Asymmetric total synthesis of a putative sex pheromone component from the parasitoid wasp Trichogramma turkestanica

Article abstract of DOI:10.3762/bjoc.10.71

Virgin females of the parasitoid wasp Trichogramma turkestanica produce minute amounts of a sex pheromone, the identity of which has not been fully established. The enantioselective synthesis of a putative component of this pheromone, (6S,8S,10S)- 4,6,8,10-tetramethyltrideca-2E,4E-dien-1-ol (2), is reported as a contribution to this identification. Catalytic asymmetric conjugate addition of methylmagnesium bromide and stereoselective Horner-Wadsworth-Emmons olefinations are used as the key steps, and 2 was obtained in 16 steps with an overall yield of 4.4%.

Full text of DOI:10.3762/bjoc.10.71

Asymmetric total synthesis of a putative sex
pheromone component from the parasitoid wasp
Trichogramma turkestanica
Danny Geerdink1, Jeffrey Buter1, Teris A. van Beek2
and Adriaan J. Minnaard*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 761–766.
1Stratingh Institute for Chemistry, University of Groningen, Nijenborgh
7, 9747 AG, Groningen, The Netherlands and 2Natural Products
Chemistry Group, Laboratory of Organic Chemistry, Wageningen
University, Dreijenplein 8, 6703 HB Wageningen, The Netherlands
doi:10.3762/bjoc.10.71
Received: 17 December 2013
Accepted: 04 March 2014
Published: 02 April 2014
Email:
Adriaan J. Minnaard* - a.j.minnaard@rug.nl
This article is part of the Thematic Series "Natural products in synthesis
and biosynthesis".
* Corresponding author
Guest Editor: J. S. Dickschat
Keywords:
asymmetric catalysis; copper; deoxypropionates; natural products;
sex pheromone; Trichogramma turkestanica
© 2014 Geerdink et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Virgin females of the parasitoid wasp Trichogramma turkestanica produce minute amounts of a sex pheromone, the identity of
which has not been fully established. The enantioselective synthesis of a putative component of this pheromone, (6S,8S,10S)-
4,6,8,10-tetramethyltrideca-2E,4E-dien-1-ol (2), is reported as a contribution to this identification. Catalytic asymmetric conjugate
addition of methylmagnesium bromide and stereoselective Horner–Wadsworth–Emmons olefinations are used as the key steps, and
2 was obtained in 16 steps with an overall yield of 4.4%.
Introduction
Communication by means of pheromones is common in many cult [4]. A classification on the basis of sex pheromones might
animal species. For instance, many insects secrete air-borne help in this respect.
volatiles to attract a mate for generating offspring [1,2]. In
2005, one of us reported the isolation and partial characteriza- Apart from the above reason and the scientific challenge to
tion of the putative sex pheromone of Trichogramma elucidate the identity of a complex pheromone at the low
turkestanica, a parasitoid wasp [3]. These wasps, belonging to nanogram level, an additional reason to study these tiny wasps
the large Trichogrammatidae family, are minute in size is their possible application in an environmentally friendly way
(0.5 mm, 8 µg adult weight) as well as morphologically similar of crop protection [5]. After copulation, the female wasp
making a taxonomic characterization at the species level diffi- deposits the fertilized eggs inside the eggs of a host insect,
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Beilstein J. Org. Chem. 2014, 10, 761–766.
which is used as a food source for the hatched wasps. Bio- took the stereoselective synthesis of 2, thereby arbitrarily
logical studies have revealed that only virgin females are able to choosing the all-S configuration.
trigger casting behavior in males, which has led to the assump-
tion that virgin females of Trichogramma turkestanica produce Results and Discussion
a sex pheromone. Analysis of headspace volatiles of virgin Nowadays, a number of efficient strategies is available for the
females, collected via solid-phase microextraction, showed the synthesis of deoxypropionates [7-15]. Our approach [16] is
presence of two sex specific components which were regarded based on copper-catalyzed asymmetric conjugate addition of
to play an important role in this sex pheromone. After exten- methylmagnesium bromide to α,β-unsaturated thioesters and
sive analysis by mass spectrometry and derivatisation studies, has proven its versatility [17-19]. Arrays of up to eight methyl
the natural products were postulated to be 2,6,8,12-tetrametyl- substituents have been constructed [20]. Starting from 3, the
trideca-2,4-diene (A) and 2,6,8,12-tetramethyltrideca-2,4-dien- first conjugate addition using (R,SFe)-L1 afforded 4, as
1-ol (B) (Figure 1) [3]. Stereochemical assignments were expected in high yield and excellent enantiomeric excess
lacking. Subsequent synthesis of reference compounds led to (Scheme 1). Reduction with DIBALH, followed by
revision of the structures, and as a result, the compounds were Horner–Wadsworth–Emmons olefination and again asym-
unambiguously identified to be (2E,4E)-syn,syn-4,6,8,10- metric conjugate addition gave 6 in 77% yield over three steps.
tetramethyltrideca-2,4-diene (1) and (2E,4E)-syn,syn-4,6,8,10- To ultimately remove the carbonyl function, we introduced the
tetramethyltrideca-2,4-dien-1-ol (2, Figure 1) [6]. The absolute third methyl ramification in α,β-unsaturated ketone 7, prepar-
configurations of the putative pheromone components, ation of which was straightforward [21]. Conjugate addition to
however, remained unknown. To solve this problem we under- 7 using the conditions from step A proved clearcut and gave 8
Figure 1: Originally proposed structures A and B and revised structures 1 and 2 of putative sex pheromone components of Trichogramma
turkestanica.
Scheme 1: Application of the iterative conjugate addition protocol for the preparation of 8.
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Beilstein J. Org. Chem. 2014, 10, 761–766.
in 82% yield over three steps from 6. Both the enantiomeric vinylogous Horner–Wadsworth–Emmons olefination, offered in
excess and the diastereomeric excess of 8 were excellent which principle a very efficient procedure to obtain dienoate 13
