Identification, synthesis and mass spectrometry of a macrolide from the African reed frog Hyperolius cinnamomeoventris

Article abstract of DOI:10.3762/bjoc.12.269

The contents of the gular glands of the male African reed frog Hyperolius cinnamomeoventris consist of a mixture of aliphatic macrolides and sesquiterpenes. While the known macrolide gephyromantolide A was readily identified, the structure of another major component was suggested to be a tetradecen-13-olide. The synthesis of the two candidate compounds (Z)-5- and (Z)-9-tetradecen-13-olide revealed the former to be the naturally occurring compound. The synthesis used ring-closing metathesis as key step. While the Hoveyda-Grubbs catalyst furnished a broad range of isomeric products, the (Z)-selective Grubbs catalyst lead to pure (Z)-products. Analysis by chiral GC revealed the natural frog compound to be (5Z,13S)-5-tetradecen-13-olide (1). This compound is also present in the secretion of other hyperoliid frogs as well as in femoral glands of male mantellid frogs such as Spinomantis aglavei. The mass spectra of the synthesized macrolides as well as their rearranged isomers obtained during ring-closing metathesis showed that it is possible to assign the location of the double bond in an unsaturated macrolide on the basis of its EI mass spectrum. The occurrence of characteristic ions can be explained by the fragmentation pathway proposed in the article. In contrast, the localization of a double bond in many aliphatic open-chain compounds like alkenes, alcohols or acetates, important structural classes of pheromones, is usually not possible from an EI mass spectrum. In the article, we present the synthesis and for the first time elucidate the structure of macrolides from the frog family Hyperoliidae.

Full text of DOI:10.3762/bjoc.12.269

Identification, synthesis and mass spectrometry of a
macrolide from the African reed frog
Hyperolius cinnamomeoventris
Markus Menke1,§, Pardha Saradhi Peram1,§, Iris Starnberger2, Walter Hödl2,
Gregory F.M. Jongsma3, David C. Blackburn3, Mark-Oliver Rödel4, Miguel Vences5
and Stefan Schulz*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 2731–2738.
1Technische Universität Braunschweig, Institute of Organic
Chemistry, Hagenring 30, 38106 Braunschweig, Germany,
2Department for Integrative Zoology, Althanstraße 14, 1090 Vienna,
Austria, 3Florida Museum of Natural History, University of Florida,
Gainesville, Florida 32611, United States of America, 4Museum für
Naturkunde, Leibniz Institute for Evolution and Biodiversity Science,
Invalidenstr. 43, 10115 Berlin, Germany and 5Technische Universität
Braunschweig, Institute of Zoology, 38106 Braunschweig, Germany
doi:10.3762/bjoc.12.269
Received: 28 September 2016
Accepted: 02 December 2016
Published: 13 December 2016
This article is part of the Thematic Series "Lipids: fatty acids and
derivatives, polyketides and isoprenoids".
Email:
Guest Editor: J. S. Dickschat
Stefan Schulz* - stefan.schulz@tu-bs.de
© 2016 Menke et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
§ Βoth authors share first authorship.
Keywords:
chemical communication; chiral gas chromatography; macrocyclic
lactones; ring-closing metathesis; pheromones
Abstract
The contents of the gular glands of the male African reed frog Hyperolius cinnamomeoventris consist of a mixture of aliphatic
macrolides and sesquiterpenes. While the known macrolide gephyromantolide A was readily identified, the structure of another
major component was suggested to be a tetradecen-13-olide. The synthesis of the two candidate compounds (Z)-5- and (Z)-9-
tetradecen-13-olide revealed the former to be the naturally occurring compound. The synthesis used ring-closing metathesis as key
step. While the Hoveyda–Grubbs catalyst furnished a broad range of isomeric products, the (Z)-selective Grubbs catalyst lead to
pure (Z)-products. Analysis by chiral GC revealed the natural frog compound to be (5Z,13S)-5-tetradecen-13-olide (1). This com-
pound is also present in the secretion of other hyperoliid frogs as well as in femoral glands of male mantellid frogs such as Spino-
mantis aglavei. The mass spectra of the synthesized macrolides as well as their rearranged isomers obtained during ring-closing me-
tathesis showed that it is possible to assign the location of the double bond in an unsaturated macrolide on the basis of its EI mass
spectrum. The occurrence of characteristic ions can be explained by the fragmentation pathway proposed in the article. In contrast,
the localization of a double bond in many aliphatic open-chain compounds like alkenes, alcohols or acetates, important structural
classes of pheromones, is usually not possible from an EI mass spectrum. In the article, we present the synthesis and for the first
time elucidate the structure of macrolides from the frog family Hyperoliidae.
