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Recent Patents on Food, Nutrition & Agriculture, 2011, 3, 9-16 9

Use of Terpenoids as Natural Flavouring Compounds in Food Industry


Lorenzo Caputi and Eugenio Aprea*

IASMA Research and Innovation Centre, Fondazione Edmund Mach, Food Quality and Nutrition Area, Via E. Mach 1,
38010 S. Michele all'Adige, Italy

Received: September 9, 2010; Accepted: October 12, 2010; Revised: October 15, 2010
Abstract: Terpenoids represent the oldest known biomolecules, having been recovered from sediments as old as 2.5
billion years. Among plant secondary metabolites, they are the most abundant and diverse class of natural compounds.
The diversity of terpenoids is probably a reflection of their many biological activities in nature, which has made them a
widely used resource for traditional and modern human exploitation. They are usually the main constituents of essential
oils of most plants offering a wide variety of pleasant scents from flowery to fruity, to woody or balsamic notes. For this
reason terpenoids constitute a very important class of compounds for flavour and fragrance industries, in fact, in the US
alone, the demand is forecast to grow 3.7 percent per year to $5.3 billion in 2012. The recent patents on production and
extraction of terpenoids commonly used as natural flavouring compounds in food industries are reviewed in the present
manuscript.
Keywords: Flavour, flavouring agent, norisoprenoids, terpenes, terpenoids, terpene synthases.

INTRODUCTION and supplies the precursors for the production of sesqui-


terpenoids (C15) and triterpenoids (C30) (see Fig. (1)). The
Terpenes represent the oldest known biomolecules,
2-C-methyl-D-erythritol-4-phosphate (MEP) pathway, also
having been recovered from sediments as old as 2.5 billion
referred to as the deoxyxylulose-5-phosphate (DXP) path-
years [1, 2]. They are also the most diverse class of natural
way which is active in plant plastids, and supplies pre-
compounds with more than 40000 different structures
cursors for the production of monoterpenoids, diterpenoids
reported to date [3]. This enormous ‘chemodiversity’ can be (C20) and carotenoids (C40) (see Fig. (1)).
considered a peculiar characteristic of these metabolites,
which have been isolated from plant, animal and microbial Terpenes containing more than one isoprene unit are
species [4]. usually formed in reactions catalysed by prenyl transferases.
These enzymes catalyse the ‘head-to-tail’ addition of IPP
In plants, some terpenes and their oxygenated forms,
units to allylic diphosphates, typically DMAPP. These reac-
called terpenoids, are involved in primary metabolism, tions produce the C10, C15, and C20 precursors geranyl
where they play key and highly diverse roles in cellular
diphosphate (GPP), farnesyl diphosphate (FPP) and
function and maintenance. However, a large number of
geranylgeranyl diphosphate (GGPP), respectively. Reactions
structurally diverse terpenes have been characterised as
catalysed by enzymes such as squalene synthase generate
secondary metabolites of plants, such as those known or
larger terpene precursors by combining the polyprenyl
assumed to have specialised functions in mediating antago-
diphosphates. Terpene synthases catalyse the reaction of the
nistic and beneficial interactions amongst organisms in their polyprenyl diphosphates to produce the carbon skeletons of
environments. For instance, terpenes represent a large
monoterpenes, sesquiterpenes, diterpenes and so on, gene-
component of volatile floral and fruit scents, adaptations that
rating the main carbon skeletons. When the main backbones
plants have evolved to attract pollinators and seed dispersers
are completed, additional functional groups are subsequently
in order to maximize their fertilization rates and survival.
added by other enzymes to decorate the main structure,
Hence, the presence or absence of a scent may have a
resulting in the tremendous chemodiversity of the final
substantial impact on the yield of agronomical important products. Typical modifications are: hydroxylation, oxida-
crops [5]. In this review, we will refer to terpenoids to
tion, reduction, acylation and glycosylation. The reader is
indicate both terpenes and their oxygenated forms.
referred to a recent review by Nagegowda for detailed
Despite the diversity of their functions and structures, all overviews of terpene biosynthesis in plants [6].
terpenoids derive from the common 5-carbon building
The diversity of terpenoids is probably a reflection of
blocks isopentenyl diphosphate (IPP) and its isomer their many biological activities in nature, which have made
dimethylallyl diphosphate (DMAPP), also called isoprene
them a widely used resource for traditional and modern
units. In plants, two distinct pathways produce IPP. The
human exploitation [7]. The use of these compounds, in fact,
mevalonate (MVA) pathway which is active in the cytosol
has permeated human civilisation since the Egyptians,
contributing significantly to the improvement of quality of
*Address correspondence to this author at the IASMA Research and life [8]. There have been many applications of plant terpe-
Innovation Centre, Fondazione Edmund Mach, Food Quality and Nutrition noids in human society. Pharmaceutical, food and cosmetic
Area, Via E. Mach 1, 38010 S. Michele all'Adige, Italy; industries have exploited them for their potential as
Tel: ++39 0461 61 51 36; Fax: ++39 0461 61 52 00;
E-mail: eugenio.aprea@iasma.it medicines, flavour enhancers and fragrances. To have an

