北島 満里子

A number of polymeric Nb-methyltryptamine-derived alkaloids that link together two to eight pyrrolidinoindoline units have been isolated from rubiaceous plants. Some of them have a variety of biological activities involving potent opioid agonistic activity. Recently, we have investigated the alkaloidal constituents in Psychotria rostrata native to Malaysian rainforest and have found three novel tryptamine-derived alkaloids, named pscyhotrimine (1). psychotetramine (2) and psychopentamine (3). To establish their structures as well as to develop the efficient synthetic route, we embarked on the total synthesis of these structurally unique alkaloids. 1. Total synthesis of new trimeric alkaloid, psychotrimine All the hitherto known tryptamine-related polymeric alkaloids are composed of pyrrolidinoindoline units and link together at the C3a-C3a' and C3a-C7' positions. Characteristically, psychotrimine (1) is the first example of this class of alkaloid that contains the tryptamine unit in the molecule as well as possesses the linkage at C3a-Na (indole) and C7-Na (indole) positions. We planned a synthetic strategy that employs the copper mediated intramolecular and intermolecular amination of halobenzenes as key steps. Starting from 2-bromobenzaldehyde and indoline, we prepared dimeric compound (10) via intramolecular amination of amidine (8). Onto the C7 position of indoline core in 12, an additional tryptamine unit was installed by intermolecular amination to furnish the total synthesis of (±)-1. Here, we have proven the structure of psychotrimine. 2. Synthetic study of new tetrameric alkaloid, psychotetramine Psychotetramine (2) is a new tetrameric tryptamine-derived alkaloid containing the known dimeric alkaloid, chimonanthine, in the lower segment and one tryptamine unit in the upper part. To reveal the structure inferred by spectroscopic analyses, we planned the convergent strategy that involved the copper mediated intermolecular amination between iodide (12) and the stereoisomers of chimonanthine, the later of which have been synthesized by oxidative coupling of tryptamine derivatives with hypervalent iodine (III) reagent.

To discover new antitumor natural products, we carried out the chemical investigation of the alkaloids in Gelsemium elegans and G. sempervirens (Loganiaceae), and the evaluation of the cytotoxic effects of Gelsemium alkaloids on some tumor cells. Four new gelsenicine-related alkaloids (7-10) were isolated from G. elegans. Gelsedilam (7) and 14-acetoxygelsedilam (8) are unprecedented 18,19-nor-type monoterpenoid indole alkaloids. Gelsefuranidine (9) is the first example of a monoterpenoid indole alkaloid having a furan residue on the side chain. Gelseiridone (10) is a new type of alkaloid having a nitrogen-carbon linkage between a gelsenicine-type monoterpenoid indole alkaloid that possesses an α,β-unsaturated ketone residue as well as the N_b-C20 seco-form and a monoterpene unit having an iridoid skeleton. Five new sarpagine-type alkaloids, gelsempervine-A (23), -B (24), -C (25), and -D (26), and 19Z-16-epi-voacarpine (27), and one yohimbane-type alkaloid, sempervilam (29) were isolated from G. sempervirens. Spectroscopic data suggest that 23 existed as a C/D ring-opening structure with the keto-amine form (A) in such aprotic solvents as CH_3CN, and as a transannular structure with the zwitterionic form (B) in such protic solvents as CH_3OH. The structure of sempervilam (29) was confirmed by the total synthesis. The gelsedine-type alkaloids, 14-acetoxygelsenicine (18, EC_<50>=250nM), 14,15-dihydroxygelsenicine (19), gelsedine (34), and gelsemicine (35) showed relatively strong cytotoxic effects on the A431 human epidermoid carcinoma cell line (positive control, cisplatin: EC_<50>=3.5μM).

Two new monoterpene glucosides, demethylsecologanol and 3"'-O-glucosylsenburiside II, were isolated from Ophiorrhiza liukiuensis (Rubiaceae) together with 23 known compounds, including camptothecins and beta-carboline-type alkaloids. Their structures were determined by spectroscopic analysis.

