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Abstract

Frullania is one of the largest and taxonomically most complex genus of leafy liverworts. Current morphology-based estimates of Frullania diversity are close to 400 species; however, species level-classification of Frullania has been regarded notoriously difficult and subject to many studies. The liverworts classified in this genus have been studied using morphological evidence and molecular markers but also in terms of secondary metabolite composition. Up to now 98 Frullania species have been chemically investigated. As a result, it is known that Frullania species are characterized by a remarkable chemical diversity. The most characteristic compounds present in this liverwort genus are sesquiterpene lactones with eudesamnolides as the most diverse group, and aromatic compounds belonging to bibenzyls. In this review paper we report the distribution of secondary metabolites in all chemically investigated Frullania species and discuss some aspects concerning the division of this genus into chemotypes.

Keywords

liverworts sesquiterpene lactones eudesmanolides bibenzyls chemotypes

Frullania Raddi is a genus of leafy liverworts and is characterized by its often reddish pigmentation and includes both narrow endemics and nearly cosmopolitan species. This liverwort genus has a worldwide distribution with centers of diversity in the humid tropics and warm temperate regions. Many species of Frullania occur not only in moist but also in rather dry vegetation.^1,2 Frullania is also the largest and taxonomically most complex liverwort genus classified in order Porellales within family Frullaniaceae.^3,4

Species of liverworts have traditionally been circumscribed using morphological evidence. It was the time that geographical or typological species concepts was preferred and liverwort species were regarded as largely invariant units with small ranges. Then, the intraspecific morphological variation concept was accepted, and it contributed to the reduction of local binomials to synonyms of widespread liverwort species.^4,5 More recently, morphology-based species concepts have been tested using evidence from molecular markers including isozymes, and variable regions of the nuclear and the plastid genomes,^2,6 as well as secondary metabolites.^7,8

In case of Frullania there are estimated 300‐375 species;⁹ however, species level-classification of Frullania has been regarded notoriously difficult and subject to much controversy.¹ They have been various proposals for a subdivision of Frullania into natural species groups.^1,10 As a result, more than 15 subgenera and over 30 sections and subsections based on morphology were established.¹¹ Recently, Hentschel et al. (2009)² presented the most comprehensive molecular phylogeny of Frullania to date. The liverworts classified in genus Frullania have not only been studied using morphological evidence and molecular markers but also in terms of secondary metabolite composition.^12

-16 The use of the secondary metabolites as aids to plant taxonomy was popularized by the publication of Swain (1963).¹⁷ Terpenoids not only sesquiterpene lactones,^18,19 but also flavonoids²⁰ are of value in the taxonomic and evolutionary investigations of plants. In this review paper we report the distribution of secondary metabolites in all chemically investigated Frullania species and discuss some aspects concerning the division of this genus into chemotypes.

Chemistry of Frullania Species

One of the outstanding features of the liverworts is their chemistry. They produce a wide array of secondary metabolites, and up to now over several hundred new terpenoids, and aromatic compounds including bibenzyls and bisbibenzyls with more than 40 new carbon skeletons have been isolated.^16,21,22

As a result of phytochemical studies, Frullania species are now known to produce a wide array of secondary metabolites. As shown in Table 1, 98 Frullania species have been chemically investigated. Most of the compounds either detected in or isolated from these species are terpenoids, aromatic compounds, and flavonoids. Among terpenoids, the sesquiterenes are the most diverse group, but the presence of mono-, di-, and triterpenes was also confirmed. α-Pinene (1), β-pinene (2), camphene (3), β-phellandrene (4), myrcene (5), limonene (6), and α-terpinene (7) are the monoterpenoids frequently found in Frullania species (Figure 1).^16,21,22 Due to the fact that most of the Frullania species elaborate the same monoterpenoids, it is difficult to use them as chemosystematic markers.

Figure 1

Monoterpenes found in Frullania species.

Table 1

Group of Compounds Found in Chemically Investigated Frullania Species.