1876-1429/11 $100.00+.00 © 2011 Bentham Science Publishers Ltd.


10 Recent Patents on Food, Nutrition & Agriculture, 2011, Vol. 3, No. 1 Caputi and Aprea

Fig. (1). Schematic overview of terpenoid biosynthesis in plants. In the plastid, isopentenyl diphosphate (IPP) and dimethylallyl
diphosphate (DMAPP), generated through the deoxyxylulose-5-phosphate (DXP) pathway, condense to form terpenoid precursors, including
the monoterpenoid precursor geranyl diphosphate (GPP), and the diterpenoid precursor geranylgeranyl diphosphate (GGPP). Two molecules
of GGPP condense to form carotenoids. In the cytosol, IPP and DMAPP, generated through the mevalonate (MVA) pathway, condense to
form the sesquiterpenoid precursor farnesyl diphosphate (FPP). Two molecules of FPP condense to form the triterpenoids.

idea of the economic impact of these compounds in our days, and seasonal variations, political interference and other
it is worth mentioning that the demand for flavours and environmental factors. This production system sometimes
fragrances in the US is forecast to grow 3.7 percent per year does not ensure a continuous product supply and/or a
to $5.3 billion in 2012 [9]. uniform quality and yield causing significant fluctuations in
the prices of the raw material which inevitably affects the
In the past decade, the increase in consumption of
fortified food and nutraceutically enriched beverages has cost of the products.
challenged the flavour research as it has provided new In this paper, we will review the sensory properties of
applications for flavour compounds that are able to enhance some commercially relevant terpenoids used as flavours
the sensory appeal of these products while masking unplea- focusing on the recent advances in their extraction or
sant tastes and aromas of vitamins, minerals, antioxidants production methods.
and other added active ingredients. However, the big value
gain of the flavours market seems to be the increasing SENSORY PROPERTIES OF COMMERCIALLY
demand for ‘natural’ ingredients which are generally more RELEVANT TERPENOIDS
expensive than their ‘natural-like’ or synthetic counterparts.
The current legislation in the US and EU classifies ‘natural’ Terpenoids are the major constituents of essential oils,
flavours as only those that are extracted from natural sources which are widely used directly as flavouring agents [12-15]
or obtained through bioprocesses involving precursors or for further isolation of flavouring substances [16-21]. The
isolated from nature [10, 11]. This classification has led to a ranges of flavours and odours for these compounds are very
preference for the development of more efficient methods for broad and it is not possible to define common descriptors.
the extraction of essential oils from plants and to the Furthermore, several of these compounds exist in different
development of new synthetic methods involving biotech- enantiomeric forms that differ either in odour sensations, or
nology and biotransformation rather than the use of in odour intensity [22].
chemistry. However, for some compounds, such as menthol, In general, monoterpene hydrocarbons such as - and -
for which the demand greatly exceeds the supply from natu- pinene, limonene, -3-carene, -phellandrene and myrcene
ral sources, research on its chemical synthesis is still active. are found as complex mixtures in most essential oils,
Another aspect that needs to be pinpointed here is that particularly in those extracted from plant leaves, whilst seed
currently the majority of the ‘natural’ flavouring agents are and flower oils contain more specialised monoterpenes and
extracted from plants grown through conventional agricul- present fruity or flowery odours. Woody oils contain high
tural practices which are strictly dependent on geographical percentages of sesquiterpenes and sesquiterpenols with more
Terpenoids as Natural Flavourings in Food Recent Patents on Food, Nutrition & Agriculture, 2011, Vol. 3, No. 1 11

