BIOLOGICALL Y ACTIVE AGENTS IN NATURE 18 CHIMIA 52 (1998) Nr. 1/2 (Jannar/Fcb"mr) Chimia 52 (1998) 18-28 methods. The first alkaloid to be investi- © Neue Sclnveizerische Chemische Gesellschaft gated was dioncophylline A [18][19], the ISSN 0009-4293 main secondary metabolite ofT. peltatum. It is easily accessible by standard isolation procedures, and was found to have a naph- The Alkaloids of Triphyophyllum thylisoquinoline basic structure mainly by NMR investigations (Fig. 4). It has three peltatum (Dioncophyllaceae) [1] stereogenic units: two stereocenters (C( I), C(3»and astereogenic axis (C(7) ~C(I'». Its structural elucidation thus requires at Gerhard Bringrnanna)*, Guido Fran~oisb), Laurent Ake Assn, and least three pieces of stereochemical infor- U Jan Schlauer ) mation. Dedicated to Professor Meinhart H. Zenk, University of Munich, on the occasion of his 2.1. The Relative Configuration at the 65th birthday. Stereocenters: through NMR From an NOE interaction of the axial proton at C(3) (Fig. 5) with the likewise Abstract. A great diversity of naphthylisoquinolines, presumably acetogenic biaryl axial Me group at C( 1), a relative cis-array alkaloids, has been obtained from the West-African liana Triphyophyllumpeltatum. By of these two spin systems and thus trans- the example of dioncophylline A, the main alkaloid from T. peltatum, we illustrate the orientation of the two Me groups was various methods of structural elucidation established in our laboratory. The structural deduced, establishing an (R,R)- (or an peculiarities of some of the minor alkaloids from the same species are discussed. A (5,5)-!) configuration [18] - the first re- perspective on the interesting biological activities of various alkaloids from T.peltatum quired stereochemical information. and related plants is given. The most promising lead is dioncophylline C, marked by pronounced antiplasmodial activity. Chemical syntheses, especially dimerization of 2.2. The Absolute Configuration at naphthylisoquinolines, and QSAR-guided modifications of the most active structures C(3) (and thus C(1)): through Total are featured as rewarding strategies in the search for improved drugs. A chemotaxo- Synthesis nomic summary is presented. The absolute configuration at C(3) was established by a stereochemically unam- 1. Introduction precursors, named korupensamines, into biguous total synthesis of the alkaloid micheUamines [13]. from alanine (Scheme 1) [19][20]. For the Dimeric naphthylisoquinoline alka- This paper will deal mainly with such regio- and stereoselective construction of loids, e.g. michellamine B (1, Fig. ]), are monomers, especially those from Tri- the biaryl axis, the 'lactone method' was most promising novel antiviral compounds phyophyllum peltatum, since they like- applied, an efficient synthetic procedure from African plants [2-4]. They occur in wise display intriguing structural, biosyn- developed in our group [21][22]: Prefix- one single species, Ancistrocladus koru- thetic, and pharmacological (in particular ation of the two molecular moieties via an pens is, which is endemic to a small region antimalarial) properties. T. peltatum is the ester bridge «(f 2) and subsequent in- at the Cameroonian/Nigerian border and most widespread species of the Dionco- tramolecularC,C-bond formation gave the has been discovered within an anti-HIV phyllaceae, a small plant family consist- lactone-bridged biaryl 3, which is config- screening program initiated by the US ing of only three species oflianas climbing uratively unstable - it rapidly isomerizes National Cancer Institute [5][6]. In collab- up high trees, by means of hooked leaves at the axis. But out of this equilibrium of oration with Dr. Boyd and his NCI group, (cf Fig. ]9) [14]. Unique are the large thin helimericforms3aand3b, itcan be cleaved we have elucidated the stereostructure of seeds with large membranous wings (Fig. such that optionally either ofthe atropiso- michellamine B and related compounds 2), which during maturation exceed the [2][6-8] and have achieved first total syn- size ofthe fruits they are borne from [15]. theses of these challenging and attractive From these seeds, we have succeeded in target molecules [9-12]. One of the latest cultivating juvenile plants of T. peltatum achievements of our group is the detection (Fig. 3). At the end of the juvenile growth and characterization of dimerization en- period, just before it starts climbing, T. zymes which transform the monomeric peltatum forms leaves with stalked glands and reduced lamina that capture and digest invertebrates [16]; it is a 'part-time' car- *Correspondence: Prof. Dr. G. Bringmann nivorous plant [17]. Phytochemically, T. a) Institut fUrOrganische Chemie der Universitat peltatum proved to be a rich source of Am Hubland D-97074 Wi.irzburg novel alkaloids. Tel.: +49931 8885323 Fax: +49 931 8884755 E-Mail: [email protected] 2. Dioncophylline A as a Probe Alka- b) Prins Leopold Instituut voor Tropische loid for the Analytical Methodology Geneeskunde