No.	Frullania species	Collection place	Group of compounds	References
1	Frullania africana	Herbarium sample	Flavonoids	Yuzawa et al., 1987²³ Asakawa 1995²²
2	Frullania amplicrania	Miyazaki, Japan Miyake Island, Japan	Sesquiterpene hydrocarbons; Diterpenes; Bibenzyls	Asakawa et al., 1981¹²
3	Frullania anomala	South Island, New Zealand	Sesquiterpene hydrocarbons; Bibenzyls; Lipids	Asakawa et al., 2003¹⁴
4	Frullania apiculata	Cameron Highlands, Pahang, Malaysia	Sesquiterpene lactones	Asakawa et al., 1983²⁴
5	Frullania arecae	Colombia, South America	Flavonoids	Kraut et al., 1995¹³
6	Frullania asagrayama	Pounds Escarpment, Illinois, USA	Sesquiterpene lactones	Asakawa et al., 1991²⁵
7	Frullania aterrima var. aterrima	North Island, New Zealand	Sesquiterpene hydrocarbons and lactones; Diterpenes	Asakawa et al., 2003¹⁴
8	Frullania aterrima var. lepida	North Island, New Zealand	Sesquiterpene hydrocarbons and lactones	Asakawa et al., 2003¹⁴
9	Frullania bella	Prony village and Yate lake, New Caledonia	Sesquiterpene hydrocarbons; Oxygenated sesquiterpenes	Métoyer et al., 2016²⁶
10	Frullania brachyclada	Herbarium sample	Flavonoids	Yuzawa et al., 1987²³
11	Frullania bicornistipula	Panama	Sesquiterpene hydrocarbons and lactones	Asakawa 1995²²
12	Frullania bonicola	Hahajima Island, Japan	Bibenzyls	Asakawa et al., 1981¹²
13	Frullania brasiliensis	Tucuman province, Argentina Loja province, Ecuador	Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes; Sterols; Triterpenes; Bibenzyls; Other aromatic compounds	Asakawa 1995²² Bardon et al., 2002²⁷ Valarezo et al., 2020²⁸
14	Frullania brotheri	Wakayama Prefecture, Japan	Sesquiterpene lactones	Takeda et al., 1983²⁹
15	Frullania californica	Eugene, Oregon, USA	Sesquiterpene lactones	Asakawa et al., 1991²⁵
16	Frullania cesatiana	Switzerland: Tessin Italy: South Tirol	Flavonoids	Kraut et al., 1995¹³
17	Frullania chevalierii	North Island, New Zealand	Sesquiterpene hydrocarbons and lactones; Lipids	Asakawa et al., 2003¹⁴
18	Frullania clavata	Blue Mountains, New South Wales, Australia	Sesquiterpene hydrocarbons; Oxygenated sesquiterpenes	Asakawa et al., 1983²⁴
19	Frullania confertiloba	Herbarium sample	Sesquiterpene hydrocarbons and lactones	Yuzawa et al., 1987²³
20	Frullania congesta	Stewart Island, New Zealand	Sesquiterpene hydrocarbons and lactones	Asakawa et al., 2003¹⁴
21	Frullania convoluta	Paramo el Angel, Ecuador	Sesquiterpene lactones; Bibenzyls; Bisbibenzyls	Flegel et al., 1999³⁰
22	Frullania cornuta	Koghis forest, New Caledonia	Sesquiterpene hydrocarbons; Oxygenated sesquiterpenes	Métoyer et al., 2016²⁶
23	Frullania davurica	Tokushima, Japan Hokkaodo, Japan Tottori, Japan	Monoterpenes; Sesquiterpene hydrocarbons and lactones; Bibenzyls; Flavonoids; Sterols	Mues et al., 1984³¹ Asakawa 1995²²
24	Frullania densiloba	Tokushima, Japan	Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes	Asakawa et al., 1980³² Asakawa et al., 1981^¹²
25	Frullania deplanata	Tasmania, Australia North Island, New Zealand	Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes	Asakawa et al., 2003¹⁴
26	Frullania dilatata	Dordogne, France	Monoterpenes; Sesquiterpene hydrocarbons and lactones	Asakawa et al., 1980³² Asakawa et al., 1981¹² Asakawa 1982²¹
27	Frullania dilatata var. anomala	Black Sea, near Varna, Bulgaria	Monoterpenes; Sesquiterpene hydrocarbons and lactones; Bibenzyls	Asakawa et al., 1980³² Asakawa et al., 1981¹² Nagashima et al., 1994³³
28	Frullania diversitexta	Miyazaki, Japan	Monoterpenes; Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes	Asakawa et al., 1980³² Asakawa et al., 1981¹²
29	Frullania eboracensis	New York, Adirondack Mts. and Rensselaer county; New Jersey, Warren county, USA	Flavonoids; Aromatic compounds	Kraut et al., 1995¹³
30	Frullania ecklonii	Herbarium sample	Flavonoids	Yuzawa et al., 1987²³
31	Frullania ericoides	Kochi, Japan Tokushima, Japan Noumea, New Caledonia	Sesquiterpene hydrocarbons; Bibenzyls; Flavonoids	Asakawa et al., 1981³⁴ Asakawa et al., 1983²⁴ Métoyer et al., 2016²⁶
32	Frullania falciloba	Blue Mountains, New South Wales, Australia North Island, New Zealand	Monoterpenes; Sesquiterpene hydrocarbons; Oxygenated sesquiterpenes; Diterpenes, Sterols, Bibenzyls, Other aromatic compounds; Lipids	Asakawa et al., 1983²⁴ Asakawa et al., 2003¹⁴ Nagashima et al., 2006³⁵
33	Frullania falscicornuta	Koghis forest, New Caledonia	Sesquiterpene hydrocarbons; Oxygenated sesquiterpenes	Métoyer et al., 2016²⁶
