Identification and synthesis of macrolide pheromones of the grain beetle oryzaephilus surinamensis and the frog spinomantis aglavei

Article abstract of DOI:10.1002/chem.201304414

Macrolide lactones, the so called cucujolides derived from unsaturated fatty acids, are aggregation pheromones of cucujid grain beetles. Thirty years ago, Oehlschlarger etaal. showed that (3Z,6Z)-dodeca-3,6-dien-11-olide (4) and the respective 12-olide (7) attract the sawtoothed grain beetle Oryzaephilus surinamensis, whereas (5Z,8Z,13R)-tetradeca-5,8-dien-13-olide (5) increases the response synergistically. The frass of this beetle is attractive for its parasitoid Cephalonomia tarsalis, which potentially can be used for pest control. A GC/MS analysis of attractive frass showed the presence of 5, together with an unknown isomer. CucujolideaV was tentatively identified also in the femoral glands, pheromone-releasing structures, of the Madagascan mantelline frog Spinomantis aglavei. Therefore, a new route to synthesize doubly unsaturated macrolides allowing the flexible attachment of the side chain was developed. A straightforward method to obtain Zaconfigured macrolides involves ring-closing alkyne metathesis (RCAM) followed by Lindlar-catalyzed hydrogenation. This methodology was extended to homoconjugated diene macrolides by using RCAM after introduction of one Zaconfigured double bond in the precursor by Wittig reaction. A tungsten benzylidyne complex was used as the catalyst in the RCAM reaction, which afforded the products in high yield at room temperature. With the synthetic material at hand, the unknown isomer was identified as the new natural product (5Z,8Z,12R)-tetradeca-5,8-dien-12-olide, cucujolideaX (8). Furthermore, the route also allowed the synthesis of cucujolideaV in good yield. The natural products were identified by the synthesis of enantiomerically pure or enriched material and gas chromatography on chiral phases. The new macrolide (R)-8 proved to be biologically active, attracting female O.asurinamensis, but no males. The synthetic material allowed the identification of (R)-5 in both the beetle and the frog. Attractive synthesis: Females of the sawtoothed grain beetle Oryzaephilus surinamensis are attracted to the new macrolide (5Z,8Z,12R)-tetradeca-5,8-dien-12-olide, cucujolideaX, prepared by using a combination of Wittig reaction and ring-closing alkyne metathesis (RCAM; see scheme). The synthetic approach also allows the synthesis of the similar cucujolideaV, used by both the beetle and the mantellid frog Spinomantis aglavei.

Full text of DOI:10.1002/chem.201304414

DOI: 10.1002/chem.201304414
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&
Natural Products
Identification and Synthesis of Macrolide Pheromones of the Grain
Beetle Oryzaephilus Surinamensis and the Frog Spinomantis Aglavei
Susann Hçtling,[a] Birte Haberlag,[b] Matthias Tamm,[b] Jana Collatz,[c] Patrick Mack,[d]
Johannes L. M. Steidle,[d] Miguel Vences,[e] and Stefan Schulz*[a]
Abstract: Macrolide lactones, the so called cucujolides de-
rived from unsaturated fatty acids, are aggregation phero-
mones of cucujid grain beetles. Thirty years ago, Oehlschlar-
ger et al. showed that (3Z,6Z)-dodeca-3,6-dien-11-olide (4)
and the respective 12-olide (7) attract the sawtoothed grain
beetle Oryzaephilus surinamensis, whereas (5Z,8Z,13R)-tetra-
deca-5,8-dien-13-olide (5) increases the response synergisti-
cally. The frass of this beetle is attractive for its parasitoid
Cephalonomia tarsalis, which potentially can be used for
pest control. A GC/MS analysis of attractive frass showed the
presence of 5, together with an unknown isomer. Cucujol-
ide V was tentatively identified also in the femoral glands,
pheromone-releasing structures, of the Madagascan mantel-
line frog Spinomantis aglavei. Therefore, a new route to syn-
thesize doubly unsaturated macrolides allowing the flexible
attachment of the side chain was developed. A straightfor-
ward method to obtain Z configured macrolides involves
ring-closing alkyne metathesis (RCAM) followed by Lindlar-
catalyzed hydrogenation. This methodology was extended
to homoconjugated diene macrolides by using RCAM after
introduction of one Z configured double bond in the precur-
sor by Wittig reaction. A tungsten benzylidyne complex was
used as the catalyst in the RCAM reaction, which afforded
the products in high yield at room temperature. With the
synthetic material at hand, the unknown isomer was identi-
fied as the new natural product (5Z,8Z,12R)-tetradeca-5,8-
dien-12-olide, cucujolide X (8). Furthermore, the route also
allowed the synthesis of cucujolide V in good yield. The nat-
ural products were identified by the synthesis of enantio-
merically pure or enriched material and gas chromatography
on chiral phases. The new macrolide (R)-8 proved to be bio-
logically active, attracting female O. surinamensis, but no
males. The synthetic material allowed the identification of
(R)-5 in both the beetle and the frog.
