Amaryllidaceae and Sceletium alkaloids John R. Lewis Department of Chemistry, Aberdeen University, Old Aberdeen, UK AB24 3UE Covering: 1996 Previous review: 1997, 14, 303 1 Introduction 2 Occurrence and structural studies 3 Synthetic studies 4 References 1 Introduction In this annual review seven new alkaloids have been described, while new analytical techniques have shown that additional alkaloids are present in previously investigated plant extracts. Interest in galanthamine 1 continues, due to its proposed role in the treatment of Alzheimer’s disease.1 Although viable yields have been achieved in the synthesis of this alkaloid,1 commercial production via plant culture methodology remains a goal yet to be reached.A study of in vitro culturing of Narcissus confusus by the ‘shoot clump’ procedure has achieved an alkaloid yield of 2.50 mg l"1 of culture; most of the alkaloid (1.97 mg) being found in the medium. Interestingly the addition of trans-cinnamic acid, a known precursor in the biosynthesis of galanthamine 1, inhibited the production of this alkaloid while the concentration of its congener, N-formylgalanthamine 2, was enhanced.1 A report on the analgesic properties of the four alkaloids lycorine 3, haemanthidine 4, haemanthamine 5 and tazettine 6, isolated from Sternbergia clusiana found in Turkey, showed that lycorine 3 and haemanthidine 4 possessed greater activity than that of aspirin.2 Using circular dichroism (CD) measurements on eight alkaloids obtained from the plant Hippeastrum equestre it was possible to determine, relatively easily, their basic ring systems and the stereochemistry of their ring junctions.Six other alkaloids were also obtained from other plant sources so as to complement the analyses. In all, this method provides a useful addition to the armoury for structure/stereochemical assignments.3 2 Occurrence and structural studies A reinvestigation of the alkaloid content of Amaryllis belladonna, using a multidimensional screening system involving liquid chromatography following by UV and MS detection, has led to the identification of nine additional alkaloids: anhydrolycorin-7-one 7, 6·-hydroxybuphanisine 8, R5O O N R1 R3 R4 R2 a 1 Galanthamine R1 = lone pair; R2 = R5 = Me; R3 = H; R4 = OH; ab unsat. 2 N-Formylgalanthamine R1 = lone pair; R2 = CHO; R3 = H; R4 = OH; R5 = Me; ab unsat. 35 Norgalanthamine R1 = lone pair; R2 = R3 = H; R4 = OH; R5 = Me; ab unsat. 45 Lycoramine R1 = lone pair; R2 = R5 = Me; R3 = H; R4 = OH; ab sat. b N R1O R2 R4 H R3 H b a 3 Lycorine R1R2 = CH2O; R3 = R4 = OH; ab unsat. 11 Galanthine R1 = R2 = Me; R3 = b-OMe; R4 = a-OH; ab sat. 48 Pseudolycorine R1 = H; R2 = R4 = OH; R3 = OMe; ab sat. N R3 O O R1 R2 R4 4 Haemanthidine R1 = H; R2 = R4 = b-OH; R3 = a-OMe 5 Haemanthamine R1 = R2 = H; R3 = b-OH; R4 = a-OH 8 6a-Hydroxybuphanisine R1 = R4 = H; R2 = a-OH; R3 = a-OMe 9 6-Hydroxycrinine R1 = R4 = H; R2 = R3 = a-OMe 10 Crinine R1 = R2 = R 4 = H; R3 = a-OH 16 Buphanisine R1 = R2 = R4 = H; R3 = b-OMe 17 Buphanidrine R1 = OMe; R2 = R4 = H; R3 = a-OMe 18 Epibuphanisine R1 = R2 = R4 = H; R3 = a-OMe 30 Vittatine R1 = R2 = R4 = H; R3 = b-OH 34 6b-Hydroxybuphanisine R1 = R4 = H; R2 = b-OH; R3 = a-OMe O O O R4 NMe R3 R2 R1 6 Tazettine R1 = b-OMe; R2 = R4 = H; R3 = a-OH 26 Criwelline R1 = a-OMe; R2 = R4 = H; R3 = a-OH 32 Littoraline R1 = b-OH; R2 = OH; R3 = b-H; R4 = H 43 Pretazettine R1 = Me; R2 = R3 = b-H; R4 = O 44 Macronine R1 = R2 = H; R3 = a-OH; R4 = O N O O O 7 Lewis: Amaryllidaceae and Sceletium alkaloids 1076-hydroxycrinine 9, crinine 10, galanthine 11, hippadine 12, ismine 13, pratorimine 14 and pratosine 15.All these compounds are new additions to the alkaloid content of this plant.4 In the bulbs of Brunsvigia orientalis, 12 alkaloids were found,5 namely lycorine 3, crinine 10, buphanisine 16, buphanidrine 17, epibuphanisine 18, undulatine 19, crinamidine 20, crinamine 21, 6-hydroxycrinamine 22 and the new alkaloids 1-epibowdensine 23, 1-epidemethoxybowdensine 24 and 1-epideacetylbowdensine 25.Crinum firmifolium var hygrophilium whole plant extracts6 contain eight alkaloids, lycorine 3, ismine 13, crinamine 21, 6-hydroxycrinamine 22, hamayne 27, criwelline 26, trisphaeridine 28 and the novel alkaloid 3-hydroxy-8,9- methylenedioxyphenanthridine 29. Dried plant and bulbs obtained from Hippeastrum solandri- florum have been shown to contain five alkaloids.7 They are the cytotoxic lycorine 3, ismine 13, hamayne 27, vittatine 30, and ungeremine 31.Because extracts of Hymenocallis littoralis showed in vitro cytotoxic activity, a reinvestigation of this plant’s alkaloidal content identified 14 alkaloids. One of these, littoraline 32, is new,8 and the others are quoted in Table 1. A new crinane type alkaloid cantabricine 33 has been found in extracts of the whole plant Narcissus cantabricus.9 Also present in the extract were tazettine 6, crinamine 21, vittatine 30, 6·-hydroxybuphanisine 8, and 6‚-hydroxybuphanisine 34.The cultivated daVodil Narcissus CV salome has now been investigated for its alkaloidal content.10 The bulbs contained six known alkaloids, namely crinamine 21, norgalanthamine 35, hippeastrine 38, tortuosine 39, vasconine 40, pseudolycorine 48, and the hitherto unreported alkaloid 2·-hydroxy- 6-O-methyloduline 41. 3 Synthetic studies In the first part of a study on the synthesis of crinum type alkaloids it is now possible11 to generate tetracyclic N O R1O R2O 12 Hippadine R1R2 = CH2 14 Pratorimine R1 = H; R2 = Me 15 Pratosine R1 = R2 = Me CH2OH MeNH O O 13 Ismine N O O R5 R3 R2 R1 R4 19 Undulatine R1R2 = b-O; R3 = a-OMe; R4 = H; R5 = OMe 20 Crinamidine R1R2 = b-O; R3 = a-OH; R4 = H; R5 = OMe 23 1-Epibowdensine R1 = b-OMe; R2 = b-OAc; R3 = R4 = H; R5 = OMe 24 1-Epidemethoxybowdensine R1 = R2 = b-OAc; R3 = R4 = R5 = H 25 1-Epideacetylbowdensine R 1 = R2 = b-OH; R3 = R4 = H; R5 = OMe R3 N R1O R2O R5 R4 a b 21 Crinamine R1R2 = CH2; R3 = b-OH; R4 = a-OMe; R5 = H; ab unsat. 22 6-Hydroxycrinamine R1R2 = CH2; R3 = b-OH; R4 = a-OMe; R5 = OH; ab unsat. 27 Hamayne R1R2 = CH2; R3 = b-OH; R4 = a-OH; R5 = H; ab unsat. 33 Cantabricine R1 = R3 = R5 = H; R2 = Me; R4 = a-OAc; ab sat. 46 Demethylmaritidine R1 = Me; R2 = R3 = R5 = H; R4 = b-OH; ab unsat. N R O O 28 Trisphaeridine R = H 29 3-Hydroxy-8,9-methylenedioxyphenanthridine R = OH + 31 N O– O 36 Homolycorine R1 = R2 = Me; R3 = O; R4 = H 37 Lycorenine R1 = R2 = R4 = H; R3 = b-OH 38 Hippeastrine R1R2 = CH2; R3 = O; R4 = a-OH 41 2a-Hydroxy-6- O-methyloduline R1R2 = CH2; R3 = a-OMe; R4 = a-OH 42 O-Methyllycorenine R1 = R2 = R4 = H; R3 = b-OMe O R1O R2O R3 MeN R4 H N MeO R1O