34	Frullania fragilifolia	Haut-Rhin, France	Monoterpenes; Sesquiterpene hydrocarbons	Asakawa et al., 1980³⁶ Asakawa et al., 1981¹²
35	Frullania franciscana	Ecola State Park, Cannon Beach, Oregon, USA	Sesquiterpene lactones	Sass 1981³⁷
36	Frullania fugax	North Island, New Zealand	Sesquiterpene hydrocarbons, Diterpenes; Sterols; Aromatic compounds	Asakawa et al., 2003¹⁴
37	Frullania gaudichaudi	Kalimantan Timur, Borneo	Sesquiterpene hydrocarbons; Oxygenated sesquiterpenes	Asakawa et al., 1983²⁴
38	Frullania gibbosa	Herbarium sample	Flavonoids	Kraut et al., 1995¹³
39	Frullania gradsteinii	Galapagos Island, Ecuador	Flavonoids	Yuzawa et al., 1987²³
40	Frullania hamatiloba	Tokushima, Japan Shanxi Province, China	Monoterpenes; Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes; Diterpenes; Flavonoids; Sterols	Toyota et al., 1988³⁸ Hashimoto et al., 1998³⁹ Qiao et al., 2019⁴⁰
41	Frullania incumbens	North Island, New Zealand	Sesquiterpene hydrocarbons and lactones; Diterpenes; Bibenzyls; Lipids	Asakawa et al.,1996⁴¹ Asakawa et al., 2003¹⁴
42	Frullania inflata	Mie, Japan	Sesquiterpene hydrocarbons and lactones	Asakawa et al., 1980³² Asakawa et al., 1981¹²
43	Frullania inflata var. mayebarae	Herbarium sample	Monoterpenes	Asakawa et al., 1981³⁴
44	Frullania inouei	Yunnan Province, China	Diterpenes; Bibenzyls	Guo et al., 2010⁴²
45	Frullania jackii	Herbarium sample	Sesquiterpene hydrocarbons; Sterols, Bibenzyls, Flavonoids	Mues et al., 1984³¹ Asakawa 1995²²
46	Frullania kagoshimensis	Miyazaki, Japan	Sesquiterpene hydrocarbons	Asakawa et al., 1980³⁶ Asakawa et al., 1981¹²
47	Frullania laxiflora	Herbarium sample	Flavonoids	Yuzawa et al., 1987²³
48	Frullania lobulata	Brunswick Peninsula, Chile	Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes; Lipids	Asakawa et al., 2003¹⁴
49	Frullania magellanica	Bahia Buen Suceso, Argentine	Sesquiterpene hydrocarbons and lactones; Lipids	Asakawa et al., 2003¹⁴
50	Frullania mammillosa	Creek Pernod and Prony village, New Caledonia	Sesquiterpene hydrocarbons and lactones	Métoyer et al., 2016²⁶
51	Frullania media	Stewart Island, New Zealand	Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes; Diterpenes	Asakawa et al., 2003¹⁴
52	Frullania microcaulis	Prov. Magallanes, Chile	Aromatic compounds	Asakawa et al., 2003¹⁴
53	Frullania monocera	Mie, Japan Stewart Island, New Zealand	Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes; Diterpenes; Bibenzyls	Asakawa et al., 1981¹² Asakawa et al., 1981³⁴ Asakawa et al., 2003¹⁴
54	Frullania motoyana	Miyazaki, Japan Mie, Japan	Sesquiterpene hydrocarbons	Asakawa et al., 1980³² Asakawa et al., 1981¹²
55	Frullania multilacera	Koghis forest, New Caledonia	Sesquiterpene hydrocarbons	Métoyer et al., 2016²⁶
56	Frullania muscicola (=Frullania brittoniae spp. truncatifolia)	Miyazaki, Japan Hiroshima, Japan Shandong Province, China llha Terceira, Azores	Sesquiterpene lactones; Flavonoids; Bibenzyls; Phthalides; Other aromatic compounds	Asakawa et al.,1976⁴³ Asakawa et al., 1981¹² Kraut et al., 1993⁴⁴ Kraut et al., 1994⁴⁵ Lou et al., 2002⁴⁶
57	Frullania nepalensis	Arishan, Taiwan	Sesquiterpene lactones; Oxygenated sesquiterpenes;	Tori et al., 1990⁴⁷ Asakawa et al., 1991²⁵ Asakawa 1995²²
58	Frullania nisquallensis	Oregon, USA	Sesquiterpene lactones; Aromatic compounds	Asakawa et al., 1991¹⁵ Kim et al., 1996⁴⁸
59	Frullania obscura	Herbarium sample	Flavonoids	Yuzawa et al., 1987²³
60	Frullania osumiensis	Miyazaki, Japan	Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes; Bibenzyls	Asakawa et al., 1980³² Asakawa et al., 1981¹²
61	Frullania ovistipula	Herbarium sample	Flavonoids	Yuzawa et al., 1987²³
62	Frullania parvistipula	Kyoto, Japan	Sesquiterpene hydrocarbons and lactones; Bibenzyls	Asakawa et al., 1981¹² Asakawa et al., 1981³⁴
63	Frullania patula	North Island, New Zealand	Sesquiterpene hydrocarbons; Diterpenes; Bibenzyls	Asakawa et al., 2003¹⁴
64	Frullania pedicellata	Tokushima, Japan Miyazaki, Japan	Monoterpenes; Sesquiterpene hydrocarbons; Bibenzyls	Asakawa et al., 1979⁴⁹ Asakawa et al., 1981¹²
65	Frullania pluricarinata	Herbarium sample	Flavonoids	Yuzawa et al., 1987²³
66	Frullania polysticta	Madeira	Flavonoids	Kraut et al., 1993⁴⁴
67	Frullania probosciphora	Tasmania, Australia South Island, New Zealand	Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes; Fatty acids; Aromatic compounds	Asakawa et al., 2003¹⁴