Introduction
this ground-breaking work, macrolides with ring sizes between
10 and 19 were identified as pheromones or other semiochem-
icals in various other insects[2] and frogs,[3,4] and constitute
a major motif of pheromones. Both males and females of cucu-
joidae are attracted to species-specific combinations of several
macrolides.[1] The aggregation pheromones of five species of
the genera Cryptolestes (Laemophloeidae) and Oryzaephilus (Sil-
vanidae) were elucidated, comprising seven macrolides as
active pheromone components: (4E,8E)-4,8-dimethyldeca-4,8-
dien-10-olide (ferrulactone I or cucujolide I, 1) produced by
About 30 years ago, Oehlschlager et al. discovered a new class
of pheromones, macrolide lactones, in economically important
grain beetles of the superfamily Cucujoidea (Figure 1).[1] After
[a] S. Hçtling, Prof. Dr. S. Schulz
Institut fꢀr Organische Chemie
Technische Universitꢁt Braunschweig
Hagenring 30, 38106 Braunschweig (Germany)
E-mail: stefan.schulz@tu-bs.de
[b] Dr. B. Haberlag, Prof. Dr. M. Tamm
Institut fꢀr Anorganische und Analytische Chemie
Technische Universitꢁt Braunschweig
Hagenring 30, 38106 Braunschweig (Germany)
[c] Dr. J. Collatz
Eidgençssische Forschungsanstalt
Agroscope Reckenholz-Tꢁnikon ART
Reckenholzstrasse 191, 8046 Zꢀrich (Switzerland)
[d] P. Mack, Prof. Dr. J. L. M. Steidle
Institut fꢀr Zoologie, Universitꢁt Hohenheim
70593 Stuttgart (Germany)
[e] Prof. Dr. M. Vences
Zoologisches Institut, Technische Universitꢁt Braunschweig
Spielmannstrasse 8, 38106 Braunschweig (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304414. Experimental procedure, copies
Figure 1. Cucujolides used as aggregation pheromones by cucujoid beetles.
The cucujolides are numbered according to Oehlschlager et al.[1]
1
of the H NMR and 13C NMR spectra.
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C. ferrugineus, (Z)-3-dodecen-11-olide (ferrulactone II or cucujo-
lide II, 2) produced in the S configuration by C. ferrugineus and
in the R configuration by O. mercator, (Z)-tetradec-5-en-13-olide
(cucujolide III, 3) used in the S configuration by C. pusillus and
in a 33:67 R/S mixture by C. turcicus, (3Z,6Z,11R)-dodeca-3,6-
dien-11-olide (cucujolide IV, 4) by O. surinamensis, and O. mer-
cator, (5Z,8Z,13R)-tetradeca-5,8-dien-13-olide (cucujolide V, 5)
produced by O. surinamensis and also by C. turcicus in a 85:15
R/S mixture, (Z)-dodec-3-en-12-olide (cucujolide VIII, 6) by
C. pusillus and (3Z,6Z)-dodeca-3,6-dien-12-olide (cucujolide IX,
7).[5,6] Both males and females of the sawtoothed grain beetle
Oryzaephilus surinamensis L. are attracted by cucujolides IV (4)
and IX (7). Cucujolide V (5) increases the response synergistical-
ly. A reinvestigation by our group revealed the existence of
a hitherto unknown compound named cucujolide X (8) in the
frass of O. surinamensis exhibiting a mass spectrum similar to
that of cucujolide V (5). The biosynthesis of the macrolides was
reported by the group of Vanderwel and Oehlschlager.[6] They
have shown that cucujolides II–V, VIII, and IX are produced
through the modification of fatty acids, whereas ferrulactone I
(1) is derived from farnesol.
Ferrulactone I (1) is also the aphrodisiac pheromone of male
small cabbage white butterflies, Pieris rapae.[7] This butterfly is
the only other known source of cucujolide pheromones.
O. surinamensis is one of the most common pests in stored
grain worldwide.[8] The application of insecticides in stored
grain is problematic because of residues remaining on the
grain. Therefore, we became interested in the identification of
the newly discovered cucujolide X and the improved synthesis
of these macrolides in general, allowing their use as lures for
mass trapping or monitoring of O. surinamensis in the protec-
tion of stored products. These compounds are also potential
kairomones for the parasitic wasp Cephalonomia tarsalis
(Asmead), Bethylidae, which is used for the biological control
of O. surinamensis.[9]
this synthesis that allowed the identification of a new natural
macrolide and confirmed the presence of 8 in O. surinamensis.
Furthermore, the absolute configuration of the natural com-
pounds and the biological activity of the synthetic material are
reported (Figure 2).
Figure 2. Structures of cucujolide V (5) and cucujolide X (8).
Results and Discussion
Feces of Oryzaephilus surinamensis was collected from a labora-
tory culture and extracted with dichloromethane. Fractionation
by column chromatography on basic alumina removed the
fatty acids and furnished a fraction that was able to attract
beetles. Analysis by GC/MS revealed a mass spectrum of com-
pound A matching that published for cucujolide V.[11] In addi-
tion, the active fraction contained an unknown compound B
exhibiting a mass spectrum very similar to that of A (Figure 3).
Both compounds showed a molecular ion at m/z 222 and
a typical macrolide-type fragmentation pattern, characterized
by unsaturated ion series and small peaks at m/z [MÀ18] and
[MÀ36]. The ion at m/z 180 [MÀ42] in the spectrum of A indi-
cates a loss of propene, most likely formed by the fragmenta-
tion shown in Figure 4. Ionization at the ether oxygen atom in-
duces the loss of two carbon atoms of the ring together with
the substituent by cleavage of the a-bond. A small [MÀ15] ion
is visible, likely formed by loss of the methyl side chain. The re-
spective ions move to m/z 166 [MÀ56] and [MÀ29] in the
spectrum of B, indicating the loss of butene and an ethyl side
chain. Therefore, the target compound should contain an ethyl
side chain and was proposed to be the so far unknown
(5Z,8Z)-tetradeca-5,8-dien-12-olide (8), a positional isomer of
cucujolide V.
Macrolides are also common constituents of the femoral
glands of male mantelline frogs from Madagascar.[3,4] Most
male mantelline frogs possess femoral glands on the ventral
side of their shanks, using their constituents for pheromone
communication. Interestingly, cucujolide V (5) seemed also to
be a constituent of femoral gland extracts of the mantelline
frog Spinomantis aglavei.
