Phytochem Rev

https://doi.org/10.1007/s11101-020-09697-2 (0123456789().,-volV)
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89().,-volV)

Phloroglucinols from Myrtaceae: attractive targets

for structural characterization, biological properties
and synthetic procedures
Odeta Celaj . Alexandra G. Durán . Pasqualina Cennamo .
Monica Scognamiglio . Antonio Fiorentino . Assunta Esposito .
Brigida D’Abrosca

Received: 31 January 2020 / Accepted: 5 June 2020

Ó Springer Nature B.V. 2020

Abstract Myrtaceae Juss. is a very large family of
flowering plants, that are a valuable source of bioac-
tive compounds. From the phytochemical point of
view, apart from ubiquitous tannins, flavonoid deriva-
tives and volatile oils, Myrtaceae plants are very rich
in phloroglucinol derivatives, divided in two principal
subclasses: oligomeric acylphloroglucinols and
phloroglucinol-terpene adducts. Despite this large
structural variability, many studies on phloroglucinols
from the Myrtaceae have focused on unique bioactive
acylphloroglucinol compounds, named
myrtucommulones. Nevertheless, many studies also
reported other interesting phloroglucinol derivatives.
Therefore, in this review, a comprehensive description
of the chemical features of acylphloroglucinols and
meroterpenoid-acylphloroglucinols from the Myr-
taceae family is presented along with their biological
activities. Moreover, since myrtucommulones and
their derivatives have become attractive targets for
organic chemists, thanks to their structural features
and biological activities, relevant approaches and
synthetic procedures are herewith discussed.

Keywords Antimicrobial-activity
Myrtaceae

The last two authors (Assunta Esposito and Brigida Phloroglucinols
Terpene-adduct
Myrtucommulones
D’Abrosca) contributed equally to this work.

O. Celaj
P. Cennamo
M. Scognamiglio

A. Fiorentino
A. Esposito
B. D’Abrosca (&)
Dipartimento di Scienze e Tecnologie Ambientali Introduction
Biologiche e Farmaceutiche –DiSTABiF, Università degli
Studi della Campania ‘‘Luigi Vanvitelli’’, Via Vivaldi 43, Plants belonging to the Myrtaceae family have been
81100 Caserta, Italy
e-mail: brigida.dabrosca@unicampania.it
used in traditional medicine and as food or spices since
ancient times. They are indeed an invaluable source of
A. G. Durán bioactive metabolites, including ubiquitous tannins,
Allelopathy Group, Department of Organic Chemistry, flavonoid derivatives, volatile oils, etc. However,
Institute of Biomolecules (INBIO), Campus de Excelencia
Internacional (ceiA3), School of Science, University of
Myrtaceae plants are also a very rich source of
Cadiz, C/República Saharaui n8 7, 11510 Puerto Real, phloroglucinol derivatives.
Cadiz, Spain Phloroglucinols are a major class of natural com-
pounds widely occurring in biological systems: they
A. Fiorentino
B. D’Abrosca
Dipartimento di Biotecnologia Marina, Stazione
are synthesized and accumulated by plants from
Zoologica Anton Dohrn, Villa Comunale, 80121 Naples, different families, as well as by microorganisms and
Italy

123

marine organisms (Singh and Bharate 2006). The
simple phloroglucinol unit (1,3,5-trihydroxybenzene)
is synthesized starting from three malonyl-CoA units
(Xiang et al. 2017). However, one of the interesting
features of phloroglucinols is a certain versatility from
the structural standpoint deriving from possible
oligomerization as well as conjugation with units
originating from different biosynthetic pathways.
In case of phloroglucinols from the Myrtaceae, they
can be classified in two principal subclasses: oligo-
meric acylphloroglucinols and phloroglucinol-terpene
adducts. Different biogenetic precursors as cyclic
polyketones (leptospermone, tasmanone, syncaric
acid), polymethylated phloroglucinols and 3,5-
dimethyl-2,4,6-trihydroxy-benzophenone are
believed to be involved in the biosynthetic pathways
of simple acyl phloroglucinols as well as of dimeric
and oligomeric phloroglucinol derivatives (Hou et al.
2017a; Jian et al. 2015; Zhang et al. 2016). On the
other hand, phloroglucinol-terpene adducts are
hypothesised to biosynthetically arise from hetero
and carbon Diels–Alder reactions. The enzymes
involved in the biosynthesis use the same aforemen-
tioned biogenetic precursors and combine them with
mono/sesquiterpene units (Su et al. 2016; Wu et al.
2015a, b).
With reference to their biological activity, all
phloroglucinol derivatives and in particular myrtu-
commulones, unique non-prenylated phloroglucinols
(Ogur 2014), have shown numerous properties includ-
ing antibacterial, anti-inflammatory and antitumor
(Meng et al. 2018; Hennia et al. 2018).
Based on these interesting biological activities and
thanks to their structural features, these compounds
have become attractive targets for organic chemists
and pharmacologists. In an effort to deepen structure–
activity relationship studies (SAR) to obtain analogues
with improved effects and higher selectivity, synthetic
strategies have been recently started in several
research groups worldwide (Nicoletti et al. 2018).
However, to the best of our knowledge, no compre-
hensive review has been previously published on the
most relevant approaches and synthetic procedures of
myrtucommulones and their derivatives as well as on
acylphloroglucinol and phloroglucinol-terpene
adducts.
The aim of this review is to furnish an overview of
phloroglucinols from the Myrtaceae, focusing both on
their chemical properties and biological activities. In
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Phytochem Rev
order to allow the readers to contextualize the reported
compounds in terms of botanical origin, a brief
description of the plant family is reported. A collection
of the monomeric and dimeric phloroglucinols as well
as of phloroglucinol-terpene adducts reported from the
Myrtaceae family follows and it is paired with the
discussion on the relevant synthetic procedures of
acylphloroglucinols and myrtucommulones. Finally,
the huge body of literature on the biological activity of
the compounds object of this review is reported,
discussed and integrated in order to furnish a clear
overview of the state of the art, including the important
aspects related to the possible modes of action of
promising compounds.
Morphology, taxonomy and distribution
of Myrtaceae
The Myrtaceae Juss. (Chase et al. 2016) is the ninth
largest family of flowering plants, with recent esti-
mates of about 5.950 species in 132 genera (Biffin
et al. 2010; Wilson 2011; Christenhusz and Byng
2016; WCSP 2019).
This family represents an old, mid-Cretaceous
lineage within the order Myrtales that, based on fossils
records, may date back to 87–95 Ma (Biffin et al.
2010; Wilson 2011; Thornhill and Macphail 2012;
Berger et al. 2016; Vasconcelos et al. 2017). Its
postulated origin is in Gondwana (Johnson and Briggs
1984; Sytsma et al. 2004).
Species of this family occur mainly in the Southern
Hemisphere (Fig. 1) with main centers of diversity in
the wet tropics, particularly South America, Australia,
and tropical Asia and lower species occurrence in
Africa and Europe (Ladiges et al. 2003; Wilson 2011).
The family is commonly found in many of the world’s
biodiversity hotspots such as south western Australia,
and the Cerrado and Atlantic Rainforest in Brazil
(Govaerts et al. 2008).
The species belonging to this family are all woody
plants, generally distinguished by a number of mor-
pho-anatomical characters. Among these: the presence
of essential oil glands (usually secreting terpenes);
alternate to mostly opposite leaves, evergreen or
deciduous (e.g., Eucalyptus species); flower parts
present in multiples of four or five, though in several
genera the petals are minute or absent; moreover the
flowers are polystemonous, mostly bisexual,
Phytochem Rev
Fig. 1 Present-day distribution of Myrtaceae and selected subfamily: Myrtoideae (black) and Psiloxyloideae (grey) (from Thornhill
et al. 2015 adapted)
actinomorphic with usually very conspicuous, brightly
colored and numerous stamens, while the ovary is
half-inferior to inferior. The phloem is located on both
sides of the xylem, rather than just outside as in most
other plants; vestured pits are present on the xylem
vessels (Ciccarelli et al. 2008; Wilson et al. 2001;
Govaerts et al. 2008; Wilson 2011). The fruits are
classified as either fleshy (berry, drupes) or dry
(capsular, nut) (Wilson 2011) and its consistency
(fleshy vs. dry) was a very important trait used until
recently to divide the family into subfamilies: the
Leptospermoideae with capsular fruits and alternate
leaves and the Myrtoideae fleshy-fruited and with
opposite leaves (Niedenzu 1893).
This natural classification was challenged by a
number of morphological and molecular phylogenetic
studies (Briggs and Johnson 1979; Gadek et al. 1996;
Wilson et al. 2001, 2005), highlighting the unreliabil-
ity of fruit consistency to delimitate tribes or subfam-
ilies in Myrtaceae (Johnson and Briggs 1984). These
studies also found Myrtoideae to be polyphyletic
(Johnson and Briggs 1984).
Several molecular studies confirmed that fleshy
fruits evolved twice from capsular fruits and, there-
fore, the two-subfamily classification does not accu-
rately describe the phylogenetic history of the family
(Wilson et al. 2001, 2005; Craven and Biffin 2010;
Snow et al. 2011; Murillo et al. 2012; Mazine et al.
2014).
The most recent classification recognizes, on the
basis of a molecular matK gene phylogenetic analysis
of plastid DNA 17, two subfamilies: Myrtoideae
Sweet (15 tribes) and Psiloxyloideae (Croizat) Schmid
(2 tribes), with Myrtoideae (Fig. 2) comprising the
vast majority of genera and species (Udovicic and
Ladiges 2000; Wilson et al. 2005; Biffin et al. 2010;
Edwards et al. 2010; Grattapaglia et al. 2012).
Myrtoideae are found worldwide in subtropical and
tropical regions, with centers of diversity in the
Neotropics, Northeastern Australia, and Malesia.
The genera of Myrtoideae can be very difficult to
distinguish in the absence of mature fruits.
About half of the species of Myrtaceae are in the
tribes Syzygieae and Myrteae (Fig. 2) and include
fleshy-fruited species distributed mainly in wet forests
across the tropics with some prominent genera such as
Syzygium, Eugenia, and Psidium (Biffin et al. 2010).
For example, Syzygium genus contains between 1200
and 1500 species, Eugenia approximately 1050
species (Craven and Biffin 2010).
Myrteae, in particular, represent half of the family’s
biodiversity (Wilson 2011; WCSP 2019) and is mainly
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Fig. 2 Infra-familial
classification and tribal
diversity of Myrtaceae with
Vochysiaceae as outgroup.
For each tribe number of
genus and species are shown
in brackets respectively
(from Grattapaglia et al.
2012 adapted)
distributed in Central and South America, with some
genera in the Australasian region (Lucas et al. 2007).
Syzygieae has a native range that extends from Africa
and Madagascar through southern east Asia through
the Pacific (Tuiwawa et al. 2013) and its highest levels
of diversity occur from Malaysia to Northeastern
Australia where many species are very poorly known
and many more have not been described
taxonomically.
The species richness in the tribes Syzygieae and
Myrteae may be related to biotic dispersal possibly
supporting allopatric speciation or reducing risk of
extinction (Biffin et al. 2010).
The tribes Leptospermae, Eucalyptae, and Chame-
lauciae, characterized by woody-fruited species, rep-
resent a second large group that have radiated in
Australia and include Leptospermum, Eucalyptus and
Melaleuca (Wilson et al. 2001). The genus Eucalyptus
is the richest with about 700 species (Brooker 2000)
that are dominant or co-dominant in most of the
vegetation types (Wiltshire 2004) and are considered
keystone species for ecological studies in their natural
ranges (Williams and Woinarski 1997).
Moreover, Thornhill et al. (2015) highlighted that
most of the transoceanic distribution patterns in
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Phytochem Rev
Myrtaceae groups can be interpreted as a result of
either vicariance or long-distance dispersal and estab-
lishment (LDDE) but enigmatic occurrences of genera
such as Arillastrum in New Caledonia and Myrtus in
southern Europe are difficult to explain, possibly
because of information lost through extinction.
Distribution, taxonomic and nomenclatural history
of Myrtaceae are complex. Moreover, the high sim-
ilarity of species and the distinctiveness of many
widely recognized genera is being questioned (e.g.,
Biffin et al. 2010; Edwards et al. 2010). Works on
molecular phylogenetics and population genetics,
linkage and association mapping, quantitative trait
loci (QTL) analysis, transcriptomics, proteomics, and
metabolomics, and, finally, molecular breeding are
needed to improve the knowledge status of Myrtaceae.
In a recent review (Grattapaglia et al. 2012) the current
standing of genomics and other related fields in the
Myrtaceae are reported and highlight Eucalyptus as
the pivotal genus for which genomic resources have
been developed and currently represent the bulk of the
genomics literature for the family.
The Myrtaceae species occur in a wide range of
habitats, including seasonally dry areas, coastal sands,
rainforests, tropical moist forests, savannahs, and
Phytochem Rev
mangroves (Biffin et al. 2010; Wilson 2011). Several
genera of Myrtaceae are well known for their
economic importance and are cultivated worldwide
for their fleshy fruit (Psidium, Myrciaria, Syzygium,
Eugenia) trees; spices (Syzygium, Pimenta); antiseptic
oils (Eucalyptus, Melaleuca, Myrtus); or as important
sources of timber or fiber (Eucalyptus, Corymbia,
Syncarpia).
Chemical structures of phloroglucinols
It is impossible to talk about phloroglucinols from the
Myrtaceae, without referring to myrtucommulones.
These unique bioactive acylphloroglucinol com-
pounds were first reported from Myrtus communis
(Nicoletti et al. 2018). Nevertheless, subsequent
studies have demonstrated the presence of this kind
of compounds in other plant species belonging to the
Myrtaceae family.
General structural features of myrtucommulones
(Fig. 3) are an acylphloroglucinol nucleus coupled via
isobutyl bridge(s) with one or more syncarpic acid
residues (Appendino et al. 2002; Koeberle et al. 2009;
Cottiglia et al. 2012). These structures are also closely
related to filixic acid (Fig. 3, from Dryopteris filix-mas
L.), as well as to uliginosins (Hypericum uliginosum
L.) and kosins (isolated from Hagenia abyssinica
J.F.Gmel., Kashman et al. 1974).
It is worth underlying that the nomenclature of
these compounds is often based on the plants from
Fig. 3 General structure of myrtucommulone and related compounds
which they were isolated, hence many related com-
pounds are not named myrtucommulones, but for
example rhodomyrtone A from Rhodomyrtus tomen-
tosa and callistenone A from Callistemon lanceolatus
that differ by myrtucommulone B only for acyl
functionalities (Nicoletti et al. 2018).
It is proposed that these specific phloroglucinols are
generated from common biosynthetic pathways. A
plausible biogenesis suggests the residues of isobu-
tyrylphloroglucinol and isobutylidenesyncarpic acid
derived from the Claisen reaction of three units of
malonyl CoA and one of isobutyryl CoA as possible
precursors (Ghisalberti 1996; Cao et al. 2016; Nico-
letti et al. 2018).
Besides, myrtucommulones and structurally related
compounds, a plethora of other phloroglucinols, have
been reported from the Myrtaceae (Nicoletti et al.
2018; Brezáni and Šmejkal 2013). These compounds
are characterized by a wide structural variability. So,
phloroglucinols from the Myrtaceae family can be
further divided in two principal subclasses: phloroglu-
cinol-terpene adducts and oligomeric acylphloroglu-
cinols (Fig. 4).
Phloroglucinol terpene-adducts are characterized
by the presence of mono or sesquiterpene units
coupled with diverse phloroglucinol precursors such
as tasmanone, syncarpic acid, polymethylated
phloroglucinols etc., biosynthesised under control of
terpene cyclases and polyketide synthases, respec-
tively. Despite the variability in the molecular skele-
ton, all the reported hybrids possess the original
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Fig. 4 Structural variation of acylphloroglucinols