68	Frullania ptychantha	Stewart Island, New Zealand	Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes; Bibenzyls	Asakawa et al., 2003¹⁴
69	Frullania pycnantha	North Island and Stewart Island, New Zealand	Monoterpenes; Sesquiterpene hydrocarbons; Diterpenes; Bibenzyls; Lipids	Asakawa et al., 2003¹⁴
70	Frullania ramuligera	Miyazaki, Japan	Sesquiterpene hydrocarbons and lactones	Asakawa et al., 1980³⁶ Asakawa et al., 1981¹²
71	Frullania riojaneirensis	Colombia, South America	Flavonoids	Yuzawa et al., 1987²³
72	Frullania rostrata	Stewart Island, New Zealand	Sesquiterpene lactones	Asakawa et al., 2003¹⁴
73	Frullania scalaris	Yate lake, New Caledonia	Sesquiterpene hydrocarbons and lactones	Métoyer et al., 2016²⁶
74	Frullania scandens	North Island, New Zealand	Sesquiterpene hydrocarbons; Bibenzyls; Lipids	Asakawa et al., 2003¹⁴
75	Frullania serrata	Cameron Highlands, Pahang, Malaysia Yunnan Province, China	Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes; Bibenzyls	Asakawa et al., 1983²⁴ Asakawa et al., 1991⁵⁰ Li et al., 2014⁵¹
76	Frullania solanderiana	North Island, New Zealand	Sesquiterpene hydrocarbons; Lipids	Asakawa et al., 2003¹⁴
77	Frullania spinifera	North Island, New Zealand	Monoterpenes; Sesquiterpene hydrocarbons; Bibenzyls; Lipids	Asakawa et al., 2003¹⁴
78	Frullania sphaerocephala	Herbarium sample	Sesquiterpene hydrocarbons and lactones; Flavonoids	Asakawa 1995²² Yuzawa et al., 1987²³
79	Frullania squarrosula	North Island, New Zealand	Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes; Diterpenes, Triterpenes, Aromatic compounds	Asakawa et al., 2003¹⁴ Asakawa et al., 2008⁵²
80	Frullania tamarisci	Dordogne, France Jura, France Corsica, France	Monoterpenes; Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes	Asakawa et al., 1979⁴⁹ Asakawa et al., 1980³² Asakawa 1995²² Asakawa et al., 2013¹⁴ Pannequin et al., 2017⁵³
81	Frullania tamarisci subsp. tamarisci	Cote de Jor, France Jula, France Vosges, France	Monoterpenes; Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes	Asakawa et al., 1979⁴⁹ Asakawa et al., 1980³² Asakawa et al., 1991²⁵ Asakawa 1995²²
82	Frullania tamarisci subsp. asagrayama	Pounds Escarpment, Illinois, USA	Oxygenated sesquiterpenes	Asakawa et al., 1991²⁵
83	Frullania tamarisci subsp. obscura	Japan (Hiroshina, Miyazaki, Hokkaido, Ehime, Kochi, Tokushima) Travas, East Java, Indonesia	Monoterpenes; Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes; Bibenzyls	Asakawa et al., 1979⁴⁹ Asakawa et al., 1980³⁶ Asakawa et al., 1981¹² Asakawa et al., 1991²⁵
84	Frullania tamarisci subsp. nisqualensis	Eugene, Oregon, USA	Sesquiterpene lactones	Asakawa 1982²¹ Asakawa et al., 1991²⁵
85	Frullania taradakensis	Tokushima, Japan	Sesquiterpene hydrocarbons	Asakawa et al., 1980³² Asakawa et al., 1981¹²
86	Frullania ternatensis	Kalimantan Seratan, Borneo	Sesquiterpene lactones	Asakawa et al., 1983²⁴
87	Frullania teneriffae	Madeira: Juncal, near Fanal, Lombo dos Cedros Portugal: Estremadura	Flavonoids	Kraut et al., 1995¹³
88	Frullania tolimana	Herbarium sample	Flavonoids	Yuzawa et al., 1987²³
89	Frullania ‘truncata’	Stewart Island, New Zealand	Sesquiterpene hydrocarbons	Asakawa et al., 2003¹⁴
90	Frullania usamiensis	Ehime, Japan	Monoterpenes; Sesquiterpene hydrocarbons and lactones; Bibenzyls	Asakawa et al., 1979⁵⁴ Asakawa et al., 1980³² Asakawa et al., 1981¹²
91	Frullania wallichiana	Herbarium sample	Flavonoids	Yuzawa et al., 1987²³
92	Frullania vethii	Miyazaki, Japan	Sesquiterpene hydrocarbons and lactones; Flavonoids	Asakawa et al., 1979⁵⁴ Asakawa et al., 1980³² Asakawa et al., 1981¹²
93	Frullania yunnanensis	Darjeeling, India	Monoterpenes; Sesquiterpene lactones	Asakawa et al., 1979⁵⁴ Asakawa et al., 1981¹²
94	unidentified Frullania sp. 1 (Venezuela)	Caracas, Venezuela	Sesquiterpene hydrocarboPns and lactones; Oxygenated sesquiterpenes; Triterpenes; Bibenzyls	Hasimoto et al., 1993⁵⁵ Tori et al., 1995⁵⁶ Asakawa 1995²²
95	unidentified Frullania sp. 2 (New Zealand)	New Zealand	Oxygenated sesquiterpenes; Triterpenes	Asakawa et al., 1996⁴¹
97	unidentified Frullania sp. 3 (Indonesia)	West Sumatra, Indonesia	Sesquiterpene hydrocarbons; Diterpenes; Bibenzyls; Aromatic compounds	Komala et al., 2010⁵⁷ Komala et al., 2011⁵⁸
98	unidentified Frullania sp. 4 (Tahiti)	Mount Marau, Tahiti	Sesquiterpene hydrocarbons and lactones; Oxygenated sesquiterpenes	Komala et al., 2010⁵⁷ Komala et al., 2011⁵⁸

