Progress in the Chemistry of Organic Natural Products 113 3030530272, 9783030530273

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Progress in the Chemistry of Organic Natural Products

A. Douglas Kinghorn · Heinz Falk Simon Gibbons · Jun’ichi Kobayashi Yoshinori Asakawa · Ji-Kai Liu Editors

113 Progress in the Chemistry of Organic Natural Products

Progress in the Chemistry of Organic Natural Products Volume 113

Series Editors A. Douglas Kinghorn , College of Pharmacy, The Ohio State University, Columbus, OH, USA Heinz Falk , Institute of Organic Chemistry, Johannes Kepler University, Linz, Austria Simon Gibbons , School of Pharmacy, University of East Anglia, Norwich, UK Jun'ichi Kobayashi, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan Yoshinori Asakawa , Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan Ji-Kai Liu , School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China Advisory Editors Giovanni Appendino , Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy Roberto G. S. Berlinck , Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, Brazil Verena M. Dirsch , Department of Pharmacognosy, University of Vienna, Vienna, Austria Agnieszka Ludwiczuk , Department of Pharmacognosy, Medical University of Lublin, Lublin, Poland Rachel Mata , Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico Nicholas H. Oberlies , Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC, USA Deniz Tasdemir , Marine Natural Products Chemistry, GEOMAR Helmholtz Centre for Ocean Research Kiel, Kiel, Germany Dirk Trauner , Department of Chemistry, New York University, New York, NY, USA Alvaro Viljoen , Department of Pharmaceutical Sciences, Tshwane University of Technology, Pretoria, South Africa Yang Ye , State Key Laboratory of Drug Research and Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Shanghai, China

The volumes of this classic series, now referred to simply as “Zechmeister” after its founder, Laszlo Zechmeister, have appeared under the Springer Imprint ever since the series’ inauguration in 1938. It is therefore not really surprising to find out that the list of contributing authors, who were awarded a Nobel Prize, is quite long: Kurt Alder, Derek H.R. Barton, George Wells Beadle, Dorothy Crowfoot-Hodgkin, Otto Diels, Hans von Euler-Chelpin, Paul Karrer, Luis Federico Leloir, Linus Pauling, Vladimir Prelog, with Walter Norman Haworth and Adolf F.J. Butenandt serving as members of the editorial board. The volumes contain contributions on various topics related to the origin, distribution, chemistry, synthesis, biochemistry, function or use of various classes of naturally occurring substances ranging from small molecules to biopolymers. Each contribution is written by a recognized authority in the field and provides a comprehensive and up-to-date review of the topic in question. Addressed to biologists, technologists, and chemists alike, the series can be used by the expert as a source of information and literature citations and by the non-expert as a means of orientation in a rapidly developing discipline. All contributions are listed in PubMed. More information about this series at http://www.springer.com/series/10169

A. Douglas Kinghorn  •  Heinz Falk Simon Gibbons  •  Jun’ichi Kobayashi  Yoshinori Asakawa • Ji-Kai Liu Editors

Progress in the Chemistry of Organic Natural Products 113

Editors A. Douglas Kinghorn College of Pharmacy Ohio State University Columbus, OH, USA

Heinz Falk Institute of Organic Chemistry Johannes Kepler University Linz, Oberösterreich, Austria

Simon Gibbons School of Pharmacy University of East Anglia Norwich, UK

Jun’ichi Kobayashi Graduate School of Pharmaceutical Science Hokkaido University Fukuoka, Japan

Yoshinori Asakawa Faculty of Pharmaceutical Sciences Tokushima Bunri University Tokushima, Japan

Ji-Kai Liu School of Pharmaceutical Sciences South Central University for Nationaliti Wuhan, China

ISSN 2191-7043     ISSN 2192-4309 (electronic) Progress in the Chemistry of Organic Natural Products ISBN 978-3-030-53027-3    ISBN 978-3-030-53028-0 (eBook) https://doi.org/10.1007/978-3-030-53028-0 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Contents

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity in East Asia ������������������������������������������������������������������������  1 Motoo Tori and Chiaki Kuroda

v

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity in East Asia Motoo Tori and Chiaki Kuroda

Contents 1  I ntroduction 2  C  ompounds 3  L  igularia Species 3.1   Ligularia virgaurea (Maximowicz) Mattfeld ex Rehder & Kobuski 3.2   Ligularia dentata (A. Gray) H. Hara 3.3   Ligularia japonica (Thunberg) Lessing 3.4   Ligularia hookeri (C. B. Clarke) Handel-Mazzetti 3.5   Ligularia atroviolacea (Franchet) Handel-Mazzetti 3.6   Ligularia kanaitzensis (Franchet) Handel-Mazzetti 3.7   Ligularia intermedia Nakai 3.8   Ligularia vellerea (Franchet) Handel-Mazzetti 3.9    Ligularia wilsoniana (Hemsley) Greenman 3.10  Ligularia melanothyrsa Handel-Mazzetti 3.11  Ligularia lapathifolia (Franchet) Handel-Mazzetti 3.12  Ligularia macrophylla (Ledebour) de Candolle 3.13  Ligularia knorringiana Pojarkova (= L. thyrsoidea) and Ligularia narynensis (C. Winkler) O. Fedtschenko & B. Fedtschenko 3.14  Ligularia rumicifolia S. W. Liu 3.15  Ligularia songarica (Fischer) Y. Ling 3.16  Ligularia stenocephala (Maximowicz) Matsumura & Koidzumi 3.17  Ligularia alticola Voroschilov 3.18  Ligularia brassicoides Handel-Mazzetti

  3   7    59    59    79    82    83    84    86    92    96    99  101  107  109  119  126  130  135  137  140

M. Tori (*) Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, Japan e-mail: [email protected] C. Kuroda Department of Chemistry, Rikkyo University, Tokyo, Japan e-mail: [email protected] © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2020 A. D. Kinghorn, H. Falk, S. Gibbons, J. Kobayashi, Y. Asakawa, J.-K. Liu (eds.), Progress in the Chemistry of Organic Natural Products 113, Progress in the Chemistry of Organic Natural Products 113, https://doi.org/10.1007/978-3-030-53028-0_1

1

2

M. Tori and C. Kuroda 3.19  3.20  3.21  3.22  3.23 

 igularia caloxantha (Diels) Handel-Mazzetti L Ligularia przewalskii (Maximowicz) Diels Ligularia sagitta (Maximowicz) Mattfeld ex Rehder & Kobuski Ligularia pleurocaulis (Franchet) Handel-Mazzetti Ligularia fischeri (Ledebour) Turczaninow, Ligularia anoleuca HandelMazzetti, and Ligularia veitchiana (Hemsley) Greenman 3.24  Ligularia cyathiceps Handel-Mazzetti 3.25  Ligularia cymbulifera (W. W. Smith) Handel-Mazzetti 3.26  Ligularia dictyoneura (Franchet) Handel-Mazzetti 3.27  Ligularia duciformis (C. Winkler) Handel-Mazzetti, Ligularia konkalingensis Handel-Mazzetti, Ligularia nelumbifolia (Bureau & Franchet) HandelMazzetti, and Ligularia limprichtii (Diels) Handel-Mazzetti 3.28  Ligularia hodgsonii J. D. Hooker 3.29  Ligularia lamarum (Diels) C. C. Chang and Ligularia subspicata (Bureau & Franchet) Handel-Mazzetti 3.30  Ligularia lankongensis (Franchet) Handel-Mazzetti 3.31  Ligularia latihastata (W. W. Smith) Handel-Mazzetti and Ligularia villosa (Handel-Mazzetti) S. W. Liu 3.32  Ligularia villosa Handel-Mazzetti 3.33  Ligularia oligonema Handel-Mazzetti 3.34  Ligularia tongolensis (Franchet) Handel-Mazzetti 3.35  Ligularia tsangchanensis (Franchet) Handel-Mazzetti 3.36  Ligularia yunnanensis (Franchet) C. C. Chang 3.37  Hybrid Ligularia Species 3.38  Further Ligularia Species I: altaica de Candolle, L. dolichobotrys Diels, L. franchetiana (H. Léveillé) Handel-Mazzetti, L. persica Boissier, L. speciosa Fischer et Meyer, and L. thyrsoidea (Ledebour) de Candolle 3.39  Further Ligularia Species II: L. achyrotricha (Diels) Y. Ling, L. nanchuanica S. W. Liu, L. purdomii (Turrill) Chittenden, L. odontomanes Handel-Mazzetti, L. sibirica (Linnaeus) Cassini, and L. thomsonii (C. B. Clarke) Pojarkova 3.40  Further Ligularia Species III: L. angusta (Nakai) Kitamura, L. calthifolia Maximowicz, L. fauriei (Franchet) Koidzumi, L. hiberniflorum (Makino) Kitamura, L. kangtingensis S. W. Liu, L. lingiana S. W. Liu, L. myriocephala Y. Ling ex S. W. Liu, L. platyglossa (Franchet) Handel-Mazzetti, and L. schmidtii (Maximowicz) Makino 3.41  Further Ligularia Species IV: L. brachyphylla Handel-­Mazzetti (= L. latihastata), L. calthifolia (Maximowicz) Diels, L. clivorum Maximowicz (= L. dentata), L. sachalinensis Nakai, L. tangutica (Maximowicz) Bergmans, L. trichocephala (Maximowicz) Matsumura et Koidzumi, and L. vorobierii Worosh 4  Genetic Analyses 5  Synthesis Aspects 5.1   Synthesis of Ligularol (= Petasalbin), Ligularone, and Related Compounds 5.2   Synthesis of Tetrahydroligularenolide Using Biogenetic Type Rearrangement 5.3   Synthesis of Furanoeremophilan-15,6-olide 5.4   Synthesis of Isopetasol 5.5   Synthesis of Eremophila-9,11-dien-8-one, Dehydrofukinone, and Furanoeremophilanes 5.6   Synthesis of Eremoligenol and Eremophilone 5.7   Synthesis of Eremophiladienes 5.8   Synthesis of Fukinone and Related Compounds 5.9   Synthesis of Eremophiladiene

 143  145  150  156  158  165  167  169  172  176  179  185  186  187  189  190  191  193  194  197  199

 201

 204  206  209  210  211  212  213  213  214  214  215  215

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 5.10  Synthesis of 6-Hydroxyeuryopsin 5.11  Synthesis of 3β-Angeloyloxyfuranoeremophilane 5.12  Synthesis of Ligularone and Isoligularone 5.13  Synthesis of (−)-(R)-Ligularenolide and (−)-(R)-PF1092C 5.14  Synthesis of Nootkatone 5.15  Synthesis of Cacalol 5.16  Synthesis of Noreremophilanes 5.17  Synthesis of Bakkane-type Sesquiterpenoids 5.18  Synthesis of Bisabolane-type Sesquiterpenoids 5.19  Synthesis of Nelumol A 6  Biological Activities References

3  216  217  218  219  220  220  221  223  226  228  229  230

1  Introduction To understand diversification of secondary metabolites in plants is a major theme in natural product chemistry. The genus Ligularia Cass., belonging to the family Asteraceae tribe Senecioneae, is highly diversified in the Hengduan Mountains area of China. More than a hundred species are recorded in the “Flora of China” [1, 2] and the evolution and diversification is considered to be still ongoing [3]. Ligularia species in this area occupy a great variety of habitats from streams to alpine meadows, ranging from 1000 to 5000 m in elevation [2]. Thus, Ligularia species in this domain provide natural products scientists with very interesting materials for the study of the diversity of their secondary metabolite profiles [4, 5]. Ligularia species have been studied with respect to secondary metabolites for a long time, and many sesquiterpenoids have been isolated from them [6, 7]. It is well known that Ligularia is a major source of eremophilane sesquiterpenoids, which have also been isolated from other genera in the family Senecioneae, including Parasenecio (Cacalia), Senecio, and Petasites [8–10]. Certain derivatives, such as rearranged- or seco-compounds as well as dimers, have been recorded. Among various eremophilane sesquiterpenoids, furanoeremophilanes and eremophilan-­12,8-­olides constitute the major class. During the 1960s and the 1970s, many furanoeremophilanes were isolated from roots of Japanese Ligularia species by the groups of Minato and Takahashi [11, 12]. The structure of ligularol (= petasalbin) (161), the most commonly isolated furanoeremophilane, was determined by Minato’s group. During this same period, Bohlmann’s group also obtained a large number of eremophilanes and related compounds from European Ligularia species [13]. Many eremophilanes and other types of sesquiterpenoids have been isolated and characterized from a number of other species in the family Senecioneae as well. Following these pioneering reports, especially from around 2000 and over the last two decades, an abundance of related compounds has been obtained from Chinese Ligularia species [14]. Over the last 20 years, the individual groups of the current authors have studied the diversity of compounds present in the roots of Ligularia species growing in the in northwestern Yunnan Province, western Sichuan Province, and, in part, in southern Qinghai and Gansu Provinces of (Hengduan Mointains area) (Plates 1 and 2). In

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M. Tori and C. Kuroda

Plate 1  A typical collection site in Aba, Sichuan Province, China

Plate 2  A typical collection site in Shangri-La, Yunnan Province, China

our studies on the diversity of Ligularia species, root phytochemicals and evolutionary neutral DNA sequences were chosen as indices, in addition to morphological identification and ecological observation in the field. As neutral DNA samples, internal transcribed spacer (ITS1-5.8S-ITS2) sequences were analyzed in the ribosomal RNA gene, and, for chemical investigations, EtOH or AcOEt extracts of dried roots were selected. The root phytochemical profiles and the ITS sequences were examined as independent parameters to one another. To date, many sesquiterpenoids, euparin-type benzofurans, and phenylpropanoids have been isolated. Eremophilanes, particularly furanoeremophilanes and eremophilan-­ 12,8-­ olides,

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

5

were the major class found among the sesquiterpenoids, although bisabolanes, bakkanes, and other types of compounds were also obtained. In this contribution are described phytochemical studies carried out by our groups mainly from 2000 onward, inclusive of our results on the diversity in secondary metabolites of Ligularia growing in the Hengduan Mountains area, focusing on eremophilane sesquiterpenoids and other metabolites. The present contribution deals with 1049 compounds, not only those that were new when first characterized but also known analogs, as isolated from Ligularia species. Genetic analyses, synthesis aspects, and biological activities will also be discussed. In our own work, plants were collected from selected locations in Yunnan, Sichuan, Qinghai, and Gansu Provinces, and Chongqing City, China. They were identified by Dr. Xun Gong, Kunming Institute of Botany, China. The DNA (ITS1-5.8S-ITS2) sequences were also investigated, as carried out by Prof. Ryo Hanai, Rikkyo University, Tokyo Japan (see Sect. 4). Plant collection expeditions have been conducted since the summer of 2000. In this contribution, the plant names and their constituents will be tabulated for each species, with the year of collection included if mentioned in the literature. In the case of our own work, the first four digits provide the year of collection and the latter two or three digits are specimen numbers for that year. Collection locations and their elevation (m) are indicated, if known. For our own work, the county and city/province are given (C = Chongqing, G = Gansu, Q = Qinghai, S = Sichuan, Y = Yunnan; other provinces are spelled out in full). Chemical constituents were grouped roughly into eight categories: (1) bicyclic eremophilanes (without ring C and nor-eremophilanes); (2) 10H tricyclic eremophilanes (furans and lactones (12,8-olides) with a hydrogen at C-10); (3) 10-OH tricyclic eremophilanes (furans and lactones with a hydroxy group at C-10); (4) tricyclic eremophilanes with 1(10)ene, 9-ene, and 1,10-epoxide; (5) the cacalol group; (6) bakkanes and other sesquiterpenoids; (7) aromatics; and (8) others. Mono-, di-, and triterpenes are grouped within the “others” category. The groups have been slightly changed for each table depending on the species. The major constituents are underlined, if they were described. In this work, alkaloids and sterols are not acquired. Furanoeremophilanes can be detected by TLC using Ehrlich’s reagent. Thus, their trisubstituted furan ring reacts with p-dimethylaminobenzaldehyde in the presence of HCl to show a yellow, pink, purple, or blue color, depending on the nature of the substituent [15]. Examples are included in Plate 3. Preliminary TLC experiments may be conducted in a facile manner, so that diversity in chemical composition can be indicated without the isolation of each compound (Sect. 3.1). However, because a TLC experiment does not yield any structural detail, conventional phytochemical analysis investigations, involving isolation and structure determination, were also carried out. Total ion chromatograms (TIC) of extracts were measured in LCMS analysis to compare chemical constituents. Typical TICs are shown in Plate 4. For example, these represent five chemotypes found in L. virgaurea. Although the V, C, N, and H types are more or less continuous, typical samples show characteristic peaks corresponding to their representative compounds. By obtaining their LC-MS profiles, it

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M. Tori and C. Kuroda

Plate 3  Typical TLC patterns visualized by spraying Ehrlich’s reagent. Left: the L type of L. virgaurea; the largest pink spot is ligularol (160). Right: the V type of L. virgaurea; the two yellow spots are virgaurenones A (273) and B (272) 500

400

300

200

100

0 0

5

10

15

20

25

min

Plate 4  Typical TIC profiles of L. virgaurea; from top to bottom: the L, V, C, H, and N types

is relatively facile to compare chemical constituents of each sample and to see if intraspecific similarities are present or not. The following conditions for LC-MS measurement were used: HPLC 1100 system with a DAD detector and an automatic sample injector (column, 5C18-MS-II (COSMOSIL) 4.6  ×  150  mm; solvent, MeOH-H2O gradient; flow rate, 0.5  cm3/ min). An Agilent 1100 series LC/MSD mass spectrometer was employed with an atmospheric pressure chemical ionization interface (APCI) (capillary voltage, 3.5 kV; corona current, 4 μA; capillary exit voltage (fragmentor), 90 V; drying temperature, 330°C; drying flow, 9 dm3/min; nebulizer pressure, 50 psig; positive ion mode; scan range, m/z 100–1000 amu).

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

7

2  Compounds Most compounds reported from Ligularia spp. are sesquiterpenoids belonging to the eremophilane, bakkane, oplopane, bisabolane, and eudesmane types. Only minor amounts of germacrane, guaiane, aromadendrane, caryophyllane, valencane, and cadinane types are produced. Cacalol and its derivatives have been categorized within a separate cacalol group, in which the C-14 eremophilane methyl group is shifted to the C-6 position. There has been some confusion in compound numbering in the literature, particularly for the C-14 and C-15 methyl groups, and the numbering herein is that proposed by Connolly and Hill [16]. Plate 5 shows the major skeletons and their numbering as used in this contribution. The structures drawn show relative configurations, and absolute configurations are presented where they have been determined. When X-ray structural analysis has been used, this is also mentioned. Questionable structures that have been proposed are pointed out, as necessary. A total of 1049 compounds isolated from Ligularia spp. are listed in Table 1. The plant sourcing for each compound is also listed in this table along with appropriate references. Structures of compounds isolated from Ligularia spp. are shown in Figs. 1–72.

Plate 5  Skeletons of sesquiterpenoids isolated from Ligularia plants and their numbering

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M. Tori and C. Kuroda

Table 1  Compounds isolated from Ligularia Structure number 1

Name of compound

2

Plant source L. cyathiceps L. duciformis/L. cyathiceps L. franchetiana L. intermedia L. kanaitzensis L. lamarum L. subspicata L. tsangchanensis L. vellerea L. virgaurea L. dictyoneura L. fischeri L. kanaitzensis L. lamarum L. longihastata L. nelumbifolia/C. stenoglossum L. subspicata

3

4

Fukinone

L. tsangchanensis L. dictyoneura L. kanaitzensis L. longihastata L. subspicata L. tsangchanensis L. duciformis L. fischeri L. kanaitzensis L. lamarum L. lamarum/L. subspicata L. melanothyrsa L. persica L. subspicata L. subspicata/L. cyathiceps L. vellerea L. virgaurea

Ref. [17] [18]

Comments

[19] [20] [21, 22] [23] [23, 24] [25] [26] [27, 28] [29] [30] [21, 22, 31] [23] [32] [33] [23, 24, 34] [35] [29] [22] [32] [23, 24] [35] [36] [37] [21, 22, 31] [23] [38] [21] [39] [23, 34] [38, 40] [26] [27] (continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

9

Table 1 (continued) Structure number 5

6 7 8 9 10 11 12 13 14

Name of compound Dehydrofukinone

Isofukinone

Eremoligenol

15 16 17 18 19 20

21 22 23 24 25

Ligudicin C Ligudicin D

Ligudicin A

Plant source L. alticola L. dictyoneura L. duciformis L. fischeri L. intermedia L. kanaitzensis L. longihastata L. subspicata L. intermedia L. speciosa L. subspicata L. melanothyrsa L. virgaurea L. intermedia L. intermedia L. virgaurea L. cyathiceps L. brassicoides L. cymbulifera L. fischeri L. nelumbifolia L. subspicata L. virgaurea L. veitchiana L. pleurocaulis L. veitchiana L. fischeri L. dictyoneura L. dictyoneura L. alticola L. duciformis L. kanaitzensis L. lamarum L. subspicata L. kanaitzensis L. dictyoneura L. alticola L. lamarum L. lamarum L. subspicata

Ref. [41] [29, 42] [36] [30] [20] [22] [32] [23, 34] [20] [43] [23] [44] [28] [20] [20] [45] [17] [46, 47] [48, 49] [50] [51] [34] [45] [52] [53] [52] [54] [55] [55] [41] [36] [31] [23] [23] [56, 57] [55] [41] [23] [23] [23]

Comments

X-ray (continued)

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M. Tori and C. Kuroda

Table 1 (continued) Structure number 26 27 28

Name of compound

Kanaitzensol

29 30 31 32 33

34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

Petasol

49 50

Neopetasol Isopetasol

51 52 53

Rumicifoline K

Plant source L. cymbulifera L. fischeri L. fischeri L. kanaitzensis L. subspicata L. sagitta L. macrophylla L. sagitta L. sagitta L. sagitta L. kanaitzensis L. lamarum L. melanothyrsa L. subspicata L. virgaurea L. przewalskii L. virgaurea L. veitchiana L. macrophylla L. sagitta L. melanothyrsa L. virgaurea L. brassicoides L. virgaurea L. atroviolacea L. atroviolacea L. przewalskii L. sagitta L. myriocephala L. macrophylla L. veitchiana L. fischeri L. rumicifolia L. speciosa L. speciosa L. fischeri L. virgaurea L. longihastata L. longihastata L. rumicifolia

Ref. [49] [58] [54] [22] [34] [59] [60] [61] [62] [62] [22] [23] [44] [23, 34] [27, 28, 63] [64] [65] [66] [67] [68] [44] [27] [46, 47] [27] [69] [69] [70] [68, 71] [72] [73] [74] [30] [75] [43] [43] [30] [76] [32] [32] [75]

Comments

Both C-11(S) and (R) determined

(continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

11

Table 1 (continued) Structure number 54

Name of compound Petasin

55 56

Isopetasin

57 58 59 60

Rumicifoline J 1-epi-Rumicifoline J

61 62 63

64 65 66 67 68

Rumicifoline L

Plant source L. dictyoneura L. fischeri L. intermedia L. lamarum L. lingiana L. longihastata L. nelumbifolia/C. stenoglossum L. rumicifolia L. sagitta L. subspicata L. tsangchanensis L. dictyoneura L. tangutica L. dictyoneura L. fischeri L. intermedia L. sagitta L. subspicata L. rumicifolia L. rumicifolia L. dentata L. fischeri L. kanaitzensis L. lamarum L. longihastata L. rumicifolia L. subspicata L. longihastata L. longihastata L. subspicata L. kanaitzensis L. lamarum L. longihastata L. rumicifolia L. subspicata L. subspicata L. rumicifolia L. pleurocaulis L. przewalskii L. hodgsonii

Ref. [29] [30] [77] [23] [78] [32] [33]

Comments X-ray structure

[75] [62] [23, 24] [35] [29] [13] [55] [30] [77] [62] [23] [75] [75] [13] [30] [22] [23] [32] [75] [23, 24] [32] [32] [23] [22] [23] [32] [75] [23, 24] [23] [75] [79] [64] [80] (continued)

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M. Tori and C. Kuroda

Table 1 (continued) Structure number 69 70 71

Name of compound

72 73 74 75 76 77 78 79 80 81

Ligumacrophyllatin Alticoloside A

82

Alticoloside B

83 84

Alticoloside C Alticoloside D

85 86 87 88 89 90 91 92 93 94 95 96 97 98

Alticoloside E Alticoloside F Alticoloside G Alticoloside H Alticoloside I 2′-O-Acetylalticoloside A 6′-O-Acetylalticoloside A 2′-O-Acetylalticoloside D

99 100

Knorringianalarin B

Plant source L. przewalskii L. przewalskii L. kanaitzensis L. longihastata L. virgaurea L. rumicifolia L. rumicifolia L. lingiana L. lingiana L. lingiana L. lingiana L. lapathifolia L. macrophylla L. alticola L. calthifolia L. alticola L. calthifolia L. alticola L. alticola L. calthifolia L. alticola L. alticola L. alticola L. alticola L. alticola L. calthifolia L. calthifolia L. calthifolia L. virgaurea L. fischeri L. sagitta L. sagitta L. tsangchanensis L. kanaitzensis L. lamarum L. subspicata L. tsangchanensis L. virgaurea L. knorringiana L. virgaurea

Ref. [64] [64] [22] [32] [27] [75] [75] [78] [78] [78] [78] [81] [67] [82] [83] [82] [83] [82] [82] [83] [82] [82] [82] [84] [84] [83] [83] [83] [65] [85] [59, 61] [59] [86] [22] [23] [34] [86] [27, 28, 63, 87] [88] [27]

Comments

(continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

13

Table 1 (continued) Structure number 101

102 103 104 105 106 107

Name of compound

Sagittacin E

108 109 110 111 112 113 114 115 116 117 118

Ligudentatol

119

Platyphyllide

120 121

2-Hydroxyplatyphyllide

Plant source L. knorringiana L. sagitta L. veitchiana L. sagitta L. virgaurea L. virgaurea L. sagitta L. sagitta L. sagitta L. veitchiana L. sagitta L. veitchiana L. sagitta L. przewalskii L. japonica L. hodgsonii L. hodgsonii L. japonica L. virgaurea L. japonica L. lapathifolia L. hodgsonii L. dentata L. intermedia L. rumicifolia L. fischeri L. intermedia L. przewalskii L. veitchiana L. fischeri L. dentata L. fischeri L. hodgsonii L. intermedia L. knorringiana L. macrophylla L. przewalskii L. songarica L. speciosa L. veitchiana

Ref. [88] [61, 62] [62] [62] [87] [89] [59] [61] [62] [62] [61] [66] [59] [64] [90] [91] [80] [90] [87] [90] [92] [93] [94, 95] [77] [75] [85, 96] [20] [70] [66] [58, 96] [94, 95, 97] [85] [91] [20] [88] [67, 98] [70] [99] [43] [66]

Comments

(continued)

14

M. Tori and C. Kuroda

Table 1 (continued) Structure number 122 123

124 125

Name of compound Ligujapone

Liguhodgsonal

Plant source L. fischeri L. dentata L. hodgsonii L. intermedia L. japonica L. odontomanes L. przewalskii L. brachyphylla L. clivorum L. dentata L. dolichobotrys L. hodgsonii L. intermedia L. japonica L. kangtingensis L. lamarum L. nanchuanica L. odontomanes L. sagitta L. speciosa L. veitchiana

126

Ligudentatin A

127 128 129 130

Ligudentatin B Ligukangtinol Rumicifoline A Norsubspicatin A

131 132

Normelanothyrsin A

133

L. dentata L. kangtingensis L. nanchuanica L. dentata L. kangtingensis L. rumicifolia L. subspicata/L. cyathiceps L. melanothyrsa L. lamarum L. melanothyrsa L. vellerea L. virgaurea L. virgaurea

Ref. [96] [94, 95, 97] [93] [77] [13] [100] [64] [13] [13] [13, 94, 95, 97] [101] [13] [20, 77, 102] [13] [103] [23] [104] [100] [105, 106] [43] [107, 108] [94] [103] [104] [94] [109] [75] [40]

Comments

[44] [23] [44] [26] [27, 28, 63] [28] (continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

15

Table 1 (continued) Structure number 134

Name of compound

135 136 137 138 139 139a 140

Ligupleurol Eremopetasinorol

141 142 143 144 145 146 147 148 149

Secovirgaurenol A Secovirgaurenol B Secovirgaurenol C

150 151

Secovirgaural Secobakkane A

152 153 154 155 156 157 158

Secobakkane B

159

Ligulolide C Ligumacrophyllal

Plant source L. lapathifolia L. macrophylla L. przewalskii L. fischeri L. melanothrsa L. virgaurea L. fischeri L. fischeri L. pleurocaulis L. tsangchanensis L. fischeri L. hodgsonii L. intermedia L. virgaurea L. virgaurea L. lapathifolia L. virgaurea L. cymbulifera L. dictyoneura L. virgaurea L. virgaurea L. virgaurea L. virgaurea L. lamarum L. melanothyrsa L. virgaurea L. lamarum L. hodgsonii L. brassicoides L. virgaurea L. virgaurea L. macrophylla L. virgaurea

Ref. [81] [73] [70] [96] [44] [27, 28] [96] [96] [53] [86] [110] [80] [111] [27] [27] [92] [112] [49] [113] [45] [76] [45, 76, 114] [45] [23] [44] [76] [115] [116] [117] [118] [118] [67, 119] [27, 28]

Comments

X-ray structure

(continued)

16

M. Tori and C. Kuroda

Table 1 (continued) Structure number 160

Name of compound

Plant source L. brassicoides L. dictyoneura L. fischeri L. hodgsonii

161

Ligularol = petasalbin

L. schmidtii L. subspicata/L. cyathiceps L. vellerea L. dictyoneura L. duciformis L. fischeri L. kanaitzensis L. lamarum L. lamarum/L. subspicata L. nelumbifolia L. nelumbifolia/L. subspicata L. schmidtii L. subspicata

162

L. subspicata/L. cyathiceps L. tongolensis/L. cymbulifera L. vellerea L. virgaurea L. kanaitzensis L. lamarum L. subspicata L. vellerea L. virgaurea

Ref. Comments [46, 47] [29, 120, 121] [37, 50, 122] [123– 125] [20] [40] [21] [29, 120] [126] [11, 37, 50] [22, 31] [23] [38] [51] [127] [20] [24, 38, 127] [38, 40] [128] [21, 26] [27, 63] [22] [23] [24] [26] [63] (continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

17

Table 1 (continued) Structure number 163

Name of compound

164

165

166 167

168

Ligularone

Plant source L. brassicoides L. dictyoneura L. fischeri L. lamarum L. lamarum/L. subspicata L. subspicata L. subspicata/L. cyathiceps L. tsangchanensis/L. vellerea L. vellerea L. virgaurea L. kanaitzensis L. lamarum L. tsangchanensis/L. vellerea L. lamarum L. subspicata/L. cyathiceps L. lamarum L. lamarum L. macrophylla L. subspicata/L. cyathiceps L. dictyoneura L. fischeri

169 170

Subspicatol A

L. lamarum L. macrophylla L. lamarum L. subspicata/L. cyathiceps

Ref. [46, 47] [120] [37] [23, 115] [38]

Comments

[24, 38] [38, 40] [25] [21, 26] [63] [22] [23] [25] [23] [40] [23] [23] [129] [40] [29, 120] [11, 37, 50, 110, 122] [115] [129] [115] [40] (continued)

18

M. Tori and C. Kuroda

Table 1 (continued) Structure number 171

172

Name of compound Subspicatin A

Subspicatin B

173

Subspicatin C

174 175

Subspicatin G Subspicatin O1

176

Subspicatin O2

177 178 179 180 181

182

183 184 185 186 187

Plant source L. lamarum L. lamarum/L. subspicata L. nelumbifolia/L. subspicata L. subspicata L. subspicata/L. cyathiceps L. lamarum L. lamarum/L. subspicata L. subspicata L. subspicata/L. cyathiceps L. lamarum/L. subspicata L. subspicata L. lamarum L. subspicata/L. cyathiceps L. subspicata/L. cyathiceps L. lamarum/L. subspicata L. vellerea L. vellerea L. tsangchanensis/L. vellerea L. lamarum/L. subspicata L. subspicata/L. cyathiceps L. lamarum/L. subspicata L. subspicata/L. cyathiceps L. cyathiceps L. brassicoides L. subspicata/L. cyathiceps L. macrophylla L. oligonema

Ref. [23] [38]

Comments

[127] [23, 24, 38, 127] [38, 40] [23] [38] [24, 38] [38, 40] [38] [24] [23] [40] [40] [38] [21, 26] [21] [25] [38] [38, 40] [38] [38, 40] [17, 38] [117] [40] [60] [130] (continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

19

Table 1 (continued) Structure number 188 189 190 191

Name of compound

192 193 194 195 196 197 198 199

200

201 202 203

204

Franchetianone B

Plant source L. oligonema L. dictyoneura L. virgaurea L. cymbulifera L. tongolensis/L. cymbulifera L. dictyoneura L. virgaurea L. franchetiana L. oligonema L. thyrsoidea L. intermedia L. macrophylla L. melanothyrsa L. alticola L. dictyoneura L. hodgsonii L. melanothyrsa L. vellerea L. dictyoneura L. macrophylla L. melanothyrsa L. vellerea L. cymbulifera L. schmidtii L. cymbulifera L. tongolensis/L. cymbulifera L. atroviolacea L. cymbulifera L. schmidtii L. tongolensis

205 206

L. tongolensis/L. cymbulifera L. atroviolacea L. tongolensis

207

L. tongolensis

Ref. [130] [29] [27] [128] [128]

Comments

[29] [27] [19] [130] [131] [132, 133] [134] [21] [135] [120] [136] [21] [21, 26] [120] [129] [21] [21, 26] [128] [20] [128] [128] [48] [128] [20] [128, 137] [128] [48] [48, 137] [137] (continued)

20

M. Tori and C. Kuroda

Table 1 (continued) Structure number 208

209 210 211

212

Name of compound

Plant source L. tongolensis L. tongolensis/L. cymbulifera L. hookeri L. tongolensis L. melanothyrsa L. persica L. thyrsoidea L. vellerea L. alticola L. angusta L. atroviolacea L. calthifolia L. dictyoneura L. fauriei L. hodgsonii

L. intermedia

L. knorringiana L. lapathifolia L. macrophylla L. melanothyrsa L. persica L. przewalskii

213 214

L. thyrsoidea L. vellerea L. hookeri L. hookeri

Ref. [128, 137] [128]

Comments

[138] [48, 137] [21] [39] [131] [21, 26] [135] [139] [69] [13] [29, 120] [139] [123– 125, 136] [132, 133, 140, 141] [88] [142] [129, 143] [21] [39] [13, 144, 145] [131] [21, 26] [138] [138] (continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

21

Table 1 (continued) Structure number 215

Name of compound

Plant source L. atroviolacea L. cymbulifera L. hookeri L. tongolensis

216

L. dictyoneura

217 218

L. dictyoneura L. alticola L. calthifolia L. tongolensis L. hookeri L. tongolensis

219 220

221 222

L. hookeri L. cymbulifera

223 224

L. hookeri L. atroviolacea L. cymbulifera L. lapathifolia L. tongolensis

225

Tetradymol

L. tongolensis/L. cymbulifera L. cymbulifera

L. dictyoneura L. fischeri L. kanaitzensis L. lamarum L. lamarum/L. subspicata L. nelumbifolia/L. subspicata L. subspicata L. subspicata/L. cyathiceps L. tongolensis L. tongolensis/L. cymbulifera L. virgaurea

Ref. Comments [69, 146] [48, 147] [138] [48, 137] [29, 121] [120] [135] [13] [128] [138] [48, 128] [138] [48, Revised 128] [138] [48] [48, 49, Revised 147] [148] [48, 128, 137] [128] [48, 49, 128, 147] [120] [37] [31] [23] [38] [127] [24] [38] [137] [128] [27, 63] (continued)

22

M. Tori and C. Kuroda

Table 1 (continued) Structure number 226

Name of compound

Plant source L. brassicoides L. japonica L. kanaitzensis L. lamarum

227

228

L. lamarum/L. subspicata L. subspicata L. subspicata/L. cyathiceps L. virgaurea L. brassicoides L. japonica L. kanaitzensis L. subspicata L. virgaurea L. brassicoides L. duciformis L. kanaitzensis L. lamarum L. oligonema L. subspicata

229

230

231

L. kanaitzensis L. lamarum L. subspicata/L. cyathiceps L. kanaitzensis L. lamarum L. subspicata/L. cyathiceps L. japonica L. kanaitzensis L. lamarum L. subspicata L. subspicata/L. cyathiceps

Ref. [46, 47] [12, 149] [22] [23, 115] [38]

Comments

[23, 24] [38, 150] [63] [46, 47] [12, 149] [22] [24] [63] [46, 47] [126] [22] [23, 115] [151] [24, 38, 127] [22, 31] [23] [40, 150] [22, 31] [23] [38, 40, 150] [12, 149] [22, 31] [23] [23] [40] (continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

23

Table 1 (continued) Structure number 232

Name of compound

Plant source L. dictyoneura L. lamarum L. macrophylla

242 243

L. sachalinensis L. subspicata L. subspicata/L. cyathiceps L. thyrsoidea L. kanaitzensis L. kanaitzensis L. subspicata/L. cyathiceps L. virgaurea L. atroviolacea L. atroviolacea L. atroviolacea L. sagitta L. atroviolacea L. fischeri L. fischeri L. oligonema

244

L. hodgsonii

245 246

L. oligonema L. hodgsonii L. oligonema L. dictyoneura

233 234 235 236 237 238 239 240 241

247 248 249 250 251 252 253 254 255 256

6-Hydroxyeuryopsin

6-Acetoxyeuryopsin

L. lamarum L. virgaurea L. anoleuca L. fischeri L. virgaurea L. virgaurea L. virgaurea L. fischeri L. brassicoides L. anoleuca L. brassicoides L. dictyoneura L. fischeri

Ref. [29] [23] [129, 143] [13] [23, 24] [40, 150] [131] [22] [22, 31] [150] [152] [69] [69] [69] [59] [69] [96] [96] [130, 151] [136, 153] [151] [136] [151] [29, 121] [23] [45, 76] [154] [155] [45, 76] [45] [45] [155] [117] [154] [117] [29] [155]

Comments

X-ray structure

X-ray structure

(continued)

24

M. Tori and C. Kuroda

Table 1 (continued) Structure number 257

258 259

Plant source L. fischeri L. pleurocaulis L. virgaurea L. pleurocaulis L. pleurocaulis

260

L. pleurocaulis

261 262 263 264 265 266

L. pleurocaulis L. anoleuca L. anoleuca L. anoleuca L. anoleuca L. anoleuca L. pleurocaulis L. anoleuca L. anoleuca L. fischeri

267 268

Name of compound

Furanoligularenone

L. pleurocaulis 269 270 271 272 273

Virgaurenone C Virgaurenone B

L. pleurocaulis L. kanaitzensis L. anoleuca L. virgaurea L. virgaurea

274

Virgaurenone A

L. virgaurea

275 276 277

Virgaurenone D

L. virgaurea L. platyglossa L. virgaurea

278 279 280

Decompostin

L. virgaurea L. virgaurea L. cyathiceps L. virgaurea

281 282 283

Adenostylone

Neoadenostylone

L. virgaurea L. virgaurea L. cyathiceps L. macrophylla L. virgaurea

Ref. [155] [156] [45] [156] [53, 156] [53, 156] [53] [155] [155] [155] [155] [155] [156] [155] [155] [157, 158] [79, 156] [159] [31] [155] [45, 63] [45, 63, 114] [45, 63, 114] [63] [160] [45, 114] [45, 76] [45] [17, 38] [45, 76, 152] [45] [45, 76] [17] [67] [45, 76]

Comments

(continued)

Table 1 (continued) Structure number 284 285

286 287 288

289

290

291

292 293

Name of compound

Plant source L. brassicoides L. fischeri L. wilsoniana L. macrophylla L. fischeri L. cyathiceps L. dictyoneura L. macrophylla L. trichocephala L. virgaurea L. vorobierii L. cyathiceps L. duciformis/L. cyathiceps L. fischeri L. virgaurea L. fischeri L. intermedia L. sachalinensis L. trichocephala L. virgaurea L. vorobierii L. wilsoniana L. anoleuca L. dictyoneura L. fischeri

L. intermedia L. sachalinensis L. trichocephala L. vorobierii L. wilsoniana L. intermedia L. cyathiceps L. duciformis/L. cyathiceps L. fischeri L. intermedia L. kanaitzensis L. sachalinensis L. trichocephala L. virgaurea L. vorobierii L. wilsoniana

Ref. [117] [161, 162] [163] [60] [37] [17] [29] [98] [13] [45, 76] [164] [17] [18]

Comments

[37] [45] [37] [20] [13] [13] [45, 76] [164] [163] [154] [29] [37, 155, 161, 162] [20] [13] [13] [164] [163] [20] [17] [18] [37] [20] [31] [13] [13] [45, 76] [164] [163] (continued)

26

M. Tori and C. Kuroda

Table 1 (continued) Structure number 294 295

296

297 298 299 300

301 302 303 304 305

306

307 308

Name of compound

Plant source L. macrophylla L. anoleuca L. intermedia L. macrophylla L. sachalinensis L. trichocephala L. vorobierii L. wilsoniana L. anoleuca L. anoleuca L. vorobierii L. anoleuca L. trichocephala L. vorobierii L. longihastata L. anoleuca L. vorobierii L. trichocephala L. vorobierii L. cyathiceps L. cyathiceps L. virgaurea L. wilsoniana L. cyathiceps L. duciformis/L. cyathiceps L. fischeri L. subspicata/L. cyathiceps L. veitchiana L. virgaurea L. wilsoniana L. virgaurea L. cyathiceps L. duciformis/L. cyathiceps L. macrophylla L. veitchiana L. virgaurea L. wilsoniana

Ref. [60] [155] [20] [60] [13] [13] [164] [163] [155] [155] [164] [155] [13] [164] [32] [155] [164] [13] [164] [17] [17] [45, 76, 163] [163] [17, 38] [18]

Comments

X-ray structure

X-ray structure

[165] [38] [108, 166] [45, 76] [163] [45, 76] [17] [18] [67] [108] [45, 76] [163] (continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

27

Table 1 (continued) Structure number 309 310 311 312 313 314 315 316

Name of compound

Cacalol

Plant source L. virgaurea L. virgaurea L. virgaurea L. virgaurea L. longihastata L. lamarum L. sagitta L. cyathiceps L. duciformis/L. cyathiceps L. nelumbifolia L. tsangchanensis L. virgaurea

317

L. virgaurea

318 319

L. tsangchanensis L. cyathiceps L. tsangchanensis L. virgaurea L. macrophylla L. macrophylla L. cyathiceps L. tsangchanensis L. virgaurea L. cyathiceps L. nelumbifolia L. tsangchanensis L. virgaurea L. virgaurea L. virgaurea L. virgaurea L. virgaurea L. intermedia L. virgaurea

320 321 322

Cacalone

323

Epicacalone

324 325 326 327 328 329

Hydroperoxycacalone Hydroperoxyepicacalone Virgauride Epivirgauride Tetrahydromaturinone

Ref. [45, 76] [45] [45] [45, 76] [32] [115] [105, 167] [17, 38] [18]

Comments

X-ray structure

[126] [25, 35] [45, 76, 118, 168– 171] [45, 168, 169, 171] [25] [38] [25] [45] [60] [60] [17] [25, 35] [45, 76] [17] [126] [25, 35] [45, 76] [45] [45] [172] [172] [140] [173] (continued)

28

M. Tori and C. Kuroda

Table 1 (continued) Structure number 330

Name of compound

331 332 333

Farfugin A

334 335

Isoligularonic acid

Plant source L. cyathiceps L. duciformis/L. cyathiceps L. fischeri L. longihastata L. macrophylla L. virgaurea L. sagitta L. veitchiana L. intermedia L. tsangchanensis L. virgaurea

336

L. virgaurea

337 338

L. macrophylla L. virgaurea

339 340

341

342 343

Virgauronin

L. virgaurea L. alticola L. lamarum L. subspicata L. alticola L. lamarum L. subspicata L. alticola L. hodgsonii

Ref. [17, 38] [18]

Comments

[37, 155] [32] [60] [45] [167] [174, 175] [176] [25] [45, 76, 118, 152, 168– 171] [168, 169, 171] [60] [169, 170] [172] [41] [23] [23] [41] [23] [23] [41] [123– 125] (continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

29

Table 1 (continued) Structure number 344

Name of compound

Plant source L. dictyoneura L. duciformis L. fauriei L. fischeri L. kanaitzensis L. lamarum L. melanothyrsa L. persica L. subspicata L. subspicata/L. cyathiceps L. vellerea L. virgaurea

345

L. dictyoneura L. fischeri L. tsangchanensis L. veitchiana L. virgaurea L. fischeri

346

347 348 349 350 351 352 353 354 355 356

Melanothyrsin A Melanothyrsin E

L. subspicata L. virgaurea L. virgaurea L. virgaurea L. tsangchanensis L. dictyoneura L. melanothyrsa L. dictyoneura L. atroviolacea L. melanothyrsa L. melanothyrsa L. lapathifolia L. brassicoides L. caloxantha L. dictyoneura L. fischeri L. lamarum L. pleurocaulis L. subspicata L. virgaurea