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Beilstein J. Org. Chem. 2016, 12, 2731–2738.
Introduction
The lactone motif is found in many compounds that are used in the case in many insect pheromones. In typical pheromone com-
chemical communication. Among them, macrocyclic lactones ponents of insects, including long chain alkenes, alkenols, or
are an important class because of their biosynthetic availability unsaturated aldehydes, the location of the double bond can
and their inherent compound properties. During the biosynthe- usually not be determined by analysis of their mass spectra.
sis of macrocyclic lactones, a fatty acid precursor is often Positional isomers often exhibit almost identical spectra [6] and
oxidized near the end of the chain to form a polar hydroxy acid. derivatization or special mass spectrometric techniques are
The following ring-closure reduces the hydrophilicity of the needed to localize double bonds [7-9]. Because this might also
compound and increases its vapor pressure, making the result- be the case for macrolides [10], it is of interest for their identifi-
ing macrocycle well-suited to serve as a signal [1]. Fatty acid cation to compare mass spectra of positional isomers of unsatu-
derived macrolactones were therefore repeatedly invented rated macrolactones. Furthermore, a fast synthetic strategy is
during evolution and are used by different animals such as bees, needed to synthesize various isomers. In the present work we
beetles, butterflies, cockroaches, or frogs as pheromones [1].
describe 1) the identification of macrolides from H. cinnamo-
meoventris, 2) discuss EI mass spectra of unsaturated macrolac-
Finding and choosing mates in frogs is usually regarded as tones, and 3) show how ring-closing metathesis reaction condi-
being primarily acoustically mediated. Nevertheless, some tions can be selected to obtain either pure compounds or a
families like the Mantellidae from Madagascar also use chemi- library of compounds useful for evaluation of their mass spec-
cal cues. Macrocyclic lactones such as phoracantholide I (3), tra.
phoracantholide J (4) or gephyromantolide A (5), are released
by males from femoral glands to serve as signals, often accom- Results and Discussion
panied by secondary alcohols (Figure 1) [2-4]. Another frog The GC–MS analysis of a gular gland extract of Hyperolius
family most likely using volatile compounds during courtship cinnamomeoventris showed the presence of several unknown
are the African reed frogs, Hyperoliidae. The males of most compounds, sesquiterpenes and macrolides (Figure 2).
species emit acoustic cues to attract females. During the call, an
often conspicuously colored gland on their vocal sac (the gular
gland), only innervated during the mating season in at least
some species, releases a complex blend of volatiles when
exposed [5]. A first analysis revealed the presence of mostly
unknown terpenes, macrolides and other components in species
specific compositions [5].
Detailed exploration of the function of these frog volatiles
requires the analysis of the secretion and the synthesis of the
identified compounds for biological testing. Because of the
small amount of natural material available, only GC–MS inves-
tigations can be used to identify the compounds. The analysis
revealed unsaturated macrocyclic lactones to be major
constituents of the secretion of the cinnamon-bellied reed frog,
Figure 2: Total ion chromatogram of the gular gland extract of Hyper-
olius cinnamomeoventris. X: frog anaesthetic ethyl 3-aminobenzoate.
Hyperolius cinnamomeoventris. The location and configuration
of the double bond might be relevant for their function, as it is
Figure 1: Macrolactones produced in scent glands of frogs: (Z)-Tetradec-5-en-13-olide (1) or (Z)-tetradec-9-en-13-olide (2), phoracantolide I (3),
phoracantolide J (4), gephyromantolide A (5).
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Beilstein J. Org. Chem. 2016, 12, 2731–2738.
Gephyromantolide A (5), known from the mantellid frog canoic acid, on which a common Δ9-desaturase is acting,
Gephyromantis boulengeri [4], was readily identified. A second leading after ω − 1 oxidation and ring closure to tetradec-9-en-
macrolide (A in Figure 2) showed a mass spectrum similar to 13-olide (2). Therefore, we opted to synthesize 2 as well.
that reported for (Z)-tetradec-5-en-13-olide (1) by Millar et al.
