Alkyl-substituted δ-lactones derived from dihydrojasmone and their stereoselective fungi-mediated conversion: Production of new antifeedant agents

Article abstract of DOI:10.3390/molecules21091226

A chemoenzymatic method was applied to obtain optically pure alkyl-substituted δ-lactones. First, chemical Baeyer-Villiger oxidation of dihydrojasmone (1) was carried out, affording two new alkyl-substituted δ-lactones: 3,4-dihydro-5-methyl-6-pentyl-2H-pyran-2-one (2) and 5-methyl-6-pentyl-1,13-dioxabicyclo[4.1.0]heptan-2-one (3). In the next step, fungal strains were investigated as biocatalysts to enantioselective conversion of δ-lactones (2) and (3). The fungal cultures: Fusarium culmorum AM10, Fusarium equiseti AM15 and Beauveria bassiana AM278 catalyzed the stereoselective hydration of the double bond of lactone (2) (ee = 20%-99%) while Didymosphaeria igniaria KCh6670 proved to be the best biocatalyst for the reduction of carbonyl group in the epoxylactone (3) (ee = 99%). In both cases, chiral oxyderivatives were obtained in low to high yields (7%-91%). The synthetic lactones (2), (3) and its derivatives (4), (5) were tested for their antifeedant activity towards larvae and adults of lesser mealworm (Alphitobius diaperinus Panzer) and peach potato aphid (Myzus persicae [Sulzer]) and some of them were active towards studied insects.

Full text of DOI:10.3390/molecules21091226

molecules
Article
Alkyl-Substituted δ-Lactones Derived from
Dihydrojasmone and Their Stereoselective
Fungi-Mediated Conversion: Production of
New Antifeedant Agents
Anna Gliszczyn´ska 1,*, Damian Semba 2, Maryla Szczepanik 3, Katarzyna Dancewicz 4 and
4
Beata Gabrys´
1
Department of Chemistry, Wroclaw University of Environmental and Life Sciences, Norwida 25,
Wrocław 50-375, Poland
2
Bioprocess and Biomedical Engineering Division, Wroclaw University of Technology, Norwida 4/6,
Wrocław 50-373, Poland; damiansmb@gmail.com
Department of Invertebrate Zoology, Nicolaus Copernicus University, Lwowska 1, Torun´ 87-100, Poland;
3
mszczep@umk.pl
4
Department of Botany and Ecology, University of Zielona Góra, Szafrana 1, Zielona Góra 65-516, Poland;
k.dancewicz@wnb.uz.zgora.pl (K.D.); b.gabrys@wnb.uz.zgora.pl (B.G.)
*
Correspondence: anna.gliszczynska@wp.pl; Tel.: +48-71-320-5183; Fax: +48-71-320-7744
Academic Editor: Tobias A. M. Gulder
Received: 18 July 2016; Accepted: 8 September 2016; Published: 13 September 2016
Abstract: A chemoenzymatic method was applied to obtain optically pure alkyl-substituted
δ
-lactones. First, chemical Baeyer–Villiger oxidation of dihydrojasmone (
affording two new alkyl-substituted -lactones: 3,4-dihydro-5-methyl-6-pentyl-2H-pyran-2-one (
and 5-methyl-6-pentyl-1,13-dioxabicyclo[4.1.0]heptan-2-one ( ). In the next step, fungal strains were
investigated as biocatalysts to enantioselective conversion of -lactones (2) and (3). The fungal
cultures: Fusarium culmorum AM10, Fusarium equiseti AM15 and Beauveria bassiana AM278
catalyzed the stereoselective hydration of the double bond of lactone ( ) (ee = 20%–99%) while
Didymosphaeria igniaria KCh6670 proved to be the best biocatalyst for the reduction of carbonyl group
in the epoxylactone ( ) (ee = 99%). In both cases, chiral oxyderivatives were obtained in low to
high yields (7%–91%). The synthetic lactones ( ), ( ) and its derivatives ( ), ( ) were tested for their
1) was carried out,
δ
2)
3
δ
2
3
2
3
4
5
antifeedant activity towards larvae and adults of lesser mealworm (Alphitobius diaperinus Panzer) and
peach potato aphid (Myzus persicae [Sulzer]) and some of them were active towards studied insects.
Keywords: dihydrojasmone; alkyl-substituted δ-lactones; oxyfunctionalization; Baeyer–Villiger
oxidation
1. Introduction
Over the last few decades, numerous research papers about isolation and synthesis of
alkyl-substituted -lactones have been widely published in the literature [ ]. These compounds have
been isolated from various natural sources: plants, marine organisms and terrestrial animals [ ].
Because of their manifold biological properties, they are of marked interest not only from a chemical,
but also from a practical point of view. Chiral alkyl-substituted -lactones as the carriers of specific
δ
1–3
4–6
δ
odor have considerable industrial value in the flavor, cosmetic and food industries. They are also
a large group of compounds that play important roles in insect’s lives as pheromones, and are
the key intermediates for the synthesis of other biologically active compounds.
been reported by Lopez and Morgan as a component of the warning odor of North America
porcupine Erethizon dorsatum [ ]. That compound has been also detected in venom-producing
δ-Decalactone has
7
Molecules 2016, 21, 1226; doi:10.3390/molecules21091226
www.mdpi.com/journal/molecules