Ref. [42, 121] [177] [178] [50, 58, 179] [22] [23] [44] [39] [23, 34] [40]

Comments

[149] [27, 28, 63] [121] [58] [86, 180] [52] [87, 89] [58, 179] [34] [27, 28] [112] [63] [86] [42] [44] [121] [69] [44] [44] [81] [46, 47] [181] [182] [58, 179] [23] [79] [23, 34] [28, 45] (continued)

30

M. Tori and C. Kuroda

Table 1 (continued) Structure number 357

Name of compound

358 359

Plant source L. kanaitzensis L. vellerea L. alticola L. brassicoides L. duciformis L. fauriei L. fischeri L. lamarum L. melanothyrsa L. subspicata L. tsangchanensis L. virgaurea

360

361

L. duciformis L. fischeri L. virgaurea L. fischeri

362

L. virgaurea L. tsangchanensis L. virgaurea L. fischeri L. virgaurea L. fischeri L. hiberniflorum L. fischeri

363 364 365 366

6-Oxoeremophilenolide

367 368 369 370 371 372

373

Melanothyrsin B Melanothyrsin C

L. fischeri L. melanothyrsa L. virgaurea L. melanothyrsa L. songarica L. melanothyrsa L. melanothyrsa L. intermedia L. przewalskii L. purdomii L. przewalskii

Ref. Comments [56, 57] Revised [149] [41] [46, 47] [177] [178, 183] [58, 179] [23] [44] [23, 34] [86] [27, 44, 87, 184] [177] [58] [28, 87] [58, 179, 185] [63, 87] [86, 180] [28] [179] [87] [179] [186] [179, 185] [187, 188] [44] [27] [44] [99] [44] [44] [141] [70, 144, 189] [190] [144] (continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

31

Table 1 (continued) Structure number 374 375

Name of compound

Plant source L. hodgsonii L. dolichobotrys L. intermedia L. hodgsonii L. hodgsonii L. tsangchanensis L. virgaurea L. virgaurea L. virgaurea L. virgaurea L. virgaurea L. hiberniflorum L. hiberniflorum L. hiberniflorum L. hiberniflorum L. hiberniflorum L. brassicoides L. cymbulifera

376 377 378 379 380 381 382 383 384 385 386 387 388 389

390 391 392 393

L. dictyoneura L. fischeri L. virgaurea L. hodgsonii L. macrophylla L. dictyoneura L. cymbulifera

394 395 396 397

L. dictyoneura L. fischeri L. myriocephala L. cymbulifera L. sagitta L. lamarum L. sagitta

Farformolide B

398 399

L. sagitta L. lamarum

400

L. kanaitzensis L. lamarum L. lamarum L. subspicata

401

Ref. [191] [101, 192] [141] [191] [191] [86] [112] [112] [27] [27] [27] [186] [186] [186] [186] [186] [46, 47] [49, 147] [121] [58] [27, 63] [91] [193] [121] [49, 147] [121] [58] [72] [49] [194] [115] [194, 195] [61] [38, 115] [22] [115] [115] [34]

Comments

(continued)

32

M. Tori and C. Kuroda

Table 1 (continued) Structure number 402 403 404

Name of compound

Plant source L. sagitta L. sagitta L. sagitta

405 406 407 408 409 410

L. sagitta L. virgaurea L. virgaurea L. myriocephala L. myriocephala L. myriocephala

411

L. myriocephala

412 413 414 415 416 417 418

L. fischeri L. fischeri L. virgaurea L. macrophylla L. sagitta L. dictyoneura L. macrophylla L. platyglossa L. pleurocaulis L. virgaurea L. macrophylla

419

420 421 422 423 424 425 426 427 428 429 430 431 432

L. virgaurea L. virgaurea L. fischeri L. fischeri L. hodgsonii L. veitchiana L. veitchiana L. duciformis L. hodgsonii L. duciformis L. hodgsonii L. japonica L. hodgsonii L. fischeri L. fischeri L. hodgsonii

Ref. [194] [194] [194, 195] [194] [196] [87] [72] [72] [72, 197] [72, 197] [158] [158] [198] [193] [59] [113] [98] [160] [53] [198] [98, 193] [199] [198] [110] [110] [80] [74] [200] [201] [80] [201] [80] [90] [80] [110] [110] [91]

Comments

(continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

33

Table 1 (continued) Structure number 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447

Name of compound Toluccanolide A

Plant source L. hodgsonii L. virgaurea

Toluccanolide B

L. fischeri L. virgaurea

Toluccanolide C

Ligularenolide

448 449 450

L. virgaurea L. virgaurea L. virgaurea L. pleurocaulis L. cymbulifera L. virgaurea L. hodgsonii L. duciformis L. duciformis L. virgaurea L. platyglossa L. fischeri

451

L. virgaurea L. przewalskii L. fischeri L. pleurocaulis L. fischeri

452

L. pleurocaulis L. fischeri

453 454 455

L. pleurocaulis L. pleurocaulis L. veitchiana L. virgaurea

456

L. virgaurea

457

L. virgaurea

458 459

Virgaurenolide C

L. virgaurea L. virgaurea

460

Virgaurenolide B

L. virgaurea

Ref. [80] [45, 198] [58] [45, 76, 198] [198] [198] [199] [53] [49] [27] [91] [201] [201] [202] [160] [58, 158] [45, 76] [64] [158] [53, 79] [157, 158] [53, 79] [157, 158] [79] [53] [74] [45, 114] [45, 114] [45, 114] [199] [45, 114] [45, 63, 114, 199]

Comments

Revised

(continued)

34

M. Tori and C. Kuroda

Table 1 (continued) Structure number 461 462

Name of compound Virgaurenolide D Virgaurenolide E

Plant source L. virgaurea L. virgaurea

463

Virgaurenolide A

L. virgaurea

464 465 466

L. platyglossa L. pleurocaulis L. macrophylla L. veitchiana

467 468 469 470 471 472 473

L. sagitta L. veitchiana L. virgaurea L. virgaurea L. virgaurea L. veitchiana L. sagitta

474 475 476 477 478 479 480 481 482 483 484 485 486

L. veitchiana L. veitchiana L. veitchiana L. veitchiana L. virgaurea L. virgaurea L. virgaurea L. sagitta L. sagitta L. veitchiana L. veitchiana L. sagitta L. sagitta L. sagitta

Sagittacin D Sagittacin C

487 488 489

L. sagitta L. macrophylla L. macrophylla

490

L. dolichobotrys L. fauriei L. macrophylla L. przewalskii

Ref. [114] [45, 114] [45, 63, 114] [160] [159] [193] [174, 175] [61] [175] [45, 76] [112] [87] [107] [61, 175] [175] [107] [175] [66] [45, 76] [112] [87] [61] [61] [175] [175] [203] [203] [106, 203] [203] [134] [73, 193] [101] [178, 183] [143] [70, 144, 189]

Comments

Revised

X-ray structure

X-ray structure

(continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

35

Table 1 (continued) Structure number 491

Name of compound

Plant source L. atroviolacea L. fauriei L. intermedia

L. macrophylla L. przewalskii

492

493

L. purdomii L. vellerea L. intermedia

L. dolichobotrys L. intermedia L. przewalskii

494 495 496 497 498

L. pleurocaulis L. hodgsonii L. hodgsonii L. hodgsonii L. atroviolacea L. cymbulifera L. dictyoneura L. lapathifolia L. tongolensis

499

L. atroviolacea

500 501

L. dictyoneura L. lapathifolia L. atroviolacea L. atroviolacea

502

L. lapathifolia L. kangtingensis L. lapathifolia

Ref. [69] [178, 183] [77, 132, 133, 141, 204] [193] [70, 144, 189] [190] [26] [132, 133, 141] [101] [77, 141] [70, 144, 189] [79] [191] [191] [191] [69, 146] [49] [121] [142, 205] [206, 207] [69, 208] [121] [81] [208] [69, 208] [81] [103] [81]

Comments

X-ray structure

X-ray structure

X-ray structure

(continued)

36

M. Tori and C. Kuroda

Table 1 (continued) Structure number 503

Name of compound

504

Plant source L. atroviolacea L. tongolensis L. atroviolacea L. lapathifolia L. tongolensis L. lapathifolia L. lapathifolia L. lapathifolia L. lapathifolia L. dolichobotrys L. przewalskii

505 506 507 508 509

510 511

L. atroviolacea L. dictyoneura L. intermedia L. przewalskii

512 513

L. hodgsonii L. przewalskii

514 515 516 517

Eremopetasitenin A4 Eremopetasitenin A8

518 519

Subspicatin E Subspicatin M

520

Subspicatin N

521 522

Subspicatin D Eremopetasitenin B4

L. lapathifolia L. lapathifolia L. lamarum L. subspicata/L. cyathiceps L. lamarum L. subspicata/L. cyathiceps L. subspicata/L. cyathiceps L. subspicata L. intermedia L. przewalskii L. pleurocaulis

523

524 525

526

Eremopetasitenin B6

L. lamarum L. cyathiceps/L. subspicata L. kanaitzensis L. kanaitzensis

Ref. Comments [69] [206, 207] [69] [148] [207] [205] [148] [148] [148] [101] [70, 144, 145, 189] [69] [121] [140] [70, 144] [191] [70, 144] [148] [148] [23] [40] [23] [40] [40] [24, 34] [140] [145] [79]

Revised Stereochemistry at C-11 not established

[115] [150] [22] [22] (continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

37

Table 1 (continued) Structure number 527 528 529 530

Plant source L. cyathiceps/L. subspicata L. virgaurea L. brassicoides L. virgaurea

531

L. virgaurea

532

L. virgaurea

533

L. virgaurea

534

L. virgaurea

535 536 537 538

Eremofarfugin C

539 540

Eremofarfugin B Subspicatin F

541 542 543 544

Melanothyrsin D Eremofarfugin D Eremofarfugin E Eremofarfugin G

L. virgaurea L. cyathiceps L. wilsoniana L. kanaitzensis L. lamarum L. melanothyrsa L. virgaurea L. virgaurea L. lamarum L. subspicata/L. cyathiceps L. melanothyrsa L. vellerea L. vellerea L. intermedia L. przewalskii

[44] [26] [26] [140] [145]

L. intermedia L. przewalskii

[140] [145]

L. virgaurea L. tsangchanensis L. virgaurea

[45, 76] [25] [45, 172] [25] [45, 172] [45, 76] [45, 76]

545

Name of compound Eremopetasitenin B5

Eremofarfugin F

546 547

Cacalolide

548

Epicacalolide

549 550

L. tsangchanensis L. virgaurea L. virgaurea L. virgaurea

Ref. [150]

Comments

[45, 76] [117] [45, 114] [45, 114] [45, 114] [45, 114] [45, 114] [45, 76] [17] [163] [22] [23] [44] [27, 28] [27, 63] [23] [40]

Configuration at C-11 determined Configuration at C-11 determined

(continued)

38

M. Tori and C. Kuroda

Table 1 (continued) Structure number 551

Name of compound Adenostylide

Plant source L. virgaurea

552

Adenostylide

L. virgaurea

553 554 555 556

L. brassicoides L. fischeri L. subspicata L. fischeri

557

L. melanothyrsa L. subspicata L. tsangchanensis

558 559

Subspicatolide

560

Subspicatolide acetate

561 562 563 564 565 566 567 568 569 570

Virgaurenolidol B Virgaurenolidol C Virgaurenolidol D Virgaurenolidol A Adenostin A

571

(Virgaurin A)

L. virgaurea

572 573 574 575 576 577 578

Virgaurin B Ligupleurolide Virgaurin D Fischerisin A Fischerisin B Fischelactone B Fischelactone

L. virgaurea L. pleurocaulis L. virgaurea L. fischeri L. fischeri L. fischeri L. fischeri

579

L. lamarum L. melanothrsa L. subspicata L. lamarum L. melanothyrsa L. cymbulifera L. cymbulifera L. brassicoides L. brassicoides L. brassicoides L. virgaurea L. virgaurea L. virgaurea L. virgaurea L. tsangchanensis L. virgaurea

L. brassicoides L. fischeri L. virgaurea

Ref. [118, 173] [118, 173] [46, 47] [158] [34] [58, 179] [44] [23] [86, 209] [23] [44] [23, 24] [23] [44] [49] [49] [46, 47] [46, 47] [46, 47] [114] [114] [114] [114] [25, 35] [45, 170, 173] [45] [45] [53] [45, 76] [210] [210] [211] [158, 212] [46, 47] [158] [27]

Comments Mixture of 551 and 552

Name should be changed (cf. 615) X-ray structure

(continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

39

Table 1 (continued) Structure number 580

Name of compound

Plant source L. fischeri L. virgaurea L. lapathifolia L. atroviolacea L. tsangchanensis

584 585 586 587 588

Biligupleurolide

Virgaurol A

L. pleurocaulis L. tsangchanensis L. tsangchanensis L. lingiana L. virgaurea

589

Virgaurol B

L. virgaurea

590 591 592 593 594 595

Virgaurol C Virgaurol D Ligulacymirin A Ligulacymirin B

L. virgaurea L. virgaurea L. cymbulifera L. cymbulifera L. brassicoides L. sagitta

581 582 583

Sagittolactone

596

597 598 599 600 601 602 603 604 605 606 607 608 609 610

L. sagitta L. sagitta L. sagitta L. sagitta L. sagitta

Ref. [158] [27] [213] [69] [86, 209] [53] [214] [214] [78] [215, 216] [215, 216] [215] [215] [147] [147] [46, 47] [62, 105, 217] [218] [219, 220] [221] [61] [61] [221] [218]

L. sagitta L. sagitta L. veitchiana L. veitchiana L. veitchiana L. veitchiana L. knorringiana L. sagitta L. sagitta

[218] [218] [220] [220] [220] [220] [88] [222] [222]

L. sagitta L. veitchiana Ligulasagitin B Sagittacin A Sagittacin B Ligulasagitin C

Ligulaverin C Ligulaverin B Ligulaverin D Ligulaverin E Knorringianalarin A Ligusaginoid A Ligusaginoid B

Comments

X-ray structure

X-ray structure X-ray structure X-ray structure

X-ray structure X-ray structure X-ray structure

X-ray structure after acetylation

X-ray structure (continued)

40

M. Tori and C. Kuroda

Table 1 (continued) Structure number 611 612

Name of compound

Plant source L. platyglossa L. virgaurea

613 614

Biliguhodgsonolide

L. virgaurea L. hodgsonii

615

Virgaurin A

L. virgaurea

616 617 618 619 620 621 622 623 624 625 626 627 628 629

Adenositin B Virgaurin C Ligusaginoid C Ligusaginoid D

Bakkenolide A

L. virgaurea L. virgaurea L. virgaurea L. virgaurea L. virgaurea L. virgaurea L. virgaurea L. sagitta L. sagitta L. sagitta L. sagitta L. sagitta L. atroviolacea L. brassicoides L. calthifolia L. dictyoneura L. dolichobotrys L. fischeri L. hodgsonii L. intermedia L. kanaitzensis L. melanothyrsa L. persica L. sagitta

630 631 632 633

Franchetianone A

L. subspicata L. subspicata/L. cyathiceps L. dolichobotrys L. dolichobotrys L. macrophylla L. franchetiana

Ref. [160] [152, 199] [152] [116] [170, 173] [171] [152] [171] [170] [170] [170] [45, 76] [222] [222] [221] [221] [221] [69] [46, 47] [13] [42, 120] [101] [37, 58] [123– 125] [140] [22] [44] [39] [105, 167] [24, 34] [40]

Comments

X-ray (structure drawing difficult) cf. 571

[101] [101] [143] [19] (continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

41

Table 1 (continued) Structure number 634 635 636

Fukinospirolide A Fukinospirolide B

Plant source L. subspicata L. virgaurea L. virgaurea

637 638

Virgaurenospirolide B

L. brassicoides L. virgaurea

639

Virgaurenospirolide C

L. virgaurea

640

Virgaurenospirolide A

L. virgaurea

641

Virgaureno-anhydride A

L. virgaurea

642

Virgaureno-anhydride B

L. virgaurea

643

Fukinospirolide C

L. virgaurea

644 645 646 647

Ligulactone A Ligulactone B

L. fischeri L. fischeri L. virgaurea L. altaica L. songarica L. tongolensis L. lamarum L. longihastata L. virgaurea L. kanaitzensis L. hookeri L. songarica L. speciosa L. altaica L. cymbulifera L. songarica L. rumicifolia L. altaica L. lankongensis L. cymbulifera L. rumicifolia L. rumicifolia L. songarica L. altaica L. rumicifolia

Name of compound

648

649 650 651 652 653 654 655 656 657 658 659 660 661 662

Altaicalarin C

Songaricalarin F Altaicalarin D

Ref. [34] [45, 76] [45, 76, 114] [117] [45, 114] [45, 114] [45, 114] [45, 114] [45, 114] [45, 76, 114] [165] [165] [202] [223] [224] [137] [115] [32] [28] [22] [138] [224] [43] [223] [225] [224] [75] [223] [226] [225] [75] [75] [224] [223] [75]

Comments

X-ray structure

(continued)

42

M. Tori and C. Kuroda

Table 1 (continued) Structure number 663 664 665 666 667 668 669 670 671 672 673 674 675

Name of compound

Plant source L. hodgsonii L. dentata L. rumicifolia L. songarica L. rumicifolia L. rumicifolia L. dentata L. dentata L. dentata L. dentata L. dentata L. rumicifolia L. lankongensis

676

L. lankongensis

677 678 679

L. cymbulifera L. lankongensis L. lankongensis

680

L. songarica

681 682 683 684

L. songarica L. lankongensis L. cymbulifera L. lankongensis

685 686 687 688 689 690 691 692 693 694 695 696 697

L. cymbulifera L. cymbulifera L. cymbulifera L. cymbulifera L. cymbulifera L. songarica L. cymbulifera L. cymbulifera L. cymbulifera L. lankongensis L. lankongensis L. cymbulifera L. lankongensis

Songaricalarin H

Ref. [153] [102] [75] [227] [75] [75] [102] [102] [97] [97] [97] [75] [226, 228] [226, 228] [225] [226] [226, 228] [99, 224] [227] [226] [229] [226, 228] [225] [225] [229] [229] [230] [224] [230] [229] [225] [231] [231] [230] [226]

Comments

(continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

43

Table 1 (continued) Structure number 698 699 700

Name of compound

Songaricalarin G

701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718

Tussfararin F Altaicalarin B

719 720 721 722 723 724 725

Altaicalarin A

726 727 728 729 730

Plant source L. songarica L. altaica L. songarica L. songarica L. songarica L. songarica L. songarica L. cymbulifera L. rumicifolia L. cymbulifera L. lankongensis L. thyrsoidea L. thyrsoidea L. thyrsoidea L. thyrsoidea L. thyrsoidea L. rumicifolia L. rumicifolia L. dentata L. rumicifolia L. rumicifolia L. altaica L. rumicifolia L. altaica L. dentata L. dentata L. dentata L. dentata L. dentata L. kangtingensis L. virgaurea L. veitchiana L. knorringiana L. knorringiana L. konkalingensis L. duciformis L. konkalingensis

Ref. Comments [99, 224, 232] [223] [224, 227] [227] [227] [227] [227] [225] [75] [225] [228] [233] [233] [233] [233] [233] [75] [75] [234] [75] [75] [223] [75] [223] [234] [102] [102] [234] [234] [103] [118] [108] [235] [235] [36] [126] [36] (continued)

44

M. Tori and C. Kuroda

Table 1 (continued) Structure number 731

Name of compound

L. konkalingensis L. duciformis

732

733 734

735 736 737 738 739 740 741 742 743 744 745 746 747 748 749

Songaricalarin E

Songaricalarin D Songaricalarin C Rumicifoline D Rumicifoline E Rumicifoline F (4E)-Rumicifoline G (4Z)-Rumicifoline G (4E)-Rumicifoline H (4Z)-Rumicifoline H Rumicifoline I Songaricalarin B

750 751

755 756 757

L. konkalingensis L. songarica L. knorringiana L. narynensis L. songarica L. narynensis L. songarica L. songarica L. songarica L. rumicifolia L. rumicifolia L. rumicifolia L. rumicifolia L. rumicifolia L. rumicifolia L. rumicifolia L. rumicifolia L. rumicifolia L. songarica L. knorringiana L. narynensis L. knorringiana L. knorringiana L. narynensis L. narynensis L. narynensis

752 753 754

Plant source L. duciformis

Knorringianalarin D Songaricalarin A Rumicifoline B Rumicifoline C

L. knorringiana L. songarica L. rumicifolia L. rumicifolia L. knorringiana

Ref. [36, 126, 236] [36] [36, 236] [36] [237] [235] [238] [237] [238] [237] [237] [237] [75] [75] [75] [75] [75] [75] [75] [75] [75] [237] [235] [238– 240] [235] [235] [238] [238] [238– 240] [235] [237] [75] [75] [235]

Comments

X-ray structure X-ray structure X-ray structure

(continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

45

Table 1 (continued) Structure number 758

Name of compound (–)-Germacrene D

759 760 761 762 763 764 765 766 767 768 769

770 771 772 773

LB Liguloxidol acetate

774

Liguloxidol

775

Liguloxide

776 777 778

Plant source L. brachyphylla L. clivorum L. dentata L. hodgsonii L. intermedia L. japonica L. sachalinensis L. sibirica L. speciosa L. stenocephala L. tangutica L. thyrsoidea L. vorobierii L. thyrsoidea L. persica L. persica L. persica L. persica L. persica L. persica L. persica L. persica L. hodgsonii L. brachyphylla L. clivorum L. dentata L. hodgsonii L. brachyphylla L. hodgsonii L. brachyphylla L. hodgsonii L. virgaurea L. fischeri L. veitchiana L. fischeri L. veitchiana L. fischeri L. veitchiana L. veitchiana L. macrophylla L. nelumbifolia

Ref. [13] [13] [13] [13] [20] [13] [13] [13] [43] [13] [13] [131] [164] [131] [39] [39] [39] [39] [39] [39] [39] [39] [13] [13] [13] [13] [13] [13] [13] [13] [13] [27, 28] [122] [108] [122] [108] [122] [108] [108] [98] [68]

Comments

(continued)

46

M. Tori and C. Kuroda

Table 1 (continued) Structure number 779 780 781 782 783 784 785 786

Name of compound

Plant source L. nelumbifolia

Liguducin A

L. duciformis L. duciformis L. narynensis L. duciformis L. virgaurea L. virgaurea L. veitchiana L. wilsoniana L. dolichobotrys L. fischeri L. dolichobotrys L. brassicoides L. longihastata L. persica L. tongolensis L. brassicoides L. hookeri L. virgaurea L. persica L. fischeri

Spathulenol

787 788 789

790

791 792

Intermedeol Intermedeol Intermedeol Intermedeol

796

L. longihastata L. virgaurea L. wilsoniana L. cyathiceps L. longihastata L. hodgsonii L. tongolensis L. duciformis L. fischeri L. odontomanes L. stenocephala L. virgaurea L. stenocephala

797

L. veitchiana

798 799

L. fischeri L. fischeri

793 794 795

Ref. [68, 241] [242] [242] [240] [242] [173] [173] [108] [163] [101] [54] [101] [46, 47] [32] [39] [137] [46, 47] [138] [45] [39] [187, 188] [32] [27, 28] [163] [17] [32] [93] [207] [242] [54] [100] [243] [118] [243, 244] [108, 166] [54] [54]

Comments

(continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

47

Table 1 (continued) Structure number 800 801 802 803 804 805 806 807 808 809 810 811

Name of compound Liguducin B Ligucyperonol

Caryophyllene

812

813 814 815 816 817 818 819 820 821 822 823 824 825 826 827

Fischericin A Fischericin B Fischericin C Fischericin D Fischericin E Fischericin F

Plant source L. duciformis L. kangtingensis L. dentata L. duciformis L. dentata L. platyglossa L. pleurocaulis L. kanaitzensis L. virgaurea L. songarica L. dentata L. tongolensis L. hodgsonii L. virgaurea L. brachyphylla L. dentata L. hodgsonii L. japonica L. cymbulifera L. caloxantha L. fischeri L. fischeri L. fischeri L. fischeri L. fischeri L. fischeri L. fischeri L. fischeri L. fischeri L. fischeri L. fischeri L. fischeri L. fischeri

Ref. [242] [103] [95] [242] [234] [160] [53] [22] [45, 76] [99] [95] [207] [153] [27] [13] [13] [13] [13] [147] [245] [246] [246] [246] [246] [246] [246] [246] [246] [246] [246] [246] [246] [246]

Comments

X-ray structure X-ray structure

X-ray structure

(continued)

48

M. Tori and C. Kuroda

Table 1 (continued) Structure number 828

Name of compound Lupeol

Plant source L. alticola L. brassicoides L. caloxantha L. dentata L. duciformis

L. duciformis/L. yunnanensis L. intermedia L. kanaitzensis L. kangtingensis L. konkalingensis L. lamarum L. lapathifolia L. longihastata L. nanchuanica L. nelumbifolia L. odontomanes L. pleurocaulis L. purdomii L. sagitta L. subspicata L. veitchiana L. virgaurea

829 830 831 832 833

β-Amyrin β-Amyrin acetate

L. wilsoniana L. yunnanensis L. nanchuanica L. intermedia L. kanaitzensis L. veitchiana L. kanaitzensis L. kanaitzensis L. kangtingensis L. pleurocaulis

Ref. [135] [46, 47] [181, 247] [248] [18, 36, 49, 126, 249] [18]

Comments

[77, 250] [22, 56, 57] [103] [36, 126] [115] [142] [32] [104] [33, 36, 126] [100] [159] [190] [167, 194] [34] [174] [27, 28, 76] [163] [18] [104] [77] [56, 57] [174] [56, 57] [56, 57] [103] [159] (continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

49

Table 1 (continued) Structure number 834 835 836 837

Name of compound

849

Plant source L. intermedia L. intermedia L. caloxantha L. fischeri L. odontomanes L. stenocephala L. odontomanes L. sagitta L. intermedia L. intermedia L. przewalskii L. stenocephala L. virgaurea L. lapathifolia L. dolichobotrys L. lapathifolia L. stenocephala L. veitchiana L. virgaurea L. alticola L. kangtingensis L. dolichobotrys L. kangtingensis L. macrophylla L. sagitta L. tongolensis

850

L. tongolensis

Gummosogenin

838 839 840 841 842 843

Friedelanol

844 845

Epifriedelanol Friedelin

846 847 848

Ursolic acid

851 852 853 854 855 856 857 858 859 860 861 862

Taraxerol

L. lapathifolia L. kangtingensis L. alticola L. alticola L. veitchiana L. alticola L. alticola L. alticola L. alticola L. dentata L. przewalskii L. przewalskii

Ref. [250] [250] [247] [158] [100] [243] [100] [59] [250] [250] [144] [243] [45] [142] [101] [142] [243] [174] [45, 76] [41] [103] [101] [103] [67] [194] [207, 251] [207, 251] [142] [103] [41] [41] [174] [41] [41] [41] [41] [248] [252] [252]

Comments

(continued)

50

M. Tori and C. Kuroda

Table 1 (continued) Structure number 863 864 865

Name of compound Liguveitoside A Liguveitoside B

867 868 869

Plant source L. veitchiana L. veitchiana L. kangtingensis L. wilsoniana L. cymbulifera L. kangtingensis L. lapathifolia L. narynensis L. sagitta L. tongolensis L. tsangchanensis L. narynensis L. narynensis L. intermedia

870 871 872

L. tsangchanensis L. narynensis L. intermedia

873

L. intermedia

866

874 875

cis-β-Ocimene

876 877 878

(E,E)-α-Farnesene

879 880 881 882

L. alticola L. brachyphylla L. calthifolia L. clivorum L. dentata L. hodgsonii L. japonica L. sachalinensis L. sibirica L. tangutica L. wilsoniana L. schmidtii L. macrophylla L. speciosa L. thyrsoidea L. virgaurea L. macrophylla L. duciformis L. duciformis

Ref. [253] [254] [103] [163] [147] [103] [142] [240] [194] [207] [86] [240] [240] [132, 133] [86] [240] [132, 133] [132, 133] [82] [13] [13] [13] [13] [13] [13] [13] [13] [13] [163] [20] [129] [43] [131] [63] [129] [36] [36]

Comments

(continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

51

Table 1 (continued) Structure number 883

884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907

908 909 910 911

Name of compound

Squalene Spiciformisin a Spiciformisin b

Roseoside

Plant source L. brachyphylla L. dentata L. hodgsoni L. japonica L. thyrsoidea L. veitchiana L. fischeri L. duciformis/L. cyathiceps L. fischeri L. fischeri L. duciformis L. dentata L. rumicifolia L. rumicifolia L. hodgsonii L. dentata L. hodgsonii L. dentata L. dolichobotrys L. dentata L. alticola L. virgaurea L. fischeri L. przewalskii L. thomsonii L. purdomii L. thomsonii L. thomsonii L. caloxantha L. vellerea L. caloxantha L. odontomanes L. veitchiana L. dentata L. purdomii L. fischeri L. pleurocaulis

Ref. [13] [13] [13] [13] [131] [13] [187] [18]

Comments

[187] [187] [36] [102] [255] [255] [256] [102] [256] [102] [101] [248] [82] [65] [257] [70] [258] [190] [258] [258] [181] [149] [181] [100] [259] [248] [190] [37] [159] (continued)

52

M. Tori and C. Kuroda

Table 1 (continued) Structure number 912 913

Name of compound Knorringianalarin C

914 915 916

Umbelliferone

917 918 919

Scopoletin

920

Isoscopoletin

921 922 923

Cinnamic acid p-Coumaric acid

924 925 926

Coniferyl alcohol Caffeic acid

927 928 929 930

Ferulic acid

931

Methyl ferulate

932

Plant source L. knorringiana L. intermedia L. macrophylla L. stenocephala L. veitchiana L. stenocephala L. stenocephala L. fischeri L. vellerea L. pleurocaulis L. sagitta L. przewalskii L. purdomii L. rumicifolia L. duciformis L. rumicifolia L. thomsonii L. thomsonii L. cyathiceps L. sagitta L. thomsonii L. caloxantha L. achyrotricha L. nanchuanica L. nelumbifolia L. purdomii L. sagitta L. thomsonii L. dentata L. nelumbifolia L. veitchiana L. duciformis L. duciformis L. nelumbifolia L. purdomii L. sagitta L. veitchiana L. dentata L. speciosa L. duciformis L. subspicata

Ref. [88] [260] [98] [243] [259] [244] [243] [257] [149] [159] [106] [144] [190] [255] [249] [255] [258] [258] [17] [167] [258] [247] [261] [104] [262] [190] [167] [258] [248] [262] [174] [126] [36] [262] [190] [167] [174] [248] [43] [36] [24]

Comments

(continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

53

Table 1 (continued) Structure number 933

Name of compound

Plant source L. duciformis L. duciformis/L. yunnanensis L. nelumbifolia

L. yunnanensis L. duciformis L. dentata L. duciformis L. dentata

934 935 936 937 938 939 940

Hydroxytremetone

L. veitchiana L. veitchiana L. intermedia L. purdomii L. speciosa L. stenocephala L. veitchiana

941

L. przewalskii

942 943

L. sibirica L. speciosa L. veitchiana L. caloxantha L. intermedia L. veitchiana

944 945 946 947

948 949

950

L. fischeri L. latihastata L. speciosa L. subspicata/L. cyathiceps L. sibirica L. latihastata L. subspicata/L. cyathiceps L. stenocephala

Ref. [18, 249] [18] [126, 262, 263] [18] [249] [248] [177] [248]

Comments

Absolute configuration (S)

[259] [259] [20] [190] [43] [264] [13, 259] [70, 144, 265] [13] [43] [259] [181] [20] [154, 259] [37] [266] [43] [40] [13] [266] [40] [243] (continued)

54

M. Tori and C. Kuroda

Table 1 (continued) Structure number 951

Name of compound

Plant source L. fischeri L. przewalskii

952

Euparin

L. caloxantha L. fischeri L. intermedia L. latihastata L. nanchuanica L. odontomanes L. przewalskii

L. purdomii L. speciosa L. stenocephala L. subspicata/L. cyathiceps L. veitchiana

953

L. villosa L. caloxantha L. intermedia L. nanchuanica L. veitchiana

Ref. Comments [85] [70, 265] [181, 247] [37] [20, 260] [266] [104] [100] [70, 144, 145, 189] [190] [43] [244, 264] [40] [13, 66, 154, 259] [266] [181] [260] [104] [259] (continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

55

Table 1 (continued) Structure number 954

Name of compound

Plant source L. fischeri L. intermedia L. latihastata L. nanchuanica L. odontomanes L. przewalskii L. sibirica L. speciosa L. stenocephala

L. subspicata/L. cyathiceps L. veitchiana L. villosa L. caloxantha L. veitchiana L. intermedia L. nanchuanica L. veitchiana L. caloxantha

955 956

957

L. intermedia L. nanchuanica L. odontomanes L. przewalskii

L. stenocephala L. veitchiana L. veitchiana L. konkalingensis L. nelumbifolia

958 959

960 961 962

Ligulaodonin A

L. purdomii L. przewalskii L. caloxantha L. odontomanes

Ref. Comments [37] [20] [266] [104] [100] [13, 144, 189] [13] [43] [13, 244, 264, 267] [40] [13, 154, 259] [266] [247] [259] [260] [104] [259] [181, 247] [260] [104] [100] [70, 144, 145, 189, 265] [244] [259] [259] [36] [262, 263] [190] [189] [247] [100] (continued)

56

M. Tori and C. Kuroda

Table 1 (continued) Structure number 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979

980

981 982 983 984 985 986 987

Name of compound

Ligustenin A Ligustenin B Ligustenin C Ligustenin D Ligulacephalin C Ligulacephalin A Ligulacephalin B

Citrusin A Citrusin B

Plant source L. veitchiana L. przewalskii L. stenocephala L. stenocephala L. stenocephala L. stenocephala L. stenocephala L. stenocephala L. stenocephala L. stenocephala L. stenocephala L. stenocephala L. veitchiana L. veitchiana L. duciformis L. duciformis L. cyathiceps L. duciformis

L. duciformis/L. cyathiceps L. kanaitzensis L. konkalingensis L. lamarum L. duciformis L. duciformis/L. yunnanensis L. kanaitzensis L. achyrotricha L. duciformis L. achyrotricha L. duciformis L. achyrotricha L. duciformis L. duciformis L. duciformis L. duciformis/L. cyathiceps

Ref. Comments [259] [189] [268] [268] [268] [268] [244] [264] [264] [264] [244] [244] [254] [254] [126] [36] [17, 38] [36, 126, 236, 269] [18] [22] [36] [23, 38] [36, 126] [18] [31] [261] [269] [261] [269] [261] [269] [36] [36] [18] (continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

57

Table 1 (continued) Structure number 988

Name of compound

Plant source L. duciformis L. konkalingensis L. limprichtii L. nelumbifolia

989

Nelumol A

L. achyrotricha L. duciformis L. duciformis/L. cyathiceps L. intermedia L. konkalingensis L. nelumbifolia

L. nelumbifolia/L. subspicata L. purdomii L. achyrotricha L. duciformis L. achyrotricha L. intermedia L. achyrotricha L. intermedia L. duciformis L. konkalingensis L. nelumbifolia

990 991 992 993

994 995

Nelumol B

L. nelumbifolia L. nelumbifolia

996 997

Nelumol C Nelumol D

L. nelumbifolia L. nelumbifolia

998

Nelumol E

L. nelumbifolia

Ref. [36] [36, 126] [126] [51, 126] [261] [36, 269] [18]

Comments

[260] [36, 126] [36, 51, 126, 127, 262, 263, 270] [127] [190] [261] [269] [261] [260] [261] [260] [36] [36] [51, 126, 262, 263, 270] [126] [270, 271] [270] [270, 271] [270, 271] (continued)

58

M. Tori and C. Kuroda

Table 1 (continued) Structure number 999

Name of compound

Plant source L. duciformis L. nelumbifolia

1000 1001 1002 1003

L. duciformis L. duciformis L. duciformis L. nelumbifolia

1004 1005 1006

L. nelumbifolia L. nelumbifolia L. brassicoides L. duciformis L. virgaurea L. sagitta L. pleurocaulis L. fischeri L. przewalskii

1007 1008 1009 1010 1011

1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025

Questin

Plucheoside D1 Tortoside F Apigenin

1026 1027

Luteolin

1028

Chrysoeriol

1029

Kaempferol

L. veitchiana L. dentata L. macrophylla L. nanchuanica L. thomsonii L. thomsonii L. thomsonii L. thomsonii L. fischeri L. fischeri L. fischeri L. alticola L. alticola L. macrophylla L. przewalskii L. rumicifolia L. przewalskii L. rumicifolia L. fischeri L. przewalskii L. rumicifolia L. przewalskii L. rumicifolia L. macrophylla

Ref. [269] [270, 271] [269] [272] [272] [262, 263] [271] [271] [117] [36] [45] [167] [159] [257] [70, 265] [259] [94] [98] [104] [258] [258] [258] [258] [257] [257] [257] [84] [84] [98] [144] [255] [144] [255] [257] [144] [255] [144] [255] [98]

Comments

(continued)

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

59

Table 1 (continued) Structure number 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039

Name of compound

Diosmin Sesamin

Pinoresinol

1040 1041 1042 1043 1044 1045 1046 1047 1048

Samsesquinoside

Plant source L. macrophylla L. dictyoneura L. dictyoneura L. fischeri L. przewalskii L. fischeri L. thomsonii L. przewalskii L. duciformis L. kanaitzensis L. purdomii L. achyrotricha L. purdomii L. achyrotricha L. kanaitzensis L. purdomii L. achyrotricha L. nanchuanica L. virgaurea L. virgaurea L. alticola L. virgaurea L. fischeri L. narynensis

Ref. [98] [182] [182] [257] [144] [257] [258] [144] [36] [273] [190] [261] [190] [261] [273] [190] [261] [104] [65] [65] [84] [65] [257] [274]

Comments

3  Ligularia Species 3.1  L  igularia virgaurea (Maximowicz) Mattfeld ex Rehder & Kobuski Ligularia virgaurea is distributed widely in the Hengduan Mountains area, particularly in Yunnan, Sichuan, Gansu, and Qinghai Provinces in China, and in Nepal and Bhutan. This plant grows in alpine meadows at 4000 m and higher in elevation and is a highly abundant species in Sichuan Province (Plate 6) [2]. Our groups have collected more than 50 samples in this area and analyzed their chemical constituents (Tables 2–4) [27, 28, 45, 63, 76, 114, 275, 276]. Phytochemical studies of each sample resulted in the isolation of various types of terpenoids and aromatics. Interesting observations shown on TLC plates are that at least five patterns (L, V, C, H, and N types) could be observed of spots visualized by spraying with Ehrlich’s reagent [15], which displayed yellow, pink, blue, and purple colors if they were

60

M. Tori and C. Kuroda

Fig. 1  Bicyclic eremophilanes (1)

furanoeremophilanes. The first one (L type) showed several pink spots identified as ligularol (= petasalbin) (161) and its derivatives; the second (V type), one or two spots with yellow color identified as virgaurenones A (274) and B (273); the third one (C type), a blue spot, with the coloring developing in 10–24  h, identified as cacalol (316); the fourth (H type), a purple spot, identified as 6-hydroxyeuryopsin (248); and the last one (N type), a rapidly developed blue spot, identified as neoadenostylone (283). Each sample examined showed one or more TLC spots of these types. Chemical studies revealed that there were at least five chemotypes in L. virgaurea, although the companion genetic studies indicated the presence of three different types (Sect. 4). The number of samples belonging to the L and V types is particularly large, so that they are the major ones that occur.

Fig. 2  Bicyclic eremophilanes (2)

Plate 6  Photograph of L. virgaurea

62

M. Tori and C. Kuroda

Fig. 3  Bicyclic eremophilanes (3)

Ligularol (161) was the major constituent of samples 4, 5, and 9 (L type) (Table 2). However, lactone 344 and its ethyl ether 348 apparently are derived from ligularol (161), and, hence, samples 2, 8, 10, and 12 are also grouped to the L type. The epimers at C-11 of acid 33 were separated successfully by HPLC, and the absolute configurations were determined by the X-ray analysis of a crystalline p-­ bromophenacyl derivative (vide infra) [22]. The interesting dimers 579 and 580 were isolated from samples 9 and 12, and their biogenetic formation has been discussed in the literature [86, 199, 277–280]. A simple lactone 441 (sample 12) was assigned previously as having a 8β-H substituent by Bohlmann et al. [281]. However, its configuration was revised to 8α-H using the results of a NOE experiment [27].