Since the amount of material available by extraction of the
frass excluded the isolation of the macrolides, a synthetic
access was planned to verify the identity of the compounds
and to evaluate their biological activity. In addition, the already
known compound 5 was needed for biological evaluation and
to confirm whether the mass spectrum and the gas chromato-
graphic retention index match with those of the natural prod-
uct.
Cucujolide V was synthesized before by Oehlschlager et al.
as R- and S enantiomers, and also in racemic form.[10,11] They
used macrolactonization of the precursor hydroxyacid as the
key step to form the macrolide. The origin of chirality in the
stereoselective syntheses were (S)- and (R)-propylene oxide, re-
spectively. Opening of the epoxide and establishment of a 1,4-
diyne precursor by using standard alkyne methodology[12] was
followed by catalytic hydrogenation to the desired diene-hy-
droxyacid. Lactonization with 2-chloro-1-methylpyridinium
iodide[13] afforded 5 in an overall yield of 8%.
To prove the identity of cucujolide X (8) and to have access
to similar compounds, we developed a general synthesis to
obtain doubly unsaturated macrolides like cucujolide V (5). The
approach is centered around the ring-closing alkyne metathe-
sis of an enyne precursor as the key step. We report here on
The Oehlschlager synthesis[10,11] of 5 was improved by Boden
et al.[8] They reported a new approach for the synthesis of a
hydroxy acid precursor based on
a Wittig olefination.
Macrolactonization under Yonemitsu conditions of the Yama-
guchi protocol led to the target macrolide.
These synthetic routes to racemic or enantiomerically pure 5
were quite long and used macrolactonization as a key step.
During the last decade, ring-closing metathesis (RCM) estab-
lished itself as a method to allow an easy access to unsaturat-
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ring-closing olefin metathesis
because the two bonds have
almost identical reactivity.[15] To
overcome this problem, we plan-
ned to use an alternative ap-
proach employing ring-closing
alkyne metathesis (RCAM),[16] in
particular with regard to the
recent progress in the develop-
ment of highly active homoge-
neous alkyne metathesis cata-
lysts.[17] One double bond is con-
ventionally introduced into an
alkyne-containing
precursor,
which is then subjected to
RCAM, followed by Lindlar hy-
drogenation to the final product.
A prerequisite of this approach
is that alkyne metathesis is strict-
ly orthogonal to alkene metathe-
sis,[16,17] leaving the double bond
unaffected by the metal alkyli-
dyne catalysts. Independently
from us, this strategy was re-
cently used by Fꢁrstner et al. in
the total synthesis of lactimido-
mycin[18] and in the total synthe-
sis of the antimitotic agent leio-
dermatolide.[19]
Our retrosynthetic plan is
shown in Scheme 1. The target
macrolide 8 can be obtained
from the ester 10. This fixes the
double bonds in the 5,8 posi-
tion, but allows flexibility on ring
size and substituents on the
other side. The ester can be
formed from the enyne acid 11
and the alcohol 12. Through
synthesis of the alcohol from al-
dehyde 15, enantiomers can be
obtained by enantioselective al-
Figure 3. Gas chromatogram and mass spectra of an extract of the feces of O. surinamensis. a) Active fraction;
b) mass spectrum of compound A, (5Z,8Z)-tetradeca-5,8-dien-13-olide (5); c) mass spectrum of compound B,
(5Z,8Z)-tetradeca-5,8-dien-12-olide (8).
kylation. The acid 11 can be formed by a Wittig reaction of the
aldehyde 13 with the Wittig salt 14. Our aim was to synthesize
the enantiomers of both macrolides to prove the structural as-
signment and the general feasibility of the synthesis, to eluci-
date the absolute configuration of the unknown compound,
and to provide material for bioassays. The enantiomers of both
5 and 8 were synthesized as shown in Scheme 2 and
Scheme 3.
The starting compound for the synthesis of the Wittig salt
14 was pent-3-yn-1-ol (16), which was first converted into the
iodide and then transformed into the Wittig salt 14. Secondly,
5-hexen-oic acid (17) was esterified with methanol, and the re-
sulting ester was oxidatively cleaved with RuCl3 and NaIO4 af-
fording aldehyde 18.[20] Compound 14 and aldehyde 18 were
coupled in a stereoselective Z configured Wittig reaction with
Figure 4. Proposed mass spectrometric fragmentation pattern of macrolides
leading to a loss of CH2=CHÀR from the molecular ion.
ed macrolides.[14] However, doubly unsaturated macrolides
with two similar double bonds cannot be synthesized by using
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Scheme 1. Retrosynthetic plan to macrolides 5 and 8.
sodium bis(trimethylsilyl)amide (NaHMDS),[21] yielding the de-
sired ester in excellent stereoselectivity (Z/E=99.5:0.5). Subse-
quent saponification with KOH in ethanol led quantitatively to
acid 11. The second required triple bond was introduced into
the appropriate position by isomerization of 5-hexynol (19) to
4-hexynol (20) under basic conditions,[22] followed by transfor-
mation into the aldehyde 15 by using the Swern oxidation.