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mandibular glands of ponerine ant Pachycondyla apicalis [
8
]. A chiral building block, which is
a synthetically versatile precursor and has attracted attention over the years, is a parasorbic acid.
Its (+)-enantiomer isolated from mountain ash berries (Sorbus aucuparia) is an intermediate for the
synthesis of cis-3,6-dimethyltetrahydropyran-2-one, the major component of the male carpenter bee
pheromone [
9]. The component of defence secretion of two species of formicin ants of the genus
Camponotus [
6
] is another naturally occurring alkyl-substituted -lactone, (R)-( )-massoialactone
δ
−
isolated from the bark oil of Cryptocarya massoia (Lauraceae) [10] and jasmine flowers and leaves
of Polianthes tuberosa L. [11]. Goniothalamin, a bioactive styryl lactone, isolated from the leaves of
Goniothalamus species [12] possesses insecticidal activity against beet armyworm Spodoptera exigua
Hübner (Lepidoptera: Noctuidae) [13]. This compound increases mortality of beet armyworm by
reducing food consumption, moulting inhibition and damage to the gut. Goniothalamin is also
highly effective against larvae of the mosquito, Culex quinquefasciatus Say [14], and possesses valuable
medicinal properties [15,16].
In our research project, we are exploring new compounds that can be useful for insect control.
Based on the literature data, we identified alkyl-substituted δ-lactones as an aim of our next
studies. Searching the appropriate substrate for their synthesis, we focused our attention on
the recent findings in research of jasmonates (JAs). The various JAs are described as compounds
that allow plants to respond specifically to alterations in the environment and play the role of
hormones [17
-lactones. The chemoenzymatic pathway of novel jasmonate signaling compounds generated in
this study was initiated with the Baeyer–Villiger oxidation of dihydrojasmone ( ) to alkyl-substituted
-lactones ( ) and ( ). Biological properties of lactones are often strongly related with occurrence
–19]. We selected dihydrojasmone (1) as a substrate for the synthesis of alkyl-substituted
δ
1
δ
2
3
in their structure, the additional oxygen function, and the absolute configuration of chiral centers.
Therefore, looking for stereoselective methods of synthesis of optically pure oxyderivatives of lactone
(2) and (3), we applied microbial transformations as the method from the field of green chemistry,
which possesses overwhelming advantages over chemical synthesis, and we employed the wild
fungal strains from our collection as biocatalysts. In the present work, we also describe the results
of evaluation of biological activity of obtained lactones (2), (3) and their enantiomerically enriched
oxyderivatives ( ), ( ) towards larvae and adults of lesser mealworm (Alphitobius diaperinus Panzer)
4
5
and the peach potato aphid (Myzus persicae [Sulzer]) and discuss their possible modes of action.
2. Results and Discussion
2.1. Chemical Oxidation of Dihydrojasmone (1)
Taking into consideration the broad spectrum of alkyl-substituted
it was purposeful to check whether lactone moiety introduced into the structure of dihydrojasmone
) indicate the antifeedant activity. The Baeyer–Villiger oxidation of commercially available
dihydrojasmone ( ) with meta-chloroperbenzoic acid (m-CPBA) generated the mixture of
two new -lactones: 3,4-dihydro-5-methyl-6-pentyl-2H-pyran-2-one ( ) and 5-methyl-6-pentyl-1,13-
dioxabicyclo[4.1.0]heptan-2-one ( ) as the products (Figure 1) that were separated by silica-gel column
δ-lactones properties,
(1
1
δ
2
3
chromatography. These products were obtained in 23% and 5% yields, respectively. Their structures
were confirmed by spectral data (Figures S1–S14). Relatively low yields can be caused by the formation
of further oxidation products in the reaction with highly reactive m-CPBA. The possible product could
also be diol formed by the opening of a oxirane ring, which, due to its high polarity, was not isolated
from the reaction mixture or chromatographic separation.

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1
2
3
Figure 1. Oxidation of dihydrojasmone (1) with m-CPBA.
The absorption bands at 1761 cm−1
of the -lactone ring in these molecules. The value of chemical shifts of carbonyl carbon atom C-2
(210.13 ppm and 212.13 ppm for lactones ( ) and (
), respectively) found in the 13C-NMR spectra are
characteristic for disubstituted -enol lactones, which was reported by Mandal and Jawalkar [20].
The place of insertion of oxygen atoms to ketone rings was determined on the basis signals from
carbon atoms C-6 of lactones ( ) and (
) in 13C-NMR spectra, which were shifted from 170.0 ppm
(C-2 in substrate ( )) to 175.19 ppm (lactone ) and 67.44 ppm (lactone ). These facts clearly proved
that oxygen atoms were inserted into cyclopentenone rings between carbon atoms C-1 and C-2 of
dihydrojasmone ( ). Moreover, the presence in the spectrum of (
) signals at 13C-NMR confirmed that
the double bond in the cyclopentene ring was not affected during the oxidation process. The opposite
observation was confirmed for lactone ( ), where spectral data provide evidence that the oxirane ring
was formed in the place of double bond. In the 13C-NMR spectrum of lactone (
), the signals of atoms
C-5 and C-6 (69.51 and 67.44 ppm) undoubtedly confirm the presence of epoxy ring in the structure of
product ( ) and ( ).
). The signals found in the 1H-NMR spectra also proved the structures of lactones (
(2 (3) in the IR spectra indicate the presence
) and 1743 cm−1
δ
2
3
γ,δ
2
3
1
2
3
1
2
3
3
3
2
3
The data presented above confirmed the high regioselectivity of chemical Baeyer–Villiger oxidation,
and, according to the mechanism of this reaction, the more substituted carbon atom migrated to the
electrophilic oxygen atom.
2.2. Biotransformation of 3,4-Dihydro-5-methyl-6-pentyl-2H-pyran-2-one (2)
Our studies concentrated on the evaluation of the usefulness of wild fungal strains in the obtaining
of enantiomerically enriched oxyderivatives of alkyl-substituted
δ-lactones from the corresponding
lactones ( ) and ( ). In the first step, we performed small-scale biotransformations, using portions of
2
3
10 mg of substrates. The screening experiments were performed using 13 fungal strains of the genus:
Absidia, Penicillum, Cunninghamella, Fusarium, Botrytis, Beauveria, Chaetomium, Didymosphaeria,
Mortierella and Syncefalastrum. Those biocatalysts were selected based on their proven ability to
enantioselective hydroxylation [18
AM10, Fusarium equiseti AM15 and Beauveria bassiana AM278—were able to catalyze the conversion of
lactone ( ) into the more polar derivative. No formation of any biotransformation products of ( ) in
,21]. Among the tested fungal strains, three—Fusarium culmorum
2
2
the culture of another microorganisms was observed even after nine days of incubation. The reaction
course was monitored by means of thin layer chromatography (TLC) and gas chromatography (GC).
The GC analysis provided the information about changes in quantitative ratio of product in the course
of the process. The optical purity of isolated products was determined by GC analysis with application
of chiral column (CP-Chirasil-DEX CB).
Selected strains of fungi performed regio- and enantioselective hydration of C=C double bond
of 3,4-dihydro-5-methyl-6-pentyl-2H-pyran-2-one (2) to 5-hydroxy-5-methyl-6-pentyltetrahydro-2H-
pyran-2-one (4) (Figure 2).

