Enantioselective synthesis and absolute configuration of the sex pheromone of Hedypathes betulinus (Coleoptera: Cerambycidae)

Article abstract of DOI:10.1016/j.tetlet.2010.10.024

The male-produced sex pheromone of Hedypathes betulinus was identified as a mixture of (E)-6,10-dimethyl-5,9-undecadien-2-one (geranylacetone) (1) and its respective alcohol (2) and acetate (3). Kinetic resolution of alcohol (2) promoted by CAL-B in organic media provided both, (R)-(-)-(E)-6,10-dimethyl-5,9- undecadien-2-yl acetate (3) and (S)-(+)-(E)-6,10-dimethyl-5,9-undecadien-2-ol (2) in high enantiomeric purity. Comparative GC analysis using a chiral column revealed the natural constituents as being (R)-(3) and a mixture of (R)- and (S)-(2) in a ratio of 82.3% and 17.6%, respectively.

Full text of DOI:10.1016/j.tetlet.2010.10.024

Tetrahedron Letters 51 (2010) 6704–6706
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective synthesis and absolute configuration of the sex pheromone of
Hedypathes betulinus (Coleoptera: Cerambycidae)
⇑
Diogo M. Vidal, Marcy G. Fonseca, Paulo H. G. Zarbin
Departament of Chemistry, Federal University of Parana, 81531-990, Curitiba-PR, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The male-produced sex pheromone of Hedypathes betulinus was identified as a mixture of (E)-6,10-
dimethyl-5,9-undecadien-2-one (geranylacetone) (1) and its respective alcohol (2) and acetate (3).
Kinetic resolution of alcohol (2) promoted by CAL-B in organic media provided both, (R)-(À)-(E)-6,10-
dimethyl-5,9-undecadien-2-yl acetate (3) and (S)-(+)-(E)-6,10-dimethyl-5,9-undecadien-2-ol (2) in high
enantiomeric purity. Comparative GC analysis using a chiral column revealed the natural constituents as
being (R)-(3) and a mixture of (R)- and (S)-(2) in a ratio of 82.3% and 17.6%, respectively.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 23 July 2010
Revised 6 October 2010
Accepted 6 October 2010
Available online 15 October 2010
Keywords:
Hedyphates betulinus
Sex pheromone
Kinetic resolution
Absolute configuration
Hedypathes betulinus (Coleoptera: Cerambycidae: Lamiinae)
(Klug, 1825) is the most serious pest of green mate (Ilex paraguari-
ensis) in the southern region of Brazil.1 Three male-specific compo-
nents were detected by gas chromatography, and the presence of a
pheromone regulating the mating behavior of this insect was
determined.1 The chemical structure of these compounds were re-
cently identified as (E)-6,10-dimethyl-5,9-undecadien-2-one
(gera-nylacetone) (1), (E)-6,10-dimethyl-5,9-undecadien-2-ol (2),
and (E)-6,10-dimethyl-5,9-undecadien-2-yl acetate (3) (major
component) (Fig. 1).2
The compound (E)-6,10-dimethyl-5,9-undecadien-2-ol (2) was
identified as the main component of the sex pheromone of Tetropi-
um fuscum and Tetropium acinnamopterum and was named fuscu-
mol3, whereas (E)-6,10-dimethyl-5,9-undecadien-2-yl acetate (3)
is unprecedented in pheromone chemistry.
O
(1)
(2)
(3)
OH
*
O
O
*
Figure 1. Male-produced sex pheromone of H. betulinus.
Behavioral tests using the synthetic racemic compounds
showed that these compounds are attractive for female H. betuli-
nus.2 However, the presence or absence of the unnatural isomer
may have an influence on the behavior of the insects, supporting
the importance of knowing the stereochemistry of naturally pro-
duced compounds.4 H. betulinus aeration extracts provided a few
microgram of each compound, making it impractical to use con-
ventional methods of absolute configuration assignment.2
Therefore, the best way to establish the absolute configuration
of the pheromone is by enantioselective gas chromatography and
comparison of retention times of synthetic enantiomers with cor-
responding data of the natural compounds.4 Biocatalysis is a pow-
erful tool to obtain enantiopure molecules in organic synthesis.5
Several secondary alcohols have been resolved with high enantio-
meric excess employing CAL-B (Novozymes 435Ò—immobilized
Candida antarctica lipase B) over the past few years.5
This paper describes the enantioselective synthesis and deter-
mination of the absolute configuration of the sex pheromone com-
ponents from H. betulinus employing a kinetic resolution promoted
by CAL-B.
Racemic alcohol (2) and acetate (3) were synthesized by the
reduction of geranylacetone (1) with LAH6, followed by acetylation
of the hydroxyl group using Ac2O and pyridine7 to afford alcohol
(2) and acetate (3) in 90% and 85% yield, respectively (Fig. 2).
The studies started with the investigation of the reaction time
and the solvent type in the kinetic resolution of (2), (Fig. 2). The
kinetic resolution of the racemic secondary alcohol was evaluated
⇑
Corresponding author. Tel.: +55 41 3361 3174; fax: +55 41 3361 3186.
E-mail address: pzarbin@quimica.ufpr.br (P.H.G. Zarbin).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.024