2003-62

2003-68

2003-79

2005-32

2005-38

2005-42

2005-45 2005-52 2005-54 2005-58

2009-36

2

3

4

5

6

7

8 9 10 11

12

Specimen No. number 1 2003-54

Collection place Xiangcheng (S) Daocheng (S) Daocheng (S) Daocheng (S) Xiangcheng (S) Daocheng (S) Daocheng (S) Litang (S) Litang (S) Yajiang (S) Kangding (S) Litang (S)

4300

3800 4100 4300 4200

4400

4100, 4300 4400

4100

4000

4300

33 33 33 −

1, 4, 33, 39, 40, 72, 98, 100, 132, 136, 142, 143

− − − 272, 273, 274, 275, 460 −

− 579 − − 389 225 389 − 389

161, 344 161, 190, 538 161, 344 − 344, 346

441, 579, 580

272, 274, 460

−

−

273, 274, 460, 463

−

−

−

−

−

−

−

389

33

−

−

227

161, 162, 190, 361 161, 192, 190, 344, 359, 539 −

33

−

−

226, 389

162, 163, 539

33, 98

−

−

−

348

10H Tricyclic eremophilanes −

1(10)-En-2-one, and 1(10)-en-2-ol tricyclic eremophilanes 273, 274

1(10)-Ene, 9-ene, and 1,10-epoxy 10-OH Tricyclic tricyclic eremophilanes eremophilanes − −

33, 98, 132

Elevation Bicyclic (m) eremophilanes 4000 −

Table 2  Samples 1–12 of L. virgaurea and their chemical constituents

159, 828

− − − −

[27]

[63] [27] [63] [63]

[63]

[63]

− 879

[27]

[63]

[63]

[63]

−

−

−

−

Others Ref. − [63]

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 63

64

M. Tori and C. Kuroda

Fig. 4  Bicyclic eremophilanes (4)

Sample 12 produced many bicyclic compounds, 1, 4, 33, 39, 40, 72, 98, 100, 132, 136, 142, and 143. Compound 159 was also isolated from sample 12, and the structure of this compound is interesting, because this lactone ether is thought to be derived from an eremophilane. Samples 1, 6, 7, and 11 produced virgaurenone A (274) and related compounds (Table 1). Virgaurenones A (274), B (273), C (272), and D (275) and virgaurenolides A (463), B (460), C (459), D (461), and E (462) all have a common partial structure, 1(10)-en-2-one, and presumably they are derived from 6-hydroxyeuryopsyn (248), a compound having a 1(10)-ene system belonging to the H type, by oxidation at the C-2 position. These samples were grouped into the V type. Samples 13 and 14 produced cacalol (316), cacalone (322), epicacalone (323), and their derivatives, and thus these samples were grouped to the C type (Table 3) [45]. Cacalol (316) is postulated to be derived from neoadenostylone (283) and its derivatives by rearrangement reaction. Therefore, the absolute configuration at C-4 of

2010-13

2010-15

2010-21

2010-26

2010-44

14

15

16

17

18

Hongyuan/ Aba (S) Aba (S)

Hongyuan (S)

Hongyuan (S)

Li (S)

Specimen Collection No. number place 13 2009-56 Ganzi (S)

3500

3600

3600

3600

3700

248, 528

251

−

− 344, 346, 356, − 359, 360, 362, 538

−

14

1, 10, 33, 98, 132, 133, 136

−

−

−

−

−

−

1(10)-Ene, 9-ene, and 1,10-epoxy Elevation Bicyclic 10H Tricyclic tricyclic (m) eremophilanes eremophilanes eremophilanes 3700 − − 252

Table 3  Samples 13–25 of L. virgaurea and their chemical constituents

−

−

−

1(10)-En-9-­ one, and 1,10-epoxy-­9one tricyclic Cacalol eremophilanes derivatives 280, 282 316, 317, 322, 323, 324, 325, 332, 335, 547, 548, 549, 550, 570 − − 316, 319, 322, 323, 332, 335 − 273, 274, 456, − 459, 460, 530, 531, 532, 534, 566 − 279, 280, 306 316, 322, 323, 332, 335, 547, 548 273, 274, 531 278, 283 − 1(10)-En-2-­ one, and 1(10)-en-2-ol tricyclic eremophilanes −

−

639

635

636, 638, 639, 642

−

159, 648, 792, 772, 828

790

571, 622

−

−

[28]

[45]

[45]

[114]

[45]

Ref. [45]

(continued)

Bakkanes Others − 1007

2010-50

2010-51

2010-52

2010-63

2010-68

2012-16

20

21

22

23

24

25

Kangding (S)

Luqu (G)

Songpan (S)

Ruoergai/ Hongyuan (S)

Ruoergai (S)

Ruoergai (S)

Specimen Collection No. number place 19 2010-46 Aba (S)

Table 3 (continued)

4100

3400

3600

3600

3500

3500

1, 33, 98, 132, 136, 142

−

−

280, 283, 305, − 306, 307, 308, 312 − 251, 288, 293, − 278, 283, 308, − 469, 477, 535 312 − 277, 455, 457, − − − 459, 461, 462, 463, 530, 533, 534, 566, 567, 568, 569 344, 367, 381, − − − − 382, 383

−

−

248, 251, 253, − 257, 288, 289, 434, 448, 546, 574 290, 293 −

−

280, 281, 283, − 306, 307, 308, 310, 311, 312 − 316, 317, 322, 323, 335

12

−

Cacalol derivatives 316, 322, 323, 335, 549, 550

289, 290, 293

1(10)-En-9-­ one, and 1,10-epoxy-­9one tricyclic eremophilanes 280, 282, 306, 309

−

1(10)-En-2-­ one, and 1(10)-en-2-ol tricyclic eremophilanes −

−

1(10)-Ene, 9-ene, and 1,10-epoxy Elevation Bicyclic 10H Tricyclic tricyclic (m) eremophilanes eremophilanes eremophilanes 3600 50 − 248, 436, 448, 528, 546, 574

−

638, 640, 641

636, 643

−

772, 792, 811

149, 845 −

828

[27]

[114]

[76]

[76]

[45]

−

147, 572

[45]

Ref. [76]

Bakkanes Others 635 148, 152, 622, 807, 828 − 150

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

67

Fig. 5  Bicyclic eremophilanes (5)

cacalol (316) is the same as that of the eremophilanes. Sample 15 produced virgaurenones A (274) and B (273) and their derivatives [114]. Virgaurenolides A–E (463, 460, 459, 461, 462) are oxidized derivatives of virgaurenones found in samples of the V type (samples 15 and 24). Cacalol (316) and 6-hydroxyeuryopsyn (248) were the major constituents of sample 16 [45]. Sample 16 also produced two eremophil-1(10)ene derivatives (528 and 571; a dimer of 1(10)-ene and cacalol), three 1(10)-en-9-one

68

M. Tori and C. Kuroda

Fig. 6  Noreremophilanes (1)

derivatives (279, 280, and 306), six cacalol derivatives (322, 323, 332, 335, 547, and 548), bakkane (635), as well as two dimers (571 and 622). Compound 571 was named virgaurin A [45], but the same name was already used in Refs. [12, 173]. Accordingly, the name in Ref. [45] should be changed. Virgaurin C (622) is a dimer consisting of cacalol-type and bicyclic compound units. Therefore, this sample was grouped as H/C, a mixture of both types [45]. Sample 17 produced 6-acetoxyeuryopsyn (251), neoadenostylone (283), and virgaurenone A (274) as major constituents, and this sample was grouped to the H/N/V type. Their derivatives, virgaurenone B (273), virgaurenospirolide B (639), 6β-acetoxyeremophil-1(10)-en-9-one (278), and 11βH-6β-acetoxy-7α,8α-epoxy-2-oxoeremophil-1(10)-en-12,8β-olide (531) were

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

69

Fig. 7  Noreremophilanes (2)

also isolated. Among the samples of the L type, sample 18 was particularly interesting in terms of the phytochemical profile of its roots, with the major constituent being compound 359. Also, there were several norsesquiterpenoids (98, 132, 133, 136, and 159) present in this sample. The biosynthesis pathway is postulated to start from fukinone (4) → 20 → 98 → 100 → 136 → 133 → 132 [28]. Sample 19 produced 6-hydroxyeuryopsyn (248), cacalol (316), and 6β-(2-­ methylpropanoyloxy)furanoerephil-1(10)-en-9-one (280) and thus was grouped to the H/C/N type [45]. A typical compound of the N type was neoadenostylone (283), for which the carbonyl group at C-9 is presumably formed by oxidation from 248 and its derivatives (samples 20 and 22) [45, 76]. The C-9 position is doubly allylic both from the furan and the double bond at C-1/C-10, and thus this position is readily oxidized. Sample 21 also produced 6-hydroxyeuryopsyn (248) and cacalol (316) as major constituents as well as their related compounds, 251, 253, 257, 288, 289, 317, 322, 323, 335, 434, and 448. Sample 21 was assigned to the H/C type as well. 6-Acetoxyeuryopsyn (251) and neoadenostylone (283) were major constituents of sample 23 (H/N type). Sample 24 (V type) produced five 1(10)-en-2-one type compounds (455, 457, 530, 533, and 534), four 1(10),8-diene type compounds (463, 459, 461, and 462), and four 1(10),8-dien-12-ol type compounds (569, 566, 567, and 568) as well as 1(10)-ene-2,9-dione 277. The 1(10)-en-2-one type bakkanes, virgaurenospirolides A (640) and C (638), were also produced. It is interesting to note that virgaureno-­ anhydride A (641) was isolated from this sample, since it has an anhydride partial structure instead of a lactone moiety in ring C of a bakkane skeleton. This type of

70

M. Tori and C. Kuroda

Fig. 8  Noreremophilanes (3)

compound has not been reported previously. Sample 25 was grouped in the L type. Lactones derived from ligularol (344, 367, 381, 382, and 383) were isolated along with five noreremophilanes (33, 98, 132, 136, and 142). A guaiane-type sesquiterpenoid, LB (772), was isolated. This compound was obtained previously from the Chinese drug “Shanziyuan” (Chinese name) or “San-Shion” (Japanese name) by Takahashi’s group [282–284]. Although L. sibirica, L. hodgsonii, L. veitchiana, L. latihastata, and L. franchetiana are registered as components of “Shanziyuan,” LB (772) had not been obtained previously. These findings may indicate that “San-­ Shion” is constituted in part from the roots of L. virgaurea or a related species.

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

71

Fig. 9 Secoeremophilanes

In Table 4, samples investigated by research teams other than our own groups are listed. Samples 26–28, 32, 34, and 36 can be grouped to the C type [12, 74, 118, 152, 168, 171–173]. Cacalol (316) and its methyl ether 317 and farfugin B (335) and its methyl ether 336 were isolated from samples 26 and 27 [169, 171]. Sample 26 also produced cacalolide (547) and epicacalolide (548), which are derived from cacalol (316), and virgauronin (339) in being related to farfugin B (335). Compounds 551 and 552 in samples 28 and 32 are interesting [118, 173], because they have an enol-­type triene moiety similar to cacalol (316). Sample 28 produced pseudoguaiane-­type sesquiterpenoids 784 and 785, which were the only examples of chemical constituents of L. virgaurea. Previously, the dimeric compounds virgaurin A (615) (vide supra) and adenostin A (570) were isolated from this species [173]. Compounds 157 and 159 are of the 8,9-seco-cacalol type (sample 32), and the presence of both these isomers indicated that they may be formed

−

−

2002

32

− 419

− −

Huzhu (Q) Huzhu (Q)

2002

− −

a

a

30 31

−

−

Huzhu (Q)

2002

29

414, 418, 420

−

−

Zhang (G) −

1988

28

−

−

1988

27

Zhang (G) −

−

434, 436, 437, 438 445 439, 612

−

−

1(10)-Ene, 9-ene, and 1,10-epoxy 10-OH tricyclic Collection Collection Bicyclic 10H Tricyclic Tricyclic No. year place eremophilanes eremophilanes eremophilanes eremophilanes 26 1988 Zhang (G) − − − −

Table 4  Samples 26–39 of L. virgaurea and their chemical constituents

−

− 458, 460

316, 335, 551, 552

− −

1(10)-En-2-one, and 1(10)-en-2-ol tricyclic Cacalol eremophilanes derivatives − 316, 317, 326, 327, 335, 336, 338, 339, 547, 548 − 316, 317, 335, 336, 616, 618 − 329, 551, 552, 570, 615 − −

− − 156, 157, 725, 795

−

−

784, 785

−

646 −

−

−

−

[118]

[202] [199]

[198]

[173]

[171]

Bakkanes Others Ref. − − [168, 169, 172]

72 M. Tori and C. Kuroda

2002

2005

2005

2005

2005

2012

34

35

36

37

38

a

39

Not described

a

33

35, 93

345

−

345, 359, 360, 406, 407 361, 363

98, 103, 114

−

−

−

−

470, 478

−

347, 379, 380

−

471, 479

−

−

612, 613

−

236

−

−

−

−

Golog (Q) 104

Gannan (G)

Gannan (G)

Huzhu − (Q) Gannan 145 (G) Lintao (G) −

Huzhu (Q)

−

−

−

−

−

316, 335, 338, 570, 615, 619, 620, 621 −

−

335, 617

−

−

−

280

−

−

−

−

588, 589, 590, 591 −

−

−

−

−

900, 1043, 1044, 1046 −

−

−

−

[87, 184, 196] [89]

[215, 216]

[12]

[112]

[152]

[65]

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 73

74

Fig. 10 10H-Furanoeremophilanes (1)

M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

75

Fig. 11 10H-Furanoeremophilanes (2)

through a C-6 cation by bond fission and electron transfer. Cacalol (316), farfugin B (335), an oplopane 725, and an eudesmane 795 were also isolated from sample 32 [118]. Sample 29 produced toluccanolides A–C (434, 436, and 438), as well as compounds 437, 414, 418, and 420 [198]. It is very interesting to note that the configurations at C-6 and C-10 of 414 and 420 are completely opposite and also 1-oxo derivatives are not very often reported from Ligularia species. Sample 30 requires a comment, however. Although the structure of compound 646 was determined by X-ray crystallographic analysis, the structure drawn in Ref. [202] unfortunately is completely wrong. This is because bakkanes have a spiro carbon, so sometimes a structural error may become apparent [275]. The corrected structure 646 has been drawn in this contribution, rather than that published in the literature. Sample 31 probably belongs to the V type, because virgaurenolide B (460) and 458 are included [199]. The dimeric compound 612, connected between C-8/C-8′ and C-6/C-12′ of eremophilenolide and furanoeremophilane, was isolated. Sample 33 produced five glucosides (93, 900, 1043, 1044, and 1046) and an acid (35) [65]. In turn, sample 34 produced three dimers, (612, 613, and 617), two 9-ones (236 and 280), and farfugin B (335) [152]. The structural representations of 612 and 613 in the original paper [152] should be revised as depicted, however, because each part of a sesquiterpenoid should have the same absolute configuration. The epoxides,

76

Fig. 12 10H-Furanoeremophilanes (3)

M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

77

Fig. 13 10H-Furanoeremophilan-15,6-olides

379 and 380, in sample 35 exhibit a 3α,4α-epoxide moiety [112], which is rather rare in Ligularia. Sample 36 produced five dimeric compounds (570, 615, 619– 621), related to cacalol (316) [12]. Virgaurin A (615), also isolated from sample 28, is linked between C-6 and C-6′ of two farfugin B (335) units, while, in turn, adenostin A (570) is linked between C-14 and C-12′ of two cacalol (316) units. Compound 619 is linked between C-15 of cacalol (316) and C-12′ of compound 338, a quinone derivative of farfugin B (335). The structures of compounds 620 and 621 are complex, since they are hetero-Diels-­Alder-type derivatives between a 1(10)-en-9-one moiety and the C-11/C-12 double bond of cacalol or farfugin B. The relative configurations at C-11′ and C-12′ of 620 and 621 are cis concerning H3-13′ and H-12′. 6α-Hydroxyeremophil-7(11)-en-12,8α-olide (345) proved to be the major constituent of samples 38 and 39, being grouped into the L type. Five

78

Fig. 14 10-OH-Furanoeremophilanes

M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

79

10H-eremophilanolides (345, 359, 360, 361, and 363), a 10-OH lactone (407), two 1β,10β-epoxides (471 and 481), and three noreremophilanes (98, 103, and 114) were isolated from sample 38 [87, 184, 196]. Sample 39 produced noreremophilane 104 as well as compound 345 [89].

3.2  Ligularia dentata (A. Gray) H. Hara Bohlmann and his associates studied the chemical constituents of many Ligularia species, among which L. dentata afforded isohumulene (812) as a major constituent (sample 1, Table 5) [13]. 3α-Angeloyloxy-9β-hydroxyeremophil-11-en-8-one (59), liguhodgsonal (125), the hydrocarbon 875, two germacranes (758 and 769), and the enyne compound 883 were isolated from sample 1 collected at a botanical garden in Berlin [13]. Naya et al. reported that ligudentatol (118), 2-hydroxyplatyphyllide (121), ligujapone (123), liguhodgsonal (125), ligucyperonol (802), and caryophyllene (809) were isolated from Japanese sample 2 [95]. Gao et al. published the isolation of chemical constituents from sample 3, collected in Gansu Province, China. Ligudentatol (118), 2-hydroxyplatyphyllide (121), ligujapone (123), liguhodgsonal (125), ligudentatin A (126), ligudentatin B (127), three bisabolanes (671, 672, and 673), and a diphenyl ether (1012) were all isolated from sample 3 [94, 97].

Table 5  Samples 1–5 of L. dentata and their chemical constituents Collection Collection Bicyclic No. year place eremophilanes 1 1977 Berlin 59, 125 (Germany)

2

a

3

1992

4

2004

Sendai (Japan)

5

2004

Sendai (Japan)

Not described

a

Nagano (Japan) Zhang (G)

118, 121, 123, 125, 802 118, 121, 123, 125, 126, 127 −

−

Bisabolanes −

Aromatics −

Ref. [13]

−

Others 758, 769, 812, 875, 883 809

− 671, 672, 673

1012

−

664, 669, 670, 716, 720, 721, 722, 723, 724

−

−

908, 927, 931, 935, 937

803, 890, 894, 896 828, 860, 898

[94, 97] [102, 234]

[95]

[248]

80

M. Tori and C. Kuroda

Fig. 15  Furanoeremophil-1(10)-enes and furanoeremophil-9-ene

Kikuchi and his group reported the isolation of nine bisabolanes (664, 669, 670, 716, 720, 721, 722, 723, and 724), eudesma-4,11-diene-1β,14-diol (803), and three monoterpenoids (890, 894, and 896), from sample 4 collected in Japan [102, 234]. Compounds 721, 722, and 724 seem to be derived from a bisabolane derivative by the formation of ether rings. The absolute configurations of both 716 and 724 were

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

81

Fig. 16  Furanoeremophil-1(10)-en-2-ones and furanoeremophil-1(10)-en-2-ol

Fig. 17 Furanoeremophil-1(10)-en-9-ones

established by ECD spectroscopy. This group also identified five aromatic derivatives (908, 927, 931, 935, and 937), as well as lupeol (828), and compounds 860 and 898 from the same plant source (sample 5) [248]. The absolute configuration at C-3 of 937 was determined to be (S), by comparing the specific rotation of 937 with that of the 3′,4′-dihydroxy derivative, taraxafolin. Two chemotypes may exist in this species based on these results, namely, a bisabolane-producing type and a non-bisabolane-­producing type. A review of this species by Yaoita was published in 2012 [285].

82

M. Tori and C. Kuroda

Fig. 18 1,10-Epoxyfuranoeremophilanes

3.3  Ligularia japonica (Thunberg) Lessing Takahashi’s group studied the chemical constituents of L. japonica sourced in Japan (sample 1) (Table 6) and reported the isolation of the three furanoeremophilanes, 226, 227, and 231 [12, 286]. These three compounds had a hydroxy group at the

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

83

Table 6  Samples 1–3 of L. japonica and their chemical constituents

a

Collection No. year a 1

Collection place (Japan)

Bicyclic eremophilanes −

10-OH Tricyclic eremophilanes 226, 227, 231

2

1977

123, 125

−

3

a

München (Germany) Dali (Y)

111, 113, 115

429

Others − 758, 812, 875, 883 −

Ref. [12, 286] [13] [90]

Not described

C-10 position. Bohlmann et al. reported the chemical constituents of sample 2 collected in Munich (Germany) [13]. Thus, two norsesquiterpenoids, ligujapone (123), liguhodgsonal (125), and four hydrocarbons (758, 812 (major constituent), 875, and 883) were documented. Three norsesquiterpenoids (111, 113 (major constituent), 115), and the 3,6,10-trioxygenated eremophilanolide 429 were reported from sample 3, obtained from Dali (Yunnan Province, China) [90]. The configuration of the 6,7-epoxide of 113 was assigned as α, but without discussing any supportive evidence.

3.4  Ligularia hookeri (C. B. Clarke) Handel-Mazzetti Ligularia hookeri grows on glassy slopes, forest understories, stream banks, scrubland, and alpine meadows, at altitudes of about 3000–4500 m (Plate 7) [2]. Four specimens, collected in 2002 and 2003 from Sichuan Province, China (Table  7, sample 1), were combined and analyzed to characterize the four purified eremophilanes, 215, 220, 221, and 223, with the last-mentioned compound as the major constituent [138]. The chemical constituents of sample 2 were found to be slightly different, as constituted by the 15-oic acid 209, the epimers 213 and 214, the 15,6-lactone 223, a bisabolane (650), and a eudesmane (790). It is interesting to note that the C-15 carbon atoms of all these compounds isolated from L. hookeri are oxidized to a carboxylic acid or a lactone. The previously proposed 6α-H configuration for the related compounds 222 and 224 by Bohlmann and Knoll [287] was revised to 6β-H [138]. For this species, no distinct variations were found among the two samples examined (Table 7).

84

M. Tori and C. Kuroda

Plate 7  Photograph of L. hookeri

Table 7  Samples 1 and 2 of L. hookeri and their chemical constituents Specimen No. number a 1 2 2012-30

Collection place

Elevation (m)

a

a

Kangding (S)

3900

10H Tricyclic eremophilanes 215, 220, 221, 223 209, 213, 214, 223

Others − 650, 790

Ref. [138] [138]

Mixture of four samples; 2002-80, 2003-03, 2003-70, 2003-81

a

3.5  Ligularia atroviolacea (Franchet) Handel-Mazzetti Three samples of L. atroviolacea were investigated, inclusive of our own work (Table  8). Sample 1 (Yulong, Yunnan Province, China) produced three 3β-­angeloyloxyfuranoeremophilanes (204, 205, and 224) [48], with compounds 204 and 205 being 15-oic acids. As suggested by Bohlmann et al. [288] and Kuroda et al. [289], 6β-acyloxy-15-oic acid can cyclize to a 15,6α-olide derivative, and thus many derivatives, such as compounds 211–224, 458–515, 522, 544, and 545, are known. From sample 2 (Lijiang, Yunnan Province), the bislactones 499–501 and 510 were reported [208]. However, there are many errors evident in this paper; for example, according to the abstract, five compounds were isolated, but, in the text, only four compounds were described. The same group published another paper [146] describing the isolation of 215 and 498 from the same sample as described in Ref. [208]. It was also stated that compound 215 was a new natural product when isolated. However, 215 was already known [290] at that time of publication [208]. Moreover, the MS data for 215 were expressed incorrectly (i.e., M  =  260, but

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

85

Fig. 19  1,10-Epoxyfuranoeremophilan-9-ones and 1,10-epoxyfuranoeremophilan-9-ols Table 8  Samples 1–3 of L. atroviolacea and their chemical constituents Specimen number Collection Elevation place (m) No. (year) 1 2002-01 Yulong 2900 (Y) a 2 (2001) Lijiang (Y) a 3 (2001) Lijiang (Y)

a

Bicyclic eremo­ philanes − − 41, 42

10H Tricyclic eremophilanes 204, 205, 224 215, 498, 499, 500, 501, 510 212, 215, 352, 491, 498, 499, 501, 503, 504, 510, 582

10-OH Tricyclic eremophilanes −

Others Ref. − [48]

−

−

237, 238, 628 239, 241

[146, 208] [69]

Not described

M = 244). An additional contribution was published on L. atroviolacea reporting the characterization of two cis- and trans-dicarboxylic acids (41 and 42), six furanoeremophilanes (212, 215, 237, 238, 239, and 241), eight eremophilanolides (352, 491, 498, 499, 501, 503, 504, and 510), and two dimeric compounds (582 and 628) [69]. The structure of 241 was determined as a 1α-chlorinated compound by X-ray crystallographic analysis. Compound 582 is a homodimer of eremophil-3-ene(12,8α),(15,6α)-diolide. The structure of 628 is interesting as it contains a dimeric

86

M. Tori and C. Kuroda

ether of an enolate of butane-2,3-dione together with a phenol moiety. The characteristic feature of the phytochemistry of L. atroviolacea is compound oxidation at the C-15 position, and thus many 15-oic acids and 15,6-lactones are produced.

3.6  Ligularia kanaitzensis (Franchet) Handel-Mazzetti Ligularia kanaitzensis is distributed widely in Yunnan Province, and our groups have collected 17 samples of this species (Plate 8, Table  9). Chemical analysis revealed that these plants could be divided roughly into two chemotypes: (i) those producing bicyclic eremophilanes (eremophilan-8-one type) and (ii) those producing furanoeremophilanes [22]. For example, sample 2 produced eremophila-­8,11-­ dien-­8-one (2), fukinone (4), 10βH-3α-tigloyloxyeremophila-8,11-dien-8-one (60), and 10βH-3α-senecioyloxyeremophila-8,11-dien-8-one (63), with all of these being bicyclic eremophilanes. In turn, sample 1 afforded ligularol methyl ether (162), furanoeremophilane-6β,10β-diol (226), and its methyl and ethyl ethers (227 and 228), and all are furanoeremophilanes. Fukinone (4) was isolated from samples 2–4, 6, 7, 14, 16, and 17, while ligularol (161) was isolated from samples 5, 8–10, 12, and 16. The 6,10-dioxygenated compounds 226–231, 233, and 234 were produced from samples 1, 5, 6, 8–13, and 16. Kanaitzensol (28) was isolated from sample 4, with this compound thought to occur in plants because the biosynthesis process stops and it cannot cyclize into a furan. The absolute configuration of C-2′ in the 2-methylbutanoyloxy group of compound 231 was determined to be (S) by comparing the NMR data of both the (2′-R) and (2′-S) derivatives prepared from the corresponding hydroxy compound [22].

Plate 8  Photograph of L. kanaitzensis

2002-69

2003-10

2004-05 2004-78

2005-04 2005-12

2005-18

2005-19

2005-20

2006-20 2006-22

2006-31

2

3

4 5

6 7

8

9

10

11 12

13

Specimen number No. (year) 1 2002-51

Weixi (Y)

Collection place Shangri-La (Y) Jianchuan (Y) Jianchuan (Y) Yulong (Y) Ninglang (Y) Yulong (Y) Jianchuan (Y) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Weixi (Y) Weixi (Y)

2900

3300 3200

3600

3000

3000

2900 3500

3200 2700

2800

2400

Elevation (m) 3600 − − − 226, 228, 230, 231 234 −

− − − 161 − − 161, 344 161, 164 161, 164, 344, 538 − 161 −

2, 4, 60, 63 4 2, 4, 5, 28 1 4 3, 4 − 33 33, 98 2, 3, 60, 63, 71 − −

226, 229, 230, 231, 233 229, 230, 231, 233 226, 229, 230, 231, 400 226, 230, 231 229, 230, 231, 233, 234, 525, 526 226, 229, 230, 231, 234

10-OH Tricyclic eremophilanes 226, 227, 228

10H Tricyclic eremophilanes 162

Bicyclic eremophilanes −

Table 9  Samples 1–19 of L. kanaitzensis and their chemical constituents

− 979 − −

− − − −

−

979

−

−

− −

− −

−

−

828

828 828

806

−

−

629 −

− −

649

−

[22]

[22] [22]

[22]

[22]

[22]

[22] [22]

[22] [22]

[22]

[22]

Ref. [22]

(continued)

Aromatics Others − −

− −

− −

−

−

1(10)-Ene, 9-ene, and 1,10-epoxy tricyclic eremophilanes −

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 87

2008-59

2012-55

a

(1999)

16

17

18

19

a

Not described

2008-58

15

Specimen number No. (year) 14 2007-31

Lijiang (Y)

Collection place Yanyuan (S) Jianchuan (Y) Jianchuan (Y) Yanbiang (S) Lijiang (Y)

Table 9 (continued)

a

a

3200

2700

2500

Elevation (m) 3000

357

21

−

−

−

−

−

−

2, 4

293

−

225, 229, 230, 231, 234 −

161

4

270

1(10)-Ene, 9-ene, and 1,10-epoxy tricyclic eremophilanes −

−

−

−

−

10-OH Tricyclic eremophilanes −

10H Tricyclic eremophilanes −

Bicyclic eremophilanes 2, 4, 20

1038, 1042 −

−

981

−

[273] [56, 828, 57] 831, 832, 833

−

[21]

[31]

− −

[31]

Ref. [31]

−

Aromatics Others 981 −

88 M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

Fig. 20  Cacalol and related compounds

89

90

M. Tori and C. Kuroda

Fig. 21 10H-Eremophilan-12,8-olides (1)

Coniferyl alcohol geranyl ether (979) was isolated from samples 8 and 10 and its acetate 981 from samples 14 and 16. Interestingly, furanoeremophil-9-ene (270) was isolated from sample 15, although most of the constituents were found have a double bond at C-1/C-10 [31]. An intriguing phytochemical contribution appeared in 2005 describing the isolation of only the lignans 1038 and 1042, with no terpenoids being reported at all (sample 18) [273]. Sample 19 produced a hydroperoxide (21) and four triterpenoids (828 and 831–833) [56, 57]. The original report describing the isolation of 6α-hydroxyeremophil-7(11)-en-12,8β-olide cited an erroneous paper. However, the 13C NMR resonances attributed to C-6 and C-8 appeared at δ 34.9 and δ 104.3 ppm, respectively; with both of these chemical shift values indicating that the compound was actually 8-hydroxyeremophil-7(11)-en-12,8-olide. After looking for a substitute candidate, compound 357 from L. vellerea was found to have the same spectroscopic data. Therefore, compound 357 is listed in Table  9. Isolation of a hydroperoxide from Ligularia, such as 21, is rather rare. Although a hydroperoxide proton (-OOH) of 21 was reported in neither Refs [56] nor [57], it was observed at δ 8.59 ppm (s) in the 1H NMR spectrum published in Ref. [291]. The corresponding 11-hydroxy compound also is known [292]. This species usually

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

Fig. 22 10H-Eremophilan-12,8-olides (2)

91

92

M. Tori and C. Kuroda

Fig. 23 10H-Eremophilan-12,8-olides (3)

produces either eremophilan-8-ones or furanoeremophilanes, so two chemotypes are known. Moreover, aromatics and other types of terpenoids are also produced.

3.7  Ligularia intermedia Nakai Several aromatic compounds (913, 952, 953, 956, 957, and 989) and hydroperoxides (991 and 992), along with five triterpenoids (828, 834, 835, 840, and 841), were isolated from L. intermedia by Jia’s group (sample 1, Table 10) [250, 260]. Another sample of this species (sample 2) from Hubei Province, China, was found to produce 10H-furanoeremophilanes, inclusive of the 15,6-lactones 212 (major constituent) and eremofarfugins B4 (522), G (544), and F (545), and two other eremophilanes (328 and 511), as well as bakkenolide A (629) [140]. The original structure of a 7α,8α-epoxide of compound 522 was later revised as a 7β,8β-epoxide, as depicted

2004

2008

a

1995

2004

a

3

4

5

6

7

a

8

Not described

(Hebei)

1995

2

a

Xinglong Mt (Hubei) (Shanxi)

a

Luanchuan (Henan)

(Shanxi)

Collection place Shenlongjia (Hubei)

Collection No. year 1 1994

290, 291, 292, 293, 295 940, 944, 952, 954 − − −

− − 389

196, 212, 491, 492 491, 493 −

54, 56, 118, 123, 125 141

−

−

−

−

−

−

−

−

−

−

1, 5, 6, 11, 12, 119, 121, 125 −

−

−

−

511

−

Aromatics 913, 952, 953, 956, 957, 989, 991, 992 −

212, 328, 522, 544, 545 212, 372, 375, 491, 492, 493 334

1(10)-Ene, 9-ene, and 1,10-epoxy tricyclic eremophilanes −

−

10-OH Tricyclic eremophilanes −

10H Tricyclic eremophilanes −

Bicyclic eremophilanes −

Table 10  Samples 1–8 of L. intermedia and their chemical constituents

−

869, 872, 873 828, 830

758

−

−

Others 828, 834, 835, 840, 841 629

[132, 133] [77, 204] [111]

[20]

[176]

[141]

[140]

Ref. [250, 260]

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 93

94

Fig. 24 10-OH-Eremophilan-12,8-olides

M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

95

Fig. 25 10-OH-Eremophila-7(11),8-dien-12,8-olides

in Fig. 31 [145]. The configurations of H-11 of compounds 544 and 545 also were determined unambiguously [145]. Compound 328 is an enol form of a 9-one compound. Sample 3 from Shanxi Province, China, afforded the 10H-furanoeremophilane 212, three eremophilenolides (491–493), and two 15-oic acids (372 and 375) [141]. From sample 4 collected in Henan Province, China, isoligularonic acid (334) was isolated [176]. This compound has a rearranged furan unit from the C-8 to the C-6 positions. Eighteen constituents were isolated from sample 5 by Bohlmann and Knoll [20]. These comprised five bicyclic eremophilanes (1, 5, 6, 11, and 12), three noreremophilanes (119, 121 (2-hydroxyplatyphyllide; “8-hydroxy” in the numbering of the original report), and 125), four 1,10-epoxides (290, 291, 293, and 295 (the major constituent)), and four aromatic compounds (940, 944, 952, and 954) [20]. Although the (S)-(+)-form for hydroxytremetone (940) was shown without appropriate detail in Ref. [20], the absolute configuration of natural (−)-940 was determined to be (R), by transformation and degradation of this substance into a known chiral compound [293].

96

M. Tori and C. Kuroda

Fig. 26 10-OH-3-Acetoxyeremophilan-12,8-olides

Sample 6 produced four 10H-eremophilanes (196, 212, 491, and 492) and three p-menthane monoterpenoids (869, 872, and 873) [132, 133]. Three noreremophilanes (118, 123, and 125), petasin (54), isopetasin (56), two dilactones (491 and 493), and two triterpenoids (828 and 830) were isolated from sample 7 (Shanxi Province, China) [77, 204]. Sample 8 produced the noreremophilane 141 and the 10-OH eremophilanolide 389 [111]. Compound 141 exhibits a double bond between C-7 and C-9 (Fig. 8), which is the first such example for a norbakkane type compound, since normally these have a double bond between C-6 and C-7.

3.8  Ligularia vellerea (Franchet) Handel-Mazzetti Two lactones (344 and 357) as well as umbelliferone (916) and 4-­hydroxyacetophenone (906) were isolated from sample 1 of L. vellerea (Yunnan Province, China) (Table  11, Plate 9) [149]. Three L. vellerea samples (samples 3, 4, and 8) were found to produce the bicyclic eremophilanes eremophila-1(10),11-diene (1) and fukinone (4), and the norketone 132 [26]. Typical compounds occurring in this species are 15-oic acids, such as 199, 542, and 543. An acid (199), a methyl ester (200), and a 15,6-ether derivative (211) were isolated from sample 5 [26]. Compound 212

2008-10

2008-15

2012-53

9

10

11

a

12

Not described

2004-74 2004-77 2006-01, 2006-06 2006-79

6 7 8

Specimen No. number a 1 2 2003-06, 2005-13 3 2004-10 4 2004-15 5 2004-68 200, 211, 491 199, 200 199, 200, 211 − − 542, 543 199, 491 199, 200, 211, 212 199, 200, 211, 212 −

1, 4 1 − − − 1, 4, 132 − − − −

3200

3200

Yulong (Y) Yulong (Y) Shangri-La (Y) Ninglang (Y) Ninglang (Y) Chenggong (Y) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Yanbiang (S)

4000

3300

3000 2700 2700

3600 3300 3600

15-Oxygenated tricyclic eremophilanes − 212

Bicyclic eremophilanes − −

Collection Elevation place (m) a Lijiang (Y) Jianchuan (Y) 3300

Table 11  Samples 1–12 of L. vellerea and their chemical constituents

[26] [26] [26] [26] [26] [26] [26] [21] [21] [21]

− − − − − − − − − −

− − − 161, 163, 178 161, 162, 178 − −

160, 163, 178, 179

161

160

Aromatics Ref. 906, 916 [149] − [26]

15-Non-oxygenated tricyclic eremophilanes 344, 356 −

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 97

98

M. Tori and C. Kuroda

Plate 9  Photograph of L. vellerea

occurred in all of samples 2, 10, and 11 [21, 26]. Ligularol (161) was isolated from samples 6, 7, and 11. Sample 9 produced the above-mentioned compound 199 and a lactone derivative (491) [26]. Sample 12 elaborated a furanoeremophilane (160), ligularol ethyl ether (163), 1α-angeloyloxyfuranoeremophilan-6β-ol (178), and an ethyl ether 179 [21]. Compound 178 is a C-1 epimer of subspicatin B (172). The configurations at C-11 of compounds eremofarfugins D (542) and E (543) were deduced by the NMR chemical shift values of H-11 and H3-13, because no decisive NOE observations were made in these cases. It has been determined that 15,6-­lactones are formed from their 15-oic acid derivatives, with relevant chemical evidence obtained by Bohlmann’s group and Kuroda et al. (Sect. 3.5). For this reason, the 15,6-lactones have a 6α-configuration (6β-H). Most of the L. vellerea samples produced 15-oic acids, 15,6-lactones, and ligularol (161), all of which are 10H derivatives. Our collected samples could be grouped into two in terms of their geographical origin: the Shangri-La type (samples 2–5 and 8–11) and the Luguhu type (samples 6, 7, and 12). The major compounds obtained proved to be 15-­oxygenated and non-oxygenated eremophilanes, respectively, and these two chemotypes were separated clearly.

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

99

Fig. 27  Eremophiladienolides and eremophilatrienolides

3.9  Ligularia wilsoniana (Hemsley) Greenman Compound 306 and its 6-angeloyloxy derivative 308 were determined as the major constituents common to samples 1, 3, and 4 of L. wilsoniana (Plate 10, Table 12) [163]. Compound 305 was characterized as a rarely isolated 6-propanoyloxy derivative. In contrast to these three samples, sample 2 was observed as being somewhat different, since six furanoeremophilanes and eremophilenolides with no oxygenated

100

M. Tori and C. Kuroda

Plate 10  Photograph of L. wilsoniana

Table 12  Samples 1–4 of L. wilsoniana and their chemical constituents Specimen No. number 1 2013-01 2

2013-10

3

2013-27

4

2013-32

Collection place Nanchuan (C) Chengkou (C)

Chengkou (C) Wuxi (C)

1,10-Epoxy Elevation tricyclic eremophilanes (m) 2100 −

1,10-Epoxy-9-­ one tricyclic eremophilanes 305, 306, 308

Others −

Ref. [163] [163]

[163] [163]

1900

285, 290, 291, 293, 297, 537

−

1700

−

305, 306, 308

786, 792, 828, 876 −

1800

−

306, 308

865

functionality at C-9 were isolated (285, 290, 291, 293, 297, and 537), while the co-­ isolated compounds 305 and 306 have a carbonyl group at C-9. Sample 2 exhibited the occurrence of guaiane (786), eudesmane (792), triterpenoid (828), and monoterpenoid (876) derivatives. This species seems to be relatively uniform in chemical composition and thus is representative of only a very small diversity.

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

101

3.10  Ligularia melanothyrsa Handel-Mazzetti Samples 1 and 2 of L. melanothyrsa were collected, in turn, in Sichuan and Yunnan Provinces, China (Table 13, Plates 11a and 11b). However, the phytochemical studies conducted revealed the constituents of these two samples to be quite different in their composition. Sample 1 produced 11 eremophilanolides (344, 350, 353 (melanothyrsin A), 354 (melanothyrsin E), 359, 367, 368, 370 (melanothyrsin B), 371 (melanothyrsin C), 538 (eremofarfugin C), and 541 (melanothyrsin D)), three rearranged lactones (557, 559 (subspicatolide), and 560 (subspicatolide acetate)), three bicyclic eremophilanes (9, 33, and 39), secobakkane A (151), three

Fig. 28 2-Oxoeremophil-1(10)-en-12,8-olides Table 13  Samples 1 and 2 of L. melanothyrsa and their chemical constituents Specimen No number 1. 2007-51

Collection place Jiulong (S)

2

Shangri-La 4000 (Y)

2008-08

Elevation Bicyclic (m) eremophilanes 3400 9, 33, 39, 131, 132, 136

4

10H Tricyclic eremophilanes 344, 350, 353, 354, 359, 367, 368, 370, 371, 538, 541, 557, 559, 560 198, 199, 200, 211, 212

Others Ref. 151, [44] 629 −

[21]

102 Plate 11a  Photograph of L. melanothyrsa

Plate 11b  A close-up photograph of L. melanothyrsa

M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

Fig. 29 1,10-Epoxyeremophilan-12,8-olides

103

104

Fig. 30 Eremophilane-(12,8)(15,6)-diolides

M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

105

Fig. 31  7,8-Epoxyeremophilan-12,8-olides (1)

norsesquiterpenoids (131 (normelanothyrsin A), 132, and 136), and bakkenolide A (629) [44]. Characteristic features of these compounds are the substitution by an angeloyloxy group at the C-1α position and the occurrence of a hydrogen atom at C-10. The rearranged lactones, 557, 559, and 560, were each derived from a 12,8-lactone through hydrolysis and recyclization to C-6. The phytochemical profile of sample 2 was observed as being completely different from that of sample 1 [21]. Sample 2 produced fukinone (4), 198, 199, 200, 212, and 211, with all of these bearing no substituent at C-1. However, the fact that all these compounds have a hydrogen atom at C-10 was consistent with the constituents determined for sample

106

Fig. 32  7,8-Epoxyeremophilan-12,8-olides (2)

Fig. 33 Eremophil-7-en-12,8-olides

M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

107

Fig. 34  Cacalolide derivatives and other lactones

1. This species is of considerable interest, so additional samples should be analyzed in the future.

3.11  Ligularia lapathifolia (Franchet) Handel-Mazzetti Sample 1 of L. lapathifolia produced two 3β-angeloyloxynoreremophilan-15-oic acids, 116 and 144 (Table 14), with the structure of 144 being determined by X-ray crystallographic analysis [92]. In the case of sample 2, six 10H-3β-­ angeloyloxyeremophilanes (224, 504, 506, 507, 508, and 515) and the 10-OH eremophilanolide 514 were afforded [148]. All these compounds bear a 15,6-lactone moiety. A symmetrical dimer (581) was isolated from sample 3 [213]. Sample 4 from Sichuan Province, China, furnished six 15-oxidized compounds: the nor-­ methyl ester 134, the simple dimethyl ester 79 (as a major constituent), three 15,6-lactones (499, 501, and 502), and the 15-methyl ester 355 [81]. The structure

2000 2003 2003

3 4 5 6

a

Collection year 1999 2000

No. 1 2

Lijian (Y) Muli (S) Muli (S) Muli (S)

Collection place Lijian (Y) Lijiang (Y)

a

3600

a

2500

Elevation (m) 2500 2500 − 79, 134 − −

Bicyclic eremophilanes 116, 144 −

Table 14  Samples 1–6 of L. lapathifolia and their chemical constituents 10H Tricyclic eremophilanes − 224, 504, 506, 507, 508, 515 581 355, 499, 501, 502 498, 505 212, 498 − − − −

10-OH Tricyclic eremophilanes − 514

− − − 828, 844, 845, 851, 866

Others − −

[213] [81] [205] [142]

Ref. [92] [148]

108 M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

109

Fig. 35  Tricyclic lactols

of 499 was determined by X-ray diffraction analysis. From sample 5, the bislactone 498 and the epoxylactone 505 were isolated [205]. Zhang et al. reported the isolation of seven compounds from sample 6 [142]. Two 10H compounds (212 and 498), lupeol (828), friedelin (845), epifriedelanol (844), taraxerol (851), and a monoterpene (866) were isolated. The absolute configuration of compound 866 was studied in detail [294], but, unfortunately, the specific rotation was not described [142]. While lupeol (828) has been isolated frequently among Ligularia species, the occurrence of friedelane-type triterpenoids is quite rare.

3.12  Ligularia macrophylla (Ledebour) de Candolle In 1979, Bohlmann and Grenz studied the chemical constituents of L. macrophylla (sample 1, Table 15) for the first time and isolated four 10H-furanoeremophilanes (167, 168, 200, and 212) and the 10-OH-furanoeremophilane (232), as well as two hydrocarbons (878 and 880) [129]. Sample 2 (from Kashikar, Xinjiang Autonomous Region of China) was shown to accumulate 2-hydroxyplatyphillide (121), a methyl ester (37), neoadenostylone (283), an epoxide (308), ursolic acid (848), and two rather complex compounds, ligumacrophyllatin (80) and ligumacrophyllal (158) [67, 119]. Ligumacrophyllal (158) is a dimeric ether like secovirgaural (134), and

a

2005 2009

a

6 7 8

a

Not described

(Kazakhstan) (Xinjiang)

2005

5

(Xinjiang)

2002 2005

3 4

Kashikar (Xinjiang) a (Xinjiang)

1997

a

Collection place

2

Collection No. year 1 1979

a

a

a

2100

2100

a

418, 419

−

212, 490 489, 491 197, 488

121

− − − 232 391, 415, 419 −

− −

489 186

46, 134 30

− 466 −

288

− 286, 294, 295

1(10)-Ene, 9-ene, and 1,10-epoxy 10-OH tricyclic Elevation Bicyclic 10H Tricyclic Tricyclic (m) eremophilanes eremophilanes eremophilanes eremophilanes a − 167, 168, 200, 232 − 212 a 37, 80, 121 − − −

Table 15  Samples 1–8 of L. macrophylla and their chemical constituents 1(10)-En-9-­ one, and 1,10-epoxy-9-­ one tricyclic Cacalol eremophilanes derivatives Aromatics Others − − − 878, 880 283, 308 − − 158, 848 − − − − − 320, 321, − − 331, 337 − − 913, 1013, 777 1024, 1029, 1030 − − − 632 − − − − − − − −

[143] [193] [134]

[98]

[67, 119] [73] [60]

Ref. [129]

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

Fig. 36  Dimeric eremophilanes (1)

111

112

Fig. 37  Dimeric eremophilanes (2)

M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

113

Fig. 38  Dimeric eremophilanes (3)

ligumacrophyllatin (80) was assigned as a highly oxygenated bicyclic 15,6-olide, which is unusual, and hence its structure should be checked carefully. A norbakkane-type ester (134), a 15,6-lactone with an isopropylidene unit (46), and an ether-type lactone (489) were isolated from sample 3 [73]. The structure of compound 489 was determined by X-ray crystallographic analysis. From sample 4, three 1,10-epoxides were purified, namely, compounds 286, 294, and 295 [60]. Four cacalol derivatives (320, 321, 331, and 337), a 10H-furanoeremophilan-1-one (186), and an aldehyde (30) were also obtained. The structure of 295 was confirmed by X-ray diffraction analysis, and the configurations the epoxide moieties of compounds 286 and 294 were reported to be α, while that of 295 was β. However, any

114

Fig. 39  Dimeric eremophilanes (4)

M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

115

Fig. 40  Di(tri)meric eremophilanes (5)

configuration proposed for an epoxide ring of a sesquiterpenoid always should be checked carefully. From sample 5,2-hydroxyplatyphyllide (121), an epoxide (288), two 1-oxoeremophilenolides (418 and 419), five aromatic compounds (913, 1013, 1024, 1029, and 1030), and a guaiane-type sesquiterpenoid (777, major constituent) were isolated [98]. Sample 6 was collected in Kazakhstan and produced the furanolactone 212, the dilactone 490, the 10-OH-furanoeremophilane 232, and the bakkane-type sesquiterpenoid 632 [143]. Recently, the isolation and characterization of a dilactone (491),

116

M. Tori and C. Kuroda

Fig. 41  Bakkane-type sesquiterpenoids

a 15,6-epoxy lactone (489), and three 10-OH lactones (391, 415, and 419) as well as a 1,10-epoxide (466) were reported [193]. Although the authors indicated compound 391 as possessing a 6α-OH substituent, they cited an incorrect reference, and there is no earlier publication describing this compound, while instead an 8α-H derivative with a 6α-OH functionality has been found [295]. Thus, the structure proposed for compound 391 should be checked carefully. Sample 8 produced

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

Fig. 42  Bisabolane-type squiterpenoids (1)

117

118

M. Tori and C. Kuroda

Fig. 43  Bisabolane-type sesquiterpenoids (2)

methyl 6-oxofuranoeremophilan-15-oate (197) and 15,6α-epoxy lactone 488 [134]. However, the structure of 197 was described erroneously as “a methyl ketone,” and the nomenclature used was also wrong. 6-Oxo compounds are rare and include ligularone (168) and its 1α-acetoxy derivative in Fig. 10.