Molecules 2016, 21, 1226
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2
4
Figure 2. Biotransformation of (2) with F. culmorum AM10, F. equiseti AM15 and B. bassiana AM278.
The structure of (
4
) was−1established on the basis of its spectral data (Figures S15–S18).
The absorption band at 3445 cm in the IR spectrum of this product confirms the presence of hydroxy
group in the molecule of (
untouched. Hydration of the double bond of (
of ( ). The signal from the carbon atom C-6 observed at 89.39 ppm in the spectrum of substrate (
4
), whereas the band at 1765 cm−1 proved that the
) was confirmed by signals in the 13C-NMR spectrum
) is
δ-lactone moiety stays
2
4
2
shifted up to the higher frequency at 76.90 ppm. Additionally, the value of chemical shift of C-5 carbon
atom (89.26 ppm in the 13C-NMR spectrum) is characteristic for carbon atoms connected with oxygen
atoms. The presence of doublet of doublets at
δ
= 3.46 ppm with the coupling constants J = 8.9 and
) not visible in the spectrum of
3.1 Hz from proton H-6 in the 1H-NMR spectrum of hydroxylactone (
4
substrate indicates the hydration of the double bond in the lactone ring. Singlets from the protons of
methyl group at C-5 in the spectrum of product are shifted (1.30 ppm) in comparison with its location
in the 1H-NMR spectrum of
2
(1.41 ppm). Such a difference in chemical shift of these protons indicates
that the methyl group is connected to carbon atoms bonded directly with hydroxy group. The product
of biotransformation 5-hydroxy-5-methyl-6-pentyltetrahydropiran-2-one (
not been published before.
4) is a new compound has
Microbial transformation of
high rate (Table 1, entry 1). After 24 h of biotransformation, 98% (according to GC (S23)) of
hydroxylactone ( ) in the reaction mixture was observed (Figure 3). On the next day, the substrate
was fully converted and no further oxidation products were detected in the reaction mixture.
δ-lactones (2) in the culture of F. culmorum AM10 proceeded with
4
5-Hydroxy-5-methyl-6-pentyl-tetrahydropiran-2-one (4) was obtained in high yield 91% after one day
as (−)-isomer with ee = 20%.
Table 1. The reaction rates of production of hydroxylactone (4) by selected microorganisms.
Transformation Period
Entry
Microorganism
Reaction Rate (mg/h) of Product
(Days)
−1
1
2
4
6
9
4.1 × 10
−3
8.3 × 10
Full conversion
Full conversion
Full conversion
1
F. culmorum AM10
−1
1
2
4
6
9
2.2 × 10
−2
9.2 × 10
−2
−2
F. equiseti AM15
2
3
3.9 × 10
1.5 × 10
Full conversion
−1
1
2
4
6
9
1.6 × 10
−2
7.1 × 10
−2
−2
B. bassiana AM278
6.5 × 10
2.9 × 10
Full conversion

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100
90
80
70
60
50
40
30
20
10
F. culmorum AM10
F. equiset AM15
B. bassiana AM278
0
0
1
2
4
6
9
Time of incubation [days]
Figure 3. Time course of the transformation of lactone (2) by selected fungal strains.
In the case of biotransformation of ( ) catalyzed by enzymatic system of F. equiseti AM15, after the
2
first 24 h, 48% of the unreacted substrate was observed in the reaction mixture (GC) (Figure 3).
In the next days of incubation, the reaction rate was reduced and the process of hydration proceeded
slower. The amount of substrate (
proportionally. The complete conversion of (
Product ( ) was isolated from F. equiseti AM15 culture at high yield (53%) in optically pure form
2
) gradually decreased, whereas the amount of product (
4) increased
2) was achieved after six days (Table 1, entry 2).
4
as dextrorotatory enantiomer.
As it is presented in Table 1 (entry 3), the reaction rate performed by B. bassiana AM278 was lower
than in the case of F. culmorum AM10 and F. equiseti AM15. After one-day incubation of substrate
(
2
), the products mixture contained only 38% of product (
rate during the progress of the biotransformation and after six days reached 100%. B. bassiana AM278
turn out to be an effective biocatalyst for the enantiospecific oxidation of -lactones ( ) and produced
4) (Figure 3). Its amount increased at a low
δ
2
hydroxylactone (4) as pure (+)-enantiomer, although in a much smaller isolated yield of only 7%.
2.3. Biotransformation of 5-Methyl-6-pentyl-1,13-dioxabicyclo[4.1.0]heptan-2-one (3)
In the next step of our project, leading to optically active oxygenated derivatives of alkyl-substituted
δ
-lactones, epoxylactone (
microbial conversion of 6-methyl-1-pentyl-2,7-dioxabicyclo[4.1.0]heptan-3-one (
microorganisms, only the culture of D. igniaria KCh6670 catalyzed the conversion of lactone (
This time, we observed the enantioselective reduction of carbonyl group (Figure 4). After 24 h
of incubation, the conversion of epoxylactone ( ) reached 65% and systematically increased with
time (Figure 5). After four days, epoxylactone ( ) was completely transformed to the product (5)
The preparative biotransformation of 5-methyl-6-pentyl-1,13-dioxabicyclo[4.1.0]heptan-2-one (
3
) was subject to the biotransformation. Surprising results were found for
). Among tested
).
3
3
3
3
.
3
)
in the culture of D. igniaria KCh6670 gave after four days (+)-5-methyl-6-pentyl-1,13-
dioxabicyclo[4.1.0]heptan-2-ol (5), which was isolated in 48% yield as single enantiomer (ee = 99%).
3
5
Figure 4. Biotransformation of (3) with D. igniaria KCh6670.