[11], exhibiting a molecular ion at m/z 224. This macrolide, To allow later enantiomer determination of A, an enantioselec-
called cucujolide III, is used by the flat grain beetle Cryp- tive synthetic strategy was followed. Several synthetic routes
tolestes pusillus as pure (S)-enantiomer and by C. turcicus as a for the synthesis of 1 have been reported [16-20]. These synthe-
33:67 R/S mixture [12], and acts as a synergist to the respective ses were performed before the advent of ring-closing metathe-
pheromones [11,13]. Microhydrogenation of the frog extract sis (RCM), requiring more than 10 steps each. RCM can shorten
furnished 13-tetradecanolide, thus confirming compound A to the synthesis remarkably, but requires careful selection of the
be a 13-tetradecenolide. The double bond position in this RCM catalyst to control the double bond configuration. For ex-
macrolide likely is at C-5, because of the similarity of the mass ample, Fürstner and Langemann obtained rac-1 in 31:69 (E/Z)-
spectrum to that of the beetle macrolide. Nevertheless, because mixture using a Ru-carbene type catalyst similar to a Grubbs I
locating double bonds in such compounds based on the mass catalyst [21].
spectrum alone seemed not to be reliable, we opted to synthe-
size two positional isomers.
The synthesis of (R)-2 using RCM as key step is shown in
Scheme 1. Enantiomerically pure 1,2-epoxyhex-5-ene (6) was
Compound 1 is biosynthetically formed by the Cryptolestes obtained by Jacobsen hydrolytic kinetic resolution on commer-
beetles starting from oleic acid [14] that is shortened to cially available 6 (Scheme 1) [22,23]. Surprisingly, the yield of
5-tetradecenoic acid, followed by ω − 1 oxidation and ring 69% of the (R)-enantiomer was higher than the theoretically
closure [15]. Another possibility would be that a common satu- upper limit of 50%. We discovered that 6, sold by Acros
rated acid such as stearic acid is chain-shortened first to tetrade- Organics as racemic compound, was actually enriched in the
Scheme 1: Synthesis of (9Z,13R)-tetradec-9-en-13-olide (2).
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desired (R)-enantiomer (see Supporting Information File 1 for
optical rotation values). Diene (R)-9 was obtained by reduction
of the epoxide 6 with LiAlH4 to form alcohol (R)-7, followed
by esterification with 9-decenoic acid (8) using 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (EDC) and 4-(dimethyl-
amino)pyridine (DMAP) [24,25]. The following RCM was per-
formed using Grubbs–Hoveyda II catalyst (11) and hexafluoro-
benzene as an additive [26]. During the reaction isomerization
occurred, leading to a mixture of positional isomers and chain
shortened as well as elongated products. Addition of p-benzo-
quinone [27] and improved purification methods [28] sup-
pressed isomer formation only partially. Replacing catalyst 11
with the Grubbs second generation catalyst (1,3-bis(2,4,6-tri-
methylphenyl)-2-imidazolidinylidene)dichloro(phenylmeth-
ylene)(tricyclohexylphosphine)ruthenium reduced the isomeri-
zation, leading to an (E/Z)-mixture of 2. Finally, the (Z)-selec-
tive Grubbs catalyst 12 furnished the best results [29,30]. This
catalyst yielded only the desired product (R)-2 with a (Z)-
configured double bond, although in moderate yield (see Sup-
porting Information File 1 for full experimental data).
A similar synthetic strategy was applied for the synthesis of
macrolide 1 (Scheme 2). The stereogenic center was introduced
using commercially available (R)-propylene oxide (13) as
starting material. After copper-catalyzed opening of the epoxide
with 6-heptenylmagnesium bromide obtained from 7-bromo-1-
heptene (14) and Steglich esterification with 5-hexenoic acid
(16), RCM using (Z)-selective Grubbs catalyst 12 was used to
synthesize macrolide (R)-1 without any isomerization. Compar-
ison of the mass spectra (Figure 3) and gas chromatographic
retention times of pure (Z)-1, the (E/Z)-mixture obtained by the
Hoyveda–Grubbs II catalyst, and 2 with those of the natural
compound proved the frog compound to be (Z)-tetradec-5-en-
13-olide (1).
Figure 3: Mass spectra of A) the natural compound A, B) (Z)-tetradec-
5-en-13-olide (1), and C) (Z)-tetradec-9-en-13-olide (2). Characteristic
ions useful for location of the double bond are marked in red.
Scheme 2: Synthesis of (5Z,13R)-tetradec-5-en-13-olide ((R)-1). The enantiomer was obtained in a similar sequence, starting from (S)-propylene
oxide instead of 13.
