Stereoselective synthesis of trans-fused iridoid lactones and their identification in the parasitoid wasp Alloxysta victrix, Part II: Iridomyrmecins

Article abstract of DOI:10.3762/bjoc.8.141

Following our earlier approach to the synthesis of dihydronepetalactones, all eight stereoisomers of trans-fused iridomyrmecins were synthesized starting from the enantiomers of limonene. Combined gas chromatography and mass spectrometry including enantioselective gas chromatography revealed that volatiles released by the endohyperparasitoid wasp Alloxysta victrix contain (4S,4aR,7S,7aR)-iridomyrmecin of 95-97% ee and stereochemically pure (4S,4aS,7R,7aS)-iridomyrmecin as a minor component.

Full text of DOI:10.3762/bjoc.8.141

Stereoselective synthesis of trans-fused iridoid
lactones and their identification in the parasitoid
wasp Alloxysta victrix, Part II: Iridomyrmecins
Robert Hilgraf, Nicole Zimmermann, Lutz Lehmann, Armin Tröger
and Wittko Francke*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1256–1264.
Department of Chemistry - Organic Chemistry, University of Hamburg,
Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany
doi:10.3762/bjoc.8.141
Received: 16 March 2012
Accepted: 20 July 2012
Published: 08 August 2012
Email:
Wittko Francke* - francke@chemie.uni-hamburg.de
* Corresponding author
This article is part of the Thematic Series "Biosynthesis and function of
secondary metabolites". Part I [1] describes the synthesis of
dihydronepetalactones by this approach.
Keywords:
Alloxysta victrix; identification; iridoid; stereoselective synthesis;
trans-fused iridomyrmecin
Guest Editor: J. S. Dickschat
© 2012 Hilgraf et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Following our earlier approach to the synthesis of dihydronepetalactones, all eight stereoisomers of trans-fused iridomyrmecins
were synthesized starting from the enantiomers of limonene. Combined gas chromatography and mass spectrometry including
enantioselective gas chromatography revealed that volatiles released by the endohyperparasitoid wasp Alloxysta victrix contain
(4S,4aR,7S,7aR)-iridomyrmecin of 95–97% ee and stereochemically pure (4S,4aS,7R,7aS)-iridomyrmecin as a minor component.
Introduction
In the course of our studies on volatile signals of the endohyper- of this suite, we started from optically active limonene
parasitoid wasp, Alloxysta victrix, we identified several acyclic following a strategy similar to our route leading to trans-fused
terpenoids and the trans-fused (4S,4aR,7R,7aS)-dihydronepeta- dihydronepetalactones [1]. The realization of this task and the
lactone (X) as volatile components of cephalic secretions unambiguous structure assignment of the natural products Y
released by this species (Figure 1) [1,2]. However, gas chro- and Z is subject of the present paper.
matograms showed the presence of two additional major
volatiles Y and Z which, according to their mass spectra, were Results and Discussion
suggested to be trans-fused iridomyrmecins [3,4]. Since no syn- Upon coupled gas chromatography/mass spectrometry
thetic reference compounds were available, all eight trans-fused (GC/MS), two major components, Y and Z, of the volatile
iridomyrmecins had to be prepared. To complete the synthesis secretions of both sexes of Alloxysta victrix (although in much
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structures and their interesting physiological properties,
iridomyrmecins are attractive targets in stereoselective
synthesis.
Similar to dihydronepetalactones, the iridomyrmecin skeleton
shows four contiguous stereogenic centers giving rise to four
trans-fused stereoisomers A–D and four corresponding enan-
tiomers A'–D' (Figure 3, D' is identical to 2 in Figure 1). The
presence of the four chiral centers complicates a stereoselective
synthesis despite the small size of the molecule. Several
methods have been published for the preparation of optically
active cis-fused bicyclic iridoid lactones [7-10], whereas only a
Figure 1: Structures of cis- and trans-fused iridoid lactones.
higher amounts in males) gave almost identical 70 eV EI-mass few syntheses of trans-fused ring systems have been reported
spectra (Figure 2); somewhat resembling that of the trans-fused [11]. Starting from enantiomerically pure (R)-pulegone,
dihydronepetalactone that we had already found in the insects mixtures of (7R)-configured diastereomers A' and B' as well as
[1]. Gas chromatography coupled with chemical ionization C and D have been synthesized by Wolinsky [12]. The set
mass spectrometry (GC/CIMS) proved the molecular mass of of stereochemically pure (7S)-configured, trans-fused
the target compounds to be [M]+ = 168, while high resolution iridomyrmecins A, B, C', and D' has been prepared by Trave
mass spectrometry (GC/HRMS) showed their atomic compos- [13]. Though Wolinky’s route may generally be used for the
ition to be C10H16O2, confirming the compounds to be isomers synthesis of all eight stereoisomers of trans-fused
of dihydronepetalactone. Though the fragmentation pattern iridomyrmecins, it suffers from several major disadvantages
showed some similarities to that of the cis-fused iridomyrmecin such as high costs of (S)-pulegone and difficult separations of
(1), a comparison with mass spectral data published for the diastereomeric mixtures.
