LACTONAS

Tetrahedron 84 (2021) 132001
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tetrahedron report 1226
Lactones: Classification, synthesis, biological activities, and industrial

applications
Suelen Karine Sartori a, Marisa Alves Nogueira Diaz b, Gaspar Diaz-Munoz ~ a, *
a
Department of Chemistry, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil
b
Department of Biochemistry and Molecular Biology, Federal University of Viçosa, Viçosa, Minas Gerais, 36570-900, Brazil
article info This review summarizes the current knowledge on lactones, a class of biologically
active natural products isolated from a wide range of living organisms. Butenolide,
Article history: 5,6-dihydropyran-2-one, and sesquiterpene lactones display an impressive variety
Received 10 September 2020 Received in revised form of bioactivities and are the most abundant in nature. This paper provides a
28 January 2021 compilation of ring construction strategies for the synthesis of small, medium, and
Accepted 3 February 2021 Available online 13 February 2021 macro lactones and discusses their biological activities and industrial,
pharmaceutical, and agrochemical applications.
Keywords:
Lactone family
Butenolide
5,6-Dihydropyran-2-one
Bioactivity
Macrolactone
© 2021 Elsevier Ltd. All rights reserved.

Contents
abstract
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............................. 2 2. Major classes

of lactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............................. 2 2.1. g-
Lactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................................................2 2.2. d-
Lactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................................................2 2.3. Medium-sized lactones . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .................................................3 2.4.
Phthalides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................................................4 2.5.
Coumarins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................................................4 2.6. Sesquiterpene lactones . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .................................................5 2.7. Spirolactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . .....................................................7 2.8.
Strigolactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .................................................7 2.9. Macrolactones . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .................................................8 3. Synthetic approaches for the construction of lactone
rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............................. 9 3.1. Lactonization of hydroxy
esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................................9 3.1.1. Lactonization in acidic medium . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .................................9 3.1.2. Lactonization in basic medium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3.2. Iodolactonization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3.3. Yamaguchi
lactonization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.4. Shiina
macrolactonization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 3.5.
BodeneKeck lactonization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 3.6.
CoreyeNicolaou macrolactonization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 3.7. Other
strategies for lactone formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3.7.1. HWE
olefination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 3.7.2. Ring-closing
metathesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
* Corresponding author.
E-mail address: [email protected] (G. Diaz-Munoz). ~
https://doi.org/10.1016/j.tet.2021.132001
0040-4020/© 2021 Elsevier Ltd. All rights reserved.
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001
3.7.3. Stille reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 3.7.4.

DielseAlder reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 4. Biological
activities of lactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 4.1.
Antimicrobial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 4.2.
Anti-inflammatory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 4.3.
Antitumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 4.4.
Leishmanicidal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 4.5.
Trypanocidal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 5.
Industrial applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
5.1. Pharmaceutical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
5.1.1. Antihypertensive drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 5.1.2.
Antibiotic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 5.1.3. Antifungal
drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 5.1.4. Antiparasitic drugs . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 5.1.5. Anticancer drugs . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 5.1.6. Dermatological
drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 5.2. Cosmetics and perfume
industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 5.3. Food
industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 5.4.
Agrochemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 6.
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Consent for publication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Declaration of competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
List of abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
37
1. Introduction dustrial applications of this remarkable family of organic compounds.
Natural products, or secondary metabolites, are key players in the 2. Major classes of lactones
discovery and development of novel bioactive substances [1,2].
Lactones are outstanding exponents of secondary metabolites 2.1. g-Lactones
because of their remarkable biological activities and chemical ar
chitectures. These compounds are produced by plants, bacteria, fungi,
g-Lactones are present in the structure of several natural products,
marine sponges, and other organisms [3,4].
such as the g-saturated butyrolactone and the a-b-un saturated
Lactones are defined by IUPAC as “cyclic esters of hydroxy car
butenolides. Butenolides exhibit fascinating biological activities (Fig. 3)
boxylic acids, containing a 1-oxacycloalkan-2-one structure, or analogs
[14]. 3-Methyl-2H-furo[2,3-c]pyran-2-one show potent herbicidal
having unsaturation or heteroatoms replacing one or more carbon
activity [15e17], flupyradifurone is an effective insecticide [18,19],
atoms of the ring.” [5] The smallest compounds of the class, a-, b-, g-,
rubrolide M and basidalin show anticancer properties [20,21], and 5-
d-, and u-lactones, contain 3-, 4-, 5-, 6-, and 7-membered rings, octylfuran-2(5H)-one exhibits antifouling activity [22].
respectively (Fig. 1) [6]. g- and d-Lactones are the most abundant in
Butenolides and butyrolactones are also known for their fragrance
nature because of the high stability of their lactone rings [7,8]. It is
and, thus, have great applicability in the food and perfume industries
estimated that more than 3000 g-lactones occur in nature [4]. a-
[4,23].
Lactones can only be obtained synthetically. Medium
sized lactones are 8- to 11-membered, and macrolactones contain
rings with 12 or more members [9e13]. 2.2. d-Lactones
Other variants of this family of compounds include aliphatic or a,b-
unsaturated lactones and lactones fused with aromatic systems (e.g., d-Lactones, or 5,6-dihydropyran-2-ones, have wide represen
coumarins, sesquiterpene lactones, spirolactones, and phthalide) (Fig. tativeness in nature (Fig. 4). Like g-lactones, d-lactones can be divided
2). into saturated and a-b-unsaturated lactones, the latter being the most
In this review, we focus on the major classes of lactones and frequent. The d-lactone moiety is common in several natural
address the main synthetic methods, biological activities, and in compounds with diverse biological activities [24e26], such as HIV
protease inhibition [27,28], apoptosis induc
Fig. 1. Structural representation of a-, b-, g-, d-, and u-lactones. tion (goniothalamin and rasfonin) [29,30], antileukemic 2

Fig. 2. Chemical structures of other types of lactones.
Fig. 3. Chemical structures of biologically active butenolides.
(dictyopyrone C) [29], antitumor (pironetin) [31,32], leishmanici dal, 3

trypanocidal, antifungal (argentilactone) [33], antibacterial, anti- okadai, found on the coast of Japan, and topsentolides from marine
inflammatory, and anticancer [7]. sponges of the genus Topsentia [10,34]. Seven topsentolides (A1, A2,
B1, B2, B3, C1, and C2) were found to have moderate cytotoxic activity
against human tumor cell lines. Antimycin dilactones are known for
2.3. Medium-sized lactones their antibiotic and antifungal properties and their ability to induce
cancer cell apoptosis [34].
Medium-sized lactones contain 8- to 11-membered rings. The most Decalactones, or nonanolides, are the best-known natural medium-
abundant in nature are the 10-membered decalactones [34]. Among sized lactones (Fig. 7) and show a variety of biological properties.
natural 8-membered lactones, we highlight octalactins A and B (Fig. Decarestrictin was isolated from the fermentation broth of Penicillium
5). These compounds were first isolated from acti nomycetes of the and stands out for its inhibitory effect on cholesterol biosynthesis
genus Streptomyces collected from corals of the Mexican coast. [10,35,36]. Herbarumins, isolated from the fungus Phoma herbarum,
Octalactins A and B have potential cytotoxic activity against melanoma showed phytotoxic activity against Amaranthus hypochondriacus,
and colon tumor cells [10,34]. Cephalosporolides and solandelactones inhibiting seed germination and plant growth. Diplodialide A, isolated
are other examples of naturally occurring 8- membered lactones (Fig. from Diplodia pinea, can inhibit the steroi dal enzyme hydroxylase.
5) [34]. Phoracantholides were isolated from metasternal gland secretion of
Oxylipins, halicholactone, neohalicholactone, and topsentolides are Phoracantha synonyma [35e37]. Phoracantholides I and J, because of
some representatives of 9-membered lactones (Fig. 6). Neo- and their simple structure, are used as synthetic models to obtain more
halicholactone were isolated from the marine sponge Halichondria complex representatives of this
Fig. 4. Chemical structures of some 5,6-dihydropyran-2-ones. d-Lactones not only have important biological activities but also are widely applied in the perfume and food industries for their
organoleptic properties.23.
Fig. 5. Chemical structures of lactones with 8-membered rings.
class [36].
Some 11-membered lactones of note are ferrulactone (ferru
b
lactone I), isolated from Cryptolestes ferrugineus; aspercyclids
(aspercyclid B); biphenyl lactones; and cyclic esters isolated from e
extracts of Aspergillus sp. and Daphniphyllum (crispatine), which act
as insect pheromones (Fig. 8) [35,36]. e
n
2.4. Phthalides
Phthalides, or 3H-isobenzofuran-1-ones, are important organic s

molecules produced by several plant genera of the family Apiaceae
t
[38e40]. These compounds also occur in Asteraceae, Acanthaceae,
Amaranthaceae, and Magnoliaceae [41]. Phthalides are bicyclic u
molecules formed by fusion of a g-lactone and a benzene ring [38e40].
d
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and numerous reports can be found in the literature on its diverse

h ethnobotanical applications and biological activities [39,40]. (S)-3- n-
Butylphthalide, for instance, is commercialized as an anticon vulsant
a medication for the treatment of cerebral ischemia, iso pestacin has
antifungal and antioxidant properties, fuscinarin exerts antiamnesia
s
effects, and ()-concentricolide has anti-HIV activity (Fig. 9) [38,42].
Phthalides also show antimicrobial, anti platelet, and analgesic
properties [43]. Coumarins (2H-chromen-2-ones) are plant and fungal second ary
metabolites of great relevance. These heterocyclic compounds contain
a benzene ring fused to a-pyrone [44,45]. They attract attention
2.5. Coumarins because of their anti-HIV [46], antitumor [46], anti Alzheimer,
antidepressant, antibiotic (armillarisin), anti
Fig. 6. Chemical structures of 9-membered lactones.
Fig. 7. Chemical structures of nonanolides.
inflammatory (scopoletin), and anticoagulant (warfarin and dicoumarol) 11), are produced by plants in response to stress and as protection
activities (Fig. 10) [44,45]. against predators such as fungi, bacteria, and insects [47].
Coumarins find wide application in the cosmetics, dye, and food Furanocoumarins are used to treat skin diseases [48].
industries and as luminescent materials [45]. Furanocoumarins,
compounds containing a furan ring fused to the coumarin skeleton and
occurring in either linear (psoralen) or angular (angelicin) forms (Fig.
5 isoprenoid units and a lactone function. Currently, there are more than
2.6. Sesquiterpene lactones 7 000 specimens identified in nature, making sesquiterpene lactones
the largest set of secondary metabolites. The compounds can be
Sesquiterpene lactones are another widely known group of found in plants of the families Lauraceae, Apiaceae, Aster aceae, and
lactones. Sesquiterpenoids (15 carbon atoms) are composed of Euphorbiaceae and are important constituents of
Fig. 8. Lactones with 11-membered rings.
Fig. 9. Chemical structures of phthalides with biological activities.
Fig. 10. Chemical structures of coumarins used as drugs.
essential oils [49e53]. antiplasmodial, antibacterial, insect repellent, molluscicidal,