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100"
90"
80"
70"
60"
50"
40"
30"
20"
10"
product (5)
epoxylactone (3)
0"
0"
1"
2"
4"
6"
9"
Time of incubation [days]
Figure 5. Time dependence of transformation of lactone (3) in D. igniaria KCh6670 culture.
The structure of formed 5-methyl-6-pentyl-1,13-dioxabicyclo[4.1.0]heptan-2-ol (5) was established
by means of 1H-NMR and 13C-NMR (S19–S22). Reduction of carbonyl group in lactone ring is proved
by doublet at 4.31 ppm (J = 6.0 Hz) from proton H-2 in the 1H-NMR spectrum. The evidence for the
presence of the hydroxy group in the structure of product (
the signal of C-2 was moved from = 212.13 ppm for substrate (3) to δ = 73.52 ppm for the product (5).
5
) provided also 13C-NMR spectrum, where
δ
Furthermore, the absorption band at 3430 cm−1 in the IR spectrum indicates that bioreduction had
taken place.
2.4. Feeding Deterrent Activity Against the Lesser Mealworm
In the present studies, the antifeedant activity of the tested compounds varied significantly.
The results presented in Table 2 clearly revealed that activity is dependent on the developmental
stage. Considering the total coefficients of deterrence, it may be concluded that dihydrojasmone
(1) was a better deterrent for larvae than adults. A detailed analysis shows, however, that in the
choice tests, this compound was a very strong deterrent for both stages, and these differences were
minor. The marked differences were observed in no-choice tests. For adults, dihydrojasmone
(
1
) was an attractant, whereas for larvae was a moderate antifeedant. The introduction of lactone
moiety into the structure of dihydrojasmone ( ) leads to a change in activity of the resulting lactones.
The increase in activity against both stages was observed in the case of the unsaturated -lactone ( ).
1
δ
2
The particularly strong increase in activity against adults was observed. The weak antifeedant activity,
also against both stages, was showed by a second obtained lactone, i.e., saturated bicyclic δ-lactone (3).
Hydroxylactone (
4
) as pure ( )-enantiomer, obtained by biotransformation of δ-lactone (2) in the
−
culture of F. culmorum AM10, was a very strong feeding deterrent against larvae and adults of the lesser
mealworm. Its (+)-enantiomer produced by F. equiseti AM15 was a very strong antifeedant against
adults, but its activity against larvae was weak. In the no-choice test, this compound showed attractant
properties. The product of biotransformation of bicyclic
KCh6670 ( ) was a very good deterrent for larvae, but only in the choice test. In the no-choice situation,
its antifeedant properties were very weak.
δ-lactone (3) with participation of D. igniaria
5

Molecules 2016, 21, 1226
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Table 2. Feeding deterrent activity of the studied compounds in choice and no-choice tests against
A. diaperinus.
Deterrence Coefficients ± SE a
Compound
Larvae
R
Adults
R
A
T
A
T
(1)
(2)
(−)-(4)
(+)-(4)
(3)
29.37 ± 0.91bc
40.88 ± 3.77c
74.95 ± 3.57d
−8.99 ± 2.67a
8.35 ± 2.85ab
4.93 ± 2.09ab
71.40 ± 4.17bc
88.84 ± 0.65c
78.29 ± 3.59c
53.21 ± 9.14ab
47.39 ± 4.64a
90.05 ± 4.09c
100.77 ± 3.70b
129.72 ± 3.97bc
153.24 ± 7.09c
44.22 ± 8.36a
55.74 ± 7.34a
94.98 ± 14.68b
−20.69 ± 7.61a
57.17 ± 14.42b
90.21 ± 0.3b
82.69 ± 3.27b
−28.64 ± 9.50a
nt
91.48 ± 1.02b
93.19 ± 0.51b
72.26 ± 7.51a
97.02 ± 0.49b
64.48 ± 2.31a
nt
70.79 ± 8.04a
150.36 ± 11.87b
162.46 ± 7.69b
179.71 ± 2.81b
35.84 ± 8.38a
nt
(+)-(5)
a
Values are the means of the four replicates ( SE = Standard Error), each set up with ten larvae or adults
±
(n = 10). A: absolute coefficients; R: relative coefficients; T: total coefficients. nt: Not tested. Means followed by
the same letters within each column are not significantly different (one-way ANOVA and Tukey’s test (p < 0.05).
The comparison of the antifeedant activities of the compounds studied against two developmental
stages of the lesser mealworm shows the stronger sensitivity of adults than larvae. The phenomenon
of higher sensory sensitivity of adults of A. diaperinus to antifeedants in our previous studies was also
observed [22].
In light of these results, only
both larvae and adults, would be the best candidate for practical use in integrated pest management
of A. diaperinus. Two very strong antifeedants against adults, i.e., -lactone ( ) and -hydroxylactone
(+)-( ) may also affect the population size. The starvation is also often associated with other biological
δ-hydroxylactone (
−
)-(4), due to the strong inhibition of feeding in
δ
2
δ
4
effects against insects, such as antioviposition and reduction of fertility [23].
2.5. Deterrent Activity against the Peach Potato Aphid
Aphids possess the piercing-sucking mouthparts composed of four thin stylets, which determine
their mode of feeding. The stylets pierce through the plant surface and probe through outer plant
tissues—epidermis and parenchyma—to reach vascular elements from which the phloem sap is
ingested [24]. Moreover, aphids do not have external taste chemoreceptors on their mouthparts,
so they are not able to distinguish between attractant and deterrent components of their food prior to
the insertion of stylets into the plant [25]. Due to these circumstances, the process of aphid feeding is
hidden from the human eye and impossible to monitor directly. The monitoring of settling and/or
behaviour during settling in a choice-test is therefore the commonly applied method to evaluate aphid
responses to various chemicals applied to their otherwise accepted host plants [26]. In the present
study, the settling success of the peach potato aphid on plants treated with hydroxyjasmone (1), and its
derivatives varied depending on the compound applied and the duration of time after exposure
(Table 3).
Table 3. Settling success of Myzus persicae on leaves treated with dihydrojasmone (
alkyl-substituted δ-lactones (2), (3), and (−)-(4).
1) and
Number of Aphids ± SE a
Compound
1 h
2 h
24 h
C
T
C
T
C
T
(1)
(2)
7.9 ± 0.8
8.1 ± 1.1
5.8 ± 0.7
5.5 ± 1.0
6.0 ± 0.9
7.0 ± 1.0
7.5 ± 0.5
7.8 ± 0.9
7.6 ± 1.1
6.4 ± 1.0
6.4 ± 0.9
8.0 ± 0.8
6.1 ± 1.3
7.5 ± 0.7
7.9 ± 0.8
8.4 ± 1.3
7.8 ± 0.7
7.0 ± 0.8
7.5 ± 0.6
6.5 ± 1.1
7.6 ± 0.6
(−)-(4)
(3)
10.5
±
0.9 *
10.6
±
0.6 *
11.0
±
0.7 *
a
Values are means of the eight replicates ( SE = Standard Error), each set up with 20 adult apterae (n = 20).
* Asterisks indicate statistically significant differences between the number of aphids settled on control leaves
±
(C) and leaves with a tested compound (T) at 1, 2, and 24 h intervals (Student t-test; p < 0.05).