Poly-pyrrolidinoindoline alkaloids, such as (-)-chimonanthine and hodgkinsine, have been isolated from the plants belonging to Calycanthaceae, Idiospermaceae, and Rubiaceae, as well as from the dendrobatid frog. Recent pharmacological study revealed this type of alkaloids has the potent antinociceptive activities that interact with opioid receptors. To discover the new poly-pyrrolidinoindoline alkaloids, we carried out the chemical investigation of the constituents in Psychotria rostrata (Rubiaceae), Chimonanthus praecox (Calycanthaceae), and Chimonanthus praecox f. concolor (Calycanthaceae), and the synthetic studies on polymeric pyrrolidinoindoline alkaloids isolated from these plants. 1) New type of poly-pyrrolidinoindoline alkaloids from P. rostrata (Rubiaceae) The leaves of Psychotria rostrata Bl. were used as folk medicine for the treatment of constipation in Malaysia. We succeeded in isolation of two new alkaloids, psychotrimine (1) and psychopentamine (2), from the MeOH extract of P. rostrata leaves. These alkaloids are the first example that contains the tryptamine and pyrrolidinoindoline unit in the same molecule. Attempts at the total synthesis of 1 are under investigation in our laboratory. 2) New Chimonanthus alkaloids from C. praecox and C. praecox f. concolor We isolated two new alkaloids, (-)-chimonanthidine (3) and chimonamidine (4), from the MeOH extract of C. praecox seeds, as well as two new alkaloids, CPC-1 (12) and CPC-2 (13), from the MeOH extract of C. praecox f. concolor seeds. The structures of 3, 4, and 13 were elucidated by means of spectroscopic analysis and biomimetic total synthesis. Interestingly, it was found that natural chimonamidine (4) comprises a mixture slightly enriched with the (R)-(-)-enantiomer. 3) Total synthesis of chimonanthidine and structure reinvestigation of isochimonanthine Recently, we have developed a new synthetic method for the dimerization of indole derivatives using hypervalent idodine(III) reagent. We utilized this method for the synthesis of rac-chimonanthidine (rac-3) and rac-isochimonanthine (rac-22), the later of which was isolated from an Indonesian rubiaceous Argostemma yappii. The data for the proposed structure of isochimonanthine were not identical with those of the natural product. Careful structure reinvestigation led us to the conclusion that so-called isochimonanthine was the mixture of (+)-chimonanthine (25) and meso-chimonanthine (26) in the ratio of 1: 1.

The genus Lycopodium (Lycopodiaceae), which produces a potential therapeutic agent, huperzine A (1), for the treatment of Alzheimer 's disease, has been extensively studied in recent years, resulting in the isolation of a number of new alkaloids. We also succeeded in the isolation of several new alkaloids from the crude basic fraction of Lycopodium serratum Thunb. collected at Chiba prefecture. The structures of new alkaloids were elucidated by spectroscopic analyses and chemical correlations, as follows. A new alkaloid, lycoposerramine-A (2), was obtained as colorless needles (mp. 169-171℃, C_<18>H_<29>N_3O_2). The one- and two-dimensional NMR data enabled us to construct the basic skeleton of 2 possessing a fused tricyclic ring system with five- and six-membered cycloalkanes and a 1-azacyclononane, which retains the fundamental backbone of the known alkaloid, fawcettimine (3). The structure was finally established by X-ray crystallographic analysis. Lycoposerramine-A (2) is the first example of a natural product that contains a 1,2,4-oxadiazolidine-5-one residue in the molecule. The structure of second new alkaloid, lycoposerramine-B (4), was initially elucidated by spectroscopic data including the J-resolved HMBC spectra. The novel structure having a oxime function was confirmed by chemical transformation from a known alkaloid, serratinine (5), via an eight-steps operation, which included a reductive ring-opening of an α-immonium ketone group and a regioselective oximation as the key reactions. Lycoposerramine-C (14) was obtained as colorless prisms (mp. 164-165℃) and its structure possessing the fawcettimine-skeleton was determined by spectroscopic and X-ray analyses. It was found that treatment of 14 with NaOMe in MeOH afforded two known alkaloids, phlegmariurines A (15) and B (16). Other fawcettimine-related new alkaloids (20, 22-26) were isolated and these structures were inferred by spectroscopic analyses and/or chemical transformations. The biogenetic route of these new fawcettimine-related alkaloids starting from fawcettimine (3) was proposed. Ten new alkaloids (27, 29-37) having lycopodine-related structure were also isolated and their structures were elucidated on the basis of spectroscopic analyses and/or chemical transformations.