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

119

Fig. 44  Bisabolane-type sesquiterpenoids (3)

3.13  L  igularia knorringiana Pojarkova (= L. thyrsoidea) and Ligularia narynensis (C. Winkler) O. Fedtschenko & B. Fedtschenko Two reports have been published [88, 235] on the chemical constituents of L. knorringiana (= L. thyrsoidea) [2] (samples 1 and 2 from the Xinjiang Autonomous Region, China, but both seem the same source) (Table 16). Sample 1 afforded three noreremophilanes (99 (knorringianalarin B), 101, and 121 (2-­hydroxyplatyphilide)), 212 (furanoeremophilan-15,6α-olide), the intramolecularly Diels-Alder cyclized compound knorringianalarin A (608), and the aromatic knorringianalarin C (912) [88]. Sample 2 produced eight interesting oplopane sesquiterpenoids (knorringianalarin F (727), 728, 734, 749, knorringianalarin E (750), 751, knorringianalarin D

L. 2009 knorringiana

L. narynensis 2003

L. narynensis 2003

2

3

4

Collection No. Plant source year 1 L. 2009 knorringiana

Collection place (Xinjiang Autonomous Region) (Xinjiang Autonomous Region) (Xinjiang Autonomous Region) (Xinjiang Autonomous Region)

10H Tricyclic eremophilanes 212 − − −

Bicyclic eremophilanes 99, 101, 121 − − −

−

−

−

10-OH Tricyclic eremophilanes 608

Table 16  Samples 1–4 of L. knorringiana and L. narynensis and their chemical constituents

749, 753

727, 728, 734, 749, 750, 751, 754, 757 734, 735, 749, 751, 752, 753

Oplopanes −

1048

−

−

[238, 239]

[235]

Ref. [88]

782, 866, [240, 867, 868, 274] 871

−

−

Aromatics Others 912 −

120 M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

Fig. 45  Bisabolane-type sesquiterpenoids (4)

121

122

Fig. 46  Bisabolane-type sesquiterpenoids (5)

Fig. 47  Bisabolane-type sesquiterpenoids (6)

M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

123

Fig. 48  Bisabolane-type sesquiterpenoids (7)

(754), and 757 (major constituent)) [235]. The structure of 754 was supported by X-ray crystallographic analysis. This compound was already reported as songaricalarin A (754) in 2013 (Sect. 3.15). [237]. The unresolved stereochemistry at C-14 (in this 2013 report, a different numbering was used) was determined unambiguously by X-ray diffraction analysis. Compound 757 was found as a glucoside of compound 728. There have been four reports on the chemical constituents of L. narynensis (samples 3 and 4 were from the Xinjiang Autonomous Region, China; they seem to be from the same source). Six oplopanes (734, 735, 749 (major constituent), 751, 752, and 753) were isolated [238, 239]. The absolute configurations of compounds 734 and 735 were determined from their ECD spectra. Two oplopanes (749 and 753),

124

Fig. 49  Oplopane-type sesquiterpenoids (1)

M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

Fig. 50  Oplopane-type sesquiterpenoids (2)

125

126

M. Tori and C. Kuroda O OH

O

OH

758 ((–)-germacrene D)

759

OH

760

761

O

O

O O

O

OH

O

O

OH

762

O

763

O

OAc

764

O O

O

O

OH

O

O O

O

OH

765

O

OAc

766

O

O

O

767

O

O

O

O

O

O

O

O

O

O

O

O O

768

O

O O

OH

O

O

769

O

O

O

O

O

770

771

Fig. 51  Germacrane-type sesquiterpenoids

four p-menthane derivatives (866, 867, 868, and 871), a guaiane-type sesquiterpenoid (782), and a neolignan (1048) were isolated from sample 4 [240, 274]. The configurations of C-7 and C-8 were determined as threo by 1H NMR spectroscopic coupling constant analysis.

3.14  Ligularia rumicifolia S. W. Liu Several bicyclic eremophilane, oplopane, and bisabolane compounds were isolated from L. rumicifolia (Table 17). Many of these types of compounds were obtained from sample 1 (Lhasa, Tibet Autonomous Region, China) [75]. Thus, ten bicyclic eremophilanes with a 9-en-8-one moiety, namely, petasol (48), rumicifoline K (53), petasin (54), rumicifoline J (57), 1-epi-rumicifoline J (58), 60, 63, rumicifoline L

Collection year 2015

2016

No. 1

2

Lhünzê (Tibet Autonomous Region)

Collection place Lhasa (Tibet Autonomous Region) −

Bicyclic eremophilanes 48, 53, 54, 57, 58, 60, 63, 65, 73, 74, 118, 129

Bisabolanes 655, 659, 660, 662, 665, 667, 668, 674, 706, 714, 715, 716, 717, 718 −

Table 17  Samples 1 and 2 of L. rumicifolia and their chemical constituents Oplopanes 739, 740, 741, 742, 743, 744, 745, 746, 747, 755, 756 −

919, 920, 1025, 1026, 1027, 1028

Aromatics −

891, 892

Others −

[255]

Ref. [75]

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 127

128

M. Tori and C. Kuroda

Fig. 52  Guaiane-, pseudoguiane-, and aromadendrane-type sesquiterpenoids

(65), 73, and 74, and two noreremophilanes, ligudentatol (118) and rumicifoline A (129), were isolated. Alcohols 57 and 58 proved to be epimeric compounds at C-1. Bisabolanes with various esters at different positions, inclusive of rumicifoline P (655), 659, songaricalarin F (660), rumicifoline Q (662), rumicifoline N (665), 667, rumicifoline M (668), rumicifoline O (674), fararone A (706), rumicifoline R (714), 5α-angeloyloxyrumicifoline R (715), 716, tussfararin F (717), and altaicalarin B (718), were purified. This sample also produced the polyoxygenated oplopanes, rumicifoline D (739), rumicifoline E (740), rumicifoline F (741), (4E)-rumicifoline G (742), (4Z)-rumicifoline G (743), (4E)-rumicifoline H (744), (4Z)-rumicifoline H (745), rumicifoline I (746), 747, rumicifoline B (755), and rumicifoline C (756). The structure of rumicifoline B (755) was confirmed by X-ray crystallographic analysis. The absolute configurations at C-4 and C-11 were determined to be (4R) and (11S). A comment should be made on how to draw properly the structures of bisabolanes. Since the bisabolane skeleton has a plane of symmetry, the substituent at C-6 of the cyclohexane ring is recommended to be oriented as β [296].

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

129

Fig. 53  Other sesquiterpenoids

Sample 2 (Lhünzê, Tibet Autonomous Region, China) produced quite different compounds from those of sample 1. A number of flavones (919, 920, 1025, 1026, 1027, and 1028) and two lactones (891 and 892) were isolated [255]. The absolute configurations of compounds 891 and 892 were determined by ECD spectroscopy. However, a NOE between H3-7 and H-10β for the conformation indicated in the literature was difficult to detect due to the large intramolecular distance involved

130

M. Tori and C. Kuroda

Fig. 54 Diterpenoids

[255]. This means that the conformation of the lactone ring must be distorted and so the NMR data obtained should be checked carefully. The differences in the chemical constituents between these two samples were clear, and so the study of additional L. rumicifolia specimens would be advisable.

3.15  Ligularia songarica (Fischer) Y. Ling Four samples of L. songarica were collected in the Xinjiang Autonomous Region, China (Table 18). Sample 1 produced 2-hydroxyplatyphyllide (121), a 10H-lactone (369), two bisabolanes (680 and 698), and a cadinane-type sesquiterpenoid (808) [99]. Seven bisabolanes (666, 681, 700, 701, 702, 703, and 704) were isolated from sample 2 [227]. Sample 3 produced seven oplopane sesquiterpenoids, namely, songaricalarins A (754), B (748), C (738), D (737), E (733), 736 (major constituent), and 734 [237]. The structure of songaricalarin A (754) was determined by X-ray diffraction analysis. Intriguingly, this compound later was reported again using

2008

2010

3

4

a

Not described

1997

2

Collection No. year 1 1997

Elevation Collection place (m) a Urumqi (Xinjiang Autonomous Region)) a Urumqi (Xinjiang Autonomous Region) (Xinjiang Autonomous 550 Region) (Xinjiang Autonomous 1900 Region)

10H Tricyclic eremophilanes 369 − − −

Bicyclic eremophilanes 121 − − −

Table 18  Samples 1–4 of L. songarica and their chemical constituents

647, 651, 654, 660, 680, 690, 698, 700

666, 681, 700, 701, 702, 703, 704 −

Bisabolanes 680, 698

[237]

733, 734, 736, − 737, 738, 748, 754 − −

[224, 232]

[227]

Others Ref. 808 [99] −

−

Oplopanes −

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 131

132

Fig. 55  Triterpenoids (1)

M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

133

Fig. 56  Triterpenoids (2)

X-ray analysis (Sect. 3.13) [235]. Sample 4 produced eight bisabolane sesquiterpenoids (647, 651, 654, songaricalarin F (660), 680, songaricalarin H (690), 698 (major constituent), and songaricalarin G (700)) [224, 232]. Six of these bisabolane sesquiterpenoids proved to be highly oxidized and similar to those isolated from L. lankongensis [228]. Among the four samples investigated, only sample 3 produced oplopanes, and hence its chemical composition was different from the other three samples. As mentioned above, the four samples described were collected in

134

Fig. 57  Triterpenoids (3)

Fig. 58  Triterpenoids (4)

M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

135

Fig. 59 Monoterpenoids

the Xinjiang Autonomous Region, so the investigation of additional samples from this area is necessary to better understand the diversity of L. songarica.

3.16  L  igularia stenocephala (Maximowicz) Matsumura & Koidzumi Bohlmann and his associates studied the French L. stenocephala (sample 1, Table 19) and isolated 2-isopropenyl-5,6-dimethoxybenzofuran (954) and the germacratriene 758 [13]. In another early study, Takahashi’s group studied sample 2 and purified benzofuran 954 [267]. Sample 3 from Henan Province, China, produced three aromatic compounds (913, 915, and 950), two eudesmane-type sesquiterpenoids (795 and 796; major constituent), and three triterpenoids (gummosogenin 6 (837), friedelanol (843), and friedelin (845)) [243]. Kikuchi and Yaoita studied the chemical constituents of sample 4 (Fukushima Japan) and isolated three benzofurans, namely, (−)-hydroxytremetone (940), euparin (952), and 954, along with three dimeric benzofurans, ligulacephalin A (971), ligulacephalin B (972), and ligulacephalin C (970) [264]. The new compounds ligulacephalins A–C (970–972) each

136

M. Tori and C. Kuroda

Table 19  Samples 1–6 of L. stenocephala and their chemical constituents Collection No. year 1 1977

Collection place Besancon (France)

Aromatics 954

Others 758

Ref. [13]

954 913, 915, 950

− 795, 796, 837, 843, 845 −

[267] [243]

− 796

[268] [244]

2 3

a

a

a

(Henan)

4

2001

5 6

2001 2001

Fukushima (Japan) (Henan) (Henan)

Not described

a

Fig. 60  Aliphatic compounds

940, 952, 954, 970, 971, 972 965, 966, 967, 968 914, 952, 954, 957, 969, 973, 974

[264]

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

137

Fig. 61  Other compounds

existed in a racemic form and the authors resolved to determine their absolute configurations using ECD spectra. Sample 5 produced four dimeric benzofurans (965, 966, 967, and 968) [268]. The same group reported the isolation of seven aromatics (914, euparin (952), 954, 957, 969, 973, and 974) and a eudesmane (796) from sample 6 (the same source as sample 5) [244]. It is quite interesting to observe that compound 969 is dimeric, 973 trimeric, and 974 tetrameric.

3.17  Ligularia alticola Voroschilov Four scientific reports were published on the chemical constituents of L. alticola collected in Russia (Table 20). From sample 1 (roots), furanoeremophilan-15,6α-­ olide (major constituent) (212), a lactone (218), a 15-oic acid (199), and lupeol (828) were obtained [135]. The polar fraction of sample 2 (leaves) was investigated, and the glucosides 81, 82, 83, 84, 85, 86, 87, 874, and 899 of eremophilanes and other compounds were isolated [82]. A further study of sample 3 (leaves) resulted

Collection year 2011, 2012

2012

2012

2012

No. 1

2

3

4

Primorsky (Russia)

Collection place Primorsky (Russia) Primorsky (Russia) Primorsky (Russia)

1684

1684

1684

Elevation (m) 1684

−

342, 358

−

88, 89

874, 899

Others 828

846, 853, 854, 856, 857, 858, 859 1022, 1023, 1045 −

−

−

Aromatics −

81, 82, 83, 84, 85, 86, 87 5, 20, 23, 339, 341

10H Tricyclic Bicyclic eremophilanes eremophilanes − 199, 212, 218

Table 20  Samples 1–4 of L. alticola and their chemical constituents

[84]

[41]

[82]

Ref. [135]

138 M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

139

Fig. 62  Aromatic compounds (1)

in the purification of the eremophilanes dehydrofukinone (5), 20, 23, 340, 341, 342, and 358 and the triterpenoids 846, 853, 854, 856, 857, 858, and 859 [41]. The structure of 23 was identified by comparison with a synthetic compound reported prior to our research [297]. The configuration of an epoxide is sometimes not easy to elucidate due to its nearly planar local shape, so chemical synthesis helped to determine the structure. There is another similar example given by compound 22 (Sect. 3.24). Five compounds (88, 89, 1022, 1023, and 1045) were isolated from sample 4 (aerial parts) [84]. It is interesting to note that both plucheoside D1 (1022) [CD: [θ] –6600°cm2  mol−1 (287  nm)] and tortoside F (1023) [CD: [θ] +7700°cm2  mol−1 (284 nm)] were isolated, since their aglycones are enantiomers of one another.

140

M. Tori and C. Kuroda

Fig. 63  Aromatic compounds (2)

3.18  Ligularia brassicoides Handel-Mazzetti Ligularia brassicoides is close morphologically and taxonomically to L. virgaurea, and a main difference between these species is related to the conspicuous/obscure reticulate veins in the leaves (Plates 12a and 12b) [2]. From sample 1, the bakkane 637 was isolated, and from sample 2, four furanoeremophilanes (184, 255, 256, and 284), a lactone (529), a bakkane (637), the seco-eremophilane secovirgaurenol D (155), and a phenol (1006) were obtained (Table 21) [117]. Sample 3 was assigned

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

141

Plate 12a  Photograph of L. brassicoides

Plate 12b  A close-up photograph of L. brassicoides

as L. brassicoides, but because its morphology is also similar to L. liatroides (C.  Winkler) Handel-Mazzetti, the species remains unidentified at present [46]. Sample 3 produced eremoligenol (14), an ethyl ester (40), two 10H-furanoeremophilanes (160 and 163), three 10-OH-furanoeremophilanes (226, 227, and 228), four eremophilanolides (356, 359, 389, and 553), three lactols (563, 564, and 565), two eudesmanes (789 and 790) the hetero-Diels-Alder-type dimer 594, the homo dimer 579, bakkenolide A (629), and lupeol (828) [47]. Compound 594 was formed from tetradymol (215) (not isolated from sample 3) and methacrylic acid by a Diels-Alder reaction, and compound 579 characterized as a homo

3

2011-57

Specimen No. number 1 2007-17 2 2007-40

Collection place Muli (S) Jiulong (S) Dege (S)

4200

Elevation (m) 3700 3700

10H Tricyclic eremophilanes – 184 160, 163, 356, 359

Bicyclic eremophilanes – –

14, 40

Table 21  Samples 1–3 of L. brassicoides and their chemical constituents

226, 227, 228, 389, 563, 564, 565, 594

579

1(10)-Ene, 9-ene, and 10-OH Tricyclic 1,10-epoxy eremophilanes eremophilanes – – – 255, 256, 529

1(10)-En-9-one tricyclic eremophilanes Bakkanes Others – 637 – 284 637 155, 1006 – 629 553, 789, 790, 828

[46, 47]

Ref. [117] [117]

142 M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

143

Fig. 64  Aromatic compounds (3)

dimer linked through C-8 of two furano-eremophila-7(11),9-diene units. Compounds 563, 564, and 565 seem to be artifacts.

3.19  Ligularia caloxantha (Diels) Handel-Mazzetti Sample 1 of L. caloxantha (Yunnan Province) produced euparin (952) (a major constituent), five aromatic compounds (906, 907, 944, 953, and 957), and 8β-hydroxyeremophilenolide (356) as well as lupeol (828) (Table 22) [181]. The isolation of the tricyclic sesquiterpene acid 814 was reported from the same source

M. Tori and C. Kuroda

144 Table 22  Samples 1–3 of L. caloxantha and their chemical constituents Collection No. year 1 2000

Collection place Lijiang (Y)

10H Tricyclic eremophilanes 356

2 3

Lijiang (Y) Lijiang (Y)

− −

2002 2002

Fig. 65  Aromatic compounds (4)

Aromatics 906, 907, 944, 952, 953, 957 − 924, 952, 955, 957, 961

Others 828

Ref. [181]

814 828, 836

[245] [247]

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

145

(sample 2) [245]. The structure of 814 ([α]D –36.5°cm2g−1) was determined by X-ray crystallographic analysis, but the Flack parameter was nearly 0.5 and thus the absolute configuration could not be determined. The isolation of an isocomene-type like compound 814 from a member of the genus Ligularia is quite rare [298]. Five aromatic compounds, 924, euparin (952), 955, 957, and 961, as well as lupeol (828) and the oleanane triterpenoid 836 were obtained from sample 3 [247].

3.20  Ligularia przewalskii (Maximowicz) Diels A recent review of L. przewalskii appeared in 2018, discussing its chemistry and biological activities in detail [299]. Seven samples of L. przewalskii have been analyzed so far (Plate 13, Table 23). Bohlmann et al. reported that the chemical constituents of sample 1 collected from a botanical garden in Berlin, Germany, were a furanoeremophilan-15,6α-olide (212) and benzofuran 954 [13]. Sample 2 (Qinghai Province, China) produced two eremophilan-15-oic acids (372 and 373), seven 15,6-olides (212, 490, 491, 493, 509, 511, and 513), six flavonoids (1025, 1026, 1027, 1028, 1033, and 1036), five aromatics (919, 941, 952, 954, and 957), and a triterpenoid (842) [144]. It is interesting to note that compound 513, a rare type of eremophilan-12,8-olide with an 8β,9β-epoxide substituent, was obtained as the major component. Compounds 372 and 373 are diastereoisomers at C-4 and

Plate 13  Photograph of L. przewalskii

2010-76 (2012)

a

a

2002

3 4

5

6

7

a

Not described

(2010)

2

Specimen number No. (year) 1 (1977)

Qingyang (G)

Hefei (Anhui) Zhang (G)

Lintan (G) Huzhu (Q)

Collection place Berlin (Germany) Beishan National Forest Park (Q) − − −

522, 544, 545 − − 372, 490, 491, 493, 509 372, 490, 491, 493, 509

− − 34, 67, 69, 70, 110, 124 43, 119, 121, 134 −

a

a

a

2900 2100– 2500

902, 941, 951, 952, 957, 1011 952, 954, 957, 960, 964

− −

511, 513 −

919, 941, 952, 954, 957, 1025, 1026, 1027, 1028, 1033, 1036 − − −

− −

−

Aromatics 954

449

511, 513

212, 372, 373, 490, 491, 493, 509

−

a

10H Tricyclic eremophilanes 212

1(10)-Ene, 9-ene, and 1,10-epoxy 10-OH Tricyclic tricyclic eremophilanes eremophilanes − −

Elevation Bicyclic (m) eremophilanes a −

Table 23  Samples 1–7 of L. przewalskii and their chemical constituents

−

−

− 861, 862 −

842

[70, 265] [189]

[64]

[145] [252]

[144]

Others Ref. − [13]

146 M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

147

Fig. 66  Aromatic compounds (5)

C-6. The 4α-substituted carboxy group present in compound 373 is of considerable interest. Our research team has made a preliminary communication on the isolation of three lactones (522, 544, and 545) from sample 3 (from Gansu Province) [145]. Eremopetasitenin B4 (522) and eremofarfugins F (545) and G (544) were assigned as epoxy- and enol-lactones, respectively. In 1997, Chen et al. reported compound 522 from L. intermedia, and this was assigned as having a 7α,8α-epoxide functionality [140]. However, we have revised the structure of this compound unambiguously as a 7β,8β-epoxide using NOE experiments and by X-ray diffraction analysis [145]. The stereochemistry of both epoxide at C-7/C-8 and the methyl group at C-11 may be difficult to determine in the structure determination of this type of sesquiterpenoid. A decisive NOE effect cannot always be observed, and thus the relative configurations of some compounds have been left undetermined [300]. We proposed plausible biosynthesis pathways, which supported the above results. At the same time, the configuration at C-11 of both compounds 544 and 545 was determined [145]. Two triterpenoid glycosides (861 and 862) were isolated from sample 4 (Qinghai Province, China) [252]. No terpenoids were found in sample 4. Sample 5 (Anhui Province, China) produced six bicyclic compounds (41, 67, 69, 70, 110, and 124), and an eremophilatrienolide (449; major constituent) [64]. Sample 6 (Gansu Province, China) produced four bicyclic compounds (43, 119, 121, and 134), seven eremophilanolides (372, 490, 491, 493, 509, 511, and 513), and six aromatic derivatives (902, 941, 951, 952, 957, and 1011) [70, 265]. Five eremophilanolides (372, 490, 491, 493, and 509) and five aromatics (952, 954, 957, 960, and 964) were isolated from sample 7 (Gansu Province) [189].

148

Fig. 67  Aromatic compounds (6)

M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

Fig. 68  Aromatic compounds (7)

149

150

M. Tori and C. Kuroda

Fig. 69  Aromatic compounds (8)

3.21  L  igularia sagitta (Maximowicz) Mattfeld ex Rehder & Kobuski Chemical studies on L. sagitta have long been carried out (Plate 14). In 1992, the first report on this plant (Gansu Province, China) documented the isolation of liguhodgsonal (125) (major constituent), bakkenolide A (629), a cacalol-type compound (315), and the hetero-Diels-Alder-type dimeric compound 595 (sample 1, Table 24) [105]. The structure of 595 was determined by X-ray structural analysis [217]. This compound exhibits a complex structure derived from a 7,9-diene moiety and 2-hydroxymethylpropenoic acid through a Diels-Alder reaction followed by lactonization (Fig. 73). The previously assigned structure of 315 with a double bond at C-2/C-3 was revised with this being present instead at C-1/C-2 by X-ray crystallographic analysis, as depicted in Fig. 20 [301]. From sample 2 (Gansu Province), compound 595 and seven bicyclic eremophilanes (31, 32, 54 (petasin), 56 (isopetasin), 101, 102, and 107) were isolated [62]. Compound 32 is an enol acetate of compound 31, and, as such, is quite rare as a natural product. Compound 44 was afforded from sample 3 [71] and compounds 38 and 44 from sample 4 (Gansu Province) [68]. Compound 38 corresponds to the ring opened and acetylated derivative of compound 44. Sample 5 (Gansu Province) produced two 8-methoxy eremophilanolides, farformolide B (397) and 404 [195]. From sample 6 (Gansu Province), six tricyclic eremophilanolides (395, 397 (farformolide B), 402, 403, 404, and 405), the two triterpenoids 828 (lupeol) and 848 (ursolic acid), and a monoterpenoid (866) were isolated [194]. Compounds 402 and 403 are

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… Plate 14  Photograph of L. sagitta

Fig. 70  Aromatic compounds (9)

151

Zhang (G) (G) Hezuo (G)

a

(1999)

(2002)

(2002)

(2003)

(2005)

a

(2005)

(2010)

a

7

8

9

10

11 12

13

14

Not described

a

a

Zhang (G)

Gannan (G) Gannan (G)

Gannan (G)

Mengyuan (Q) Mengyuan (Q) Datong (Q)

a

a

a

3 4 5 6

a

a

Zhang (G)

(1989)

2

a

a

2000– 3800

a

2300– 2400 2000– 3800

a

a

a

a

a

a

Elevation (m)

Collection place Zhang (G)

Specimen No. number (year) 1 (1988)

− −

− −

30, 95, 101, 106, 108 −

398, 467, 473, 480, 481, 598, 599 609, 610, 623, 624

− −

− −

−

−

597, 600

625, 626 − 596, 601, 602, 603 29, 95, 96, 105, 109 240, 416

629

315

333

−

−

486

125

−

− − − − −

− − − −

− − 397, 404 395, 397, 402, 403, 404, 405 484, 485, 486, 487

−

−

−

− −

923, 926, 930, 1008 −

918

−

− − − −

−

Bakkanes Aromatics 629 −

−

−

−

31, 32, 54, 56, 101, 102, 107 44 38, 44 − − −

Cacalol derivatives 315

Tricyclic eremophilanes −

Bicyclic eremophilanes 125

Table 24  Samples 1–14 of L. sagitta and their chemical constituents

−

−

− 839

627

828

−

− − − 828, 848, 866 −

595

Others 595

[222]

[61]

[218] [59]

[221]

[167]

[106]

[203]

[71] [68] [195] [194]

Ref. [105, 217] [62]

152 M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

Fig. 71  Aromatic compounds (10)

153

154

Fig. 72  Aromatic compounds (11)

M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

155

Fig. 73  Formation of compound 595

epimeric at C-8. Four tricyclic eremophilanolides (484, 485, 486, and 487) were isolated from sample 7 collected in Qinghai Province [203]. All these isolated compounds had 1β,10β-epoxide and 3β-tigloyloxy substituents. Sample 8 seems to have been produced from the same extracts as sample 7, and liguhodgsonal (125), 486 (analyzed by X-ray structural analysis), and 918 were isolated [106]. Sample 9 was collected in Qinghai Province and produced bakkenolide A (629), 315, 333, lupeol (828), and 1008, as well as three acids (923, 926, and 930) [167]. Compound 333 has an interesting structure, with a dihydrofuran moiety rearranged to C-6. Sample 10 (Gansu Province) produced five dimeric compounds, ligulasagitins A–E (625, 597, 600, 626, and 627) [221]. Ligulasagitins B (597) and C (600) exhibited structures arising from an intramolecular Diels-Alder reaction with 2-­hydroxymethylpropenoic acid. The structure of 597 was established by X-ray analysis. The relative configurations of the three dimers 625, 626, and 627 at C-11 and C-12 were determined as cis (H3-13/H-12), but the absolute configurations were not ascertained. Four Diels-Alder-type dimers (596, 601, 602, and 603) were isolated from sample 11 collected in Gansu Province [218]. The structure of 601 was established by X-ray crystallographic analysis of its acetate. Sample 12 (Gansu Province) produced four noreremophilanes (95, 96, 105, and 109), a bicyclic diol (29), a 10-OH furan (240), a 10-OH lactone (416), and a triterpenoid (839) [59]. Sample 13 from Gansu Province produced two Diels-Alder-type derivatives, sagittacins A and B (598 and 599), five eremophilanolides (398, 467, 473, sagittacin D (480), and sagittacin C (481)), and six bicyclic eremophilanes (30 (both isomers), 95, 101, 106, and 108) [61]. The structure of sagittacin A (598) was established by X-ray diffraction analysis. However, there is some doubt about the stereochemistry of sagittacin D (480), as published by Chen et  al. in 2014 [61]. The configuration at C-8 was assigned originally as C-8β-OH, but our analysis of the NOESY data presented has indicated that C-8 should be α-OH, or otherwise the NOE data cannot be explained. We have concluded that the structure of compound 480 should be revised as having an 8α-hydroxy group, as depicted in Fig.  29. The ECD spectrum of sagittacin C (481) was calculated in order to establish its absolute configuration, as depicted in the formula. Recently, Li et al. isolated two dimers (ligusaginoids A and B; 609 and 610) and two trimers (ligusaginoids C and D; 623 and 624) (sample 14) [222]. The structure of ligusaginoid A (609) was supported by X-ray structural analysis. The measurement of ECD spectra was used for the determination of the absolute configurations of four dimeric and trimeric compounds. From L. sagitta, many 1β,10β-­ epoxy tricyclic eremophilanes (having oxidation at C-1) and those bearing 6β-(2-hydroxymethyl)propenoyloxy substituents have been isolated. The

156

M. Tori and C. Kuroda

characteristic features of this species are the presence of Diels-Alder-type reaction products, particularly those involving 2-hydroxymethylpropenoic acid.

3.22  Ligularia pleurocaulis (Franchet) Handel-Mazzetti Sample 1 of L. pleurocaulis (obtained from Sichuan Province, China) produced 6β-­ angeloyloxyfuranoligularenone (269), a highly conjugated enolide (465), lupeol (828), oleanolic acid (833), and three aromatic compounds (911, 917, and 1009) (Plate 15, Table  25) [33]. Chemical studies of samples 2–4 revealed that 6β-­ angeloyloxyfuranoeremophil-­1(10)-en-3β-ol (259) was the major constituent in each case [156]. As a group, these three samples produced also the furanoeremophil-­1(10)-enes 257, 258, 260, and 266 and furanoligularenone (268). From sample 3 (from Sichuan Province), furanoligularenone (268) was isolated, but this compound was not detected in samples 2 and 4, collected in Yunnan Province. Therefore, the presence of two chemotypes, a Yunnan type and a Sichuan type, has been proposed [156]. Sample 5 produced a noreremophilane (139), a bicyclic eremophilane (16), three furanoeremophilanes (259, 260, and 261), five eremophilanolides (450, 451, 453 (the major constituent), 418, and 440), an aromatic ether of eremophilanolide (573), a dimer (584), and a eudesmane (805) [53]. The structures of compounds 573 and 584 were determined by X-ray crystallographic analysis. Sample 6 from Sichuan Province produced the bicyclic eremophilane carboxylic acid 66, an 8β-hydroxyeremophilanolide (356), the 8β-ethoxy dilactone 494, the 7α,8α-­ epoxylactone 523, and furanoligularenone (268) and its lactone derivatives 450, 451, and 452 [79]. This sample belongs to the Sichuan chemotype, according to Ref. [156]. However, furanoligularenone (268) was not isolated from sample 5, also

Plate 15  Photograph of L. pleurocaulis

2003-53

2004-44

(2010)

a

3

4

5

6

a

Not described

2003-17

2

Specimen number No. (year) 1 (2001)

Collection place Kangding (S) Shangri-La (Y) Xiangcheng (S) Shangri-La (Y) Kangding (S) Kangding (S)

a

3600

4000

3800

3500

− 418

− − 356, 494, 523

− 16, 139 66

−

−

−

−

−

10-OH Tricyclic eremophilanes −

−

10H Tricyclic eremophilanes −

−

Elevation Bicyclic (m) eremophilanes a −

Table 25  Samples 1–6 of L. pleurocaulis and their chemical constituents

259, 260, 261, 440, 450, 451, 453, 573, 584 268, 450, 451, 452

257, 258, 259, 260, 266

257, 258, 259, 260, 268

257, 258, 259, 260, 266

1(10)-Ene, 9-ene, and 1,10-epoxy, and 1-en-3-one tricyclic eremophilanes 269, 465

−

−

805

−

− −

−

−

[79]

[53]

[156]

[156]

Others Ref. 828, [159] 833 − [156]

Aromatics 911, 917, 1009 −

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 157

158

M. Tori and C. Kuroda

collected in Sichuan Province. From these observations, the chemical diversity of L. pleurocaulis should be carefully assessed in the future.

3.23  L  igularia fischeri (Ledebour) Turczaninow, Ligularia anoleuca Handel-Mazzetti, and Ligularia veitchiana (Hemsley) Greenman Ligularia fischeri, L. anoleuca, and L. veitchiana are close taxonomically to one another (Plate 16). These species have been documented as differing both in terms of the shape of their bracts and concerning the presence or absence of petioles in the basal leaves [2]. L. fischeri is distributed widely in China, Far Eastern Russia, Korea, and Japan. We have analyzed seven L. fischeri, six L. anoleuca, and three L. veitchiana samples. Ligularia fischeri is one of the most highly investigated Ligularia species (Table 26). In 1965, the furanoeremophilane 160, ligularol (161), ligularone (168), and the related eremophilanes, 14 and 344, were isolated by Minato’s group (sample 11) [11, 50]. Guaianes 773, 774, and 775 also were obtained [122]. In 1975, the 1β,10β-epoxy furanoeremophilanes 285 and 291 were purified by Takahashi’s group (sample 1) [161, 162]. Following these pioneering studies, various eremophilanes and other compounds have been isolated from samples of Chinese origin. Ligularia fischeri samples in the Hengduan Mountains area of China can be grouped into two chemotypes, a benzofuran-producing type and a furanoeremophilane-­producing type. From two benzofuran-type samples (samples 6 and 7), euparin (952) and its dimethoxy derivative 954 were isolated as the major components together with their derivatives 910 and 946 [37]. The furanoeremo­ philane-­ producing samples further were sub-grouped to a ligularol type (furanoeremophilan-6β-ol type) and a furanoeremophil-1(10)-ene type. From the

Plate 16  Photograph of L. anoleuca

2011-10

2012-35

2012-36 2013-07

2013-26

2013-30

2013-33

4

5

6 7

8

9

10 11

(1994)

(1994)

12

13

a

(2008)

3

Shennongjia (Hubei)

Shennongjia (Hubei)

a

Leibo (S) Chengkou (C) Chengkou (C) Chengkou (C) Wuxi (C)

Leibo (S)

Nanchuan (C) Baoxing (S)

Specimen number Collection place No. (year) a 1 Ishikawa (Japan) 2 (2008) Tonghua (Jilin)

a

a

a

2000

1800

2200

2500 1400

2300

3300

a

a

17, 27

−

4 14

− 163, 168 160, 161, 168, 344 344, 346, 356, 359, 361, 363, 364, 365, 556 −

− − −

− − − − −

225 − − −

160, 161, 163, 168 163

− 225

−

−

910, 952, 954 946, 952, 954

−

−

− −

− −

−

−

−

−

−

−

−

−

787, 795, 798, 799

629 773, 774, 775 −

−

−

− −

−

−

644, 645

837

− −

Others −

Aromatics −

− −

241, 242

−

119, 120, 122, 135, 137, 138 −

268, 447, 450, 451, 452, 554, 575, 576, 577, 578, 579, 580 306

1(10)-Ene, 9-ene, 1-ene, and 1,10-epoxy tricyclic eremophilanes 285, 291

250, 254, 256, 257, 291, 330 287, 289, 290, 291, 293, 330 − −

412, 413

10-OH Tricyclic eremophilanes −

−

10H Tricyclic eremophilanes −

−

Elevation Bicyclic (m) eremophilanes a −

Table 26  Samples 1–22 of L. fischeri and their chemical constituents

(continued)

[54]

[37] [11, 50, 122] [179]

[37]

[37]

[37] [37]

[37]

Ref. [161, 162] [158, 210– 212] [96, 165] [155]

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 159

a

(1999)

(2007)

(2008)

(2009)

(2013)

17

18

19

20

21

22

a

Not described

a

16

Baoji (Shanxi)

Kangwondo (South Korea) Kangwondo (South Korea) Kangwondo (South Korea) Nanchuan (C) Taihang (Henan) Hu (Shaanxi)

Specimen number Collection place No. (year) 14 a Shennongjia (Hubei) a 15 a

Table 26 (continued)

a

a

a

a

a

a

a

a

− −

− 366 −

−

−

94, 119, 121

−

−

−

435, 447

389, 393

−

−

−

−

−

268, 451, 452

−

−

1(10)-Ene, 9-ene, 1-ene, and 1,10-epoxy tricyclic eremophilanes −

2, 5, 48, 50, 54, − 56, 60 26, 120 344, 345, 346, 356, 359, 360, 361, 556

−

366

−

421, 422, 431, 432 −

10-OH Tricyclic eremophilanes −

−

10H Tricyclic eremophilanes 361, 365

140

Elevation Bicyclic (m) eremophilanes a −

901, 916, 1010, 1019, 1020, 1021, 1027, 1033, 1034, 1045 −

−

951

−

−

−

−

Aromatics −

[246]

[58, 257]

629

815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827

[30]

[85]

[187]

[157]

[188]

[110]

Ref. [185]

−

−

792, 885, 887, 888

−

792

−

Others −

160 M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

161

ligularol-type of samples (samples 8–10), fukinone (4), 160, ligularol (161), 163, ligularone (168), 225, and bakkenolide A (629) were isolated [37]. From the furanoeremophil-­1(10)-ene-type of samples (samples 4 and 5), both 1(10)-enes (250, 254, 256, and 257) and 1,10-epoxides (287, 289, 290, 291, 293, and 330) were apparent [37, 155]. Compounds 163 and 330 were deemed as artifacts, as produced during extraction with EtOH. Additional eremophilanes and other compounds have been isolated from L. fischeri samples collected at different locations. From sample 2 (obtained in Jilin Province, China), furanoligularenone (268), and compounds 412, 413, 447, 450, 451, 452, and 554, fischerisins A (575) and B (576), fischelactone B (577), fischelactone (578), and compounds 579 and 580 were isolated, together with the triterpenoid 837 [158, 210– 212]. Compounds 577, 578, 579, and 580 were characterized as dimeric lactones. From samples 12–14 (from Hubei Province, China), eremophilanes 17, 27, 344, 346, 356, 359, 361, 363, 364, 365, and 556 were produced [54, 179, 185]. An aromadendrane (787) and three eudesmanes (795, 798, and 799) were also obtained from the same sample [54]. The eremophilane composition of samples 3 and 19 from Chongqing City, China, proved to be somewhat different from those of the other specimens examined. From samples 3 and 19, the noreremophilanes 94, 119, 120, 121, 122, 135, 137, and 138 and the highly functionalized furanoeremophilanes 241, 242, and 306 occurred [85, 96, 165]. Compounds 241 and 242 were assigned structurally as chlorinated furanoeremophilanes (sample 3) [188]. Two bakkane compounds, 644 and 645 [165], and an aromatic compound, 951 [85], were also obtained. Only the eremophilan-8-one derivatives 2, 5, 48, 50, 54, 56, and 60 were obtained from sample 20 (from Henan Province, China) [30], while eremophilanolides 421, 422, 431, and 432 and the noreremophilane 140 were obtained from a commercial Chinese medicine (sample 15) [110]. From sample 21 (Shaanxi Province, China), the eremophilanolides 344, 345, 346, 356, 359, 360, 361, 389, 393, 435, 447, and 556 were isolated together with compounds 26 and 120 and bakkenolide A (629) [58]. From the same sample, the aromatic derivatives 901, 916, 1010, 1019, 1020, 1021, 1027, 1033, 1034, and 1045 were also purified [257]. Sample 22 from Shanxi Province, China, produced only diterpenoids [246], comprising fischericins A (815), B (816), C (817), D (818), E (819), and F (820), as well as other ent-kaurane-type diterpenoids (821, 822, 823, 824, 825, and 826) and a labdane-type diterpenoid (827). Interestingly, no sesquiterpenoids at all were detected in this sample. Secondary metabolites in Korean samples were also studied (samples 16–18). From these, eremophilanolides (366, 451, and 452), a furanoligularenone (268), a eudesmane (792), and linear hydrocarbons (885, 887, and 888) were isolated [157, 187, 188]. These studies indicate that the widely distributed L. fischeri produces eremophilanes as the major components but is highly diverse in its chemical composition. The chemical composition of L. anoleuca has been reported by only our group and was found to be close to the furanoeremophil-1(10)-ene type of L. fischeri. From six samples of L. anoleuca, furanoeremophil-1(10)-enes 249, 256, 262, 263, 264, 265, 266, 267, and 271 and 1,10-epoxyfuranoeremophilanes 291, 295, 298, 299, 300, and 302 were isolated. Furanoligularenone (268), a related 1-en-3-one, was also obtained (Table 27) [154, 155].

162

M. Tori and C. Kuroda

Table 27  Samples 1–6 of L. anoleuca and their chemical constituents 1(10)-Ene, 9-ene, and 1,10-epoxy Specimen Collection Elevation tricyclic eremophilanes No. number place (m) 1 2009-01 Dali (Y) 3200 249, 256, 291 2 2009-107 Xiaojin 3500 256, 291 (S) 3 2010-04 Li (S) 3200 262, 263, 265, 267 298, 299, 300, 4 2010-58 Songpan 4300 302 (S) 264, 266, 298, 5 2010-80 Wen 2100 299, 302 (Gansu) 295, 299, 300, 6 2010-84 Jiuzhaigou 2300 302 (S)

1(10)-En-2-­ one, and 1(10)-en-2-ol tricyclic eremophilanes − −

1-En-3-one tricyclic eremophilanes Ref. − [154] − [154]

271

268

[155]

−

−

[155]

−

−

[155]

−

−

[155]

The root constituents of three L. veitchiana samples (samples 13–15) were similar to those of the benzofuran-type of L. fischeri (Table  28). Accordingly, from these, the benzofuran derivatives 945, 952, and 954 were afforded [154]. Although only benzofuran derivatives could be obtained from these samples, eremophilane sesquiterpenoids were purified from various samples. The eremophilane derivatives isolated from L. veitchiana collected in northwestern China (samples 2–5, 8, 9) were mostly of the 1(10)-ene or 1,10-epoxy types: i.e., 472 and 474 [107]; 333, 466, 468, 473, 475, 482, and 483 [175]; 454 [74]; 476 [66]; and 333 and 466 [174, 253]. Other eremophilanes from these samples were liguhodgsonal (125) [107], 101 and 107 [62], 47 and 424 [74], and 36, 108, 119, and 121 [66]. The structure of compound 47 is interesting, since it has an ether bond between C-4 and C-7, which is the only such example among the eremophilane sesquiterpenoids. Aromatic compounds (928, 930, and 952) and triterpenoids (828, 831, 845, 855, and 863) also were obtained [66, 174]. The chemical profiles of samples collected from other parts of China were somewhat different in their makeup. From a Hubei sample (sample 6), eremophilanes 125, 306, and 308, an oplopane (726), guaianes (773, 774, 775, and 776), an aromadendrane (786), and a eudesmane (797) were isolated [108, 166]. Three glucosides (975, 976, and 864) were reported constituents (sample 12) [254]. From a Henan sample (sample 7), eremophilanes 15, 16, and 345 were obtained [52], while an eremophilanolide (425) was isolated from a Shaanxi sample (sample 16) [200]. Eremophilanes with an interesting 19-carbon skeleton (i.e., 596, 604, 605, 606, and 607) have been reported (sample 10) [219, 220]. These compounds are Diels-Alder adducts of furanoeremophilanes. A number of benzofurans, namely, 907, 913, 938, 939, 940, 943, 945, 952, 953, 954, 955, 956, 957, 958, 963, and 1011, were isolated from another Hubei sample (sample 11) [259]. Benzofurans 940, 952, and 954 and an enyne (884) were obtained from a European sample 1 [13]. These data suggest that the chemical composition of L. veitchiana is highly diverse.

a

a

10

a

a

a

a

a

(1989) (1989)

9

7 8

5 6

2 3 4

Specimen number No. (year) 1 (1977)

a

(Henan) Northwestern China Northwestern China

Zhang (G) Shennongjia (Hubei)

Collection place Munchen (Germany) Zhang (G) Zhang (G) NW China

a

a

a

a

a

a

a

a

a

− 476

424 −

− − −

− −

345 − − −

47 125

15, 16 36, 108, 119, 121 − −

596, 604, 605, 606, 607

333, 466, 468, 473, 475, 482, 483 454 306, 308

− − −

− − −

125 101, 107 −

−

333, 466

472, 474

1(10)-ene, 9-ene, 10-OH Tricyclic 1,10-epoxy type eremophilanes eremophilanes − −

Elevation Bicyclic (m) eremophilanes a −

10H Tricyclic eremophilanes −

Table 28  Samples 1–16 of L. veitchiana and their chemical constituents

−

928, 930

− 952

− −

− − −

Aromatics 940, 952, 954

[52] [66]

[74] [108, 166]

[107] [62] [175]

Ref. [13]

(continued)

828, 831, [174, 845, 855, 253] 863 − [219, 220]

− 726, 773, 774, 775, 776, 786, 797 − −

− − −

Others 884

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 163

2008-48, 2005-09 2008-50 2008-60 (2016)

13

a

Not described

14 15 16

(2004)

12

Specimen number No. (year) 11 a

Jianchuan (Y) 3300 Jianchuan (Y) 2400 a Ankang (Shaanxi)

Shennongjia a (Hubei) Jianchuan (Y) 2300

− − − − −

− − − −

10H Tricyclic eremophilanes −

−

Collection Elevation Bicyclic place (m) eremophilanes Enshi (Hubei) a −

Table 28 (continued)

− − 425

−

−

− − −

−

−

1(10)-ene, 9-ene, 10-OH Tricyclic 1,10-epoxy type eremophilanes eremophilanes − −

945, 952, 954 945, 952, 954 −

952, 954

Aromatics 907, 913, 938, 939, 940, 943, 945, 952, 953, 954, 955, 956, 957, 958, 963, 1011 975, 976

[254] [154] [154] [154] [200]

− − − −

Ref. [259]

864

Others −

164 M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

165

Our past research has suggested that the three species in the Hengduan Mountains area form a complex in which at least two chemical lineages, a benzofuran type and a furanoeremophilane type, are represented [37]. However, analysis of the literature indicates that the chemical diversity of this complex in eastern Asia is much higher than our own observations have shown.