trans-fused isoepiiridomyrmecin (2) suggested that the
substances Y and Z are trans-fused iridomyrmecins. While the
plotted mass spectrum of 1 showed m/z 95 as the base peak and
similar abundances of about 55% for m/z 67, m/z 81 and m/z
109 [3], the data of 2 refer to m/z 81 as the base peak and m/z 95
and m/z 109 to reach 48% and 33%, respectively [4]; this is
more close to the spectra of Y and Z (Figure 2).
Figure 3: Chemical structures of all eight stereoisomers of trans-fused
iridomyrmecins and their gas chromatographic retention times (min) on
FFAP and on a cyclodextrin column (cyclo). For experimental details
see Supporting Information File 1.
Starting from the cheaply available pure enantiomers of
limonene, we had reported a novel stereoselective route towards
Figure 2: 70 eV EI-mass spectrum of compounds Y and Z of Alloxysta
victrix.
trans-fused dihydronepatalactones [1] which we now extended
to the synthesis of all eight stereoisomers of trans-fused
iridomyrmecins. Subsequently, the volatile components Y and
Iridomyrmecin (1) was first isolated from ants (Figure 1) [5] Z – present in Alloxysta victrix – were confirmed to be trans-
and along with some other volatile iridoids it has since been fused iridomyrmecins, and their absolute configurations could
reported to be a potent insecticide and antibiotic from several be determined by comparison of their analytical data with those
natural sources [6]. Due to their challenging molecular of all eight synthetic stereoisomers.
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Synthesis of trans-fused iridomyrmecins
of hydrogen [14,15], as represented in 5, and the use of Crab-
Our approach to the eight trans-fused iridomyrmecins starting tree’s catalyst in a directed hydrogenation for a “syn” addition
from the enantiomers of limonene followed our general route of hydrogen as represented in 6 [16-18]. Subsequent to the
for the synthesis of trans-fused dihydronepetalactones hydrogenation step, the synthesis of trans-fused iridomyrmecins
(Figure 4) [1].
could be completed after some standard functional group modi-
fications. The synthesis of the corresponding enantiomers fol-
Starting from pure (R)-limonene (3), the key intermediate 4 was lowed the same way, starting from (S)-limonene (3').
prepared as described previously [1] and was used for both the
Synthesis of trans-fused iridomyrmecins A
synthesis of trans,trans and cis,trans (these designations refer to
the relative configurations between the methyl group at C-7 and and B
the substitution pattern at C-7a and C-4a, respectively) config- The aldehyde 8, derived from (R)-limonene (3), served as
ured iridomyrmecins. Key steps were two stereoselective hydro- the key intermediate for the synthesis of the trans-fused
genations: A transfer hydrogenation for a formal “anti” delivery iridomyrmecins A and B (Scheme 1). As shown in the stereo-
Figure 4: Strategy for the stereoselective synthesis of trans-fused iridomyrmecins A–D from (R)-limonene.
Scheme 1: Synthesis of the trans-fused iridomyrmecins A and B. Reaction conditions and yields: a) ammonium formate, Pd/C, MeOH, reflux (48%);
b) NaBH4, MeOH, H2O, rt (79%); c) NaH, BnBr, THF, reflux (96%); d) HF, CH3CN, rt (71%); e) CrO3, H2SO4, acetone, rt (99%); f) Pd/C, 40 bar H2,
THF, rt (100%); g) DCC, DMAP, CH2Cl2, rt (66%); h) p-TsOH, benzene, reflux (56%).
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Synthesis of trans-fused iridomyrmecins C
selective synthesis of trans-fused dihydronepetalactones [1],
this key intermediate could be obtained via a highly diastereo- and D
selective transfer hydrogenation of the known [19] trisubsti- As shown in our previous paper on the synthesis of trans-fused
tuted cyclopentene 7 with ammonium formate over palladium dihydronepetalactones, the double bond of the acetate 4 could
[1,14,15]. Starting from the aldehyde 8, the relative configura- be hydrogenated with high stereocontrol to the diastereomeri-
tion of which had been confirmed by NOE experiments [1], the cally pure acetate 13 [1] by using Crabtree’s catalyst [16-18].
synthesis of A and B was completed in six additional steps.