In comparison to monoterpenoids, the sesquiterpenoids present in this liverwort genus are characterized by a wide range of different sesquiterpene skeletons. There are especially eudesmanes, elemanes, eremophilanes, germacranes, bazzananes, pacifigorgianes, and other minor groups of sesquiterpenoids, like aromadendranes, africanes, barbatanes, cadinanes, cuparanes, drimanes, farnesanes, guaianes, monocyclofarmesanes, pinguisanes, and thujopsanes. The sesquiterpenoids, that seem to be the most characteristic of this genus are lactones (Figure 2). These components have been found in almost 50 Frullania species. Sesquiterpene lactones detected in and/or isolated from Frullania are mainly eudesmanolides The most characteristic compounds belonging to this group are (+)-frullanolide (8) and (-)-frullanolide (9), but other, for example, α- (10), β- (11), and γ-cyclocostunolides (12) are also popular. Such α-methylene-γ-butyrolactones cause very strong allergenic contact dermatitis. Their dihydroderivatives (13, 14) are also popular components in Frullania species but do not cause allergy.¹⁶ In the group of eudesmanolides it is also worth mentioning about rearranged spiroeudesmane-type lactones, called spirodilatanolides A-C (15-17) isolated from the European Frullania dilatata var. anomala.³³

Figure 2

Sesquiterpene lactones characteristic for Frullania species.

Almost all sesquiterpene lactones found in Frullania possess a 12,6-olide moiety. The exception of this rule was the isolation of densilobolides A (18) and B (19) form F. densiloba ⁵⁹ and eremofrullanolide (20) together with dihydro-derivative (21) from F. lobulata, F. media, and F. probosciphora.¹⁶ The mentioned compounds have in their structures 12,8-olide moiety.

Another interesting feature of the sesquiterpene lactones occurring in Frullania is the presence of dimeric compounds. A good example is the isolation of two dimeric lactones with eudesmanolide structure called muscicolide A (22) and B (23) from the Portuguese F. muscicola.⁴⁵

Frullania species, occasionally produce sesquiterpenes which are very rare in this genus and are characteristic for just a few species. The good example is the presence of pacifigorgianes (eg, 24-26) in F. fragilifolia, as well as F. tamarisci and their subspecies. The second example are bazzanane-type sesquiterpenoids (eg, 27-29) found in F. falciloba, F. squarossula and unidentified Frullania from New Zealand (Figure 3).¹⁶

Figure 3

Other terpenoids present in genus Frullania.

Among the diterpenoids, labdane-, and fusicoccane-type compounds are most prevalent in Frullania, but kauranes have also been found in a few species. There are two Frullania species rich in labdane-type diterpenoids. These are F. hamatiloba and F. inouei and both produce manoyl oxide derivatives.^22,40 The most characteristic components for the former species are hamatilobenes (eg., 30),²² while structurally similar labdanes, for example, 1,2-dehydro-3,7-dioxomanoyl oxide (31) were isolated from the second species (Figure 3).⁴²

Frullania species occasionally also produce triterpenoids and these mainly belongs to oleanane, taraxane, hopane, lupane, and friedelane group. The major component of an unidentified Frullania species collected in Venezuela was methyl 3α-hydroxyolean-18-en-28-onate (32).⁵⁶ F. fugax from New Zealand produces a triterpene alcohol, taraxerol, and the major component (88%),¹⁴ while α-zeorin (33) was isolated from the Argentine F. braziliensis.²⁷ Another triterpene, friedelin, was found in F. tamarisci.²¹ The ether extracts from the New Zealand F. falciloba and F. squarrosula were fractionated to give epi-betulinic acid (34) (Figure 3).⁵²

Besides terpenoids, the second group of compounds with a great diversity are bibenzyls (eg., 35-37) (Figure 4). The most abundant compounds in this group are bibenzyls possessing the methylenedioxy group. 3-Methoxy-3′,4′-methylenedioxybibenzyl (35) is the most predominant.^16,21,22 In comparison to bibenzyls, their dimers called bisbibenzyls are very rare in Frullania. Such components together with acyclic bibenzyl-dihydrophenanthrenes were found in the Ecuadorian F. convoluta.³⁰ The isolated bisbibenzyls, (40-43) are perrottetin-type compounds and are widespread in the Radulaceae and Marchantiaceae liverwort families.¹⁶ The acyclic bibenzyl-dihydrophenanthrenes, 38 and 39, seem to be good chemical markers of this liverwort, since these have been found only in this species.