woody and balsamic notes [23]. Examples of flavouring while isomenthone has a musty, sweet, herbaceous, earthy-
substances isolated from essential oils and widely used in camphoraceous, hay-like odour [31]. Menthone and
flavour and fragrance industries are menthol from wild mint isomenthone are constituents of the essential oils of penny-
(Mentha arvensis) having a strong minty odour; D-carvone royal, peppermint, Pelargonium geraniums, and others.
from caraway (Carum carvi) with its spicy and breadlike Menthol is added to confectionaries or beverages not only
odour; D-limonene from citrus species having a fresh orange for its minty odour but also as a cooling and refreshing agent
peel odour; citral from lemongrass (Cymbopogon citratus) [32-34]. Menthone can be obtained by distillation of corn
having a fresh lemon peel odour; 1,8-cineole from mint oil, by oxidation of menthol [35, 36] or by hydro-
eucalyptus (Eucalyptus globulus) having a camphoraceous- genation of thymol.
cool odour. Differently from monoterpenes and sesquiter-
As the compound responsible for the flavour of caraway,
penes that are biosynthetically originated directly from dill and spearmint, carvone (see Fig. (2) for structure) has
isoprene units through the MEP and the MVA pathways, the
been used for millennia in food [37]. Carvone is present in
C13-norisoprenoid compounds such as ionones and damas-
two enantiomeric forms: R-(+)-carvone smells like spearmint
cones are products of the oxidative cleavage of -carotene
while S-(-)-carvone smells like caraway [38]. In the past, R-
and are important sources of flavours for the food industry as
and S- carvones were extracted and isolated by fractional
well. These compounds constitute essential aroma notes in
distillation of caraway oil and spearmint oil, respectively. In
tea, grapes, roses, tobacco, and wine also showing a wide recent years, more efficient extraction methods have been
range of odour attributes. It is worth mentioning here some
proposed [39, 40] but nevertheless the synthetic production
of the most common norisoprenoids. -Ionone is present in
is preferred. In the late fifties and during the sixties, several
many fruits and plants such as black currant, black tea,
works were published describing carvone chemical synthesis
blackberries, raspberries, carrots and has an intense violet
[37] but one of the most recent patents is dated 2002 [41].
odour; -damascenone is mainly present in apricot, rose,
The preferred starting material for carvone production is
grape, kiwi, raspberries, blackberries and is described as limonene [42].
woody, sweet, fruity, earthy with green floral nuances;
safranal is mainly found in saffron, osmanthus, black tea, Although limonene (see Fig. (2) for structure) is mainly
mate, and paprika and has a woody, spicy, phenolic, cam- used as a precursor of carvone it is also used as a flavouring
phoreous, medicinal odour. agent in foods, beverages and chewing gum [43]. It is found
in non-alcoholic beverages (31ppm), ice cream and ices
EXTRACTION, PURIFICATION AND CHEMICAL (68ppm), candy (49ppm), baked goods (120ppm), gelatines
SYNTHESIS and puddings (48-400ppm), and chewing gum (2300ppm)
[43]. Limonene is a chiral molecule, and biological sources
Many plants contain considerable amounts of terpenoids produce D-limonene ((+)-limonene). The main industrial
hence some parts of the plants, such as seeds, flowers, fruits, source of this compound is orange peel, from which it is
leaves and roots, are used as starting material for the extracted using organic solvents [44].
extraction. Physical processes for isolation of natural
flavouring substances include distillation, solvent extraction Because of its flavourful and fragrant properties, linalool
(including the use of dense gases), and chromatography [24]. (see Fig. (2) for structure) is added to processed food and
To isolate low volatile terpenes with polar groups from beverages [45-47], perfumes, cosmetics and soaps as well as
plants, fungi and other organisms, the natural material is to household detergents and waxes. The Food and Drug
dried, chopped or ground and then extracted with inert Administration allows the use of numerous natural and
solvent at the lowest possible temperature in order to prevent artificial flavourings in beverages, candy, ice cream and
the formation of artefacts [25]. The extract is separated by baked goods containing various amounts of linalool and its
distillation, evaporated to dryness in vacuum or freeze-dried esters. The GRAS list of flavouring ingredients published in
and then chromatographically fractioned. Enantiomeric 1965 lists linalool and nine of its common esters. Linalool
active forms can be further resolved via fractional crystalli- has a chiral centre at C3 and therefore two stereoisomers are
sation. present: (R)-(-)-linalool and (S)-(+)-linalool. Plants produce
both enantiomeric forms. S-linalool is found, for example, as
(-)-Menthol (see Fig. (2) for structure) or 1-menthol is a major constituent of the essential oils of coriander
one of the most important flavouring chemicals and it is used (Coriandrum sativum L.) seed, palmarosa (Cymbopogon
extensively in pharmaceuticals, cosmetics, toothpastes, martinii var martinii (Roxb.) Wats), and sweet orange
chewing gum, and other toiletries as well as in cigarettes. (Citrus sinensis Osbeck) flowers. (R)-Linalool is present in
The main source of (-)-menthol is the oil of Mentha arvensis Ho oils from Cinnamomun camphora [48], rosewood oil,
that is frozen to obtain crystals of menthol which are then lavender (Lavandula officinalis Chaix), laurel (Laurus
separated by centrifugation. Since the demand for menthol nobilis), and sweet basil (Ocimum basilicum, family Lamia-
greatly exceeds the supply from natural sources, consi- ceae), among others. Each enantiomer possesses a distinct
derable effort has been devoted to the production of 1- scent: S-(+)-linalool is perceived as sweet, floral, petitgrain-
menthol by synthetic or semi-synthetic means from other like and the R-form as more woody and lavender-like.
more readily available raw materials [26-30]. Today, the major portion of linalool on the market is
Menthone (see Fig. (2) for structure) exists in two synthesized either from naturally occurring pinene [49] or
stereoisomeric forms, menthone and isomenthone, which, entirely synthetically through a series of complex reactions
having two asymmetric carbons, occur as pairs of enantio- [50].
mers. Menthone has a typical minty, peppermint-like odour
12 Recent Patents on Food, Nutrition & Agriculture, 2011, Vol. 3, No. 1 Caputi and Aprea