R2 39 Tortuosine R1 = Me; R2 = OMe 40 Vasconine R1 = Me; R2 = H 108 Natural Product Reports, 1998anhydrolycorin-7-one 7 by a palladium acetate catalysed cyclisation of the bromo dihydroindole 49.An eYcient synthesis of (&)-crinane 60 in eight steps with an overall yield of 23% has been achieved starting from 3,4-methylenedioxyphenylbromide 50, with the key step being a pyrolytic decomposition of azide 57 to imine 58 and hence to crinane (Scheme 1).12 Firstly compound 50 was condensed with cyclohexenone 51 to give 52 which upon reduction gave enol 53 and thence its acetate 54. Treatment of this acetate with tert-butyldimethylchlorosilane (TBSCl) according to the method of Keck aVorded the carboxylic acid 55 which could be reduced to alcohol 56 with LiAlH4.A ‘one pot’ transformation of this alcohol to azide 57 was accomplished under Mitsunobu conditions. Thermolysis of this azide in refluxing toluene under nitrogen, gave imine 58 which upon reduction and reaction with Eschenmoser’s salt for 48 h, gave (&)-crinane 60. A new synthesis of the membrine ring system employs the Sharpless AD reaction. This radical-inhibited procedure allows an asymmetric construction of a quaternary carbon centre by Table 1 Isolation of Amaryllidaceae alkaloids Species Alkaloid (structure) Ref.Amaryllis belladona (whole plant) Anhydrolycorin-7-one 7 6·-Hydroxybuphanisine 8 6-Hydroxycrinine 9 Crinine 10 Galanthine 11 Hippadine 12 Ismine 13 Pratorimine 14 Pratosine 15 4 Brunsvigia orientalis (bulbs) Lycorine 3 Crinine 10 Buphanisine 16 Buphanidrine 17 Epibuphanisine 18 Undulatine 19 Crinamidine 20 Crinamine 21 6-Hydroxycrinamine 22 1-Epibowdensine* 23 1-Epidemithoxybowdensine* 24 1-Epideacetylbowdensine* 25 5 Crimum firmifolium var hygrophiluim (whole plant) Lycorine 3 Criwelline 26 Crinamine 21 6-Hydroxycrinamine 22 Hamayne 27 Ismine 13 Trisphaeridine 28 3-Hydroxy-8,9-methlenedioxyphenthridine* 29 6 Hippeastrum solandrilorum Lycorine 3 Hamayne 27 Vittatine 30 Ismine 13 Ungeremine 31 7 Hymenocallis littoralis (bulbs) Littoraline* 32 Trazettine 6 O-Methyllycorenine 42 Pretazettine 43 Macronine 44 Lycorine 3 Homolycorine 36 Lycorenine 37 Hippeastrine 38 Lycoramine 45 Demethylmaritidine 46 Haemanthamine 5 Vittatine 30 5,6-Dihydrobicolorine (ismine) 13 8 Narcissus cantabricus Vittatine 30 Crinamine 21 6·-Hydroxybuphanisine 8 6‚-Hydroxybuphanisine 34 Tazettine 6 Cantabricine* 33 9 Narcissus confusus Galanthamine 1 N-Formylgalanthamine 2 1 Narcissus CV salome 2·-Hydroxy-6-O-methyloduline* 41 Norgalanthamine 35 Crinamine 21 Pseudolycorine 48 Hippeastrine 38 Tortuosine 39 Vasconine 40 10 Sternbergia clusiana Lycorine 3 Haemanthidine 4 Haemanthamine 5 Tazettine 6 2 *New alkaloids.N O O O 49 Br O O Br O O O O O O BuO O O O O O O O O O O CO2H OR OH N3 NH O O N N H N Me Me ii i iii iv v vi vii viii ix x + 50 51 52 53 R = H 54 R = Ac Heat 55 56 57 58 60 + 59 I– Scheme 1 Reagents: i, BunLi, Et2O–THF, 78 )C, then room temp.; ii, NaBH4, CeCl3 · 7H2O, MeOH, 0 )C; iii, AcCl, py; iv, LDA, THF; v, TBSCl, "78 )C]reflux; vi, LiAlH4, THF; vii, Ph3P, DEAD, (PhO)2P(O)N3, CH2Cl2; viii, toluene, reflux, 24 h; ix, NaBH3CN, AcOH; x, Eschenmoser’s salt, THF, 50 )C, 48 h Lewis: Amaryllidaceae and Sceletium alkaloids 109diastereoselective formation of the „-lactone in moderate yields when double