Molecules 2016, 21, 1226
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Hydroxyjasmone (
1
) and the unsaturated
δ-lactone (2) showed weak but not significant deterrent
properties while the
) and -hydroxylactone (
relatively persistent. The saturated bicyclic
δ
-hydroxylactone (–)-(
)-( ) ceased in the course of time while the activity of
-lactone ( ) was significantly highly attractant to the peach
4
) was a weak attractant. The activities of hydroxyjasmone
(1
δ
−
4
δ
-lactone ( ) was
2
δ
3
potato aphid: the preference of aphids for the treated leaves was revealed as soon as 1 h after treatment
and persisted at least for 24 h that was the end of the experiment (Table 3).
The results of the aphid settling choice-test can be supplemented with the results of direct
monitoring of aphid behaviour during initial 15 min of contact with the studied compounds
(no-choice test). The primarily deterrent and then inactive in the choice settling test, hydroxyjasmone (1),
evoked relatively negative initial aphid responses: the duration of presence of aphids on treated leaves
was significantly shorter and the total probing time when aphids were on a treated leaf was nearly twice
as short as on control untreated leaves. As aphids clearly avoided the hydroxyjasmone (1)-treated
leaves soon after exposure and their probing activity was repressed, hydroxyjasmone (1) can be
considered as having repellent properties. However, this repellent activity is short-lived: the deterrent
effect ceased by the second h after exposure as was shown in the aphid-settling assay (Tables 3 and 4).
Aphid initial behaviour on leaves treated with unsaturated
did not differ significantly from control. The weak deterrent activity of
activity of -hydroxylactone ( )-( ), which was found during the settling assay must have resulted
from the longer time of aphid exposure to those chemicals. In contrast, on the saturated bicyclic
-lactone ( )-treated leaves, there were less probes and an individual probe was 1.6 times longer than
on control leaves. It means that aphids were prevented from the withdrawal of their stylets from the
plant tissues by the addition of the -lactone ( ), which confirmed the strong attractant character of
δ
-lactone (
2
) and
δ
-hydroxylactone (
−
)-(4)
δ
-lactone (
2) and weak attractant
δ
−
4
δ
3
δ
3
this lactone to M. persicae that was found during the 24 h settling choice experiment.
A variety of compounds has been studied to find prospective aphid repellents or deterrents,
including DEET, the N,N-diethyl-m-methylbenzamide [27]. Very strong behaviour-modifying activities
towards M. persicae and other aphid species, e.g., Acyrthosiphon pisum and Rhopalosiphum maidis,
are shown by compounds of terpenoid character and certain plant essential oils that include lower
terpenoids, which was demonstrated by various researchers, e.g., [27–30]. Structural transformations
of the original molecule and enantiomeric purity can enhance or change the profile of this activity.
For example, the natural compound piperitone appeared rather neutral or weakly deterrent to
M. persicae and the introduction of a lactone moiety into the molecule caused a significant increase
in the deterrent activity [31].
β-Damascone appeared a weak attractant close to not active to
M. persicae, but modifications of its structure (lactonization, incorporation of halogen atoms) caused
the avoidance of treated leaves by aphids during settling and reluctance to probe in choice- and
no-choice experiments [26]. In another study, (R)-(+)-pulegone appeared a strong deterrent, while its
(S)-(−)-isomer did not have any effect on the behaviour of M. persicae [30].
Table 4. Immediate behavioural responses of Myzus persicae during initial 15 min. contact with plants
treated with dihydrojasmone (1) and alkyl-substituted δ-lactones (2), (3), and (−)-(4).
Compounds
Control
(1)
(2)
(−)-(4)
(3)
Time to 1st probe (s)
Total time on leaf (s)
Total time out of the leaf (s)
Total probing time (s)
Number of probes
25.6 (±8.5)
900.0 (±0.0)
0.0 (±0.0)
50.1 (±18.8)
21.3 (±7.1)
900.0 (±0.0)
0.0 (±0.0)
13.6 (±4.3)
900.0 (±0.0)
0.0 (±0.0)
67.9 (±37.0)
757.7 (±77.2) *
142.3 (±77.2) *
626.6 (±122.4)
1.6 (±0.3) *
644.1 (
±
±
±
118.8) *
255.9 (
118.8) *
110.0) *
735.3 (±47.4) 443.3 (
789.2 (±32.9)
2.6 (±0.5)
748.7 (±29.2)
3.7 (±0.4)
4.3 (±0.9)
2.8 (±0.8)
Mean probing time (s)
255.2 (±53.7)
236.7 (±91.7)
464.6 (±108.7)
268.2 (±75.7)
398.6 (±104.2)
Values represent means
significant differences in relation to control at p ≤ 0.05.
±
SE (= Standard Error). Time given in seconds, * asterisks indicate statistically