terpene moiety, monoterpene units as myrcene, phel-
landrene, pinene and sesquiterpene moieties such as
germacrane, b-caryophyllene and cubebane.
Due to the vast array of structural variation,
oligomeric acylphloroglucinols can be classified in
two principal groups: dimeric and trimeric structures.
Depending on the number of structural units and
additional pyranic or furanic rings, different sub-
groups can be identified as dimeric and trimeric
structures.
1. Dimeric structures These compounds possess two
moieties (acylphloroglucinol and syncarpic acid
cores) linked together by an isobutyl bridge.

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Besides these structures could present additional
cyclic structures. Acylphloroglucinols such as
semimyrtucommulone, myrtucommulone J and
bullataketals A and B belong to this group. The
group of dimeric-monopyrane structures has two
backbones but the acylphloroglucinol skeleton
contains a methylated phenolic group.
Acylphloroglucinol and syncarpic cores are linked
through an intramolecular oxygen bond forming
one pyrane ring. Myrtucommulones B and M,
isomyrtucommulone B and rhodomyrtone A are
some examples of this classification. The dimeric-
bisfurane structures are closely related to dimeric
structures (one b-triketone and one phloroglucinol
skeletons) but rather than being linked by an
isobutyl bridge, they are assembled by a bisfurane
ring. Some examples are rhodomyrtosone G and
callistenone M.
2. Trimeric structures This group consists of com-
pounds comprising three nuclei, two units of
syncarpic acid and one acylphloroglucinol moiety
linked to each other by an isoalkyl bridge.
Examples are myrtucommulones A and F. When
two of three backbones (one syncapic acid and one
acylphloroglucinol residues) are linked by one or
two additional cyclization(s) forming a monopy-
ranic or dipyranic rings, we identify trimeric-
monopyrane (for example myrtucommulone C or
eucalyptone G) and trimeric-dipyrane structures
(for instance, myrtucommulones D and E), respec-
tively. Finally, the trimeric-bisfurane-pyrane
structures contain six continuous rings as well as
a bisfuranic group (Hiranrat et al. 2012). Exam-
ples from this particular class are tomentosones A
and B.
Monomeric and dimeric acylphloroglucinols
Monomeric and dimeric acylphloroglucinols are rep-
resentative metabolites of the Baeckea genus. Baeck-
enones A–K (1–11) were isolated from leaves of
Baeckea frutescens (Fig. 5). Two of them are dimeric
acylphloroglucinols (2–3, baeckenones B–C, Nisa
et al. 2016a), while one is a peroxidic phloroglucinol
named endoperoxide (12, Fig. 5, Nisa et al. 2016b; Ito
et al. 2017). Recently, three unusual compounds,
callistemonols A–B (Wu et al. 2019) and
callistemenonone A (Xiang et al. 2017), were isolated
from Callistemon viminalis. Callistemonol A (13) and
callistemenonone A (15) are characterized by a unique
carbon skeleton with a furan ring fused to an triketone
and a phloroglucinol unit, whereas callistemonol B
(14) is an acylphloroglucinol derivative featuring two
methyl substituents on a five-membered ring and an
isovaleryl side chain (Fig. 5).
Six phloroglucinol diglucosides named kun-
zeaphlogins A–F (16–21), characterized by an unusual
O- and C-glucosylation, were isolated from the leaf
extract of Kunzea ambigua. Kunzeaphlogins B, C and
E were identified as galloylated phloroglucinols
(Kasajima et al. 2008).
Rhodomyrtosones G–H (22–23), a dimeric furofu-
rane and a monopyrane respectively, have been
isolated from the leaves of Rhodomyrtus tomentosa
(Fig. 5) (Hiranrat et al. 2017). Watsonianone A (24)
was reported as constituent of Rhodomyrtus tomentosa
fruits (Zhuang et al. 2017).
Fifteen new phloroglucinol derivatives, jamunones
A–O (25–39, Fig. 6) were isolated from Eugenia
jambolana seeds. These compounds are based on a
5,7-dihydroxychromone skeleton, with an alkyl side
chain with different unsaturation degrees (Liu et al.
2017a). They are closely related to jambones E–G
(40–42), previously reported from Syzygium jambos
(Li et al. 2015) and to samarones A–D (43–45)
acylphloroglucinol derivatives bearing a C17 alkyl
side chain, described as constituent of S. sama-
rangense (Yang et al. 2018). Acylphloroglucinol
derivatives with a different skeleton and bearing a
long alkyl chain with variable number of double bonds
(Fig. 6) have been isolated from the genus Syzygium:
jambones A–D (47–50), from Syzygium jambos (Li
et al. 2015), austroyunones A–E (51–55), and 1-(2,4-
dihydroxy-6-methoxyphenyl)-1-tridecanone (56),
from the leaves of S. austroyunnanense (Xu et al.
2018a, b) and finally four alkyl phloroglucinol
derivatives from S. levinei (57–60, Fig. 6).
Phloroglucinol monoterpene-adducts
Myrcene adducts
(±)-Calliviminones A-–H (61–68, Fig. 7) were iso-
lated from the fruits of Callistemon viminalis (Wu
et al. 2015a, b). Calliviminones C–D (63–64) are
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polymethylated phloroglucinol derivatives connected Fig. 6 Phloroglucinols bearing long alkyl chain c
with myrcene in hetero-Diels–Alder manner, while
(±)-calliviminones A–B (61–62) and E–H (65–66),
with unprecedented spiro-[5.5] undecene skeleton, are
Callistemon viminalis (Liu et al. 2016b). Callisretones
carbon-Diels–Alder adducts of polymethylated
A and B (76–77), two rearranged phloroglucinol-a-
phloroglucinol and myrcene. Calliviminone C (63)
phellandrene derivatives featuring an unprecedented
was also reported as constituent of a Hawaiian
isopropylcyclopenta[b]benzofuran backbone, were
specimen of Syncarpia glomulifera (Su et al. 2016)
reported as constituent of C. rigidus (Cao et al.
whereas (±)-calliviminones A–B were also reported
2018a) along with callistrilones A, C–E and B (78–
from the aerial parts of Baeckea frutescens (Hou et al.
82), with the [1]benzofuro[2,3-a]xanthene and [1]ben-
2017a).
zofuro[3,2-b]xanthene pentacyclic ring system
(Cheng et al. 2018; Cao et al. 2016), respectively,
Cyclic monoterpene a and b phellandrene- adducts
and callistrilones F–K (83–88) with rare triketone-
phloroglucinol a-phellandrene skeletons (Cao et al.
Meroterpenoids biogenetically derived through the
2018b). Callisalignenes A, C, G and H (89–92), from
conjugation between a phloroglucinol and a a-phel-
C. salignus and callistiviminenes K and L (93–94)
landrene unit have been reported as constituents of
from C. viminalis are hybrids of isobutylidenesyncar-
Callistemon spp.
pic acid derivatives and a-phellandrene (Qin et al.
In particular, callviminols A–B, E (71–72, 75,
2017a, b; Wu et al. 2016). Isobutyrylphloroglucinols
Fig. 8), with a hexahydrodibenzo[b,d]furan skeleton
coupled with a b-phellandrene unit were isolated from
and callviminols C–D (73–74) with a 2-phenylcyclo-
Baeckea frutescens (baeckfrutone A, 95), Callistemon
hexanolbackbone, were isolated from the leaves of
salignus (callisalignenes E–F, 96–97 Qin et al. 2017a),

Fig. 5 Acylphloroglucinols and dimeric acylphloroglucinols

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Fig. 7 Phloroglucinol myrcene -adducts