Sesquiterpene lactones show a broad range of biological activ trypanocidal, healing, and hepatoprotective [43].
ities, including antimicrobial, anti-inflammatory, antifungal, anti tumor,
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l i
d s
a h
s m
e n
t i
a i
l d
. a
4 a
9 c
] t
r v
e i
p t
y of sesquiterpene lactones present in ethanolic extracts of Calea
pinnatifida, endemic to the Brazilian Cerrado and commonly known in
Brazil as cipo-cruz . The plant extracts are used in traditional medicine
to treat stomach pain, giardiasis, and amoebiasis [49].
6 Sesquiterpene lactones (Fig. 12) can inhibit the germination of
some plant seeds. Derivatives of a-santonin were phytotoxic to
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001 Fig. 11. Chemical structures of the furanocoumarins psoralen and angelicin.
Fig. 12. Chemical structure of a-santonin, helenalin, parthenolide, and artemisinin.
Cucumis sativus and Sorghum bicolor seeds [52]. Artemisinin, iso 7

lated from Artemisia annua by You-you et al. [54], shows potent Within this class, the greatest exponent is spironolactone (Fig. 14)
antimalarial activity. The discovery of artemisinin, in addition to that of because of its antagonism to aldosterone [60], a hormone of the
dihydroartemisinin, stemmed from the authors’ investiga tion of renineangiotensinealdosterone system associated with hy pertension,
Chinese folk medicine. Shortly after discovery, the com pound was cardiac hypertrophy, and cardiac and vascular fibrosis [61].
found to have antimalarial activity, with 100% inhibition of malaria in
rodents and monkeys and 95e100% inhibition in clinical patients. This
promising result represented a breakthrough in tropical medicine in the
20th century, saving millions of lives in southern China, Asia, Africa,
and South America. Because of this remarkable scientific contribution,
Professor You-you shared the Nobel Prize in medicine in 2015 [55,56]. 2.8. Strigolactones
There are several review articles [49e51,57] on sesquiterpene
lactones, evidence of the relevance and unique properties of this Strigolactones are phytohormones isolated from plants of the
group of compounds. genera Striga and Orobanche that act as activators of rhizosphere
signals. Strigolactones stimulate seed germination of parasitic plants
after host detection, regulate plant growth, inhibit sprouting, and
2.7. Spirolactones mediate underground chemical communication between plants and
neighboring organisms [62e65]. The most well-known natural
Naturally occurring spirolactones compose a large family of exponents have an ABC tricyclic core with g-lactone as one of the
structurally diverse compounds that display a wide array of bio logical rings and an exocyclic butenolide D-ring; this structure is found in 5-
activities, such as antibacterial (spiroindicumide A), anti fungal deoxystrigol (Fig. 15) [64].
(perrenniporide A), anti-inflammatory (abiespiroside A), antiparasitic Strigolactones can be applied as soil amendment to control weeds
(plumericin), antiviral (biyouyanagin B), and cytotoxic (yaoshanenolide [66], thereby reducing agricultural losses associated with weed
A) (Fig. 13) [58]. damage [67]. The compounds induce suicidal germination; that is, the
In addition to naturally occurring compounds, spirolactones signals emitted by the presence of isolated rhizosphere compounds or
comprise synthetic steroids known as steroid-17 a-spirolactones, 17a- synthetic counterparts induce parasitic seed germination without,
spirolactosteroids, or simply 17a-spirolactones [59]. however, the presence of a host, leading to weed death [65,66].
Fig. 13. Chemical structures of natural spirolactones.
Fig. 15. Chemical structure of 5-deoxystrigol.
Macrolactins are macrolides isolated from strains of Bacillus and

Fig. 14. Chemical structure of spironolactone. 8
Actinomadura. Currently, there are 19 macrolactins (AeS) reported in
the literature. Their biological activities range from antiviral to
2.9. Macrolactones antifungal. Macrolactin A shows potent activity against Herpes simplex
virus types 1 and 2 and can control HIV replication in humans.
Macrolactones or macrocyclic lactones are cyclic esters con taining Macrolactins T and B (Fig. 18) are capable of inhibiting the fungi
rings with 12 or more members. They can be classified as olides or Alternaria solani and Pyricularia oryzae and the bacterium
diolides (Fig. 16) [68].(Fig. 17). Staphylococcus aureus. The minimum inhibitory concentration (MIC)
Cucujolides are used by several animals for chemical commu values of macrolactin T against P. oryzae, A. solani, and S. aureus are
nication, acting as aggregation and sexual pheromones [11,69]. 0.8, 2.8, and 5.5 mg mL1, respectively [72,73].
Cucujolides containing 10- to 14-membered rings were identified in Swinholide A (Fig. 19) is a symmetrical dimer isolated from the
beetles of the genera Cryptolestes (Laemophloeidae) and Ory marine sponge Theonella swinhoei. Because of its ability to bind to
zaephilus (Silvanidae). Cucujolide X, (5Z,8Z,12R)-tetradeca-5,8- dien- actin, swinholide A exhibits potent antifungal activity and is highly
12-olide (Fig. 17), was identified as the attraction phero mone of cytotoxic to cancer cells. Actin is a globular protein and one of the
female Oryzaephilus surinamensis, a secondary pest of maize and rice three fundamental components of the cytoskeleton of eukaryotic
[69e71]. organisms [74e78].
Quinolidomicins are isolated from the fermentation broth of
Fig. 16. Schematic representation of macrolactones (n 12). Some of the most relevant representatives are cucujolides (11- to 14-membered) and macrolactins (24-membered) [11,12]bib12..
Fig. 17. Chemical structures of 13- and 24-membered lactones.

Fig. 18. Chemical structures of macrolactin T and B. Other prominent macrolides are swinholide A, a 44-membered macrolactone, and quinolidomycins, 60-membered macrolactones.68.
Micromonospora sp. JY16. The major representatives are quinoli 9

protocols, evidenced by the numerous examples, contributed greatly to
domicins A1, A2, and B1 (Fig. 20). Quinolidomycins A1 and B1 inhibit the
the advancement of research on the synthesis of lactones of
growth of various tumor cells, including drug-resistant cells [79].
pharmacological interest.
Motivated by the numerous examples of naturally occurring
lactones and their wide array of biological activities, synthetic organic
chemists have directed their attention to the construction of lactone 3.1. Lactonization of hydroxy esters
rings.
Lactonization of hydroxy esters is the simplest and most com mon
method of lactonization, used in both acidic and basic media [24,80].
3. Synthetic approaches for the construction of lactone rings
In this section, we briefly address various examples of asym metric 3.1.1. Lactonization in acidic medium
syntheses of important bioactive molecules with lactone rings varying The methods included in this category comprise any reaction that
in size and shape. The versatility of these synthetic generates a lactone when a hydroxy ester is treated in acidic medium
(Scheme 1) [24].
Scheme 1. General scheme for hydroxy ester lactonization under acid catalysis.
product is a 5,6-dihydropyran-2-one. (þ)-Dodoneine [22], for

