A protecting group-free synthesis of the Colorado potato beetle pheromone

Article abstract of DOI:10.3762/bjoc.9.273

A novel synthesis of the aggregation pheromone of the Colorado potato beetle, Leptinotarsa decemlineata, has been developed based on a Sharpless asymmetric epoxidation in combination with a chemoselective alcohol oxidation using catalytic [(neocuproine)PdOAc]2OTf2. Employing this approach, the pheromone was synthesized in 3 steps, 80% yield and 86% ee from geraniol.

Full text of DOI:10.3762/bjoc.9.273

A protecting group-free synthesis of the
Colorado potato beetle pheromone
Zhongtao Wu, Manuel Jäger, Jeffrey Buter and Adriaan J. Minnaard*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2374–2377.
Stratingh Institute for Chemistry, University of Groningen,
Nijenborgh 7, 9747 AG, Groningen, The Netherlands
doi:10.3762/bjoc.9.273
Received: 20 August 2013
Accepted: 18 October 2013
Published: 06 November 2013
Email:
Adriaan J. Minnaard* - a.j.minnaard@rug.nl
* Corresponding author
This article is part of the Thematic Series "Natural products in synthesis
and biosynthesis".
Keywords:
aggregation pheromone; catalysis; Colorado potato beetle;
Leptinotarsa decemlineata; oxidation; natural product
Guest Editor: J. S. Dickschat
© 2013 Wu et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A novel synthesis of the aggregation pheromone of the Colorado potato beetle, Leptinotarsa decemlineata, has been developed
based on a Sharpless asymmetric epoxidation in combination with a chemoselective alcohol oxidation using catalytic
[(neocuproine)PdOAc]2OTf2. Employing this approach, the pheromone was synthesized in 3 steps, 80% yield and 86% ee from
geraniol.
Introduction
The Colorado potato beetle Leptinotarsa decemlineata, a world- dihydroxy-3,7-dimethyl-6-octen-2-one (1, Figure 1) [8]. (S)-1 is
wide pest causing considerable damage in the US annually, has attractive for both male and female Leptinotarsa decemlineata
developed resistance to more than 25 insecticides [1-4]. For while (R)-1 is inactive or inhibitory, as was demonstrated by the
crop protection, currently several insecticides are used such as inactivity of the racemate [7]. Since then, (S)-1 has been synthe-
the neonicotinoids imidacloprid, thiamethoxam and thiachlo- sized by the groups of Oliver [8], Mori [9], Chauhan [10] and
prid [1,5], albeit these are expensive and moreover resistance
lies in wait [6]. From the standpoint of environmental protec-
tion and economics, it is important to reduce the use of insecti-
cides controlling the Colorado potato beetle, and an attractive
alternative is to use a pheromone management strategy.
An important finding in this connection was the isolation of the
male produced aggregation pheromone by Dickens and Oliver
Figure 1: (S)-1,3-dihydroxy-3,7-dimethyl-6-octen-2-one (1).
et al. in 2002 [7], which was subsequently identified as (S)-1,3-
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Beilstein J. Org. Chem. 2013, 9, 2374–2377.
very recently by Faraldos [11] respectively, and the first field alkene in the substrate, as the orthogonality of 2-catalyzed
evaluation of synthetic (S)-1 in a trap crop pest management alcohol oxidations with alkenes had not been studied.
strategy showed its practical utility [1].
The commercial enantioselective production of chiral
pheromones of many pest insects is hampered by prohibitively
high costs. The selective introduction of stereocenters and the
number of steps are the main reasons. In 2002, Oliver described
the first synthesis of both enantiomers of 1 from (R)- and (S)-
linalool, and also the synthesis of its racemate from geraniol, to
Scheme 2: Approach of synthesis of (S)-1.
establish the absolute configuration. Although the approach is
elegant, (S)-linalool required for natural (S)-1 is not commer-
cially available. In 2005, Mori employing lipase-catalyzed
kinetic resolution of (±)-2,3-epoxynerol as the key step, synthe-
sized both (S)- and (R)-1 in gram quantities with high ee. In
Chauhan’s work, Grignard reaction, oxidation and stereo-
selective methylation using organometallic reagents are the key
steps, affording (S)-1 in high enantiomeric purity and in gram
quantities. In all these approaches, however, protection of the
primary hydroxy group of the 1,2,3-triol substructure is required
for the selective oxidation of the secondary alcohol at C-2. The
synthesis by Faraldos runs via epoxidation of fluoronerol,
subsequent acetylation of the alcohol and solvolysis.
In our approach, Sharpless asymmetric epoxidation of readily
available geraniol or nerol [16-18] followed by stereoselective
ring-opening with water would lead to the desired triol 3.
Subsequently regioselective oxidation of 3 would provide (S)-1
in a concise 3 step route. The resulting synthesis would be
interesting also for commercial application, moreover because
the oxidation pattern in 1 occurs more widespread in natural
products and pharmaceuticals such as in cortisol (hydrocorti-
