Enantioselective synthesis of (S)-3,7-dimethyl-2-oxo-6-octene-1,3-diol: a Colorado potato beetle pheromone

Article abstract of DOI:10.1016/j.tetlet.2008.10.092

The recent identification of a male-produced aggregation pheromone [(S)-3,7-dimethyl-2-oxo-6-octene-1,3-diol, (S)-CPB] offers a new tool for Colorado potato beetle (CPB) management. We developed a novel synthetic approach to produce CPB pheromone in seven

Full text of DOI:10.1016/j.tetlet.2008.10.092

Tetrahedron Letters 50 (2009) 66–67
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Tetrahedron Letters
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Enantioselective synthesis of (S)-3,7-dimethyl-2-oxo-6-octene-1,3-diol:
a Colorado potato beetle pheromone
*
Bathini Nagendra Babu, Kamlesh R. Chauhan
USDA-ARS, Invasive Insect Biocontrol and Behavior Laboratory, Beltsville, MD 20705, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The recent identification of a male-produced aggregation pheromone [(S)-3,7-dimethyl-2-oxo-6-octene-
1,3-diol, (S)-CPB] offers a new tool for Colorado potato beetle (CPB) management. We developed a novel
synthetic approach to produce CPB pheromone in seven steps and 46.54% overall yield. Grignard reaction,
oxidation, and stereoselective methylation using organometallic reagent are the key steps in the com-
mercially viable total synthesis, generating CPB pheromone in 98.6% enantiomeric purity and gram
quantity.
Received 30 September 2008
Revised 16 October 2008
Accepted 20 October 2008
Available online 1 November 2008
Keywords:
Colorado potato beetle
Pheromone
Published by Elsevier Ltd.
Methyl lithium
Lewis acids
The Colorado potato beetle1 (CPB); (Leptinotarsa decemlineata),
is a worldwide pest causing billions of dollars damage annually.
Control of the CPB has relied primarily on insecticides; however,
the beetle has evolved resistance to virtually every pesticide ever
used against it, and is now showing resistance to new insecticide
classes such as the neonicotinoids.1c At present, there are limited
alternatives to the use of synthetic pesticides. Insecticide resis-
tance management and environmental stewardship promote man-
agement using CPB pheromone as a desirable alternative. For many
insect pests, cost of synthesis of chiral pheromones is prohibitively
expensive, limiting their commercial production and general
acceptance. Because of the complexity and stereospecificity of
pheromones, it is often productive to pursue novel approaches
using natural reactants in order to develop high-yielding economic
production.
was carried out to reveal the absolute configuration of the
pheromone.2a The first field evaluation of formulations comprising
synthetic CPB-pheromone revealed practical utility in pest manage-
ment and organic farming.3
Growing awareness of an environmental friendly crop protec-
tion as well as some disadvantages in earlier synthetic approaches2
prompted us to develop novel, efficient, and enantioselective syn-
thesis of (S)-CPB pheromone. Our synthetic route includes manni-
tol, a commercially available natural sugar, as an economical
starting material (Scheme 1). Eliminating chiral/enzymatic resolu-
tion as one of the cost limiting factors, we are able to produce
CPB pheromone in high purity and gram quantity for commercial
production.
Grignard reaction of aldehyde 1 (prepared from mannitol
diacetonide4) with (4-methylpent-3-enyl)-magnesium bromide
(generated from Mg and 5-bromo-2-methyl-2-pentene) in dry
tetrahydrofuran at 0 °C afforded the secondary alcohol 2 in 91%
yield. Oxidation of compound 2 was achieved by using PCC
and 4 Å molecular sieves in dichloromethane to form the ketone
3 in 93% yield. Formation of the tertiary alcohol 4 was the key
intermediate, necessary for attaining the high enantiomeric pur-
ity of the pheromone. The stereochemistry of addition reaction
onto glyceraldehyde acetonide has been well explored and
highly stereoselective protocols have been developed generating
either syn or anti products.5 Conversely, the stereochemistry of
the organometallic addition reaction onto ketone (3) remains
unexplored.
OH
OH
O
(S)-3,7-Dimethyl-2-oxo-6-octene-1,3-diol
CPB-Pheromone
Earlier, a male-produced aggregation pheromone was identified
by USDA scientist in our laboratory.1a The formal synthesis
First we treated the ketone 3 with MeLi in dry THF at À78 °C,
which afforded tertiary alcohol with 20:80 (syn:anti) diastereo-
selectivity, which was not suitable as >80% enantiomeric excess
* Corresponding author. Tel.: +1 301 504 5166; fax: +1 301 504 6580.
E-mail address: Kamal.Chauhan@ars.usda.gov (K. R. Chauhan).
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.10.092