3.24  Ligularia cyathiceps Handel-Mazzetti According to our data from the field, L. cyathiceps is distributed only within a limited area, near Shangri-La City, Yunnan Province, China (Plate 17). We analyzed seventeen samples (Table 29) and found that the species is almost uniform both in terms of its chemical composition and ITS sequences [17]. The major components found were the 1,10-epoxyfuranoeremophilan-9-ones 304, 305, 306, and 308. Related furanoeremophilan-9-ones (183, 280, and 283) and 1,10-­epoxyfuranoeremophilanes (288, 289, and 293) were also isolated, together with cacalol (316) and its derivatives 319, 322, and 323. Compound 330, a furanoeremophilane artifact, also was obtained. Other minor components, inclusive of eremophilanes (1, 13, and 536), a eudesmane (793), and phenylpropanoids (923 and 979), were also isolated [17, 38].

Plate 17  Photograph of L. cyathiceps

2004-53

2006-51

2006-71

2006-75

2008-07

2008-27

2008-36

2008-40

2011-119

4

5

6

7

8

9

10

11

12

3

2004-33, 2006-74 2004-37

2

Specimen No. number 1 2004-27

Collection place Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y)

3900

3500

3900

3700

4000

3400

3400

3400

3600

3700

3300

Elevation (m) 3500

289

− − − − − − − − 183 183

1

−

−

−

−

−

−

−

−

−

330

288, 289, 293

289

536

288, 289, 293, 536

289

289

289

289, 330

−

−

1(10)-Ene, 9-ene, and 1,10-epoxy tricyclic eremophilanes −

10H Tricyclic eremophilanes −

Bicyclic eremophilanes 13

Table 29  Samples 1–12 of L. cyathiceps and their chemical constituents Cacalol deriv. 316

280, 283, 304, 306, 308 316, 793 322, 323 280, 306 316, 319 979

280, 283, 306, 308, 310 316, − 322, 323 280, 283, 306, 308 316, − 322, 323 306, 308 316 −

[38]

[17]

[17]

[17]

[17]

[17]

−

[17]

[17]

[17]

[17]

[17]

−

923, 979 −

Others Ref. − [17]

316, − 322, 323 316 −

316

316

280, 283, 305, 306, 308 316

306

280, 283, 306, 308

306, 308

306

280, 283, 305, 306, 308 316

1(10)-En-9-one, and 1,10-epoxy-9-one tricyclic eremophilanes 305, 306, 308

166 M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

167

3.25  Ligularia cymbulifera (W. W. Smith) Handel-Mazzetti Ligularia cymbulifera is a very abundant species in the Shangri-La area, Yunnan Province, China (Plate 18, Table 30). Initially, 13 samples were collected in Shangri-La and adjacent counties. No intraspecific diversity in chemical composition was observed by TLC analysis. The extracts of two samples (samples 1 and 2) were worked up to isolate eremoligenol (14), tetradymol (225), and the furanoeremophilan-­15,6-olides 215, 222, and 224 [48]. In addition to these compounds, a simple eremophilane (26) and seven eremophilanolides (389, 393, 394, 441 (Sect. 3.1), 498, 561, and 562), including their derivative 146, were isolated in a detailed study (sample 8) [49]. Furanoeremophilanes 191, 201, 203, and 204 (from samples 6 and 7) [128] and other terpenoids, ligulacymirins A (592), B (593), 813, and 866 (from sample 9) [147], were also recorded. Ligulacymirins (592 and 593) have an interesting 19-carbon skeleton, for which their structures were determined by X-ray crystallographic analysis. Their plausible biosynthesis pathways are illustrated in Fig. 74. Among these compounds, tetradymol (225) is the major component and is considered to be a phytotoxin to prevent the growth of other plants [147]. Plate 18  Photograph of L. cymbulifera

Fig. 74  Plausible mechanism for the formation compounds 592 and 593

(2004) (2010)

2011-103

2011-115

2014-40

(2015)

4 5

6

7

8

9

a

Not described

2002-56 (2004)

2 3

Specimen number No. (year) 1 2002-38

Zongdian (Y)

Daocheng (S) Shangri-La (Y) Shangri-La (Y)

Muli (S) Muli (S)

Collection place Shangri-La (Y) Deqin (Y) Muli (S) 215, 222, 224 − − − 191, 203, 204 201, 203, 204, 222 224, 498

215, 224

14 −

− −

−

−

14, 26

−

a

3500

3600

3900

a

a

a

4300

10H Tricyclic eremophilanes 215, 222, 224

Elevation Bicyclic (m) eremophilanes 3300 14

Table 30  Samples 1–9 of L. cymbulifera and their chemical constituents

146, 225, 389, 393, 394, 561, 562 225, 389, 393, 592, 593

225

225

− −

225 −

10-OH Tricyclic eremophilanes 225

−

813, 866

−

− 441 −

−

−

−

− −

−

−

− −

[147]

[49]

[128]

[128]

[230] [229]

[48] [225]

− −

− −

− 653, 658, 677, 685, 686, 693, 705, 707 689, 691, 696 683, 687, 688, 692 −

Others Ref. − [48]

1(10)-Ene, 9-ene, and 1,10-epoxy tricyclic eremophilanes Bisabolanes − −

168 M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

169

In contrast, Gao and co-workers obtained various bisabolane compounds (653, 658, 677, 683, 685, 686, 687, 688, 689, 691, 692, 693, 696, 705, and 707) from samples obtained from Muli County, Sichuan, China (samples 3–5) [225, 229, 230]. However, from our own observations in field, L. cymbulifera and L. lankongensis grow sympatrically in the same region where Gao et  al. collected their samples. Bisabolanes are the major components of L. lankongensis (Sect. 3.30). Since the leaves of the two species are similar to each other, it is plausible that the bisabolane compounds obtained by Gao’s group are components of L. lankongensis. According to our own work, no bisabolane compounds were detected in L. cymbulifera.

3.26  Ligularia dictyoneura (Franchet) Handel-Mazzetti This species is highly diversified in chemical composition (Plate 19). Initially, we collected 20 samples from Shangri-La County, Yunnan, and adjacent areas, and their root constituents were analyzed by TLC using Ehrlich’s reagent. About a half of these (nine samples collected near Shangri-La City) were Ehrlich-negative, while the samples collected in the surrounding area were positive. From one of the Ehrlich-­negative samples (sample 4), the eremophilan-8-one derivatives 2, 3, 5, 54 (petasin), and 55 were isolated (Table 31) [29]. The chemical composition of the Ehrlich-positive samples was highly diverse, and six chemotypes (types 1–6) could be recognized by TLC

Plate 19  Photograph of L. dictyoneura

2003-72

2004-19

2004-35

2004-75

2005-08

2005-17

2006-56 2007-25

2007-103

2

3

4

5

6

7

8 9

10

Specimen number No. (year) 1 2003-35

Litang (S)

Collection place Shangri-La (Y) Daocheng (S) Shangri-La (Y) Shangri-La (Y) Ninglang (Y) Shangri-La (Y) Shangri-La (Y) Deqin (Y) Yanyuan (S)

3900

4300 2700

2700

3400

3000

3500

2200

2900

−

225

−

629

6 7

− −

256, 288, 291 −

− −

− 160, 161, 163, 168, 199, 200, 212 160, 161, 163, 168, 199, 212

− −

1

−

232, 247

−

161, 189

−

8

3

−

−

−

160, 161

−

−

161, 189

−

Ehrlich negative 1

2

−

−

−

2, 3, 5, 54, 55

−

5

232, 247

−

−

161, 212, 216

−

−

Chemotype 4

−

−

−

192

5

Others −

−

1(10)-Ene, 9-ene, and 1,10-epoxy tricyclic eremophilanes −

10-OH Tricyclic eremophilanes −

Elevation Bicyclic (m) eremophilanes 3400 −

10H Tricyclic eremophilanes 168, 212

Table 31  Samples 1–16 of L. dictyoneura and their chemical constituents

[120]

[29] [120]

[29]

[29]

[29]

[29]

[29]

[29]

Ref. [29]

170 M. Tori and C. Kuroda

a

12 13

(2011)

2012-52

15

16

a

Not described

(2009)

14

a

a

11

a

Lijiang (Y) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y)

Yanbian (S) 2500

a

a

a

a

Lijiang (Y)

− 160, 216, 344, 345, 351, 498, 499 160, 161, 163, 200, 212, 217

− − −

− −

− 344, 350

18, 19, 22, 56 5

−

247, 389, 392, 393, 511

146, 417

−

356

−

−

−

−

− −

−

−

−

−

1031, 1032 − 629

2

−

−

− −

−

[120]

[121]

[113]

[55] [42]

[182]

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 171

172

M. Tori and C. Kuroda

analysis [29]. Among them, the chemical compositions of types 1–5 were somewhat consistent. From samples of these types (samples 1–3 and 5–7), furanoeremophilanes 160, 161, 168, 189, 192, 212, 216, 232, and 247 were isolated, as well as the nonfurano compound 5. From a type 6 sample (sample 8), furanoeremophil-1(10)-ene derivatives (256, 288, and 291) were obtained. Later, we found two more Ehrlichpositive types (types 7 and 8) [120]. From further samples (samples 9 and 10), compounds 160, 161, 163, 168, 199, 200, 212, and 225 and bakkenolide A (629) were isolated. From another type 2 sample (sample 16), compound 217 was isolated instead of 216, suggesting the occurrence of diversity within the same chemotype. In addition to these compounds, eremophilanolides 146 and 417 were isolated by Huang et al. (sample 14) [113]. Related eremophilanes of both the 10H type (344, 345, 351, 498, and 499) and 10-OH type (389, 392, 393, and 511) were also isolated by Wang et al. (sample 15) [121]. Tan et al. obtained dehydrofukinone (5), ligudicins C (18), D (19), A (22), isopetasin (56), 344, 350, 356, as well as bakkenolide A (629) and aromatic compounds 1031 and 1032 (samples 11–13) [42, 55, 182]. It is not easy to determine the relative configuration of 7,11-epoxyeremophilan-8-ones. Compound 22 was determined to be a 7α,11-epoxide by the NOE effect observed between H3-13 and H3-14. Its diastereoisomer, 7β,11-epoxide, is also known [302].

3.27  L  igularia duciformis (C. Winkler) Handel-Mazzetti, Ligularia konkalingensis Handel-Mazzetti, Ligularia nelumbifolia (Bureau & Franchet) Handel-Mazzetti, and Ligularia limprichtii (Diels) Handel-Mazzetti Ligularia duciformis, L. konkalingensis (Plate 20), and L. nelumbifolia are close to one another morphologically and are very abundant in the Hengduan Mountains area of China. Their differentiation is based on the pili on their involucres and on the length of the pappi [2]. However, from our observations, their morphological characters appear to be very similar. In addition, the three species are indistinguishable with respect to the two major indices developed by our team, namely, in their root chemical composition and their evolutionally neutral DNA (Sect. 4). L. limprichtii is also close to these species. We analyzed 17 L. duciformis (Table 32), nine L. konkalingensis (Table  33), and ten L. nelumbifolia samples as well as one sample of L. limprichtii (Table 34). The samples were grouped into four chemotypes on the basis of their root chemical composition: type 1, eremophilane sesquiterpenoids; type 2, oplopane sesquiterpenoids; type 3, phenylpropanoids; and type 4, having none of the compounds specified in types 1–3. From a type 1 sample collected in Yunnan Province (L. duciformis sample 8), fukinone (4) and its derivative 5 were isolated [36]. Furanoeremophilanes 161 and 228, including cacalol (316) and its derivative 323, were also obtained together with 15 and 20 from samples collected in Sichuan Province (L. duciformis samples 19 and 23; L. nelumbifolia samples 6 and 14) [36, 51, 126]. Oplopanes 729, 730, 731, and 732 were isolated from type 2 samples (L. duciformis samples 7, 17, and 21; L. konkalingensis sample 1) [36, 126,

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

173

Plate 20  Photograph of L. konkalingensis

236]. Most of the collected samples, including the one L. limprichtii sample, belonged to type 3 (L. duciformis samples 9–11, 14, 16, 18, 20, and 22; L. konkalingensis samples 2–5, 7, and 8; L. nelumbifolia samples 1, 2, 4, 5, 15, and 16; L. limprichtii sample 17). From these samples, the coniferyl alcohol derivatives 933, 979, and 980 and the sinapyl alcohol derivatives 988, 989 (nelumol A), and 993 were isolated [18, 36, 51, 126, 127]. Compounds 959 and 1006 also were purified and characterized. Type 4 was represented by seven samples (L. duciformis samples 12, 13, and 15; L. konkalingensis samples 6 and 9; L. nelumbifolia samples 3 and 7), from which only lupeol (828) could be identified [33, 36, 126]. Lupeol was also isolated from the other chemotypes, along with phenylpropanoids, from the sesquiterpene-­producing samples, i.e., 932, 985, 986, 988, 989, 993, and 994, from type 1, and 929, 930, 977, 978, 979, and 980, from type 2. Other isolated compounds from these samples were 881, 882, and 889 and sesamin (1037) [36]. In addition to our samples harvested in the Hengduan Mountains area, the phytochemical profiles were recorded of L. duciformis and L. nelumbifolia collected in other parts of China. From the Hubei-collected samples (L. duciformis samples 1–3 and 6), eremophilanes 344, 359, and 360, eudesmanes 795, 800, and 802, guaianes 780, 781, and 783, and the aromatic compounds 936, 979, 982, 983, 984, 989, 990, 999, 1000, 1001, and 1002 were obtained [177, 242, 269, 272]. From the central Sichuan-collected samples (L. duciformis samples 4 and 5), the eremophilanes 426, 428, 443, and 444, the aromatics 920, 933, and 934, and lupeol (828) were acquired [201, 249]. In turn, from L. nelumbifolia samples 8 and 10–13 collected from northwestern China, 14 aromatic compounds (926, 928, 930, 933, 959, 989, 993, 995, 997, 998, 999, 1003, 1004, and 1005) were isolated, together with guaianes 778 and 779 [68, 241, 262, 263, 271]. The sinapyl alcohol derivatives 989, 995, 996, 997, 998, 999, and 1003 were also obtained from an eastern Yunnan-collected sample (L. nelumbifolia sample 9) [270]. These data indicate that the major components of L. duciformis and related species are phenylpropanoids. The production of

a

a

3

4 5

a

2004-28 2004-39 2005-29 2005-47 2005-60 2007-122 2007-19 2007-71

6

7 8 9 10 11 12 13 14

a

a

2

Specimen No. number a 1

Shennongjia (Hubei) Shangri-La (Y) Shangri-La (Y) Xiangcheng (S) Litang (S) Kangding (S) Shangri-La (Y) Muli (S) Kangding (S)

Collection place Shennongjia (Hubei) Shennongjia (Hubei) Shennongjia (Hubei) Kangding (S) Meigu (S)

3700 3600 3800 4000 4000 4100 3600 3700

a

a

a

a

a

a

Elevation (m)

828 − −

− −

936 979 932 979, 988, 989, 1006 989 979, 988, 989, 993, 1006 − − 979, 988, 989, 993

− 4, 5 − − − − − −

731, 732 − − − − − − −

− − − − − 828 828 828

−

920, 933, 934 −

−

− 426, 428, 443, 444 344, 359, 360

−

979, 982, 983, 984, 989, 990, 999, 1000 1001, 1002

−

Oplopanes Others − 780, 781,783, 795, 800, 802 − −

Aromatics −

Eremophilanes −

Table 32  Samples 1–23 of L. duciformis and their chemical constituents

2 1 3 3 3 4 4 3

−

− −

−

−

[236] [36] [36] [36] [36] [36] [36] [36]

[177]

[249] [201]

[272]

[269]

Chemotype Ref. − [242]

174 M. Tori and C. Kuroda

2007-88 2008-31 2008-44 2009-47 2009-96 2011-12 2012-28 2014-27 2015-37

a

Not described

15 16 17 18 19 20 21 22 23

Yajiang (S) Shangri-La (Y) Shangri-La (Y) Litang (S) Maerkang (S) Baoxing (S) Kangding (S) Shangri-La (Y) Heishui (S)

4300 3900 4300 4200 4000 3900 3200 3900 3800

− − − − 20 − − − 161, 228

− 979, 989 930, 978, 979, 980, 1037 989 985, 986 979, 980 929, 977 933 −

− − 731, 732 − − − 730, 731 − − 828 889 881, 882, 889 828 − − 828 828 − 4 3 2 3 1 3 2 3 1

[36] [36] [36] [36] [36] [126] [126] [18] [126]

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 175

176

M. Tori and C. Kuroda

Table 33  Samples 1–9 of L. konkalingensis and their chemical constituents Specimen No. number 1 2005-65

Collection place Luding (S)

Elevation (m) Aromatics 3500 −

2

2007-110

4600

3

2007-70

4

2007-75

5 6 7

2009-54 2009-74 2009-93

8 9

2011-82 2012-10

Xiangcheng (S) Kangding (S) Kangding (S) Ganzi (S) Dege (S) Maerkang (S) Xinlong (S) Kangding (S)

Oplopanes 729, 730, 731, 732 −

Others Chemotype Ref. − 2 [36] 828

3

[36]

−

−

3

[36]

−

−

3

[36]

3700 4000 3700

959, 988, 989, 993 979, 988, 989, 993 979, 988, 989, 993 989 − 989

− − −

828 828 828

3 4 3

[36] [36] [36]

2900 3800

988, 989 −

− −

− 828

3 4

[126] [126]

3700 4300

terpenoids in a limited number of the samples scrutinized (types 1 and 2) may be the result of introgression from other species [36].

3.28  Ligularia hodgsonii J. D. Hooker Ligularia hodgsonii is considered to be one of the oldest species within the genus Ligularia and is distributed widely in China, Far Eastern Russia, Korea, and Japan (Plate 21) [2]. An initial study on a Japanese sample was conducted by Takahashi’s group, which led to the isolation of the furanoeremophilanes 160 and 212, the eremophilanolide 343, and bakkenolide A (629) (sample 2) [123–125] (Table 35). We compared the chemical compositions of plant samples acquired in both Japan and China. From Japanese samples collected in Hokkaido (samples 4 and 5) and Iwate (sample 6), the 15-oxygenated furanoeremophilanes 199 and 212 were isolated [136]. From the workup of Chinese samples collected in Yunnan Province (samples 3 and 9), the furanoeremophilan-10-ols 244 and 246 were produced [136, 153]. Eremophilanolides 121, 390, 432, and 442 and the eremophilan-8-one 112 were also isolated by Xu et al. from a sample collected in Yunnan Province (sample 11) [91]. In contrast, eremophilanes were absent in samples collected in Sichuan Province, and only the bisabolane 663 and γ-humulene (811) were detected (samples 7 and 8) [153]. Eremophilanes were isolated from L. hodgsonii samples collected in other locations. From an Anhui sample (samples 13), compounds 374, 376, 377, 495, 496, 497, and 512 were obtained [191]. However, the structures proposed for compounds 377 and 495 are questionable, because unexpected NOEs inconsistent with the conformation assigned were described. An eremophilane dimer 614 (biliguhodgsonolide), a

2010-11

a

a

a

Not described

15 2010-16 16 2010-47 L. limprichtii 17 2010-32

14

12 13

989 988, 989, 993 988

15, 161 − − −

Aba (S)

3400

a

a

a

a

− −

− −

Maerkang/Hongyuan 4000 (S) Hongyuan (S) 3700 Aba (S) 3600

Zhang (G) Zhang (G)

a

Northwestern China Northwestern China

a

a

10 11

989, 993, 995, 996, 997, 998, 999 933, 959, 989, 993, 1003 995, 997, 998, 999, 1004, 1005 − 926, 928, 930, 933, 959, 989, 993, 1003 −

−

a

Zhaotong (Y)

(2000)

9

989 989 − 989 933, 988 988, 989, 993, 994 − −

− − − − − 316, 323 − −

4200 3800 4000 3900 3700 3400 4700

Jiulong (S) Shangri-La (Y) Xiaojin (S) Shangri-La (Y) Daofu (S) Heishui (S) Ganzi (S) Zhang (G)

Aromatics

Elevation (m)

Eremophilanes and cacalol derivatives

Collection place

Specimen number No. (year) L. nelumbifolia 1 2007-54 2 2009-07 3 2009-108 4 2009-12 5 2011-29 6 2015-33 7 2016-40 a 8

Table 34  Samples 1–17 of L. nelumbifolia and L. limprichtii and their chemical constituents

−

3

3 3

1

− − −

− −

− −

−

3 3 4 3 3 1 4 −

[126]

[51] [51]

[51]

[241] [262]

[263] [271]

[270]

[36] [127] [36] [127] [126] [126] [33] [68]

Chemotype Refs.

779 −

− −

828 − 828 − 828 828 828 778, 779 −

Others

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 177

2006-91

2006-H10

2006-H4

2008-H9 2009-105 2010-01 2014-06

3

4

5

6 7 8 9 10

(2005)

(2005)

13

14 15

a

Not described

a

(2004) (2005)

11 12

a

a

2

Specimen number No. (year) 1 (1977)

Jixi (Anhui) Jixi (Anhui)

Songming (Y) Hokkaido (Japan) Hokkaido (Japan) Iwate (Japan) Xiaojin (S) Li (S) Yunlong (Y) Shennongjia (Hubei) Kunming (Y) Enshi (Hubei) Jixi (Anhui)

Iwate (Japan)

Collection place Halle (Germany)

390, 432 423, 427, 428, 430, 433 512

199, 212 199, 212 199, 212 − − − − − − 374, 376, 377, 495, 496, 497 614 −

− − − − − − 117, 123 112, 121 68, 113, 140 −

a

a

a

a

a

a

1300 2900 2600 2600

70

a

− −

− − − 244 −

−

−

2300

− −

−

−

− −

−

442 −

− − − − −

−

−

−

−

244, 246

−

160, 212, 343

−

a

10H Tricyclic eremophilanes −

1(10)-Ene, 9-ene, and 1,10-epoxy 10-OH Tricyclic tricyclic eremophilanes eremophilanes − −

Elevation Bicyclic (m) eremophilanes a 125

Table 35  Samples 1–15 of L. hodgsonii and their chemical constituents

− −

−

− −

− − − − −

−

−

−

154 893, 895

−

− −

− 811 663 − 794

−

−

−

Bakkanes and germacranes Others 758, 768, 769, 812, 770, 771 875, 883 629 −

[116] [256]

[191]

[91] [80]

[136] [153] [153] [153] [93]

[136]

[136]

[123– 125] [136]

Ref. [13]

178 M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

179

Plate 21  Photograph of L. hodgsonii

seco-eremophilane 154 (sample 14) [116], and monoterpenoids 893 and 895 were also isolated (sample 15) [256]. The dimer 614 has an interesting [2 + 2] structure, which was determined by X-ray diffraction analysis. From a sample collected in Hubei (sample 12), the eremophilanes 68, 113, 140, 423, 427, 428, 430, and 433 were isolated [80]. Five of these are 10-hydroxy derivatives. From another Hubei sample (sample 10), 117, 123, and the eudesmane 794 were afforded [93]. Compound 117 is a rare type of highly oxygenated 13-­noreremophilane. From a European sample (sample 1), liguhodgsonal (125), germacrene D (758), four highly oxygenated germacranes 768, 769, 770, and 771, humulane (812), a monoterpene (875), and a polyyne (883) were isolated by Bohlmann et  al. [13]. These results suggest the presence of geographically dependent diversity within this species.

3.29  L  igularia lamarum (Diels) C. C. Chang and Ligularia subspicata (Bureau & Franchet) Handel-Mazzetti These two species are very close to one another in morphology and are distinguished by the presence (L. lamarum) (Plate 22) or absence (L. subspicata) (Plate 23) of ray florets [2]. We collected 18 L. lamarum and 23 L. subspicata samples and found that the two species could not be distinguished readily in terms of our two indices, root chemical composition and ITS sequences (Tables 36 and 37). Eremophilanes were isolated from all samples, including both bicyclic

180 Plate 22  Photograph of L. lamarum

Plate 23  Photograph of L. subspicata

M. Tori and C. Kuroda

2005-26

2005-64 2007-121

2007-124

2007-126

2007-127

2008-25

2008-55 2009-95 2010-09

4

5 6

7

8

9

10

11 12 13

Specimen No. number 1 2002-57, 2002-64, 2006-59 2 2003-01, 2008-51 3 2004-23

151 979

− − −

− − 231, 232

171

Jianchuan (Y) 4000 Maerkang (S) 3900 Maerkang/ 3900 Hongyuan (S)

3500

4100

4100

− − −

33, 132

344, 359, 516, 559, 560 161, 165, 166, 167, 171, 172, 344, 518, 538, 540 161, 171, 172, 359 161 −

−

−

356

4, 20, 24, 25, 125, 340, 341 1

4100

33, 98

− −

− −

− −

4 1, 4

3500 4100

− 226, 229, 230 228

− − 314

[23] [23] [115]

[23]

[23]

[23]

[23]

[23] [23]

(continued)

− − 153, 648

−

−

− −

[23]

248

−

231

161

[23]

−

2, 54, 60, 63

3600

225, 228

−

−

3500

[23]

−

−

Shangri-La (Y) Shangri-La (Y) Luding (S) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y)

231

161, 171, 172, 174, 359, 540 161, 162, 163, 171

33, 132

1(10)-Ene, and 1,10-epoxy-9-ol tricyclic eremophilanes Others Ref. − − [23]

Jianchuan (Y) 4000

10-OH Tricyclic eremophilanes −

10H Tricyclic eremophilanes 161, 164, 172, 344, 359, 540

Elevation (m) 4100

Bicyclic eremophilanes 33

Collection place Deqin (Y)

Table 36  Samples 1–18 of L. lamarum and their chemical constituents

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 181

2011-118

2011-53 2011-54 2011-56

15

16 17 18

Specimen No. number 14 2010-10

Collection place Maerkang/ Hongyuan (S) Shangri-La (Y) Dege (S) Dege (S) Dege (S)

Table 36 (continued)

4100 4100 4400

3900

Elevation (m) 3900

10H Tricyclic eremophilanes 169 − 163 163, 168, 169 163, 168, 169

Bicyclic eremophilanes − − − − − 228, 396, 399 226, 228 228, 399, 400, 401, 524

399

10-OH Tricyclic eremophilanes 228 979

828

− − − −

[115] [115] [115]

[38]

1(10)-Ene, and 1,10-epoxy-9-ol tricyclic eremophilanes Others Ref. − − [115]

182 M. Tori and C. Kuroda

2007-73

2007-­123 2007-95

2007-­125 2009-34 2009-45

2004-26 2005-25 2002-55 2003-34 2003-51 2005-30 2003-­38, 2003-47 2004-25

2005-50 2005-61

3

4 5

6 7 8

9 10 11 12 13 14 15

17 18

16

Specimen number 2007-13 2007-44

No. 1 2

Litang (S) Kangding (S)

Shangri-La (Y)

Shangri-La (Y) Shangri-La (Y) Deqin (Y) Shangri-La (Y) Xiangcheng (S) Xiangcheng (S) Shangri-La (Y)

Shangri-La (Y) Batang (S) Litang (S)

Shangri-La (Y) Batang (S)

Kangding (S)

Collection place Muli (S) Jiulong (S)

4000 4000

3800

3900 3700 4200 3700 3800 3800 3800

4100 4500 4200

4100 4200

3700

Elevation (m) 3700 3600

− − − − 228 − − 161, 162, 171, 172 161, 171 172 171 − 161, 172 172 161, 162, 163, 171, 172, 173 161 161, 162, 172

1 2, 3, 54, 60, 63 − − − − − −

225, 226, 227, 232 227

− −

−

401, 555

− −

[24]

− − 629, 634, 828 − − − − − − 932

−

344, 359, 557, 559 356 344, 346, 359, 521

228

[24] [24] [24] [24] [24] [24] [24]

− −

− −

356 356

[24] [24] (continued)

[23] [34] [34]

[23] [23]

[23]

−

−

Ref. [23] [23]

−

Others − −

10-OH Tricyclic eremophilanes − −

10H Tricyclic eremophilanes − −

Bicyclic eremophilanes 1, 2, 3, 54, 60, 63 2, 5, 54, 56, 60, 62, 63 2, 3, 5, 54, 56, 60, 62, 63, 64 4, 20, 25, 340, 341 4, 5, 8, 20, 25, 125, 340 33 2, 4, 5, 28 14, 33, 98

Table 37  Samples 1–23 of L. subspicata and their chemical constituents

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 183

No. 19 20 21 22 23

Specimen number 2009-08 2011-­121 2008-22 2006-58 2003-69

Table 37 (continued)

Collection place Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Deqin (Y) Daocheng (S)

Elevation (m) 3900 3900 3500 4100 4000

Bicyclic eremophilanes − − − − −

10H Tricyclic eremophilanes 161, 171 161, 163, 171, 172 171, 359 161, 172, 521, 559 161, 172

10-OH Tricyclic eremophilanes 228 228 226, 231, 232 − − Others − − − − 629, 932

Ref. [127] [38] [23] [24] [24]

184 M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

185

eremophilanes and furanoeremophilanes [23, 24, 34, 38, 115, 127]. From some samples (L. lamarum sample 8, L. subspicata samples 1–3), only bicyclic eremophilanes were purified. For the other samples, it was not possible to classify the samples into chemotypes, since they could not be differentiated readily. As bicyclic eremophilanes, compounds 1, 2, 3, 4, 5, 8, 14, 20, 24, 25, 28 (kanaitzensol), 33, 54, 56, 60, 62, 63, and 64 were isolated together with their derivatives 98, 125, 132, 340, and 341. Among these, compounds 4, 60, and 62 were obtained as major components. For the furanoeremophilanes, both the 10H derivatives, 161, 162, 163, 164, 165, 166, 167, 168, and 169, including also subspicatins A (171), B (172), C (173), and G (174), and the 10-OH derivatives 225, 226, 227, 228, 229, 230, 231, and 232 were isolated. Related eremophilanolides were also present, inclusive of 344, 346, 356, 359, eremopetasitenin A4 (516), subspicatins E (518), D (521), and F (540), eremofarfugin C (538), 557, subspicatolide (559), and subspicatolide acetate (560) (10H type) and 396, 399, 400, 401, 524, and 555 (10-OH type). Compound 555 was assigned as a mixture of two orthoacetates. The major furanoeremophilanes were 161, 171, and 172. Subspicatins A (171) and B (172) are characteristic components of the furanoeremophilane-­ producing type of L. lamarum and L. subspicata. Other isolated compounds were 6-hydroxyeuryopsin (248), 314, secobakkane A (151), seco-eremophilane 153, bakkenolide A (629), its derivative 634, (−)-α-bisabolol (648), lupeol (828), and phenylpropanoids 932 and 979. The relative configuration of the epoxide 25 was determined by X-ray crystallographic analysis (Sect. 3.26). Secobakkane A (151) has a rare 6,7-seco-bakkane skeleton and may be regarded as a rearranged seco-­eremophilane. The structure of ethyl ferulate (932) in the original report [24] must be corrected as depicted in the present contribution.

3.30  Ligularia lankongensis (Franchet) Handel-Mazzetti This is a bisabolane-producing species. Eight samples (samples 1–8) were collected in northwestern Yunnan Province, China, and one (sample 9) from southern Sichuan Province (Plate 24, Table 38). Nine highly oxygenated bisabolanes (657, 675, 676, 678, 679, 682, 684, 697, and 708) were isolated (see Sect. 5.18 for the structures of 657 and 682) [226, 228]. Among these, compound 676 was isolated from all samples. Differences in chemical composition and in their ITS sequences were small between these samples. Interestingly, compound 678, the major component of the Sichuan sample (sample 9), was not isolated from the Yunnan samples. Tan et al. isolated the 3,4-diol derivatives 694 and 695 from another Yunnan sample [231].

186

M. Tori and C. Kuroda

Plate 24  Photograph of L. lankongensis

Table 38  Samples 1–10 of L. lankongensis and their chemical constituents No. 1 2 3 4 5 6 7 8 9

Specimen number (year) 2004-03 2004-55 2004-72 2004-73 2004-82 2005-03 2006-53 2007-01 2007-27

Collection place Yulong (Y) Shangri-La (Y) Ninglang (Y) Ninglang (Y) Ninglang (Y) Yulong (Y) Shangri-La (Y) Ninglang (Y) Yanyuan (S)

Elevation (m) 3100 2900 3000 3100 3300 2800 3200 2900 3100

10

(2001)

Lijiang (Y)

a

Bisabolanes 676 675, 676 675, 676, 679 675, 676, 684, 708 676, 684, 708 676 675, 676 675, 676, 682, 684 657, 675, 676, 678, 679, 684, 697 694, 695

Ref. [228] [228] [228] [228] [228] [228] [228] [226] [226] [231]

Not described

a

3.31  L  igularia latihastata (W. W. Smith) Handel-Mazzetti and Ligularia villosa (Handel-Mazzetti) S. W. Liu Ligularia latihastata and L. villosa (= L. changiana S. W. Liu) are taxonomically close to one another [2]. We analyzed two L. latihastata samples and one L. villosa sample, all collected in Yunnan Province (Plate 25, Table 39) [266]. From both species, 946, 949, 952, and 954 were produced as the major components. Eremophilane sesquiterpenes were not detected in the EtOH extracts.

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

187

Plate 25  Photograph of L. villosa

Table 39  Samples 1–3 of L. latihastata and L. villosa and their chemical constituents No. 1 2 3

Plant source L. latihastata L. latihastata L. villosa

Specimen number 2004-07 2005-07 2004-71

Collection place Yulong (Y) Yulong (Y) Ninglang (Y)

Elevation (m) 3300 3200 2900

Aromatics 946 949, 952, 954 952, 954

Ref. [266] [266] [266]

3.32  Ligularia villosa Handel-Mazzetti Five samples, three from Kangding County and two from Baiyu County, Sichuan Province, China (Plate 26, Table 40), were collected [32]. The major components in the Kangding samples (samples 3–5) were eremophilan-8-ones, viz., 2, 3, 5, 51, 52, 54, 60, 61, 62, 63, and 71. Lupeol (828) and the eudesmanes 789, 792, and 793 were also isolated. In contrast, the major component of the Baiyu samples (samples 1 and 2) were the furanoeremophilanes 301 and 313. Compound 330, an artifact generated from furanoeremophilane, and α-bisabolol (648) were also isolated. The results indicate the occurrence of intraspecific diversity for this species.

188

M. Tori and C. Kuroda

Plate 26  Photograph of L. longihastata

Table 40  Samples 1–5 of L. longihastata and their chemical constituents

No. 1 2 3

Specimen number 2011-68 2011-69 2012-13

4

2012-14

5

2012-15

Collection place Baiyu (S) Baiyu (S) Kangding (S) Kangding (S)

Kangding (S)

Elevation (m) 3500 3500 4100 4100

4100

Bicyclic eremophilanes − − 2, 3, 5, 54, 60, 63, 71 2, 3, 5, 51, 52, 54, 60, 61, 62, 63, 71 2, 3, 5, 51, 54, 60, 61, 62, 63

1,10-epoxy and 1,10-epoxy-9-one tricyclic eremophilanes 301, 313 330 − −

−

Others 648 − 828

Ref. [32] [32] [32]

789, 792, 793, 828 −

[32]

[32]

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

189

3.33  Ligularia oligonema Handel-Mazzetti Two samples were collected in Yunnan Province, China, and their chemical constituents were analyzed (Plate 27, Table 41). From a sample collected in Jianchuan County, Yunnan Province (sample 1), the 10-OH-furanoeremophilanes 228, 243, 245, and 246 were isolated [130, 151]. From a second sample from Lushui County (sample 2), the 10H-furanoeremophilanes 187, 188, and 194 were obtained together with a 10-OH derivative (243) [130]. LC-MS analysis indicated that sample 2 included a greater variety of furanoeremophilanes than sample 1.

Plate 27  Photograph of L. oligonema

Table 41  Samples 1 and 2 of L. oligonema and their chemical constituents Specimen No. number 1 2008-49 2

2014-01

Collection place Jianchuan (Y) Lushui (Y)

Elevation (m) 2900

10H Tricyclic eremophilanes −

10-OH Tricyclic eremophilanes 228, 243, 245, 246

3100

187, 188, 194

243

Ref. [130, 151] [130]

190

M. Tori and C. Kuroda

3.34  Ligularia tongolensis (Franchet) Handel-Mazzetti Ligularia tongolensis is close taxonomically to L. cymbulifera and is distributed from northwestern Yunnan to southwestern Sichuan (Plate 28). Initially, we collected 19 samples in these areas, but no intraspecific diversity was observed among them by TLC analysis. Five of these (samples 1–5) were investigated further, and the furanoeremophilan-15,6-olides 215, 220, and 224 and the furanoeremophilan15-oic acids 206 and 210 were isolated [48] (Table 42). Subsequently, the related compounds 204, 207, 208, and 219 were also generated from samples 6–14 [128, 137]. Tetradymol (225), a bisabolane 647, and eudesmane 789 were also obtained [137]. The ability to produce tetradymol may be acquired from L. cymbulifera by hybridization [137]. In addition, Han et  al. isolated the eremophilane-(12,8) (15,6)-bisolides 498, 503, and 504, and the other sesquiterpenoids 794 and 810 (sample 15) [206, 207]. The triterpenoids 849 and 850 [207, 251] and a monoterpenoid 866 [207] were also isolated. The intraspecific diversity found among L. tongolensis samples proved to be quite small, and their chemical constituents are similar to those of L. cymbulifera.

Plate 28  Photograph of L. tongolensis

191

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… Table 42  Samples 1–15 of L. tongolensis and their chemical constituents Specimen No. number (year) 1 2002-15 2

2002-25

3

2002-37

4

2002-45

5

2002-50

6

2011-102

7

2011-114

8

2015-04

9

2015-05

10

2016-220

11

2016-221

12 13 14 15

2017-02 2017-06 2017-27 (2003)

Collection place Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Shangri-La (Y) Daocheng (S) Shangri-La (Y) Wenchuan (S) Wenchuan (S) Shangri-La (Y) Shangri-La (Y) Muli (S) Muli (S) Muli (S) Muli (S)

Elevation (m) 3500

10H Tricyclic eremophilanes 210, 215, 220, 224

Others −

Ref. [48]

3200

210, 215, 220, 224

−

[48]

3300

210, 215, 220, 224

−

[48]

3100

210, 215, 220, 224

−

[48]

3600

206, 215, 220, 224

−

[48]

3900

204, 208, 224

−

[128]

3600

[128]

3100

204, 208, 219, 220, − 224 204, 206, 207, 208, − 215 204, 206, 207, 224 −

[137]

3600

208, 210, 215

−

[137]

3600

204, 206, 207, 208

225

[137]

3600 4000 3900

204, 206, 207, 208 210 204, 206, 207, 208 498, 503, 504

647, 789 − − 794, 810, 849, 850, 866

[137] [137] [137] [206, 207, 251]

2900

a

[137]

Not described

a

3.35  Ligularia tsangchanensis (Franchet) Handel-Mazzetti We compared initially samples collected in Yunnan and Sichuan provinces in China (Plate 29, Table 43). From the Sichuan sample (samples 2–4), the eremophilan-­8-­ one derivatives 2, 3, and 54 were isolated, while from the Yunnan sample (sample 1), cacalol (316) and its derivatives, cacalone (322), epicacalone (323), and adenostin A (570), were obtained [35]. L. tsangchanensis is closely related taxonomically to L. muliensis, and their main difference results from the length of the respective raceme. However, a recent morphological study has led to a merging of L. muliensis with L. tsangchanensis [303]. Prior to our study, noreremophilanes 97, 98, and 139a (eremopetasinorol), eremophilan-12,8-olides 345, 349, 359, 362, and 378, the eremophilan-­12,6-olide 558, the dimers 583, 585, and 586, and the monoterpenoids

Shangri-La (Y) Shangri-La (Y) Muli (S)

Muli (S)

2011-­122 2016-­229 2017-13

(2003)

(2003)

6 7b 8c

9c

10c

a

Not described b Hybrid with L. vellerea c Previously assigned as L. muliensis

Muli (S)

Xiangcheng (S) Litang (S) Litang (S) Shangri-La (Y)

2005-33 2005-46 2005-48 2008-28

2 3 4 5

Collection place Yulong (Y)

Specimen number (year) 2004-17

No. 1

a

a

3900 3700 3500

4100 3800 4000 3800

Elevation (m) 3500

10H Tricyclic eremophilanes − − − − − − 163, 164, 180 − 345, 349, 359, 362, 378, 558, 583 585

Bicyclic eremophilanes − 54 2, 3, 54 54 − − 1 − 97, 98, 139a −

Table 43  Samples 1–10 of L. tsangchanensis and their chemical constituents

586

Cacalol derivatives 316, 322, 323, 570 − − − 316, 318, 319, 322, 323, 335, 547, 548, 570 316, 318 − 316, 322, 323, 570 − −

866, 870

− − −

− − − −

Others −

[86, 180, 209] [214]

[25] [25] [25]

[35] [35] [35] [25]

Ref. [35]

192 M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

193

Plate 29  Photograph of L. tsangchanensis

866 and 870 were isolated from L. muliensis (samples 9, 10) [86, 180, 209, 214]. Next, we compared the chemical composition of the former L. tsangchanensis with that of L. muliensis. Cacalol derivatives from both species were isolated, namely, cacalol (316), 322, 323, and 600 from sample 8 (former L. muliensis) and 316, 318, 319, 322, 323, 335 (farfugin A), 547 (cacalolide), 548 (epicacalolide), and 570 from samples 5 and 6 (L. tsangchanensis) [25]. From these results, it was confirmed that these two former individual species are identical in chemical composition. In addition, from sample 7 (a hybrid sample with L. vellerea) (vide infra), furanoeremophilanes 163, 164, and 180 were isolated together with an eremophila-1(10),11-diene (1) [25]. Compound 180 may be a precursor of cacalol.

3.36  Ligularia yunnanensis (Franchet) C. C. Chang Ligularia yunnanensis is taxonomically close to L. duciformis. We analyzed two samples collected in Jianchuan and Shangri-La Counties, Yunnan Province (Plate 30, Table 44). Only a phenylpropanoid docosyl ferulate (933) and lupeol (828) were isolated from these samples [18].