sone).
Results and Discussion
The synthesis of (S)-1 is summarized in Scheme 3. The choice
In 2010, Waymouth reported the chemoselective, catalytic oxi- for either geraniol or nerol should have been based on the
dation of glycerol to dihydroxyacetone (Scheme 1) using stereoselectivity of the Sharpless epoxidation. For both reac-
catalytic [(neocuproine)PdOAc]2OTf2 (2) in the presence of tions, however, varying enantioselectivities had been reported,
either benzoquinone or air as the terminal oxidant [12]. More so both substrates were studied. According to the published
recently, the transformation of unprotected vicinal polyols to procedure, upon treatment of freshly distilled geraniol
α-hydroxy ketones was achieved by regio- and chemoselective (Scheme 3) with tert-butyl hydroperoxide in the presence of
oxidation using catalyst 2 [13]. We used this method for the D-(−)-diisopropyl tartrate (DIPT) and Ti(OiPr)4 in dry CH2Cl2
catalytic regioselective oxidation of glycosides (Scheme 1) [14] at –10 to –23 °C for 2 h, the desired epoxide (2R,3R)-4 was
and expected that the approach might also be applicable in the obtained in 93% yield and 88% ee. The ee was determined by
synthesis of (S)-1. Triol 3, with vicinal primary, secondary, and HPLC analysis of its corresponding TBDPS ether. This result
tertiary hydroxy groups should be a suitable substrate for compares well with the ones reported in the literature: 77–95%
chemoselective oxidation with catalyst 2, enabling a protecting yield and 81–95% ee [17-21]. According to Sharpless et al.
group-free synthesis of the Colorado potato beetle pheromone [18], 5 mol % of Ti(OiPr)4 and 7.5 mol % of DIPT were used,
(Scheme 2). An additional challenge was the presence of an so at least 20% excess of tartrate ester in order to obtain the
Scheme 1: Selective oxidation of glycerol [15] and methyl α-D-glucopyranoside.
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Beilstein J. Org. Chem. 2013, 9, 2374–2377.
Scheme 3: Synthesis of (S)-1 from geraniol. Reagents and conditions: a) D-(−)-diisopropyl tartrate, Ti(OiPr)4, tert-butyl hydroperoxide, CH2Cl2,
4 Å MS, –10 to –23 °C, 2 h, 93%, 94:6 er; b) HClO4 (70%), THF/water, rt, 30 min, 94%; c) 0.5 mol % 2, p-benzoquinone, CH3CN/water, rt,
overnight, 91%.
maximum enantiomeric excess. The use of freshly distilled Conclusion
DIPT and Ti(OiPr)4 was important to obtain consistently 88% In summary, we have developed an efficient synthesis of the
ee. With epoxide (2R,3R)-4 at hand, an acid-catalyzed ring- aggregation pheromone of the Colorado potato beetle (S)-1,3-
opening reaction was carried out using HClO4 in THF/water at dihydroxy-3,7-dimethyl-6-octen-2-one (1). Combining
room temperature [22]. In the process of ring-opening, close to Sharpless asymmetric epoxidation, stereoselective epoxide ring-
quantitative inversion of configuration at C-3 takes place opening and catalytic chemoselective alcohol oxidation with
[23,24], a result which was confirmed in our research as [(neocuproine)PdOAc]2OTf2 (2), (S)-1 was synthesized in 80%
determination of the ee of both substrate and product shows a overall yield and 86% ee over 3 steps from geraniol. Nerol
slight drop in ee from 88% to 86% (see Supporting Information turned out to be less suitable as starting material as its asym-
File 1). Triol (2R,3S)-3 was obtained from (2R,3R)-4 in high metric epoxidation provided a lower ee. It has been shown that
yield by this regio- and stereoselective ring-opening reaction. (S)-1 with an ee of 92% is as active as enantiopure (S)-1 (99%
Subsequently (2R,3S)-3 was converted into (S)-1 by treatment ee), therefore it is probably safe to conclude that the currently
with 0.5 mol % of catalyst 2 and benzoquinone in CH3CN/ obtained 86% ee suffices.
water at room temperature. The reaction turned out to be very
selective for the secondary alcohol and neither oxidation of the
Supporting Information
primary alcohol nor of the alkene was observed. (S)-1 was
obtained in 91% yield and both 1H NMR and 13C NMR spectra
Supporting Information File 1
coincided with those reported in the literature [8,9].
Experimental and spectroscopic details for 1, 3 and 4, and
determination of the ee of 3 and 4.
Starting from nerol, Sharpless asymmetric epoxidation afforded
the epoxide (2S,3R)-4 in a disappointing 74% ee, a result which
is nevertheless in accordance with the reported values: 70–94%
[25-30] (Scheme 4). Applying the same ring-opening reaction
to epoxide (2S,3R)-4, triol (2S,3S)-3 was obtained in high yield
but a 6% loss in enantiomeric excess was observed (see
Supporting Information File 1). Considering these disap-
pointing results using nerol as the starting material, oxidation to
(S)-1 was not performed.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-273-S1.pdf]
Acknowledgements
This work was supported by the NRSC-Catalysis program. J. G.
Edens is kindly acknowledged for support in literature studies.
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