The synthesis of the iridomyrmecins C and D was completed in
three additional steps (Scheme 2). The oxidation with Jones
First, the aldehyde 8 was reduced with sodium borohydride, and reagent yielded 14, and subsequent saponification of the acetate
the resulting alcohol 9 was protected as the benzyl ether to form group with methanolic KOH afforded the hydroxy acid 6.
10. Deprotection of the TBDMS ether was carried out with HF Similar to the approach described above, careful lactonization
in acetonitrile to yield the mono-protected diol 11. Using Jones with DCC and DMAP gave iridomyrmecin C, whereas treat-
reagent, the free hydroxy group of 11 was oxidized to the ment with p-toluenesulfonic acid in benzene under reflux condi-
carboxylic acid 12, and the benzyl ether was cleaved upon tions led to complete epimerization at C-4 and afforded
catalytic hydrogenation over Pd/C to produce the hydroxy acid iridomyrmecin D. All reaction steps were also carried out
5. The latter served as the immediate precursor for the forma- starting from enantiomerically pure (S)-limonene (3') and
tion of either of the two diastereomeric iridomyrmecins A and afforded iridomyrmecins C' and D'.
B: Careful cyclization using dicyclohexylcarbodiimide (DCC)
and 4-dimethylaminopyridine (DMAP) in dichloromethane at rt
afforded iridomyrmecin A. In contrast, treatment of 5 with
catalytic amounts of p-toluenesulfonic acid in benzene under
reflux conditions for 12 h resulted in a complete epimerization
at the CH-acidic C-4 position, exclusively yielding the thermo-
dynamically more stable iridomyrmecin B. All reaction steps
were also carried out starting from enantiomerically pure (S)-
limonene affording trans-fused iridomyrmecins A' and B'.
Relative configurations of iridomyrmecins A, A' and B, B' were
confirmed by NOESY experiments. In A (Figure 5, A) decisive
NOEs could be observed between 1-Hb and 4a-H as well as
between 1-Hb and 7-H which showed 4a-H and 7-H to be
located at the same side of the molecule. In addition, NOEs
between 4-CH3 and 7a-H as well as between 7-CH3 and 7a-H
proved the two methyl groups to be located at the same side of
Scheme 2: Synthesis of the trans-fused iridomyrmecins C and D.
Reaction conditions and yields: a) Crabtree's catalyst
[Ir(cod)PCy3(py)]PF6 (10 mol %), 1 bar H2, CH2Cl2, rt (81%); b) CrO3,
the molecule. In contrast, as shown in Figure 5, B', NOEs
between 4-H and 7a-H as well between 7-CH3 and 7a-H, prove
H2SO4, acetone, rt (86%); c) KOH, MeOH, rt (97%); d) DCC, DMAP,
CH2Cl2, rt (41%); e) p-TsOH, benzene, reflux (59%).
that in B' the two methyl groups are situated at opposite sides of
the molecule.
Figure 5: Configurations of the trans-fused iridomyrmecins A and B’.
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Structure assignment of volatile components
Y and Z in the parasitoid wasp Alloxysta
victrix
Comparison of mass spectra and GC retention times of syn-
thetic iridomyrmecins with corresponding data of the volatile
substances Y and Z – which are present in pentane extracts of
heads of Alloxysta victrix – allowed their unambiguous identifi-
cation as trans-fused iridomyrmecins.