194

M. Tori and C. Kuroda

Plate 30  Photograph of L. yunnanensis

Table 44  Samples 1 and 2 of L. yunnanensis and their chemical constituents No. 1 2

Specimen number 2008-52 2014-30

Collection place Jianchuan (Y) Shangri-La (Y)

Elevation (m) 3900 3900

Aromatics 933 −

Others 828 828

Ref. [18] [18]

3.37  Hybrid Ligularia Species Natural hybridization is an important step in plant diversification and evolution [304–306]. During the course of our searching in the field, we were able to collect several hybrid Ligularia species. The phytochemical profiles of these hybrids were found to be diverse, depending on the individual sample examined (Table 45). A number of furanoeremophilanes were obtained from hybrids of furanoeremophilane-­ producing species. For example, from seven samples of hybrids between L. cyathiceps and L. subspicata (samples 1–7), 23 furanoeremophilanes were isolated. The isolated compounds were 160, ligularol (161), 163, 165, 167, subspicatol A (170), subspicatins A (171), B (172), C (173), O1 (175), O2 (176), 177, 181, 182, 185, tetradymol (225), 226, 229, 230, 231, 232, 235, and 306. Seven eremophilan-­12,8-­ olides (344, eremopetasitenin A8 (517), subspicatins M (519), N (520), eremopetasitenins B6 (525), B5 (527), subspicatin F (540)) were also obtained. Other isolated compounds were fukinone (4), norsubspicatin A (130), bakkenolide A

L. subspicata/ L. cyathiceps

L. subspicata/ L. cyathiceps

L. subspicata/ L. cyathiceps

L. subspicata/ L. cyathiceps

L. subspicata/ L. cyathiceps

3

4

5

6

7

3900

Shangri-La 3900 (Y)

Shangri-La 3900 (Y)

2011-­120 Shangri-La 3900 (Y)

2011-­117 Shangri-La 3900 (Y)

2008-­34

2008-­37

2008-­33

No. Plant source 1 L. subspicata/ L. cyathiceps 2 L. subspicata/ L. cyathiceps

Elevation (m) 3300

Shangri-La 3900 (Y)

Specimen Collection number place 2007-­133 Shangri-La (Y) 2008-­32 Shangri-La (Y)

−

4

−

−

130

4

232

231, 232

229, 230, 231, 232

226, 229, 230, 232, 235, 525, 527 161, 163, 171, 225, 226, 230 172, 173, 177, 181, 182 182 −

171, 172, 175, 176, 181, 182, 344 161, 171, 172, 181, 182, 185, 344, 519, 520, 540 160, 165, 167, 170, 181, 182, 185, 517 181, 182, 185

10-OH Bicyclic 10H Tricyclic Tricyclic eremophilanes eremophilanes eremophilanes − − −

Table 45  Samples 1–16 of hybrid species and their chemical constituents

−

−

− 306

−

−

− −

−

−

−

−

−

−

−

−

−

629

−

[38]

[38]

[150]

[40]

[40]

[40]

Ref. [40]

(continued)

Cacalols Aromatics Others − 947, 949, − 952, 954 − − −

−

−

1(10)-Ene, 9-ene, and 1,10-epoxy tricyclic eremophilanes −

No. Plant source 8 L. tongolensis/ L. cymbulifera 9 L. tongolensis/ L. cymbulifera 10 L. tongolensis/ L. cymbulifera 11 L. nelumbifolia/ L. subspicata 12 L. nelumbifolia/ L. subspicata L. nelumbifolia/ L. subspicata 13 L. duciformis/ L. cyathiceps 14 L. duciformis/ L. yunnanensis 15 L. nelumbifolia/ Cremanthodium stenoglossum 16 L. nelumbifolia/ Cremanthodium stenoglossum

Table 45 (continued)

− − −

− − −

− 2, 54

54

3900

4700

4700

2016-­39

Ganzi (S)

−

−

1

3900

−

−

161, 171

−

3900

−

161, 171

−

3900

−

−

289, 293, 306, 308, 330 −

−

−

−

171

−

3900

225

225

203, 204, 208

−

−

−

−

316

−

−

−

−

−

−

979, 987, 989 933, 980

−

−

989

−

−

−

−

828

886

−

−

−

−

−

−

−

3600

3900

225

Cacalols Aromatics Others − − −

10-OH Tricyclic eremophilanes 225

Bicyclic 10H Tricyclic eremophilanes eremophilanes − 161, 191, 203, 204, 224 − 203, 204

Elevation (m) 3900

Specimen Collection number place 2011-­101 Daocheng (S) 2011-­104 Daocheng (S) 2011-­116 Shangri-La (Y) 2009-­10 Shangri-La (Y) 2009-­11 Shangri-La (Y) 2011-­113 Shangri-La (Y) 2014-­26 Shangri-La (Y) 2014-­29 Shangri-La (Y) 2016-­38 Ganzi (S)

1(10)-Ene, 9-ene, and 1,10-epoxy tricyclic eremophilanes −

[33]

[33]

[18]

[18]

[127]

[127]

[127]

[128]

[128]

Ref. [128]

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

197

(629), euparin (952), and its derivatives 947, 949, and 954 [38, 40, 150]. Among these compounds, subspicatins (1-angeloyloxyfuranoeremophilanes and -eremophilan-­ 12,8-olides) are characteristic compounds of L. subspicata (Sect. 3.27). From three hybrid samples between L. tongolensis and L. cymbulifera (samples 8–10), furanoeremophilanes 161, 191, 203, 204, 208, 224, and 225 were found [128]. These two species are close to each other in their chemical composition except that tetradymol (225) is the major characteristic component of L. cymbulifera (Sects. 3.25 and 3.34). From three hybrid samples 11–13 between L. nelumbifolia and L. subspicata, three furanoeremophilanes (161, 171, and 225) and a sinapyl alcohol derivative (989) (nelumol A) were obtained [127]. Compounds 171 and 989 may originate from L. subspicata and from L. nelumbifolia, respectively. From sample 14, a hybrid between L. duciformis and L. cyathiceps, the eremophilanes 1, 289, 293, 306, 308, and 316 and the aromatic compounds 979, 987, and 989 as well as squalene (886) were isolated [18]. Of these, the aromatic compounds might originate from L. duciformis and the eremophilanes from L. cyathiceps, respectively. From sample 15, a hybrid between L. duciformis and L. yunnanensis, both aromatic compounds (933 and 980) and lupeol (828), were obtained. This sample did not produce eremophilanes, because both of the parent species do not produce this class of sesquiterpenoids [18]. Finally, in addition to the Ligularia hybrid mentioned above, two samples of intergenic hybrids between L. nelumbifolia and Cremanthodium stenoglossum (samples 16 and 17) were analyzed, leading to the purification of two eremophilanes, namely, eremophila-9,11-dien-8-one (2) and petasin (54) [33]. The genus Cremanthodium is close to Ligularia taxonomically [3, 296].

3.38  F  urther Ligularia Species I: altaica de Candolle, L. dolichobotrys Diels, L. franchetiana (H. Léveillé) Handel-Mazzetti, L. persica Boissier, L. speciosa Fischer et Meyer, and L. thyrsoidea (Ledebour) de Candolle The following are the results obtained for several other Ligularia specimens, with information on the phytochemical analysis of 31 samples of 29 Ligularia species summarized below. In 2010, Wang et al. reported on the isolation of altaicalarins A–D (719, 718, 656, and 661) and two bisabolane derivatives (653 and 699) as well as a hydrocarbon (647) from L. altaica de Candolle (sample 1 from the Xinjiang Autonomous Region, China) (Table 46) [223]. Altaicalarins A and B (719 and 718) are aromatized derivatives each bearing a bisabolane skeleton. This is the only published report on L. altaica. Ligularia dolichobotrys Diels (sample 2 from Shaanxi Province) produced four 10H-furanoeremophilanes (375, 490 (the major constituent), 493, and 509), three bakkanes (629 (bakkenolide A), 630, and 631), two triterpenes (845 (friedelin) and 848 (ursolic acid)), and four additional compounds (125, 787, 788, and 897) [101,

L. franchetiana L. persica

L. speciosa

L. thyrsoidea

L. thyrsoidea

3

5

6

7

a

Not described

4

L. dolichobotrys

2

No. Plant source 1 L. altaica

(1994)

a

a

(2007)

2004-87

(2000)

−

−

232

195, 211, 212

−

−

−

211, 212, 344

4

−

7, 48, 49, 121, − 125

193

1

125

− Tiaoshan (Xinjiang Autonomous Region)

a

Turku (Finland)

Tehran (Iran)

Luquan (Y)

Qinling Mt. (Shaanxi)

Specimen number Collection Bicyclic 10H Tricyclic (year) place eremophilanes eremophilanes − − (2005) (Xinjiang Autonomous Region)

709, 710, 711, 712, 713

−

652

−

758, 759 −

−

760, 761, 762, 763, 764, 765, 766, 767 758

−

−

931, 940, 943, 947, 952, 954

878, 883 −

878

789, 791

−

−

[233]

[131]

[43]

[39]

[19]

[101]

787, 788, 845, 848, 897 −

−

−

Ref. [223]

Gernacranes Aromatics Others − − −

−

−

629

633

10-OH Tricyclic eremophilanes Bisabolanes Bakkanes − − 647, 653, 656, 661, 699, 718, 719 375, 490, 493, − − 629, 630, 509 631

Table 46 Various Ligularia samples 1–7 and their chemical constituents

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

199

192]. Compounds 787 and 788 are aromadendrane-type sesquiterpenoids, which have been isolated from Ligularia plants only rarely. Ligularia franchetiana (H.  Léveillé) Handel-Mazzetti (sample 3 from Yunnan Province) produced franchetianones A and B (633 and 193) as well as eremophila-­1(10),11-diene (1) [19]. Franchetianone A (633) is a bakkane-type sesquiterpenoid bearing a carbonyl group at the C-9 position. A carbonyl group at C-9 was also found in franchetianone B (193), a furanoeremophilane. Ligularia persica Boissier was collected in Tehran (Iran) (sample 4), and its chemical constituents included fukinone (4), 211, 212, 344, bakkenolide A (629), 789, 791, and eight germacrane-type sesquiterpenoids (760–767) [39]. Ten-­ membered carbocyclic rings are flexible, and it is especially important to pay attention to the epoxide configurations in these as well as to draw the representative stereochemistry without any ambiguity. Germacranes have not been isolated frequently from Ligularia species, but they occur quite often in members of the genus Eupatorium. The Finnish L. speciosa Fischer et Meyer (sample 5) (also termed L. speciosa (Schrader ex Link) Fischer & C. A. Meyer and L. fischeri (Ledebour) Turczaninow [2]) was investigated by Bohlmann et al. to obtain isofukinone (7), petasol (48), neopetasol (49), 2-hydroxyplatyphillide (121), liguhodgsonal (125), methyl ferulate (931), 940, 943, 947, euparin (952), 954, 652, (−)-germacrene D (758), and (E,E)-α-farnesene (878) [43]. Fukinone and petasol-type compounds have a double bond at C-9/C-10, but isofukinone (7) has a double bond at C-1/C-10. The cytotoxic peroxide 652 has been found only infrequently as a constituent of Ligularia species. Two reports on the constituents of L. thyrsoidea (Ledebour) de Candolle (samples 6 and 7) were reported, one from Bohlmann and Ziesche (1980) [131] and the other by Jia’s group (1999) [233] (Sect. 3.13). Interestingly, they proved to be quite different from each other. The German sample 6 afforded furanoeremophilan-15-oic acid 195 as the major constituent, in addition to two 15-oxygenated furanoeremophilanes (211 and 213), two germacratrienes (758 and 759), and two hydrocarbons (878 and 883). In turn, the Chinese sample 7 accumulated five bisabolane derivatives (709, 710, 711, 712, and 713) [233]. These results suggest that there is some chemical diversity for this species, although additional samples are required to be examined.

3.39  F  urther Ligularia Species II: L. achyrotricha (Diels) Y. Ling, L. nanchuanica S. W. Liu, L. purdomii (Turrill) Chittenden, L. odontomanes Handel-Mazzetti, L. sibirica (Linnaeus) Cassini, and L. thomsonii (C. B. Clarke) Pojarkova Ligularia achyrotricha (Diels) Y. Ling (sample 8 from Gansu Province, China) produced 11 aromatic compounds, which were, in turn, 925, 982, 983, 984, 989, 990, 991, 992, 1039, 1040, and 1042 (Table 47) [261].

L. nanchuanica

L. purdomii

L. odontomanes

L. sibirica L. thomsonii

9

10

11

12 13

a

Not described

Plant source L. achyrotricha

No. 8

2007

a

2007

2015

2006

Collection year 2009

372, 491

−

−

123, 125 − −

−

10H Tricyclic eremophilanes −

125, 127

Halle (Germany) − Naltar (Pakistan) −

Muli (S)

Guoluo (Q)

Nanchuan (C)

Bicyclic Collection place eremophilanes Maqu (G) −

Table 47 Various Ligularia samples 8–13 and their chemical constituents Aromatics 925, 982, 983, 984, 989, 990, 991, 992, 1039, 1040, 1042 926, 952, 953, 954, 956, 957, 1014, 1043 904, 909, 919, 926, 930, 940, 952, 959, 989, 1038, 1039, 1041 907, 952 954, 957, 962 942, 948, 954 903, 904, 905, 921, 922, 923, 926, 1015, 1016, 1017, 1018, 1035

795, 828, 837, 838 758, 875 −

828

828, 829

Others −

[13] [258]

[100]

[190]

[104]

Ref. [261]

200 M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

201

From the Chinese L. nanchuanica S.W.  Liu (sample 9 from Chingqing City, China) liguhodgsonal (125), ligudentatin A (126), and two tritepenes (828 and 829) were isolated [104]. Ligularia purdomii (Turrill) Chittenden (sample 10 from Qinghai Province) produced 372 and 491 and 12 aromatic derivatives (904, 909, 919, 926, 930, 940, 952, 959, 989, 1038, 1039, and 1041) as well as lupeol (828) [190]. The dilactone 491 resulted from the cyclization of acid 372. Ligularia odontomanes Handel-Mazzetti (sample 11 from Sichuan Province) produced euparin (952), and the other aromatic compounds 907, 954, 957, and 962, with three triterpenoids (828, 837, and 838), two noreremophilanes (123 and 125), and a eudesmane derivative (795) [100]. These isolated secondary metabolites were similar to those obtained from L. veitchiana or L. latihastata (Sects. 3.23 and 3.31). L. odontomanes is closely related taxonomically to L. latihastata [2]. Three benzofurans (942, 948, and 954), (−)-germacrene D (758), and cis-β-­ ocimene (875) were isolated from L. sibirica (Linnaeus) Cassini (sample 12 from Halle, Germany) [13]. Ishii et al. studied L. sibirica (from Japan) in 1965 and found ligularol (161) and ligularone (168) [11], although this species was later revised taxonomically to L. fischeri (Ledebour) Turczaninow (Sect. 3.23, Table 26) [50]. Ligularia thomsonii (C.  B. Clarke) Pojarkova from Pakistan (sample 13) produced 12 aromatic compounds (903, 904, 905, 921, 922, 923, 926, 1015, 1016, 1017, 1018, and 1035), of which five were glucosides [258]. The six species mentioned above may be seen in common to produce aromatic compounds. Lupeol (828) was isolated from three species listed in Table 46. It is still not obvious why lupeol (828), among the many triterpenoids biosynthesized in the plant kingdom, is found so frequently in Ligularia.

3.40  F  urther Ligularia Species III: L. angusta (Nakai) Kitamura, L. calthifolia Maximowicz, L. fauriei (Franchet) Koidzumi, L. hiberniflorum (Makino) Kitamura, L. kangtingensis S. W. Liu, L. lingiana S. W. Liu, L. myriocephala Y. Ling ex S. W. Liu, L. platyglossa (Franchet) Handel-Mazzetti, and L. schmidtii (Maximowicz) Makino Furanoeremophilan-15,6-olide (212) was isolated from L. angusta (Nakai) Kitamura (sample 14 from Tokyo, Japan) (Table 48) [139]. Ligularia calthifolia Maximowicz (sample 15) produced six glucosides of eremophil-­11-en-2-one derivatives (81, 82, 84, 90, 91, and 92) [83]. Glycosides of terpenoids have rarely been isolated so far from Ligularia species (Fig. 5). Takahashi’s group studied the chemical constituents of Japanese L. fauriei (Franchet) Koidzumi (sample 16 from Iwate Prefecture, Japan). Five lactones, 212,

L. angusta

L. calthifolia

L. fauriei

L. hiberniflorum L. kangtingensis L. kangtingensis

14

15

16

17

a

Not described

23 24

22

L. (2001) myriocephala a L. myriocephala L. platyglossa (1999) a L. schmidtii

21

2007-74

L. lingiana

(2010)

(2010)

(1997)

a

(2013)

a

20

19

18

Plant source

No.

a

a

a

Elevation (m)

a

a

a

a

a

3700

Lijiang (Y)

a

Kangding (S) Ling Zhi (Teibei)

Kagoshima − (Japan) Kangding a (S) Kangding a (S)

Tokyo (Japan) Primorsky (Russia) Iwate (Japan)

Specimen number Collection (year) place

−

−

− 212, 344, 359, 490, 491

81, 82, 84, 90, 91, 92 −

393, 408, 409, 410, 411 410, 411

− − − 160, 161, 202, 204

− − −

418 −

−

−

54, 75, 76, 77, 78, 587 45

446, 611 −

−

−

−

−

−

502

125, 126

−

−

128

−

364, 384, 385, 386, 387, 388 −

−

−

−

−

212

−

−

−

Bicyclic 10H Tricyclic eremophilanes eremophilanes

276, 464 −

−

−

−

−

−

−

−

−

− −

−

−

−

744

−

−

−

−

−

804 877

−

−

828, 833, 848, 865, 866, 801, 847, 852 −

−

−

−

−

−

1(10)-Ene, and 9-en-1-­one 1(10)-en-2-­ tricyclic one tricyclic eremophilanes eremophilanes Oplopanes Others

10-OH Tricyclic eremophilanes

Table 48 Various Ligularia samples 14–24 and their chemical constituents

[160] [20]

[197]

[72]

[78]

[103]

[109]

[139, 178, 183] [186]

[83]

[139]

Ref.

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

203

344, 359, 490, and 491, were isolated [139, 178, 183]. These compounds are thought to be derived from ligularol (161) by oxidation processes. The Japanese L. hiberniflorum (Makino) Kitamura collected in 1979 at Yakushima, Kagoshima Prefecture, Japan (sample 17), produced six eremophilanolides, 364, 384, 385, 386, 387, and 388 [186]. Compounds 384 and 385 are epimers at C-8. The lactone 388 exhibited a methylthio group at C-3′ of an acryloyloxy moiety at C-6β. The conformation of the molecule was investigated using the ECD spectra, which depended on the configuration at C-8. Sample 18 of L. kangtingensis S.W. Liu from Sichuan Province produced ligukangtinol (128), which is a noreremophilanetriol [109]. Liguhodgsonal (125), ligudentatin A (126), a bislactone (502), an oplopane (744), lupeol (828), oleanolic acid (833), ursolic acid (848), two triterpenoids (847 and 852), two monoterpenes (865 and 866), and a eudesmane (801) were isolated from sample 19 (seemingly the same source as sample 18) [103]. Ligularia lingiana S.W. Liu (Plate 31, sample 20 from Sichuan Province) produced six 3-angeloyloxyeremophil-9-en-8-one derivatives, 54, 75, 76, 77 (major constituent), 78, and 587 [78]. Compound 587 was characterized as a Diels-Alder-­ type dimer between compound 77 and a monoterpene, ocimene. The stereochemistry was not fully determined due to limited NOE cross peaks being observed. Compound 77 exhibited weak cancer cell line cytotoxicity.

Plate 31  Photograph of L. lingiana

204

M. Tori and C. Kuroda

Ligularia myriocephala Y.  Ling ex S.W.  Liu (sample 21 from Teibei) was investigated, and the bicyclic eremophilane methyl ester 45, 8β,10β-­ dihydroxyeremophilan-­12,8α-olide (393), and four polyoxygenated eremophilanolides (408, 409, 410 (major constituent), and 411) were isolated [72]. All these compounds except for 393 have a 1β-angeloyloxy substituent and all except 45 a hydroxy group at C-10. Sample 22 afforded compounds 410 and 411 [197]. Ligularia platyglossa (Franchet) Handel-Mazzetti (sample 23 from Yunnan Province) produced the 10-OH lactone 418, two 1(10)-ene compounds (276 and 464), the 9-ene lactone 446 (the major constituent), and a dimeric lactone 611, as well as a eudesmane, 804 [160]. The dimeric compound, 611, was connected between the 2- and 8-positions of eremophilatrienolide units. Both compounds 418 and 446 possess a 1-oxo group and compound 464 an enolic hydroxy group at C-1. Bohlmann and Knoll reported the chemical constituents of L. schmidtii (Maximowicz) Makino (sample 24) [20]. Ligularol (161) was found to be a major constituent, and a furanoeremophilane (160), two 15-oic acids (202 and 204), and a hydrocarbon (877) were isolated.

3.41  F  urther Ligularia Species IV: L. brachyphylla Handel-­Mazzetti (= L. latihastata), L. calthifolia (Maximowicz) Diels, L. clivorum Maximowicz (= L. dentata), L. sachalinensis Nakai, L. tangutica (Maximowicz) Bergmans, L. trichocephala (Maximowicz) Matsumura et Koidzumi, and L. vorobierii Worosh Bohlmann and his group reported on the chemical composition of some rare Ligularia species in 1977 (Table 49), and their results may be mentioned here [13]. From L. brachyphylla Handel-Mazzetti (= L. latihastata) [2] (sample 25), humulene (812) was isolated as a major constituent, and four germacranes (758, 769, 770, and 771), the noraldehyde, liguhodgsonal (125), cis-β-ocimene (875), and the polyacetylene 883 also were identified. L. calthifolia (Maximowicz) Diels (sample 26) produced two 10H-furanoeremophilan-15,6-olides (212 and 218), bakkenolide A (629), and cis-β-­ ocimene (875) (found as the major constituent). These two species were collected at botanical gardens in Giesen and Munich, Germany, respectively [13]. Liguhodgsonal (125), (−)-germacrene D (758), a germacrane ketone (769) (major constituent), and cis-β-ocimene (875) were isolated from L. clivorum Maximowicz (= L. dentata) [2], collected in Nijmegen, The Netherlands (sample 27) [13]. Sample 28 of L. sachalinensis Nakai collected in Munich, Germany, produced the 10-OH furanoeremophilane 232, four 1,10-epoxyfuranoeremophilanes (290, 291, 293, and 296), (−)-germacrene D (758), and cis-β-ocimene (875) [13].

31

30

29

28

27

26

Munchen (Germany) L. clivorum Nijmegen (The Netherlands) L. Munchen sachalinensis (Germany) L. tangutica Berlin (Germany) L. Moscow trichocephala (Russia) L. vorobierii Moscow (Russia)

L. calthifolia

No. Plant source 25 L. brachyphylla

Collection place Giessen (Germany)

− 232 −

− − − − −

125

−

55

−

−

−

−

−

212, 218

−

10-OH Tricyclic eremophilanes −

10H Tricyclic eremophilanes −

Bicyclic eremophilanes 125

Table 49 Various Ligularia samples 25–31 and their chemical constituents

−

629

−

288, 290, 291, − 293, 296, 300, 303 − 288, 290, 291, 293, 296, 299, 300, 302, 303

−

758

−

758

758

758, 769

−

Bakkanes Germacranes − 758, 769, 770, 771

290, 291, 293, 296 −

−

−

1,10-Epoxy tricyclic eremophilanes −

[13] [164]

−

[13]

[13]

[13]

[13]

Ref. [13]

−

875

875

875

Others 812, 875, 883 875

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 205

206

M. Tori and C. Kuroda

Ligularia tangutica (Maximowicz) Bergmans obtained from Berlin, Germany (sample 29), afforded 3α-angeloyloxyeremophila-9,11-dien-8-one (55), (−)-germacrene D (758), and cis-β-ocimene (875) [13]. Sample 30, L. trichocephala (Maximowicz) Matsumura et Koidzumi (from Moscow, Russia), produced seven 1,10-epoxyfuranoeremophilanes (288, 290, 291, 293 (major constituent), 296, 300, and 303) [13]. The chemical constituents of L. trichocephala were found to be similar to those of L. sagitta (Sect. 3.21). Ligularia vorobierii Worosh (sample 31 from Moscow, Russia) produced nine 1β,10β,-epoxyfuranoeremophilanes (288, 290 (major constituent), 291, 293, 296, 299, 300, 302, 303) and (−)-germacrene D (758) [164]. All of the above specimens except for samples 30 and 31 produced cis-β-ocimene (875).

4  Genetic Analyses In our study on the chemical diversity in Ligularia species growing in the Hengduan Mountains area of China, also DNA sequences of each sample have been studied. We chose base sequences of atpB-rbcL (a segment between the atpB and the rbcL genes on the plastid DNA) [305] and the two internal transcribed spacers (ITS1-5.8S-­ ITS2) of the ribosomal RNA gene in the nuclear genome [304]. These sequences are noncoding, and variations therein are thought to be neutral to evolution, i.e., these sequences indicate the history of each sample. Therefore, a combination of the chemical aspects (isolation and structure determination) and the genetic aspects (DNA sequences) should help in understanding diversification and evolution in a correct manner. In this section, studies conducted on L. virgaurea and L. kanaitzensis are described briefly as examples. The ITS (internal transcribed spacer) sequences of L. virgaurea samples collected in southwestern Sichuan Province are shown in Table 50; the sample numbers are the same as shown in Table 1. The 11 analyzed samples could be grouped into 2 clades, A and B.  These clades correspond to the L and V types, respectively, in terms of their chemical composition. This indicates that the differences observed in chemical composition (Sect. 3.1) originate from their genetic differences [63]. Subsequently, 41 additional samples of L. virgaurea were analyzed, which were collected widely in northern to central Sichuan Province and partly in Gansu and Qinghai Provinces. We found the occurrence of five chemotypes, the L, V, C, H, and N types, although the number of samples of the C type was not very high [45, 114] (Sect. 3.1). The ITS sequences of these samples were determined to produce three clades, A, B, and C. Samples belonging to the new clade, Clade C, were also different from the other samples in the atpB-rbcL sequences. Correlations between the chemotypes and the DNA clades were observed; thus, samples of chemotypes C and H belonged to clade C, while chemotypes V and N belonged to clade B. As described earlier, chemotypes V, H, N, and C were continuous [76], while samples belonging to the type L (= ITS clade A) had no correlation with the other samples. As another example, DNA sequences of L. kanaitzensis are shown in Table 51. Twelve samples collected in Shangri-La County, Yunnan Province, and adjacent

2005-38 2005-42 2005-58

6 7 11

ITS1b Collection place 11 65 Daocheng (S) Y A Daocheng (S) Y R Daocheng (S) Y A Xiangcheng C A (S) Litang (S) C A Litang (S) C A Yajiang (S) C A Xiangcheng C G (S) Daocheng (S) C G Daocheng (S) C G Kangding (S) C G

b

a

Y Y Y C

C C C C C C

C C C Y C Y C

C C C C G G G

R R R G C C C

C C C C T T T

T T T T C C C

Y Y Y C G G G

G G G G T T T

Y Y C T

A T A T A T R Y

73 T T T T R R R G

84 R R R R C C C C

A A W

A A A A

A A W

A A A W

G G G

A A A G

C C C

A A A C

C C C

C C C C

C Y C

C C C Y

C C C

C C C Y

B B B

A A A B

91 162 168 175 179 188 217 220 Clade C A A A A C C C A M A A R A Y C C A C A A A A C C C A C A A A A C C C A

A R Y G C A R Y G C A A C G C

G G G A

ITS2b 66 74 124 130 132 134 135 235 240 32 34 C Y C R Y T Y G Y G A C Y C R C T Y G Y G A C Y C R C T Y G Y G A C C C R Y Y Y S C G A

Sample numbers correspond to those of Table 2 Y=C+T; R=A+G; M=A+C; S=C+G; W=A+T

2005-45 2005-52 2005-54 2003-54

8 9 10 1

a

Specimen No. number 2 2003-62 3 2003-68 4 2003-79 5 2005-32

Table 50  The ITS sequences of L. virgaurea collected in southwestern Sichuan Province

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… 207

1 1 1 1 1 1 2 2 2

c

1 1 1 1 1 1 1 1

5.8S

c

1 1 3 6 7 7 9 9 9 0 0 1 6 9 9 9 0 0 0 1 1 2 2

1 1 1 1 1 1 1 2 2 2 2 2 2 2

ITS2

g a t g y c g c t A g g y – y c C C G Y C Y C Y Y C C A C – AAYWYT Y C C C WY T T C C C C A

g a t g y c g c t A g g y – y c C C G Y C Y C Y Y C C A C – AAYWYT Y C C C WY T T C C C C A

g a t g y c g c t A g g y – y c C C G Y C Y C Y Y C C A C – AAYWYT Y C C C WY T T C C C C A

g a t g y y g c t A g g y – y c Y Y K C C C C C C C C A Y – AR KA YT Y C C C WC T T C C C Y A

2006–90 Dali (Y)

2005–12 Jianchuan (Y)

2002–51 Shangri La (Y) y t c r t

2005–18 Shangri La (Y) y t c r t

2005–19 Shangri La (Y) y t c r t

2005–20 Shangri La (Y) y t c r t

y t c r t

2006–28 Weixi (Y)

b

b

b

1

8

9

10

F F F N

C AC AT G AT G T C G T C C G G C G C C C C G C S C C C C T Y G C C T AT A AC C T C Y T T C T C T C C B

C AY AT G AT G T C G T C C G G C G C C C C G Y C C C C C T C G C C T AT A AC C T M C T T C T C T C C B t y t c t c c B

C AC AWG R T G T C G T C C G R C G C c c c g c c c c c c t c g c c t a t a a c c t C c t

C AC AWG R T G T C G T C C G G C G C C C C G C C C C C C T C G C C T AT A AC C T C C T T Y T C T C C B

c a c a t

b Samples not given in Table 9

c K=G+T; M=A+C; R=A+G; S=C+G; W=A+T; Y=C+T; bases in lower-case letters were determined from data on only one strand (see ref. 256 for the detail)

N

F

F

F

F

F F

C AC AT G AT G T C G T C C R G C G C C C C G C C C C C C T C G C C T AT A AC C T C C T T C KC T Y C B

a Sample numbers correspond to those of Table 9

2004–05 Yulong (Y)

g a t g y c g c t A g g y – y c C C G Y C Y C Y Y C C A C – AAYWYT Y C C C WY T T C C C C A

2006–31 Weixi (Y)

13

4

g a t g t c k t c S g g c g c c C C G C C C C C C T C G C C T AT A AC C T C C T T Y T C T C C B

2006–22 Weixi (Y)

12

N

2004–78 Ninglang (Y)

5

N

t c t c t c c B

C AC AWK R YK T C G T C C G R C G C c c c g c c c c c c t c g c c t a t a a c c t C c t

2006–20 Weixi (Y)

11

C AC AT G AT G T C G T C C G G C G C C C C G Y C C Y C C T C G C C T AT A AC C T C C T T C YC T C C B

2005–04 Yulong (Y)

6

N N

t c t c t c c B

2003–10 Jianchuan (Y)

g a t g t c g t c C g g c g c c c c g c c c c c c t c g c c t a t a a c c t C c t

2002–69 Jianchuan (Y)

c a c a t

Clade Chemicals

C AC AT G AT G T C G T C C G G C G C Y C C G C C C C C C T C G C C T AT A AC C T S Y T T C KY T C C B

2 3 5 0 1 4 5 6 7 0 4 9 5 6 7 7 6 6 6 5 8 3 3 4 6 7 8 1 7 5 1 9 2 1 1 2 1 2 3 1 5 6 8 1 2 5 3 4 5 0 8 1 2

1 2 6 8 8 8 8 8 9 9 0 2 2 2 7 9 1 3 5 9 2 3 3 3 3 4 5 5

c

3

place

ITS1

2

(year)

number

n

a No. Specime Collection

Table 51  The pattern of DNA sequences in L. kanaitzensis

208 M. Tori and C. Kuroda

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

209

areas were grouped into two clades, A and B. The chemical compositions of these samples could be grouped into two types, the furan ring-producing (F) and non-­ furan ring-producing (N) types (Sect. 3.6 and Table  8). However, in contrast to L. virgaurea, the chemotypes and the genetic clades did not necessarily correspond to each other [22]. In addition, later, two additional samples were found that were furan ring-producing specimens but did not belong to either clade A or B [31]. These data indicate that the diversity among L. kanaitzensis samples is complex. Analyses of the ITS sequences were especially useful for hybrid samples (Sect. 3.37). Some samples of hybrids between L. subspicata (or L. lamarum) and L. cyathiceps showed different parameters from each other in terms of morphology, chemical composition, and ITS sequences. Specifically, the ITS sequences of one sample (sample 6 in Sect. 3.37) were identical to those of L. cyathiceps, while, in sample 7, the phytochemical profile was close to that of L. cyathiceps [38]. Sample 15 of L. lamarum (Sect. 3.29) was shown to be a hybrid with L. cyathiceps in the ITS sequence [38]. Sample 7 of L. tsangchanensis (Sect. 3.35) was pure L. tsangchanensis in both its morphology and chemical composition but was a hybrid [25]. These results indicate that hybridization and backcrossing occur very often to acquire the ability to produce a variety of compounds. Comparative analysis based on two different aspects, chemical composition and neutral DNA sequencing, are useful to better comprehend plant diversification. Similar analyses have been carried out for other samples, including for L. anoleuca [154, 155], L. cyathiceps [17, 38], L. duciformis [36, 126], L. fischeri [37, 155], L. lamarum [23, 40, 115], L. melanothyrsa [21, 44], L. nelumbifolia [126, 127], L. oligonema [130], L. subspicata [24, 34, 38, 40, 127], L. veitchiana [154], and L. vellerea [21, 25, 26], and for hybrid samples [18, 21, 25, 33, 38, 40, 127, 128, 150, 306].

5  Synthesis Aspects Synthesis efforts toward eremophilane sesquiterpenoids have been carried out for a long time, almost since they were first isolated from natural sources, because these secondary metabolites have unique cis-1,2-arranged dimethyl groups and cis-­ decalin systems within their major groups. Historical work in this area has been well documented in the literature [307–309]. In this contribution, the chemical synthesis of compounds isolated from Ligularia species is introduced briefly, in addition to various aspects covered on the synthesis aspects of compounds included in Sect. 3.

210

M. Tori and C. Kuroda

5.1  S  ynthesis of Ligularol (= Petasalbin), Ligularone, and Related Compounds There are several reports on the synthesis of ligularol (161) and its derivatives. Among them the investigations by Yamakawa and Satoh, published in 1977–1981, are introduced here [310–314]. The Diels-Alder reaction of 1049 with 1050 afforded 1051, which was converted to 1052 and 1053 (Scheme 1). Dehydroxylation of 1053 gave both the cis and trans diketones, 1054 and 1055, of which the latter was transformed further to 3β-hydroxyfuranoeremophilane (1056). Ligularone (168), 3β-furanoligularanol (1057), and furanoeremophilane (160) were synthesized from 1052, 1054, and 1055, respectively [310, 311]. Another route to ligularone (168) and ligularol (161) was reported (Scheme 2) [312]. The intermediate 1051 was converted to 1058, from which ligularone (168) and ligularol (161) were synthesized. In addition, 1058 was converted to furanofukinol (1059) by stepwise reductions. The furan derivative 1060, prepared by a similar method to that described above, was used for the introduction of a double bond at C-1/C-10 (Scheme 3) [314]. Thus, compound 1060 was converted to 1062 via 1061 in several steps. Decompostin (278) and adenostylone (280) were synthesized from 1063.

Scheme 1  Synthesis scheme of ligularone (168) and other terpenoids by Yamakawa and Satoh

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

211

O O EtO

O O

O 1051

O HO

O

HO

1058

1059 (furanofukinol)

O

O

O

HO

168 (ligularone)

161 (ligularol)

Scheme 2  Synthesis scheme of ligularol (161) and other terpenoids by Yamakawa and Satoh

Scheme 3  Synthesis scheme of decompostin (278) and adenostylone (280) by Yamakawa and Satoh

5.2  S  ynthesis of Tetrahydroligularenolide Using Biogenetic Type Rearrangement Before the contributions of Yamakawa and Satoh were made, in 1972 Kitagawa’s group published the first successful biogenetic-type rearrangement from a eudesmane to an eremophilane skeleton (Scheme 4) [315, 316]. When epoxide 1065, prepared from dihydroalantolactone (1064), was treated with formic acid in acetone, four products (1066, 1067, 1068, and 1069) were obtained, of which three were rearranged compounds with an eremophilane skeleton. Compound 1068 was used for the synthesis of tetrahydroligularenolide (1071) via 1070.

212

M. Tori and C. Kuroda

Scheme 4  Synthesis scheme for tetrahydroligularenolide (1071) by Kitagawa’s group

5.3  Synthesis of Furanoeremophilan-15,6-olide Tada et  al. synthesized some furanoeremophilanes from a furan compound (Scheme 5) [317]. The dianion of 2,4-dimethyl-3-furoic acid (1073) was coupled with cyclohexenone 1072 to afford 1074, which was cyclized further to 15-­norfuranoeremophilane 1075. Compounds 212 and 1078 were synthesized from 1075 via the one-carbon elongated compounds 1076 and 1077, respectively.

Scheme 5  Synthesis scheme for furanoeremophilan-15,6-olide (212) by Tada et al.

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

213

5.4  Synthesis of Isopetasol Torii et  al. synthesized isopetasol (50) starting from a tricyclic lactone 1079 by introduction of a cis-dimethyl group through cyclopropanation (1080 to 1081) and methylation (Scheme 6) [318]. The intermediate ketone 1082 was converted to isopetasol (50) in several steps via 1083.

O

O

O

O

O

O

O

O

O

OTs

1079

1080

1081

O

O

AcO

HO

AcO 1082

1083

50 (isopetasol)

Scheme 6  Synthesis scheme for isopetasol (50) by Torii’s group

5.5  Synthesis of Eremophila-9,11-dien-8-one, Dehydrofukinone, and Furanoeremophilanes Hagiwara et al. reported syntheses of eremophila-9,11-dien-8-one (2) and dehydrofukinone (5) starting from bicyclic enone 1084 via 1085 obtained by an aldol reaction. Furanoeremophil-9-ene (270) and furanoeremophilone (1086) were also prepared from compound 1084 (Scheme 7) [319]. O

O

O

OH 1084

1085

5 (dehydrofukinone)

O O

O

O 7

1086 (furanoeremophilone)

270 (furanoeremophil-9-ene)

2

Scheme 7 Synthesis scheme for eremophila-9,11-dien-8-one (2), dehydrofukinone (5), furanoeremophil-­9-ene (270), and furanoeremophilone (1086) by Hagiwara et al.

214

M. Tori and C. Kuroda

5.6  Synthesis of Eremoligenol and Eremophilone An intramolecular Diels-Alder route to the title compounds, starting from tetraene 1087, was developed by Näf et al. This afforded the bicyclic enone 1088 (Scheme 8) [320], which was transformed to eremophilone (1091) through enone 1089. The enone 1089 was also converted to eremoligenol (14) via 1090. O

O

CO2Et

CO2Et

CO2Et

1087

1088

1089 O

CO2Et

OH 1090

14 (eremoligenol)

1091 (eremophilone)

Scheme 8  Synthesis scheme of eremoligenol (14) and eremophilone (1091) by Näf et al.

5.7  Synthesis of Eremophiladienes Coates’ group prepared six eremophiladiene isomers (1, 1095, and 1097–1100) from capsidiol (1096), obtained by elicitation from green peppers (Scheme 9) [321]. 5-Epiaristrochene (1095) was also obtained from the incubation of H

A H H H

OPP 1092 ((E,E )-farnesyl diphosphate)

1095 (5-epiaristrochene)

1094

1093

OH

HO 1096 (capsidiol)

1097

1098

1100

1

1099

Scheme 9  Synthesis scheme for eremophiladienes 1095, 1097–1100, and 1 by Coates’ group

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215

(E,E)-farnesyl diphosphate (1092). Eremophilane-type sesquiterpenoids are thought to be biosynthesized from 1092 through a germacrene (1093) and eudesmane (1094) by cyclization and skeletal rearrangement reactions. Spectroscopic data for compounds 1, 1095, and 1097–1100 are listed in the literature. These data have been useful for the structural and configurational determinations of various eremophilanes.

5.8  Synthesis of Fukinone and Related Compounds Reddy et  al. reported low-temperature Diels-Alder reaction of diene 1101 and (E)-2-methylbut-2-enal (1102) catalyzed by an aluminum reagent, to produce 1103 (Scheme 10) [322]. A metathesis reaction applied to enyne 1104 followed by hydrolysis produced 1105, which was transformed to fukinone (4) and hydrocarbons 1106 and 1107.

OBn 1101 +

OBn

CH3AlCl2

OTIPS

O

O

1103

1104

1102

O

O 1105

1106

1107

4 (fukinone)

Scheme 10  Synthesis scheme for fukinone (4) by Reddy et al.

5.9  Synthesis of Eremophiladiene A rearrangement reaction from a eudesmane to an eremophilane was also applied by Blay et al. (Scheme 11) [323]. (+)-Carvone (1108) was annulated using a silyl reagent in two steps to produce 1109, which was converted further to 1110. The following rearrangement reaction from a eudesmane to an eremophilane skeleton was

216

M. Tori and C. Kuroda Si(CH3)3

O

Si(CH3)3

O

O

1108

1109

1110 TiF4

HO 1097

1111

Scheme 11  Synthesis scheme for eremophila-9,11-diene (1097) by Blay et al.

accomplished by treatment with TiF4. Thus, the 1,2-shift of the methyl group of 1110 was conducted to afford 1111, which was converted to chiral eremophila-­9,11-­ diene (1097) in several steps. Note that the absolute configuration of the eremophilane skeleton is opposite to that of 1097.

5.10  Synthesis of 6-Hydroxyeuryopsin Another method for constructing ring B of an eremophilane skeleton at a later step was reported by White’s group (Scheme 12) [324]. 6-Hydroxyeuryopsin (248) was synthesized starting from 2-methylcyclohex-2-en-1-one (1112) and the furan carboxylic acid 1115 via 1113 and 1116, respectively. Bromide 1114 and furan derivative 1117 were coupled using palladium chemistry to afford 1118, which was further converted to 6-hydroxyeuryopsin (248) in several steps. This same group published a detailed paper on the synthesis of 6-­hydroxyeuryopsin (248) and toluccanolides A (434) and C (436) (Scheme 13) [325]. 2,3-Dimethylcyclohexanone (1119) was alkylated followed by a several-step reaction via 1120 to afford the coupling moiety 1114. A furan unit (1117) was coupled with 1114 to furnish 1118. Cyclization at the C-6/C-7 position gave 1121, which was further converted to 6-hydroxyeuryopsin (248), toluccanolide A (434), and toluccanolide C (436) in several steps.

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… O

O

OTIPS

O

O

1114

TBS

O

Br

1113

1112

Bu3Sn

O

217

TBS

OTIPS

AsPh3 Pd2(dba)3

1118

O

TBS

OH

CO2H

OH 1115

1116

1117

248 (6-hydroxyeuryopsin)

Scheme 12  Synthesis scheme for 6-hydroxyeuryopsin (248) by White’s group

Scheme 13  Synthesis scheme for 6-hydroxyeuryopsin (248), toluccanolide A (434), and toluccanolide C (436) by White’s group

5.11  Synthesis of 3β-Angeloyloxyfuranoeremophilane Hsu et al. reported that an intermolecular Diels-Alder reaction between α-quinone derived from 1122 and ethyl vinyl ketone afforded 1123 (Scheme 14) [326]. A Claisen-type rearrangement of silyl enolate of 1123 produced 1124. A several-step transformation through 1125 gave norketone 1127. 3β-Angeloyloxyfuranoeremoph ilane (191) was obtained by another alkylation of 1125 to 1126 and formation of the furan ring.

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Scheme 14  Synthesis scheme for norketone 1127 and 3β-angeloyloxyfuranoeremophilane (191) by Hsu et al.

5.12  Synthesis of Ligularone and Isoligularone Koike et  al. prepared ligularone (168) and isoligularone (1131) starting from an intermolecular Diels-Alder reaction of silyl enol ether 1128 with 2-methylcyclohex-­2en-1-one (1112) (Scheme 15) [327]. Diketone 1129 thus obtained was converted to ligularone (168) and isoligularone (1131) via diketone 1130. A Diels-Alder reaction for construction of a cis-1,2-dimethyl moiety was again used by Kraus et al. (Scheme 16) [328]. A boron trifluoride ethrate-catalyzed reaction of diene 1132 and aldehyde 1102 afforded a bicyclic alcohol 1133. Isoligularone (1131) was prepared using ketone 1134 as an intermediate.

TMSO

O

O

+ O 1128

O

O 1112

O

1129

1130 O

O + O 168 (ligularone)

O 1131 (isoligularone)

Scheme 15  Synthesis scheme for ligularone (168) and isoligularone (1131) by Koike et al.

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

219 O

1132 +

O

OH 1133

O

O

1134

O 1131 (isoligularone)

1102

Scheme 16  Synthesis scheme for isoligularone (1131) by Kraus et al.

5.13  Synthesis of (−)-(R)-Ligularenolide and (−)-(R)-PF1092C The synthesis of eremophilan-12,8-olides was reported by Groot’s group (Scheme 17) [329]. Hence, (+)-(S)-carvone (1108) was subjected to conjugate addition and annelation to afford enone 1135. Oxidative elimination sequences produced dienone 1136. The enolate of 1136 was condensed with ethyl pyruvate and cyclized to give the desired (−)-(R)-ligularenolide (447). The intermediate 1135 was transformed to 1139 and (−)-(R)-PF1092C (1140) in several steps via 1137 and 1138.

Scheme 17  Synthesis scheme for (−)-(R)-ligularenolide (447) and (−)-(R)-PF1092C (1140) by Groot’s group

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5.14  Synthesis of Nootkatone An intermolecular Diels-Alder reaction was used by Reddy’s group in their synthesis of nootkatone (1146) (Scheme 18) [330]. A boron trifluoride-promoted Diels-­ Alder reaction of (E)-octa-5,7-dien-2-one (1141) and 1102 followed by alkaline treatment afforded cyclized hydrindane 1142, which was converted further to 132. When the one methylene longer ketone 1143 was used, decalin 1144 was produced, which was transformed to racemic nootkatone (1146) in several steps via 1145. The absolute configuration of natural nootkatone (1146) is the enantiomeric form of the structure drawn in Scheme 18.

O BF3 . Et2O

O

O

1141 +

O 132

1142 1102 O

1143

O O

O

O

+ 1102

1144

1145

1146 (nootkatone)

Scheme 18  Synthesis scheme for nootkatone (1146) by Reddy’s group

5.15  Synthesis of Cacalol Cacalol (316) has been a synthesis target for many scientists. An early study by Huffman and Pandian was published in 1979 using alkylation of a benzocyclohexanone derivative [331]. The first enantioselective synthesis of (+)-(S)-cacalol (316) was accomplished by Akita’s group starting from the chiral epoxide 1147 (Scheme 19) [332]. Arylation with 1148 gave the chiral alcohol 1149, which was converted further to 1151 via 1150. Demethylation and construction of a furan moiety finished the synthesis of (+)-(S)-cacalol (316).