The stereogenic center was introduced by an enantioselec-
tive alkylation according to Kobayashi et al.[23] by using a chiral
titanium catalyst with N,N-(1S,2S)-cyclohexane-1,2-bis(trifluoro-
methanesulfonamide) as the ligand. The diethylzinc reagent
used attacks the aldehyde from the Si face, producing the alco-
hol (R)-oct-6-yn-3-ol (12a) in moderate yield, but excellent
enantiomeric excess (ee, 99%), as expected from the known se-
lectivity of this catalyst system.[24] The opposite S enantiomer
of 12 was obtained with the enantiomeric (1R,2R)-ligand, lead-
ing to (S)-oct-6-yn-3-ol (12b) again with an excellent ee value
of 99%. The enantiomeric purity was determined by using the
Mosher esters[25] of 12a and 12b, using (S)-(+)-a-methoxy-a-
trifluoromethylphenylacetyl chloride ((S)-MTPA-Cl). Both esters
showed a purity of 99% in 19F NMR spectroscopy (see the Sup-
porting Information for spectra of the respective derivatives 32
and 33). By esterification and activation of the carboxylic acid
11 with 4-dimethylaminopyridine (DMAP) and N’-(3-dimethyl-
aminopropyl)-N-ethylcarbodiimide (EDC), the diynoate 10
could be obtained. This precursor was then submitted to
RCAM using the (pre-)catalyst 22 as a representative of the
family of highly active imidazolin-2-iminato tungsten alkylidyne
complexes.[26] RCAM proceeded smoothly at room temperature
in an argon-filled glovebox, isolating the product 21 in good
yield. As expected, the catalyst 22 is able to distinguish selec-
Scheme 2. Synthesis of (5Z,8Z)-tetradeca-5,8-dien-12-olide (8): a) PPh3, I2, im-
idazole, MeCN, Et2O, RT, 100%; b) PPh3, toluene, 12 h, 1208C, 92%; c) MeOH,
08C, 1 equiv BF3·OEt2, 95%; d) K2OsO4·2H2O, THF/H2O, NaIO4, RT, 3 h, 59%;
e) compound 14, 18, NaHMDS (1m in THF), THF, toluene, À308C, H2O, 87%;
f) KOH, EtOH, 2 h, heated at reflux, 99%; g) DMSO, KOtBu, 3 h, RT, 98%;
h) oxalyl chloride, DMSO, abs. CH2Cl2, À508C, NEt3, H2O, 100%; i) N,N-cyclo-
hexane-1,2-diyl-bis(1,1,1-trifluoromethanesulfonamide), toluene, [Ti(iOPr)4],
À788C, Et2Zn (1m in hexane), RT, 2 h, 49%; j) Compound 11, 12, abs. CH2Cl2,
DMAP, EDC·Cl, 08C, 3 h, 60%; k) Compound 22 (5 mol%), toluene, molecular
sieve 5 ꢂ, 24 h, RT, 67%; l) abs. MeOH, Lindlar catalyst, H2, 90%.
tively between double- and triple bonds and does not affect
the double bond in any way.
Subsequent hydrogenation with Lindlar catalyst delivered
the desired target molecule 8 in a yield of 90% and with an ee
of 99%, determined by chiral GC (Figure 6a–c) by using
a quite long temperature program (480 min at 808C, then with
208CminÀ1 to 2108C) for optimal separation of the enantio-
mers. The comparison of mass spectrometric data and reten-
tion times indicated that the synthetic product was indeed
identical to the natural compound, which was therefore identi-
fied to be tetradeca-5,8-dien-12-olide (8), a new natural prod-
uct (Figure 5).
A similar approach was used to synthesize the methyl-
branched cucujolide V (5; Scheme 3). A Zipper reaction[27] of
hept-3-yn-1-ol (23) furnished hept-6-yn-1-ol in excellent yield,
followed by isomerization with KOtBu to hept-5-yn-1-ol (24)
and Swern oxidation to aldehyde 25. The subsequent enantio-
selective alkylation, this time using dimethylzinc instead of di-
ethylzinc, yielded the desired alcohol 26. Both enantiomers
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were synthesized as described
above. Again esterification, RCAM
and subsequent selective hydroge-
nation afforded the two enantio-
mers of macrolide 5. Analysis of
the product by using GC on
a chiral stationary phase estab-
lished an enantiomeric excess of
33% ee for 5a and of 50% ee for
5,8-dien-12-olide 8a is the naturally occurring compound B
(Figures 6 and Figure 7).
Comparison of the enantiomers of 5a and 5b with the natu-
ral extract of O. surinamensis and the femoral gland extract of
S. aglavei revealed that (5Z,8Z,13R)-tetradeca-5,8-dien-13-olide
(5a) occurs in nature in both cases (Figure 7). Thus, the earlier
assignment by the group of Oehlschlager for cucujolide V in
O. surinamensis was confirmed. Because of the overlapping
peaks the enantiomeric purity of the natural R configured com-
pounds could not be established, but the S enantiomer was
present in low amounts only or absent. Macrolide 5a is here
also reported for the first time from the skin glands of amphib-
ians. It adds to the remarkable diversity of macrolides pro-
duced by mantelline frogs for communication.[3,4] Although the
cosmopolitan O. surinamensis might occur in Madagascar, a di-
etary origin of 5a in the frog seems unlikely, because the habi-
tats of the beetle and the strictly forest-dwelling frog do not
match.
Figure 5. Imidazolin-2-iminato
benzylidyne tungsten com-
plex 22.
The biological activity of the enantiomers of (5Z,8Z)-tetra-
deca-5,8-dien-12-olide 8 to male and female beetles was
tested in a four-chamber olfactometer[28] (Figure 8). The study
revealed sex-specific, enantioselective reactions to the R- and
S enantiomer. Whereas male beetles did not react either to the
R- or the S enantiomer, female beetles were attracted by the
(R)-macrolide. This confirms that this compound is a new pher-
omone of O. surinamensis. By analogy to cucujolides IV (4) and
IX (7) the new compound is attractive by itself and not only
active in synergy with (5Z,8Z,13R)-tetradeca-5,8-dien-13-olide
(5) in O. surinamensis,[1] which might facilitate its use in traps
to control the beetles. Interestingly, only females reacted to
the new cucujolide in our experiments, whereas the other cu-
cujolides seem to be attractive for both sexes.[29] This differ-
ence might be a result of the different bioassay methods used
or it might be due to a different function of the compounds.