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For the determination of the absolute configuration of the With the synthetic material in hand, we analyzed the EI mass
natural compound, the other enantiomer (S)-1 was needed as spectra of 1 and 2. No significant differences were detectable
well. It was synthesized according to the synthesis shown in between the E/Z-isomers of each compound. Nevertheless, con-
Scheme 2, starting from (S)-propylene oxide instead of the (R)- trary to open chain compounds, characteristic differences could
enantiomer 13. The stereochemistry was determined by chiral be found for the positional isomers. While most ions are similar
gas chromatography as shown in Figure 4. The coinjection of in both spectra, the prominent ion m/z 126 present in 1 is shifted
pure (S)-1 with the racemic mixture proved the first eluting to m/z 182 in 2. These ions can be used to assign the location of
peak to be this enantiomer. Injection of the natural sample as the double bond in the macrocyclic ring.
well as (S)-1 showed both compounds to be enantiomerically
pure. Finally, coinjection of both samples showed their identity. A possible fragmentation pathway leading to these ions is
shown in Figure 5. One can speculate that after ionization of the
double bond in 1 an allylic cleavage occurs, leading to the
radical cation 18 along pathway a. An additional bond cleavage
of a C–O single bond releases a neutral molecule, e.g., methyl-
cyclohexane, giving rise to ion m/z 126 (20). High-resolution
mass spectral data support the hypothesis because the ions
m/z 126 as well as m/z 182 (25) formed from 2 have a molecu-
lar composition of C7H10O2 (HRMS: 126.07005 found, calcd.
126.0681) or C11H18O2 (HRMS: found 182.13206, calcd.
182.1307), respectively. Ion 20 is accompanied by the ion
m/z 140 (HRMS: found 140.08545, calcd. 140.08373) of the
same ion series CnH2n–4O2 that occurs in lower abundance. Its
formation along pathway b can be explained by homoallylic
cleavage of 18 into 21 and further fragmentation into 22. The
formation of the ions of this series is obviously determined by
the position of the double bond in the chain. Therefore, ion
m/z 182 of 2 arises by the same mechanism, indicating the loca-
tion of the double bond at C-9 (Figure 5). A b-type ion cannot
be formed, because pathway b is not operative due to the close
proximity of the C–O group. The pathways shown in Figure 5
are speculative. Another possible mechanisms leading to the
same ions and starting with ionization of the C–O oxygen atom
instead of the double bond is shown in Supporting Information
File 1 (see Figure S1). Nevertheless, the proposal is useful to
predict the position of double bonds in mono-unsaturated
macrolides. This position can be deduced from the ion
Cn+4H2n+4O2, generated by a double bond in the n + 2 position,
as shown in 26.
We subsequently tested our method with mass spectra of other
macrolides previously reported or present in our compound
library. In the mass spectra of (Z)-octadec-9-en-13-olide [31]
and octadec-9-en-17-olide peaks at m/z 182 with higher and
m/z 196 with lower intensity are present, consistent with a C-9
Figure 4: Total ion chromatogram of the enantiomer separation of
(Z)-1 on a chiral β-TBDMS- Hydrodex phase. Temperature program:
isothermal for 60 min at 110 °C, then with 2 °C/min to 160 °C, followed
by a sharp ramp with 25 °C/min to 220 °C. A) Racemic mixture,
B) coinjection of racemic mixture and (S)-1, C) natural extract, D) coin-
jection of the natural extract and (S)-1, E) Overlay of A and C showing
that the minor peak present in the extract is not the (R)-enantiomer of
1. Black: racemate, red: natural extract. Peak identities were con-
firmed by mass spectrometry.
double bond. In contrast, (Z)-octadec-11-en-13-olide does not
show such ions, because the close proximity of the double bond
and the C–O group does not allow fragmentation along path-
way a or b. The spectra of 4-methyl-5-decen-9-olide and
8-methyl-5-decen-9-olide [3] exhibit the expected ions m/z 140
and m/z 126, respectively. Pathway b is not operative because of
the proximity of the C–O group. A slight alteration of the frag-
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Figure 5: Proposed mass spectrometric fragmentation of macrolides 1 and 2 leading to diagnostic ions of the ion series CnH2n−4O2 (Cn+4H2n+4O2 in
the figure), indicating the position of the double bond in the ring.
mentation can be observed if the double bond is located at C-4, unsaturated macrolides. The procedure may also be applicable
as in phoracantholide J, 4-decen-9-olide [32]. Now in pathway for di- or triunsaturated compounds.