HO O

Menthol p-Menthone -Limonene Carvone

O
O
HO

Eucalyptol Linalool Nootkatone

O O
O O

-Damascenone -Ionone -Ionone Safranal

O
O
O
O
Geranyl isobutyrate trans-Geranyl acetate

Fig. (2). Chemical structures of some terpenoid flavouring compounds.

Eucalyptol (see Fig. (2) for structure), or 1,8-cineole, has Damascenone (see Fig. (2) for structure) is characterised
a pleasant camphor-like smell, spicy aroma and taste, and is by an intense “stewed apple” odour described as woody,
thus used in flavourings, fragrances, and cosmetics. Cineole sweet, fruity, earthy with green floral nuances. Its charac-
based eucalyptus oil is used as a flavouring at low levels teristic floral scent contributes to the odour character of
(0.002%) in various products, including baked goods, Bulgarian rose oil, tobacco, black tea, raspberry oil and
confectionery [51], meat products and beverages. Eucalyptol many other fruits. Biochemically, is a product of the -
with purity from 99.6 to 99.8 percent can be obtained in carotene degradation but it is industrially synthesised from
large quantities by fractional distillation of eucalyptus oil or pironenes [58]. Most recently a process for conducting an
can be synthetically prepared from -terpineole [52]. organic reaction in ionic liquids for the production of -
damascenone and -ionone has been patented [59].
Nootkatone (see Fig. (2) for structure) is used for
flavouring beverages and is the most important and - and -Ionone (see Fig. (2) for structures) are aroma
expensive aromatic compound of grapefruit. It has been compounds found in a variety of essential oils, including
isolated from grapefruit peel and juice. Nootkatone can be rose oil and are widely used by the flavour industry [60],
prepared from oxidation of valencene [53, 54] and recently hence their importance in foods. -ionone is also a raw
its production from ()--pinene has been proposed [55]. It material for the production of retinol. Similarly, to damas-
exits in two enantiomeric forms: (+) nootkatone is the cenone, the ionones derive from the degradation of carote-
natural produced form and has a strong grapefruit odour noids [61]. They are the main volatile compounds found in
while the synthetic ()-nootkatone shows a weak woody and the headspace of raspberry fruits [62, 63].
spicy flavour with no grapefruit character [56, 57].
The -ionone is sometimes used in conjunction with
anethole, liquorice or menthol to flavour sugar confectionery
Terpenoids as Natural Flavourings in Food Recent Patents on Food, Nutrition & Agriculture, 2011, Vol. 3, No. 1 13

