Enantioselective synthesis and determination of the absolute configuration of the male sex pheromone of the parasitoid wasp: Urolepis rufipes

Article abstract of DOI:10.1039/d0ob00614a

Males of the parasitoid wasp Urolepis rufipes use 2,6-dimethyl-7-octene-1,6-diol as a sex pheromone to attract virgin females. Herein, we determine the absolute configuration of the pheromone to be (2S,6S)-2,6-dimethyl-7-octene-1,6-diol (2S,6S-6) and present a stereoselective synthesis of the natural enantiomer of this new linalool derivative. In addition, we show that female wasps respond to the natural 2S,6S-6 stereoisomer while 2R,6S-6 is behaviorally inactive.

Full text of DOI:10.1039/d0ob00614a

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Enantioselective synthesis and determination
of the absolute configuration of the male
sex pheromone of the parasitoid wasp
Urolepis rufipes†
Cite this: DOI: 10.1039/d0ob00614a
Received 24th March 2020,
Accepted 8th April 2020
Kristina Melnik,a Christopher Grimm,a Johannes Wittbrodt,b Joachim Ruther b and
DOI: 10.1039/d0ob00614a
a
rsc.li/obc
Stefan Schulz
*
Males of the parasitoid wasp Urolepis rufipes use 2,6-dimethyl-7- thetic precursor of various iridoid monoterpenes used for
octene-1,6-diol as a sex pheromone to attract virgin females. defence by leaf beetles.7 Chrysomela leaf beetles obtain
Herein, we determine the absolute configuration of the phero- 8-hydroxylinalool from plant glycosides and esterify the
mone to be (2S,6S)-2,6-dimethyl-7-octene-1,6-diol (2S,6S-6) and terpene alcohol with short-chain amino acid-derived acids to
present a stereoselective synthesis of the natural enantiomer of obtain an array of defensive esters (5), with a 7 : 3 R/S ratio.8
this new linalool derivative. In addition, we show that female wasps Finally, we described recently the identification and functional
respond to the natural 2S,6S-6 stereoisomer while 2R,6S-6 is be- characterization of 2,6-dimethyloct-7-ene-1,6-diol (6) as the
haviorally inactive.
male sex pheromone of the wasp Urolepis rufipes, a fly parasi-
toid, although the relative and absolute configuration of the
pheromone remained elusive.9 Compound 6 also occurs in the
volatile secretion of the butterfly Danaus genutia.10 Male
Urolepis rufipes wasps release a whitish secretion from the tip
of their abdomen, which contains only diol 6 9 to attract
females.11 Virgin females stay much longer in areas marked by
males.9 Diol pheromone 6 is of special interest, because it rep-
resents a biosynthetic switch within the so-called ‘Nasonia
group’ of parasitoid wasps from the fatty acid biosynthetic
pathway to mevalonate terpene biosynthesis.
Insects extensively use chemical cues and signals to transfer
information between individuals. Intraspecific sex phero-
mones are used by many species to attract or convince individ-
uals of the opposite sex to mate. These mostly volatile phero-
mones are derivatives of major biosynthetic pathways, e.g. fatty
acid derivatives or terpenes.1 The number of known terpenoid
compounds that elicit intraspecific behavioural responses is
large.2 Besides pheromones, volatile defensive compounds of
insects comprise also terpenoids. While hydrocarbons or
monofunctionalized mono- and sesquiterpenes constitute the
majority of these compounds, few insects have developed the
biosynthetic machinery to oxidize the terminal end of the
terpene backbone. Some examples are shown in Fig. 1.
(E)-3,7-Dimethyloct-2-ene-1,8-diol (1) is a component of the
secretion of males of the butterfly Danaus chrysippus, the
African monarch, used in courtship.3 The Azuki bean weevil
Callosobruchus chinensis uses the diacid callosobruchusic acid
(2) as copulation releasing pheromone,4 while some rove
beetles defend themselves with 8-oxocitronellyl acetate (3).5
8-Oxogeranial (4) is used as defensive compound by larvae of
Pseudodineura sawflies.6 This compound is also the biosyn-
aTechnische Universität Braunschweig, Institute of Organic Chemistry, Hagenring 30,
38106 Braunschweig, Germany. E-mail: stefan.schulz@tu-bs.de
bUniversität Regensburg, Institute of Zoology, Universitätsstraße 31,
93053 Regensburg, Germany
†Electronic supplementary information (ESI) available: Experimental details.
See DOI: 10.1039/d0ob00614a
Fig. 1 Terminally oxidized monoterpenes used as semiochemicals by
insects.
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In this contribution we now report on the stereochemical
A new stereoselective synthetic route to 6 was devised using
characterization of 6 by enantioselective synthesis and the Myer’s pseudoephedrine method as key step (Scheme 2). To