Fig. 8 Phloroglucinol a (71–94) and b (95–102) phellandrene-adducts

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Phytochem Rev
C. viminalis (callistiviminenes M–O, 98–100, Wu
et al. 2016) and Eucalyptus robusta (euglobals R1 and
R2, 101–102). These latter were identified by means of
spectroscopic analysis and single-crystal X-ray
diffraction as two formyl-isovaleryl phloroglucinol-
coupled b-phellandrene (Jian et al. 2012).
Bicyclic monoterpene: a and b pinene-adducts
a and b pinene adducts with different phloroglucinol
precursor are described as constituent of Baeckea
frutescens, Callistemon viminalis, Melaleuca leuca-
dendron, Psidium guajava, and Rhodomyrtus tomen-
tosa (Fig. 9). Four b-pinene-based phloroglucinols
with an oxirane ring, were isolated from the aerial
parts of Baeckea frutescens: frutescone P (103, Hou
et al. 2017a) and three polymethylated phloroglucinol
meroterpenoids, baeckfrutone E, H, and L (104–106).
Baeckfrutone H is a demethyl derivative of baeckfru-
tone E, while baeckfrutone L bears two methyl
functions on the phloroglucinol ring. Baeckfrutone L
shared the same absolute configuration as those of
baeckfrutone E and H (Qin et al. 2018a). Cal-
lisalignene I (107) is a b-triketone and b-pinene
hybrid isolated from Callistemon salignus (Qin et al.
2017b), whereas malaleucadiene A (108) is a rare
benzylic phloroglucinol-b-pinene hybrids from Me-
laleuca leucadendron (Xie et al. 2019). Callis-
tiviminene I and J (109–111), identified as a pair of
epimers, were isolated from the fruits of Callistemon
viminalis. In particular, Wu et al. (2016) suggested
that (-)-b-pinene and (?)-b-pinene were the monoter-
pene units in (-)-callistiviminene I and (?)-callis-
tiviminene I, respectively. a-pinene and b-pinene,
respectively, are also part of guadials B and C (102–
113), constituents of leaves of Psidium guajava (Jian
et al. 2015), in which they are linked to the
phloroglucinol precursor (3,5-dimethyl-2,4,6-
trihydroxybenzophenon).
Tomentosenol A (114), along with a pair of
epimers, 4S-focifolidioneand 4R-focifolidione (115–
116), were identified as constituent of leaves of
Rhodomyrtus tomentosa. Tomentosenol A was the
first example of a new meroterpenoid class with a
unique skeleton that contained a free syncarpic acid
coupled with a terpenoid moiety (Liu et al. 2016a).
Bicyclic monoterpene sabinene and thujene-
adducts
Thujene represents the monoterpene unit of nine
phloroglucinol meroterpenoids: baefrutones A–D
(117–120, Hou et al. 2018), baeckfrutone M (121,
Zhi et al. 2018), callistivimenenes F–H (122–124, Wu
et al. 2016) and guajavadial A (125, Qin et al. 2016).
Biogenetically, the phloroglucinol precursors tasman-
one, syncarpic acid derivative and 3,5-diformylbenzyl
phloroglucinol, could undergo hetero–Diels–Alder
reactions with thujene, to yield baeckfrutone M,
callistivimenenes F–H, guajavadial A, respectively
(Fig. 9). Baeckfrutones B–D, F, I–K and N–S (126–
139, Fig. 9) polymethylated phloroglucinol meroter-
penoids, isolated from leaves of Baeckea frutescens,
sharethe same phloroglucinol moiety and a tetracyclic
structure. Biosynthetically, as proposed by Qin et al.
(2018a) and Zhi et al. (2018), these compounds, as
other baeckfrutones, could derive from tasmanone and
demethylated tasmanone, by hetero-Diels–Alder reac-
tions with a sabinene unit. Psiguajavadial A (140, Qin
et al. 2017c), guadial A (141, Shao et al. 2012) and its
epimer psiguajadial K (142, Tang et al. 2017) from
Psidium guajava are two benzylphloroglucinol dialde-
hyde-sabinene derivatives that share the same planar
structure, except for the difference in the configura-
tions of chiral centres bearing the phenyl and sabinene
units, respectively.
Phloroglucinol sesquiterpene adducts
Germacrane adducts
Diformylphloroglucinol germacrane-adducts were
isolated and characterized by conventional 1D and
2D NMR and mass spectrometry techniques from
Eucalyptus genus. In particular, macrocarpals P, Q and
eucalypglobulusals A, E–G (143–148, Fig. 10) were
isolated from leaves and fruits of E. globulus, respec-
tively (Chenavas et al. 2015; Qin et al. 2018b), and
eucalteretials A–C, E (149–152) from the twigs and
leaves of E. tereticornis (Liu et al. 2018b). Likewise,
six bicyclogermacrane coupled-3,5-diformylbenzyl
phloroglucinols, the two isomers guajavadials B–C,
psidial B, psiguajavadial B and psiguadial C–D (153–
158, Fig. 10) were isolated from the leaves of Psidium
guajava L. (Qin et al. 2016; Fu et al. 2010; Qin et al.
123
 Phytochem Rev

123
 Phytochem Rev
b Fig. 9 Phloroglucinol a and b pinene (103–116), sabinene
(117–125) and thujene (126–142)-adducts
2017c; Shao et al. 2012). Bicyclogermacrane is also
the terpene moiety of two b-triketone phloroglucinols,
callistiviminene C–D (159–160, Fig. 10). These com-
pounds, reported as constituent of Callistemon vimi-
nalis, differ in the linkage between the dihydropyran
ring and bicyclogermacrene.
b-caryophyllene adducts
Hou et al. (2017b, 2018) proposed tasmanone as the
biogenetic precursor involved in the biosynthesis of
baefrutones E–F and frutescones A–F (161–168,
Fig. 11) and b-caryophyllene as the key intermediate.
Frutescones A and D, isolated from the aerial part of
Fig. 10 Germacrane sesquiterpene adducts
Baeckea frutescens, shared a rare carbon skeleton with
an oxa-spiro[5.8] tetradecadiene ring system.
From the leaves of Rhodomyrtus tomentosa, Zhang
et al. (2016) described rhodomyrtials A and B (169–
170) possessing an unprecedented triketone-sesquiter-
pene-triketone framework constructed from the con-
jugation of two-1,1,3,3-tetramethyl-isopentyl
cyclohexatrione and caryophyllene moieties, as well
as nine related triketone-coupled caryophyllenes:
rhodomentone A, tomentodiones A–E (171–176,
Zhang et al. 2016; Liu et al. 2018a, 2016d) and O–R
(177–180, Zhang et al. 2018). Recently, from the same
species rhodomyrtusials A–C (181–183, Fig. 11),
three unusual triketone-sesquiterpene meroterpenoids
featuring a unique 6/5/5/9/4 fused pentacyclic ring
system, have been isolated (Qin et al. 2019). Guap-
sidial A and psidial A (184–185), two caryophyllene-
based Psidium meroterpenoids, were identified as
constituent of Psidium guajava (Jian et al. 2015; Fu
123

Fig. 11 b-caryophyllene sesquiterpene adducts
et al. 2010) whereas littordials A–F (186–191), were
isolated from the leaves of Psidium littorale. In
particular, littordials E–F (190–191, Fig. 11) are
characterized by presence of a unique 6/7/9/4-tetra-
cyclic and6/8/9/4-tetracyclic nucleus, respectively
(Zhu et al. 2019). Three b-caryophyllene—deriva-
tives, myrtucommulones K, N, O (192–194, Fig. 11)
were also isolated from the leaves of Myrtus communis
(Liu et al. 2016c; Lv et al. 2017).
Synthesis of myrtucommulones and related
compounds
Thanks to their structural features and biological
activities, myrtucommulones and their derivatives
have become attractive targets for organic chemists.
So, in this section, the most relevant approaches and
synthetic procedures of myrtucommulones from Myr-
tus communis as well as the others related are
summarized.
123
Phytochem Rev
Synthesis of myrtucommulones from Myrtus
communis
Synthesis of myrtucommulones belonging
to dimeric, trimeric and related structures
Myrtucommulone A (trimeric structure, 195,
Scheme 1) is the founder compound of this series,
which was isolated from leaf extracts of myrtle
(Kashman et al. 1974; Nicoletti et al. 2014). Its total
synthesis was firstly described from commercially
available precursors and later through stereoselective
synthesis (Nicoletti et al. 2018).
Its total synthesis within 3 h at room temperature
has been carried out by Müller and co-workers in just
two steps (Müller et al. 2010): (1) a Mannich reaction
of syncarpic acid (196) and isobutyraldehyde followed
by an elimination under acid conditions to yield
isobutylidenesyncarpic acid (197) (Michael acceptor)
and (2) a double Michael addition of isobu-
tyrylphloroglucinol (198) to two equivalents of 197
in the presence of sodium hydride. A key point is that
the Michael acceptor has to be prepared shortly before
Phytochem Rev
Scheme 1 Total synthesis of myrtucommulone A (195) by Müller et al. (2010)
use in order to avoid the isomerization to give
5-hydroxy-2,2,6,6-tetramethyl-4-(2-methyl-1-propen-
1-yl)-4-cyclohexene-1,3-dione (iso-197) (scheme 1).
The direct determination and analysis of this kind
of compounds by NMR spectroscopy are very difficult
due to numerous rotamers and tautomers which are
stabilized by intramolecular hydrogen bonds.
Thereby, in order to determine the structure of 195,
it was dehydrated in hot toluene in the presence of
toluenesulfonic acid (pTsOH) to obtain the penta-
cyclic derivative. After this reaction and purification
process, a mixture of three stereoisomers was
obtained, confirming two enantiomers and one meso
form (Scheme 2).
Based on the observation that the synthetic com-
pound 195 (mixture of three stereoisomers) showed
the same activity as natural myrtucommulone A with
respect to anti-inflammatory properties and induction
of apoptosis, it was questioned whether the natural
compound is a pure stereoisomer or a mixture. Further
studies performed by Hans and co-workers demon-
strated that natural myrtucommulone A is an 1:1
mixture of racemate and meso form (Hans et al. 2015).
The synthetic strategy described above (modifying
the three building blocks: syncarpic acid,
acylphloroglucinol residues and isobutyl bridge as
shown in Fig. 3) and varying the equivalents of 197
and 198 led to the preparation of other myrtucommu-
lones and new analogues as mixtures of all stereoiso-
mers. Thus, the synthesis of myrtucommulone C
(trimeric-monopyrane structure, Fig. 4) occurs
through two myrtucommulone intermediates: nor-
semimyrtucommulone (dimeric structure) and
myrtucommulone B (dimeric-monopyrane structure,
Fig. 4). In this way, a Michael addition (scheme 3)
with deprotonated 198 and 197 gives the nor-
semimyrtucommulone compound (199) which can
be cyclized in the presence of pTsOH affording, after
dehydration, myrtucommulone B (200). This myrtu-
commulone can be combined anew with the Michael
acceptor 3 under basic conditions to obtain myrtu-
commulone C (201). In the same way, the synthesis of
myrtucommulone A (195) could be also carried out
with the addition of 197 over two steps through
compound 199 (Charpentier et al. 2013) (Scheme 3).
Following the same strategy, Müller et al. syn-
thetized three myrtucommulone analogues with tri-
meric and dimeric structures (202–204, Scheme 4).
These synthetic derivatives were evaluated for anti-
inflammatory activity (inhibition of microsomal
prostaglandin E2 synthase 1) and induction of apop-
tosis. The derivative 204 showed similar anti-inflam-
matory activity with respect to myrtucommulone A,
whereas derivative 202 induced apoptosis, with an
IC50 value lower than myrtucommulone A (195)
(Müller et al. 2010). It has also been reported that
acylphloroglucinols 199 and 200 are both racemates
(Hans et al. 2015).
In further studies, the first enantioselective synthe-
sis of myrtucommulones A (195) and B (200) and nor-
semimyrtucommulone (199) through metal catalysis
was described for the first time by Charpentier and co-
workers (2013) in order to determine whether these
derivatives racemized during the derivatization reac-
tion and to get less hazardous synthetic conditions.
Taking into account the synthetic procedure described
123