(candy), and both are typically included in raspberry- acting on earlier biosynthetic steps. Recently, it has been
flavoured beverages [64]. As for other economically valued reported that increasing the level of IPP available through
chemicals, methods for their synthetic production have been engineering of hydroxymethylglutaryl-CoA reductase
patented too [59, 65, 66]. (HMGR), the rate-controlling enzyme of the MVA pathway,
Safranal (see Fig. (2) for structure) is the most abundant led to a significant increase of terpenes production in both
microorganisms [86] and plants [87]. Further, it has been
volatile component and the major flavour compound present
shown that the overexpression of small subunit of geranyl
in Saffron (Crocus sativus L.) [67] and its natural bio-
diphosphate synthase, the enzyme responsible for the
chemical origin is from carotenoids degradation. Saffron is
formation of the precursor of monoterpenes, led to signifi-
considered to be the most expensive spice in the world and
cant increase of such compounds [88]. Examples of host
nowadays its main use is as a foodstuff [67]. Safranal for
aroma or food additive is extracted from saffron [68] or organisms engineered with a complete heterologous pathway
that enhances the terpenoids production have also been
synthetically prepared [69]. Its odour is described as
reported [89].
"saffron, dried hay like".
C13-Norisoprenoids are compounds naturally present in
Geranyl esters (see Fig. (2) for structures) are essential
plants at very low concentrations deriving from the oxidative
oils widely used in food industry [70] and most of them have cleavage of carotenoids by the action of carotenoid cleavage
a hint of rose. Geranyl acetate is a liquid with a fruity rose
dioxygenase (CCD) enzymes. A recent invention [90]
odour reminiscent of pear added in small amounts to fruity
describes the engineering of microorganisms with plant
aromas. Geranyl isobutyrate also has a fruity rose odour and
CCDs to produce - and -ionone, theaspirone, -damas-
usually is used in combination with the acetate ester.
cenone, -damascone.
BIOTECHNOLOGICAL PRODUCTION Research has been also carried out on the identification
and exploitation of the enzymes responsible for further
In the last few years, metabolic pathway engineering in modifications of the terpene backbones, since they are
both plants and whole-cell systems (plant cell cultures and responsible for a greater structural diversity. In particular,
microorganisms) and the discovery of new enzymes have attention has been devoted to cytochrome P450 enzymes
received great attention for the production of commercially which can hydroxylate terpenes [91, 92], reductases [93] and
relevant terpenoids. Research in this field has been driven by to glycosyltransferases, enzymes responsible for the forma-
the fact that flavouring compounds produced from natural tion of monoterpenoid [94] and sesquiterpenoid glycocon-
raw materials by microbial or enzymatic methods can be jugates [95].
labelled as 'natural', thereby satisfying the consumer request
The metabolic engineering of both microorganisms and
of 'bio' or 'natural' products in the food sector. Furthermore,
plants for the biotechnological production of relevant terpe-
the biotechnological approach could also ensure a conti-
noids has seen, in the last decade, enormous advancements
nuous product supply through a well standardized process
in terms of yields of the products making this technology
with high productivity.
more attractive for industrial processes. It is worth
This strategy has been largely supported by the recent mentioning that in some cases the advancements have been
boost in genome sequencing projects which have provided so fast that, for instance, within about a year the yield of the
vast resources for gene discovery. In fact, to date, many sesquiterpenoid farnesol produced in the bacterium E. coli
patents have been filed reporting new genes involved in has been increased from 389 g/L [96] to 135.5 mg/L [97].
terpenoids biosynthesis, especially terpene synthases. The Metabolic engineering has also allowed the production in
interest in this class of enzymes arises from the fact that they good yields of other relevant prenyl alcohols, such as
are responsible for the wealth of terpene carbon skeletons nerolidol [98], geranylgeraniol [98], geraniol [99], and
found in nature. In addition, some terpene synthases are able cubebol [100, 101] in yeasts. Several attempts in advancing
to generate multiple products starting from the same plant systems as efficient terpenoids production platforms
substrate, hence producing a complex aroma. For instance, a have also been made. Although the first results were not very
sesquiterpene synthase has been recently discovered that encouraging, recent work report significant improvements of
produces a mixture of sesquiterpenes composed of -santa- product yields, suggesting that this approach also represents
lene, epi--santalene, cis--bergamotene, trans--bergamo- a valid alternative route for terpenoids production. For
tene, and endo--bergamotene [71]. Also, bifunctional enzy- instance, the expression of a heterologous limonene synthase
mes capable of efficient formation of both monoterpenes and in tobacco only led to the production of 40 ng/g of product in
sesquiterpenes depending on substrate availability have been the cytoplasm and 143 ng/g in the plastids [102]. However,
recently discovered [72]. A list of terpene synthases patented the work of Wu et al. [103] showed that by applying a more
in the last decade and their activities is given in Table 1 [71, sophisticated engineering strategy, in which carbon flux is
73-84]. For an up-to-date list of monoterpene and sesqui- redirected by targeting the cell compartment not normally
terpene synthases reported in literature we refer the reader to used for that class of isoprenoids, it is possible to signi-
a recent review [85]. However, the engineering of these ficantly increase the amount of product formed. In fact, the
genes in plants and whole-cell systems (both plant cells and co-expression of a limonene synthase with a geranyl
microorganisms) has revealed that in order to increase the diphosphate synthase targeted to the cytosol or to the plastid,
metabolic flux through the pathway and to obtain significant led to the production of 374 ng/g and 513 ng/g, respectively.
yields of products further pathway engineering is required. The same work also reported a 25000-fold increase in
In particular, it is necessary to remove possible metabolic sesquiterpene amorpha-4,11-diene synthesis using the same
bottle-necks and to provide additional flux of substrates by strategy.
14 Recent Patents on Food, Nutrition & Agriculture, 2011, Vol. 3, No. 1 Caputi and Aprea