example, is a d-lactone found in Tapinanthus dodoneinfolius, a
parasitic plant that feeds on the shea tree in Burkina Faso, West
Africa, and in Agelanthus dodoneifolius, a plant used in traditional
African medicine for the treatment of cardiovascular diseases. It has
significant biological activities, such as HIV protease inhibition,
apoptosis induction, antileukemic effect, and potent vasorelaxant
effect on pre-restricted rat aortic rings [81,82].
Among the various synthetic methods reported for this lactone,
we highlight that described by Allais and Ducrot [81]. The authors
used methyl 3-(4-hydroxyphenyl)-propanoate ester (1) as starting
material. The key step in the construction of the lactone ring was a
cascade sequence starting from 2 using 80% acetic acid solution for
deprotection of the 2,2-propylidene acetal group and, conse
quently, cyclization of the d-hydroxy ester Z formed in situ (Scheme
2). The possibility of obtaining the product of interest in a single
step motivated the authors to use this protocol. The presence of an
Fig. 19. Chemical structure of swinholide A. d-hydroxy acid is (Z)-a,b-unsaturated, the acid cyclization
a,b-unsaturated ester with Z stereochemistry allowed the forma tion of
the d-lactone ring after deprotection of the acetonide group in 2.
In some cases, lactonization may occur spontaneously. When the
Another example that uses acidic medium for the construction
Fig. 20. Chemical structures of quinolidomicins A1, B1, and A2. 10
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001 Scheme 2. Total synthesis of (þ)-dodoneine [81].
of the d-lactone ring is the protocol reported by Shen and collab potassium hydride in THF (Scheme 5) [88].
orators [83] for the synthesis of ()-pironetin. ()-Pironetin is an a,b- The synthesis of salicylihalamide A reported by Holloway et al. [90]
unsaturated d-lactone isolated from fermentation broths of is another example of the construction of a macrolactone ring in basic
Streptomyces. It inhibited leukemia tumor cell growth in mice at a dose medium. Salicylihalamide A, a 12-membered macrolactone containing
of 6.3 mg kg1 through intravenous injection. Furthermore, ()-pironetin is an enamide in its side chain, was isolated from marine sponges of the
the only natural compound capable of binding to a tubulin, thereby genus Haliclona, found in waters around Rottnest Island, off the coast
disrupting the polymerization dynamics of mi crotubules [84,85]. of Western Australia. The compound has anti tumor activity, being the
Shen et al. [83] initiated the synthesis of ()-pironetin from propionyl first representative of a new class of compounds that inhibit vacuolar
chloride (3). A sequence of 12 steps from acid chloride 3 allowed (Hþ) ATPase, a set of mammal specific enzymes [90] that perform
obtaining b-keto ester 4. Reduction of the b-keto ester 4 with NaBH4 maintenance functions in eukaryotic cells and are linked to diseases,
and ethanol, followed by treatment of the dihydroxy ester with p- such as osteoporosis and cancer [91].
toluenesulfonic acid (TsOH) under reflux, resulted in the hydrolysis of Holloway et al. [90] synthesized salicylihalamide A (Scheme 6)
tert-butyl ester, removal of the silyl ether group, and concomitant from 2-hydroxy-6-methylbenzoic acid (10) by performing Boeckmann-
lactonization and dehydration, generating ()-pironetin (Scheme 3). type macrolactonization of hydroxy dioxinone 11 with sodium hydride
Given its practicality and applicability, cyclization in acid medium from diluted in THF, thereby providing benzlactone 12 in 64% yield. This
b-keto ester 4 was used by the authors to obtain the product of 12-membered key intermediate contains the ster eocenters present in
interest. the product of interest [90,92].
The previous method has been used to obtain not only 5,6-
dihydropyran-2-ones but also macrolactones, such as oxacyclodo 3.2. Iodolactonization
decan-2-one or 11-undecanol (Scheme 4). Guillerm and Linstru melle
[86] reported the synthesis of 11-undecanol in five steps from methyl
Iodolactonization involves the formation of an iodonium ion and
pentanoate (5). Of note, cyclization of hydroxy acid 6 with TsOH under
intramolecular opening of the ring by a carboxylate group to afford a
reflux afforded lactone 7 in 74% yield. Catalytic hy drogenation of 7
lactone ring [93e95]. This cyclofunctionalization process has great
with PtO2 in ethyl acetate provided 11-undecanol in 85% yield. The applicability and preferably produces cis- g-lactone as a kinetic product
high lactonization efficiency, attributed to the rigidity of the (Z)-ene- of 5-exo-tet cyclization (Scheme 7) [93].
dyne structure, was the main reason why the authors opted for this The method was first reported in 1904 by J. Bougault for the
protocol, as it favored cyclization of 6 instead of intermolecular synthesis of lactones and, since then, it has been one of the most
esterification [86]. used tools for the construction of lactone rings [94].
Zhou and Snider [96] used iodolactonization in the synthesis of lactone
3.1.2. Lactonization in basic medium intermediates (15 and 16) of vibralactone (Scheme 8). Vibralactone is
Although lactonization of hydroxy esters or hydroxy acids in acidic a fused b-lactone commonly found in cultures of Basidiomycota
medium is more common, the reaction can also be per formed under (Borestereum vibrans). The compound was shown to inhibit pancreatic
basic conditions [87]. The synthesis of milbemycin b3 reported by lipase (half-maximal inhibitory concentration, IC50, of 0.4 mg mL1), a
Smith et al. [88] (Scheme 5) is an example of this method. property found in drugs used to treat obesity. In their synthesis
(þ)-Milbemycin b3 is a representative of the family of antipar asitic protocol, Zhou and Snider [96] used methyl 2- methoxybenzoate (13)
macrolactone spiroacetals. The compound was first isolated by as starting material (Scheme 8). Basic hy drolysis of 14 with KOH in
Mishima et al. [89] in 1975 from Streptomyces B-41-146 and found to MeOH at 60 C, followed by treatment with NaHCO3, I2, and KI in
possess antibiotic activity and potent agrochemical ac tivity against aqueous THF solution, afforded iodo lactones 15 and 16 in 63 and
larval forms of insects of the order Lepidoptera. Smith et al. [88] 32% yields, respectively. Some addi tional steps provided the
synthesized this macrolactone using 3-methyl-p-anisic acid (8) as conversion of these iodolactones to (±)-vibralactone. Majetich and
starting material. The 16-membered macrolide ring was obtained in Grove [96] used the same protocol in the first asymmetric total
76% yield by treatment of hydroxy ester 9 with synthesis of three abietane diterpe noids: ()-icetexone, (þ)-5-epi-
icetexone, and (þ)-19-
Scheme 3. Total synthesis of ()-pironetin [83]. 11
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001 Scheme 4. Synthesis of 11-undecanolide [86].
Scheme 5. Total synthesis of the macrolide (þ)-milbemycin b3 [88].
Scheme 6. Synthesis of salicylihalamide A [90].
deoxyicetexone (Fig. 21). 12
The authors started the synthesis of abietane diterpenoids from with an excess of tri-n-butyltin hydride, treatment with BBr3, and
carvacrol (17) (Scheme 9). Carvacrol (17) was converted to the al oxidation with ceric ammonium nitrate, afforded the lactones ()-
cohols 18-a and 18-b, then the diastereoisomers were separated by icetexone and (þ)-5-epi-icetexone, respectively. (þ)-19-
column chromatography, subjected to oxidation with DesseMartin Deoxicetexone, in turn, was obtained by subjecting epimeric alcohol
periodinane, and treated with NaClO2, generating the respective 18-a to a sequence of iodocyclization, dehalogenation, demethylation,
carboxylic acid derivatives. Iodolactonization of the acids provided oxidation of catechol to o-benzoquinone, and in situ isomerization to o-
iodine lactones 19-a and 19-b, respectively, which, after reduction quinone [97].
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001 Scheme 7. Kinetic and thermodynamic control of iodolactonization.
Scheme 8. Synthesis of (±)-vibralactone [96].

Fig. 21. Chemical structures of ()-icetexone, (þ)-5-epi-icetexone, and (þ)-19-deoxyicetexone.
13
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001 Scheme 9. Synthesis of the abietane diterpenoids icetexone, 5-epi-icetexone, and 19- deoxyicetexone [97].
3.3. Yamaguchi lactonization 14

to hydroxy acid 21 after 16 steps. Yamaguchi macrolactonization of
The Yamaguchi esterification reaction, named in honor of Masaru hydroxy acid 21 is used to afford macrolactone 22 in 64% yield.
Yamaguchi, one of its discoverers [98], is carried out in the presence Deacetylation of 22 with 6 N HCl solution produces xylarolide in 86%
of carboxylic acids and alcohols using 2,4,6- trichlorobenzoyl chloride yield [100].
as an activation reagent for carboxylic acids and a stoichiometric Vema et al. [102] applied Yamaguchi lactonization for the syn
amount of 4-dimethylaminopyridine (DMAP) (Scheme 10). When this thesis of (3R,5R)-5-hydroxy-de-O-methyl-lasiodiplodine. This lactone
protocol is used to obtain lac tones, it is called Yamaguchi was isolated from micellar extracts of the fungus Lasiodi plodia
lactonization [99]. theobromae IFO 31059 and exhibits antimicrobial and anti leukemic
This approach is mainly used to obtain macrolactones, in which activities [102e104].
case it is termed Yamaguchi macrolactonization. The reaction The authors used 1,3-dihydroxy-5-methylbenzoic acid (23) as
proceeds in two stages: (a) formation of a highly reactive anhydride starting material (Scheme 12). Application of the macro lactonization
between the carboxylic acid and the Yamaguchi reagent in the protocol to 24 provided macrolactone 25 in 64% yield. Simultaneous
presence of triethylamine and (b) esterification of the anhydride with demethylation and debenzylation of 25 by treatment with BBr 3
alcohol in the presence of DMAP, thus forming the ester of interest produced lasiodiplodin [102].
[99]. Below, we discuss synthetic routes to lactones and macrolides Snider and Zhou [105] used the Yamaguchi protocol for the total
that use Yamaguchi lactonization. synthesis of Sch 642305 (Scheme 13), isolated from cultures of
Xylarolide is a decanol isolated from the fungal strain Xylaria sp. Penicillium verrucosum. The lactone has antibacterial properties and
101, found in Gaoligong Mountains, southwest China. The lactone was inhibited HIV-1 Tat, a regulatory protein necessary for viral repli cation,
shown to have cytotoxic and antibacterial activities [100,101]. at an IC50 of 1 mmol L1 [105].
Xylarolide synthesis, first reported by Mopuri et al. [100] in 2019 Synthesis of Sch 642305 started with the conversion of oct-7- enal
(Scheme 11), starts from (E)-hex-2-en-1-ol (20), which is converted (26) to carboxylic acid 27 in 12 steps. Hydroxy acid 27 was subjected
to Yamaguchi macrolactonization, which generated macrolactone 28
in 66% yield. Deprotection of the dioxolane group with TsOH at 50 C,
transannular Michael reaction using NaH (1.2 equiv), epimerization of
C-6 with 1.5% TFA in CDCl 3 at 120 C, irradiation with a microwave
device, and TBAF desilylation afforded Sch 624305 in 1.6% overall
yield (17 steps) [105].
()-Colletallol is a 14-membered bis-macrolactone isolated from the
fermentation broth of Colletotrichum capsici. Its total synthesis was
reported by Kauloorkar and Kumar [106] in 2016, with the Yamaguchi
protocol as key esterification steps (Scheme 14) [106].
Synthesis of ()-colletallol started by conversion of (R)-29 and
Scheme 10. General representation of Yamaguchi lactonization.