Scheme 2 Cyclization and dehydration of myrtucommulone A (195) to obtain the pentacyclic derivative
Scheme 3 Synthesis of myrtucommulones A (195) and C
(201). (a) 1 eq. NaH, THF, r.t., 5 min and then the solution of
the Michael acceptor 197 is added, r.t., 3 h, 98%. (b) pTsOH,
for myrtucommulone 195 through derivative 199 in
just two steps (Scheme 3), researchers considered this
scheme as starting point for its enantioselective
synthesis to perform two enantioselective Michael
additions. After several tests, aluminium–lithium-
1,1’-bi-2-naphthol (Al–Li-BINOL complex,
Scheme 5) was selected as the optimum chiral reagent
to substitute to NaH and to transfer the chirality to the
less sterically hindered phloroglucinol core (198).
This complex was developed by Arai et al. and it is
easily prepared by mixing 2 equivalents of (S)- or (R)-
BINOL and lithium aluminum hydride (Scheme 5
Arai et al. 1996. Stereoselectivity to one or the other
123
Phytochem Rev
benzene, reflux 1 h, 95%. (a*) 2 eq. NaH, THF, r.t., 5 min and
then the solution of the Michael acceptor 197 (1.5 eq.) is added,
r.t., 1 h
enantiomer could be performed using the correspond-
ing enantiomer of metal complex. As a result, the
synthesis of nor-semimyrtucommulone (199) and
myrtucommulone B (200) with up to 62% enan-
tiomeric excess and myrtucommulone A (195) with
70% ee was achieved (Charpentier and Jauch 2017).
Furthermore, racemization was not produced during
the cyclization process.
In an effort to improve the enantioselectivity of
these reactions, different catalysts, temperature and
solvent conditions were studied. After numerous
experiments, the following conditions were deter-
mined: lithium in the metal complex plays an
Phytochem Rev
Scheme 4 Synthesis of myrtucommulones analogues (202–
204). (c) isobutyraldehyde, piperidine, CH2Cl2, r.t., 10 min.
(d) 1 M HCl/NH4Cl, CH2Cl2, r.t., 15 min. (e) 2 eq. NaH, THF,
isobutyrylphloroglucinol (198), r.t., 5 min., then the solution
Preparation of aluminium-lithium-1,1’-bi-2-naphtol complex
Scheme 5 Preparation of Al–Li-BINOL complex and enan-
tioselective synthesis of nor-semimyrtucommulone (199),
myrtucommulone B (200) and myrtucommulone A (195).
(a) i: 3 eq. (S, S)-Al–Li-BINOL complex, THF, r.t., 10 min.;
from Michael acceptor is added, r.t., 3 h, quantitative.
(f) 2 eq. NaH, THF, acetylphloroglucinol, r.t., 5 min., then the
solution from Michael acceptor is added, r.t., 3 h, quantitative.
(g) isovaleraldehyde, piperidine, CH2Cl2, r.t., 10 min
Enantioselective synthesis
ii: 1.5 eq. 197, THF, 0 °C, 1.5 h., 55% yield. (b) pTsOH
H2O,
toluene, 95 °C, 1 h., 49–82% yield. (c) i: 3 eq. (R, R)-Al–Li-
BINOL complex, THF, r.t., 1 h.; ii: 3.3 eq. 197, THF, 0 °C,
overnight, 77% yield
123

important role on the enantioselectivity; metal com-
plex and isobutylidene syncarpic acid (197) solutions
should be freshly prepared; temperature should be
fixed at 0 °C; and the use of a mixture 10:1 (v:v) of
CH2Cl2 and THF as solvent significantly improved the
yield and enantioselectivity of the reaction. Based on
these considerations and following the same
scheme of reaction as it was described above in
scheme 5, the synthesis of (R)-199, and hence 200,
both with 72% ee and (R, R)-195 with 81% ee was
carried out. Firstly, 1 eq. of 198 solved in CH2Cl2:-
THF (10:1) was added dropwise to the freshly
prepared (R, R)-Al–Li-BINOL complex (0.18 M in
CH2Cl2:THF, 3.2 eq.). After 1 h and stirring at room
temperature, 1.4 eq. of 197 dissolved in CH2Cl2:THF
was added dropwise to the mixture at 0 °C for 2 h.
Work-up reaction was performed with 1 M HCl/
NH4Cl and obtained 81% yield. Afterwards, condi-
tions detailed in scheme 5 were applied to obtain
myrtucommulone 200 with 65% yield. Finally,
1 eq. of (-)-(R)-199 was added to the freshly prepared
(R, R)-Al–Li-BINOL complex (3.3 eq.) in the same
way, to get derivative 199. Then, 2 eq. of 197
dissolved in CH2Cl2:THF were added to the reaction
mixture at 0 °C.
On the other hand, a one-pot synthesis of myrtu-
commulones was developed by Charpentier and Jauch
(2017) in order to get less hazardous synthetic
conditions and to achieve an attractive synthetic
method for their exploitation in pharmaceutical com-
panies. The use of proline and other amino acids
allowed longer reaction times and use of lower amount
of the Michael acceptor (197). This synthesis is
performed by of mixing the compounds isobutyryl
phloroglucinol (198), isobutyraldehyde, syncarpic
acid (196, scheme 1) and proline in one single vial
for 24 h to yield myrtucommulone A (195) (66%)
(scheme 6).
Likewise, other chiral amines were studied for the
formation of myrtucommulones, but in almost all
Scheme 6 Proline-
catalysed one-pot synthesis
of myrtucommulone A
(195)
123
Phytochem Rev
cases, the synthesis was in favour of the meso-form.
Therefore, it can be concluded, that metal catalysis
provides better enantioselectivity in myrtucommulone
synthesis, whereas organocatalysis is the best option to
afford myrtucommulones in the meso-form.
As indicated in Fig. 3, modifying the three main
cores (phloroglucinol and syncarpic acid skeletons, as
well as the isobutyryl bridge), different acylphloroglu-
cinols can be obtained. A structure–activity relation-
ship (SAR) study was performed by Wiechmann et al.
(2015) to identify the structural requirements to inhibit
microsomal prostaglandin E2 synthase (mPGES) and
5-lipoxygenase (5-LO). A total of 28 myrtucommu-
lones analogues were synthesized following these
three structural variations: (1) use of dimedone or
indandione instead of syncarpic acid; (2) cyclization
of syncarpic acid with the acylphloroglucinol back-
bone and (3) replacement of the acyl residue and
isobutyryl bridge with isopropyl, isobutyl, n-pentyl or
phenyl groups (Jauch et al. 2014). The most active
analogues were those synthesized by double Michael
addition in one step (Scheme 7). The introduction of
aromatic indandione residues, an hexanoylphloroglu-
cinol core and a branching more distant to the methine
bridge lead to higher activity. Noteworthy is the
activity shown by n-pentyl-substituted indandione
derivative and n-pentyl-substituted indandione deriva-
tive with phenyl substitution in the methine bridge.
They were significantly more potent than myrtucom-
mulone A.
Moreover, the synthesis of two myrtucommulones
from M. communis, with potential antibacterial activ-
ity, has been carried out: myrtucommulone J (205) and
myrtucommuacetalone (206, Scheme 8) (Choudhary
et al. 2013; Liu et al. 2017b). This is the first
biomimetic total synthesis described and this strategy
consists of the following four steps: hemiacetalization,
dehydration, [3 ? 3] cycloaddition and dimerization.
Several contributing factors were screened to get the
best yield and selectivity. Thus, a Michael addition
Phytochem Rev

Scheme 7 Synthesis of myrtucommulones analogues

Scheme 8 Biomimetic total synthesis of myrtucommulone J (205) and myrtucommuacetalone (206)

between isobutyrylphloroglucinol (198) and isobutyli- semimyrtucommulone compound (199) in 87% yield.
denesyncarpic acid (197) was carried out to give nor- Later, p-toluenesulfonic acid (PTSA) was added to a

123

solution of a,b-unsaturated ketone and compound 199
in toluene at room temperature for 24 h to afford
myrtucommulone J (205), myrtucommuacetalone
(206), epi-myrtucommulone J (207), and epi-myrtu-
commuuacetalone (208) in 89% combined yield with a
ratio about 1:1.7:1.4:1.2. These isomeric forms were
due to the tautomeric equilibrium of the enolized
syncarpic acid (Scheme 8).
In this section, the total synthesis of myrtucommu-
lones K, N and O (Fig. 11) will be discussed. Total
synthesis of myrtucommulone K (192) and its struc-
ture confirmation was investigated by Zhou and co-
workers (2017, Scheme 9). Retrosynthetic approach
was stablished in a first Knoevenagel condensation
between syncarpic acid (196) and isobutyraldehyde,
followed by a heteroatom Diels–Alder cycloaddition
sequence of Michael acceptor (197, Scheme 9) and b-
caryophyllene to finally afford the desired compound
(Zhou et al. 2017). In this case, one of the most critical
transformations was to obtain the Michael acceptor
isobutylidenesyncarpic acid (197). After trying sev-
eral experimental conditions, the authors determined
that the morpholin-4-ium 2,2,2-trifluoroacetate cata-
lyst was the most effective to afford compound 197 in
almost quantitative yield. Subsequently, Diels–Alder
cycloaddition between compounds 197 and mor-
pholin-4-ium 2,2,2-trifluoroacetate catalyst was car-
ried out in reflux for 24 h. In addition to the desired
product myrtucommulone K (192), two structurally
analogues were also obtained (compounds 193 and
194, Scheme 9).
The synthetic strategy for myrtucommulones N and
O (Fig. 11, derivatives 193 and 194 obtained in the
scheme 9) were also inspired via a Hetero–Diels–
Alder reaction Total synthesis (Lv et al. 2017) of these
myrtucommulones was achieved through synthesis of
isobutylidenesyncarpic acid (197) from flavenose by a
reduction and dehydration sequence and later, the
treatment with b-caryophyllene as in previous studies.
Nevertheless, this step should be operated in neat with
heating to avoid the isomerization of compound 197
and undesirable products. In this way, myrtucommu-
lones K (192), N (193) and O (194) were obtained in
25%, 10% and 42% yield, respectively (scheme 10).
123
Phytochem Rev
Synthesis of other myrtucommulones belonging
to Myrtaceae family
As previously mentioned, the use of proline provides
longer reaction times and lower amounts of the
Michael acceptor. A similar proline-catalysed one-
pot synthesis was carried out for the synthesis of
myrtucommulone F, trimeric structure (Corymbia
scabrida) (Charpentier and Jauch 2017). The synthetic
procedure consists of mixing the compounds hexanoyl
phloroglucinol (209), isobutyraldehyde, syncarpic
acid (196) and proline in one single vial for 48 h to
yield myrtucommulone F (210) (60% yield)
(scheme 11).
On the other hand, total synthesis of myrtucommu-
lone H (Wiechmann et al. 2015) (from Corymbia
scabrida species and also a trimeric structure) (212)
was carried out trough a Michael addition between
hexanoylphloroglucinol (209) and isobutylidenesyn-
carpic acid (197) to give 4-(1-(3-hexanoyl-2,4,6-
trihydroxyphenyl)-2-methylpropyl)-5-hydroxy-
2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (211).
This compound can be deprotonated in situ and added
to Michael acceptor to afford myrtucommulone H
(212) (Scheme 12).
Likewise, the biomimetic synthesis of baefrutones
E and F, two b-cariophyllene-adduct (Fig. 11) has
been reported. Thereby, the synthesis of these terpene-
adduct structures was conducted through an oxidative
hetero-Diels–Alder reaction, with the oxidation of
(±)-baeckenon B (2) with (2,2,6,6-Tetram-
ethylpiperidin-1-yl)oxyl (TEMPO) and silver oxide
in the presence of b-caryophyllene (scheme 13).
Baefrutones E (161) and F (162) were obtained in
12% and 13.5% yield respectively (Hou et al. 2018).
Other interesting structurally complex natural
products are bullataketals dimeric structures with an
interesting tricyclic ketal skeleton (Fig. 4, Nicoletti
et al. 2018) and potent cytotoxic and antimicrobial
activities as reported in the next section. Tan and co-
workers (Tan et al. 2015) have successfully developed
a strategy for the synthesis of bullataketals analo
thegues. Upon improvement of the reaction condi-
tions, including solvents, amounts and catalyst, and
after exploration of a vast range of substrates, they
concluded that the possible key point of the reaction
was the formation of the intermediate 2H-furan-1-ium
Phytochem Rev

