北島 満里子

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.

A number of indole and oxindole alkaloids have been isolated from the Uncaria plants (Rubiaceae) and found to possess pharmacologically significant activities. The chemical investigation of Uncaria attenuata Korth in Thailand was first carried out by UK-Thai researchers, resulting in the isolation of many Corynanthe- and heteroyohimbine-type indole and oxindole alkaloids. By the chemical re-investigation of this plant, we found novel types of oxindole alkaloids, i.e., Us-7 (1), Us-8 (2), and Us-9 (3a, 3b). Their structures have been deduced based on spectroscopic analysis and biogenetic speculation. In order to elucidate the structures unambiguously, we carried out the synthesis of these alkaloids. I. Based on the biogenetic speculation, Us-7 (1) and -8 (2), D-seco Corynanthe-type oxindole alkaloids, would be formed from normal corynanthe-type compounds through an oxidative cleavage at the enamine double bond at the C_<20>-C_<21> positions. According to this hypothesis, the stereochemistry at the C15 is most likely to be R. To elucidate the structures including the absolute stereochemistry at C15, we planned the asymmetric total synthesis of Us-7 (1) and -8 (2). Starting from (S)-glycidol (4), a chiral (R)-γ-butenolide (10) was prepared via 7 steps reactions, which was then converted to a key intermediate (14), corresponding to the monoterpenoid part of the target molecules, through a stereoselective addition of a malonate derivative (11) to the butenolide (10). Condensation of 14 with tryptamine (15) gave the lactam (16), which was transformed to the tetrahydro-β-carboline derivatives (20a, 20b) via Bischler-Napieralski reaction and N_b-formylation. The structure of 20a was determined by X-ray crystallographic analysis. The thus obtained indoles were respectively converted to oxindole derivatives. Their stereochemistry at C7 was elucidated by the comparison of CD spectra as well as NOE experiments. The final stage, i.e., hydrolysis of the acetyl ester at C20 and oxidation of the resulting secondary hydroxy group leading to Us-7 (1) and -8 (2), is in progress. II. Us-9 (3a, 3b) was deduced to be 3-oxo-7-hydroxy-3,7-secorhynchophylline by spectroscopic analysis. Based on the biogenetic speculation, Us-9 was prepared from isorhynchophylline via modified Polonovski reaction of its N-oxide and then the introduction of a hydroxy group at the C7. Two diastereomers ascribable to C7 of the natural and semi-synthetic (3a, 3b) were separated by chiral column chromatography. The absolute configulation at C7 was elucidated by comparison of the CD spectra with those of the known oxytryptophan derivatives (28a, 28b), which were prepared from L-tryptophan by Labroo's procedure.