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In plant protection strategies that include the use of semiochemicals, both the attractants and
the deterrents may play an important role. The so-called stimulo-deterrent diversionary strategy
(=‘push–pull’ system) proposes the use of deterrents to ‘push’ the insect pest away from the crop and
attractants to ‘pull’ the pests to non-crop plants away from the protected field [32]. Considering the
results of the present experiments, the saturated bicyclic δ-lactone (3) with clear attractant properties
towards M. persicae seems a very prospective candidate for incorporation in integrated aphid control.
3. Materials and Methods
3.1. General Experimental Procedures
Analytical TLC was performed on aluminium plates coated with silica gel (Kieselgel 60, F254
,
Merck, Darmstadt, Germany) with mixture of hexane, acetone and diethyl ether in various ratios
as developing systems. Compounds were detected by spraying the plates with the solution of:
Ce(SO4)2 (1 g), H3[P(Mo3O10)4] (2 g) in 10% H2SO4, followed by heating to 120–200 ◦C.
Column chromatography was performed on silica gel (Kieselgel 60, 230–400 mesh ASTM, Merck)
with mixture of hexane, acetone and diethyl ether in various ratios as eluents.
Gas chromatography (GC) analysis was carried out on an Agilent Technologies 6890N Network
GC (Agilent Technologies, Waldbronn, Germany) equipped with flame ionization detector (FID) using
H2 as the carrier gas and capillary column (HP-5, 30 m
×
0.32 mm
×
0.25
µm). The temperature
◦
◦
◦
program was as follows: injector 250 C, detector (FID) 250 C, column temperature: 70 C, 70–175 ◦C
◦
◦
◦
◦
(rate 20 /min), 175–300 C (rate 40 /min), 300 C (hold 2 min); Rf (
Rf ( ) = 0.29, Rf ( ) = 0.50; tR ) = 2.8 min, tR ) = 3.5 min, tR
tR (5) = 3.1 min.
2) = 0.44, Rf (
3) = 0.35, Rf (4) = 0.58,
5
6
(
1
(
2
(3
) = 2.4 min, tR (4) = 4.2 min
,
Chiral gas chromatography was carried out on a CP-Chirasil-DEX CB (25 m × 0.25 mm × 0.25 µm
)
column (Varian/Chrompack, Middelburg, The Netherlands). Enantiomeric excesses were determined
with the following temperature program: injector 250 ◦C, detector (FID) 250 ◦C, column temperature:
80 ◦C, 80–200 ◦C (rate 0.6◦/min), 200 ◦C (hold 1 min); tR (+)-(
tR (+)-(5) = 110.4 min.
4
) = 113.7 min, tR ( )-(4) = 106.9 min,
−
1H-NMR, 13C-NMR, DEPT 135, HSQC and 1H-1H COSY spectra were recorded in CDCl3 solutions
on a Brüker Avance AMX 300 and 600 spectrometer (Bruker, Rheinstetten, Germany). Chemical shifts
were referenced to the residual solvent signal (δH 7.26, δC 77.0). IR spectra were determined using
Mattson IR 300 Thermo-Nicolet spectrophotometer (Mattson, Warszawa, Poland). Optical rotations
were determined on a JASCO P-200-Na polarimeter (Easton, PA, USA) in a version with an iRM
controller using dichloromethane as a solvent, concentration denoted in g/100 mL.
High resolution mass spectra (HRMS) were recorded using electron spray ionization (ESI)
technique on spectrometer Waters ESI-Q-TOF Premier XE (Waters Corp., Millford, MA, USA).
3.2. Chemical Synthesis
The solution of meta-chloroperbenzoic acid (m-CPBA) (16.17 g, 0.072 mol, 77%, Aldrich,
Saint Louis, MO, USA) in dichloromethane (20 mL) was dried over anhydrous MgSO4 and then
filtered on a funnel. Such prepared solution of peracid was added dropwised to the stirring solution of
dihydrojasmone (1) (4 g, 0.024 mol) (purchased from Sigma Aldrich) in anhydrous dichloromethane
(30 mL) cooled in ice bath. The mixture was then stirred for 48 h at room temperature. The progress of
the reaction was monitored with TLC and GC. When the reaction was completed the reaction mixture
was washed with sodium sulphite (Na2SO3) and sodium bicarbonate (NaHCO3), brine, dried over
anhydrous MgSO4 and filtered. The solvent was evaporated in vacuo. The crude mixture of products
was subjected to column chromatography. Elution with hexane/ether (2:1) (v/v) gave lactone (
2) and
epoxylactone (3) (23% and 5% yield, respectively).
1
3,4-Dihydro-5-methyl-6-pentyl-2H-pyran-2-one (
2
): Colorless liquid; H-NMR (CDCl3):
δ
(ppm) 0.88
(t, 3H, J = 7.2 Hz, CH3-11), 1.30–1.32 (m, 4H, CH2-9, CH2-10), 1.41 (s, 3H, CH3-12), 1.53-1.64 (m, 2H,