Relative configurations of the iridomyrmecins C, C' and D, D'
were confirmed by NOESY experiments. In C (Figure 6, C)
decisive NOEs between 1-Hb and 4a-H as well as between
1-Hb and 7-CH3 proved 4a-H and 7-CH3 to be located at the
same side of the molecule. The NOE between 4-CH3 and 7a-H
showed them to be geometrically close and the two methyl
groups to be in opposite positions. In contrast, as shown in
Figure 6, D' NOEs between 4a-H and 4-CH3 as well as between
4a-H and 1-Hb and furthermore between 1-Hb and 7-CH3
proved the methyl groups in D' to be at the same side of the Coupled GC/MS analysis using FFAP as the stationary phase
molecule. This is confirmed by a NOE between 4-H and 7a-H. revealed the natural iridoid lactones Y and Z to show the same
mass spectra and retention times as the two early eluting race-
In summary, we have completed the first enantioselective syn- mates of the synthetic iridomyrmecins, i.e., B/B' and A/A', res-
thesis of all eight stereoisomers of trans-fused iridomyrmecins, pectively (Figure 3). Enantioselective gas chromatography on
starting from either of the cheaply available enantiomers of heptakis(6-O-tert-butyldimethylsilyl-2,3-di-O-methyl)-β-
limonene. The acetate 4 is the decisive intermediate, and key cyclodextrin showed that A and A' were well separated with an
reaction steps are two stereoselective hydrogenations: A α-value of A:A' = 1.05 (Figure 3). Consequently, the structure
transfer hydrogenation for a formal “anti” delivery of hydrogen of Z could be easily determined to be A', namely
and the use of Crabtree’s catalyst in a directed hydrogenation (4S,4aS,7R,7aS)-iridomyrmecin. Under the same experimental
for a “syn”-addition of hydrogen. Starting from pure enan- conditions, B and B' were only poorly resolved, however,
tiomers of limonene [1] these novel synthetic routes provided heptaiks(2,6-di-O-methyl-3-O-pentyl)-β-cyclodextrin produced
iridomyrmecins A, A' and B, B' in 2–3% yield over 15 steps as a good α-value of B':B = 1.015 [20]. As a result, Y was unam-
well as iridomyrmecins C, C' and D, D' in 10–15% yield over 9 biguously identified to be (4S,4aR,7S,7aR)-iridomyrmecin. A
steps.
careful inspection of the analytical data obtained with the
cyclodextrin column revealed the presence of small amounts of
All eight stereoisomers of trans-fused iridomyrmecins could be (4R,4aS,7R,7aS)-iridomyrmecin B' in the natural extract,
separated by gas chromatography using a capillary column showing the ee of natural B to be ca. 95–97%. Figure 7 shows a
coated with FFAP as an achiral polar stationary phase and a typical gas chromatogram (obtained with FFAP as the
second capillary coated with a 1:1 mixture of OV1701 and stationary phase) of an extract of heads of male A. victrix. Iden-
heptakis(6-O-tert-butyldimethylsilyl-2,3-di-O-methyl)-β- tified structures are assigned.
cyclodextrin as an enantioselective stationary phase. Figure 3
Structural relations between the Alloxysta-
shows the structures and retention times of all eight stereoiso-
mers of trans-fused iridomyrmecins on both capillary column compounds and other insect iridoids
systems. Despite the small differences in retention times The iridoid lactones which are present in the cephalic secre-
between B and B' on the cyclodextrin column, the enantiomers tions of Alloxysta victrix show an unusual trans-fusion. Among
could be well distinguished under the experimental conditions. the compounds showing this structure, only the lactone X [1]
Figure 6: Configurations of the trans-fused iridomyrmecins C and D’.
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Figure 7: Volatile terpenoids in the cephalic secretion of Alloxysta victrix. For the identification of compounds other than Y and Z see [1].
(Figure 1) and a compound with the same relative configura-
tion [21] have been described from insects so far. In contrast to
that, the cis-fused nepetalactone 15 and diastereomers thereof
are typical components of many species of the plant genus
Nepeta [22,23]. Along with the corresponding hemiacetal 16,
which shows (1R)-configuration, 15 is also a most important
sex pheromone of aphids [24] (Figure 8). Nevertheless, iridoids
are usually associated with defense chemistry. Whilst configu-
rations at the stereogenic centers of 15 and related iridoid
lactones in insects appear to be stereotypic, several monocyclic
iridoids show further stereochemical variation. Lactol 16 and
iridodial (17) have first been identified as defense compounds
of ants [25]. More recently, 17 – which shows (R)-configura-
tion at C1 of the side-chain – was found to be a male-produced
aggregation pheromone of lacewings [26,27].
The cis-fused iridomyrmecin (1) and dolichodial (18) are
constituents of the anal gland secretion of the Argentine ant
Iridomyrmex humilis [28]. More recently, (1S,2R,3S)-
dolichodial (18) has been identified as an electrophysiologi-
cally active volatile released from the rosy apple aphid
Dysaphis plantaginea oviparae and has been discussed apart
from 15 and 16 as a possible third component of the aphid sex
pheromone [29]. Actually, 18 was first identified in the defen-
sive secretions of dolichoderine ants [25]. The same substance
Figure 8: Structures of iridoids from insects and plants. Absolute
configurations of 19 and 20 are "educated guesses".