Scheme 9 Total synthesis of myrtucommulone K (192) and its analogues (193 and 194) by Zhou and co-workers (2017)

Scheme 10 Total synthesis of myrtucommulones K, N and O (192–194)

123

Scheme 11 Proline-catalysed one-pot synthesis of myrtucommulone F (210)
Scheme 12 Total synthesis of myrtucommulone H (212)
Scheme 13 Synthesis of baefrutones E (161) and F (162)
(213). This synthetic approach mimics a biosynthetic
olefin isomerization, hemiacetalization and dehydra-
tion (from a,b-unsaturated ketone), followed by a
(3 ? 3) type cycloaddition between isobu-
tyrylphloroglucinol (198) and the generated interme-
diate 213 (Scheme 14).
Recently, Ivanov and co-workers (Ivanov et al.
2018) have developed a novel approach for the
synthesis of this particular tricyclic backbone. This
synthetic procedure is carried out through a Brønsted
acid-triggered domino transformation of 3-keto- and
3-ester-4,5-dihydrofurans, functionalized with meth-
oxymethyl (MOM)-protected orto-hydroxyaryls at C4
position (214) to afford methanobenzodioxepines
(215). Optimal conditions were stablished as the use
of aqueous HCl (10 eq.) in ethanol under reflux,
123
Phytochem Rev
obtaining reaction times between 1 and 9 h, with
yields of 63–85% (Scheme 15).
Other structures with unique scaffold are cal-
listrilones (Fig. 8). These compounds have a particular
[1]benzofuro[2,3-a]xanthene ring system. The first
asymmetric total synthesis and isolation of myrtu-
commuacetalone B (from Myrtus communis), cal-
listrilones C–E (80–82, Fig. 8) have been described by
Cheng and co-workers (2018). For this purpose, it is
essential to achieve the enantioselective synthesis of
nor-semimyrtucommulone (199) from Michael accep-
tor (197) and isobutyrylphloroglucinol (198) by
Friedel–Crafts-type Michael additions, followed by
pTsOH-mediated cyclization to give myrtucommu-
lone B (200). As before mentioned, the first enantios-
elective synthesis of 199 and 200 was performed
through the use of Al–Li-BINOL complex
Phytochem Rev
Scheme 14 Synthetic strategy for the synthesis of the tricyclic ketal core and bullataketals analogs
Scheme 15 Synthesis of methanobenzodioxepines
(scheme 5). Nevertheless, the conditions to get a
highly enantioselective synthesis are still needed. In
order to optimize the reaction conditions and to
examine various substituted acylphloroglucinols and
sterically hindered Michael acceptors, Friedel–Crafts-
type Michael addition was carried out under nitrogen
atmosphere and anhydrous conditions with
5–10 mol% of chiral phosphoric acid (CPA) in toluene
at -76 °C, aluminium fluoride as additive and 3 Å
molecular sieve (scheme 16). Good yields with enan-
tiomeric ratio values of 91:9–95:5 were obtained.
With the optimized conditions for the synthesis of
compound 200 and with the use of 2,2,6,6-tetram-
ethyl-4-(2-methyl-1-propen-1-yl)-4-cyclohexene-1,3-
dione (216), the synthesis of myrtucommuacetalone B
was investigated. The treatment of these substrates
with CPA and p-toluenesulfonic acid in toluene at
60 °C and subsequent basic conditions with KOH in
ethanol gave myrtucommuacetalone B (217) in good
yield (Scheme 17).
Finally, the synthesis of callistrilones A, C–E
(Fig. 8, 78–82 Scheme 18) was carried out with
compound ent-200 or 200 and commercially available
(-)-a-phellandrene through an intermolecular oxida-
tive [3 ? 2] cycloaddition, followed by cyclization
and epoxidation.
It is also highlighted that compound 82 showed
potent antibacterial activities against several mul-
tidrug-resistant strains even better than vancomycin.
On the other hand, the biomimetic synthesis of
callistrilones A–E (78–82, Scheme 19) have been
described by Guo and co-workers (2018) using
isobutyrylphloroglucinol (198) and (-)-a-phellan-
drene as starting materials via an oxidative [3 ? 2]
cycloaddition as well. This first cycloaddition affords
intermediates 218 and 219. Intermediate 218 coupled
with Michael acceptor 197 give a mixture of cal-
listrilone E (82) and 13-epi-callistrilone E (58% yield).
Then, this mixture is successfully converted to
callistrilone D (81) and 13-epi-callistrilone D with p-
toluenesulfonic acid in benzene in reflux (21% and
39% yield respectively). The treatment of these last
compounds with NaI/oxone and then NaH give the
desired callistrilones A (78) and C (80) (Scheme 19).
In this step, it worth mentioning that the direct
epoxidation with meta-chloroperoxybenzoic acid
(mCPBA) or dimethyldioxirane (DMDO) failed to
afford the desired products 78 or 80.
Moreover, the acetylation of intermediate 219,
followed with the addition of Michael acceptor 3 and
successive intramolecular nucleophilic additions pro-
vide callistrilone B (79) with a 62% yield
(Scheme 19).
Additionally, Dethe and co-workers (2018) have
also reported the biomimetic total synthesis for
callistrilones A, B and D in 10, 4 and 7 steps
respectively with 21, 22 and 26% overall yield. These
reactions occur through Friedel–Crafts alkylation,
palladium-catalyzed Wacker-type oxidative cycliza-
tion and stereoselective epoxidation as key steps.
Recently, Hu and co-workers (2018) have devel-
oped a new approach for the asymmetric total
synthesis of callistrilones B, G and J (79, 84, 87,
123

Scheme 16 Enantioselective synthesis of myrtucommulone B (200) and derivatives
Scheme 17 Synthesis of myrtucommuacetalone B (217)
Fig. 8) in just 3–4 steps from compounds 197, 198 and
(-)-a-phellandrene as building blocks and without the
need for protecting groups (Scheme 20).
Other interesting compounds which have shown
potent antimicrobial activities are rhodomyrtosones
and related isomers.
The total synthesis of rhodomyrtusials A–C, rhoto-
mentodiones A–B and tomentodiones Q–R (Fig. 11)
was investigated by Qin and co-workers (2019). These
compounds after isolation and characterization (Qin
123
Phytochem Rev
et al. 2019) were successfully synthesized in six steps
(55% combined yield) utilizing a reactive enetrione
generated in situ from a readily available hydroxy-
endoperoxide (220). Photoenolization of Michael
acceptor and subsequent [4 ? 2] cycloaddition with
oxygen afforded endoperoxide 220 in 72% combined
yield (Scheme 21).
The synthetic strategies of other acylphlorogluci-
nols isolated from R. tomentosa have been also
reported (Morkunas and Maier 2015; Liu et al.
Phytochem Rev
Scheme 18 Asymmetric synthesis of callistrilones A (78), C (80), D (81) and E (82)
2016b). Thus, the synthesis of rhodomyrtone (226)
and the isomer rhodomyrtosone B (Morkunas et al.
2013) (227) were obtained from the hydroxyl ketone
224 by cyclization of 224 to xanthene derivative 225
and subsequent acylation; and acid-catalyzed cycliza-
tion of 224 respectively. This hydroxyl ketone inter-
mediate was successfully obtained from
isovalerylphloroglucinol (223) and the Michael accep-
tor 2,2,4,4-tetramethyl-6-(3-methylbutylidene)-1,3,5-
cyclohexanetrione (Scheme 22).
There is also an increasing interest in the synthesis
of related analogues. For instance, a methodology for
the synthesis of methoxylated phloroglucinol deriva-
tives with a backbone similar to rhodomyrtosone I
(dimeric-monopyrane structure from R. tomentosa)
and BF-6 (Baeckea frutescens) has been developed by
dos Santos and co-workers (2017). These derivatives
were synthesized using a multicomponent reaction
between dimethoxylated phloroglucinol, dihydrore-
sorcinol, and different aryl aldehydes, promoted by
niobium pentachloride, reaching 45–69% yield.
The total synthesis of rhodomyrtosone A (228,
Nicoletti et al. 2018), another peculiar structure with a
bisfurane fused ring, was carried out via cyclization
between the endoperoxidic phloroglucinol 220 and
isovalerylphloroglucinol (223) under acid conditions
(Gervais et al. 2015, Scheme 23). It was obtained in
60% yield.
Endoperoxidic phloroglucinol (220) was revealed
also as key intermediate for successfully preparation
of an other structurally related natural product is
watsonianone B (Nicoletti et al. 2018). A recent work
carried out by Zhang and co-workers (2019) described
the optimized conditions for the synthesis of this
endoperoxidic phloroglucinol (220), as well as for the
acylphloroglucinol 229 (3-phenyl-1-(2,4,6-trihy-
droxy-3-methylphenyl)propan-1-one). An efficient,
mild reaction conditions and simplicity method was
developed and provided watsonianone B (230) and
iso-watsonianone B (231) in 41% combined yield
(Scheme 24).
Overall, these natural products have become attrac-
tive targets in chemistry because of to their complex
structural features and biological activities reported.
All these synthetic approaches and strategies
described above, provide further investigations and
preparation of new acylphloroglucinol-derived prod-
ucts for their exploitation in drug discovery.
Biological properties
The large structural diversity of phloroglucinol
derivatives from Myrtaceae species provides a variety
of bioactive compounds that could be used as medic-
inal and supplementary healthcare products. Crude
123