Nationalestraat 155 For the rapid and unambiguous attri- B-2000 Antwerpen o configuratively unstable C) Centre National de Floristique bution of the full stereostructures of such Universite d' Abidjan compounds, we have established and fur- Fig. I. Michellamille n, a dimeric naphthyliso- 22 B.P. 582 Abidjan 22, Ivory Coast ther developed a broad series of analytical quinoline with high anti-HIV activity BIOLOGICALL Y ACTIVE AGENTS IN NATURE 19 CHIMIA 52 (1998) Nr. 1/2 (Jan"ar/Fehn,"r) Fig. 2. Seeds of Triphyophyllum peltatum (Dioncophyllaceae), showing Fig. 3. A juvenile plant ofT. peltatum, several weeks after germination the large circular wing meric products is obtained in high selec- possible conditions to avoid isomeriza- tivity [20] - a stereochemically efficient tion at the axis. From the positive first and mechanistically remarkable reaction. Cotton effect in the experimental CD spec- One of the products ultimately obtained is trum of 5, a likewise 'positive chirality' fully identical with natural dioncophylline was deduced, thus establishing P-config- A, whereas the other one is diastereomeric uration at the biaryl axis. - when starting from D-alanine, while L- alanine leads to the wrong enantiomeric 2.4. Further Support for the Axial series [19]. This shows dioncophylline A Configuration: Quantum Chemical CD to have (R)-configuration at C(3) (and Calculations thus also at C(l)) - the second stereoinfor- By these three pieces of stereoin- mation achieved. formation, the full absolute stereostruc- ture 4 of dioncophylline A as shown in 2.3. The Absolute Axial Configuration: Scheme 2 had become evident. Possibly Fig. 4. Constitution ofdioncophylline A by select- by Experimental CD Spectroscopy the same compound, but named 'triphyo- ed HMBC and NOE interactions and chemical While we had selectively produced phylline', had previously been isolated by shifts dioncophylline A and its stereoisomers, a French group [24][25], who had correct- its axial configuration was still unclear at ly assigned the constitution and the rela- ~H~N~Me this point. This missing third stereoinfor- tive configuration at C(l) and C(3), but 1 H 3 mation was acquired by CD spectroscopy, had erroneously assumed the absolute con- Me H for which the molecule first had to be figuration at the stereocenters to be (5,5), modified by dehydrogenation to give 5 so while the chirality of the biaryl axis had that, by enlargement of the isoquinoline been disregarded. Additional severe in- u chromophor, the Exciton Chirality meth- consistencies in the literature [24-26] ne- ~ trans od [23] became applicable (Scheme 2). cessitated a new naming for 4, subse- Fig. 5. Relative configuration at C( J) VS. C(2) of This had to be done under the mildest quently termed dioncophylline A [18]. dioncophylline A by NOE BIOLOGICALLY ACTIVE AGENTS IN NATURE 20 CHIMIA 52 (1998) Nr. 1/2 (JonunrlFebl1lnr) Scheme 1. Total Synthesis Establishing the Absolute Configuration at C(3) (and C(1)) e R 04- H02C~Me I • 04- Br:::"" R N .... ;::,... I R RN.... : Bn "\ MeO M ~(- Bn NH2 Wo Me HO Me 2 D-Ala o MeO CI 0 Me Me MeO Me MeO Me (rapid) 3a o - 7-epi- atropisomer- Dioncophylline A selective 1~fast cleavage ~ Me Me MeO - Me Me 3b MeO o Bn = CH Ph 2 (slow) Dioncophylline A m.p.214 o,[a]D-14.9 natural m.p.215°,[a]D-14 Scheme 2. Absolute Configuration at the Axis by Scheme 3. An Atropisomer-Dif.ferentiating Reaction for the Chemical Analysis of the Relative Exciton Chirality CD Configuration at the Axis 7-epi-6 (Dioncophylline A, full absolute stereostructure) 7-epi-4 4 PdlC ~ toluene, 1200 Me MeO MeO Forthis reason, we kept looking for further further developed in our group [27-29]. confirmation of our revised structure 4. As shown in Fig. 6, the theoretical CD Therefore, any new method that we in- spectrum (dotted) for the dehydrogena- troduced into naphthylisoquinoline chem- tion product of dioncophylline A matches istry was first tested on this important very well with the experimental one (full alkaloid, exemplarily. line), in particular in the region of the For a first additional support of the crucial couplet. This unambiguously con- absolute stereostructure, we have applied firms the absolute axial P-configuration the quantum chemical calculation and thus of dioncophylline A [30] - stereochemi- prediction of CD spectra, established and cal information no. 4. BIOLOGICALLY ACTIVE AGENTS IN NATURE 21 CHI MIA 52 (1998) Nr, 1/2 (Jnnunr/Fcbruor) 2.5. Relative Axial vs. Centrochirality: 200 positive first a Chemical Method / Cotton effect Furthermore, we have developed a 120 chemical method for the analysis of the .. relative configuration at the biaryl axis as 40 compared to the stereocenters [31]. Ofthe L1£ -40 two atropo-diastereomeric synthetic pre- -- experimental cursors 6 and 7 to dioncophylline A -epi-6 -120 calculated (4) and its atropisomer (7-epi-4) (Scheme A 3), specifically only the syn-compound 7- -200 epi-6 can be bridged by a succinate unit to 200 230 260 290 320 give 7, whereas the anti-diastereomer 6 Fig.