Hexacylinol, a New Antiproliferative Metabolite of Panus rudis HKI 0254.

Abstract

During our continuing screening for new bioactive metabolites from fungi we discovered recently hexacyclinol(1) as a novel, unusual, oligocyclic metabolite in cultures of the fungal strain Panus rudis HKI 0254. The strain was isolated from basidiospores of this fungus found on dead betula woods collected near Irkutsk (Sibiria, specimen herb. H, DORFELT, Sibiria 299). Panus rudis is of widespread occurrence throughout the world in many different ecotypes and has been reported to produce bioactive secondary metabolites1,2). The basidiomata of Panus rudis from the Sibirian source are growing singly or basal confluent to little tufts, excentric to central, stipitate, infundibuliform, with hazel-brown, strong tomentous pilei until 4.5cm in diameter; pilei and stipes with hairs until 2.5mm, shows in cultures a white to light-brownish mycelium, tomentous with clamped connections.For cultivations a small piece of a mature slant culture of the strain HKI 0254 grown on malt extract agar (malt extract 4%, yeast extract 0.4%, agar 1.5%, deionized water ad 1 liter, pH 6.0) was used to inoculate 1000ml Erlenmeyer bottles containing 250ml of the producing medium consisting of glucose 1%, sucrose 1%, corn starch 1%, yeast extract 0.8%, casein peptone 0.1%, soybean meal 0.5%, (NH4)2HPO4 0.05%, CaCO3 0.03%, (NH4)SO4 0.5%.The fermentation broth (15 liters) was extracted twice overnight by stirring with ethyl acetate (1:1). The combined extracts were dried and evaporated to dryness Table 1.Structure elucidation of 1 (Fig. 1a) was done using optical spectroscopy, mass spectrometry, 1D and 2D NMR spectroscopy spectroscopy (1H, 13C Table 2) displayed signals of four methyl (1.78ppm, 1.78ppm, 1.28ppm, 1.15ppm), one methoxyl (3.01ppm), twelve methine and

Computer-Guided Total Synthesis of Natural Products. Recent Examples and Future Perspectives

“…Finally, treatment of 139 with K10 clay generated the target compound 138 following a S N 2'/ cyclization path. The NMR data of the synthetic sample, whose structure was confirmed by X-ray analysis, was identical to those reported by Gräfe and co-workers 63 for hexacyclinol. 68 After this work, there were two synthesis of remarkably different structures (134 and 138), for which both were claimed having identical NMR data compared to natural hexacyclinol.…”

“…In 2002, Udo Gräfe and co-workers 63 isolated a novel compound from the fungal strain Panus rudis HKI 0254 and termed it hexacyclinol. The structural elucidation, which relied on different techniques such as high resolution mass spectrometry (HRMS), infrared (IR) and NMR, including 1 H, 13 C, distortionless enhancement by polarization transfer (DEPT), COSY, HMQC, HMBC and NOESY experiments, led to the proposal depicted in Figure 27.…”

Peroxy natural products

“…315 The structure of hexacyclinol was subsequently revised, and an alternative structure 541 was confirmed via total synthesis. In addition, an X-ray crystal structure was obtained, providing unequivocal structural confirmation.…”

Total Synthesis and Structure Assignment of (+)‐Hexacyclinol

“…[1] The proposed structure contains both reactive epoxyketone and highly strained endoperoxide moieties. A synthesis of the structure proposed by Gräfe and co-workers, as well as preliminary evaluation of non-peroxide-containing precursors as antimalarial agents, was recently reported by La Clair.…”

“…Under these conditions, "pre-hexacyclinol" (4) was cleanly obtained in 87 % yield as a single diastereomer. [5,10] To assess the transformation [7] of panepoxydon (6) to monomeric precursor 5, we treated commercially available [16] 6 with K10 clay in CD 3 OD (40 8C, 10 h) which afforded epoxyquinol diene monomer 5 (60 % conversion according to 1 H NMR spectroscopy). [11] After considerable experimentation, we found that the final S N 2' substitution/cyclization of 4 to hexacyclinol (2) was efficiently mediated by K10 clay [17] (EtOAc, room temperature, 3 min, 99 %).…”