D. M. Vidal et al. / Tetrahedron Letters 51 (2010) 6704–6706
6705
O
O
OH
O
Ac2O
LiAlH4
Py, 85%
THF, 90%
(1)
(2)
(3)
O
CAL-B, org. solv.
(see conditions and yields
in table 1)
O
O
O
OH
+
(R)-(3)
(S)-(2)
Ac2O, Py
85%
LiAlH4, THF
89%
O
O
OH
(R)-(2)
(S)-(3)
Figure 2. Synthesis of enantiopure (S)-(2), (S)-(3), (R)-(2), and (R)-(3).
in organic media with vinyl acetate as acetate donor.8 Three organ-
ic solvents, TBME, hexane, and THF, and five different reaction
times were employed in the assays (Table 1).
The assays were performed by addition of CAL-B to a solution of
alcohol (2) and vinyl acetate in the appropriate solvent at 32 °C.
The conversions were determined by analyzing the formed prod-
ucts by enantioselective GC. In all reactions, the formation of the
enantiopure acetate (R)-(3) and the reminiscence of the alcohol
(S)-(2) was observed (Fig. 2), which agrees with Kazlauska’s rule
for CAL-B.5,9
Assays in THF showed a lower level of conversion of the sub-
strate in all reaction times investigated (maximum of 34.4%). Tests
in hexane and TBME showed a better level of conversion (almost
50%), and the best enantioselectivity was achieved with TBME that
yielded (S)-(2) and (R)-(3) in an enantiomeric excess of 93.7% and
>99%, respectively, within 120 min (Table 1). Madyastha and
The best condition was obtained on a preparative scale to syn-
thesize the alcohol (R)-(2) ([
D = À3.6) by LAH reduction of the
acetate (R)-(3) ([ D = +2.9),
by acetylation of the alcohol (S)-(2), using Ac2O and pyridine
(Fig. 2).
The absolute configuration of the alcohol and the acetate pres-
ent in the natural extract were assigned according to results from
enantioselective GC employing a b-CD column (HP-Chiral 20B (20%
a
]
a]
D = À2.8) and the acetate (S)-(3) ([
a]
permethylated b-CD, 30 m  0.25 mm  0.25
lm), maintaining the
oven in an isothermal of 100 °C during 170 min) to compare the
retention times of the compounds of the extracts with the stan-
dards obtained from CAL-B resolution. Alcohol (2) (the minor com-
ponent of the pheromone) is present in the extract in both
enantiomeric forms in a ratio of 82.3% (R)-(2) and 17.6% (S)-(2),
as shown in Figure 3A. The major component released by Hedypa-
thes betulinus was determined to be the enantiopure (R)-(À)-(E)-
6,10-dimethyl-5,9-undecadien-2-yl acetate, (R)-(3), which is
unprecedented in pheromone chemistry (Fig. 3B).
Gururaja (1994) found an [a]D = +3.4 (c 5.0, CHCl3) for the alcohol
(S)-(2).10 In our experiments, we found an [
for the alcohol (S)-(2).
a]D = +3.2 (c 5.0, CHCl3)
Table 1
Kinetic resolution of the alcohol ( )-(2) employing CAL-B and different organic mediaa with five different reaction times
Enzyme
Solvent
TBME
Time
Conversion (c)b (%)
ee (S)-(2)c (%)
ee (R)-(3)d (%)
Ee
Abs. config. (acetate)
CAL-B (Novozymes 435)Ò
15 min
30 min
60 min
120 min
24 h
20.5
33.8
47.9
48.6
38.6
25.6
50.5
90.9
93.7
60.9
99
99
99
>99
97
>200
>200
>200
>200
123
R
R
R
R
R
Hexane
THF
15 min
30 min
60 min
120 min
24 h
12.1
32.7
45.4
42.3
40.1
13.6
48.2
82.4
72.6
65.1
99
99
99
99
97
>200
>200
>200
>200
129
R
R
R
R
R
15 min
30 min
60 min
120 min
24 h
5.8
9.1
23.2
34.4
32.0
6.2
9.9
29.9
52.0
46.5
99
99
99
99
99
>200
>200
>200
>200
>200
R
R
R
R
R
a
b
c
TBME, Hexane, or THF.
Conversion (%)—calculated from the ee’s of the substrate (ees) and the product (eep): ees/(ees + eep).
Enantiomeric excess of (S)-(2) after resolution.
Enantiomeric excess of (R)-(3) after resolution.
Enantiomercic ratio (describes the enantioselectivity of the enzyme): E = ln[1 À c(1 + eep)]/ln[1 À c(1 + eep)].
d
e