Scheme 11. Synthesis of xylarolide [100].
Scheme 12. Synthesis of (3R,5R)-5-hydroxy-of-O-methyl-lasiodiplodin [102].
(S)-29 epoxides to acid 30 and hydroxy ester 31, respectively 15

[106e108]. Yamaguchi lactonization of acid 30 with ester 31 afforded acid. Another protocol was reported in 2002, in which 2-methyl-6-
ester 32 in 87% yield. Desilylation and ester hydrolysis of 32 with nitrobenzoic anhydride (MNBA) is used with triethylamine in the
presence of DMAP for ester formation [111] (Scheme 15). Here, we
(Bu3Sn)2O gave hydroxy acid 33. Yamaguchi lactonization of 33
discuss the synthesis of some natural lactones based on protocols
furnished macrolactone 34 in 82% yield. Desilylation of 34 with TBAF
developed by Shiina.
in methanol under reflux allowed obtaining ()-(6R,11R,14S)-colletallol
in 22% overall yield (11 steps) [106]. ()-Cephalosporolide D (Fig. 5), a metabolite of the fungus
Cephalosporium aphidicola, exhibits potent cytotoxic activity against
tumor cell lines. Its synthesis was first carried out by Shiina et al. [112]
3.4. Shiina macrolactonization
starting from acetaldehyde (35) (Scheme 16). The key step was the
lactonization of hydroxy acid 36, obtained from 35. Activation of 36
In addition to Yamaguchi, Isama Shiina developed protocols for the with TFBA and esterification of the resulting mixed anhydride with
lactonization of hydroxy acids based on the activation of the carboxylic alcohol afforded lactone 37 in 77% yield. Removal of the benzyl group
acid function using anhydrides, which, after reaction with alcohols, led to ()-cephalosporolide D in 73% yield.
leads to the formation of the respective ester [109]. The first protocol
Another key macrolactonization procedure that uses the Shiina
was reported in 1994 and consisted of the use of 4-
protocol was developed for the synthesis of erythro-aleuritic acid
(trifluoromethyl)benzoic anhydride (TFBA) and a Lewis [110]
lactone (Scheme 17). The authors treated hydroxy acid 39 with
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001 Scheme 13. Synthesis of the macrolactone (þ)-Sch 642305 [105].
Scheme 14. Synthesis of ()-(6R,11R,14S)-colletallol [106e108].

anhydride MNBA in the presence of DMAP to form lactone 40 in 90% 16
yield. The Yamaguchi protocol was also used, whereby lactone 40 these reagents did not promote lactonization. However, when amine
was obtained in only 52% yield [111]. hydrochloride salts were added, the reaction proceeded efficiently. It
was found that amine salts act as mediators in the proton transfer
processes of activated species, constituting a crucial step in
3.5. BodeneKeck lactonization
lactonization. The best results were obtained by using 4- (N,N-
dimethylamino)pyridine hydrochloride (DMAP$HCl) as addi tive. The
Dicyclohexylcarbodiimide (DCC) was used for the first time by
use of DCC, DMAP, and DMAP$HCl in this type of reaction became
Steglich et al. [113] in 1978 as a coupling reagent in esterification
known as BodeneKeck macrolactonization [92,114].
reactions of carboxylic acids in the presence of a catalytic amount of
Keck et al. [115] used this method in the synthesis of ()-colletol
DMAP. This protocol became known as Steglich esterification and is
(Scheme 18), a macrocyclic bislactone isolated from the fungus C.
one of the most used methods in bimolecular esterification re actions
capsici. The authors used BodeneKeck macrolactonization for
[114]. construction of the lactone ring. Hydroxy acid 42, obtained in 14 steps
In 1985, Boden and Keck [114] studied the use of DCC and DMAP from b-keto ester 41, was treated with DCC, DMAP, and DMAP$HCl
in macrolactonization reactions. They observed that the use of
and subjected to acid treatment with Dowex-Hþ resin to
Scheme 15. Lactonization protocols developed by Shiina [109e111].
Scheme 16. Synthesis of ()-cephalosporolide D [112].
Scheme 17. Synthesis of erythro-aleuritic acid lactone [111].

Scheme 18. Synthesis of ()-colletol [115].
remove the TBS group, generating ()-colletol in 71% yield (2 steps). 17
The synthesis of ()-cytovaricin, carried out by Evans et al. [116], is method. ()-Cytovaricin is a natural 22-membered macrolactone with
another example of the relevance of this macrolactonization potent antibiotic activity isolated from cultures of Strepto myces
diastatochromogenes. Application of BodeneKeck macro lactonization
(Scheme 19) afforded macrolactone 45, an advanced
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001 Scheme 19. Total synthesis of ()-cytovaricin [116].
cytovaricin intermediate, from hydroxy acid 44, in 92% yield. In a electrostatically driven lactonization product as well as 2- pyridinatione
preliminary attempt to synthesize ()-cytovaricin, the au thors applied and triphenylphosphine oxide as by-products (Scheme 21) [92].
HornereWadswortheEmmons (HWE) olefination of seco-aldehyde 46 Hansen and Stenstrøm [118] used this protocol in the first total
to construct the 22-membered macrolactone ring (45); however, 45 synthesis of ()-aplyolide A, a 16-membered macrolactone isolated from
was obtained in only 35% yield (Scheme 20). This meager result the skin of the sea hare (or sea slug) Aplysia depilans occurring in the
motivated the authors to develop a new method for obtaining Mediterranean Sea. The natural product belongs to the group of
macrolactone 45 in higher yield, as shown in Scheme 19 [116]. hydroxy fatty acid lactones isolated from marine organisms and acts as
a defensive and ichthyotoxic allomone. Starting from methyl 4-
3.6. CoreyeNicolaou macrolactonization pentynoate (47), the authors synthesized ()-aplyolide A using the
CoreyeNicolaou protocol as a key step for the construction of the
Macrolactonization using thioesters is a useful strategy for the macrolactone ring, by which hydroxy acid 48 was converted into the
formation of macrolactones, described by Corey and Nicolaou [117] in final product in 78% yield (Scheme 22).
The same protocol was used by Xie et al. [119] to obtain bata
1974. In this method, hydroxy acid is treated with 2,2 0-dipyridyl
toside L, a resin glycoside isolated from tubers of Ipomoea batatas (L.)
disulfide (PyS)2 in the presence of triphenylphosphine (PPh3), initially Lam. (Convolvulaceae), or sweet potato, as it is commonly known.
forming a 2-pyridine thioester of carboxylic acid through Mukaiyama The molecule has significant cytotoxic activity against laryngeal
oxidation-reduction via condensation of (PyS)2 and PPh3. Internal carcinoma cells (HEp-2), with a median effective dose (ED 50) of 3.5
proton transfer, promoted by heating, generates a highly reactive
mg mL1. Its synthesis was performed by using methyl 11(S)-
intermediate, in which both carbonyl and hydroxyl groups are
activated, which leads to the formation of the jalapinolate (49) as starting material to give hydroxy acid 50,
Scheme 20. Attempt to obtain intermediate 45 from seco-aldehyde 46 using HornereWadswortheEmmons olefination [116]. 18
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001 Scheme 21. CoreyeNicolaou lactonization [117].
Scheme 22. Synthesis of ()-aplyolide A [118].
which was needed for the construction of the 18-membered mac 3.7. Other strategies for lactone formation
rolactone ring by treatment with (PyS)2 and PPh3 in toluene under
reflux for 5 days, providing macrolactone 51 in 88% yield (Scheme 23). Using traditional approaches to lactonization may not always
Another resin glycoside obtained using this protocol is tricolorin A, a provide the expected results. In some cases, the formation of the
19-membered macrolactone isolated from Ipomoea tricolor Cav. lactone CeO bond may be inefficient or might not occur at all, despite
(Convolvulaceae) with cytotoxic activity against human brain cancer the application of a wide range of synthetic approaches (Fig. 22).
cells (ED50 ¼ 2.2 mg mL1). Its synthesis was also performed using When faced with such a problem, chemists need to rely on the use of
compound 49 as starting material [120]. After preparing dihydroxy acid novel or alternative lactonization strategies, one of which is the
52, Sun et al. [120] applied the CoreyeNicolaou macrolactonization construction of C]C bonds.
method to obtain lactones 53 and 54 in 14 and 74% yield, respectively. Here, we will examine some methods of construction of C]C bonds
The preferential formation of isomer 54 was justified by the kinetic that can be applied to the formation of lactone rings.
control of the reaction, given that acylation occurs, preferably, at the
least sterically hindered hy droxyl (Scheme 24). This selectivity in the
lactonization step was
the key to choosing the macrolactonization method.
Scheme 23. Synthesis of batatoside L [119]. 19
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001 Scheme 24. Total synthesis of tricolorin A [120].
Fig. 22. Examples of failed and successful lactonization protocols involving the formation of a C]C bond [107,121,122]. RCM, ring-closing metathesis.
3.7.1. HWE olefination 20

The HWE reaction is an interesting strategy to obtain lactone rings. carbanions of alkyl diphenylphosphine oxides. The protocol was
In 1958, L. Horner described, for the first time, a method for the refined by W. Emmons and W. Wadsworth and today bears the names
preparation of alkenes from aldehydes and ketones using of the three scientists in honor of their great contributions [123].
An important application of the HWE reaction to obtain natural Olefin metathesis is a powerful tool for the formation of new C]
macrolides is the synthesis of palmerolide A developed by Nicolaou et C bonds, generating cyclic systems through intermolecular or
al. [124] Palmerolide A is a natural marine compound isolated from the intramolecular reactions. This synthetic approach, which involves the
circumpolar tunicate Synoicum adareanum, found on the Anvers rearrangement of unsaturated carbon-carbon bonds of the acyclic
Island in the Antarctic peninsula. It was discovered by the Baker group precursor in the presence of an appropriate transition metal catalyst,
in 2006 and was shown to exert potent cytotoxic ef fects against has been widely used in the construction of medium-sized ring
UACC-62 melanoma cancer cells (median lethal dose, LC 50, of 18 systems [127,128].
nmol L1). It also shows moderate activity against HCC 2998 colon The first documented application of metathesis for the synthesis of
cancer cells (LC50 ¼ 6.5 mmol L1) and RXF 393 kidney cancer cells lactones took place in 1980, when chemist Didier Villemin syn
(LC50 ¼ 6.5 mmol L1) [124]. thesized exaltolides 62 and 63 using tungsten and tin salts as cat
The synthesis of palmerolide A involved the use of acyl oxazo alysts (Scheme 28) [127e129].
lidinone (55) as starting material to obtain aldehyde 56, which contains Subsequently, Jiro Tsuji applied a metathetic approach to syn
a phosphonoacetate group in one of its side chains (Scheme 25). thesize a 19-membered macrolactone (65), also using a tungsten
HWE olefination of aldehyde 56 using N,N-diisopro pylethylamine in catalyst (Scheme 29) [128,130].
the presence of LiCl afforded macrolactone 57 in 73% yield. The The applicability of metathesis reactions was improved by Richard
construction of the 20-membered lactone ring was one of the key R. Schrock and Robert H. Grubbs through the development of new
steps in this strategy. In addition to the HWE reac tion, the authors catalysts for the formation of metal-carbene species. Schrock was the
also tested the use of the Stille protocol for for mation of the lactone first to propose a molybdenum catalyst, known as the Schrock catalyst
ring from compound 58; in this case, macrolactone 57 was obtained in (Fig. 23), for use in reactions with electron deficient and/or highly
45% yield (Scheme 26) [124]. substituted olefins. However, this catalyst is unstable in the presence
An interesting application of HWE olefination is seen in the total of oxygen and moisture. Grubbs developed stable ruthenium catalysts
synthesis of the oxopolyene ()-marinisporolide C, reported by Dias and commonly referred to as first- and second-generation Grubbs catalysts
de Lucca Jr [125]. This macrolide contains a 34-membered lactone (Fig. 23) [127,128,131,132].
ring and 11 stereogenic centers. ()-Marinisporolide C was isolated Metathesis reactions became a common laboratory procedure after
from cultures of the marine actinomycete Marinispora [125,126]. The commercialization of the first-generation Grubbs catalyst (Grubbs-I),
first synthesis started from (R)-pent-4-en-2-ol (59) (Scheme 27). A which was soon followed by commercial availability of the more
sequence of 21 steps converted alcohol 59 to phosphonate 60 with a reactive second-generation catalyst (Grubbs-II). Olefin metathesis was
mean yield of 83%. HWE olefination of 60 allowed the construction of studied simultaneously by Schrock, Grubbs, and Yves Chauvin, who,
the lactone ring with a C]C bond and E-geometry. Finally, deprotection for their great contribution to organic synthe sis, were awarded the
of hydroxyl groups provided the product of interest in 1.15% overall Nobel Prize in Chemistry in 2005 [127,128,131,132].
yield [125]. The reaction begins with the formation of a metal-carbene complex
(Scheme 30). The first alkene undergoes a [2 þ 2] cyclo addition with
the metal-carbene complex, forming a
3.7.2. Ring-closing metathesis
Scheme 25. Total synthesis of palmerolide A [124]. 21
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001 Scheme 26. Preparation of intermediate 57 using Stille reaction [124].
Scheme 27. Total synthesis of ()-marinisporolide C [125].
Scheme 28. Synthesis of exaltolides 62 and 63 [129].
metallocyclobutane intermediate, which, after rearrangement, re u

