. Res. (S) 1986 112. 5 S. Ghosal U. Kumar S. K. Singh and A. Shanthy J. Chem. Res. (S) 1986 28. 6 D. A. Murav'eva and D. I. Popova Khim. Prir. Soedin. 1986 518. 7 S. Ghosal and S. K. Singh J. Chem. Res. (S) 1986 312. 8 S. Ghosal R. Lochan Ashutosh V. Kumar and R. S. Srivastava Phytochemistry 1985 24 1825. 9 S. Kobayashi M. Kihara K. Yuasa Y. Imakura T. Shingu A. Kato and T. Hashimoto Chem. Pharm. Bull. 1985 33 5258. 10 J. M. Llabres F. Viladomat J. Bastida C. Codina and M. Rubiralta Phytochemistry 1986 25 2637. 11 J. Bastida F. Viladomat J. M. Llabres C. Codina M. Feliz and M. Rubiralta Phytochemistry 1987 26 15 19. 12 J.M. Llabres F. Viladomat J. Bastida C. Codina M. Serrano M. Rubiralta and M. Feliz Phytochemistry 1986 25 1453. 13 G.-E. Ma H.-Y. Li C.-E. Lu X.-M. Yang and S.-H. Hong Heterocycles 1986 24 2089. 14 A. Evidente J. Nut. Prod. 1986 49 90. 15 S. Ghosal S. K. Singh and S. G. Unnikrichnan Phytochemistry 1987 26 823. 16 S. Ghosal S. K. Singh and R. S. Srivastava Phytochemistry 1986 25 1975. 17 A. W. Frahm A. A. Ali and M. A. Ramadan Magn. Reson. Chem. 1985 23 804. 18 M. F. Grundon in 'The Alkaloids' ed. M. F. Grundon (Specialist Periodical Reports) The Royal Society of Chemistry London 1983 Vol. 13 p. 189. 19 M. F. Grundon Nut. Prod. Rep. 1987 4 (a) p. 91; (6) p. 94. 20 B. S. Joshi H. K. Desai and S. W. Pelletier J. Nut. Prod. 1986 49 445. 21 S.F. Martin S. K. Davidsen and J. A. Puckette J. Org. Chem. 1987 52 1962. 22 S. F. Martin and C. L. Campbell Tetrahedron Lett. 1987 28 503. 23 R. K. Boeckman Jr. J. P. Sabatucci S. W. Goldstein D. M. Springer and P. F. Jackson J. Org. Chem. 1986 51 3740. 24 D. J. Ackland and J. T. Pinhey Tetrahedron Lett. 1985 26 533 1. 25 M. F. Grundon Nut. Prod. Rep. 1985 2 251. 26 S. Prabhakar A. M. Lobo and M. M. Marques. J. Chem. Res. (S) 1987 167.