北島 満里子

In the last few years, numerous new indole and oxindole alkaloids were isolated from the Chinese medicinal plant, Gelsemium elegans Benth., by us and other researchers. Our interest in the relationship of various skeletons of Gelsemium alkaloids has led us to consider their biogenetic pathway and to investigate our proposal by chemical transformations. Here, we describe the following three newly developed chemistry on the Gelsemium alkaloids. I: 3,3-Disubstituted oxindole (16) could be converted to the Na-methoxy-oxindole (20) via tungstate-catalyzed oxidation of the indoline derivative (17). This method was applied to the synthesis of the Gelsemium alkaloids, (5), (27), (28) and (56). II: Based on a biogenetic speculation, a humantenine-type Na-methoxyoxindole alkaloid, humantenirine (27), was prepared from a sarpagine-type indole alkaloid, gardnerine (21), via stereoselective rearrangement to the oxindole, olefin inversion, and introduction of a methoxy group onto the Na-function. III: 20-Hydroxydihydrorankinidine (28), a biogenetically hypothetical intermediate to the new skeletal type alkaloid, gelselegine (8) (Fig. 5), was synthesized from ajmaline (33) in 22 steps. Gardnerine (21) was transformed into the gelselegine skeleton (53), which was then converted to the natural gelsedine-type alkaloid, gelsemicine (56) in a highly stereoselective manner. Starting from 21 the first and biomimetic construction of another gelselegine-type alkaloid (60) having a hydroxy group at C-19 was achieved via a biogenetically hypothetical aziridine intermediate (59).

The technology of plant cell suspension cultures to generate useful secondary metabolites was emploied for two medicinal plants originally producing the indole alkaloids. I. Biotransformation of Ajmaline in Plant Cell Cultures of Rauwolfia Serpentina Benth. From the methanol extracts of the plant cell suspension cultures of R. serpentina, which have been cultivated in the alkaloid-production medium after feeding of ajmaline (1), three new indole alkaloids, raumacline (2), N_b-methylraumacline (3), and 19(S)-hydroxy-N_b-methylraumacline (4), were isolated. These structures first elucidated by spectroscopic analysis were unambiguously determined by the chemical synthesis from ajmaline (1). These new compounds are the first examples of the macroline-type indole alkaloids having the trans relationship between C15 and C16 positions. II. Isolation of Novel Indole Alkaloids from Cell Cultures of Aspidosperma Quebracho Blanco Schlecht. From the cell suspension cultures of A. quebracho blanco, two novel monoterpenoid indole alkaloids, aspidochibine (19) and 3-oxo-14,15-dehydrorhazinilam (21), were isolated, though the production amounts of them were very low at this stage. The structure elucidation and the stereochemical analysis were made by mainly 2D NMR technique. Aspidochibine (19), which has a characteristic ten-membered lactone, is a completely new structural class of the quebrachamine series.

Ajmaline was converted into new Gelsemium alkaloids, 19Z- anhydrovobasinediol [(19Z)-taberpsychine] and N-demethoxyrankinidine, via koumidine along the biomimetic sequence, and the absolute configuration of these alkaloids was determined by these transformations.

We have recently investigated the alkaloidal constituents of Gelsemium elegans, a toxic medicinal plant from Thailand and proposed the biogenetic route of these alkaloids having novel polycyclic systems. In order to support the biogenetic speculation and to develop the efficient synthetic method of these alkaloids including the minor constituents, we designed the biomimetic partial synthesis of some gelsemium alkaloids from easily obtainable compounds. Koumidine (4) is a plausible biogenetic precursor of the new alkaloid, 19-(Z)-taberpsychine (5) and its structure was revised. Both to provide support for the spectroscopic analysis and to determine the absolute configuration of these compounds, we have synthesized them from ajmaline (16). Koumidine (4) was also prepared from gardnerine (22) by the demethoxylation from indole nucleus and the inverting the configuration of the ethylidene side chain with palladium catalyst. Along the biogenetic speculation, a principal gelsemium alkaloid, koumine (6) was synthesized from 18-hydroxygardnutine (28) by the demethoxylation from indole ring and palladium-catalyzed cyclization between C_7 and C_<20> of biogenetic intermediate (27). A synthetic intermediate (45), which was corresponding to the biogenetic intermediate (12) for gelsedine (13), was prepared from ajmaline (16) in 21 steps via the deformylation (C_<21>) and the construction of five-membered D-ring having an α-ethyl group on C_<20>. Talcarpine (49), one of the macroline-type pleiocarpa alkaloid, was synthesized from (16) in 10 steps and the configuration at C_<19> was determined to be (R) by the analysis of 2D-NMR spectra.

Chemical investigation of Gelsemium elegans collected in Thailand resulted in the isolation of 6 new indole alkaloids, along with 7 known compounds, i.e. gelsemine(1), gelsevirine(2), koumine (3), gelsenicine(4), 14-hydroxygelsenicine(5), humantenine(6), and 14-hydroxygelsedine(7). The structures of new alkaloids, 16-epi-voacarpine(11), 19-hydroxydihydrogelsevirine(12), 19-(Z)-taberpsychine(15), koumine-N-oxide(16), gelsemine-N-oxide(18), and 19-oxo-gelsenicine(19) were determined by the spectroscopic analysis, chemical reactions, and/or X-ray analysis. Furthermore, structures of two indole alkaloids, "akuammidine" and koumidine, previously isolated from the same plants, were revised to be (8) and (10), respectively. We propose here the biosynthetic route of Gelsemium alkaloids. (Chart2) Intermediate (21) formed from strictosidine (20) will serve as a precursor of sarpagine type alkaloids, such as koumidine (10), which will be further transformed by oxidation and rearrangment into taberpsychine (15), koumine (3), humantenine (25), and gelsemine (1) alkaloids. Intermediate (21) will also be metabolized to C_<21>-norsarpagine type (22), which will be converted to the gelsedine (24) series. In order to support the biogenetic proposal above, we designed the biomimetic synthesis of koumine and humantenine skeletons from gardneria alkaloids. The synthesis of 11-methoxykoumine (30) was accomplished starting from 18-hydroxygardnerine (27) through the intramolecular C-C bond formation between the indole part (C_7) and allylic cation (C_<20>) using Pd catalysis. The biomimetic synthesis of des-N(a)-methoxyhumantenirine (35) was also achieved from gardnerine (16) in a highly stereoselective manner. Thus, OsO_4 oxidation of C/D-ring opening product (31) gave exclusively oxindole (37) which had desired configuration at C_7. (37) was further transformed into (35) via the olefine inversion process and deprotection of N(b) group.