Scheme 19 Synthesis of callistrilones A, B, C, D and E (78–82) by Guo and co-workers (2018)
formulations (i.e., extracts, essential oils, etc.) deriv-
ing from these plants are generally used, as docu-
mented and highlighted in several reviews (Pérez
Gutiérrez et al. 2008; Alipour et al. 2014; Vuong et al.
2015, Hamid et al. 2017; Cock and Cheesman 2019).
These traditional Myrtaceae-based medicines support
the need for studies aimed at the isolation and
structural elucidation of phloroglucinol derivatives,
in order to discover new bioactive compounds, to
determine their bioactivity to assign single compound/
bioactivity relationship and to produce analogues with
increased bioactivity/bioavailability. The number of
records on the topic (Fig. 12a), as well as the wide
range of potential pharmacological and therapeutic
properties explored for these metabolites (Fig. 12b),
corroborates Myrtaceae plants as a promising source
of bioactive compounds.
123
Phytochem Rev
An overview of structures and bioactive properties
of phloroglucinol derivatives from Myrtaceae species
until 2019 is provided in the next section.
Antimicrobial activity
The use of plants as potential antimicrobial treatments,
both as crude drugs or as a source of anti-infection
natural products, has a long history, being also an
important focal point of ethnopharmacology (Rios and
Recio 2005).
Recent decades have witnessed a remarkable
increase in studies reporting antimicrobial agents
against pathological microorganisms from Myrtaceae
species (Fig. 12). These data have been recently
summarized in Nicoletti et al. (2018) and in Zhao
et al. (2019), highlighting two important aspects. The
Phytochem Rev
Scheme 20 Asymmetric synthesis of callistrilones B (79), G (84) and J (87) by Hu and co-workers (2018)
first concerning the antibiotic activity effectiveness
against several Gram-positive species, especially
multi-resistant bacterial strains, with details concern-
ing their minimum inhibitory concentration (MIC).
The second one focuses on the progress in the
investigation of the mechanisms of action of
rhodomyrtone A and on the increase in the antibac-
terial activity in synthetic analogues.
These reviews represent a fundamental synthesis,
providing a solid ground for further investigations on
myrtucommulone-related acylphloroglucinols from
Myrtaceae. Here, we integrate them with the most
recent data.
Panels of new acylphloroglucinols with antimicro-
bial activity are quite quickly broadening. Recently,
the eugenials C and D, macrocarpal-like compounds
isolated from Eugenia umbelliflora, have been
reported to exhibit a good activity against Bacillus
subtilis (MIC of 0.78 lg/mL) and different strains of
methicillin-resistant Staphylococcus aureus (MRSA)
with activity (MIC 0.39–3.12 lg/mL) comparable to
that of the antibiotic vancomycin (0.5–1 lg/mL)
(Faqueti et al. 2015; Farias et al. 2018).
Callistemenonone A (15, Fig. 5) also showed a
potent antibacterial activity anti-MRSA JCSC2172
(MIC 20 lg/mL), (Xiang et al. 2017). Although, its
MIC was higher than that of vancomycin (1.25 lg/
mL), the data remains interesting.
The synthetically challenging structural motifs of
polyciclic polymethylated phloroglucinols (PPPs),
together with their promising and potent antibacterial
properties, mainly against multidrug resistant strains,
is of great and current interest. Based on a new total
asymmetric synthesis approach (Scheme 19) cal-
listrilone E (Fig. 5) was found (Cheng et al. 2018) to
exhibit greater antibacterial activity than vancomycin
against multidrug-resistant strains as MRSA (0.25 lg/
mL), vancomycin-intermediate Staphylococcus aur-
eus (VISA; 0.25 lg/mL) and vancomycin-resistant
Enterococcus faecium (VRE; 0.5 lg/mL). The result
against VRE was the most promising since van-
comycin has a MIC value [ 128 lg/mL.
Antimicrobial activity of phloroglucinols from
Myrtaceae was evaluated also against periodonto-
pathic bacteria. Macrocarpals A, B, and C, the major
components of the Eucalyptus globulus leaf extract,
showed relatively strong antimicrobial activity against
the etiologic agents of periodontal disease. Porphy-
romonas gingivalis displayed the greatest sensitivity
to macrocarpals (1 lg/mL for macrocarpals A and B,
0.5 lg/mL for macrocarpal C). This compound
inhibited proteinase activity and was able to bindto
saliva-coated hydroxyapatite beads, suggesting its use
in the prevention of periodontal disease (Nagata et al.
2006).
123
 Phytochem Rev

Scheme 21 Synthesis of novel meroterpenoids from R. tomentosa

Scheme 22 Synthesis of rhodomyrtone (226) and rhodomyrtosone B (227)

123
Phytochem Rev

Scheme 23 Synthesis of rhodomyrtosone A (228)

Scheme 24 Synthesis of watsonianone B (230) and iso-watsonianone (231) B by Zhang and co-workers (2019)

Fig. 12 Studies on 120 A B

60
biological properties of
N. of Publications

phloroglucinol from
Myrtaceae: number of
works per decades (a) and 60 30
investigated activities (b)

0 0
1990/1999

2000/2009

2010/2019
Before 1990

Anti-Viral

Anti-Diabetes
and Anti-Fungal

Neuroprotective
Anti-Plasmodial
Anti-Proliferative
Anti-Microbial

Anti-Inflammatory
and Citotoxic

Macrocarpal G showed discrete antibacterial activ-
ity against Staphylococcus aureus (0.53 lg/mL) and
MRSA (\ 0.8 lg/mL), in comparison with the corre-
sponding positive control, ciprofoxacin (IC50 0.08 lg/
mL) (Tian et al. 2014).
Another phloroglucinol, Rhodomyrtone exhibited a
potent anti-staphylococcal activity ainst planktonic
cultures and inhibited biofilms formation of Staphy-
lococci strains (0.25–1 lg/mL), demonstrating better
activity than vancomycin (0.5–2 lg/mL). The ability
to reduce biofilm formation and kill mature biofilms
occurred in a dose-dependent manner suggesting that
rhodomyrtone can be selected as potential lead
compound to develop for the treatment of biofilm-
forming staphylococcal infections (Saising et al.
2011). This property is very important because
pathogenic bacteria (and especially the ones resistant
to antibiotics) are able to resist for long on superficial
skin, mucosa or on different surfaces such as medical
facilities. They can adhere and form biofilm on the
surfaces, causing a range of very serious problems, as
well as common problems like acne. Biofilm forma-
tion is one of the most important staphylococcal
virulence factors and research on bioactive natural
compounds as potent agent to control biofilm-produc-
ing staphylococci are currently ongoing.
Antiviral activity
Several phloroglucinols from Myrtaceae showed
interesting activities against two human pathogen of
the Herpesviridae family: Epstein-Barr virus (EBV)
and herpes simplex virus (HSV). This latter has been
differentiated into two distinct types: HSV-1 or HSV-

123

2. The insurgence of resistance in patients treated with
acyclovir, the most commonly used drug in herpetic
therapies (Kitazato et al. 2007), recommended the
search for new antiherpetic agents from natural source.
Callistrilones H and I displayed moderate inhibitory
activities against HSV-1, with IC50 values of 10.00
and 12.50 lM respectively, whereas acyclovir had
IC50 values of 1.04 lM (Cao et al. 2018b). Over the
years, several studies have been carried out on HSV-1
(Bloor 1992; Brezáni et al. 2018). The recent work by
Brezáni et al. (2018) reports that grandinol, from
Eucalyptus globulus, with an IC50 value of 1.23 lM is
more active than acyclovir (1.92 lM).
Euglobals showed significant inhibitory effects also
on EBV early antigen activation (EBV-EA) induced
by the tumor promoter 12-O-tetradecanoylphorbol-
13-acetate (TPA). In particular at 1000 mol ratio/TPA
100% inhibition was registered in presence of euglob-
als G1-G5, G8-G10, G12, Am-2 and III (Takasaki
et al. 1995; Umehara et al. 1998) and 80% inhibition
for the less active euglobals G6–G7, euglobal-In-1 and
euglobal-V (Singh et al. 1998; Takasaki et al.
1990, 1994).
Moreover, Eucalyptus globulus is a source of
compounds with anti-HIV activity. In particular,
macrocarpals A–E inhibit HIV-RTase with IC50
values ranging between 5.3 and 12 lM, with macro-
carpal B as the most active compound (Nishizawa
et al. 1992).
Myrtucommulone K (192), tomentodiones B–C
(173–174), tomentosenol A (114) and callistiviminene
J (111), as well as callistiviminenes K, M, N (93, 98–
99) were evaluated for their activity in vitro against
respiratory syncytial virus (RSV), a pathogen of the
Paramyxoviridae family (Chen et al. 2017; Liu et al.
2018a). The most active compounds callistiviminenes
K (11.7 lM) and myrtucommulone K (10 lM), with
IC50 values comparable to the positive control rib-
avirin (10.20 lM), indicated that the side chains of the
phloroglucinol moiety might influence their anti-viral
activity (Chen et al. 2017; Liu et al. 2018a).
Anti-inflammatory activity
As already underlined, the great structural variety of
Myrtaceae phloroglucinols makes them good candi-
dates for a variety of biological properties, including
123
Phytochem Rev
the anti-inflammatory activity (Fiorini-Puybaret et al.
2011; Hennia et al. 2018; Nicoletti et al. 2018).
Phytoconstituents have be proposed to exert this
activity by many different mechanisms of action,
including, but not limited to, radical scavenging
activities, modulation of autoimmunity and modula-
tion of proinflammatory enzymes or their expression.
Good inhibitors of nitric oxide (NO) were reported
from Callistemon genus (Cao et al. 2018a). A com-
pound isolated from the flowers of this plant, 1-(2,6-
dihydroxy-4-methoxyphenyl)-3-methylbutan-1-one,
seems to act on oxidant-mediated inflammation.
Furthermore, it has anti-nociceptive properties (Radu-
lovic et al. 2015).
Baeckea frutescens produces different bioactive
phloroglucinols: baefrutones, baeckfrutones and fru-
tescones. Baefrutones A–D (117–120) and baeckfru-
tones A–S displayed a good inhibitory effect on
lipopolysaccharides (LPS)-induced NO production in
macrophage cell line RAW 264.7, with rates of 36.21
and 20.86 lM for baeckfrutones N and S respect to
N-monomethyl-L-arginine (L-NMMA) with
54.07 lM lower value (Hou et al. 2018; Qin et al.
2018a; Zhi et al. 2018). Frutescones N and O showed
the most promising inhibitory activity on NO produc-
tion (1.80 and 0.36 lM, respectively) in Baeckea
genus, while the IC50 value (30.92 lM) of L-NMMA
was considerably higher (Hou et al. 2017a). The same
authors suggest that the activity of frutescone O is
related to the suppression of the NF-jB p65 nuclear
translocation and the decrease of pro-inflammatory
cytokine TNF-a.
Among the various anti-inflammatory active com-
pounds from Rhodomyrtus (Zhang et al. 2018),
watsonianone A displayed a reduction on respiratory
syncytial virus (RSV-induced NO) (37.2 lM) and
prostaglandin E2 (PGE2) release (27.9 lM) (Zhuang
et al. 2017). Furthermore, western blot analysis
demonstrated that watsonianone A also suppressed
the expression of the inducible nitric oxide synthase
(iNOS) and cyclooxygenase-2 (COX-2) genes and
inhibited NO and PGE2 production in RSV-infected
RAW 264.7 cells.
Good anti-inflammatory activity was also shown by
meroterpenoids from Psidium guajava. Psiguajadials
A–K are promising inhibitors of phosphodiesterase-4
(1.34–7.26 lM), a therapeutic drug target for inflam-
matory and respiratory diseases. These results are
Phytochem Rev
promising since the positive control, rolipram, has an
IC50 value of 0.62 lM (Tang et al. 2017).
Almost all chronic and acute diseases are linked to
inflammation. Moreover, inflammation occurs as a
reaction to injuries such as physical injury, infection,
autoimmunity, arthritis and atherosclerosis.
Oxidative stress and low density lipoproteins
(LDL) are widely believed to play a role in the
atherosclerotic process. Myrtus communis has differ-
ent compounds able to preserve LDL from oxidative
damage (Rosa et al. 2008) and some compounds, such
as myrtucommuacetalone (scheme 8) that showed
also a good prevention of autoimmune disorders
thanks the reduction the T cell proliferation (IC50-
\ 0.5 lg/mL, comparable to prednisolone) (Choud-
hary et al. 2013). Furthermore, myrtucommuacetalone
suppressed the activation of NFkB, but not through
activation of p38 kinase. The compound significantly
suppressed the iNOS gene and protein expression
in vitro and exhibited a strong binding pattern in the
binding site of iNOS enzyme in silico (Soomro et al.
2019).
To better understand the mode of action of myrtu-
commulone, Feißt et al. (2005) performed in vitro and
in vivo studies. Myrtucommulone is an inhibitor of
5-lipoxygenase and COX-1, being able to suppress the
biosynthesis of prostaglandins (PGs) and leukotrienes
(LTs). Meanwhile, the anti-inflammatory effect of
myrtucommulone is related to PGE2 suppression and
only in part with COX enzymes inhibition (Koeberle
et al. 2009).
Because of the side effect of a large number of
immunosuppressive agents, Pham et al. (2019) eval-
uate in vitro the effect of different phloroglucinols on
the concanavalin-induced T-cell proliferation. Euca-
lyptin C seemed to be the most promising compound
since it reduced T-cell proliferation probably through
a mitochondrial pathway. Moreover, it decreased the
level of interleukin-4 (IL-4) and other factors related
to cytokine secretion.
Despite all these studies, bio-functional activities of
many molecules remain unexplored while essential
oils’ traditional use can be a good input for future
assays. For examples, Kunzea ambigua extract is a
remedy for inflammation (Thomas et al. 2009) but
there are no biological assays about characteristic
diglucosides phloroglucinols (kunzeaphlogins A–F)
of this plant.
Antiproliferative and cytotoxic activities
Several classes of anticancer drugs have been devel-
oped and many of them are of natural origin (Soliman
et al. 2014). There are a lot of studies and reviews
(Fig. 13) focusing on antiproliferative and cytotoxic
activities of different phloroglucinols, from Myr-
taceae, tested on different cell lines and showing a
wide response range depending on both the compound
doses and the cell line types.
Myrtus, Rhodomyrtus, and Eucalyptus genus are the
ones for which larger information is available both for
number of compounds, and for the biological activity,
including the mechanisms of action (Fig. 13).
In a recent review, Nicoletti et al. (2018) analyze
myrtucommulones and related acylphloroglucinols
from Myrtaceae, underlining their cytotoxic activities
with particular attention to myrtucommulone A, one of
the most studied phloroglucinols.
Thanks to the work by Tretiakova et al. (2008), it is
possible to indicate the mitochondrial caspase-3-8-9
and poly(ADP-ribose)polymerase (PARP) pathway as
responsible for the apoptosis in peripheral blood
mononuclear (PBMC) cells treated with myrtucom-
mulone A. Furthermore, Jurkat lymphoblastic leuke-
mia cells deficient in caspase-9 were resistant to the
treatment, implying that a select apoptotic signaling
pathway involving caspase-9 is required to evoke cell
death. Nevertheless, there are also extrinsic factors
caused by the treatment with myrtucommulone A,
such as an increase in apoptotic genes including Fas,
FasL, Gadd45a, Tnf, Tnfsf12, Trp53, a decrease in
caspase 4 and an upregulation of transformation
related protein 53 (p53) on 4T1 cancer cells (Izgi
et al. 2015).
An important biological process regulated by
myrtucommulone A involves human mesenchymal
stem cells that promote tumor progression via
paracrine signaling. In fact, myrtucommulone A
reduces the growth factor expression in human
mesenchymal stem cells (hMSC), which might be
clinically important. As described by Iskender et al.
(2016a) there is a decrease in the production of 29
cytokine, such as IL-6, IGF-1, PDGF, VEGF, TNF-a,
EGF and MCP-1, IGF-1 and FGF-2.
Epithelial-mesenchymal transition (EMT) is
another important biological process that could be
regulated by interfering with the extracellular signal-
regulated kinase ERK/MAPK and
123
 Phytochem Rev