Whereas the cucujolides identified earlier are considered ag-
gregation pheromones, which attract males and females, the
new compound might well be a male-released sexual phero-
mone acting only on females. Further studies are required to
clarify this point. In addition, the synthesized compounds will
be tested for activity to attract the parasitic wasp C. tarsalis, to
demonstrate their involvement in the host location. This would
enable their application in the context of biological control
measures, for instance, to retain wasps in the area of applica-
tion after their release.
Scheme 3. Synthesis of (5Z,8Z)-tetradeca-5,8-dien-13-olide (5): a) 1,3-diami-
nopropane, NaH, 1 h, 708C, KOtBu, 99%; b) KOtBu, DMSO, 3 h, 88%;
c) DMSO, oxalyl chloride, abs. CH2Cl2, À508C, NEt3, H2O, 85%; d) N,N-cyclo-
hexane-1,2-diyl-bis(1,1,1-trifluoromethanesulfonamide), toluene, [Ti(iOPr)4],
À788C, Me2Zn (2m in toluene), RT, 24 h, 43%; e) 11, 26, abs. CH2Cl2, DMAP,
EDC·Cl, 08C, 2 h, 60%; f) compound 22 (5 mol%), toluene, molecular sieve
5 ꢂ, 24 h, RT, 52%; g) abs. MeOH, Lindlar catalyst, H2, 90%.
5b (Figure 6d–f). This time separation of the enantiomers by
chiral GC was possible by using a more conventional tempera-
ture program (5 min at 508C, then with 58CminÀ1 to 2108C)
for optimal separation. A reversal of the elution order of both
enantiomers of the methyl- and ethyl-branched macrolide was
observed. An error on our side can be excluded because the
optical rotation values of the samples showed similar direc-
tions.
The results were also confirmed by Mosher experiments of
the alcohols 26a and 26b (for the experimental data see the
Supporting Information, compounds 35 and 36). This shows
a sharp decline in the enantioselectivity compared to diethyl-
zinc, as it is known for the Kobayashi method.[23]
Conclusion
We have described an expedient enantioselective total synthe-
sis of the new natural macrolide (5Z,8Z,12R)-tetradeca-5,8-dien-
12-olide 8 (seven linear steps, 29% overall yield from alcohol
19). The flexible approach is also useful for the synthesis of
other diene macrolides, for example, cucujolide V (5). Key fea-
tures of the synthesis include the enantioselective alkylation
according to Kobayashi et al. and the successful RCAM meth-
odology catalyzed by a tungsten alkylidyne complex at room
temperature with subsequent hydrogenation to yield diene-
The separation of the natural enantiomers of 8 proved to be
difficult. Although a very long temperature program was used,
additional compounds in the extract interfered with the elu-
tion. The use of other phases was not an option, because they
did not allow separation of the enantiomers. By use of mass
spectrometry and ion traces, the identity of 8 could be con-
firmed and the coinjection showed that (5Z,8Z,12R)-tetradeca-
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of 0.2 mm was suitable to allow
fecal pellets to pass but retained
most of the grain components.
Feces (1 g) were kept in CH2Cl2
(1 mL) for 1 h. The extract was con-
centrated to 20 mL in a water bath
at 608C and was than fractionated
on a 6 cm silica gel column (dia-
meter 5 mm) with pentane (2 mL),
pentane (2 mL)/CH2Cl2 (8:1), CH2Cl2
(2 mL), and methanol (2 mL). The
dichloromethane fraction was con-
centrated to 10 mL in a water bath
at 608C and fractionated with pen-
tane, followed by pentane/CH2Cl2
mixtures of the following composi-
tion 8:1; 5:1; 2:1; 1:1 and 1:2; two
mL of each mixture was used.
Bioassays
The reaction of male and female
adult beetles towards synthetic
cucujolides was assessed in a static
four-chamber olfactometer.[28] The
sex of experimental beetles was
determined under the stereo-mi-
croscope according to the charac-
ters described by Arbogast.[31] The
olfactometer consists of a cylinder
(2 cm high, 10 cm diameter) divid-
ed by vertical plates into four
equally shaped chambers. The
whole device was made of odor
repellent synthetic material. Above
the cylinder was a walking arena
(1 cm high, 8 cm diameter) of
metal gauze with a rim of synthet-
ic material (0.9 cm high) located.
The whole device was covered by
a glass plate. One chamber con-
tained a filter paper with macrolide
Figure 6. Determination of the ee value by using chiral GC on a hydrodex-6-TBDMS phase (25 m), temperature
program: 480 min at 808C, then with 208CminÀ1 to 2108C. a) (5Z,8Z,12R)-tetradeca-5,8-dien-12-olide (8a);
b) (5Z,8Z,12S)-tetradeca-5,8-dien-12-olide (8b); c) mixture of 8a and 8b. Temperature program: 5 min at 508C,
then with 58CminÀ1 to 2108C; d) (5Z,8Z,13R)-tetradeca-5,8-dien-13-olide (5a), ratio 2:1 (R/S); e) (5Z,8Z,13S)-tetra-
deca-5,8-dien-13-olide (5b), ratio 1:3 (R/S); f) mixture of 5a and 5b.
8
(20 mL) dissolved in hexane
(0.01 mgmLÀ1, equivalent to 200 ng 8) in a small glass vial (test
chamber), the opposite chamber contained filter paper with
hexane (20 mL) in a small glass vial (control chamber). The two
other chambers remained empty and served as transition zones.