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity… O

O

O O

O

H3CO2C

221 O

O

O

+

H3CO2C

HO 1148

1147

1149

1150 OH

O O

O

O 1151

316 ((+)-(S )-cacalol)

Scheme 19  Synthesis scheme for cacalol (316) by Akita’s group

5.16  Synthesis of Noreremophilanes An aluminum-catalyzed Diels-Alder reaction of diene 1141 with dienophile 1152 was studied by Reddy’s group, affording an adduct 1153 (Scheme 20) [333]. After hydrogenation of the double bond, an aldol reaction produced the desired norketone 134. The synthesis of noreremophilanes and the evaluation of their biological activities have been carried out by this same group (Scheme 21) [334]. An intermolecular Diels-Alder reaction of diene 1141 with aldehyde esters 1154 and 1155 afforded cyclohexenes 1156 and 1157, respectively. Cyclization and transesterification gave norketone 134. Using this strategy, several norketones (1158–1162) were prepared, and their biological activities were assessed, namely, antiangiogenic effects on developing zebrafish embryos and tumor-induced angiogenesis in a zebrafish xenograft model. Meng and Liu synthesized both eremophilane and noreremophilanes (Scheme 22) [335]. The conjugated methylation of 2-methylcyclohex-2-en-1-one (1112) with MeMgBr and alkylation with methyl vinyl ketone afforded diketone 1163. Aldol cyclization of diketone 1163 followed by oxidation gave 1164, which was converted to eremophilane 1165 by application of palladium chemistry using borane reagent 1169. O O 1141

O

+

O O

H3CO2C

H3CO2C 1153

H3CO2C 1152

Scheme 20  Synthesis scheme for norketone 134 by Reddy et al.

134

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M. Tori and C. Kuroda O

1141 O O EtO2C

O

O

+

R

1154 R = H 1155 R = CH3

EtO2C

R

H3CO2C

1156 R=H 1157 R=CH3

134

O

RO2C 1158 R = isobutyl 1159 R = n-butyl 1160 R = benzyl 1161 R = CH2CF3

O

EtO2C 1162

Scheme 21  Synthesis scheme for norketones by Muthukumarasamy et al.

Scheme 22  Synthesis for norsesquiterpenoids 1164, 1165, 1170, 101, and 102 by Meng and Liu

The diketone 1164 was converted to 1168 via allylic alcohols 1166 and 1167. Treatment of 1168 with allylic borane 1169 using palladium chemistry afforded 1171. Osmium oxidation furnished the 13-noreremophilanes 102 and 101. A norterpenoid 1170 was also synthesized starting from 1168. The asymmetric synthesis of norsesquiterpenoids has been achieved by Abe et al., using Shi’s method for the 1,4-diene 1173 derived from 2,6-dimethylbenzoic acid (1172) (Scheme 23) [336]. The chiral epoxide 1174 thus prepared was converted to 1175. A Claisen rearrangement for the introduction of a two-carbon unit to

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

223

Scheme 23  Synthesis for norsesquiterpenoids 101, 102, sagittacin E (106), and 107 by Abe et al.

1175 followed by an aldol-type cyclization of 1177, prepared through 1176, afforded 1178. The β-epoxide 1179 derived from 1178 was converted to 1180, which was then oxidized to 102 and 107, respectively, using different conditions. Their acetyl groups were hydrolyzed to give 101 and (+)-sagittacin E (106), respectively. The specific rotations of (−)-101, (−)-102, and (+)-106 were the same as the reported values for the natural products. However, the value for synthetic 107 and that of the natural product were different, although the reason for this has remained unclear. The absolute configuration was determined by X-ray crystallographic analysis of the p-nitrobenzoate derivative of 1180, as drawn in the structure. The configurations of compounds 102 and 107 also were confirmed by X-ray structural analyses.

5.17  Synthesis of Bakkane-type Sesquiterpenoids A route to the bakkane skeleton from cyclohexene was established by Greene’s group (Scheme 24) [337]. The (2 + 2) addition of 1,6-dimethylcyclohexene (1181) with trichloroacetyl chloride afforded an adduct 1182, which was converted to diester 1185 through diol 1183 and sulfonate 1184. The mixed ester 1185 was

224

M. Tori and C. Kuroda O Cl Cl 1181

1182

CH2OH

CH2Cl SO3C2H5

CH2OH 1183

1184 O

7

O

CO2But

1186

11 8

O

O

O 1185

O

1

CO2CH3

1187 (palmosalide C)

Scheme 24  Synthesis scheme for palmosalide C (1187) by Greene’s group

hydrolyzed followed by spontaneous lactonization to 1186. The spiro-lactone 1186 was transformed to palmosalide C (1187) in several steps. This same group further studied the methodology to construct a bakkane skeleton with a variety of functional groups (Scheme 25) [338]. The cyclohexene ketal 1188 was used as the starting material, and 1190 was prepared via 1189 by a similar route described above. Formation of the cyclopentane ring (from 1190 to 1191) and its lactonization afforded 1192. Homogynolide B (1193) was synthesized in several steps from 1192. Starting from (+)-carvone (1108), (−)-homogynolide A (1195), having an angeloyloxy group at C-2α, was prepared via 1194. It is interesting that palmosalide C (1187) has the C-8 carbonyl group in the lower side of a spiro γ-lactone while homogynolides A (1195) and B (1193) have this in the upper side [275]. An intramolecular Diels-Alder reaction was employed by Back et al. in the synthesis of a hydrindane skeleton (Scheme 26) [339]. The benzyloxy ketone 1196 was

Scheme 25  Synthesis scheme for (−)-homogynolide A (1195) and (±)-homogynolide B (1193) by Greene’s group

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

225

Scheme 26  Synthesis scheme for bakkenolide A (629) and its isomers by Back et al.

converted to the (E,E)- and (E,Z)-trienes 1197 and 1198, which were heated to afford 1199 (as a mixture of diastereoisomers). This mixture was lactonized to 1200 followed by Wittig methylenation to give bakkenolide A (629) and compounds 1201–1203. For construction of a cis-dimethylcyclohexane moiety, Constantino’s group used a Diels-Alder reaction of a diene (1204) and a dienophile (1102), catalyzed by NbCl5 (Scheme 27) [340]. The resulting compound 1205 was converted to the iodide 1207 via the diiodide 1206. Cyclization of 1207 gave a hydrindane 1208, which was brominated to yield 1209. By hydrolysis of its t-butyl ester, bakkenolide A (629) and its isomer 1210 were prepared. Since compounds 1207 and 1208 were obtained as a mixture of diastereoisomers at C-7, both isomers were produced. Jiang et  al. reported the synthesis of (−)-bakkenolide III (1219) starting from (+)-carvone (1108) (Scheme 28) [341]. (+)-Carvone (1108) was converted to (S)-3,4-dimethylcyclohex-2-en-1-one (1211), and conjugate addition of a magnesium reagent 1212 to 1211 and trapping with trimethylsilyl group gave 1213. Oxidative iodination and tin-catalyzed radical cyclization afforded cis-ketone 1214.

Scheme 27  Synthesis scheme for bakkenolide A (629) by Constantino’s group

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Scheme 28  Synthesis scheme for (−)-bakkenolide III (1219) by Jiang et al.

The latter compound was converted to alkene 1215. α-Acylation of the ketone derived from 1215 using acyl cyanide afforded 1216. Radical cyclization of 1216 with manganese acetate produced the lactone 1217 stereoselectively. Deprotection from the silyl group and reduction of the resulting ketone using samarium diiodide gave diol 1218. Finally, treatment of 1218 with TBAF effected retro-aldol and aldol reactions to produce (−)-bakkenolide III (1219).

5.18  Synthesis of Bisabolane-type Sesquiterpenoids In addition to eremophilanes, many bisabolane sesquiterpenoids have been isolated from Ligularia species, including L. lankongensis (Sect. 3.30) and L. hodgsonii (Sect. 3.28). Most of these compounds are highly oxygenated and have an aliphatic side chain with chiral centers (compounds 653–724). However, the relative and absolute configurations of the side chain have been left undetermined, because elucidation of the stereochemistry using ordinary spectroscopic techniques, such as NMR, IR, and MS methods, is difficult. However, when Kuroda and co-workers started their synthesis work on bisabolanes, several such stereochemical determinations for the bisabolane skeleton became clarified (Scheme 29) [342]. Starting from (−)-isopulegol (1220), allylic oxidation of the isopropenyl group followed by alkylation afforded 1221 as a mixture of isomers at C-8, which were separated. Homoallylic epoxidation of each isomer gave C-10 mixtures of 1222, and this was further converted to esters 1223a–1223c, 1224a–1224c, 1225a–1225c, and 1226a–1226c (a, acetate; b, 2-methylpropanoate; c, tiglate) after separation. Differences in the 1H and 13C NMR signals of the side chain (C-7 to C-14 positions) among these compounds were derived.

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

227

Scheme 29  Synthesis of diastereoisomers of chiral bisabolanes by Kuroda’s group

Scheme 30  Synthesis of highly oxygenated chiral bisabolanes by Kuroda’s group

To determine the structure of the natural bisabolane compound 682, a component of L. lankongensis, all four possible stereoisomers were synthesized (Scheme 30) [343]. Starting from (−)-carvone ((−)-1108), compounds 1229a–1229c, 1230a–1230c, 1231a–1231c, and 1232a–1232c (a, acetate; b, angelate; c, tiglate) were synthesized by an analogous route via 1227 and 1228. Both the 1H and 13C NMR data were assigned and compared to discern that diangelate 1230b was

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identical to 682. Then, the stereoselective synthesis of 1230b (= 682) was accomplished to establish the structure of the natural product. By supposing that the carbon skeleton of all bisabolane compounds from the same plant are formed via the same biosynthesis pathways, the absolute configuration of compound 657, isolated from L. lankongensis, may be depicted as in Scheme 30 [342, 343]. More detailed syntheses of related compounds may be anticipated, in order to gain a better understanding of the absolute configurations of bisabolanes.

5.19  Synthesis of Nelumol A Among many synthesis efforts toward phenylpropanoids, a synthesis of nelumol A (989) and its derivatives reported by Zhao et al. is introduced herein (Scheme 31) [270]. Nelumol A (989) is a major component of L. nelumbifolia (Sect. 3.27) and related species. 4-Hydroxy-3,5-dimethoxycinnamic acid (1233) was converted to ether 1234 in two steps. The methyl ester was reduced to afford nelumol A (989) followed by oxidation to nelumal A (993). Alternatively, methyl ester 1235 was prepared from gallic acid (905), followed by a similar pathway to obtain nelumol A (989) and nelumal A (993). These compounds were used for screening (Sect. 6) (note: the structure of nelumal A (993) drawn in Ref. [270] must be corrected).

Scheme 31  Synthesis scheme for nelumol A (989) and nelumal A (993) by Zhao et al.

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229

6  Biological Activities Several studies on the biological activities of compounds isolated from Ligularia species are described below in this contribution. The cytotoxicity of dehydrofukinone (5), and of compounds 20, 23, 340, 341, 342, and 358, was evaluated using several cancer cell lines, including HeLa, HL-60, NCI-H460, and Raji cells [41]. Compounds 341 and 342 showed significant inhibitory activities against HL-60 (IC50 2.8, 5.8 μM) and Raji (IC50 2.9, 4.2 μM) cells. Spiciformisin b (888), isolated from L. fischeri, demonstrated cytotoxicity against HL-60 cells, while spiciformisin a (887) exhibited no discernible cytotoxicity [187]. The allelopathic effects of compounds 97, 98, and 343 have been assessed using germination and seedling growth assays using lettuce [344]. Compounds 97 and 343 inhibited the growth of both hypocotyls and radicles; 97 was much more potent than 343 in this regard. All 12 compounds isolated from L. thomsonii (Table  47; 903–905, 921– 923, 926, 1015–1018, and 1035) were tested for antioxidant activity using a 1,1-­diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging assay [258]. Of these, caffeic acid (903), 895, and 979 showed strong activities (IC50 values of 19.6, 23.3, and 8.9 μM). Anti-complimentary activities have been measured for compounds 727, 728, 734, 749, 750, 751, and 754, isolated from L. knorringiana [235]. Compound 757 was found to be about one fifth as active (CH50 0.33 mM), when compared with the standard used, heparin (CH50 0.06 mM). Three compounds, cacalol (316), farfugin B (335), and 336, isolated from L. virgaurea (Table 3), have been found to inhibit [3H]-nitrendipine binding to pig heart membranes (IC50 3.98 × 10−5, 2.00 × 10−5, 2.75 × 10−5 M, respectively). Farfugin B (335) and 336 inhibited the contraction of arteries induced by high K+ ion levels and blocked Ca2+ ion influx by occupying the binding sites of dihydropyridine [168]. A series of 29 oxyprenylated and azoprenylated phenylpropanoids, comprised by nelumol A (989), nelumal A (993), 979, 980, and related compounds, was synthesized and tested in transfected cultured HepG2 cells as farnesoid X receptor (FXR) agonists [345]. Nelumol A (989) and nelumal A (993) showed potent activity. Nelumal A (993) was regarded as a novel lead compound in the search for FXR agonists. However, both compound 989 and 993 were found to be cytotoxic to KB cells (IC50 3.0 × 10−6, 2.6 × 10−6 M, respectively) [270, 346]. Synthetic compounds with a hydrindane skeleton similar to noreremophilanes have been tested for their antiangiogenic effects on developing zebrafish embryos as well as for tumor-inducing angiogenesis activity in a zebrafish xenograft model [334]. Among these compounds, noreremophilanes 1158, 1160, and 1161 showed potent effects (Sect. 5.16). Compound 1161 was the most active angiogenesis inhibitor.

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Fig. 75  Structures of 1146 and 1236

An interesting study on the insect-repellent and mosquitocidal effects of some noreremophilanes and related compounds was published [347]. Many compounds with a hydridane skeleton similar to nootkatone (1146), which is known as an insect repellent, were synthesized and tested. Among these compounds, the synthetic analogue 1236 exhibited potent repellent and knockdown effects on the mosquito. (+)-Nootkatone (1146) and norketone 1236 (Fig. 75) showed similar activities. Three diterpenoids, fischericin E (819), and 821 and 827, isolated from L. fischeri [246] inhibited the proliferation of human B lymphoblast HMy2.CIR cells at a concentration of 2.5–40  μM. Antiinflammatory and antiadipogenic activities of Ligularia taquetii have been tested, and chlorogenic acid was identified as an active compound [348]. Acknowledgments  We are indebted to Professor Yoshinori Asakawa, of Tokushima Bunri University, for his initial recommendation that we write this contribution and also for all of his subsequent encouragement. We also thank Professor Heinz Falk for his editorial guidance and many helpful suggestions. In addition, we are indebted to all those who have been involved in laboratory work, as carried out by our respective Ligularia species-related research team.

References 1. Illarionova I (2014) Taxonomic notes on sections Corymbosae and Subracemosae of genus Ligularia (Asteraceae). J Jap Bot 89:365 2. Liu S, Illarionova ID (2011) Flora of China, vol 20–21. Science Press, Beijing and Missouri Botanical Garden Press, St. Louis, p 376 3. Liu JQ, Wang YJ, Wang AL, Ohba H, Abbott RJ (2006) Radiation and diversification within the Ligularia-Cremanthodium-Parasenecio complex (Asteraceae) triggered by uplift of the Qinghai-Tibetan plateau. Mol Phylogen Evol 38:31 4. Kuroda C, Hanai R, Nagano H, Tori M, Gong, X (2012) Diversity of furanoeremophilanes in major Ligularia species in the Hengduan mountains. Nat Prod Commun 7:539 5. Kuroda C, Hanai R, Tori M, Okamoto Y, Saito Y, Nagano H, Ohsaki A, Hirota H, Kawahara T, Gong X (2014) Diversity in furanoeremophilane composition produced by Ligularia species (Asteraceae) in the Hengduan mountains area of China. J Synth Org Chem Jpn 72:717 6. Hou C, Kulka M, Zhang J, Li Y, Guo F (2014) Occurrence and biological activities of eremophilane-­type sesquiterpenes. Mini-Rev Med Chem 14:664 7. Wu L, Liao Z, Liu C, Jia H, Sun J (2016) Eremophilane sesquiterpenes from the genus Ligularia. Chem Biodivers 13:645

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

231

8. Fraga BM (2013) Natural sesquiterpenoids. Nat Prod Rep 30:1226 9. Seaman FC (1982) Sesquiterpene lactones as taxonomic characters in the Asteraceae. Bot Rev 48:121 10. Yaoita Y, Kikuchi M, Machida K (2012) Terpenoids and related compounds from plants of the family Compositae (Asteraceae). Nat Prod Commun 7:533 11. Ishii H, Tozyo T, Minato H (1965) Studies on sesquiterpenoids-IX. Structure of ligularol and ligularone from Ligularia sibirica Cass. Tetrahedron 21:2605 12. Tada M, Moriyama Y, Tanahashi Y, Takahashi T, Fukuyama M, Sato K (1971) New furanosesquiterpenes from Ligularia japonica Less. Furanoeremophilane-6β,10β-diol, 10β-hydroxy-6β-methoxyfuranoeremophilane and 10β-hydroxyfuranoeremophilan-6β-yl 2′ξ-methylbutanoate. Tetrahedron Lett 10 4007 13. Bohlmann F, Ehlers D, Zdero C, Grenz M (1977) Über Inhaltsstoffe der Gattung Ligularia. Chem Ber 110:2640 14. Yang JL, Wang R, Shi YP (2011) Phytochemicals and biological activities of Ligularia species. Nat Prod Bioprospect 1:1 15. Kuorda C, Nishio E (2007) Substituent effect in color of Ehrlich’s test of tetrahydrobenzofuran. Nat Prod Commun 2:581 16. Connolly JD, Hill RA (1991) Dictionary of terpenoids. Chapman & Hall, London 17. Nagano H, Torihata A, Matsushima M, Hanai R, Saito Y, Baba M, Tanio Y, Okamoto Y, Takashima Y, Ichihara M, Gong X, Kuroda C, Tori M (2009) Chemical and genetic study of Ligularia cyathiceps in Yunnan Province of China. Helv Chim Acta 92:2071 18. Hanai R, Tanabe S, Aoyama N, Okamoto Y, Tori M, Zhang N, Gong X, Kuroda C (2016) Chemical and genetic study of two Ligularia hybrids in Shangri-La county, Yunnan province, China. Nat Prod Commun 11:1057 19. Tori M, Tanio Y, Okamoto Y, Saito Y, Gong X, Kuroda C, Hanai R (2008) Chemical constituents of Ligularia franchetiana collected in Yunnan Province of China. Heterocycles 75:2029 20. Bohlmann F, Knoll KH (1979) Ein neues Norsesquiterpen und andere Inhaltsstoffe aus Ligularia-Arten. Phytochemistry 18:877 21. Shimizu A, Inoue K, Ichihara M, Hanai R, Saito Y, Okamoto Y, Tori M, Gong X, Kuroda C (2015) Chemotypes of Ligularia vellerea, its hybrids, and L. melanothyrsa. Nat Prod Commun 10:9 22. Tori M, Watanabe A, Matsuo S, Okamoto Y, Tachikawa K, Takaoka S, Gong X, Kuroda C, Hanai R (2008) Diversity of Ligularia kanaitzensis in sesquiterpenoid composition and neutral DNA sequences. Tetrahedron 64:4486 23. Saito Y, Hattori M, Iwamoto Y, Takashima Y, Mihara K, Sasaki Y, Fujiwara M, Sakaoku M, Shimizu A, Chao X, Kuroda C, Gong X, Hanai R, Tori M (2011) Overlapping chemical and genetic diversity in Ligularia lamarum and Ligularia subspicata. Isolation of ten new eremophilanes and a new seco-bakkane compound. Tetrahedron 67:2220 24. Tori M, Okamoto Y, Tachikawa K, Mihara K, Watanabe A, Sakaoku M, Takaoka S, Tanaka M, Gong X, Kuroda C, Hattori M, Hanai R (2008) Isolation of new eremophilane-type sesquiterpenoids, subspicatins A–D and subspicatolide from Ligularia subspicata, and chemical and genetic diversity of the species. Tetrahedron 64:9136 25. Kuroda C, Itoh T, Suzuki Y, Suzuki Y, Okamoto Y, Tori M, Hanai R, Gong X (2018) Chemical and genetic identity of Ligularia tsangchanensis and L. muliensis. Isolation of a cacalol precursor from a hybrid of L. tsangchanensis and L. vellerea. Nat Prod Commun 13:389 26. Tori M, Nakamizo H, Mihara K, Sato M, Okamoto Y, Nakashima K, Tanaka M, Saito Y, Sono M, Gong X, Shen Y, Hanai R, Kuroda C (2008) Chemical and genetic diversity of Ligularia vellerea in Yunnan, China. Phytochemistry 69:1158 27. Nakashima K, Hoshiyama K, Hayami C, Sakaoku M, Okamoto Y, Kuroda C, Gong X, Tori M (2018) Eremophilane sesquiterpenoids and nor- and dinorsesquiterpenoids from Ligularia virgaurea collected in China. Nat Prod Commun 13:795

232

M. Tori and C. Kuroda

28. Saito Y, Taniguchi M, Komiyama T, Ohsaki A, Okamoto Y, Gong X, Kuroda C, Tori M (2013) Four new compounds from Ligularia virgaurea: isolation of eremophilane and ­noreremophilane sesquiterpenoids and the absolute configuration of 2α-hydroxyeremophil-11-­ en-9-one by CD spectrum and DFT calculation. Tetrahedron 69:8505 29. Nagano H, Iwazaki Y, Matsushima M, Sato M, Gong X, Shen Y, Hirota H, Kuroda C, Hanai R (2007) High diversity of Ligularia dictyoneura in chemical composition and DNA sequence. Chem Biodivers 4:2874 30. Wang C, Li J, Yang R, Zhau Y, Cheng Y, Zhang Z, He L (2014) Petasins from the rhizomes of Ligularia fischeri and its derivatives. Rec Nat Prod 8:156 31. Shimizu A, Suzuki Y, Torihata A, Hanai R, Saito Y, Tori M, Gong X, Kuroda C (2012) Complex diversity in Ligularia kanaitzensis. Nat Prod Commun 7:431 32. Okamoto Y, Taniguchi M, Terada K, Nakashima K, Gong X, Hanai R, Tori M, Kuroda C (2016) Diversity in chemical constituents of Ligularia longihastata collected in China. Nat Prod Commun 11:145 33. Okamoto Y, Fukui A, Hashida T, Shiojiri K, Kuroda C, Tori M, Gong X, Hanai R (2019) Chemical composition of intergeneric hybrids between Ligularia and Cremanthodium collected in Sichuan province of China. Nat Prod Commun 14: doi: https://doi.org/10.117 7/1934578X19878931 34. Saito Y, Otsubo T, Iwamoto Y, Nakashima K, Okamoto Y, Gong X, Kuroda C, Tori M (2015) Four new sesquiterpenoids from Ligularia subspicata collected in China: Isolation of a bakkane-type lactone, an eremophilane-type lactone, and two orthoesters. Nat Prod Commun 10:831 35. Torihata A, Hanai R, Gong X, Shen Y, Kuroda C (2007) Chemical and genetic differentiation of Ligularia tsangchanensis in Yunnan and Sichuan provinces of China. Chem Biodivers 4:500 36. Nagano H, Hanai R, Yamada H, Matsushima M, Miura Y, Hoya T, Ozawa M, Fujiwara M, Kodama H, Torihata A, Onuki H, Nezu Y, Kawai S, Yamazaki M, Hirota H, Saito Y, Tori M, Ohsaki A, Gong X, Kuroda C (2012) Chemical and genetic study of Ligularia duciformis and related species in Sichuan and Yunnan Provinces of China. Chem Biodivers 9:789 37. Kuroda C, Shibayama C, Inoue K, Okamoto Y, Tori M, Saito Y, Hanai R, Gong X (2016) Chemical lineages of Ligularia fischeri. Nat Prod Commun 11:139 38. Shimizu A, Watanabe S, Hanai R, Okamoto Y, Tori M, Gong X, Kuroda C (2014) Chemical and genetic studies on hybrid of Ligularia subspicata and Ligularia cyathiceps collected in Yunnan province of China. Chem Biodivers 11:1438 39. Marco JA, Sanz JF, Garcia-Sarrion A, Rustaiyan A (1991) Germacrane esters from roots of Ligularia persica. Phytochemistry 30:2325 40. Saito Y, Ichihara M, Takashima Y, Okamoto Y, Gong X, Hanai R, Kuroda C, Tori M (2017) Chemical constituents of hybrids of Ligularia cyathiceps and L. lamarum/L. subspicata collected in China: structures of subspicatins M, N, O1, and O2, and related compounds. Phytochemistry 140:69 41. Ponomarenko LP, Kalinovsky AI, Berdyshev DV, Kuzmich AS, Menchinskaya ES, Pislyagin EV, Kim NY, Glazunov VP, Dmitrenok PS, Silchenko AS, Avilov SA, Gorovoy PG, Stonik VA (2016) Chemical constituents of Ligularia alticola Worosch. leaves and their biological activities. Phytochem Lett 15:46 42. Tan A, Wang Z, Hong X, Li S, Hao X (2002) Study on the chemical constituents of Ligularia dictyoneura. Chin Pharm Univ 33:104 43. Bohlmann F, Fritz U (1980) Isofukinone, an eremophilane from Ligularia speciosa. Phytochemistry 19:2471 44. Saito Y, Ichihara M, Okamoto Y, Gong X, Kuroda C, Tori M (2014) Twelve new compounds from Ligularia melanothyrsa; isolation of melanothrsins A-E, normelanothyrsin A, and other eremophilane sesquiterpenoids. Tetrahedron 70:2621

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

233

45. Saito Y, Takashima Y, Kamada A, Suzuki Y, Suenaga M, Okamoto Y, Matsunaga Y, Hanai R, Kawahara T, Gong X, Tori M, Kuroda C (2012) Chemical and genetic diversity of Ligularia virgaurea collected in northern Sichuan and adjacent areas of China. Isolation of 13 new compounds. Tetrahedron 68:10011 46. Okamoto Y, Taniguchi M, Hanai R, Nakashima K, Gong X, Kuroda C, Tori M (2015) New chemical constituents of Ligularia liatroides collected in China. In: The 59th Symposium on the Chemistry of Terpenes, Essential Oils, and Aromatics, Abashiri, Japan. Abstract 1AI-5 47. Taniguchi M, Nakashima K, Okamoto Y, Gong X, Kuroda C, Tori M (2015) Constituents of Ligularia brassicoides collected in China: A new Diels-Alder adduct of eremophilan-10β-ol and methacrylic acid. Nat Prod Commun 10:827 48. Hanai R, Gong X, Tori M, Kondo S, Otose K, Okamoto Y, Nishihama T, Murota A, Shen Y, Wu S, Kuroda C (2005) Chemical and genetic study of Ligularia tongolensis, Ligularia cymbulifera, and Ligularia atroviolacea in the Hengduan Mountains of China. Bull Chem Soc Jpn 78:1302 49. Kato T, Hirota H, Kuroda C, Gong X, Ohsaki A (2017) New eremophilane-type sesquiterpenes from Ligularia cymbulifera. Nat Prod Commun 12:1165 50. Ishii H, Tozyo T, Minato H (1966) Studies on sesquiterpenoids. Part XIII. Components of the root of Ligularia fischeri Turcz. J Chem Soc (C): 1545 51. Hirota H, Horiguchi Y, Kawai S, Hanai R, Gong X, Kuroda C (2014) The first isolation of furanoeremophilane from Ligularia nelumbifolia. Nat Prod Commun 9:325 52. Wang CF, Zhao Y, Liu YL, Zhang ZZ (2008) Two new eremophilane-type sesquiterpenoids from the rhizomes of Ligularia veitchiana (Hemsl.) Greenm. Helv Chim Acta 91:1712 53. Xie GB, Xie Y, Hu YZ, Zhu ZX (2016) Cytotoxic sesquiterpenoids from Ligularia pleurocaulis. Phytochemistry 125:99 54. Wang WS, Zhu QX, Gao K, Jia ZJ (2000) Sesquiterpenes from Ligularia fischeri. J Chin Chem Soc 47:1291 55. Tan A, He H, Yang H, Zhang M, Wang Z, Hao X (2003) Chemical constituents of Ligularia dictyoneura. Acta Pharm Sin 38:924 56. Li YS, Wang ZT, Zhang MA, Luo SD, Chen JJ (2002) Study on the terpene compounds from Ligularia kanaitzensis. J Chin Pharm Sci 11:115 57. Li YS, Wang ZT, Zhang MA, Luo SD, Chen JJ (2002) Study on identification of terpenes from Ligularia kanaitzensis. Chin Pharm J 37:12 58. Liu X, Li J, Luo J, Li D, Zhang H, Guo Z (2016) A new sesquiterpene from Ligularia fischeri. Chem Nat Comp 52:642 59. Li PL, Jia ZJ (2008) A triterpene and new sesquiterpenes from the roots of Ligularia sagitta. Helv Chim Acta 91:1717 60. Wang Q, Mu Q, Shibano M, Morris-Natschke SL, Lee KH, Chen DF (2007) Eremophilane sesquiterpenes from Ligularia macrophylla. J Nat Prod 70:1259 61. Chen JJ, Chen CJ, Yao XJ, Jin XJ, Gao K (2014) Eremophilane-type sesquiterpenoids with diverse skeletons from Ligularia sagitta. J Nat Prod 77:1329 62. Zhao Y, Peng HR, Jia ZJ (1994) Six new eremophilane derivatives from two Ligularia species. J Nat Prod 57:1626 63. Tori M, K Honda, H Nakamizo, Y Okamoto, M Sakaoku, S Takaoka, X Gong, Y Shen, C Kuroda, R Hanai (2006) Chemical constituents of Ligularia virgaurea and its diversity in southwestern Sichuan of China. Tetrahedron 62:4988 64. Xu JQ, Hu LH (2008) Five new eremophilane sesquiterpenes from Ligularia przewalskii. Helv Chim Acta 91:951 65. Li Y, Shi YP (2006) Sesquiterpenoids and lignans from Ligularia virgaurea ssp. oligocephala. Helv Chim Acta 89:870 66. Zhao Y, Jia Z, Yang L (1994) Novel sesquiterpenes from Ligularia veitchiana. Planta Med 60:91

234

M. Tori and C. Kuroda

67. Fu B, Zhu QX, Yang XP, Jia ZJ (2002) New sesquiterpenes from Ligularia macrophylla. Pharmazie 57:275 68. Peng HR, Shi YP, Jia ZJ (1997) New sesquiterpenes from two Ligularia species. Planta Med 63:335 69. Wang XY, Sun LL, Huang KX, Shi SY, Zhang LJ, Xu JH, Peng H, Sun XF, Wang LW, Wu XM, Zhao Y, Li XK, Stöckigt J, Qu J (2009) Phytochemical investigation and c­ ytotoxic evaluation of the components of the medicinal plant Ligularia atroviolacea. Chem Biodivers 6:1053 70. Zhao Y, Jia ZJ, Peng HR (1995) Eight new eremophilane derivatives from the roots of Ligularia przewalskii. J Nat Prod 58:1358 71. Yang L, Peng HR, Jia ZJ (1995) New sesquiterpene from Ligularia sagitta. Chin Chem Lett 6:875 72. Liu JX, Wei XN, Shi YP (2006) Eremophilane sesquiterpenes from Ligularia myriocephala. Planta Med 72:175 73. Shen T, Li PL, Yuan CS, Jia ZJ (2007) Three new eremophilane-type sesquiterpenes from Ligularia macrophylla. Acta Chim Sin 65:1638 74. Jia ZJ, Zhao Y, Tan RX (1993) New sesquiterpenes from the roots of Ligularia veitchiana. J Nat Prod 56:494 75. Ye Y, Dawa D, Liu GH, Zhao M, Tseden D, Gu YC, Ding LS, Cao ZX, Zhou Y (2018) Antiproliferative sesquiterpenoids from Ligularia rumicifolia with diverse skeletons. J Nat Prod 81:1992 76. Saito Y, Iga S, Hoshiyama K, Nakashima K, Okamoto Y, Kuroda C, Gong X, Tori M (2019) Eremophilane, bakkane, secoeremophilane, and secobakkane sesquiterpenoids from Ligularia virgaurea collected in China. Tetrahedron 75:2239 77. Xue HQ, Ma XM, Wei XN, Wu SX, Wang HQ (2007) Study on chemical constituents from Ligularia intermedia of Shanxi. China J Chin Mat Med 32:1044 78. Saito Y, Sasaki Y, Komiyama T, Ohsaki A, Okamoto Y, Gong X, Kuroda C, Tori M (2014) Structure and cytotoxic evaluation of five 12-oxygenated eremophilanes from Ligularia lingiana. Tetrahedron 70:5878 79. Zhang CF, Zhang M, Qu R, Wang ZT (2004) Studies on sesquiterpenes constituents of Ligularia pleurocaulis. Chin J Nat Med 2:341 80. Li WX, Lei M, Fei DQ, Gao K (2009) Eremophilane-type sesquiterpene derivatives from Ligularia hodgsonii. Planta Med 75:635 81. Fei DQ, Li SG, Liu CM, Wu G, Gao K (2007) Eremophilane-type sesquiterpene derivatives from the roots of Ligularia lapathifolia. J Nat Prod 70:241 82. Silchenko AS, Kalinovsky AI, Ponomarennko LP, Avilov SA, Andryjaschenko PV, Dmitrenok PS, Gorovoy PG, Kim NY, Stonik VA (2015) Structures of eremophilane-type sesquiterpene glucosides, alticolosides A–G, from the Far Eastern endemic Ligularia alticola Worosch. Phytochemistry 111:169 83. Ponomarenko LP, Ermoraeva SD, Doudkin RV, Dyshlovoy SA, Gorovoy PG (2017) Eremophilane-type glucosides from the leaves of Ligularia calthifolia Maxim. Phytochemistry Lett 21:264 84. Silchenko AS, Ponomarenko LP, Kalinovsky AI, Berdyshev DV, Avilov SA, Andryjaschenko PV, Lyakhova EG, Kuzmich AS, Terentieva NA, Gorovoy PG (2017) Structures of minor glucosides from the Far Eastern high-mountain endemic plant Ligularia alticola Worosch. Screening of bioactivity for some glycosides from L. alticola. Phytochem Lett 20:234 85. Guo Z, Weng CW, Liu WX, Shen T (2010) A new norsesquiterpenoid from the roots of Ligularia fischeri. J Chem Res:390 86. Wu QH, Liu CM, Chen YJ, Gao K (2006) Terpenoids from the roots of Ligularia muliensis. Helv Chim Acta 89:915 87. Zhang ZX, Fei DQ, Jia ZJ (2008) Eremophilane-type sesquiterpenes from the roots of Ligularia virgaurea. Helv Chim Acta 91:1045

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

235

88. Dai W, Li H, Cong W, Zhao W, Wang Q (2016) Two new eremophilane sesquiterpenes and one new resorcinol from Ligularia knorringiana. Nat Prod Commun 11:135 89. Dong LL, Xiong HY, Qi FM, Li HH, Fan GX, Che JM, Guo DD, Zhang ZX, Fei DQ (2015) A new norsesquiterpenoid from Ligularia virgaurea. J Asian Nat Prod Res 17:415 90. Xu JQ, Hu LH (2009) New eremophilane sesquiterpenes from Ligularia japonica. Helv Chim Acta 92:357 91. Xu JQ, Li YS, Li YM, Jiang SH, Tan CH, Zhu DY (2006) New eremophilane-type sesquiterpenes from Ligularia hodgsonii. Planta Med 72:567 92. Li YS, Wang ZT, Zhang M, Chen JJ, Luo SD (2004) Two new norsesquiterpenes from Ligularia lapathifolia. Nat Prod Res 18:99 93. Liao JL, Zhu QX, Yang XP, Jia ZJ (2002) Sesquiterpenes from Ligularia hodgsonii. J Chin Chem Soc 49:129 94. Gao K, Jia ZJ (1998) Phenolic norsesquiterpenes from Ligularia dentata. Phytochemistry 49:167 95. Naya K, Okayama T, Fujiwara M, Nakata M, Ohtsuka T, Kurio S (1990) Sesquiterpenes from the rhizomes of Ligularia dentata Hara. Bull Chem Soc Jpn 63:2239 96. Zhang WJ, Qi HY, Shi YP (2010) Norsesquiterpene derivatives from the roots of Ligularia fischeri. Planta Med 76:159 97. Gao K, Yang L, Jia ZJ (1997) New sesquiterpenes from the roots of Ligularia dentata. Planta Med 63:461 98. Wang Q, Chen DF (2007) A guaianolide sesquiterpene, a chromenone, and a flavanone from Ligularia macrophylla. Helv Chim Acta 90:2432 99. Fu B, Zhu QX, Yang XP, Jia ZJ (1999) New sesquiterpenes from Ligularia songarica. Pharmazie 54:620 100. Fei DQ, Wu G, Liu CM, Gao K (2007) A novel benzofuran derivative, a new olean-type triterpene and other constituents from Ligularia odontomanes. Chem Pharm Bull 55:577 101. Li EW, Gao K, Jia ZJ (2004) Two new compounds from Ligularia dolichobotrys. Pharmazie 59:646 102. Baba H, Yaoita Y, Kikuchi M (2007) Sesquiterpenoids and lactone derivatives from Ligularia dentata. Helv Chim Acta 90:1028 103. Tian J, Xie GB, Li TN (2015) Terpenoids from Ligularia kangtingensis. Pharmacog Magazine 11:44 104. Ma XM, Shi YP (2011) Chemical constituents from Ligularia nanchuanica. Chem Nat Comp 46:997 105. Chen HM, Jia ZJ, Yang L (1992) Sesquiterpenes and a diterpene lactone with an unusual carbon skeleton from Ligularia sagitta. Phytochemistry 31:2146 106. Li L, Xu LW, Jiang YF, Xi CJ, Wang HQ, Suo YR (2004) Isolation, characterization and crystal structure of natural eremophilenolide from Ligularia sagitta. Z Naturforsch 59b:921 107. Jia ZJ, Zhao Y, Tan RX (1992) New eremophilane type lactones from the roots of Ligularia veitchiana. Planta Med 58:365 108. Wang Y, Yuan CS, Han YF, Jia ZJ (2003) Sesquiterpenes from roots of Ligularia veitchiana. Pharmazie 58:349 109. Xie G, Tian J, Kover KE, Mandi A, Kurtan T (2014) Structural and stereochemical studies of a tetralin norsesquiterpenoid from Ligularia kangtingensis. Chirality 26:574 110. Deng MC, Dong WW, Jiao W, Lu RH (2009) New eremophilane sesquiterpenes from the roots of Ligularia fischeri. Helv Chim Acta 92:495 111. Li SL, Liu YH, Hao QJ, Zhang XM, Jia YM, Li N (2014) A new eremophilane derivative from Ligularia intermedia. China J Mat Med 39:2281 112. Zhang ZX, Lin CJ, Li PL, Jia ZJ (2007) New weakly cytotoxic eremophilane sesquiterpenes from the roots of Ligularia virgaurea. Planta Med 73:585 113. Li S, Huang H, Liu J, Song T, Wu K, Han Y, Xia M (2013) Two new sesquiterpenes from Ligularia dictyoneura. Phytochem Lett 6:315

236

M. Tori and C. Kuroda

114. Saito Y, Iga S, Nakashima K, Okamoto Y, Gong X, Kuroda C, Tori M (2015) Terpenoids from Ligularia virgaurea collected in China: the first example of two bakkane derivatives with an anhydride-type ring C and nineteen new chemical constituents. Tetrahedron 71:8428 115. Saito Y, Hidaka M, Fukuda A, Okamoto Y, Nakashima K, Tori M, Hanai R, Gong X, Watanabe E, Kuroda C (2017) Intra-specific diversity of the chemical composition of Ligularia lamarum in the Hengduan Mountains, China: The structures of four new eremophilanes and a new seco-eremophilane. Phytochem Lett 20:139 116. Huang LH, Xu YJ, Liu HL, Liu XQ, Shang JN, Han GT, Yao MJ (2011) Eremophilane-type sesquiterpene lactones from Ligularia hodgsonii Hook. Phytochemistry 72:514 117. Saito Y, Sasaki Y, Ohsaki A, Okamoto Y, Gong X, Kuroda C, Tori M (2014) Structures of six new compounds from Ligularia brassicoides. Tetrahedron 70:9726 118. Wu QX, Wei QY, Shi YP (2006) Sesquiterpenes with various carbon skeletons from Ligularia virgaurea ssp. oligocephala. Pharmazie 61:241 119. Fu B, Zhu QX, Yang XP, Jia ZJ (2002) A new bisesquiterpene from Ligularia macrophylla. Chin Chem Lett 13:249 120. Hanai R, Watanabe S, Matsushima M, Nagano H, Kuroda C, Gong X (2019) Diversity in eremophilane components of Ligularia dictyoneura in Yunnan and Sichuan provinces of China. Nat Prod Commun 14: doi: https://doi.org/10.1177/1934578X19878935 121. Wang WJ, Zhan R, Chen Y (2019) Two new eremophilane sesquiterpenoids from Ligularia dictyoneura. Nat Prod Res doi: https://doi.org/10.1080/14786419.2018.1556652 122. Ishii H, Tozyo T, Nakamura M, Minato H (1970) Studies on sesquiterpenoids– XIX. Structure and absolute configuration of liguloxide, liguloxidol and liguloxidol acetate. Tetrahedron 26:2911 123. Ishizaki Y, Tanahashi Y, Takahashi T, Tori K (1969) Furanoeremophilan-14β,6α-olide, a new furanosesquiterpene lactone from Ligularia hodgsonii Hook.f. The structure and nuclear Overhauser effects. J Chem Soc Chem Commun:551 124. Ishizaki Y, Tanahashi Y, Moriyama Y, Takahashi T, Koyama H (1974) Sesquiterpenes from the roots of Ligularia hodgsonii. Phytochemistry 13:674 125. Ishizaki Y, Tanahashi Y, Tsuyuki T, Takahashi T, Tori K (1979) Furanoeremophilan-14β,6α-­ olide. A new furanosesquiterpene lactone of an eremophilane-type from Ligularia hodgsonii Hook.f. Bull Chem Soc Jpn 52:1182 126. Kuroda C, Kobayashi R, Nagata A, Nakadozono Y, Itoh T, Okamoto Y, Tori M, Hanai R, Gong X (2017) Terpenoids and phenylpropanoids in Ligularia duciformis, L. kongkalingensis, L. nelumbifolia, and L. limprichtii. Molecules 22:2062 127. Hanai R, Yamada H, Suzuki Y, Nagano H, Kawahara T, Yu JJ, Gong X, Kuroda C (2012) Chemical constituents of Ligularia nelumbifolia and L. subspicata hybrid collected in Shangri-La county, Yunnan province of China. Nat Prod Commun 7:1565 128. Shimizu A, Hanai R, Okamoto Y, Tori M, Yu JJ, Gong X, Kuroda C (2016) Chemical constituents in hybrids of Ligularia tongolensis and L. cymbulifera: chemical introgression in L. tongolensis. Chem Biodivers 13:837 129. Bohlmann F, Grenz M (1979) Ein neues Furanoeremophilan-Derivat aus Ligularia macrophylla. Phytochemistry 18:491 130. Kuroda C, Inagaki K, Okamoto Y, Tori M, Hanai R, Yamada H, Nagano H, Gong X (2017) Chemical diversity in Ligularia oligonema. Nat Prod Commun 12:1161 131. Bohlmann F, Zdero C (1980) New furanoeremophilane derivatives from Ligularia thyrsoidea. Phytochemistry 19:1550 132. Chen HM, Zhang KQ, Cai MS, Jia ZJ (1997) Terpenes from Ligularia intermedia. Ind J Chem 36B:1198 133. Chen HM, Zhang KQ, Cai MS, Jia ZJ (1997) Terpenes from Ligularia intermedia. Ind J Chem 37B:720

