Provided for non-commercial research and educational use only. Not for reproduction, distribution or commercial use. This chapter was originally published in the book The Alkaloids, published by Elsevier, and the attached copy is provided by Elsevier for the author’s benefit and for the benefit of the author’s institution, for non-commercial research and educational use including without limitation use in instruction at your institution, sending it to specific colleagues who know you, and providing a copy to your institution’s administrator. All other uses, reproduction and distribution, including without limitation commercial reprints, selling or licensing copies or access, or posting on open internet sites, your personal or institution’s website or repository, are prohibited. For exceptions, permission may be sought for such use through Elsevier’s permissions site at: http://www.elsevier.com/locate/permissionusematerial From Bruce K. Cassels, Alkaloids from the Genus Duguetia. In: Geoffrey A. Cordell, editors, The Alkaloids. Chennai: Academic Press, 2010, pp. 83-156. ISBN: 978-0-12-381335-0 © Copyright 2010 Elsevier Inc. Academic Press. Author’s personal copy 3 CHAPTER Alkaloids from the Genus Duguetia Edwin G. Pe´rez1,3,w and Bruce K. Cassels2,3,* Contents I. Introduction 84 II. BotanicalConsiderations 84 III. Alkaloidsfrom ChemicallyInvestigated Duguetia species 86 A. Benzyltetrahydroisoquinolines 106 B. Bisbenzyltetrahydroisoquinolines 107 C. Berbines and Protoberberines 107 D. Morphinandienone 109 E. Aporphinoids 109 F. Miscellaneous Aporphinoid- and Berbinoid-Related Alkaloids 114 IV. Structureand Chemistry 117 A. Benzyltetrahydroisoquinolines 117 B. Bisbenzyltetrahydroisoquinoline 117 C. Berbinoids 117 D. Morphinandienone 117 E. Aporphinoids 117 F. Miscellaneous Aporphinoid- and Berbinoid-Related Alkaloids 119 V. Biosynthesis, Biogenesis, and Chemosystematics 122 VI. Ethnopharmacology andPharmacology 132 A. Benzyltetrahydroisoquinolines 133 B. Bisbenzylisoquinoline 134 C. Berbinoids 134 1 DepartmentofChemistry,FacultyofChemistryandBiology,UniversityofSantiago,Santiago,Chile 2 DepartmentofChemistry,FacultyofSciences,UniversityofChile,Chile 3 MillenniumInstituteforCellDynamicsandBiotechnology,Santiago,Chile wPresentaddress:FacultaddeQu´ımica,PontificiaUniversidadCato´licadeChile,Santiago,Chile *Correspondingauthor. E-mailaddress:[email protected](B.K.Cassels) TheAlkaloids,Volume68 r2010ElsevierInc. ISSN:1099-4831, DOI10.1016/S1099-4831(10)06803-3 Allrightsreserved 83 Author’s personal copy 84 EdwinG.Pe´rezandBruceK.Cassels D. Protoberberines 137 E. Glaziovine 139 F. Aporphines 139 G. Oxoaporphines 143 H. Aminoethylphenanthrenes 144 I. Copyrine Alkaloids 145 J. 1-Aza-9,10-anthraquinones 146 VII. Concluding Remarks 146 Acknowledgments 147 References 147 I. INTRODUCTION DuguetiaA.St.-Hil.(Annonaceae)isagenusofusuallysmall,understory treesgrowingalmost exclusively in thetropics of South America, with a small extension across the Panama Isthmus. It is now regarded as comprising close to 100 species, considering the recent inclusion of four African taxa, of which three werepreviously known as Pachypodanthium Engler&Diels.ItisthereforeoneofthelargestAnnonaceousgeneraafter Guatteria and Annona. Many studies have been conducted on the secondarymetabolites presentindifferentpartsofDuguetiaplants,from which essential oils, aromatic compounds, monoterpenes, diterpenes, triterpenes, flavonoids, and most typically alkaloids have been isolated and characterized. In common with the other ‘‘primitive angiosperms,’’ Duguetia speciesaccumulate isoquinoline alkaloids, and more specifically 1-benzyl-1,2,3,4-tetrahydroisoquinolines, usually referred to simply as ‘‘benzylisoquinolines,’’ and their biosynthetic or biogenetically presumed derivatives. The literature reports studies on the alkaloids of about 16 Duguetiaspecies(oneofwhichwasnotclearlyidentified),resultinginthe isolation and identification or characterization of 105 different alkaloids. Although many of these alkaloids are widely distributed, a few unusual groups of alkaloids appear to be specific to this genus. II. BOTANICAL CONSIDERATIONS The plants of the Annonaceae have traditionally been classed as part of theorderMagnoliales.Inthemostrecentconsensus,theMagnolialesand LauralesconstituteoneofthetwosistercladesintheMagnoliidae,which are commonly regarded as the most ‘‘primitive’’ angiosperms in older classifications (1,2). Author’s personal copy AlkaloidsfromtheGenusDuguetia 85 Regarding the occurrence of benzylisoquinoline alkaloids in the Annonaceae, other magnoliids, and more distantly related families, it is of interest to note that there is now good biochemical and molecular phylogenetic evidence for the evolution of benzylisoquino- line alkaloid biosynthesis in angiosperms from a common ancestor. Activity ascribable to the first enzyme in this biosynthetic tree, (S)-norcoclaurine synthase, occurs in 90 different plant species, and compares well with a molecular phylogeny. Phylogenetic analyses of norcoclaurine synthase, the berberine bridge enzyme, and several O-methyltransferases ‘‘suggest a latent molecular fingerprint for benzylisoquinoline alkaloid biosynthesis in angiosperms not known to accumulate such alkaloids’’ (3). Duguetia was thought, on the basis of inflorescence and floral characters, to form an alliance with the very small neotropical genera Duckeanthus, Fusaea, and Malmea, and the African Letestudoxa (4). The monotypic Pseudartabotrys was later included and Malmea excluded (5), but incorporation of leaf, flower, fruit, and seed characters that had not been considered previously has led to a different grouping in which Duguetia(includingPachypodanthium)constitutesacladeofitsown,close toaseparatesistergroupincludingFusaea,Duckeanthus,Letestudoxa,and Pseudartabotrys (6). Despite the inclusion of Pachypodanthium as ‘‘African species of Duguetia,’’ these plants still form a small, distinct cluster, perhaps not surprisingly together with Duguetia riberensis of Venezuela, in this cladistic analysis. The genus has been further subdivided into 14 sections by Fries based on their morphological characters, but leaving some species in uncertain positions (7,8). These subdivisions have largely been upheld by a more recent study (9), and it is the system used in this review (Table I). One third of all Duguetia species were analyzed in a study based on their genomic DNA sequences (41). That work supported the notion that Duguetia, like Guatteria, is monophyletic, with its most recent common ancestor dating back to 29.0474.52 million years ago (in the case of Guatteria this figure is 36.6572.50mybp), although the authors concede that ‘‘the accuracy of the absolute dates remains unassessed.’’ A fossilized leaf from the middle Eocene period (about 38(cid:1)48mybp) from Western Tennessee, when the local climate was subtropical to tropical, has been classified as belonging to a Duguetia species (42), a conclusion that seems to conflict with the estimated DNA age of the genus. On the basis of its present geographic, trans-Atlantic distribu- tion it was suggested that the Duguetia clade might predate the break-up of Gondwana (6). As the separation of Africa and South Author’s personal copy 86 EdwinG.Pe´rezandBruceK.Cassels America is believed to have been completed in the early Cretaceous (about110millionyearsago),andtheageoftheAnnonaceaeasafamily is estimated to be as little as 82 million years (43), it seems necessary to assumelong-distancedispersalover thewideningearlyAtlantic Ocean, possibly across stepping-stones along the 80 million-year-old volcanic Sierra Leone Rise (to which the Ceara´ Rise should be added) (44) or, less likely, the more southerly Walvis Ridge (and Rio Grande Rise) (45). This hypothesis seems reasonable given the presence of Annonaceae in the Lesser Antilles, which would represent much more recent (Pliocene or even Pleistocene) events of a similar character (46). III. ALKALOIDS FROM CHEMICALLY INVESTIGATED DUGUETIA SPECIES The Duguetia species studied to date for their alkaloidal content are listed in Table I, ordered by sections, and in alphabetical order when appropriate. All of the alkaloids isolated from this genushave at least a formal isoquinoline-derived structure; including the 1-azaanthraqui- none cleistopholine and the rare copyrine alkaloids, the 1-aza-7- oxoaporphines and 1-aza-4,5-dioxoaporphines. These alkaloids are classified as benzyltetrahydroisoquinolines, a single bisbenzyltetrahy- droisoquinoline, berbines (tetrahydroprotoberberines), protoberberines, a morphinandienone, a proaporphine, and many aporphinoids and aporphinoid-related compounds. A large proportion of the aporphines are oxygenated at C7, a fairly common feature in the Annonaceae. 