is important as the response of insects to their pheromones can (Scheme 3), and would leave only a single step in the synthesis
be highly sensitive to the stereoisomeric composition.
of 2 [25]. Therefore, reagent 12 was prepared in two steps.
After quantitative conversion of 10 into 11 using Ley–Griffith
A number of procedures exist to reduce ketones to their corres- oxidation, its reaction with 12, using LiHMDS as the base,
ponding methylene groups. Initial attempts focused on the afforded 13 in 75% yield, though as a 1:1 mixture of 2E,4E- and
formation and subsequent removal of the corresponding 2E,4Z-isomers. Moreover, the 1H NMR spectra indicated the
hydrazones. Regrettably, the Myers modification of the presence of an impurity, which appeared as a multiplet between
Wolf–Kishner reduction did not afford detectable amounts of 10 5.00 and 5.45 ppm. Although minimal amounts of 2E,4Z-13
[22]. Also the modification of Caglioti proved only moderately could be isolated, 2E,4E-13 was inseparable from this impurity.
successful with 30% isolated yield of 10 over two steps [23]. As We decided to continue the synthesis with impure 13, which
an alternative deoxygenation procedure, we relied on the was reduced with DIBALH at low temperature to give crude 1
so-called Mozingo reduction. Although the procedure for in 96% yield. TLC analysis indicated the presence of two major,
dithiane formation has been reported to be catalytic in Lewis separable, products. Purification by flash-column chromatog-
acid, we found a linear correlation between the amount of raphy over either silica gel or neutral aluminium oxide,
BF3·Et2O used and the conversion (Scheme 2) [24]. The use of however, led to rapid degradation of 2. In the process, we were
1.2 equiv of BF3·Et2O led to 9 in 84% isolated yield. Reduction unable to isolate a pure sample of either isomer. This approach
of 9 with freshly prepared Raney nickel and subsequent desily- was ultimately abandoned, and only delivered the knowledge
lation afforded 10 over two steps in 73% yield.
that 2 is unstable upon purification by column chromatography.
This sensitivity to acid has been reported before for similar
To introduce the desired E,E-diene present in 2 and 1, we real- compounds [26], and can be explained by the readily formed
ized that the procedure reported by Markiewicz, comprising a dienyl cation.
Scheme 2: Deoxygenation and desilylation of 8.
Scheme 3: Vinylogous Horner–Wadsworth–Emmons olefination.
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Beilstein J. Org. Chem. 2014, 10, 761–766.
We realized that, in order to obtain a pure sample of 2, it was mixture gave no conclusive evidence for the nature of the impu-
essential to avoid chromatographic purification after the final rity, double bond isomers of 15 could account for the observed
step. As the reduction of 13 with DIBALH is a clean reaction, 1H NMR signals.
affording essentially pure 2 after work-up, the preparation of
pure 13 was highly desirable. A stepwise olefination approach As the Wittig reaction of 11 did afford 15, although with the
was therefore considered.
simultaneous formation of an inseparable side-product, we were
curious to see how the analogous Horner–Wadsworth–Emmons
Wittig reaction of aldehyde 11 with phosphorane 14 to give 15 olefination towards 15 would perform. Thus, aldehyde 11 was
was carried out first (Scheme 4) [27]. Next to ~60% of the freshly prepared and subjected to the conjugate base of 16
desired product, around 40% of the mass balance consisted of (Scheme 5). This olefination proved to be much faster, but
an inseparable impurity. 1H NMR spectroscopy again showed a afforded 15 as a 1:1 mixture of E- and Z-isomers as determined
set of multiplets between 4.95–5.00 ppm. Although repeated by 1H NMR spectroscopy. This is attributed to a destabilizing
recrystallization of commercial reagent 14 reduced the impurity interaction of the α-methyl moiety of the HWE reagent in the
to 6%, pure 15 could not be obtained, not even with freshly transient four-centered intermediate, leading to a mixture of
prepared 14. Moreover, in none of the successive steps the double bond isomers. The impurity previously observed as a
impurity could be separated and therefore also this approach result of the Wittig reaction was not present. In addition, the E-
was abandoned. Although NMR and GC–MS analysis of the and Z-isomers could be separated using column chromatog-
Scheme 4: Synthesis of α,β-unsaturated ester 15 using a Wittig reaction.
Scheme 5: Completion of the synthesis of the putative sex pheromone 2.
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achieved using DIBALH, affording allylic alcohol 17 in 90%
yield, which in turn was oxidized to aldehyde 18 using
Dess–Martin periodinane. Given that the conversion of 18 into
19 using a Wittig reaction had proven to be sluggish, we
switched again to a Horner–Wadsworth–Emmons olefination,
expecting to observe high E-selectivity. Indeed, 19 was
obtained in 64% yield over two steps, as the pure E,E-isomer.
Reduction of pure 19 with DIBALH finally afforded 2 in 96%
yield after work-up. The compound showed to be identical to
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In summary, after two unsuccessful attempts, (E,E,S,S,S)-2 has
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yield. As the absolute configuration of natural 2 is yet unknown,
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racemic 2 by chiral GC has up till now shown impossible,
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Supporting Information
Supporting Information File 1
Detailed experimental procedures and spectral data of all
new compounds.
18.ter Horst, B.; Feringa, B. L.; Minnaard, A. J. Org. Lett. 2007, 9,
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Acknowledgements
This work was financially supported by The Netherlands Orga-
nization for Scientific Research (NWO-CW). Mr. K. Ward of
Ward Illustration is acknowledged for providing artwork.
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