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(or its enantiomer) has been found as a defensive compound of
Nematine larvae [30] and in adults and larvae of the thrips
Calloccithrips fuscipennis [31]. A stereoisomer of dolichodial –
anisomorphal (19) – is a component of the defensive secretion
of the walking stick Anisomorpha buprestoides [32], whilst a
third stereoisomer – peruphasmal (20) – has been identified in
another walking stick, Peruphasma schultei [33,34]. Recent
investigations show that the qualitative and quantitative com-
position of cyclopentanoid iridoids in the defensive secretion of
A. buprestoides may vary with age and population. The secre-
tion may contain all three isomers 18, 19 and 20 which the
insect can produce from glucose [35]. The absolute configura-
tions of 19 and 20 are still unknown. It should be mentioned
that along with other iridoids 18 and 19 are also components of
the essential oil of some plant species [36]. A related cyclopen-
tene derivative is chrysomelidial (21), a relatively widespread
defense compound in larvae of phytophagous leaf beetles
Chrysomelidae [37,38], which has been found in other insects,
too. In the defensive secretion of oribatid mites it keeps the
depicted (5S,8S)-configuration [39]. In some species, chrysome-
Figure 9: Biosynthetic ways to iridoids from geraniol.
lidial is accompanied by the dehydronepetalactone 22 (gastro- During these investigations the stereochemistry of the subse-
lactone) [40] or the didehydroiridomyrmecin 23 (plagiolactone) quent cyclization to iridoids was found to be different in larvae
[37]. To the best of our knowledge, the two iridomyrmecins Y of herbivorous leaf beetles and in carnivorous rove beetles. In
and Z are new natural products, representing the first trans- Phaedon cochleariae (Chrysomelidae), cyclization of 29
fused iridoid lactones of this type.
directly affords chrysomelidial (21). In contrast, in Phylonthus
sp. (Staphylinidae) the first step is the formation of plagiodial
Whilst the trans-fused nature of the new iridoid lactones is very (30), which was first identified from larvae of several leaf
unusual, their stereochemical pattern (Figure 7) is even more beetle species [49,50]. Subsequently, 30 may rearrange to the
puzzling: The configurational arrangements of the substituents thermodynamically more stable, conjugated 21. Despite these
in X and Y are strictly opposite, whereas the relations between results, there are still a lot of open questions concerning the
X and Z are relatively close, showing inversion at C-4 only. biosynthesis of iridoids. Recently, it could be shown that leaf
Strangely, Z is not the expected C-4-epimer of Y, but the C-4- beetles may produce iridoid monoterpenes de novo [33] but
epimer of its enantiomer.
they are also able to sequester glycosidically bound terpene
precursors from their food plants [51-53] which is highly
Apart from very few exceptions such as methoxymyodesertene interesting with regards to the evolution of insect-plant relation-
(24) [41], the 4-nor-nepetalactone mitsugashiwalactone (25) ships and insect defense chemistry. At present, nothing is
[42] and its “nor-iridomyrmecin-complement” boschnialactone known about the formation of “saturated” iridoids such as irido-
(26), [43] which all are plant volatiles, the methyl group in the dial (17) or the iridoid lactones in Alloxysta. The strange stereo-
typical five-membered ring of iridoids keeps its (S)-configura- chemical relations between these compounds may well be the
tion (see also Figure 8), which is just in contrast to X and Z result of different mechanisms in the enzymatic hydrogenation
[44]. However, recently, two stereoisomers of iridomyrmecin steps.
showing (7R)-configuration have been reported to be compo-
nents of the defense chemistry of the Drosophila parasitoid Conclusion
Leptopilina heterotoma [45].
The new iridoid lactones have been found in the mandibular
gland secretions of several alloxystine wasps [54] and their
activity in intraspecific and interspecific communication has
Remarks on the biosynthesis of iridoids
Today it is generally accepted that the biosynthesis of iridoids been discussed [55]. According to first bioassays, the new
starts from the acyclic geraniol (27). In a series of careful, iridoids seem to play a multifunctional role in the tritrophic
elegant experiments it was shown that 27 is oxidized to system of the aphid Sitobion avenae, its parasite, the wasp
8-hydroxygeraniol (28) which is further transformed to Aphidius uzbekistanicus, and the hyperparasitoide Alloxysta
8-oxogeranial (29) [46-48] (Figure 9).
victrix as they obviously sedate Sitobion and repell Aphidius.
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monocyclic iridoids, behavior experiments using synthetic com-
pounds may shed some more light on the complex relationships
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Supporting Information File 1
Experimental details and characterization data for
synthesized compounds.
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Acknowledgements
The biological material used in this investigation was kindly
provided by Prof. Dr. Urs Wyss, University of Kiel, Germany.
Financial support by the German Science Foundation, Deutsche
Forschungsgemeinschaft (DFG – Fr 12/1), is gratefully
acknowledged.
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