Figure 4

Bibenzyls and bisbibenzyls characteristic for Frullania species.

Flavonoids are ubiquitous minor components in the liverworts, also in genus Frullania. Among the flavonoids found in Frullania species more common are flavones, but also some flavanones were also detected. As in all liverworts, luteolin and apigenin derivatives dominate in this genus.¹⁶ It is worth mentioning that the most common flavonoid glycosides are glucuronides, for example, luteolin-7-O-glucuronide (44), luteolin-7,4′-diglucuronide (45), or apigenin-7-O-glucuronide (48). Besides O-glucosides, flavone-C-glycosides were also found, but the most popular flavonoids are flavone methyl ethers (eg., 46, 47, 49) and hydroxy and methoxy derivatives of flavone and flavanone (Figure 5).^13,16,21,22

Figure 5

Flavonoids present in Frullania species.

Chemosystematic Approach

On the basis of the sesqui- and diterpenoids as well as bibenzyls composition, the Frullania species have been divided into six groups, namely, type I: sesquiterpene lactone-bibenzyl, type II: sesquitepene lactone, type III: bibenzyl, type IV: labdane, type V: bazzanane, and type VI: pacifigorgiane-type (Table 2). As shown in this table, the most significant markers of Frullania species are sesquiterpene lactones and bibenzyls. Five types of sesquiterpene γ-lactones have been recognized in Frullania species. There are the eudesmanolides, elemanolides, eremophilanolides, germacranolides, and guaianolides, and, among these, the eudesmane-type sesquiterpene lactones are the most prevalent. In case of bibenzyls found in Frullania, compounds possessing the methylenedioxy group and polymethoxylated bibenzyls occur much more often.^16,21,22

Table 2

Chemotypes of Frullania Species.

Type	Frullania species	SES				SL	DI		BB	BB₂	AR
Type	Frullania species	Pac	Ger	Baz	Eud	SL	Lab	Fus	BB	BB₂	AR
I	F. brasiliensis		+			+++			+
	F. convoluta					+++			++	+++
	F. davurica		+		+	+			+++
	F. dilatata var. anomala					+++			+
	F. incumbens		+			++		+	+
	F. monocera		+			++		++	++
	F. muscicola					+++			++		+++
	F. osumiensis					+++			+
	F. parvistipula				+	++			+++
	F. ptychantha		++			+			+
	F. serrata				+	+++			+++		+
	F. usamiensis					+++			+
	unidentified Frullania sp. 1					++			+
II	F. apiculata					++
	F. asagrayama					++
	F. aterrima var. aterrima		+		+	++
	F. aterrima var. lepida		++			++
	F. bicornistipula					+++
	F. brotheri					++
	F. californica					+
	F. chevalierii					++
	F. congesta					+++
	F. densiloba					+++
	F. deplanata					+
	F. dilatata				++	+++
	F. diversitexta					+
	F. franciscana					+
	F. inflata		+		++	+++
	F. lobulata					+++
	F. magellanica					+++
	F. mammillosa				+	+
	F. media		+			++		+
	F. nisquallensis					++					+
	F. probosciphora					+++					+
	F. ramuligera					+++
	F. rostrata					++
	F. scalaris				+	+
	F. sphaerocephala					++
	F. tamarisci subsp. nisqualensis					+++
	F. ternatensis					+
	F. vethii				++	+
	F. yunnanensis					++
	unidentified Frullania sp. 4				+	+++
III	F. amplicrania		+		+				++
	F. anomala								+++
	F. bonincola								++
	F. ericoides								+++
	F. jackii		+						+++
	F. patula		+					+++	+
	F. pedicellata								+
	F. pycnantha				+			+++	++
	F. scandens								+++
	F. spinifera		+						++
	unidentified Frullania sp. 3				+			+	++		+++
IV	F. fugax						+				+
	F. hamatiloba					+	+++	+++
	F. inouei						+++		+++
V	F. falciloba		+	+++				++	+++		++
	F. squarrosula			+++		+		+			+++
	unidentified Frullania sp. 2			+++
VI	F. fragilifolia	+++	++		++
	F. nepalensis	+				+++
	F. tamarisci	+++	++		+++	+++
	F. tamarisci subsp. asagrayama	+
	F. tamarisci subsp. obscura	+	+		+++	+++			+
	F. tamarisci subsp. tamarisci	+			+++	+++

unclassified	Detected compounds	unclassified	Detected compounds
F. bella	SES	F. africana	FLA
F. clavata		F. arecae
F. cornuta		F. brachyclada
F. falscicornuta		F. cesatiana
F. gaudichaudi		F. confertiloba
F. kagoshimensis		F. ecklonii
F. multilacera		F. gibbosa
F. motoyana		F. gradsteinii
F. solanderiana		F. laxiflora
F. taradakensis		F. obscura
F. ‘truncata’		F. ovistipula
		F. pluricarina
F. eboracensis	AR	F. polystricta
F. microcaulis	AR	F. riojaneirensis
F. inflata var. mayebarae	MON	F. tenerifae
		F. tolimana
		F. wallichiana

Abbreviations: SES, sesquiterpenes; Pac, pacifigorgianes; Ger, germacranes; Baz, bazzananes; Eud, eudesmanes; SL, sesquiterpene lactones; DI, diterpenes; Lab, labdanes; Fus, fusicoccanes; BB, bibenzyls; BB₂, bisbibenzyls; AR, aromatic compounds; MON, monoterpenes; FLA, flavonoids.