The experiments were performed in the dark with the olfactometer
illuminated from above with red light. Experiments started five mi-
nutes after application of the solutions. An individual beetle was
placed in the walking arena and allowed to move freely for 420 s.
The behavior (walking or resting) and the position of the beetle
(test field, control field, or transition zone) was recorded by using
“The Observer 5.0” software (Noldus, Wageningen, The Nether-
lands). The time the beetle spent in the field above the test cham-
ber with the odor (test field) or in the opposite field (control field)
was compared with the Wilcoxon-matched pairs test for nonpara-
metric data using the software package STATISTICA for Windows
5.5 (StatSoft, Tulsa, Oklahoma USA, 1999). Beetles remaining mo-
tionless for more than 150 s were excluded from the statistical
analysis. After each beetle, the olfactometer was cleaned with eth-
anol (99%). Each beetle was tested only once.
macrolides. The biological activity of the new macrolide was
shown in behavioral assays.
Experimental Section
Insect cultures
Specimens for cultures of O. surinamensis were collected in August
2005 from a flourmill near Pforzheim, Germany. Cultures were kept
at 278C in glass jars (height 10 cm, diameter 8 cm) at a natural
day/night cycle. Approximately 500 adults were kept on a mixture
of 70 g rolled oats and 100 g crimped wheat with one teaspoon of
dried yeast for oviposition. The grain mixture was moistened to
14% water content. After 7 days, the grain mixture containing
eggs and larvae was separated from adults by sieving with two
sieves (2 mm and 0.63 mm mesh-size).
Preparation of feces extracts
Beetle feces were collected from rearing jars by gentle sieving rear-
ing medium from O. surinamensis onto a glass plate. The mesh size
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for 19F, 50.5 MHz for 13C, 162 MHz
for 31P), Bruker Avance II 300
(300.1 MHz for 1H, 75.5 MHz for
13C), Bruker DRX-400 (400.1 MHz
for 1H, 100.6 MHz for 13C), and
1
Bruker AV II-600 (600.1 MHz for H,
150.9 MHz for 13C) instruments
with CDCl3 as solvent. Tetramethyl-
silane was used as internal stan-
dard (d=0). J values are given in
Hz and chemical shifts are report-
ed in ppm. IR spectra were record-
ed with a Bruker Tensor 27 spec-
trometer. UV/Vis spectra were
measured with a Varian Cary 100
Bio UV/Vis spectrometer. Optical
rotation values were obtained with
a Propol Digital Automatic Polar-
imeter (Dr. Kernchen) with a 1 cm
cuvette at a wavelength of 578 nm
using dry dichloromethane as sol-
vent. The [a]D20 values are given in
10À1 degcm2 gÀ1. The RCAM reac-
tions with the precatalyst 22 were
performed in a glovebox (MBraun
200B) under an atmosphere of dry
argon. Toluene was purified and
dried by
a solvent purification
system from MBraun and stored
over molecular sieves (4 ꢂ). The
precatalyst 22 was prepared ac-
cording to literature procedur-
es,[26d] and the molecular sieves
(MS 5 ꢂ; Sigma–Aldrich, bead of
particle size <10 mm) were dried
for 24 h at 1808C under vacuum
prior to use.
Figure 7. Determination of the absolute configuration of: a) natural (5Z,8Z,12R)-tetradeca-5,8-dien-12-olide (8a)
from O. surinamensis; b) natural (5Z,8Z,13R)-tetradeca-5,8-dien-13-olide (5a) from O. surinamensis; c) natural
(5Z,8Z,13R)-tetradeca-5,8-dien-13-olide (5a) from S. aglavei. The identity of the peaks was proven by mass spec-
trometry. The arrows indicate the natural compounds. The separation was complicated by coeluting other compo-
nents.
General procedures
General procedure for the ring-closing alkyne metathesis
A toluene solution (18 mm for 9, 12 mm for 10) of the enyne was
charged with molecular sieves 5 ꢂ (for adsorption of 2-butyne) in
a glovebox. Then, the catalyst 22 (5 mol%) was added. The reac-
tion mixture was stirred for 24 h at ambient temperature, and af-
terwards, it was filtered through silica gel to remove the catalyst.
Elution with Et2O afforded the cyclization product.
Technical solvents were distilled before use. All other starting ma-
terials were commercially available (Sigma–Aldrich, Acros, Fluka,
Merck) and used without further purification. All reactions involv-
ing water-sensitive chemicals were carried out in heat gun dried
glass equipment under a nitrogen atmosphere. Reactions were
monitored by TLC on Polygram SIL G/UV254 plates with detection
by UV (254 nm) or by visualization with heat gun treatment with
10% molybdato phosphoric acid in ethanol or 0.5% potassium
permanganate in sodium hydroxide. Column chromatography was
performed on silica gel M 60 under low pressure. All GC/MS analy-
ses were performed on a HP 6890 gas chromatograph connected
to an MSD 5973 (EI 70 eV; Hewlett–Packard) and on a GC 7890 A
coupled to an MSD 5975C (Agilent Technologies) using a BPX-5
fused silica capillary column (SGE Inc, 25 mꢃ0.22 mm i.D.ꢃ0.25 mm
film thickness), a HP5-MS (Agilent Technologies, 30 mꢃ0.25 mm i.
General procedure for the selective hydrogenation
Lindlar catalyst was added at room temperature to a stirred solu-
tion of the alkyne (0.23 mmol) in dry methanol (5 mL). H2 was bub-
bled through the reaction mixture for 2 h.[30] The reaction progress
was monitored by TLC. The solution was filtered through a short
column filled with silica gel to remove the catalyst and the solvent
was removed under reduced pressure.