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

237

134. Shen TS, Xie WD, Jia ZJ (2005) Two new sesquiterpenes from Ligularia macrophylla. Chin Chem Lett 16:1220 135. Ponomarennko LP, Kalinovskii AI, Gorovoi PG, Stonik VA (2014) Chemical composition of the ethyl acetate extract of Ligularia alticola roots. Chem Nat Comp 49:1006 136. Torihata A, Chao X, Kuroda C, Hanai R, Hirota H, Gong X (2009) Chemical and genetic differentiation of Ligularia hodgsonii in Japan and China. Chem Biodivers 6:2184 137. Okamoto Y, Nakadozono Y, Shiojiri K, Suehiro S, Saito Y, Matsuo Y, Tanaka T, Kuroda C, Tori M, Gong X, Hanai R (2019) Diversity of furanoeremophilane composition of Ligularia tongolensis. Nat Prod Commun 14: doi: https://doi.org/10.1177/1934578X19878937 138. Saito Y, Shiosaki Y, Fujiwara M, Mihara K, Nakamizo H, Otose K, Okamoto Y, Nakashima K, Hanai R, Kuroda C, Gong X, Matsuo Y, Tanaka T, Tori M (2018) Eremophilanes from Ligularia hookeri collected in China and structural revision of 3β-acyloxyfuranoeremophilan-15,6-olide. Chem Pharm Bull 66:668 139. Moriyama Y, Tsuyuki T, Takahashi T, Koyama H (1974) Furanoeremophilan-14β,6α-olide from Ligularia species. Phytochemistry 13:288 140. Chen HM, Cai MS, Jia ZJ (1997) Sesquiterpenes from Ligularia intermedia. Phytochemistry 45:1441 141. Xue HQ, Ma XM, Xing XL, Wang HQ (2007) Eremophilane sesquiterpene lactones from Ligularia intermedia Nakai of Shanxi. Chem Nat Comp 43:746 142. Zhang ZX, Li HH, Dong LL, Fan GX, Fei DQ (2015) Chemical constituents of the roots of Ligularia lapathifolia. Chem Nat Comp 51:375 143. Cantrell CL, Duke SO, Fronczek FR, Osbrink WLA, Mamonov LK, Vassilyev JI, Wedge DE, Dayan FE (2007) Phytotoxic eremophilanes from Ligularia macrophylla. J Agric Food Chem 55:10656 144. Liu SJ, Liao ZX, Liu C, Yao GY, Wang HS (2014) A new triterpenoid and eremophilanolide from Ligularia przewalskii. Phytochem Lett 9:11 145. Saito Y, Kamada A, Okamoto Y, Gong X, Kuroda C, Tori M (2014) Isolation and structure of three bislactones, eremopetasitenin B4 and eremofarfugins F and G, from Ligularia przewalskii and revision of the structure of an epoxy-lactone isolated from Ligularia intermedia. Chem Lett 43:1740 146. Shi SY, Zhang YP, Huang KL, Liu SQ, Zhao Y (2008) Purification of eremophilane-type sesquiterpenes from Ligularia atroviolacea by high speed countercurrent chromatography. J Liq Chromatogr 31:828 147. Chen J, Zheng G, Zhang Y, Aisa HA, Hao XJ (2017) Phytotoxic terpenoids from Ligularia cymbulifera roots. Front Plant Sci 7:2033 148. Li YS, Wang ZT, Zhang M, Zhou H, Chen JJ, Luo SD (2004) New eremophilane-type sesquiterpenes from Ligularia lapathifolia. Planta Med 70:239 149. Li YS, Luo SD, Zhang M, Chen JJ, Wang ZT (2001) Constituents of Ligularia vellerea (Franch.) Hand-Mazz. China J Chin Mat Med 26:835 150. Saito Y, Takashima Y, Okamoto Y, Gong X, Hanai R, Kuroda C, Tori M (2016) Three new eremophilanes from a Ligularia hybrid collected in China. Nat Prod Commun 11:901 151. Nagano H, Matsushima M, Yamada H, Hanai R, Gong X, Kuroda C (2010) Two new furanoeremophilane sesquiterpenoids from Ligularia oligonema. Nat Prod Commun 5:1 152. Liu X, Wu QX, Wei XN, Shi YP (2007) Novel sesquiterpenes from Ligularia virgaurea ssp. oligicephala. Helv Chim Acta 90:1802 153. Kuroda C, Inagaki K, Chao X, Inoue K, Okamoto Y, Tori M, Gong X, Hanai R (2015) Chemical and genetic diversity of Ligularia hodgsonii in China. Nat Prod Commun 10:823 154. Nagano H, Kanda M, Yamada H, Hanai R, Gong X, Kuroda C (2010) Chemical and genetic study of Ligularia anoleuca and L. veitchiana in Yunnan and Sichuan provinces of China. Helv Chim Acta 93:1945

238

M. Tori and C. Kuroda

155. Shimizu A, Suzuki Y, Hanai R, Okamoto Y, Tori M, Gong X, Kuroda C (2014) Chemical and genetic similarity and diversity of Ligularia anoleuca and L. fischeri collected in the Hengduan mountains of China. Phytochemistry 102:137 156. Nagano H, Iwazaki Y, Gong X, Shen Y, Kuroda C, Hanai R (2006) Chemical and genetic differentiation of Ligularia pleurocaulis in northwestern Yunnan and Southwestern Sichuan provinces of China. Bull Chem Soc Jpn 79:300 157. Hwang BY, Lee JH, Koo TH, Kim HS, Hong YS, Ro JS, Lee KS, Lee JJ (2002) Furanoligularenone, an eremophilane from Ligularia fischeri, inhibits the LPS-induced production of nitric oxide and prostaglandin E2 in macrophages. Planta Med 68:101 158. Xie WD, Weng CW, Li X, Row KH (2010) Eremophilane sesquiterpenoids from Ligularia fischeri. Helv Chim Acta 93:1983 159. Zhang M, Zhang CF, Wang ZT (2005) The chemical constituents of Ligularia pleurocaulis. Acta Pharm Sin 40:529 160. Liu JQ, Zhang M, Zhang CF, Qi HY, Bashall A, Bligh SWA, Wang ZT (2008) Cytotoxic sesquiterpenes from Ligularia platyglossa. Phytochemistry 69:2231 161. Moriyama Y, Sato T, Nagano H, Tanahashi Y, Takahashi T (1972) New furanosesquiterpenes from Ligularia fischeri Turcz. 1β,10β-Epoxyfuranoeremophilan-6β-ol and its derivative. Chem Lett: 637 162. Sato T, Moriyama Y, Nagano H, Tanahashi Y, Takahashi T (1975) New furanosesquiterpenes from Ligularia fischeri Turcz. 1β,10β-Epoxyfuranoeremophilan-6β-ol and its derivative. Bull Chem Soc Jpn 48:112 163. Okamoto Y, Taniguchi M, Nakashima K, Gong X, Hanai R, Kuroda C, Tori M (2016) Chemical constituents of Ligularia wilsoniana collected in Chongqing, China. Nat Prod Commun 11:149 164. Bohlmann F, Suwita A (1977) Neue Furanoeremophilane aus Ligularia vorobierii Worosh. Chem Ber 110:1759 165. Zhang WJ, Li XH, Shi YP (2010) A pair of epimeric spirosesquiterpenes from the roots of Ligularia fischeri. J Nat Prod 73:143 166. Wang Y, Yuan CS, Han YF, Jia ZJ (2002) Two new sesquiterpenes from Ligularia veitchiana. Chin Chem Lett 13:1069 167. Liu SJ, Liu JQ, Zhang M, Zhang CF, Wang ZT (2007) Secondary metabolites from Ligularia sagitta. Biochem Syst Ecol 35:245 168. Chen HM, Wang YY, Mao JM, Cai MS, Jia ZJ (1997) Synthesis and pharmacological activities of the derivatives of furanosesquiterpenes from Ligularia virgaurea. Planta Med 63:299 169. Jia ZJ, Chen HM (1991) Benzofuranosesquiterpenes from Ligularia virgaurea. Phytochemistry 30:3132 170. Sun XB, Xu YJ, Qui DF, Yuan CS (2007) Sesquiterpenoids from the rhizome of Ligularia virgaurea. Helv Chim Acta 90:1705 171. Wang BG, Jia ZJ, Yang XP (1997) Two minor benzofuranosesquiterpene dimers from Ligularia virgaurea. Planta Med 63:577 172. Wang BG, Yang L, Jia ZJ, Chen HM (1998) New sesquiterpenes from the roots of Ligularia virgaurea. Indian J Chem 37B:669 173. Chen HM, Wang BG, Jia ZJ (1996) Novel sesquiterpenes from Ligularia virgaurea. Indian J Chem 35B:1304 174. Jia ZJ, Zhao Y, Tan RX, Li Y (1992) Sesquiterpenes and other constituents from Ligularia veitchiana. Phytochemistry 31:199 175. Zhao Y, Jia ZJ, Tan RX, Yang L (1992) Eremophilanolides from the roots of Ligularia veitchiana. Phytochemistry 31:2785 176. Yuan YL, Fang LZ, Bai SP, Liang HJ, Ye DD (2013) A novel eremophilane sesquiterpenoid from Ligularia intermedia root and rhizomes. Chem Nat Comp 49:258 177. Fu K, Yu N, Zhang Y, Zhao YG (2007) Chemical constituents of Ligularia duciformis. Acta Pharm Sin 42:621

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

239

178. Moriyama Y, Takahashi T (1976) New sesquiterpene lactones of eremophilane-type from Ligularia fauriei (Fr.) Koidz. Bull Chem Soc Jpn 24:3196 179. Wang WS, Gao K, Yang L, Jia ZJ (2000) Eremophilenolides from Ligularia fischeri. Planta Med 66:189 180. Wu QH, Wang HX, Gao K (2006) Two new eremophilenolides from Ligularia muliensis. Chin Chem Lett 17:215 181. Li YS, Wang ZT, Zhang MA,Zhang MA, Tan AM, Chen L (2005) Benzofuran compounds from Ligularia caloxantha. Chin Trad Herbal Drugs 36:335 182. Tan A, Yang H, Li Y, Bi Z, Zhang M, Wang Z (2004) Study on the chemical constituents of Ligularia dictyoneura. Chin Pharm J 39:498 183. Moriyama Y, Takahashi T (1976) New eremophilane-type lactones from Ligularia fauriei (Fr.) Koidz. Chem Pharm Bull 24:360 184. Zhang ZX, Fei DQ (2011) 6β,8β-Dihydroxyeremophil-7(11)-en-8α,12-olide. Acta Cryst E67:o2957 185. Wang WS, Gao K, Jia ZJ (1999) Two new eremophilanolides from Ligularia fischeri. Chin Chem Lett 10:571 186. Nakatani M, Maeda S, Higashi K, Kurawaki J (2003) Three new eremophilenolides from Ligularia hiberniflorum (Makino) Kitam. Heterocycles 60:373 187. Lee KT, Koo SJ, Jung SH, Choi J, Jung HJ, Park HJ (2002) Structure of three new terpenoids, speciformisins A and B, and monocyclosqualene, isolated from the herbs of Ligularia fischeri var. speciformis and cytotoxicity. Arch Pharm Res 25:820 188. Park HJ, Kwon SH, Yoo KO, Sohn IC, Lee KT, Lee HK (2000) Sesquiterpenes from the leaves of Ligularia fischeri var. spiciformis. Planta Med 66:783 189. Xie WD, Gao X, Shen T, Jia ZJ (2006) Two new benzofurans and other constituents from Ligularia przewalskii. Pharmazie 61:556 190. Wang YM, Zhao JQ, Yang JL, Tao YD, Mei LJ, Shi YP (2017) Chemical constituents from Ligularia purdomii (Turrill) Chittenden. Biochem Syst Ecol 72:8 191. Xu YJ, Nan ZD, Huang HL, Yuan CS (2009) New eremophilanolides from Ligularia hodgsonii. Helv Chim Acta 92:209 192. Li EW, Gao K, Jia ZJ (2004) A new stigmasterol and a new eremophilenolide from Ligularia dolichobotrys. Chin Chem Lett 15:194 193. Lu C, Dai W, Wang Q (2019) A new eremophilanolide sesquiterpene from Ligularia macrophylla and diversity of the species. Nat Prod Commun 14: doi: https://doi.org/10.117 7/1934578X19878942 194. Li XQ, Gao K, Jia ZJ (2003) Eremophilenolides and other constituents from the roots of Ligularia sagitta. Planta Med 69:356 195. Li XQ, Gao K, Jia ZJ (2002) Two new eremophilenolides from Ligularia sagitta. Chin Chem Lett 13:963 196. Fei DQ, Zhang ZX (2009) A new eremophilane-type sesquiterpene from Ligularia virgaurea. Chin Chem Lett 20:949 197. Liu JX, Wei XN, Shi YP, Lu RH (2005) Two new eremophilane sesquiterpene lactones from Ligularia myriocephala Ling. Chin Chem Lett 16:1618 198. Wu QX, Shi YP, Yang L (2004) Eremophilane sesquiterpene lactones from Ligularia virgaurea ssp. oligocephala. Planta Med 70:479 199. Wu QX, Yang AM, Shi YP (2005) Sesquiterpenoids from Ligularia virgaurea ssp. oligocephala. Tetrahedron 61:10529 200. Wu HB, Liu TT, Deng WJ, Zhang J, Yang LW (2019) A new eremophilane sesquiterpene with nematocidal activity from Ligularia veitchiana. Chem Nat Comp 55:671 201. Wang WS, Dai X, Hong LY, Lu P, Feng JC, Jiao YG (2008) New sesquiterpenes from Ligularia duciformis. Helv Chim Acta 91:1118 202. Wu QX, Shi YP, Yang L (2004) Unusual sesquiterpene lactones from Ligularia virgaurea ssp. oligocephala. Org Lett 6:2313

240

M. Tori and C. Kuroda

203. Li L, Xu LW, Wang HQ (2004) Four novel eremophilanolides from Ligularia sagitta. Helv Chim Acta 87:1125 204. Xue HQ, Xue HF, Wu B, Wang HQ, Xin XL, Wu SX (2006) Crystal structure of 8β-hydroxyeremophil-7(11)-ene-12,8α(4β,6α)-diolide. Chin J Chem Phys 19:519 205. Fei DQ, Han YF, Wu G, Gao K (2006) Two new eremophilenolides from Ligularia lapathifolia. J Asia Nat Prod Res 8:99 206. Han YF, Fei DQ, Gao K, Jia ZJ (2005) Two new eremophilenolides from Ligularia tongolensis. Chin Chem Lett 16:1053 207. Han YF, Gao K, Jia ZJ (2005) Sesquiterpenes, nortriterpenes and other constituents from Ligularia tongolensis. Chem Pharm Bull 53:1338 208. Shi SY, Wu DY, Gong X, Peng H, Zhang RP, Zhou CX, Hao XJ, Jia ZJ, Stöckigt J, Zhao Y (2007) Four new eremophilenolides from Ligularia atroviolacea. Chin Chem Lett 18:59 209. Wu QH, Wang CM, Cheng SG, Gao K (2004) Bieremoligularolide and eremoligularin, two novel sesquiterpenoids from Ligularia muliensis. Tetrahedron Lett 45:8855 210. Xie WD, Li X, Weng CW, Liu SS, Row KO (2011) Fischerisin A and B, cytotoxic sesquiterpenoid–geranylhydroquinones from Ligularia fischeri. Chem Pharm Bull 59:511 211. Xie WD, Liu YH, Weng CW, Zhao H, Row KH (2011) Fischelactone B: a new eremophilane dimer from Ligularia fischeri. J Chin Chem Soc 58:412 212. Zhao H, Weng CW, Tian X, Lai PX, Huang JJ, Xie WD (2010) Fischelactone: a novel eremophilane dimer from Ligularia fischeri. Chin Chem Lett 21:613 213. Li YS, Li SS, Wang ZT, Luo SD, Zhu DY (2006) A novel bieremophilanolide from Ligularia lapathifolia. Nat Prod Res 20:1241 214. Fei DQ, Wu QH, Li SG, Gao K (2010) Two new asymmetric sesquiterpene dimers from the rhizomes of Ligularia muliensis. Chem Pharm Bull 58:467 215. Zhang ZX, Fei DQ, Jia ZJ (2008) Virgaurols A–D: Novel asymmetric eremophilane dimers from the root of Ligularia virgaurea. Bull Chem Soc Jpn 81:1007 216. Zhang ZX, Wang CM, Fei DQ, Jia ZJ (2008) Two novel asymmetric dimers from the roots of Ligularia virgaurea. Chem Lett 37:346 217. Jia ZJ, Chen HM, Qiu JL (1992) The structure of saggitolactone. Chin Sci Bull 37:773 218. Li PL, Zhang ZX, Jia ZJ (2008) Four new eremophilane derivatives from Ligularia sagitta. Chem Lett 37:308 219. Zhao Y, Parsons S, Baxter RL, Jia ZJ, Sun HD, Rankin DWH (1996) Ligulaverin A, a structurally novel sesquiterpenoid–derived metabolite possibly formed via a biological Diels-­ Alder reaction. Chem Commun: 2473 220. Zhao Y, Parsons S, Smart BA, Tan R, Jia Z, Sun H, Rankin DWH (1997) Eremophilane derivatives with a novel carbon skeleton from Ligularia veitchiana. Tetrahedron 53:6195 221. Li PL, Wang CM, Zhang ZX, Jia ZJ (2007) Five new eremophilane derivatives from Ligularia sagitta. Tetrahedron 63:12665 222. Li HY, Zheng ZQ, Wei WJ, Chen JJ, Gao K (2018) Ligusaginoids A–D, four eremophilane-­ type sesquiterpenoid dimers and trimers from Ligularia sagitta. Tetrahedron Lett 59:3461 223. Wang Q, Chen TH, Bastow KF, Lee KH, Chen DF (2010) Altaicalarins A–D, cytotoxic bisabolane sesquiterpenes from Ligularia altaica. J Nat Prod 73:139 224. Dai W, Xie ZJ, Li M, Wang Q (2015) Three new bisabolane sesquiterpenes from Ligularia songarica. Helv Chim Acta 98:410 225. Liu CM, Fei DQ, Wu QH, Gao K (2006) Bisabolane sesquiterpenes from the roots of Ligularia cymbulifera. J Nat Prod 69:695 226. Hirota H, Horiguchi Y, Kawai S, Kuroda C, Hanai R, Gong X (2012) Four new bisabolane-­ type sesquiterpenes from Ligularia lankongensis. Nat Prod Commun 7:451 227. Fu B, Yang L, Yang XP, Li XP, Jia ZJ (2000) New bisabolane sesquiterpenes from Ligularia songarica. Pharmazie 55:947 228. Onuki H, Yamazaki M, Nakamura A, Hanai R, Kuroda C, Gong X, Hirota H (2008) Chemical constituents and diversity of Ligularia lankongensis in Yunnan province of China. J Nat Prod 71:520

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

241

229. Wu YX, Chen YJ, Liu CM, Gao K (2012) Four new sesquiterpenoids from Ligularia cymbulifera. J Asian Nat Prod Res 14:1130 230. Liu CM, Wang HX, Wei SL, Gao K (2008) Pyrrolizidine alkaloids and bisabolane sesquiterpenes from the root of Ligularia cymbulifera. Helv Chim Acta 91:308 231. Tan AM, He HP, Zhang M, Wang ZT, Hao XJ (2007) Two new sesquiterpenes from Ligularia lankongensis. Helv Chim Acta 90:101 232. Fu B, Yang XP, Wang J, Jia ZJ (1999) A new sesquiterpene from Ligularia songarica. Chin Chem Lett 10:29 233. Liao JC, Zhu QX, Yang H, Jia ZJ (1999) Bisabolane sesquiterpenes from Ligularia thyrsoidea. J Chin Chem Soc 46:185 234. Baba H, Yaoita Y, Kikuchi M (2007) Sesquiterpenoids from Ligularia dentata. Helv Chim Acta 90:1302 235. Dai W, Lu CQ, Wang Y, Lu Y, Chen DF, Wang Q (2018) Oplopane sesquiterpenes from Ligularia knorringiana and their anti-complementary activity. Chem Biodivers 15:e1700515 236. Tori M, Fujiwara M, Okamoto Y, Tanaka M, Gong X, Shen Y, Hanai R, Kuroda C (2007) New oplopane-type sesquiterpenoids from Ligularia duciformis. Nat Prod Commun 2:357 237. Wang Q, Chen TH, Bastow KF, Morriss-Natschke SL, Lee KH, Chen DF (2013) Songaricarins A–E, cytotoxic oplopane sesquiterpenes from Ligularia songarica. J Nat Prod 76:305 238. Gao X, Lin CJ, Xie WD, Shen T, Jia ZJ (2006) New oplopane-type sesquiterpenes from Ligularia narynensis. Helv Chim Acta 89:1387 239. Gao X, Shen T, Xie WD, Jia ZJ (2006) Two new oplopanol esters from Ligularia narynensis. Chin Chem Lett 17:341 240. Gao X, Xie WD, Jia ZJ (2008) Four new terpenoids from the roots of Ligularia narynensis. J Asian Nat Prod Res 10:185 241. Peng HR, Jia ZJ, Yang L, Zhao Y (1995) A new sesquiterpene from Ligularia nelumbifolia. Chin Chem Lett 6:583 242. Gao K, Yang L, Jia Z (1999) Sesquiterpenes from the roots of Ligularia duciformis. J Chin Chem Soc 46:619 243. Yan FL, Wang AX, Jia ZJ (2004) New phenol derivatives from Ligularia stenocephala. J Chem Res:742 244. Yan FL, Wang AX, Jia ZJ (2005) Three new polymeric isopropenyl benzofurans from Ligularia stenocephala. Pharmazie 60:155 245. Shi SY, Wu DY, Zhao Y (2008) Isolation and crystal structure of 4β,6α,9α-trimethyl-2-­ carboxyltricyclo[6.3.0.0(4,5)]undec-2-ene. Chin J Struct Chem 27:1045 246. Gobu FR, Chen JJ, Zeng J, Wei WJ, Wang WF, Lin CJ, Gao K (2017) Isolation, structure elucidation, and immunosuppressive activity of diterpenoids from Ligularia fischeri. J Nat Prod 80:2263 247. Shi SY, Hu MH, Wu DY, Zhou CX, Mo JX, Xu JH, Chen LR, Dou H, Peng H, Hao XJ, Stöckigt J, Zhao Y (2008) A new dibenzofuran and other constituents from Ligularia caloxantha, a Chinese medicinal plant. Nat Prod Res 22:628 248. Baba H, Yaoita Y, Kikuchi M (2007) Constituents of the root of Ligularia dentata Hara. J Nat Med 61:472 249. Wang Q, Zhang C, Zhang M, Wang Z (2008) Study on chemical constituents in rhizomes of Ligularia duciforms II. China J Chin Mat Med 33:1018 250. Ma B, Shi YP, Jia ZJ (1997) A seco-oleane-type triterpene acids from Ligularia intermedia. Planta Med 63:573 251. Han YF, Gao K, Jia ZJ (2005) Two new nortriterpenes from Ligularia tongolensis. Chem Lett 34:892 252. Shi ZN, Wang YD, Gong Y, Li HF, Zhu Y (2019) New triterpenoid saponins with cytotoxic activities from Ligularia przewalskii. Phytochemistry Lett 30:215 253. Zhao Y, Tian J, Jia ZJ, Sun HD (1995) Liguveitoside A, a new triterpenoid saponin from Liularia veitchiana. Acta Bot Yunnan 17:356

242

M. Tori and C. Kuroda

254. Zhu H, Tu P (2004) A new triterpenoid saponin and two neolignans from Ligularia veitchiana. Z Naturforsch 59b:1063 255. Zhang J, Jiang W, Cao HJ, Qu Y, Liao ZX, Liu C, Sun JY (2018) Two new monoterpene lactones from Ligularia rumicifolia (J.R. Drumm.) S.W. Liu and their anti-proliferative activities. Phytochem Lett 28:55 256. Chen JJ, Li WX, Gao K, Jin XJ, Yao XJ (2012) Absolute structures of monoterpenoids with a delta-lactone-containing skeleton from Ligularia hodgsonii. J Nat Prod 75:1184 257. Liu X, Li J, Li J, Liu Q, Xun M (2019) A new flavonoid from Ligularia fischeri. Chem Nat Comp 55:638 258. Hussain SH, Latif A, Cox R, Simpson TJ, Ali M, Arfan M, Uddin G (2014) Phytochemicals from the aerial parts of Ligularia thomsonii and their radical scavenging activity. Phytochem Lett 7:6 259. Liu Q, Shen L, Wang TT, Chen CJ, Qi WY, Gao K (2010) Novel modified furanoeremophilane-­ type sesquiterpenes and benzofuran derivatives from Ligularia veitchiana. Food Chem 122:55 260. Ma B, Gao K, Shi YP, Jia ZJ (1997) Phenol derivatives from Ligularia intermedia. Phytochemistry 46:915 261. Hua L, Chen J, Gao K (2012) A new pyrrolizidine alkaloid and other constituents from the roots of Ligularia achyrotricha (Diels) Ling. Phytochem Lett 5:541 262. Zhao Y, Jia Z, Yang L (1994) Sinapyl alcohol derivatives and other constituents from Ligularia nelumbifolia. Phytochemistry 37:1149 263. Zhao Y, Jia ZJ, Wang L, Wang JG (1993) Sinapyl alcohol derivatives and other constituents from the roots of Ligularia nelumbifolia. Chin Chem Lett 4:895 264. Toyoda K, Yaoita Y, Kikuchi M (2005) Three new dimeric benzofuran derivatives from the roots of Ligularia stenocephala Matsum. et Koidz. Chem Pharm Bull 53:1555 265. Jia ZJ, Zhao Y (1994) Four new furans from the roots of Ligularia przewalskii. J Nat Prod 57:146 266. Kuroda C, Kikuchi K, Torihata A, Takeshita K, Gong X, Shen Y, Hirota H, Onuki H, Hanai R (2007) Chemical and genetic diversity of Ligularia latihastata and Ligularia villosa in Yunnan province of China. Chem Biodivers 4:2210 267. Murae T, Tanahashi Y, Takahashi T (1968) 5,6-Dimethoxy-2-isopropenylbenzofuran from Ligularia stenocephala Matsum. et Koidz. Tetrahedron 24:2177 268. Yan FL, Wang AX, Jia ZJ (2004) Benzofuran derivatives from Ligularia stenocephala. J Chin Chem Soc 51:863 269. Gao K, Wang WS, Jia ZJ (1998) Coniferyl and sinapyl alcohol derivatives from Ligularia duciformis. Phytochemistry 47:269 270. Zhao Y, Hao X, Lu W, Cai J, Yu H, Sevénet T, Guéritte F (2002) Syntheses of two cytotoxic sinapyl alcohol derivatives and isolation of four new related compounds from Ligularia nelumbifolia. J Nat Prod 65:902 271. Zhao Y, Peng HR, Jia ZJ (1995) Six sinapyl alcohol derivatives from Ligularia nelumbifolia. Chin Chem Lett 6:387 272. Gao K, Jia ZJ (2000) Two new compounds from Ligularia duciformis. Indian J Chem 39B:160 273. Li YS, Wang ZT, Zhang M, Luo SD, Chen JJ (2005) A new pinoresinol-type lignan from Ligularia kanaitzensis. Nat Prod Res 19:125 274. Gao X, Jia ZJ (2008) A new 8-O-4′-type neolignan from Ligularia narynensis. Chin Chem Lett 19:71 275. Tori M (2016) Terpenoid composition and base sequences of Ligularia virgaurea (Asteraceae) grown in the Hengduan mountain area in China and a comment on drawing structures. Chem Pharm Bull 64:193 276. Tori M (2016) Diversity of plants belonging to the genus Ligularia (Asteraceae) based on terpenoids and synthetic studies on some terpenoids. Yakugaku Zasshi 136:309 277. Bagal SK, Adlington RM, Baldwin JE, Marquez R, Cowley A (2003) Biomimetic synthesis of biatractylolide and biepiasterolide. Org Lett 5:3049 278. Bagal SK, Adlington RM, Marquez R, Cowley A, Baldwin JE (2003) Studies towards the biomimetic synthesis of bisesquiterpene lactones. Tetrahedron Lett 44:4993

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

243

279. Bagal SK, Adlington RM, Baldwin JE, Marquez R (2004) Dimerization of butenolide structures. A biomimetic approach to the dimeric sesquiterpene lactones (±)-biatractylolide and (±)-biepiasterolide. J Org Chem 69:9100 280. Zhao Y, Jiang H, MacLeod M, Parsons S, Rankin DWH, Wang P, Cheng CHK, Shi H, Hao XJ, Gueritte F (2004) Isomeric eremophilane lactones from Senecio tsoongianus. Chem Biodivers 1:1546 281. Bohlmann F, Jakupovic J, Mohammadi D (1984) Shikimic acid derivative from Senecio hieracioides. J Nat Prod 47:718 282. Hirota H, Tanahashi Y, Takahashi T (1975) Structure of a guaiane-type sesquiterpene ether from “San-shion”. Tetrahedron Lett:4579 283. Hirota H, Tanahashi Y, Takahashi T (1980) Structure of a guaiane-type sesquiterpene from “San-shion”. Bull Chem Soc Jpn 53:785 284. Okazaki M, Ishizaki Y, Tanahashi Y, Hirota H, Takahashi T (1974) Volatile components of “San-shion”. Yakugaku Zasshi 94:881 285. Yaoita Y (2012) New sesquiterpenoids from the rhizomes of Petasites japonicus Maxim. and the roots of Ligularia dentata Hara. Yakugaku Zasshi 132:887 286. Tada M, Moriyama Y, Tanahashi Y, Takahashi T (1974) Furanoeremophilane-6β,10β-diol and its derivatives. New furanosesquiterpenes from Ligularia japonica Less. Bull Chem Soc Jpn 47:1999 287. Bohlmann F, Knoll KH (1978) Weitere Furanoeremophilane aus Orthona-Arten. Phytochemistry 17:461 288. Bohlmann F, Zdero C, Grenz M (1974) Neue Sesquiterpene der Gattung Orthona. Chem Ber 107:3928 289. Kuroda C, Murae T, Tada M, Nagano H, Tsuyuki T, Takahashi T (1982) 3β,6β-Bis(acyloxy) furanoeremophilan-14-als and -14-oic acids from Syneilesis palmata (Thunb.) Maxim. Bull Chem Soc Jpn 55:1228 290. Bohlmann F, Suwita A (1976) Weitere Furanoeremophilane aus Orthona-Arten. Chem Ber 109:1230 291. Dupré S, Grenz M, Jakupovic J, Bohlmann F, Niemeyer HM (1991) Eremophilane, germacrane and shikimic acid derivatives from Chilean Senecio species. Phytochemistry 30:1211 292. Ahmed AA (1991) Eremophilanes from Senecio desfontainei. J Nat Prod 54:271 293. Harada I, Hirose Y, Nakazaki M (1968) The absolute configurations of (+)-marmesin and (−)-hydroxytremetone. Tetrahedron Lett: 5463 294. Pardo-Novoa JC, Arreaga-González HM, Gómez-Hurtado MA, Rodríguez-García G, Cerda-­ García-­Rojas CM, Joseph-Nathan P, del Río RE (2016) Absolute configuration of menthene derivatives by vibrational circular dichroism. J Nat Prod 79:2570 295. Yasmeen S, Riaz N, Bibi A, Afza N, Malik A, Tareen RB (2009) Herticins A and B, new sesquiterpenes from Hertia intermedia. Helv Chim Acta 92:404 296. Tori M, Saito Y, Gong X, Kuroda C (2019) Chemical studies of Cremanthodium (Asteraceae) species: sesquiterpenoids and related compounds. Nat Prod Commun 14: doi: https://doi. org/10.1177/1934578X19878594 297. Saito Y, Tori M (2011) Structures of fukinone epoxides. Configuration, conformation, and CD spectra. Heterocycles 82:1719 298. Bohlmann F, Ziesche J (1980) Eremophilane derivatives from Senecio species. Phytochemistry 19:2681 299. Liu SJ, Tang ZS, Liao ZX, Cui CL, Liu HB, Liang YN, Zhang Y, Xu HB, Zhang DB, Zhaeng YT, Shi HX, Li SY (2018) The chemistry and pharmacology of Ligularia przewalskii: A review. J Ethnopharmacol 219:32 300. Bohlmann F, Jakupovic J, Warnig U, Grenz M, Chau-Thi TV, King RM, Robinson H (1986) Sesquiterpenes with new carbon skeletons, furoeremophilanes, seco-eremophilanes, and other constituents from Argentinian Senecio species. Bull Chem Soc Chim Belg 95:707 301. Liu Z, Chen HM, Jia ZJ, Dalley NK, Kou XL, Li D, Owen NL, Grant DM (1995) Revision of the structure of sesquiterpene from Ligularia sagitta. Phytochemistry 40:1191

244

M. Tori and C. Kuroda

302. Castro SJ, Garcia ME, Padron JM, Navarro-Vazquez A, Gil RR, Nicotra VE (2018) Phytochemical study of Senecio volckmannii assisted by CASE-3D with residual dipolar couplings and isotropic 1H/13C NMR chemical shifts. J Nat Prod 81:2329 303. Illarionova I, Wang L, Yang QE (2017) Ligularia muliensis (Asteraceae, Senecioneae) is merged with L. tsangchanensis. Phytotaxa 299:169 304. Hillis DM, Dixon MT (1991) Ribosomal DNA: Molecular evolution and phylogenetic inference. Quart Rev Biol 66:411 305. Manen JF, Savolainen V, Simon P (1994) The atpB and rbcL promoters in plastid DNAs of a wide dicot range. J Mol Evol 38:577 306. Yu JJ, Kuroda C, Gong X (2014) Natural hybridization and introgression between Ligularia cymbulifera and L. tongolensis (Asteraceae, Senecionae) in four different locations. PloS One 9:e115167 307. Heathcock HC (1973) Total synthesis of sesquiterpenes. In: ApSimon J (ed) The Total Synthesis of Natural Products, vol 2. John Wiley and Sons, New York, p 361 308. Pinder AR (1977) The chemistry of the eremophilane and related sesquiterpenes. In: Herz W, Grisebach H, Kirby GW (eds) Progress in the Chemistry of Organic Natural Products, vol 34. Springer, Vienna, New York, p 81 309. Yamakawa H, Satoh T (1980) The total synthesis of natural products. J Synth Org Chem Jpn 38:783 310. Yamakawa K, Satoh T (1977) Studies on terpenoids and related alicyclic compounds. X. Total synthesis of sesquiterpenoids, (±)-ligularone. Chem Pharm Bull 25:2535 311. Yamakawa K, Satoh T (1978) Studies on terpenoids and related alicyclic compounds. XVI.  Total syntheses of furanosesquiterpenes: (±)-furanoeremophilane, (±)-furanoligularenone, (±)-9,10-dehydrofuranoeremophilane, (±)-3β-hydroxyeremophilane, and (±)-3β-furanoligularenol. Chem Pharm Bull 26:3704 312. Yamakawa K, Satoh T (1979) Studies on terpenoids and related alicyclic compounds. XVIII.  Stereoselective synthesis of (±)-furanofukinol and (±)-petasalbin. Chem Pharm Bull 27:1747 313. Yamakawa K, Kobayashi M, Hinata S, Satoh T (1980) Studies on the terpenoids and related alicyclic compounds. XXIII.  Total syntheses of (±)-phomenone, (±)-3-epiphomenone, (±)-ligularenolide, and (±)-furanoligularanone. Chem Pharm Bull 28:3265 314. Yamakawa K, Satoh T (1981) Studies on the terpenoids and related alicyclic compounds. XXVI.  Total synthesis of highly oxygenated furanoeremophilanes: (±)-6β-hydroxy-1,10-dehydrofuranoeremophylan-9-one, (±)-decompostin, (±)-dihydrodecompostin, (±)-adenostylone, (±)-3β,6β-dipropionyloxyeuryopsin, (±)-3β,6β-dihydroxy-10βH-furanoeremophilan-9-one, and (±)-3β,6β-dihydroxy-10αH-­ furanoeremophilan-9-one. Chem Pharm Bull 29:3474 315. Kitagawa I, Yamazoe Y, Takeda R, Yoshioka I (1972) Conversion of dihydroalantolactone to eremophilane-type derivatives. Biogenetic-type transformation. Tetrahedron Lett:4843 316. Kitagawa I, Shibuya H, Yamazoe Y, Takeno H, Yoshioka I (1974) Conversion of dihydroalantolactone to tetrahydroligularenolide. Biogenetic-type transformation of eudesmanolide to eremophilanolide. Tetrahedron Lett 15:111 317. Tada M, Sugimoto Y, Takahashi T (1980) Total synthesis of furanoeremophilane and 14-­norfuranoeudesmane derivatives by a route involving alkylation of 2,4-dimethyl-3-furoic acid. Bull Chem Soc Jpn 53:2966 318. Torii S, Inokuchi T, Kawai K (1979) Functionalization of trans-decalin. II. A synthesis of dl-isopetasol from trans-5-oxodecalin-8α,2-carbolactone. Bull Chem Soc Jpn 52:861 319. Hagiwara H, Uda H, Kodama T (1980) Synthetic study on several eremophilane sesquiterpenes using a common intermediate. J Chem Soc Perkin Trans I: 963 320. Näf F, Decorzant R, Thommen W (1982) A stereocontrolled entry to racemic eremophilane and valencane sesquiterpenes via an intramolecular Diels-Alder reaction. Helv Chim Acta 65:2212

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

245

321. Zhao Y, Schenk DJ, Takahashi S, Chappell J, Coates RM (2004) Eremophilane sesquiterpenes from capsidiol. J Org Chem 69:7428 322. Reddy DS, Kozmin SA (2004) Efficient and general approach to eremophilanes using siloxyalkyne-­alkene metathesis. J Org Chem 69:4860 323. Blay G, Cardona L, Collado AM, García B, Pedro JR (2006) Rearrangement of 4,5-epoxy-­9trimethylsilyldecalines. Application to the synthesis of the natural eremophilane (−)-aristolochene. J Org Chem 71:4929 324. Shanmughan MS, White JD (2004) A new route to furanoeremophilane sesquiterpenoids. Synthesis of (±)-6β-hydroxyeuryopsin. Chem Commun:44 325. Mace LH, Shanmugham M, White JD, Drew MGB (2006) A new route to furanoeremophilane sesquiterpenoids. Synthesis of Senecio metabolites (±)-6-hydroxyeuryopsin, (±)-1,10-epoxy-­ 6-hydroxyeuryopsin, (±)-toluccanolide A and (±)-toluccanolide C.  Org Biomol Chem 4:1020 3 26. Hsu DS, Hsu PY, Lee YC, Liao CC (2008) Stereocontrolled synthesis of polyfunctionalized cis-decalins from 2-methoxyphenols: total syntheses of (±)-eremopetasidione, (±)-3β-­angeloyloxyfuranoeremophilane, and (±)-3β-methacryloyloxyfuranoeremophil ane. J Org Chem 73:2554 327. Koike T, Takeuchi N, Ohta T, Tobinaga S (1999) Total synthesis of racemic ligularone and isoligularone. Chem Pharm Bull 47:897 328. Kraus GA, Bae J, Kim J (2007) Phytochemicals from Echinacea and Hypericum: a direct synthesis of isoligularone. Synth Commun 37:1251 329. Jenniskens LHD, de Groot A (1998) Enantioselective synthesis of (R)-(−)-ligularenolide and the progesterone receptor ligand (R)-(−)-PF1092C starting from (S)-(+)-carvone. Tetrahedron 54:5617 330. Handore KL, Seetharamsingh B, Reddy DS (2013) Ready access to functionally embellished cis-hydrindanes and cis-decalins: protecting group-free total synthesis of (±)-nootkatone and (±)-noreremophilane. J Org Chem 78:8149 331. Huffman JW, Pandian R (1979) Synthesis of (±)-cacalol. J Org Chem 44:1851 332. Tanikawa S, Ono M, Akita H (2005) The first synthesis of (S)-(+)-cacalol. Heterocycles 65:319 333. Reddy DS, Palani K, Balasubrahmanyam D, Kamath VB, Iqbal J (2005) The first synthesis of a noreremophilane isolated from the roots of Ligularia przewalskii. Tetrahedron Lett 46:5211 334. Muthukumarasamy KM, Handore KL, Kakade DN, Shinde MV, Ranjan S, Kumar N, Sehrawat S, Sachidanandan C, Reddy DS (2016) Identification of noreremophilane-based inhibitors of angiogenesis using zebrafish assays. Org Biomol Chem 14:1569 335. Meng Z, Liu B (2018) Total synthesis of five natural eremophilane-type sesquiterpenoids. Org Biomol Chem 16:957 336. Abe H, Fujimaki M, Nakagawa E, Kobayashi T, Ito H (2018) Enantioselective total synthesis of sagittacin E and related natural products. Chem Commun 54:6165 337. Hartmann B, Deprés JP, Greené AE, Freire de Lima ME (1993) Stereoselective bakkane synthesis: (±)-palmosalide C. Tetrahedron Lett 34:1487 338. Brocksom TJ, Coelho F, Deprés JP, Greene AE, Freire de Lima ME, Hamelin O, Hartmann B, Kanazawa AM, Wang Y (2002) First comprehensive bakkane approach: Stereoselective and efficient dichloroketene-based total synthesis of (±)- and (−)-9-acetoxyfukinanolide, (±)-bakkenolide A, (−)-bakkenolide III, B, C, H, L, V, and X, (±)- and (−)-homogynolide A, (±)-homojinolide B, and (±)-palmosalide C. J Am Chem Soc 124:15313 339. Back TG, Nava-Salgado VO, Payne JE (2001) Synthesis of (±)-bakkenolide-A and its C-7, C-10, and C-7,10 epimers by means of an intramolecular Diels-Alder reaction. J Org Chem 66:4361 340. Constantino MG, de Oliveira KT, Polo EC, da Silva GV, Brocksom TJ (2006) Core structure of eremophilanes and bakkanes through niobium catalyzed Diels-Alder reaction: synthesis of (±)-bakkenolide A. J Org Chem 71:9880

246

M. Tori and C. Kuroda

341. Jiang CH, Bhattacharyya A, Sha CK (2007) Enantiospecific total synthesis of (−)-bakkenolide III and formal total synthesis of (−)-bakkenolides B, C, H, L, V, and X. Org Lett 9:3241 342. Hirai M, Miyazaki R, Mitsui K, Kiuchi K, Onuki H, Hirota H, Kuroda C (2015) Synthesis and NMR spectroscopic elucidation of four diastereoisomers of oxygenated bisabolane side chain. Helv Chim Acta 98:1035 343. Kobayashi K, Kunimura R, Takagi H, Hirai M, Kogen H, Hirota H, Kuroda C (2018) Total synthesis of highly oxygenated bisabolane sesquiterpene isolated from Ligularia lankongensis: Relative and absolute configurations of the natural product. J Org Chem 83:703 344. Goto Y, Kojima Y, Nakayama T, Terazawa M (2001) Allelopathic sesquiterpenoids from rhizomes of Petasites japonicus ssp. giganteus Kitam. Phytochemistry 57:109 345. Epifano F, Genovese S, Squires EJ, Gray MA (2012) Nelumal A, the active principle from Ligularia nelumbifolia, is a novel farnesoid X receptor agonist. Bioorg Med Chem Lett 22:3130 346. Zhao Y, Lu W, Hao XJ, Cai JC, Yu H, Sevenet T, Guéritte F (2002) Synthesis of cytotoxic sinapyl alcohol derivatives from Ligularia nelumbifolia. Chin Chem Lett 13:201 347. Handore KL, Kalmode HP, Sayyad S, Seetharamsingh B, Gathalkar G, Padole S, Pawar PV, Joseph M, Sen A, Reddy DS (2019) Insect-repellent and mosquitocidal effects of noreremophilane- and nardoaristolone-based compounds. ACS Omega 4:2188 348. Jang S, Kim MS, Park T, Sim JH, Kim SY (2020) Screening and identification of an anti-­ inflammatory and anti-adipogenic constituent from Ligularia taquetii Nakai. Nat Prod Commun 15: doi: https://doi.org/10.1177/1934578X19899503

Chemical Constituents of Ligularia Species (Asteraceae) and Their Diversity…

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Motoo Tori  was born in Aichi Prefecture, Japan, in 1948. He received his B.S. degree from the Department of Chemistry, Shizuoka University, Japan, in 1972, and his Ph.D. degree from the University of Tokyo in 1977 under the supervision of Professor Takeyoshi Takahashi. He spent two-and-a-half years at the University of Alberta, Edmonton, Canada, as a Postdoctoral Fellow, working with Professor Satoru Masamune (1977–1978) and then with Professor William A.  Ayer (1978–1979). He moved to the University of Basel, Switzerland (with Professor Ch. Tamm), and stayed there until he returned to Japan in 1981. He was appointed as an Associate Professor in the Faculty of Pharmaceutical Sciences, Tokushima Bunri University, in 1983 and became a Full Professor in 1995 (until March 2015), where he also served as Dean (2003–2005). Currently, he is an Emeritus Professor. Prof. Tori received the Pharmaceutical Society of Japan Award for Divisional Scientific Contributions in 2015. His research interests are in the structure determination of natural products, the total syntheses of biologically active compounds, and the development of new reactions using samarium and ruthenium reagents. He has published about 250 original papers and reviews as well as several books. Chiaki Kuroda  was born in 1954 and grew up in Nagano Prefecture, Japan. He entered the University of Tokyo (Department of Chemistry), Japan, and received his B.S. degree in 1977. Prof. Kuroda continued research work in the Graduate School of the University and received his Ph.D. degree in 1982 under the supervision of Professor Takeyoshi Takahashi. He worked on the chemical synthesis of s­esquiterpenoids and on their natural products chemistry, particularly of those compounds occurring in Eupatorium and Ligularia species, and other related plants. After receiving the Ph.D. degree, he was appointed as a full time Research Assistant in the Department of Chemistry, Rikkyo University. Prof. Kuroda was promoted to Lecturer in 1989 and then to Associate Professor in 1992. He became a Professor in the same Department in 2000. Earlier, he worked as a Postdoctoral Fellow for 2 years (1985–1987) in the Department of Chemistry, Oregon State University, Corvallis, OR, USA, with Professor James D. White. His research interests are in the isolation and structure determination of terpenoids and investigating their diversity in Ligularia (Asteraceae) species, particularly those growing in East Asia, and on the synthesis of sesquiterpenoids using the chemistry of allylsilane. Prof. Kuroda has published about 140 original papers and reviews, and has participated in international chemical meetings as a guest speaker on many occasions.