Molecules 2016, 21, 1226
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CH2-8), 1.75 (ddd, 1H, , J = 13.8, 10.2, 6.0 Hz, one of CH2-7), 1.89 (ddd, 1H, J = 13.8, 10.2, 5.4 Hz, one of
CH2-7), 2.09 (ddd, 1H, , J = 15.0, 13.2, 5.4 Hz, one of CH2-4), 2.23 (ddd, 1H, J = 15.0, 7.8, 1.8 Hz, one of
CH2-4), 2.42 (ddd, 1H, , J = 16.8, 5.4, 1.8 Hz, one of CH2-3), 2.58 (ddd, J = 16.2, 13.2, 7.8 Hz, one of
CH2-3), 13C-NMR (CDCl3):
δ (ppm) 210.13 (C-2), 175.19 (C-6), 89.99 (C-5), 31.56 (C-9), 31.20 (C-7),
27.61 (C-3), 26.02 (C-4), 23.59 (C-8), 22.50 (C-10), 17.98 (C-12), 13.95 (C-11). IR (film, cm−1): 1761 (s),
1154 (m). HRMS: calcd for C11H18O2 [M + H]+: 183.1385, found 183.1381.
5-Methyl-6-pentyl-1,13-dioxabicyclo[4.1.0]heptan-2-one (3 δ (ppm)
): Colorless liquid; 1H-NMR (CDCl3):
0.88 (t, 3H, J = 6.6 Hz, CH3-11), 1.26–1.34 (m, 4H, CH2-9, CH2-10), 1.41–1.46 (m, 2H, CH2-8), 1.51 (s, 3H,
CH3-12), 1.60 (m, 1H, one of CH2-7), 1.77 (m, 1H, one of CH2-7), 1.87 (ddd, 1H, J = 13.8, 9.6, 8.4 Hz,
one of CH2-4), 2.04 (ddd, 1H, J = 18.0, 9.6, 1.8 Hz, one of CH2-3), 2.24 (dd, 1H, J = 13.8, 9.6 Hz one of
CH2-4), 2.32 (ddd, 1H, J = 18.0, 9.6, 8.4 Hz, one of CH2-3), 13C-NMR (CDCl3):
δ (ppm) 212.13 (C-2),
69.51 (C-5), 67.44 (C-6), 32.09 (C-9), 31.93 (C-3), 27.61 (C-4), 24.62 (C-8), 23.51 (C-7), 22.47 (C-10),
16.58 (C-12), 13.96 (C-11). IR (film, cm−1): 1743 (s), 1458 (w), 1056 (w). HRMS: calcd for C11H18O3
[M + Na]+: 221.1154, found 221.1157.
3.3. Microorganisms
All microorganisms came from the Department of Chemistry Wrocław University of
Environmental and Life Sciences, City, Country. The fungi and yeast were grown and maintained on
Sabouraud 4% dextrose-agar slopes (Difco, Detroit, MI, USA) at 4 ◦C and freshly subcultured before
use in the transformation experiments. Exponentially growing cells were used as inoculums for all
the experiments. The composition of the culture medium was as follows: 3 g glucose; 1 g aminobac;
and 100 mL of water.
3.4. Screening Procedure
Erlenmayer flasks (300 mL), each containing 100 mL of the sterile medium, were inoculated with
◦
a suspension of microorganisms and then incubated for 48–72 h at 25 C on a rotatory shaker (150 rpm).
After full growth of the culture, 10 mg of a substrate dissolved in 1 mL of acetone was added. Control
cultivation with no substrate was also performed. To monitor the reactions, after 1, 2, 4, 6 and 9 days,
a 5-mL incubation mixture was withdrawn from each flask using a sterile syringe and immediately
extracted with dichloromethane (3
×
10 mL). The extracts were dried over MgSO4, concentrated in
vacuo and analysed by TLC. Quantitative analysis of the mixtures was performed by means of GC.
All experiments were carried out in triplicates. Results in Figure 3 are reported as means of triplicate
experiments ± standard deviations (SD).
3.5. Preparative Biotransformation
A portion of 1 mL of the pre-incubation culture solution were used to inoculate two or
three 2000 mL flasks, each containing 500 mL of the cultivation medium. The cultures were inoculated
◦
at 25 C for 48–72 h on a rotary shaker (150 rpm). Then, 50 mg of a substrate dissolved in 5 mL
of acetone was added to each flask. After 1–6 days (depends on the culture) of incubation, the
mixtures were extracted with dichloromethane (3
vacuo. The transformation products were separated by column chromatography. The yields of the
reactions, physical and spectral data of obtained products are given below:
×
300 mL), dried (MgSO4) and concentrated in
Biotransformation of (2) by F. culmorum AM10. Biotransformation of lactone (2) (0.1 g), after one day,
gave ( )-(4) (ee = 20%) as the only product. After column chromatography, 0.1 g (91% yield) of product
−
(−)-(4) was isolated, [α]2D0 = −2.11◦ (c = 0.95, CH2Cl2).
Biotransformation of (2) by F. equiseti AM15. Biotransformation of lactone (2) (0.1 g), after six days,
gave (+)-(4) (ee = 99%) as the only product. After column chromatography, 0.058 g (53% yield) of
product (+)-(4) was isolated, [α]2D0 = +4.80◦ (c = 1.45, CH2Cl2).

Molecules 2016, 21, 1226
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Biotransformation of (
2
) by B. bassiana AM278. Biotransformation of lactone (
2
) (0.1 g), after six days,
gave (+)-(
4) (ee = 99%) as the only product. After column chromatography, 0.008 g (7% yield) of
product (+)-(4) was isolated, [α]2D0 = +3.17◦ (c = 0.3, CH2Cl2).
Biotransformation of ( ) by D. igniaria KCh6670. Biotransformation of epoxylactone (3) (0.1 g),
3
after four days, gave (+)-(5) (ee = 99%) as the only product. After column chromatography, 0.048 g
(48% yield) of (+)-(5) was isolated, [α]2D0 = +1.52◦ (c = 1.5, CH2Cl2).
3.5.1. Identification of Product
5-Hydroxy-5-methyl-6-pentyltetrahydro-2H-pyran-2-one (4
): Colorless liquid; 1H-NMR (CDCl3), δ: 0.83 (t, 3H,
J = 6.8 Hz, CH3-11), 1.19–1.44 (m, 8H, one of CH2-7, CH2-8, CH2-9, CH2-10, -OH), 1.30 (s, 3H, CH3-12),
1.50 (m, 1H, one of CH2-7), 1.86 (m, 1H, one of CH2-4), 2.19 (m, 1H, one of CH2-4), 2.57 (two d, 2H,
J = 7.9 Hz, CH2-3), 3.46 (dd, 1H, J = 8.9 and 3.1 Hz, H-6). 13C-NMR (CDCl3),
δ: 177.33 (C-2), 89.26 (C-5),
76.90 (C-6), 31.70, 30.69 (C-7, C-9), 30.64 (C-4), 29.29 (C-3), 25.92 (C-8), 22.57 (C-10), 21.26 (C-12),
14.05 (C-11). IR (film, cm−1): 3445 (s), 1765 (s).
5-Methyl-6-pentyl-1,13-dioxabicyclo[4.1.0]heptan-2-ol (5 δ: 0.89 (t, 3H,
): Colorless liquid; 1H-NMR (CDCl3),
J = 7.0 Hz, CH3-11), 1.25–1.36 (m, 5H, CH2-10, CH2-9, one of CH2-3), 1.39 (s, 3H, CH3-12), 1.45 (ddd, 1H,
J = 13.8, 6.6, 1.8 Hz, one of CH2-4), 1.52-1.57 (m, 2H, CH2-8), 1.61 (s, 1H, -OH), 1.68 (ddd, 1H, J = 13.8,
9.6, 5.4 Hz, one of CH2-4), 1.86–1.89 (m, 2H, CH2-7), 2.09 (ddd, 1H, J = 14.4, 9.6, 6.6, one of CH2-3),
4.31 (d, 1H, J = 6.0 Hz, H-2). 13C-NMR (CDCl3),
δ: 73.52 (C-2), 71.49 (C-5), 68.09 (C-6), 32.26 (C-9),
30.53 (C-7), 29.79 (C-4), 25.50 (C-3), 25.04 (C-8), 22.65 (C-10), 15.46 (C-12), 14.05 (C-11). IR (film, cm−1):
3430 (s), 1457 (m).
3.5.2. Feeding Deterrent Activity—Bioassays
Insect cultures. In these studies, a laboratory-reared strain of the lesser mealworm collected
from poultry house litter in a local, commercial broiler farm located near Torun´ (Poland) was used.
◦
The colony was kept in glass containers in a rearing chamber at +29 C in the dark. As a food medium,
a mixture consisting of one part of oat flakes, one part of wheat bran, and 0.01 part of brewers’
yeast was applied. To maintain moisture levels at ca. 55%, fresh apple halves were placed in the
containers. Using the culture method of Rice and Lambkin [33], we obtained large numbers of insects
of approximately the same age for the tests.
The stock culture of the peach potato aphid was maintained as a multiclonal colony on Chinese
◦
cabbage Brassica rapa L. ssp. pekinensis L. under laboratory conditions at 65% R.H., 20 C, and long day
photoperiod (L16:8D) in a growing chamber Sanyo MLR-351H (Sanyo Electronics Co. Ltd., Moriguchi,
Japan). To maintain colony vitality, apterous aphids were transferred to non-infested plants every
other week. For all experiments involving aphids, one to seven days old adult apterous females of
M. persicae were collected from the stock culture.
Feeding deterrent activity tests. The feeding deterrent activities of compounds studied against larvae
and adults of A. diaperinus were determined by using the standard method of choice and no-choice
tests as previously described by Gliszczyn´ska et al. [22]. For the feeding assays, acetone solutions of
the test compounds at a concentration of 10 mg
mL−1 were prepared. A dose of 1 mL of solution or
·
acetone alone as control was applied to 1 g of oat flakes (Melvit, Warsaw, Poland) by micropipette.
After evaporation of the solvent (30 min of air drying), the flakes were weighed and offered to 10 larvae
(25–30 days old) or 10 unsexed adults (7–10 days old) during the following three-day period. In the
choice test, both control and treated oat flakes were placed together in a Petri dish (15 cm diameter),
with the control flakes separated from the treated flakes by a thin glass capillary. In the no-choice
test, insects were exposed to only one kind of food—treated or control. Dishes were kept in the
◦
rearing chamber at 29
±
1 C in the dark. After three days of feeding and the re-weighing of the