SMMC-7721
A

CCRF-CEM

QGY-7701
BEL-7402
HCT-116

HCCLM3

B16-F10
DU-145

HepG-2

Hep-3B

SW480

LNCaP
MCF-7

Jurkat
Huh-7

DLD-1
PBMC
A-549

HL-60
U2OS

10 FS

MM6
HEP2
Caco

PC-3
MT4
4-T1

KFR
L02
COMPOUNDS

H9
Eucalrobusone C
Eucalrobusone I
Macrocarpal A
Macrocarpal E
Myrtucommulone L
Myrtucommulone A
Sideroxylonal B
P e ng e t a l. 2 0 11; C o t t iglia e t a l. 2 0 12 ; S o lim a n e t a l. 2 0 14 ; S ha ng e t a l. 2 0 16 ; Wie c hm a nn e t a l. 2 0 15 J ia n e t a l. 2 0 17 ; Q in e t a l. 2 0 18 b;
T re t ia k o v a e t a l. 2 0 0 8 ; P ha m e t a l 2 0 19

CCRF-CEM
HCT-116
DU-145
CCRF-CEM

DLD-1
A-549
NCI-H460

HCT-116
B

DU-145
HepG-2

SF-268

Huh-7
A-549
MCF-7

C O M P O UN D S Eucalypglobulusal A
Aspidinol C Eucalrobusone J Eucalypglobulusal B
Aspidinol D Eucaltereal A Eucalypglobulusal C
Liu e t a l. 2 0 16 b Eucaltereal B Eucalypglobulusal D
Eucaltereal C Eucalypglobulusal E
Eucalypglobulusal F
NCI-H460

Eucaltereal D
HepG-2

Eucalypglobulusal G
SF-268

Eucaltereal E
MCF-7

Liu e t a l. 2 0 18 b Eucalypglobulusal H
Eucalypglobulusal I
Callistenone F
Eucalypglobulusal J
Callistenone G
Callistenone H Q in e t a l. 2 0 18 b
Callistenone I
HepG-2

Callistenone J
MCF-7
U2OS

B16-F10
Callistenone K

Nalm-6
K-562
Liu et al. 2016b
Eucalrobusone A
MDA-MB-231

Eucalrobusone B Eugenial A
Eucalrobusone D Eugenial B
Eucalrobusone E Eugenial C
A-549
PSN-1

P388

Eucalrobusone F Eugenial D
Eucalrobusone G Eugenial E
Baeckenone D Eucalrobusone H F a ria s e t a l. 2 0 18
S ha ng e t a l. 2 0 16
Baeckenone E
Baeckenone F
Baeckenone G
SMMC-7721
CCRF-CEM

Baeckenone H
BGC-823
HCT-116

B16-F10
DU-145

SW480

Baeckenone I
MCF-7

Jurkat
Huh-7
A-549

HL-60

KE-97

4-T1
Baeckenone J
Baeckenone K
Eglobal IVa
Bullataketals 3 A-B Eglobal VII
La rs e n e t a l. 2 0 0 5 ; It o e t a l. 2 0 17 ; Euglobal Ib
N is a e t a l. 2 0 16 b Euglobal Ic
Euglobal-IIa
HCT-116

Euglobal-III
DU-145
A-549

Euglobal-IIIa
HeLa

Euglobal-V
(-)Baeckfrutone B Euglobal IX
Baeckfrutone C Euglobal-In-3
Baeckfrutone D Euglobal-B1-1
Baeckfrutone E Eucalyptal A
Baeckfrutone F Eucalyptal B
Baeckfrutone G Eucalyptal C
Baeckfrutone H Eucalyptal D
Baeckfrutone I Eucalyptal E
Baeckfrutone J Eucalypn A
Baeckfrutone K Eucalypn B
Baeckfrutone L P e ng e t a l 2 0 11; Wa ng e t a l. 2 0 12 ; Liu e t a l. 2 0 18 b; Q in e t a l. 2 0 18 b;
Q in e t a l. 2 0 18 a P ha m e t a l 2 0 18

123
 Phytochem Rev
b Fig. 13 Cytotoxic activities of the most tested (a) and least
tested (b) phloglucinol derivatives from Myrtaceae, on different
cell lines. The degree of inhibitory activities (lM) was reported
as follow: 0–1 ; 1.1–5 ; 5.1–10 ; 10.1–20
20.1–100 ; [ 100 . A549: adenocarcinomic human
alveolar basal epithelial cells; BEL-7402: human hepatocellular
carcinoma cells; BGC-823: human gastric carcinoma cells;
B16-F10 murine melanoma cells; Caco: human epithelial
colorectal adenocarcinoma cells; CCRF-CEM: acute lym-
phoblastic leukemia cells; DLD-1: colorectal adenocarcinoma
cells; DU145: human prostate cancer cells; HCCLM3: human
hepatocellular carcinoma cells with high metastatic potential;
HCT-116: human hepatocellular carcinoma cells; HeLa: human
cervix uteri carcinoma cells; Hep-G2: human hepatoma
carcinoma cells; Hep-G2/ADM: human multidrug-resistant
hepatocellular carcinoma cells; HEP-2: human laryngeal
carcinoma cells; Hep-3B: hepatoma cells; HL-60: human
leukemia cells; HuH-7: hepatocarcinoma cells; H9: cutaneous
T-cell lymphoma; Jurkat: T acute lymphoblastic leukemia cells;
KE-97: gastric cancer cell line; KFR: alveolar rhabdomyosar-
coma; K-562: erythro-megakaryoblastic leukemia cells;
LNCaP: androgen-sensitive human prostate adenocarcinoma;
L0-2: normal human liver cell line; MCF-7: human breast
adenocarcinoma cells; MDA-MB-231: Triple negative breast
cancer cells; MM6: human peripheral blood mononuclear cells;
MT-4: human hematological tumor cells; Nalm-6: B cell
precursor leukemia; NCI-H460: human non-small cell lung
cancer cells; PC-3: human prostate cancer cells; PSN-1:
pancreatic cancer cells; P388: Menogaril-resistant mouse
leukemia cells; QGY-7701: human hepatocellular carcinoma
cells; SF-268: human glioblastoma cells; SMMC-7721: human
hepatocarcinoma cells; SK-MEL-110: melanoma cells; SK-
MEL-28: melanoma cells; SW480: human colon cancer cells;
U2OS: human bone osteosarcoma epithelial cells; VERO:
mammalian cells; 4T1: breast cancer cells; 10-FS: fibroblast
cells; 786-O: renal carcinoma cells
phosphatidylinositol-3 kinase PI3K/Akt signaling
pathways. This signaling pathway is required for the
induction of cell motility by transforming growth
factor TGF-b that, at last, interferes with EMT-
associated marker expression. As reported by Iskender
et al. (2016b), inhibition of ERK affected migratory
ability of human bladder carcinoma (HTB-9) cells,
and in breast cancer cells (MDA-MB-231). Myrtu-
commulone A negatively regulates the ERK process
through inhibition of phosphorylation of various
components involved in PI3K/Akt in HTB-9 and
MDA-MB-231. In HTB-9 cells myrtucommulone A
also downregulates the expressions of pluripotency-
associated nuclear markers such as NANOG, SOX-2,
OCT-4, CD44, CD73, CD90 and CD105 (Iskender
et al. 2015).
Different cytotoxic compounds have been isolated
from Rhodomyrtus tomentosa and, among these,
; rhodomyrtone is particularly remarkable (Zhang
et al. 2018; Liu et al. 2016a). It exerted inhibition on
epidermoid carcinoma cell line (A-431), a cellular line
representative of late stage tumor (Tayeh et al. 2017).
During the metastatic process, proteolytic enzymes,
like the matrix metalloproteinases (MMPs), play
critical roles. MMPs are controlled by their endoge-
nous inhibitors, tissue inhibitors of metalloproteinases
(TIMPs) such as TIMP-1 and TIMP-2. In addition,
inhibition of the MAPK and PI3K/Akt pathways as
well as NF-jB and AP-1 activities may reduce cell
migration and proliferation. Rhodomyrtone could
inhibit ERK1/2, p38 and focal adhesion kinase FAK/
Akt signaling pathways via NF-jB activities involved
in the downregulation enzyme activities and protein
expression of MMP-2/9. Moreover, rhodomyrtone
increases the expression of both TIMP-1 and TIMP-2.
Therefore, rhodomyrtone could be a possible anti-
metastasis agent for treatment of skin cancer cells.
Eucalrobusone C is a bioactive phytochemical of
Eucalyptus genus with cytotoxic activity on different
cell lines, such as MCF-7, U2OS, HCCLM3, BEL-
7402, QGY-7701, Hep3B and HepG2 (Shang et al.
2016; Jian et al. 2017; Qin et al. 2018b). It induces
apoptosis in MCF-7 cells in a dose-dependent manner,
by increasing the duration of sub-G1 phase and
accumulation of the early apoptosis signals (Shang
et al. 2016). On the other hand, it induces apoptosis via
caspase activation in hepatocellular carcinoma (HCC)
cells, where it enhances the loss of MMP, increases the
level of pro-apoptotic Bax and downregulates Bcl-2
levels (Jian et al. 2017). In HepG2 and BEL-7402
cells, the treatment with eucalrobusone C increased
p38 MAPK and c-jun N-terminal kinase (JNK) levels.
Cell death was partly dependent on p38 MAPK
activation in HepG2 cell death, indicating that ROS
act as an upstream signaling molecule for activation of
the p38 MAPK/mitochondrial pathway.
There are many others promising Eucalyptus com-
pounds with cytotoxic activities (Yin et al. 2007; Peng
et al. 2011; Tian et al. 2012; Wang et al. 2012; Soliman
et al. 2014). Euglobal G1 from Eucalyptus grandis
showed a remarkable inhibitory effect on two-stage
skin carcinogenesis in mice (Takasaki et al. 2000).
Eucalteretials A–E (Liu et al. 2018b, Fig. 10) and
eucalypglobulusals A–J (Qin et al. 2018b, Fig. 10)
along with eucalrobusone C, eucarobustol C, and
123
 Phytochem Rev