B. N. Babu, K. R. Chauhan / Tetrahedron Letters 50 (2009) 66–67
67
OH
O
THF
PCC
MgBr
O
+
O
o
o
CHO
DCM, 0 C-rt, 93%
0 C- rt, 91%
O
2
1
O
OH
OH
PPTS, MeOH
MeLi, SnCl
o
4
O
OH
OH
O
o
DCM, -78 C, 85%
0 C- rt, 90%
O
O
OH
3
4
5
7
i) (COCl)2,D MSO, TEA
DCM, -78 oC, 86%
OH
OH
O
TBDPSCl, Imidazole
o
OR
ii)TBAF, THF, 0 oC-rt, 88%
DMAP(cat), DCM, 0 C-rt, 95%
6
OH
R= TBDPS
Scheme 1.
of S-CPB pheromone is required for optimum bioactivity.3 Then we
examined the reaction of ketone with combination of MeLi and Le-
wis acids (BF3ÁEt2O, TiCl4, and SnCl4). Interestingly, the optimized
combination of MeLi and SnCl4 in dichloromethane at À78 °C
was found to provide the anti-isomer of tertiary alcohol 4 as single
product in 85% yield.6 The isomeric purity was determined by the
chiral GC analysis.7 Exposure of 4 to PPTS in methanol cleaved the
acetonide protection (5), and then selective protection of primary
hydroxyl group with tertiarybutyldiphenyl silylchloride in the
presence of imidazole and catalytic amount of DMAP provided
the product 6, which set the stage for the oxidation at C-2. Swern
oxidation on 6 gave the ketone, which was treated with TBAF to
furnish the pure (S)-CPB pheromone in 88% yield.8
Our synthetic approach not only produces this pheromone
in higher enantiomeric purity, but also allows for flexibility in
production of analogues while leaving the active site intact.
Unchanged GC-EAD response of female CPB antenna to (S)-3,7-di-
methyl-2-oxo-6-octane-1,3-diol, a saturated derivative of 7, led us
to explore structure–activity relationships. We synthesized some
of the analogues of (S)-CPB pheromone containing oxygenated part
(C1–C3) intact. Using the appropriate Grignard reagent in the first
step of Scheme 1, we succeeded in modifying the tail portion, C4–
C8. This offers us a rare opportunity of exploiting bio-activity while
possibly improving on the physiochemical properties of the origi-
nal pheromone structure in terms of volatility and persistence un-
der field conditions.
Acknowledgments
We thank Dr. Fernando Otalora-Luna for GC-EAD analysis and
Dr. Joseph Dickens for providing authentic samples. Critical review
of the manuscript and helpful suggestions were gratefully provided
by Dr. Donald Weber, USDA-ARS, Beltsville, MD.
References and notes
1. (a) Dickens, J. C.; Oliver, J. E.; Hollister, B.; Davis, J. C.; Klun, J. A. J. Exp. Biol. 2002,
205, 1925–1933; (b) Weber, D. C. Pestic. Outlook 2003, 14, 256–259; (c) Whalon,
M. E.; Mota-Sanchez, D.; Hollingworth, R. M. Global Pesticide Resistance in
Arthropods; CABI: Wallingford, UK, 2008.
2. (a) Oliver, J. E.; Dickens, J. C.; Glass, T. E. Tetrahedron Lett. 2002, 43, 2641–2643;
(b) Tashiro, T.; Mori, K. Tetrahedron: Asymmetry 2005, 16, 1801–1806.
3. Kuhar, T. P.; Dickens, J. C. Agric. Forest Ent. 2006, 8, 77–81.
4. Schmid, C. R.; Bryant, J. D.; Dowlatzedah, M.; Phillips, J. L.; Prather, D. E.; Schantz,
R. D.; Sear, N. L.; Vianco, C. S. J. Org. Chem. 1991, 56, 4056–4058.
5. (a) Macdonald, T. L.; Mead, K. J. Org. Chem. 1985, 50, 422–424; (b) McGarvey, G.
J.; Kimura, M.; Oh, T.; Williams, J. M. J. Carbohydr. Chem. 1984, 8, 125; (c) Hagen,
S.; Lwande, W.; Kilaas, L.; Anthonsen, T. Tetrahedron 1980, 36, 3101–3105.
6. Procedure for the preparation of tertiary alcohol 4: An oven-dried two-necked
flask equipped with magnetic stir bar, nitrogen inlet, and septum was charged
with dichloromethane solution (20 mL) of ketone (3) (7.0 mmol, 1.5 g) and
cooled to À78 °C, then SnCl4 (7.0 mmol, 0.82 mL) was added and stirred under a
nitrogen atmosphere for 10 min. MeLi (1.6 M in diethyl ether, 14.0 mmol) was
added dropwise to the solution at the same temperature and stirred for 2 h. The
mixture was allowed to warmed to 0 °C over 1 h, then treated with saturated
ammonium chloride, and extracted with dichloromethane (2 Â 30 mL). The
combined organic phases were washed with water, brine solution, and dried
over anhydrous Na2SO4. The solvent was removed by rotary evaporation to give
a
crude oil which was purified by column chromatography (hexanes–
In summary, we demonstrated a facile and versatile method for
the synthesis of Colorado potato beetle pheromone. The synthetic
method we developed not only produces (S)-CPB economically,
but it can be used to derive novel analogues for structure–activity
research. Our ultimate goal is to optimize efficacy and utility of
semiochemicals in the integrated pest management of CPB.
ethylacetate 7:1) to give 4 as colourless oil (1.37 g, 85% yield).
7. The absolute configuration at C-3 of 4 was determined as (S), by comparing the
retention times (GC analysis) of the known compounds (6 and 7). GC method
was used for the analysis of compounds: 30 m  0.25 mm ChiraldexTM (Advanced
Separation Technologies, Inc.) B-DM, H2 carrier, 100 °C (2) min then
programmed at 2 °C/min to 200 °C and held at that temperature.
8. All the spectral properties were matched with the reported values (Ref. 2).