Table 1. Recently Patented Mono- and Sesquiterpene Synthases

Patent no. Enzyme type Product(s) Ref:

US20100138954 Sesquiterpene synthase -Santalene, epi--santalene, cis--bergamotene, trans--bergamotene, endo-- [71]


bergamotene

US20100209969 Monoterpene synthase Geraniol [73]

US20090205060 Sesquiterpene synthase Patchoulol, -curcumene, germacrane-type sesquiterpenes [74]

US20100144893 Mono-, sesquiterpene synthase Linalool, nerolidol [75]

US20100216186 Sesquiterpene synthase Valencene [76]

US7273735 Sesquiterpene synthase Valencene, bicyclogermacrene, cubebol, -cadinene [77]

US20020038001 Sesquiterpene synthase Bisabolene, -selinene, -humulene [78]

US20030166204 Sesquiterpene synthase (E)--farnesene [79]

US6342380 Sesquiterpene synthase Germacrene [80]

US20030175861 Monoterpene synthases (-)-Camphene, (-)--phellandrene, terpinolene, (-)-limonene, (-)-pinene [81]

US20090313718 Sesquiterpene synthases Caryophyllene [82]

US20060137032 Sesquiterpene synthases -Farnesene [83]

US20060162008 Sesquiterpene synthase Germacrene-D, -cadinene, -cadinene, -muurolene, -elemene, -elemene, [84]
elemol, germacrene-B

The results published in this area are very encouraging used for extraction. Furthermore, it should be mentioned that
and have already attracted the attention of companies the engineering of plants to increase terpenoids production
specialising in flavours and fragrances production. In fact, could also be exploited to increase the nutritional value of
several patents reported in this paper concerning the food crops or to enhance the plant fitness itself.
biotechnological production of terpenoids have been filed by
industries which are also directly participating in several ACKNOWLEDGEMENTS
ongoing studies on the topic.
The authors thank Dr. Urska Vrhovsek (IASMA
Research and Innovation Centre, Food Quality and Nutrition
CURRENT AND FUTURE DEVELOPMENTS Area) for reviewing the manuscript. Lorenzo Caputi is
supported by the MetaQuality project, funded by the
The patents reviewed in this paper reveal that in order to
autonomous Province of Trento (Italy).
face the increasing demand of flavouring agents new
extraction and production methods are being developed.
Typically, current approaches involve extractions from plant CONFLICT OF INTEREST
sources and chemical synthesis. In the first case, the supply The authors have no conflict of interest.
of raw material, usually obtained through conventional
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