D. ꢃ0.25 mm), and
a
ZB-5 MSi (Zebron, 30 mꢃ0.25 mm i.D.
(5Z,12R)-Tetradec-5-en-8-yne-12-olide (21a): Macrolide (R)-21 was
prepared from 10a by using the general procedure for ring-closing
alkyne metathesis. Purification by column chromatography on
silica gel (pentane/diethyl ether, 10:1) yielded the desired product
(28 mg, 0.13 mmol, 67%, 99% ee). Rf =0.5 (pentane/diethyl ether,
ꢃ0.25 mm). The GC was programmed as follows: 5 min at 508C in-
creasing with 58C minÀ1 to 3208C. Retention indices (I) were deter-
mined from a homologous series of n-alkanes (C8ÀC32). Gas chro-
matographic analyses on chiral phases were performed by using
a Hydrodex-6-TBDMS phase (2,3-di-O-methyl-6-TBDMS-b-cyclodex-
trin, Macherey–Nagel, 25 mꢃ0.25 mm i.D.). NMR spectra were ob-
1
10:1). [a]D22 =À45.3 (c=2.7 in CH2Cl2); GC (BPX-5): I=1758; H NMR
3
(400 MHz, CDCl3, TMS): d=0.87 (t, JH,H =7.48 Hz, 3H, CH3), 1.65 (m,
1
tained with Bruker Avance DPX 200 (200.1 MHz for H, 188.3 MHz
6H, 3xCH2), 2.05 (m, 2H, CH2), 2.33 (m, 2H, CH2), 2.60 (m, 4H,
Chem. Eur. J. 2014, 20, 3183 – 3191
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Full Paper
(19), 56 (6), 55 (57); HREIMS calcd for C14H22O2+: 222.16143; found:
222.16139.
The S enantiomers of compounds 21 and 8 were obtained in an
identical sequence starting with a stereoselective alkylation using
N,N-((1R,2R-cyclohexane-1,2-diyl)bis(trifluoromethanesulfonamide)
instead of the S,S enantiomer.
(5Z,12S)-Tetradec-5-en-8-yne-12-olide (21b): (27 mg, 0.12 mmol,
67%, 99% ee), [a]2D2 = +46.3 (c=2.5 in CH2Cl2).
(12R,5Z,8Z)-Tetradeca-5,8-dien-12-olide (8b): (20 mg, 0.1 mmol,
84%, 99% ee), [a]D21:2 = +13.8 (c=2.2 in CH2Cl2).
(5Z,13R)-Tetradec-5-en-8-yne-13-olide (27a): The enyne-macrolide
(R)-27 was prepared by the general procedure for ring-closing
alkyne metathesis. Purification by column chromatography on
silica (pentane/diethyl ether, 20:1) yielded the desired product
(20.7 mg, 0.09 mmol, 52%, 33% ee). Rf =0.4 (pentane/diethyl ether,
1
20:1); [a]D22 =À26.8 (c=1.5 in CH2Cl2); GC (BPX-5): I=1752; H NMR
(300 MHz, CDCl3, TMS): d=1.21 (d, 3JH,H =6.4 Hz, 3H, CH3), 1.47–
1.67 (m, 4H, 2ꢃCH2), 1.85–2.13 (m, 4H, 2ꢃCH2), 2.23–2.49 (m, 4H,
2ꢃCH2), 2.98–3.09 (m, 2H, CH2), 5.15 (m, 1H, CH), 5.36 (m, 1H, CH),
5.58 ppm (m, 1H, CH); 13C NMR (100 MHz, CDCl3): d=16.7 (CH2),
18.2 (CH2), 18.6 (CH3), 22.2 (CH2), 23.4 (CH2), 25.6 (CH2), 32.1 (CH2),
32.9 (CH2), 69.4 (CH), 78.9 (Cq), 79.9 (Cq), 125.3 (CH), 131.7 (CH),
173.1 ppm (CO); MS (EI, 70 eV): m/z (%): 220 (<1) [M+], 205 (4),
191 (2), 160 (8), 147 (26), 145 (14), 133 (20), 119 (24), 117 (26), 106
(11), 105 (58), 104 (12), 103 (12), 93 (17), 92 (19), 91 (100), 81 (14),
79 (40), 78 (23), 77 (41), 65 (30), 55 (31).
(13R,5Z,8Z)-Tetradeca-5,8-dien-13-olide (5a): Macrolide 5a
(44 mg, 0.19 mmol, 90%) was synthesized according to the general
procedure for selective hydrogenation. [a]D21:2 =À5.2 (c=4.4 in
CH2Cl2). The enantiomeric excess was determined by using chiral
GC analysis (33% ee). GC (BPX-5): I=1679; 1H NMR (600 MHz,
Figure 8. Mean walking duration +S.D. (in seconds) of males and females of
O. surinamensis (n=30) in the test and control field of a four chamber olfac-
tometer. Test field: filter paper with macrolide (20 mL) dissolved in hexane (in
which 200 ng of macrolide 8 was applied); Control field: filter paper with
hexane. Significance:*, p<0.05; n.s., p>0.05; Wilcoxon-matched pairs test.