6706
D. M. Vidal et al. / Tetrahedron Letters 51 (2010) 6704–6706
Acknowledgments
We thank Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq, Brazil) and Instituto Nacional de Ciências e
Tecnologia de Semioquímicos na Agricultura for supporting our
research.
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data, chiral chromatograms, and copies of 1H, 13C NMR for
(2) and (3) are available) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2010.10.024.
References and notes
1. Fonseca, M. G.; Zarbin, P. H. G. J. Appl. Entomol. 2009, 133, 695.
2. Fonseca, M. G.; Vidal, D. M.; Zarbin, P. H. G. J. Chem. Ecol. 2010, 36, 1132.
3. Silk, P. J.; Sweeney, J.; Wu, J. P.; Price, J.; Gutowski, J. M.; Kettela, E. G.
Naturwissenschaften 2007, 94, 697.
4. Mori, K. Bioorg. Med. Chem. 2007, 15, 7505.
5. Ghanem, A. Tetrahedron 2007, 63, 1721.
6. Zarbin, P. H. G.; de Oliveira, A. R. M.; Delay, C. E. Tetrahedron Lett. 2003, 44,
6849.
7. Zarbin, P. H. G.; Lorini, L. M.; Ambrogi, B. G.; Vidal, D. M.; Lima, E. R. J. Chem.
Ecol. 2007, 33, 555.
8. Santos, A. A.; Da Costa, C. E.; Princival, J. L.; Comasseto, J. V. Tetrahedron:
Asymmetry 2006, 17, 2252.
Figure 3. Determination of the absolute configuration of the alcohol (A) and the
acetate (B) released by H. betulinus.
9. Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org. Chem.
1991, 56, 2656.
10. Madyastha, K. M.; Gururaja, T. L. J. Chem. Technol. Biotechnol. 1994, 59, 249.
Experiments to evaluate the behavior of H. betulinus in the pres-
ence of enantiomerically pure compounds are underway.