Molecules 2016, 21, 1226
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remaining flakes, the relative (R) and absolute (A) deterrence coefficients were calculated using the
following formula:
R = (C − E)/(C + E) × 100
where C and E are the weights of the control and treated foods consumed by the insects in the choice
test, respectively. The absolute deterrence coefficient A was calculated using the same formula, but C
and E were obtained from no-choice test. The measure of the deterrent activity of tested compounds is
the total coefficient of deterrence: T = A + R. The total coefficient of deterrence, which ranged from
−
200 to 200, served as the index activity. The compounds with T values ranging from 151 to 200 are
very good deterrents, those with T values lower than 50 are weak deterrents. The remaining values
indicate good (101–150) or moderate (51–100) antifeedant activity. Negative T values point to attractant
properties of the compound.
Aphid responses to the compounds studied were measured as a settling success in the choice
situation and initial aphid responses in no-choice test, as described previously [22]. The compounds
studied were applied as 0.1% solutions in 70% ethanol to the test leaves of Chinese cabbage that were
detached from plants grown in the laboratory at 65% R.H., 20 ◦C, and long-day photoperiod (L16:8D)
in a growing chamber Sanyo MLR-351H (Sanyo Electronics Co. Ltd.). For uniform distribution of the
compound, the leaves were immersed in the studied solutions for 20 s. Control leaves were immersed
in 70% ethanol. For aphid settling bioassay, control and treated leaves were placed in the Petri dish
and the test aphids were placed in an equal distance from either leaf. The leaves were offered to aphids
1 h after the application of the studied solutions to allow the evaporation of the solvent. Aphids that
settled on each leaf were counted 1, 2, and 24 h after having access to the leaves (8 replicates, 20 adult
apterous aphids/replicate). Aphids that did not settle on any of the leaves were discarded from
calculations. The results were statistically analyzed using Student t-test: the number of aphids on
control leaves was compared to the number of aphids on the test leaf for each compound/time interval
separately. In the initial response bioassay, aphid behaviour was studied by direct observation of
the freely moving individuals on a leaf treated with the tested compounds, using a video camera.
The experiment was carried out for 15 min (16 aphids/compound). The duration of probing was
recorded basing on the relationship between antennal and body movements and penetration of the
stylets as described by Hardie et al. [34]. The position of antennae parallel to the abdomen and the
cessation of body movements were associated with stylet penetration. The total time spent by aphids
on leaves, total probing time, number of probes, and mean probing time were determined from this
experiment. The data were analysed using one-way ANOVA followed by the Tukey test.
4. Conclusions
In conclusion, we introduced chemical Baeyer–Villiger oxidation and an enantioselective
fungi-mediated conversion to produce novel alkyl-substituted
The experiments confirmed that the lactone moiety and additional oxygen function introduced into
the structure of dihydrojasmone ( ) significantly increased and altered the quality of its activity.
The activities of dihydrojasmone ( ) and its derivatives ( ) were species- and developmental
stage-specific. The most potent antifeedant activity against A. diaperinus was determined for
-hydroxylactone ( )-( ), which strongly inhibited the feeding of larvae and adults. The saturated
δ-lactones from dihydrojasmone (1).
1
1
2–5
δ
−
4
bicyclic δ-lactone (3) expressed clear attractant properties towards M. persicae.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/
9/1226/s1.
Acknowledgments: This project was financed by European Union from the European Regional Development
Found Grant No. POIG.01.03.01-00-158/09-03. Publication was supported by Wroclaw Centre of Biotechnology,
programme The Leading National Research Centre (KNOW) for years 2014-2018 (http://know.wroc.pl).
Author Contributions: Anna Gliszczyn´ska suggested the research work, designed the experiments, carried out
the experimental work, chemical synthesis of lactones and biotransformation of 3,4-dihydro-5-methyl-6-pentyl-2H-
pyran-2-one (2) and epoxylactone (3) analyzed the results of chemical synthesis and microbial transformation,

Molecules 2016, 21, 1226
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determined the structures of all products discussed in the paper, and wrote the paper. Damian Semba contributed
to synthesis and biotransformations of epoxylactone ( ). Maryla Szczepanik performed the biological assay
3
towards A. diaperinus and contributed to writing the biological part of the manuscript. Katarzyna Dancewicz
evaluated the antifeedant activity of studied compounds towards M. persicae. Beata Gabrys´ analyzed the results of
antifeedant activity of studied compounds towards aphids and contributed to writing the biological part of the
manuscript. Anna Gliszczyn´ska, Maryla Szczepanik, Beata Gabrys´ contributed reagents/materials/analysis tools.
All authors read and approved the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 1–3 are available from the authors.
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