a, additionally an H-atom is transferred leading to the uneven
ion CnH2n−3O2, m/z 113, while pathway b remains unchanged, We then focused on the products of the RCM using the
furnishing m/z 126. In the methylated analog 6-methyl-4-decen- Hoveyda–Grubbs II catalyst 11. It is well known that during
9-olide [3], these ions shift to m/z 127 and 140. If the double RCM isomerization of the double bond might occur, especially
bond moves closer to the C=O group as in 3-dodecen-11-olide with the Grubbs second generation catalysts, leading to prod-
[33], both ions a and b are visible, but their abundance is so low ucts with migrated double bonds or smaller ring size [27,34-36].
that their diagnostic value is largely decreased. Another limita- Both types of products, 11-dodecenolides, 12-tridecenolides and
tion is that mass spectra of unsaturated unbranched macrolac- isomerized 13-tetradecenolides were obtained. In addition, ring
tones, formally derived from ω-hydroxy acids, do not show the expanded 14-pentadecenolides were observed. The latter can be
characteristic ions generated by pathways a or b. Obviously, the explained by dimerization of esters 9 or 17, isomerization of the
primary C–O bond is not attacked by intermediates like 19. double bond, and final ring closure, leading to either ring-
Nevertheless, the mass spectrometric interpretation presented contracted or expanded products. Such processes have been re-
here will largely ease the identification of a broad range of ported before in polymerization experiments using Grubbs cata-
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Beilstein J. Org. Chem. 2016, 12, 2731–2738.
lysts [36-38]. While the isomerization is usually regarded as a gland with the mating period, its location and use during
negative side reaction in RCM, it turned out to be advantageous calling, and its male-specific occurrence strongly hint to a func-
for the identification of naturally occurring macrolides in our tion of 1 and 5 as signaling compounds and a role in the chemi-
hands. The isomerized mixtures constitute a library of closely cal ecology of this species.
related macrolides differing slightly in position of double bonds
and ring size. With the diagnostic mass spectrometric ions
Supporting Information
discussed above, each compound can be assigned a structure
after GC–MS analysis. These mass spectra together with the
Supporting Information File 1
gas chromatographic retention index are stored in our EIMS
database, easing identification of similar compounds in the
future. Using this approach, we could collect mass spectra
of 5-dodecen-11-olide, 5- and 6-tridecen-12-olide, 5- to
9-tetradecen-13-olide, as well as 5- and 6-pentadec-14-olide
(see Supporting Information File 1 for some spectra). This set
of mass spectra allowed the identification of macrolides in other
frog species.
Experimental procedures, mass spectra of macrolides,
alternative fragmentation pathway, enantiomer separation
by GC–MS, 1H and 13C NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-269-S1.pdf]
Acknowledgements
Work in Madagascar was carried out in the framework of a
collaboration accord between TU Braunschweig and the
Université d'Antananarivo, Département de Biologie Animale.
We are grateful to the Malagasy authorities for research and
export permits. Specimen collection in Rwanda was conducted
within a collaboration between the University of Vienna and the
University of Koblenz-Landau, Germany. We would like to par-
ticularly thank M. Dehling and P. M. Maier for their support.
Specimen collection and export was authorized by the Rwanda
Development Board. The Cameroon Ministry of Forests and
Wildlife (MINFOF) and Ministry of Scientific Research and
Innovation (MINRESI) provided necessary permits for conduct-
ing research and exportation in Cameroon.
We also found macrolide 1 in the gular glands of other hyper-
oliids including H. concolor, H. adametzi, and Afrixalus
dorsalis. It occurs also outside this frog family. It is a major
constituent of the femoral gland of the mantellid frog Spino-
mantis aglavei, again in (S)-configuration. Minor amounts of 1
were also present in the glands of an undescribed species of
Guibemantis similar to G. bicalcaratus as well as in Gephyro-
mantis ceratophrys, accompanied by the isomer 8-tetradecen-
13-olide in the latter species.
Conclusion
RCM using the (Z)-selective Grubbs catalyst 12 is a convenient
strategy to prepare unsaturated macrocyclic lactones in a short
sequence. Although isomerization is usually regarded as a Our study received financial support from the Deutsche
disadvantage of RCM, it can be used to allow fast access to Forschungsgemeinschaft (DFG Schu984/10-1, MM, PP, SS),
mass spectra of several isomers, helpful for the structure eluci- the Austrian Science Fund (FWF): P25612 (IS, WH), and the
dation of natural compounds, e.g., in chemical ecology or US National Science Foundation (DEB-1202609, DCB), and
fragrance research. The mass spectral fragmentation of under the approval of the Institutional Animal Care and Use
macrolides differs markedly from that of open-chain esters, Committee (2014-2) at the California Academy of Sciences.
because initial bond cleavage often does not lead to the release
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