leases an ethylene molecule. This process is repeated with the second
alkene, generating the cyclization product [127,133]. t
Vaithegi and Prasad [134] applied this approach to the first total
synthesis of cryptopyranmoscatone B2, a d-lactone isolated from fruits h
of Cryptocarya moschata, a tree found in the Brazilian Cerrado [134].
o
h i
e n
a t
i -
a d
t e
e o
d x
t -
D
h
-
e
r
i
s
b
y
o
n
s
t
e
h
e
(
s
6
i
6
s
)
2
f
2
r (Scheme 31). Ring-closing metathesis using Grubbs-I (68) from diene

67 produced d-lactone 69 in 60% yield. Acetal deprotection using HCl
o afforded the natural product cryptopyranmoscatone B2 in 74% yield
[134].
m Metathesis can also be used to obtain larger rings, as evidenced in
the synthesis of patulolide A, performed by Subhashini et al. [135] in
2017. Patulolide A is a 12-membered macrolactone isolated by
Yamada and collaborators from cultures of Penicillium urticae
2
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001 Scheme 29. Synthesis of macrolactone 65 [128,130].
Fig. 23. Chemical structures of Schrock and Grubbs catalysts.
Scheme 30. Catalytic cycle of the ring-closing metathesis reaction [127,133].
mutant S11R59. It has antimicrobial, antibacterial, antifungal, and anti- 23

inflammatory activities, in addition to inhibiting the produc tion of 3.7.3. Stille reaction
immunoglobulin E and inducing the release of histamine from human The Stille reaction is one of the most common, efficient, and
leukocytes more efficiently than the degranulation inhibitor theophylline selective cross-coupling reactions for the construction of carbon
[135]. carbon bonds. It was reported by J. K. Stille and D. Milstein in 1978
The total synthesis of patulolide A used oct-7-enol (70) as starting and is based on the cross-coupling of organotin compounds with
material (Scheme 32). Ring-closing metathesis of diene 71 catalyzed organic electrophiles (organic halides, triflates, or acid chlo ride) in the
by Grubbs-II (72) provided macrolactone 73 in 69% yield. presence of catalytic amounts of BnPdCl(PPh 3)2 and HMPA.
Desulfurization of 73 using CaCO3 in the presence of molecular iodine Subsequently, several Pd catalysts were developed by Negishi,
Sonogashira, Suzuki, among others, and applied to the formation of
and THF/H2O (4:1) at 0 C concluded the synthesis of patulolide A in
new carbon-carbon bonds [136,137].
71% yield [135].
After developing the synthetic method, Stille conducted thor ough
studies to establish the reaction mechanism. The catalytic
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001 Scheme 31. First total synthesis of cryptopyranmoscatone B2 [134].
Scheme 32. Synthesis of patulolide A [135].

cycle is illustrated in Scheme 33. First, Pd(II) is converted to the active 24
Pd(0) species, known as the Stille pre-catalyst. Then, an oxidative stereogenic centers, and a 31-membered macrolide ring. This
addition reaction occurs in which Pd(0) reacts with the alkyl halide to compound exhibited antifungal and cytotoxic activity against rat
form a Pd(II) complex. The complex reacts with an organotin molecule fibroblasts [136,139]. The first synthesis of chivosazole F was pub
by transmetalation, whereby the halide atom is exchanged for an alkyl lished by Broadmann et al. [139] in 2010. Williams and colleagues
group, forming a dialkyl Pd(II) complex. Finally, the alkyl groups are [139] recently reported the synthesis of the macrolide in 20 steps and
coupled by reductive elimination, and the active Pd(0) species is 2.5% overall yield (Scheme 34).
regenerated, restarting the catalytic cycle [137,138]. The authors used bromodienal (74) [140], (R)-3-hydroxybutanal
Several researchers around the world have used and continue to (75), (S)-1-hydroxy-2-methylpentan-3-one (76) [141], and (Z)-3-
use Stille coupling to synthesize organic compounds. Chivosazole F, a bromoacrylaldehyde (77) [142] as starting materials, which were
polyene macrolide isolated from cultures of the bacterium Sor angium transformed into iodide 78, phosphonate 79, and organotin 80,
cellulosum (Myxococcales), contains an oxazole portion, 10 respectively. These compounds were subjected to Stille cross
coupling, employing copper(I) and Pd catalyst (Pd(PPh3)4) for the
formation of the C]C bonds in polyene phosphonate 81 with
natural products (e.g., myrocin C) (Fig. 26).

Chackalamannil and Davies [149] employed the intermolecular
DielseAlder reaction to build the g-lactone unit of himandravine, a
tetracyclic compound isolated from the bark of Galbulimima bac
cata, a rare tree found in the Australian rainforest [149]. Himan
dravine has attracted the attention of researchers for its
antimuscarinic activity and promising potential in the control of
tremor and bladder function in patients with Parkinson’s disease
[150].
The synthesis of himandravine was initiated from (S)-2-methyl
N-Boc-piperidine (93), which was converted to diene 94 in six
steps. Heating tetra-ene 94e186 C in the presence of TEMPO and
toluene promoted the formation of 95 (Scheme 37). This reaction
step proceeded stereoselectively because of the preferential for
mation of conformer 94A, as the interaction of the R group with the
methyl in C3 is minimized in this conformation (Fig. 27). Subse
quent steps provided himandravine [149].
Scheme 33. Catalytic cycle of the Stille reaction [137,138]. reaction steps. Intramolecular DielseAlder followed by a retro-
DielseAlder reaction of 90 in the presence of BHT under reflux
generated adduct 91 in 65% yield. Interconversion of the bromide
controlled stereochemistry. Then, a StilleGennari olefination be tween groups of 91 into pinacolboryl groups, followed by oxidation of the
phosphonate 81 and aldehyde 82 in the presence of NaH, followed by
respective boranes with H2O2 and selective methylation of the hydroxyl
oxidation with MnO2, furnished the corresponding oxazole derivative at C-14, generated ()-neocosmosin A in 17% overall yield (8 steps)
(83) in 26% yield. Aldehyde 83 was converted to iodide 84 by [148].
StorkeZhao olefination using NaHMDS and the salt (PPh3CH2I)þI. The This method also finds application in the synthesis of tricyclic
iodide was subjected to a second Stille reaction for the formation of a lactones, such as 92, which contains a structural skeleton found in
macrolide ring containing a new CeC bond without disruption of the
olefinic bonds (85). Finally, acetal deprotection and desilylation of
macrolactone 85 by HF in the presence of pyridine enabled the total
synthesis of chivosazole F [136,140].
Chen et al. [143] used the Stille protocol to obtain macrolactone
ZJ-101 (86), a synthetic analog of the potent anticancer macro lactone
superstolide A (Fig. 24).
The synthesis of 86 was performed from (E)-penta-2,4-dien-1-ol
(87), which was converted to stanane 88 after 22 reaction steps
(Scheme 35). Stanane 88 was subjected to the Stille coupling re
action to obtain 86 in 88% yield. This macrolactone is 7 times more
potent in suppressing HT-29 tumor cell proliferation (IC50 ¼ 7.4 nmol
L1) than superstolide A (IC50 ¼ 64 nmol L1) [142].
3.7.4. DielseAlder reaction