Thirteen among ninety-eight chemically investigated Frullania species were classified as chemotype I. These species produce sesquiterpene lactones and bibenzyls as the main components.

South American Frullania brasiliensis belongs to the type I since it elaborates sesquiterpene lactones (eg., 8, 12, 13) and 3,3′,4-trimethoxybibenzyl.²⁷ The most known eudesmanolide, frullanolide occurs in this species in both enantiomeric forms (8, 9). Besides eudesmanolides, this Argentine liverwort also produce eremophila-12,6-olides, 5-epi-dilatanolides A and B, which are very rare occurring lactones. Such kind of eremophilane lactones were also found in 2 more Frullania species, F. muscicola (type I) and F. dilatata (type II).¹⁶

From a Bulgarian collection of F. dilatata var. anomala which belongs to chemotype I, unusual spiroeudesmane-type lactones (15-17) were isolated along with C12/C6- and C12/C8-eremophilanolides and common eudesmanolides, frullanolide (8) and its dihydroderivative (13).³³ It is chemosystematically interesting to note that neither C12/C6 eremophilanolides nor spirolactones as well as bibenzyls have been found in F. dilatata from French collections.^16,22

The Ecuadorian F. convoluta is chemically very characteristic. Together with sesquiterpene lactones and bibenzyls, acyclic bisbibenzyls, perrottetins E–G (40-42), and bibenzyl-dihydrophenanthrenes (38, 39) were isolated.³⁰ F. convoluta is the only species that produce bisbibenzyls.

Two Venezuelan collections of an unidentified Frullania species have been chemically analyzed. Phytochemical studies showed that one collection should be classified within type I, since it produces 3-methoxy-3′,4′-methylenedioxybibenzyl, α-cyclocostunolide (10) and rothin A acetate. The second collection showed just the presence of the mentioned sesquiterpene lactones, thus should be classified in type II.⁵⁶

F. muscicola is another liverwort classified in chemotype I. It produces both sesquiterpene lactones and bibenzyls.^22,45 This liverwort is also known for the presence of dimeric sesquiterpene lactones, muscicolides A (22) and B (23) as well as phthalides.⁴⁵ Two other Frullania species, F. tamarisci ssp. obscura and F. yunnanensis, are known for the content of eudesmanolide dimers, while phthalides has been isolated from F. falciloba.^14,16,22

Frullania vethii, which was classified in chemotype II, produces guaianolides together with elemane-type sesquiterpene lactones.^21,34 Guaianolides have not been detected in the other Frullania species so far.

The New Zealand Frullania chevalieri (type II) elaborates eudesmane-type sesquiterpene lactones, with β-cyclocostunolide (11) and dihydro-β-cyclocostunolide (14) having been detected in this species.¹⁴ This is significant because the status of this species has remained controversial for some time. Von Konrad and coworkers⁶⁰ reported that chemical and morphological evidence strongly supports the retention of Frullania chevalieri (not Schusterella) and its allies in the genus Frullania.

Frullania species classified in chemotype III do not produce sesquiterpene lactones at all, but these species are known for the presence of bibenzyls. Among eleven liverworts classified in this chemotype, 8 species elaborate bibenzyls possessing the methylenedioxy group; 3-methoxy-3′,4′-methylenedioxybibenzyl (35) is the most predominant.^16,21,22

Frullania hamatiloba and F. fugax represent the labdane chemotype (IV), since both species produce structurally similar labdane-type diterpenoids. Manoyl oxide has been isolated from F. fugax,¹⁴ while its derivatives, hamatilobenes A-E (eg., 30), have been found in F. hamatiloba.²² A second collection of F. hamatiloba was found to produce structurally different labdanes. Labdane-type epoxides, have been isolated from this species together with the fusicoccane-type diterpenoids.³⁹ From the Chinese collection of the same species six additional labdane diterpenoids, frullanians A-F were also isolated.⁴⁰ F. hamatiloba is thus a really reach source of labdanoids. Structurally similar compounds have also been found in the another Chinese Frullania species, F. inouei. From the hydroalcoholic extract of this species seven labdane diterpenoids (eg., 31) were isolated together with highly methoxylated bibenzyl derivatives.⁴²

The New Zealand F. falciloba belongs to chemotype V of the Frullaniaceae, since it elaborates characteristic bazzanane-type sesquiterpenoids (27-29), with no sesquiterpene lactones having been detected.³⁵ Bazzanenones A-D have been isolated from an unidentified New Zealand Frullania species.⁴¹ The bazzanane sesquiterpenoids have been also found in F. squarrosula.^14,52

