Bioactive macrolides and polyketides from marine dinoflagellates*

Absolute stereochemistry of amphidinolides G and H, potent cytotoxic 27and 26-membered macrolides, respectively, isolated from a marine dinoflagellate Amphidinium sp., was determined by X-ray diffraction analysis, synthesis of a degradation product, and chemical interconversion. Six new macrolides, amphidinolides H2~H5, G2, G3, and W, have been isolated from a marine dinoflagellate Amphidinium sp. (strain Y-42), and the structures were elucidated by 2D NMR data and chemical means. The structure–activity relationship of amphidinolide H-type macrolides for cytotoxicity was examined. The biosynthetic origins of amphidinolides B, C, H, J, T1, and W were investigated on the basis of 13C NMR data of 13C-enriched samples obtained by feeding experiments with [1-13C], [2-13C], and [1,2-C2] sodium acetates in cultures of the dinoflagellates. Five novel long-chain polyhydroxyl compounds, colopsinols A~E, were obtained from the Amphidinium sp. (strain Y-5). ABSOLUTE STEREOCHEMISTRY OF AMPHIDINOLIDES G AND H Amphidinolides G and H [1] isolated from the marine dinoflagellate Amphidinium sp. (Y-25 strain) are potent cytotoxic 27and 26-membered macrolides, respectively, having unique structural features such as an allyl epoxide and vicinally located one-carbon branches (Scheme 1). The gross structures have been elucidated primarily by means of 2D NMR data, whereas the stereochemistry remains unsolved. Recently, a strain (Y-72) of the genus Amphidinium producing relatively large amounts of amphidinolides G and H has been separated from the inside cells of the marine acoel flatworm Amphiscolops sp. collected off Zanpa, Okinawa [2]. Amphidinolide H was crystallized from hexane-benzene as colorless needles, mp 131–132 °C. The relative stereochemistry of 9 chiral centers was obtained from a single-crystal X-ray diffraction analysis. Amphidinolide H was treated with NaBH4 followed by NaIO4 oxidation, NaBH4 reduction, esterification with (R)-(–)-MTPACl, and separation using C18 high-performance liquid chromatography (HPLC) to afford the tris-(S)-MTPA ester of the C22–C26 segment. Both tris-(S)and (R)-MTPA esters of the C22–C26 segment were prepared from methyl (2S)-3-hydroxy-2-methylpropionate. 1H NMR data of the tris-(S)-MTPA ester derived from the natural product were identical with those of the synthetic tris-(S)-MTPA ester, indicating 23Rand 25R-configurations. Therefore, the absolute configurations of amphidinolide H were concluded to be 8S, 9S, 11R, 16S, 18S, 21R, 22S, 23R, and 25R. The absolute stereochemistry of amphidinolide G was determined by interconversion between amphidinolides G and H under alkaline condition. All spectral data of amphidinolide G isolated from this mixture were identical with those of the natural product. Thus, the absolute configurations of amphidinolide G assigned were the same as those of amphidinolide H. *Pure Appl. Chem. 75, 141–419 (2003). An issue of reviews and research papers based on lectures presented at the 23rd IUPAC International Symposium on the Chemistry of Natural Products, Florence, Italy, 28 July–2 August 2002 on the theme of natural products. ‡Corresponding author