Imines of substituted cyclohexanone derivatives with (S)-(-)-1-phenylethylamine were reacted with methyl acrylate or methyl propiolate to yield optically active cyclohexanone derivatives after hydrolysis in good to excellent yield with good e.e. The absolute configurations of these products can not be determined by only measuring the CD spectra, because these molecules adopt conformations different from what expected in general. We have prepared differently substituted cyclohexanone derivatives and established the absolute configurations of some of the derivatives with chiral auxiliary by X-ray crystallography. All the absolute configuration of the product derived from the same phenylethylamine was same. The substituent with long carbon side chain did not enter the area of the front octant of the carbonyl group. The sign of the Cotton effect mainly depended upon the conformation of cyclohexanone ring which was regulated by the substitution pattern. The global minimum conformation of methyl (1-methyl-2-oxocyclohexyl) propionate 2 was calculated by MM2 using CONFLEX. More than 96% of the preferred conformation was that the C-3 side chain was in the axial position. In the case of methyl (1-ethyl-2-oxocyclohexyl) propionate 23, 56% had the axial side chain and 44% equatorial. These results also support the CD data as shown in Table 1. These reaction products were applied to the synthesis of the optically active sesquiterpenoids isolated from liverworts in order to establish the absolute configurations of these terpenoids. So far, tridensone 26, riccardiphenols A (31) and B (32) were synthesized and the work toward trifarienols A (36a) and B (36b) are under way.

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Four Ligularia species, L. kanaitzensis, L. vellerea, L. subspicata, and L. lamarum collected in Yunnan province of China were examined and 64 compounds were isolated. Compounds 1-15 were new. The samples of L. kanaitzensis could be divided into two groups, based on chemical composition of the root extract. Furanoeremophilane-6β,10β-diol and its derivatives were isolated from one group, while eremophilan-8-one derivatives were isolated from the other group. In contrast, intra-specific diversity was found to be small in the atpB-rbcL intergenic sequence. The samples of L. vellerea could be divided into three groups. The major components isolated from types A, B, and C were 6,15-dioxygenated furanoeremophilanes, 1,6-dioxygenated furanoeremophilanes, and 6,15-dioxygenated eremophilanolides. The difference in chemical composition is consistent with geographic distribution. Intra-specific diversity in the atpB-rbcL sequence was small. The samples of L. subspicata were grouped into two, that is, a group A producing 1-angeloyloxy derivatives and a group B producing ligularol (35) and its derivatives. Diversity was found to be present in the nucleotide sequences as well. 1,10-Dioxygenated derivatives from L. lamarum were isolated. The chemical composition was diverse. However, the DNA sequence of atpB-rbcL is currently under investigation.

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Compounds 1 and 2 were isolated from the liverwort Anastrophyllum auritum. Tormesol (3) was isolated from Halimium viscosum. Their structures were determined to possess a seven-membered ring fused with a five-membered ring, sphenolobane-type diterpene. The absolute configurations of 1 and 2 have not been determined, while tormesol (3) has been proposed to have the S-configuration at the C-13 position by NMR analysis. We have succeeded in total synthesis of 1, 2, and 3 and determined their absolute configurations. As illustrated in our retrosynthetic analysis of 1, 2, and 3, we planned to synthesize the seven-membered ring system including a tri-substituted double bond using ring closing metathesis reaction and the five-membered ring system by aldol reaction, followed by conjugate reduction of the key intermediate 7. The cyclization precursor 12 was synthesized from ethyl acetoacetate (13). The precursor 12 did not produce seven-membered ring compound 11 using Grubbs' reagent or Schrock's reagent. Therefore, 12 was reduced to alcohol, which was protected by TES, MOM, and Ac groups (14, 15, 16). Compound 17 was obtained from compound 14 using Grubbs' reagent in 94% yield (Table 1). The optically active compound 9 was prepared from 10 using (S)-(-)-phenylethylamine as a chiral auxiliary. The optical purity was 97%ee by HPLC (CHIRALCEL OD-H). The key intermediate 7 was derived from keto nitrile 8 by aldol reaction in 97% yield. Compound 25 was obtained by conjugate reduction of 7 using Mg/MeOH. Compounds 1 and 2 were derived from compound 25 (Schemes 4, 5). Tormesol (3) was synthesized from compound 25 by methylation of the cyano group and alkylation of the resulting ketone (Scheme 6). The spectral data including the specific rotation of compounds 1 and 2 were identical with those of the natural products, establishing their absolute configurations. The spectral data of 3 was also identical with those of the natural product. However, the specific rotation was opposite to that of the natural one, supporting the assigned absolute configuration.

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  The Hengduan Mountains area of China is rich in plant resources. The Ligularia species, which belong to Senecioneae and Asteraceae, distributed in this area are highly diversified and contain 6 sections and over 100 species, and are considered to be in on-going evolution and diversification. To understand the inter- and intra-specific diversity of these plants and to elucidate the mechanism of diversification, we analyzed Ligularia plants by chemical, genetic, geographical, ecological, and morphological approaches. We investigated 4 species, and isolated 26 novel compounds. Based on the chemical composition of root extract as well as nucleotide sequence variations in internal transcribed spacers (ITS), we obtained 3 findings. (i) L. virgaurea is classified into two groups, ligularol type and virgaurenone type from the view point of chemical constituents, which are phylogenetically distinguished from each other, (ii) L. subspicata and L. lamarum have an overlapped chemical spectrum, but showed no clear genetic correlation, and (iii) L. cyathiceps showed no significant variations in either chemical constituents or nucleotide sequences.

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  The terpenoid constituents of Ligularia virgaurea (30 samples), Ligularia pleurocaulis (8 samples), Ligularia dictyoneura (8 samples), Ligularia brassicoides (5 samples), Ligularia lingiana (1 sample), and Ligularia liatroides (1 sample)(all belonging to section Senecillis of Ligularia, Asteraceae and collected in Yunnan, Sichuan, Qinghai, and Gansu provinces, China), from which 220 compounds were isolated, including 113 novel ones, are reviewed. Five chemotypes were identified in L. virgaurea based on their chemical constituents, while three clades were detected from the base sequences. Although intra-specific diversity was found in L. virgaurea, more samples were needed of other species in order to reach a definite conclusion. Inter-specific diversity was also examined in section Senecillis but was restricted due to the scarcity of samples. Synthetic studies on chiral natural products to determine their absolute configurations, especially those of riccardiphenols A and B as well as crispatanolide, which were all isolated from the liverwort, are briefly reviewed.

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