response of U. rufipes to two of the possible stereoisomers. this end, the synthesis commenced with (S)-linalool (7) that
Initially, a stereoselective variant of our earlier reported was obtained by purification from coriander oil (ee 90%).
non-selective synthesis of 6 was tried.9 (R)-Linalool (7) was Alcohol 7 was protected as tert-butyldimethylsilyl ether 12,14
transformed into aldehyde 8 as reported (Scheme 1).9 The which was transformed into epoxide 13 by regioselective epoxi-
stereogenic centre at C-2 should be introduced by an enantio- dation with mCPBA.15 Oxidative cleavage in the next step with
selective organocatalytic conjugate reduction with Hantzsch periodic acid gave aldehyde 14.15 This aldehyde was reduced
ester 9 and the trifluoracetic acid salt of (S)-tert-butyl valinate with NaBH4 to alcohol 15, which was transformed into iodide
(10) according to List.12,13 Unfortunately, the reduction gave 16 16 using Appel’s conditions. To introduce the stereogenic
only a 1 : 1 diastereomeric mixture of aldehyde 11. Obviously, centre at C-2, asymmetric alkylation was performed using
the 2-methylalkenals are not suitable substrates for the pseudoephedrine (S,S-18) as chiral auxiliary. First, S,S-17 was
enantioselective reduction, in contrast to 3-methylalkenals.
acylated with propionyl chloride and then stereoselective alkyl-
Although an enantiomerically pure compound could not be ation was accomplished under Myers’s conditions by use of
obtained, this material allowed the determination of the con- iodide 16. The auxiliary was removed by reduction with
figuration at C-6 of the natural pheromone. Chiral GC and lithium amidotrihydroborate (LiH2NBH3) to form alcohol 20.17
coinjection experiments revealed an (S)-configuration (ESI, Deprotection with TBAF at 60 °C for 21 hours furnished
Fig. S2†).
alcohol 2S,6S-6 in 70% yield.18 The diastereomer 2R,6S-6 was
obtained in a similar sequence using (R,R)-pseudoephedrine
(R,R-18) and iodide 16.
GC on an enantioselective phase was then performed to
determine the absolute configuration of the natural phero-
mone. The mixture of all stereoisomers of 6 was well separated
on a β-DEX 225 phase (ESI, Fig. S1†). Our previous investi-
gation has shown that the first eluting peak of 6 is the natural
pheromone.9 The natural compound is a pure enantiomer
(ESI, Fig. S5†). Coinjection of the stereoisomeric mixture with
the diastereomers 2R,6S-6 and 2S,6S-6 as well as with the
natural product proved that (2S,6S)-2,6-dimethyl-7-octene-1,6-
diol is the sex pheromone of Urolepis rufipes (ESI, Fig. S3–S5†).
Behavioural assays were then performed as described pre-
viously.9 The residence time of virgin females near filter paper
disks treated with natural 2S,6S-6 was significantly longer
when compared to solvent treated control disks (paired t-test:
t = 2.1836, p = 0.0338, n = 50, Fig. 2). In contrast, the non-
Scheme 1 First enantioselective attempt towards (2S,6R)-2,6-
dimethyl-7-octene-1,6-diol.
Scheme 2 Stereoselective synthesis of alcohol 2S,6S-6 by asymmetric alkylation.
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Notes and references
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Fig. 2 Residence time (mean
standard error) of virgin females of
Urolepis rufipes when given the choice between different stereoisomers
of 6 (natural: 2S,6S, non-natural: 2R,6S) and pure dichloromethane as
control (Con, asterisk indicates significant difference at p < 0.05, n.s. =
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natural diastereomer 2R,6S-6 was not preferred by the females
(t = −0.2884, p = 0.7743, n = 50). This indicates a highly specific
receptor for the pheromone perception in the female parasi-
toids. Interestingly, diols are rarely encountered as insect
pheromones, likely because of the inherent decrease of vola-
tility compared to other compound classes. In the case of
U. rufipes this decrease may be instrumental, because the
pheromone is applied on surfaces. The two alcohol groups
might increase the duration the compound stays on a surface,
potentially due to H-bonds with the substrate. Therefore, a
longer presence of the signal can be expected, compared to e.g.
monools, ketones, or aldehydes.
In conclusion, we have established the absolute configur-
ation of the male sex pheromone of Urolepis rufipes as (2S,6S)-
2,6-dimethyl-7-octene-1,6-diol (2S,6S-6).
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Conflicts of interest
There are no conflicts to declare.
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