The DielseAlder reaction is a [4 þ 2] cycloaddition of a conju gated
diene (4p electrons) with a dienophile (2p electrons). Conceived by
Otto Diels and Kurt Alder in 1928, it is still one of the most powerful
tools in organic synthesis [144e147].
The DielseAlder protocol has been widely applied for the syn thesis
of lactones. One example is found in the synthetic route to ()-
neocosmosin A (Fig. 25), a polyketide macrolide containing an 18-
membered ring. The natural product was isolated from the fungus
Neocosmospora sp. (UM-031509) together with neo cosmosins B and
C (Fig. 25) [148].
The total synthesis of neocosmosin A was reported by Lee and
Cho [148] in 2016 using 3,5-dibromo-2-pyrone (89) as starting material
(Scheme 36). Dibromide 89 was converted to ketone 90 after four
25 glandins [157]. These combined effects are of great relevance
4. Biological activities of lactones because prostaglandins are inflammatory mediators [156].
Helenalin (Fig. 12) is another outstanding anti-inflammatory
4.1. Antimicrobial compound. It is a bifunctional sesquiterpene lactone containing an a,b-
unsaturated endocyclic ketone and an a-methylene-g lactone ring cis-
Antimicrobial agents are defined as natural or synthetic sub fused to a carbocyclic skeleton. These chemical functions are
stances capable of inhibiting the growth or leading to the death of alkylating centers that can act as Michael acceptors in reactions with
microorganisms such as bacteria, fungi, and algae [151]. nucleophilic agents, such as cysteine thiol groups in enzymes.
Within the lactone family, the most powerful antimicrobial agents Through this mechanism, helenalin inhibits the biosyn thesis of
for plants and animals are sesquiterpenes. They act by dis rupting the leukotrienes, which are important mediators of inflam matory
cell wall of invasive fungi and bacteria [50]. Some ex amples of processes [161].
antimicrobial sesquiterpene lactones are cnicin, onopordopicrin,
neoambrosin, damsinic acid, damsin, ambrosin, and hymenin (Fig. 28) 4.3. Antitumor
[152].(Fig. 29).
Antitumor agents are chemical substances that act in the pre
4.2. Anti-inflammatory vention or inhibition of the formation or growth of cancer cells,
generally promoting the death of abnormal cells that undergo
Inflammation is a part of the immune system’s response to cuts, accelerated division [162].
burns, and other wounds or to the presence of harmful organisms 7-Amino-4-methyl-2H-chromen-2-one, an amino coumarin (Fig.
such as viruses and bacteria [155]. Abnormal or sustained inflam 31), has significant cancer cell inhibitory activity; its mecha nism of
matory responses can result in autoimmune disorders, neurode action involves inhibition of human carbonic anhydrase isozyme II
generative diseases, and cancer [156]. [162].
Coumarins (Fig. 30) have been shown to decrease tissue Neo-tanshilactone and its analog 6-ethyl-11H-benzo[h]furo [3,2-
inflammation and edema and inhibit the biosynthesis of prosta c]chromen-11-one (Fig. 32) demonstrated in vitro antitumor
Scheme 34. Synthesis of chivosazole F [136,140e142].
26
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001 Fig. 24. Chemical structures of macrolactones ZJ-101 (86) and superstolide A.
Scheme 35. Synthesis of macrolactone 86 [143].
activity against human brain cancer cells. The referred analog, mainly brain cancer and leukemia [164].
containing an ethyl group at C-4, proved to be efficient against MCF-7
human breast adenocarcinoma cells and showed high selectivity
toward breast cancer cells [163]. 4.4. Leishmanicidal
The antitumor sesquiterpene lactones costunolide and dehy
drocostus (Fig. 33) have been used for the treatment of cancer, Although it is distributed worldwide, leishmaniasis, a disease
caused by protozoa of the genus Leishmania, is a neglected
Fig. 25. Chemical structure of neocosmosins A, B, and C. 27

Scheme 36. Total synthesis of ()-neocosmosin A [148].
Fig. 27. Representation of the conformational equilibrium of 94A and 94B in the
Fig. 26. Chemical structures of lactones 92 and myrocin C. DielseAlder reaction [149].
infectious disease. It is transmitted to human and non-human an imals L. amazonensis (ED50 ¼ 51.5 mmol L1) [166]. A study by Waechter et
through the bite of insects of the sandfly subfamily (family al. [167] compared the effects of argentilactone and a reference drug
Psychodidae), and, according to clinical manifestations, can be (N-methylglucamine antimoniate) on BALB/c mice infected with L.
classified as cutaneous or visceral leishmaniasis [49]. amazonensis. At four weeks after protozoan inoculation, the mice were
One of the drugs used to treat the disease is amphotericin B (Fig. treated for 14 days with argentilactone (25 mg kg 1 daily) orally or
34), an antifungal macrolactone indicated mainly in cases of American subcutaneously or with the antimonate drug by subcutaneous
mucocutaneous leishmaniasis [49,165]. injections (100 mg kg1 daily). Even at a lower dose, argentilactone
Argentilactone (Fig. 4) showed in vitro leishmanicidal activity showed the same efficacy as the reference drug, reducing the parasitic
against Leishmania panamensis (ED50 ¼ 51.5 mmol L1) and load in the lesion by 96% and in the spleen by
Scheme 37. Synthesis of himandravine [149]. 28
Fig. 28. Chemical structures of sesquiterpene lactones with antimicrobial activities. b-Lactones and bicyclic lactones also possess antimicrobial activity.[153, 154].
Fig. 29. Chemical structures of b-lactone F-244 and bicyclic lactones with antimicrobial activity.
Fig. 30. Chemical structures of chromen-2H-one and umbelliferone. (R)-Goniothala

min (Fig. 4) shows important anti-inflammatory activity. This natural styrene d-lactone
isolated from plants of the genus Goniothalamus exerted apoptosis-related anti
proliferative activity against cancer cell lines as well as antimicrobial, antinociceptive, larvicidal, 29
and phytoinhibitory effects.[158e160]. Fig. 31. Chemical structure of 7-amino-4-methyl-2H-chromen-2-one.
50% [166,167]. Of note, argentilactone also possesses antifungal 4.5. Trypanocidal

activity [168].
Passifloricin A, found in Passiflora foetida, is a leishmanicidal 5,6- Chagas disease is caused by the flagellated protozoan Trypano
dihydropyran-2-one (Fig. 35). It is highly effective against L. soma cruzi and transmitted to humans by insects of the genus Tri
panamensis, with a half-maximal effective concentration (EC50) of 0.36 atoma, mainly by the species T. infestans (Fig. 36), commonly known
mmol L1 and an LC50 of 2.3 mmol L1 [166]. as barber bug in its native Latin America [169,170].
Chagas disease is a neglected tropical disease. According to data
from the World Health Organization (WHO), it affects about 6 million
people and causes 10,000 deaths per year worldwide [169].
Fig. 36. Illustration of the protozoan Trypanosoma cruzi and its vector Triatoma infes
tans. Sources: Biomedicine Standards [171] and the Federal University of Minas Gerais
[172], respectively.
Fig. 32. Chemical structures of neo-tanshilactone and its analog.
Sepúlveda-Robles et al. [169] conducted a comparative study

between benznidazole, nifurtimox, and the sesquiterpene lactones
ambrosin, incomptin B, and glaucolide E (Fig. 38), isolated from
Parthenium hysterophorus, Decachaeta incompta, and Vernonia lia
troides, respectively, against T. cruzi epimastigotes.
Trypanocidal activity was evaluated against six T. cruzi strains:
Queretaro (TBAR/MX/0000/Quer etaro) (TcI), Ninoa (MHOM/MX/
1994/Ninoa) (TcI), JJO (MHOM/MX/0000/JJO) (TcI), Mor3 (MHOM/
MX/1995/Mor003) (TcI), and Ver6 (MDID/MX/1991/Ver006) (TcVI),
which were isolated from humans, marsupials, or insects from
Mexico; and Silvio (TcI) and CL Brener (TcVI), isolated from humans
and insect vectors from Brazil [169]. Ambrosin and incomptin E
were the most promising among the evaluated lactones, showing
Fig. 33. Chemical structures of costunolide and dehydrocostus lactone. Fig. 35. Chemical structure of passifloricin A.
Although the host is native to Latin America, the disease has spread to
countries in North America, Europe, and Oceania [169,170].
Benznidazole and nifurtimox are some of the most commonly used
commercial drugs for the treatment of Chagas disease (Fig. 37). The
drugs need to be administered in the acute phase, as they are
ineffective in the chronic phase [169,170].
Fig. 34. Chemical structure of amphotericin B.

30 5. Industrial applications
IC50 values lower than those of commercial drugs against all T. cruzi
strains. Overall, the lowest IC50 values were observed against CL Given their diverse biological activities, lactones are used in the
BrenerTcIV and Ver6TcIV. IC50 values ranged from 18.73 to 24.31 mmol prevention and treatment of diseases. This class of compounds also
L1 for ambrosin and from 65.46 to 66.36 mmol L1 for incomptin E, finds application as aroma compounds in the cosmetics and perfume
whereas the IC50 of commercial drugs was always greater than 400 industries [4,23], as flavorings in the food industry [23], and as
mmol L1. Glaucolide E performed satisfactorily only against Queretaro agrochemicals in crop production [35e37,52,66].
TcI
, CL BrenerTcIV, and Ver6TcIV [169].
The 5,6-dihydropyran-2-ones cryptofolione, (S)-goniothalamin, and 5.1. Pharmaceutical applications
(S)-argentilactone (Fig. 39) also show trypanocidal activity [166].
Cryptofolione, isolated from fruits of Cryptocarya alba, reduced the 5.1.1. Antihypertensive drugs
number of T. cruzi trypomastigotes by 77% at a concentration of 250 Hypertension is a condition characterized by an abnormal in
mg mL1. (S)-Goniothalamin and (S)-argentilactone, the enan tiomers crease in arterial blood pressure [173]. This chronic non
of the natural congeners (R)-goniothalamin and (R)- argentilactone communicable disease affects about 46% of the global adult popu
(Fig. 4), have IC50 values of 0.35 and 0.94 mmol L1, respectively. lation [173,174].
Interestingly, the IC50 of the non-natural enantiomer of goniothalamin Spironolactone (Fig. 14), the prominent steroidal compound
was much higher than that of its natural coun terpart (IC 50 ¼ 1.30 discussed in section 2.7, is an important drug in the antihyperten sive
mmol L1) [166]. arsenal. This lactone is a potassium-sparing diuretic marketed under
the name Aldosterone®. In addition to being indicated for
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001 Fig. 37. Chemical structures of the trypanocidal drugs benznidazole and nifurtimox.
Fig. 38. Chemical structures of the sesquiterpene lactones ambrosin, incomptin B, and glaucolide E.
Fig. 39. Chemical structures of cryptofolione, (S)-goniothalamin, and (S)-argentilactone.
the treatment of hypertension, the drug is used to treat refractory Fig. 40. Chemical structure of eplerenone.
edema in congestive heart failure and ascites (abnormal accumu lation
of protein-rich fluid inside the abdomen) [59,60,175,176].
Eplerenone (Fig. 40) is another steroidal lactone used to treat
hypertension. It is marketed under the name Inspra® and was the
31
second aldosterone antagonist marketed in the United States of
America. Currently, it is indicated for the treatment of hypertension and
as a first-line drug for secondary heart failure in patients with
myocardial infarction [61].
5.1.2. Antibiotic drugs