Chemical analysis of the New Zealand Frullania falciloba from different collections showed the presence of β-bazzanene (27), but no other bazzananes were detected. This species produces 3-methoxy-3′,4′-methylenedioxybibenzyl (35), as the main component, along with the fusicoccane diterpenoid, fusicogigantepoxide.¹⁴ On the other hand, in an Australian specimen, a large amount of the monocyclofarnesane-type sesquiterpene hydrocarbon, striatene, together with fusicoccane-type diterpenoids have been found.¹⁴ It is worth mentioning that the same fusicoccanes has also been confirmed in F. squarrosula.¹⁴ Further detailed analysis is required in order to investigate the chemical variations within Frullania falciloba.

Type VI of Frullania species produces the pacifigorgiane-type sesquiterpenoids. (–)-Tamariscol (24), a pacifigorgiane alcohol, has been demonstrated to be the main component in the American F. tamarisci and F. tamarisci subsp. asagrayana.^22,61 The same compound has also been isolated from F. tamarisci subsp. tamarisci and F. nepalensis, while the (+)-enantiomer has been found in the European F. tamarisci subsp. obscura.²² Besides tamariscol (24), F. tamarisci produces other pacifigorgianes (eg, 26), together with the rearranged pacifigorgiane, tamariscene (25).⁶¹ Tamariscene (25) is the major constituent of the German F. fragilifolia, and the other pacifigorgianes have also been found.⁶¹

The phytochemical studies of the Asian collections of F. tamarisci subsp. obscura showed that this species is not homogenous and should be further divided into 2 subtypes, type-T and type-O.²² Type-T produces the usual pacifigorgiane alcohol tamariscol (24) and eudesmane-4α,6α-diol as the major components, whereas type-O lacks these 2 sesquiterpenoids while eudesmanolides are predominant.²² Representatives of type T have been found in high mountains at 1500‐3000 m altitude and in the northern part of Japan (42, 44^oN), while type-O occurs more frequently at lower altitudes between 32 and 40^oN.²⁵

There are other thirty-two Frullania species difficult to classify in terms of the six chemotypes indicated above, and further chemical analysis will be necessary. However, among these species, the New Zealand F. solanderiana produces very characteristic 2-alkanones, such as 2-undecanone, 2-tridecanone, and 2-pentadecanone, as the main components.¹⁴ This is the first record of the identification of the 2-alkanones in the genus Frullania.

Frullania diversitexta produces a large amount of cyclocolorenone, an aromadendrane sesquiterpene ketone, together with other common sesquiterpenoids and fusicoccane-type diterpenoids.³⁴ Neither sesquiterpene lactones nor bibenzyls were present in F. diversitexta. Phytochemical analysis of F. gaudichaudii showed that this liverwort species is chemically very similar to F. diversitexta.²⁴ However, cyclocolorenone has been found in several other Frullania species. To describe another cyclocolorenone chemotype more chemical data are necessary.

Summary

Frullania species, although morphologically simple, are characterize by enormous diversity of secondary metabolites, especially terpenoids and aromatic compounds. The most characteristic compounds present in this liverwort genus are sesquiterpene lactones with eudesmanolides as the most diverse group, and aromatic compounds belonging to bibenzyls. It was already shown that the relationship between various types of liverworts can be predicted based on the similarity or differences in the chemical substances present in them.^{15,16,22,62,63} Frullania is, however the largest and taxonomically most complex genus of leafy liverworts. Studies concerning these liverworts classification based on morphological evidence and molecular markers showed that species level-classification of Frullania is notoriously difficult. Up to now, over 30 sections and subsections of Frullania are described, and still new synonyms, new combinations, and names are proposed.¹¹ Here, we reported the distribution of secondary metabolites in all chemically investigated Frullania species, and discussed some aspects concerning the division of this genus into chemotypes. Based on the chemical composition, the Frullania species have been divided into six chemotypes, namely, type I: sesquiterpene lactone-bibenzyl, type II: sesquitepene lactone, type III: bibenzyl, type IV: labdane, type V: bazzanane, and type VI: pacifigorgiane-type. However, it does not appear that this research could be completed at this stage. Within some of the recognized chemotypes, there are some Frullania that could be divided into some sub-chemotypes, for example, Frullania tamarisci subsp. obscura, because of the chemical differences between different collections of particular species. There are also thirty-two Frullania species that could not be classified into the proposed six chemotypes. Further studies on secondary metabolites occurring in liverworts are still needed. The most valuable would be those conducted in parallel with the morphological and genetic studies. Despite the fact that around one quarter of the available species have already been studied chemically and the abundance of morphological and genetic data available, it is still difficult to suggest the division of the genus into some natural sections or propose phylogenetic tree of Frullania genus.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Agnieszka Ludwiczuk

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Chemical Diversity of Liverworts From Frullania Genus

Abstract

Keywords

Chemistry of Frullania Species

Chemosystematic Approach

Summary

Footnotes

Declaration of Conflicting Interests

Funding

ORCID iD

References