SMMC-7721
CCRF-CEM

HCT-116

B16-F10
DU-145

HepG-2
Huh-7
A-549

HL-60

MT4
4-T1
HepG2/ADM
Macrocarpal B

HepG-2
Macrocarpal C
Macrocarpal D
Macrocarpal G
Guadial A
Macrocarpal Q
Guadial B
Myrtucommulone J
Guadial C
Myrtucommulone K
Guapsidial A
S ha o e t a l. 2 0 10 C o t t iglia e t a l. 2 0 12 ; T ia n e t a l. 2 0 12 ; Wie c hm a nn e t
J ia n e t a l. 2 0 15 a l. 2 0 15 ; Q in e t a l. 2 0 18 b; P ha m e t a l. 2 0 18

MDA-MB-231
HepG2/ADM

NCI-H460
SMMC-7721

HepG-2

SF-268
MCF-7

K-562
HL-60
SW480
MCF-7
A-549

HL-60

Psiguadial C
Guajavadial A Psiguadial D
Guajavadial B Pulverulentone
Guajavadial C Samarone A
Q in e t a l 2 0 16 Samarone B
Samarone C
Sygyzol A
Sygyzol B
Z o u e t a l. 2 0 0 6 ; S ha o e t a l. 2 0 12 ; Liu
MDA-MB-231

e t a l. 2 0 16 b; Y a ng e t a l. 2 0 18
SK-MEL-110
SK-MEL-28
HepG-2
VERO

VERO
HeLa
Jambone A
VERO

Tomentodione A
HeLa

Jambone B
Jambone C Tomentodione B
Jambone E Rhodomyrtone Tomentodione N
Rhodomyrtosone A Tomentodione O
Jambone F
Jambone G Rhodomyrtosone B Tomentodione P
Jamunone B Rhodomyrtosone C Tomentodione Q
Li e t a l 2 0 15 Rhodomyrtosone D Tomentodione R
Y a ng e t a l. 2 0 18 Rhodomyrtosone G Tomentodione S
Rhodomyrtosone I Tomentodione T
Z ha ng e t a l. 2 0 18 Z ha ng e t a l. 2 0 18

MDA-MB-231
MDA-MB-231

NCI-H460
B16-F10

HepG-2
HepG-2

SF-268

MCF-7

786-0
A-549

K-562
HL-60
KE-97
VERO
A-549

HeLa

Liordial A Tomentosenol A
Liordial B Watsonianone A
Liordial C 4Methoxyisovalerophenone
Liordial D 2,6-Dihydroxy-4-Methoxy-3-Methyl -Isopropiophenone
Liordial E 1-(acetyl)phloroglucinol-β-D-glucopyranoside
Liordial F 4S-focifolidione
X u e t a l 2 0 19 ethyl 2,4,6-trihydroxybenzoate
1-(2,6-dihydroxy-4-methoxyphenyl)-hexan-1-one
2-pentadecyl-5,7-didydroxychromone
Z o u e t a l. 2 0 0 6 ; Liu e t a l 2 0 16 a ; Liu e t a l. 2 0 16 b; S un e t
a l. 2 0 16 ; Y a ng e t a l. 2 0 18 ; Z ha ng e t a l. 2 0 18

Fig. 13 continued

123
Phytochem Rev
eucalyptin A were tested for their cytotoxic effects and
for DNA Topoisomerase I inhibitory activities, using
Top1-mediated relaxation assay with camptothecin as
positive control. Only eucalteretial C (IC50 4.8 lM)
and euglobals Ib and IX (IC50 7.8 lM for both)
showed cytotoxic activity (Liu et al. 2018b), while
eucalypglobulusal A and eucalrobustol C exhibited
moderate to high Top1 inhibition.
When Eucalypglobulusal F,eucalrobusone C,
eucarobustol C, and eucalyptin A were tested on
A549 cells, the best results were obtained from
eucalyptin A (4.9 lM) with etoposide, as positive
control, IC50 [ 10 lM (Qin et al. 2018b). This
compound had already been shown to inhibit Hepa-
tocyte Growth Factor (HGF)-induced c-Met activation
and suppress HGF-stimulated cell motility and inva-
sive behaviors in MDCK cells. (Yang et al. 2012).
Eucalyptin B is also a potential anti-cancer agent
(Pham et al. 2018), with a very strong inhibition of cell
survival in A549 cells (IC501.51 lM respect to taxol
IC50-4.1 lM). Moreover, in this cell line, eucalyptin B
increases caspase-3 expression, inhibits Bcl2 and
increases Bax levels.
Cytotoxic phloroglucinol derivatives are also
known to occur in other genera, such as Baeckea,
Syzygium, Eugenia, Calyptranthes, Lophomyrtus,
Psidium, Callistemon, and Decaspermum (Fig. 13).
Baeckenones D–K (4–11, Nisa et al. 2016b; Ito
et al. 2017), along with baeckefrutones B, F and K
(Qin et al. 2018a, Fig. 5) from the genus Baeckea,
show antiproliferative activity against pancreatic cell
lines and A549 cells.
Jambone A (47) and C (49) from Syzygium have a
weak activity in melanoma (SK-MEL-28 and SK-
MEL-110) cell lines (Li et al. 2015), while samarones
B–C (44–45, 3.91 lM and 5.56 lM, respectively) and
jambone G (1.73 lM) are active on HepG2hepatocel-
lular line (Yang et al. 2018). Furthermore, syzygiol A,
(58) syzygiol B, (60) 1-(2,6-dihydroxy-4-methoxy-
phenyl)-hexan-1-one inhibit the proliferation of leu-
kemia cells. In particular, the first compound (IC50
5 lM) induces the differentiation of K562 leukemic
cells as determined by the appearance of matured
morphology and the increase in the intracellular
hemoglobin level (Zou et al. 2006).
Several compounds from Psidium genus have been
analyzed for the cytotoxic activity (Fig. 13) (Jian et al.
2015; Qin et al. 2016; Shao et al. 2010; Xu et al. 2019;
Zhu et al. 2019). Among them, littordials B and E (187
and 190, Fig. 11) show potential cytotoxicity against
MDA-MB-321 (IC50 7.4 lM and IC50 6.6 lM,
respectively), while littordial C (188, IC50 8.9 lM)
on murine tumor cell line (B16) a model for human
skin cancers. All these data are compared to gambogic
acid, as positive control (IC50 15.3 and IC50 8.7 lM,
against MDA-MB-321 and B16 respectively) under-
lining their good activities.
Guajavadial C (113, Fig. 9) showed good cytotox-
icity toward (SMMC-7721) compared to the positive
control cisplatin.
From the genus Eugenia there are promising data
for eugenials, in particular for eugenial C (IC500.38 -
lM) with high cytotoxicity compared to doxorubicin
(IC50 0.83 lM) on K562 cells, making the good
candidates for preclinical evaluation of efficacy and
toxicity (Farias et al. 2018).
The only active phloroglucinol derivative from
Calyptranthes genus is aspidinol, which exhibits
selective activity against the human oral epidermoid
carcinoma (Lobo-Echeverri et al. 2005), while the
main cytotoxic compounds Lophomyrtus, are bul-
lataketals 3A and 3B that were active against the P388
mouse leukaemia cell line (Larsen et al. 2005).
Furthermore, phloroglucinols derivatives have
been isolated from Callistemon viminalis, Xanthoste-
mon chrysanthus and Decaspermum gracilentum.
However, they exhibited weak antitumor inhibitory
activities with an IC50 ranging from 25 to 100 lM or
were inactive (Liu et al. 2016b; Sun et al. 2016; Liu
et al. 2018c).
Type-2 Diabetes Mellitus
As a consequence, to the increasing number of patients
with type-2 diabetes mellitus (T2DM) in the latest
years, there is a continuous search of molecules able to
improve the therapies. Among potential drug target for
hypoglycemic agents, a-glucosidase, along with
dipeptidyl peptidase 4 (DPP4, an enzyme responsible
for the degradation of glucagon-like peptide 1, GLP-
1), and protein tyrosine phosphatase 1B (PTP1B, a
negative regulator of insulin signaling pathways)
inhibitors have been selected as attractive objectives.
Macrocarpal C showed strong inhibition of DPP4
(90%), even to 50 lM, while macrocarpals A and B,
that differ to macrocarpal C for hydroxyl function
instead of double bond at eptane-ring, were inactive
(Kato et al. 2018).
123

Austroyunones D–E (54–55, Fig. 6) and jambone G
showed inhibition ratio of PTP1B ranging from 85.84
to 91.06% at 100 lM (Xu et al. 2018b), values
comparable to those of the positive control 3-(3,5-
dibromo-4-hydroxybenzoyl)-2-ethylbenzofuran-6-
sulfonicacid-[4-(thiazol-2-ylsulfamyl) phenyl] amide,
(99.85% at 100 lM). Psidials A–C showed activity
with inhibition rates of enzyme PTP1B of 1.7%,
61.7%, and 38.8% in 10 lM respectively (Fu et al.
2010).
Eucarobustols A, G, and I showed inhibitory
activities against PTP1B with IC50 values of 1.3, 1.8,
and 1.6 lM, respectively (Yu et al. 2016). Greater
IC50 value (8.93 lM), similar to the reference com-
pound, RK-682 (7.35 lM), was registered for isomyr-
tucommulone B (Liang et al. 2020), whereas
jamunones A–F and J–O (25–30 and 33–39) showed
IC50 values ranging from 0.42 to 3.2 lM comparable
to positive controls, which were ursolic acid (IC50
8.9 lM) and synthetic PTP1B inhibitor (2.0 lM, Liu
et al. 2017a).
The inhibition of a-glucosidase reduces the post-
prandial blood glucose, representing a primary target
for treatment of T2D. Seven meroterpene-like com-
pounds derived from b-caryophyllene showed IC50
values between 2.73 and 9.47 lM, very promising
when compared to genistein and acarbose, 22.64 and
[ 50 lM, respectively (Ma et al. 2018). Lower IC50
value (35.3 lM) was registered for isomyrtucommu-
lone B, which was before mentioned for its PTP1B
inhibitory activity (Liang et al. 2020) while the highest
activity was ascribed to rhodomyrtosone D (Ferlina-
hayati and Eliza 2019) with an IC50 of 110.3 lM
respect to acarbose as positive control (IC50 of 383.7
lM).
Conclusion
The Myrtaceae family is characterised by a large
number of genera and species, with a rate of variability
in terms of morphology.
The biodiversity of this family also explains the
chemical variability of the specialized metabolites
produced by plants belonging to it. In addition to
tannins, flavonoids and other ubiquitous metabolites,
phloroglucinols are a major class of natural com-
pounds of Myrtaceae family. These compounds, as
well, are characterized by a wide structural variability.
123
Phytochem Rev
However, it is impossible to talk about phloroglucinols
from the Myrtaceae, without referring to myrtucom-
mulones, unique bioactive acylphloroglucinols firstly
reported from Myrtus communis.
Thanks to their structural features and biological
activities, myrtucommulones and their derivatives
have become attractive targets for organic chemists.
In this review, the most relevant approaches and
synthetic procedures of myrtucommulones from Myr-
tus communis as well as the others related compounds
are summarized.
Finally, the high structural diversity of phloroglu-
cinol derivatives from Myrtaceae species provides a
large variety of bioactive metabolites that could be
proposed as drugs or as lead compounds.An overview
of structures and bioactive properties of phlorogluci-
nol derivatives from Myrtaceae species until 2019 is
here provided.
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