Bacteria are some of the microorganisms that most affect hu man
and animal health. Antibiotics are drugs with the capacity to fight these
microorganisms.Erythromycin and azithromycin (Fig. 41) are
macrolactones used in the treatment of various bac terial infections
[177,178].
Erythromycin, isolated from Saccharopolyspora erythraea in 1952,
was the first 14-membered macrolide used clinically. It has activity
against Gram-positive and -negative bacteria involved in respiratory,
gastrointestinal, skin, and genital infections (including chlamydia and
syphilis) [177,178]. Erythromycin can be used during pregnancy to
prevent group B streptococcal infection in newborns [178].
The 15-membered macrolide azithromycin is active against
important Gram-positive and -negative pathogenic bacteria, including
Bordetella pertussis, Mycoplasma pneumoniae, Haemo philus
influenzae, Treponema pallidum, Legionella, Campylobacter, and
Chlamydia [179,180]. A recent study [181] reported that azi thromycin
possesses in vitro activity against Zika and Ebola viruses, the latter of
which was classified by WHO in 2014 as a public health emergency of
international interest [182]. Combined therapy with azithromycin and
hydroxychloroquine has been investigated for
Fig. 41. Chemical structures of the macrolides erythromycin and azithromycin.
the treatment of the coronavirus disease 2019 (COVID-19), caused

by the SARS-CoV-2 virus, which has caused the death of millions of
people worldwide. Preliminary studies concluded that this drug
combination may be useful against the virus in addition to pre
venting bacterial superinfections [181,183,184].
5.1.3. Antifungal drugs

The macrolactones amphotericin B (Fig. 34) and natamycin
(Fig. 42), marketed under the trade names of Fungizone® and
Natacyn®, respectively, are antifungal drugs [185e189].
Amphotericin B is synthesized by the bacterium Streptomyces
nodosus and is used to treat infections caused by fungi of the genus
Aspergillus, Cryptococcus, and Candida, among others [185e187].
Natamycin, isolated from the bacterium Streptomyces natalensis, is 32
Fig. 43. Chemical structure of ivermectin. Milbemycins (moxidectin, milbemectin, milbemycin
formulated as an ophthalmic solution and used for the treatment of oxime, lepimectin, and latidectin) have anthelmintic and insecticidal ac tivity.[192] Their main
fungal conjunctivitis and keratitis [188,189]. representative is moxidectin, used to control mites and nem atodes. [193,194].
5.1.4. Antiparasitic drugs

The first macrocyclic lactones to be developed and used as
antiparasitic agents were avermectins (abamectin, ivermectin,
eprinomectin, doramectin, and selamectin) [190]. The most prominent
avermectin is ivermectin (Fig. 43)(Fig. 44), whose broad-spectrum
activity encompasses clinically important para sites of humans, dogs,
and cattle [191].
Fig. 44. Chemical structure of moxidectin.
Fig. 42. Chemical structure of natamycin.

metabolite demonstrated strong antitumor activity in patients with
gastrointestinal cancer. However, camptothecin had strong side
effects, such as vomiting, diarrhea, myelosuppression, and hemor
rhagic cystic diseases, leading to the interruption of phase II clinical
trials. In the late 1980s, the compound became once again the focus
of attention of researchers after the discovery of its cellular target,
DNA topoisomerase 1 (TOP1). Subsequent studies showed
increased expression of this enzyme in cancer cells compared to
normal tissues. This finding sparked interest in the development of
TOP1 inhibitors with reduced side effects [196].
Irinotecan and topotecan (Fig. 46), two important anticancer
drugs developed by structural modification of camptothecin, are
currently used in their hydrochloride form [196e199]. Irinotecan is
Fig. 45. Chemical structure of the natural lactone 20(S)-camptothecin.
5.1.5. Anticancer drugs

Cancer is one of the leading causes of death worldwide. It is
estimated that more than 8 million people lose their lives every year to
this disease [195]. Natural and semi-synthetic lactones are part of the
arsenal of drugs available for treating different types of cancer
[196e199].
20(S)-Camptothecin (Fig. 45), a natural product isolated from the
Chinese tree Camptotheca acuminata, has a pentacyclic system
formed by a quinoline moiety, a pyrrolidine ring, a lactam ring, and an
a-hydroxy d-lactone ring. Extracts of this plant are used in traditional
Chinese medicine as a natural drug for cancer treatment [196].
In the early 1980s, clinical studies investigating this secondary
an antineoplastic agent indicated for the treatment of colon, rectum,
lung, ovary, and breast cancers [197,198]. Topotecan is a powerful
chemotherapeutic agent used to treat breast cancer [199].
Etoposide and teniposide (Fig. 47) are other examples of anti
cancer lactones. These semi-synthetic compounds derived from
podophyllotoxin (Fig. 47) have TOP1 inhibition as their mode of action
and find application in the treatment of lung and testicular cancers and
some types of leukemia [200,201].
Podophyllotoxin was first isolated in 1880 from Podophyllum
peltatum L., a plant found in North America, where it is popularly
known as the American mandrake or May apple. The compound was
also detected in the Indian plant Podophyllum emodi and in some
endophytic microorganisms found in plants of the family Cupressaceae
[200]. Although podophyllotoxin possesses anti tumor activity, it is
currently used as a topical antiviral agent for the treatment of
condylomata acuminata, an infection caused by
Fig. 46. Chemical structures of irinotecan and topotecan.
Fig. 47. Chemical structures of etoposide, teniposide, and podophyllotoxin. 33
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001 Fig. 48. Chemical structures of some furanocoumarins.
human papillomavirus (HPV) [200,202]. Fig. 51. Chemical structure of u-pentadecalactone.
5.1.6. Dermatological drugs

Vitiligo is a skin disorder characterized by lack of pigmentation and loss
of functional melanocytes and melanin in the epidermis [47]. It is
considered an autoimmune disease of unknown etiology and affects
about 0.5e2% of the world population. Another skin disorder, psoriasis, is
characterized by chronic inflammation and scaling, most commonly on
the elbows, knees, scalp, and torso [203].
Furanocoumarins (Fig. 48), a subclass of lactones with photo
chemotherapeutic properties, have long been used in the treatment of
vitiligo, psoriasis, leprosy, leukoderma, mycoses, dermatitis, and eczema
[47]. These compounds temporarily increase the sensitivity of the skin to
UV rays, promoting pigmentation of the affected area [203].
A mixture of psoralen and bergaptene is marketed as an oint ment for the
treatment of vitiligo under the name of Viticromin®
[47].
Fig. 49. Chemical structures of g-octalactone, g-nonalactone, g-decalactone, and g-undecalactone.

Fig. 50. Chemical structures of d-decalactone and d-dodecalactone.
34
S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001 5.2. Cosmetics and perfume industry
Lactones contribute to the aroma and taste of fruits, vegetables,

meat, and mushrooms [23]. Because of their organoleptic proper
ties, some lactones find application as fragrance compounds in the
manufacture of cosmetics and perfumes [4].
Five-to six-membered lactones are the most suitable for aro
matic purposes because of their chemical stability [23]. Examples of
fragrant butyrolactones are g-octalactone, g-nonalactone, g-deca
lactone, and g-undecalactone (Fig. 49); the first two compounds
have a coconut-like smell and the last two have a fruity odor, being
used in floral compositions [204]. Fig. 53. Chemical structure of 5-ethyl-g-lactone. cis-3-Methyl-4-octanolide, commonly known
as whiskey or oak lactone, contributes to the characteristic aroma of whiskey, liquor, and
Of the d-lactone class, the most widely used are d-decalactone wine.23.
(Fig. 50), which is a viscous liquid with a coconut and peach aroma,
and d-dodecalactone (Fig. 50), which is a yellowish liquid with peach
notes. Both are used in perfumes and creams [23]. of its caramel taste.23 (Fig. 54).
Larger-ringed lactones have also been used as aroma com Massoialactone ((R)-6-pentyl-5,6-dihydropyran-2-one) (Fig. 55) is
pounds. u-pentadecalactone (Fig. 51), a musk obtained easily and another example of chiral lactones found in wine and fresh juice made
abundantly from Angelica archangelica roots, is a common ingre dient from Merlot and Cabernet Sauvignon grapes. It plays a major role in
of decorative cosmetics, fine perfumes, shampoos, soaps, cleaning the aroma of dried ripe grape commonly detected in these beverages
products, and household detergents [23,205,206]. [207].
Other compounds frequently used in perfumery are the mac
rolactones cervolide, ambrettolide, exaltolide, and musks T and MC-4
(Fig. 52). Among these, the most versatile is exaltolide, a synthetic 5.4. Agrochemicals
compound with a musky odor that also serves as a fixa tive [23].
Lactones find application as insecticides. Flupyradifurone (4- [(2,2-
difluoroethyl)amino]-2(5H)-furanone) (Fig. 56), marketed under the
5.3. Food industry name of Sivanto®, is the only butenolide used in agri culture. It is
recommended for the control of sucking insects, particularly the
Flavor is a key sensory attribute of food and beverages and is one silverleaf whitefly (Bemisia tabaci), in coffee, citrus, vegetables, and
of the main factors influencing consumer preference.207 5-Ethyl- g tobacco [208,209]. Silverleaf whitefly is one of the most devastating
lactone (Fig. 53) finds application in the food industry as a flavoring hemipteran pests of agricultural crops around the world [208].
agent in tea, cognac, and beer, as well as in tobacco and oil, because
Fig. 52. Chemical structures of cervolide, ambrettolide, exaltolide, musk T, and musk MC-4. Coumarins (Fig. 30) are often added to creams to provide a pleasant coconut aroma.23. 35

Fig. 54. Chemical structure of cis-oak lactone.
Fig. 57. Chemical structures of spinosyn A and D.
6. Conclusions
This review illustrated different types of lactones, their struc

tural particularities, and some of the elegant synthetic methods for
the construction of small to macrocyclic lactone rings. It also
addressed the vast biological properties of natural and synthetic
lactones, describing the main in vitro and in vivo studies and
commercial uses for the treatment of various diseases. Finally, the
review explored the application of lactones in the pharmaceutical,
food, cosmetics, and agrochemical industries.
Fig. 55. Chemical structure of ()-massoialactone. 36