3
CDCl3, TMS): d=1.24 (d, JH,H =6.21 Hz, 3H, CH3), 1.39 (m, 2H, CH2),
1.58 (m, 2H, CH2), 1.70 (m, 2H, CH2), 1.83 (dddt, 3JH,H =13.9, 9.4,
4JH,H =4.7, 3.1 Hz, 2H, CH2), 1.99 (m, 2H, CH2), 2.26 (m, 2H, CH2),
3
3
2xCH2), 4.91 (m, 1H, CH), 5.35 (dt, 3JH,H =10.7, 4.1 Hz, 1H, CH),
5.58 ppm (m, 1H, CH); 13C NMR (100 MHz, CDCl3): d=9.6 (CH3),
15.9 (CH2), 16.7 (CH2), 22.8 (CH2), 25.3 (CH2), 27.9 (CH2), 31.0 (CH2),
31.4 (CH2), 75.1 (CH), 78.1 (Cq), 79.3 (Cq), 124.9 (CH), 132.8 (CH),
173.5 ppm (CO); MS (EI, 70 eV): m/z (%): 220 (<1) [M+], 205 (3),
191 (8), 147 (21), 133 (24), 131 (22), 119 (23), 117 (28), 105 (57), 93
(16), 92 (17), 91 (100), 81 (17), 79 (46), 78 (25), 77 (49), 67 (24);
HREIMS: m/z calcd for C14H20O2+: 220.14578; found: 220.14431.
2.41 (dt, JH,H =9.5, 3.1 Hz, 2H, CH2), 5.02 (tq, JH,H =9.7, 6.3, 3.1 Hz,
1H, CH), 5.27 (m, 1H, CH), 5.43 ppm (m, 3H, 3ꢃCH); 13C NMR
(150 MHz, CDCl3): d=20.7 (CH3), 24.9 (CH2), 25.5 (CH2), 25.8 (CH2),
26.1 (CH2), 26.2 (CH2), 33.8 (CH2), 35.1 (CH2), 69.2 (CH), 127.8 (CH),
128.1 (CH), 128.7 (CH), 129.0 (CH), 173.4 ppm (CO); MS (EI, 70 eV):
m/z (%): 222 (5) [M+], 180 (9), 140 (6), 135 (6), 121 (9), 120 (6), 119
(7), 108 (6), 107 (13), 106 (14), 105 (18), 95 (11), 94 (13), 93 (35), 92
(13), 91 (57), 84 (6), 82 (7), 81 (21), 80 (27), 79 (100), 78 (20), 77 (58),
68 (11), 67 (50), 66 (18), 65 (25), 60 (7), 56 (13), 55 (44), 54 (20), 53
(31), 52 (8), 51 (11), 45 (18), 44 (10), 43 (33), 42 (24), 41 (85), 40 (12),
39 (62).
(12R,5Z,8Z)-Tetradeca-5,8-dien-12-olide (8a): Macrolide 8a
(44 mg, 0.19 mmol, 90%) was synthesized according to the general
procedure for selective hydrogenation. [a]D21:2 =À15.7 (c=4.4 in
CH2Cl2). The enantiomeric excess was determined by using chiral
GC analysis (99% ee); GC (BPX-5): I=1697; 1H NMR (600 MHz,
The S enantiomers of compounds 27 and 5 were obtained in an
identical sequence starting with a stereoselective alkylation using
N,N-((1R,2R-cyclohexane-1,2-diyl)bis(trifluoromethanesulfonamide)
instead of the S,S enantiomer.
3
CDCl3, TMS): d=0.81 (t, JH,H =7.53 Hz, 3H, CH3), 1.46 (m, 2H, CH2),
1.71 (m, 2H, CH2), 1.82 (dddt, 3JH,H =13.8, 10.7, 6.1 Hz, 4JH,H =6.1,
3.2 Hz, 2H, CH2), 2.05 (m, 2H, CH2), 2.26 (m, 2H, CH2), 2.48 (m, 2H,
CH2), 2.84 (m, 2H, CH2), 4.82 (m, 1H, CH), 5.23 (m, 2H, 2xCH), 5.34
(m, 1H, CH), 5.39 ppm (m, 1H, CH); 13C NMR (150 MHz, CDCl3): d=
9.7 (CH3), 23.3 (CH2), 23.9 (CH2), 25.6 (CH2), 25.9 (CH2), 27.6 (CH2),
32.9 (CH2), 33.1 (CH2), 75.2 (CH), 127.1 (CH), 128.2 (CH), 128.7 (CH),
130.0 (CH), 173.6 ppm (CO); IR (ATR): n˜ =3008 (w), 2965 (w), 2926
(w), 2877 (w), 1727 (s), 1442 (w), 1161 (m), 680 cmÀ1 (m); UV/Vis
(PE): lmax (loge)=237 (2.80), 196 (3.98), 193 (3.99); MS (EI, 70 eV):
m/z (%): 222 (5) [M+], 193 (2), 166 (10), 147 (6), 135 (7), 133 (6), 121
(10), 120 (6), 119 (10), 109 (6), 108 (9), 107 (17), 106 (24), 105 (20),
104 (7), 97 (9), 96 (7), 95 (17), 94 (14), 93 (41), 92 (17), 91 (46), 84
(12), 83 (9), 82 (9), 81 (29), 80 (37), 79 (100), 78 (19), 77 (38), 73 (6),
71 (6), 69 (8), 68 (13), 67 (60), 66 (16), 65 (18), 60 (13), 59 (6), 57
(5Z,13S)-Tetradec-5-en-8-yne-13-olide
(27b):
(17.5 mg,
0.079 mmol, 60%, 50% ee), [a]D22:1 = +25.1 (c=1.8 in CH2Cl2).
(13S,5Z,8Z)-Tetradeca-5,8-dien-13-olide (5b): (40 mg, 0.18 mmol,
86%, 50% ee), [a]D21:3 = +3.5 (c=1.4 in CH2Cl2).
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft for a grant to
S.S. (Schu984/10-1) and to J.L.M.S. (Ste841/6-1).
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Received: November 11, 2013
Published online on February 12, 2014
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