dihydroxylation is applied to the diene ester 61 (Scheme 2).13 Thus treatment of 61 with the chirally modified osmium tetroxide reagent developed by Sharpless, namely AD-mix-‚, gave a mixture of diols and tetrols 62 and 63 which spontaneously cyclised to a mixture of lactone diols and triols.If excess of reagent AD-mix-‚ was used, triol lactones predominated. The triol lactones 64 were a mixture of isomers with the R conformer predominating, which upon oxidation with Pb(OAc)4 gave aldehyde 65 and thence with N-methylbenzylamine and NaBH3CN gave tertiary amine 66. Hydrogenation in the presence of di-tert-butoxycarbonic anhydride yielded urethaine 67 which upon reduction gave diol 68. Removal of the oxygen functionality was achieved by first converting 68 into the thiohemiketal 69 whereby oxidation to the ketone 70 allowed a radical initiated reductive cleavage of the thiohemiketal using But 3SnH in the presence of AIBN to give 71 which was then cyclised to cyclohexanone 72.A final treatment with dilute HCl produced (")-mesembrine 73. 4 References 1 S. Bergonon, C. Codina, J. Bastida, F. Viladomat and E. Mele, Plant Cell, Tissue Organ Cult., 1996, 45, 191 (Chem.Abstr., 1996, 126, 46 341). 2 M. Tanker, G. Citoglu, B. Gumusel and B. Sener, Int. J. Pharmacogn., 1996, 34, 194 (Chem. Abstr., 1996, 125, 316 966). 3 J. Wagner, H. L. Pham and W. Döpke, Tetrahedron, 1996, 52, 6591. 4 O. R. Queckenberg, A. W. Frahm, D. Mueller-Dobbies and U. Mueller-Dobbies, Phytochem. Anal., 1996, 7, 156 (Chem. Abstr., 1996, 125, 5487). 5 F. Viladomat, A. Francese, R. Giovanna, C. Codina, J. Bastida, W. E. Campbell and S. M. Mathee, Phytochemistry, 1996, 43, 1379. 6 J. Razafimbelo, M. Andrianlsiferana, G. Baoudouin and F. Tillequin, Phytochemistry, 1996, 41, 323. 7 J. Bastida, C. Codina, C. L. Porras and L. Paiz, Planta Med., 1996, 62, 74 (Chem. Abstr., 1996, 124, 226 600). 8 L-Z. Lin, S-F. Hu, H-B. Chai, T. Pengsuparp, J. M. Pezzuto, G. A. Cordell and N. Ruangrungsi, Phytochemistry, 1995, 40, 1295. 9 J. Bastida, J. L. Contreras, C. Codina, C. W. Wright and J. D. Phillipson, Phytochemistry, 1995, 40, 1549. 10 G. R. Almanza, J. M. Fernandez, E. W. T. Wakori, F. Viladomat, C. Cordina and J. Bastida, Phytochemistry, 1996, 43, 1375. 11 H. W. Shao and J. C. Cai, Chin. Chem. Lett., 1996, 7, 13 (Chem. Abstr., 1996, 124, 289 955). 12 J. M. Schkeryantz and I. V. H. Pearson, Tetrahedron, 1996, 52, 3107. 13 T. Yoshimitsu and K. Ogasawara, Heterocycles, 1996, 42, 135. Ar CO2Et Ar CO2Et OH H H OH H OH Ar CO2Et H HO H OH CO2Et Ar H HO OH H OH H O O O CHO HO O OMe MeO OMe MeO O N O HO OMe MeO N Boc Me OMe MeO N Boc Me O O OMe MeO O N SPh X OMe MeO O N Me HO H Ar OH H O H H OH HO H O H Ar OH H H OH H ii i iii iv v vi vii viii ix x + OMe MeO 61 O N OH HO 62 63 68 65 71 66 R = Bn 67 R = Boc 72 R Me Boc Me Boc Me 73 (–)-Mesembrine S-64 R-64 + i 69 R = H,OH 70 R = O Scheme 2 Reagents: i, AD-mix-‚ (2 equiv.), MeSO2NH2 (1 equiv.); ii, Pb(OAc)4, PhH, room temp.; iii, BnNHMe, NaBH3CN, 4 Å mol. sieve, MeOH, room temp.; iv, H2, Pd(OH)2, (Boc)2O, AcOEt–EtOH; v, DIBALH, CH2Cl2, "78 )C; vi, PhSH, BF3OEt, CH2Cl2, "78 )C]room temp.; vii, Swern oxidation; viii, But 3SnH (6 equiv.), AIBN, PhH, reflux; ix, 10% KOH–MeOH (1:2), room temp.; x, HCl–EtOH, reflux 110 Natural Product Reports, 1998