Consent for publication
Not applicable.
Funding
None to declare.
Declaration of competing interest
The authors declare that they have no known competing financial

interests or personal relationships that could have appeared to
influence the work reported in this paper.
Acknowledgements
We thank the Brazilian National Council for Scientific and

Fig. 56. Chemical structure of the insecticide flupyradifurone. Technological Development (CNPq) for awarding a doctoral fellowship
to S. K. S.
Similar to neonicotinoids, flupyradifurone acts as a reversible List of abbreviations

antagonist of the nicotinic acetylcholine receptor of insects. The
lactone has the advantage of acting at a different site from that of AAC Acyl halide-aldehyde cyclocondensation Ac
neonicotinoid insecticides, conferring selectivity to adult bees without, Acetyl
however, causing their death [210]. It is worth mentioning that the AD-mix-a AD-mix-alpha
death of pollinators is one of the biggest problems asso ciated with the AD-mix-b AD-mix-betha
use of insecticides [211]. AIBN Azobisisobutyronitrile
Spinosad is an insecticide that has the macrolactones spinosyn A BHT Butylated hydroxytoluene
and D as active ingredients (Fig. 57) [212].
(þ)-BINOL (þ)-1,10-Bi-2-naphthol
Spinosad is indicated for the treatment and prophylaxis of fleas
Bn Benzyl
(Ctenocephalides felis), and, like neonicotinoids, activates nicotinic
Boc tert-Butyloxycarbonyl group
acetylcholine motor receptors, leading to involuntary muscle con
BTF Benzotrifluoride
tractions, tremors, paralysis and, ultimately, the death of insects [212].
n-BuLi n-Butyl lithium
t-Bu tert-Butyl
CAN Ceric ammonium nitrate
Cbz Carboxybenzyl
COVID-19 Corona virus disease 2019 DME Dimethoxyethane

Cp Cyclopentadienyl DMF Dimethylformamide
m-CPBA meta-Chloroperoxybenzoic acid 2,2-DMP 2,2-Dimethoxypropane
Cy Cyclohexyl DMP Dess-Martin periodinane
DA Diels-Alder DMPU N,N-Dimethylpropyleneurea
DABCO 1,4-Diazabicyclo[2.2.2]octane DMSO Dimethylsulfoxide
dba Dibenzalacetone dppf 1,10-Bis(diphenylphosphino)ferrocene
DBU 1,8-Diazabicyclo(5.4.0)undec-7-ene EC50 Half maximal effective concentration
DCC N,N-Dicyclohexylcarbodiimide Et Ethyl
DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DEIPS EtOAc Ethyl acetate
Diethylisopropylsilyl Grubbs-I 1st Generation Grubbs catalyst
DIAD Diisopropyl azodicarboxylate Grubbs-II 2nd Generation Grubbs catalyst
DIBAL-H Diisobutyl aluminum hydride hCA II Human carbonic anhydrase isoenzymes II HDMA
DIPEA N,N-Diisopropylethylamine Hexamethylenediamine
()-DIPT ()-Diisopropyl tartrate HIV-1 Tat Human immunodeficiency virus trans-activating
DMAP 4-Dimethylaminopyridine
regulatory protein 37
HPV Human papillomavirus TBHP tert-Butyl hydroperoxide
HWE Horner-Wadsworth-Emmons TBS tert-Butyldimethylsilyl
TES Triethylsilyl
IC50 Half maximal inhibitorial concentration
Tf Triflate
IgE Immunoglobulin E
TFA Trifluoroacetic acid
KHMDS Potassium hexamethyldisilazide
TFBA 4-(Trifluoromethyl)benzoic anhydride
LC50 50% Lethal concentration THF Tetrahydrofuran
LDA Lithium diisopropylamide
TMS Trimethylsilyl
Mba (S)-2-Methylbutyl
TOP 1 Topoisomerase 1
MCF-7 Human breast adenocarcinoma cell line
Ts Tosyl
Me Methyl
WHO World health organization
Mes Mesityl
MIC Minimum inhibitory concentration
MNBA 2-Methyl-6-nitrobenzoic anhydride References
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Msc. Suelen Karine Sartori was born in Visconde do Rio

Branco, Minas Gerais, Brazil. She studied Chemistry at the
Federal University of Viçosa, Minas Gerais, Brazil, gradu
ating in 2014, and obtained a Master’s degree in Agro
chemistry from the same institution in 2016 for her work
on the synthesis and evaluation of the herbicidal activity
of amides derived from sorbic acid and hexanoic anhy
dride. She is currently a PhD student in Chemistry at the
Federal University of Minas Gerais, Belo Horizonte, Minas
Gerais, Brazil, where she works on the stereoselective
synthesis of natural exponents of the class of 5,6-dihydro
2H-pyran-2-ones that show remarkable biological activ
ities under the supervision of Professor Gaspar Diaz
Munoz. ~
Dr. Marisa A. N. Diaz was born in Belo Horizonte, Minas

Gerais, Brazil, holds a Bachelor’s degree in Pharmacy
from the Federal University of Minas Gerais, a Master’s
degree in Agrochemistry with emphasis on Chemistry of
Natural Products from the Federal University of Viçosa,
and a PhD in Sciences - Chemistry from the State Uni
versity of Campinas, focusing on the synthesis of bio
logically active molecules and natural products. She was
a post-doctoral researcher working on biocatalysis at the
State University of Campinas and on analytical chemistry
at the State University of Florida. She currently occupies
an associate professor position in the Department of
Biochemistry and Molecular Biology of the Federal Uni
versity of Viçosa, where she supervises master and
doctoral students. Her main line of research is the synthesis of molecules with anti tumor activity.
~
Dr. Gaspar Diaz-Munoz was born in Peru and received his
undergraduate degree in Chemical Engineering in 1989
from the National University of the Peruvian Amazon
(UNAP). He then moved to Brazil and obtained his mas
ter’s degree in 1997 from the Federal University of Para
(UFPA). In 2001, he earned his PhD in Chemistry from the
State University of Campinas (UNICAMP), working on the
synthesis of (þ/)-pathylactone A under the supervision
of Professor Fernando A. S. Coelho. After a short stint as an
adjunct professor at the State University of Western Par
ana (Unioeste) (2003 e2006), he moved to the Federal
University of Minas Gerais (UFMG), where he first served
as an adjunct professor and then as an associate professor
of the Department of Chemistry. In 2012, he joined Pro
fessor Gregory Dudley’s group at Florida State University (FSU), USA, as a postdoctoral fellow. Currently, he advises undergraduate, master, and doctoral students in chem istry, with emphasis on
organic synthesis, focusing mainly on the synthesis of natural products and biologically active compounds.

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Tetrahedron 84 (2021) 132001

Contents lists available at ScienceDirect

Tetrahedron report 1226

Lactones: Classification, synthesis, biological activities, and industrial

© 2021 Elsevier Ltd. All rights reserved.

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............................. 2 2. Major classes

3.7.3. Stille reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 3.7.4.

1. Introduction dustrial applications of this remarkable family of organic compounds.

S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001

Fig. 3. Chemical structures of biologically active butenolides.

(dictyopyrone C) [29], antitumor (pironetin) [31,32], leishmanici dal, 3

Phthalides, or 3H-isobenzofuran-1-ones, are important organic s

and numerous reports can be found in the literature on its diverse

Fig. 6. Chemical structures of 9-membered lactones.

Fig. 7. Chemical structures of nonanolides.

Fig. 8. Lactones with 11-membered rings.

Fig. 9. Chemical structures of phthalides with biological activities.

Fig. 10. Chemical structures of coumarins used as drugs.

essential oils [49e53]. antiplasmodial, antibacterial, insect repellent, molluscicidal,

Fig. 12. Chemical structure of a-santonin, helenalin, parthenolide, and artemisinin.

Cucumis sativus and Sorghum bicolor seeds [52]. Artemisinin, iso 7

Fig. 15. Chemical structure of 5-deoxystrigol.

Macrolactins are macrolides isolated from strains of Bacillus and

Fig. 17. Chemical structures of 13- and 24-membered lactones.

Micromonospora sp. JY16. The major representatives are quinoli 9

product is a 5,6-dihydropyran-2-one. (þ)-Dodoneine [22], for

Scheme 3. Total synthesis of ()-pironetin [83]. 11

Scheme 6. Synthesis of salicylihalamide A [90].

deoxyicetexone (Fig. 21). 12

Scheme 8. Synthesis of (±)-vibralactone [96].

3.3. Yamaguchi lactonization 14

Scheme 10. General representation of Yamaguchi lactonization.

Scheme 12. Synthesis of (3R,5R)-5-hydroxy-of-O-methyl-lasiodiplodin [102].

(S)-29 epoxides to acid 30 and hydroxy ester 31, respectively 15

Scheme 14. Synthesis of ()-(6R,11R,14S)-colletallol [106e108].

Scheme 15. Lactonization protocols developed by Shiina [109e111].

Scheme 16. Synthesis of ()-cephalosporolide D [112].

Scheme 17. Synthesis of erythro-aleuritic acid lactone [111].

remove the TBS group, generating ()-colletol in 71% yield (2 steps). 17

Scheme 23. Synthesis of batatoside L [119]. 19

3.7.1. HWE olefination 20

Scheme 27. Total synthesis of ()-marinisporolide C [125].

Scheme 28. Synthesis of exaltolides 62 and 63 [129].

metallocyclobutane intermediate, which, after rearrangement, re u

r (Scheme 31). Ring-closing metathesis using Grubbs-I (68) from diene

Scheme 30. Catalytic cycle of the ring-closing metathesis reaction [127,133].

mutant S11R59. It has antimicrobial, antibacterial, antifungal, and anti- 23

Scheme 32. Synthesis of patulolide A [135].

natural products (e.g., myrocin C) (Fig. 26).

3.7.4. DielseAlder reaction

Scheme 35. Synthesis of macrolactone 86 [143].

Fig. 25. Chemical structure of neocosmosins A, B, and C. 27

S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001

Scheme 37. Synthesis of himandravine [149]. 28

S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001

Fig. 30. Chemical structures of chromen-2H-one and umbelliferone. (R)-Goniothala

50% [166,167]. Of note, argentilactone also possesses antifungal 4.5. Trypanocidal

S.K. Sartori, M.A.N. Diaz and G. Diaz-Munoz ~ Tetrahedron 84 (2021) 132001

Sepúlveda-Robles et al. [169] conducted a comparative study