7-Methoxy derivatives are almost completely restricted to the African Duguetia species. Four N-formylnoraporphines have been identified. Three nitroso- or nitroaporphinoid derivatives isolated from Duguetia furfuracea might be artifacts, as discussed below. Several of the aporphinoids have the unusual 9,11-dioxygenation pattern in ring D which, aside from Duguetia, has only been found in one Guatteria species. As in Guatteria, some of the Duguetia aporphinoids bear a biogenetically intriguing carbon atom bonded to C7. Finally, a protoberberine(cid:1)styrene adduct is a unique alkaloid from the African Duguetia staudtii. Table II lists the 105 alkaloids, including some possibleartifacts,orderedaccordingtotheirmainstructuralfeatures,as depicted in Figure 1 (Table III). In many cases, the structures were known prior to their isolation from Duguetia species, or were very closely related to known alkaloids, Author’s personal copy TableI Chemically investigated Duguetia species andtheir contained alkaloids Section Species Alkaloid Structure Ref.(s) Duguetia R. E. Fries D. furfuracea (A. St.-Hil.) Reticuline 1 10 Benth. & Hook. Isochondodendrine 3 10 Discretamine 4 10 Isocorydine 41 10 Norisocorydine 40 10 Xylopine 28 10 Obovanine 30 10 Anonaine 23 10 Asimilobine 20 10 Atherospermidine 86 10 Liriodenine 83 10 Lanuginosine 87 10 Alk a Duguetine 76 11 loid NDi-cOexnytrdinuognueetine 7971 1111 sfrom N-Methylglaucine 36 11 th e N-Methyl-tetrahydropalmatine 8 11 G e N-Nitrosoanonaine 51 12 nu s N-Nitrosoxylopine 52 12 Du g 8-Nitroisocorydine 42 13 ue D. odorata (Diels) J. F. Macbr. Dehydrodiscretine 16 14 tia Pseudopalmatine 17 14 Oliveroline 60 14 N-Methylguatterine 66 14 87 Author’s personal copy 8 Table I (Continued) 8 Section Species Alkaloid Structure Ref.(s) D. stelechantha (Diels) R. E. Fries Oxopukateine 88 15 Ed w O-Methylmoschatoline 85 15 in Corypalmine 5 15 G. P Hadrantha R. E. Fries D. hadrantha (Diels) R. E. Fries Hadranthine A 99 16 ere´ z Hadranthine B 100 16 a n Imbiline-1 101 16 dB Sampangine 97 16 ruc e 3-Methoxysampangine 98 16 K. Sphaerantha R. E. Fries D. calycina Benoist Discretamine 4 17 Ca 10-Demethylxylopinine 11 17 ssels Xylopine 28 17 Puterine 31 17 O-Methylpukateine 32 17 Obovanine 30 17 Oxoputerine 89 17 Atherosperminine 94 17 Calycinine 43 17 Noratherosperminine 93 18 Duguecalyne 54 19 N-Formylputerine 53 19 Duguenaine 47 20 D. obovata R. E. Fries Xylopine 28 20 Isolaureline 29 20 Author’s personal copy N-Formylxylopine 48 20 Buxifoline 33 20 N-Methylbuxifoline 34 20 N-Formylbuxifoline 49 20 Anolobine 27 20 Calycinine 43 20 N-Methylcalycinine 44 20 Duguevanine 45 20 N-Formylduguevanine 50 20 N-Methylduguevanine 46 20 Oxobuxifoline 90 20 Xylopinine 12 20 Discretine 10 20 (9S)-Sebiferine 18 20 A D. spixiana Mart. (Colombia) N-Oxycodamine 2 21,22 lk a N-Methylasimilobine 21 21 loid Noroliveridine 67 21 sfro Oliveridine 68 21 m N-Oxyoliveridine 70 21 the Norpachyconfine 56 21 Ge n Pachyconfine 58 21 us N-Oxypachyconfine 59 21 Du g Spixianine 73 21 ue N-Oxyspixianine 74 21 tia Duguexine 71 21 N-Oxyduguexine 72 21 8 9 Author’s personal copy 9 Table I (Continued) 0 Section Species Alkaloid Structure Ref.(s) Lanuginosine 87 21 Ed w Atherosperminine 94 21 in N-Oxyatherosperminine 95 21 G. P Methoxyatherosperminine 96 21 ere´ z Spiduxine 13 21 a n Duguespixine 55 21,23 dB D. spixiana Mart. (Bolivia) Anonaine 23 24 ruc e Nornuciferine 22 24 K . 3-Hydroxynornuciferine 25 24 Ca O-Methylisopiline 26 24 ssels Noroliveridine 67 24 Oliveridine 68 24 N-Oxyoliveridine 70 24 Duguexine 71 24 Roemerolidine 69 24 Nornuciferidine 57 24 Rurrebanine 63 24 Rurrebanidine 62 24 Lysicamine 84 24 Lanuginosine 87 24 O-Methylmoschatoline 85 24 Spiguetidine 103 24 Author’s personal copy Spiguetine 102 24 Xylopinine 12 24 Tetrahydropalmatine 7 24 Calothrix R. E. Fries D. vallicola J. F. Macbr. N-Methyllaurotetanine 37 25 Isocorydine 41 26 Isoboldine 38 26 Oliveridine 68 27 Oliveroline 60 27 Duguevalline 92 27 O-Methylmoschatoline 85 27 Xylopinine 12 26 Discretine 10 26 Pseudopalmatine 17 26 Cleistopholine 104 27 Glaziovine 19 26 Alk a Polyantha R. E. Fries D. eximia Diels O-Methylmoschatoline 85 28 lo id OOxxooppuukteartieniene 8889 2288 sfrom Geanthemum R. E. Fries D. flagellaris Huber Nornuciferine 22 29,30 th e Isopiline 24 29,30 G e O-Methylisopiline 26 29,30 nu s Calycinine 43 29,30 Du g Duguevanine 45 29,30 ue Pachypodanthine 78 29,30 tia Oliveroline 60 29,30 9 1