Unsymmetrical double Wittig olefination on the syntheses of insect pheromones. Part 1: Synthesis of 5,9-dimethylpentadecane, the sexual pheromone of Leucoptera coffeella

Article abstract of DOI:10.1016/j.tetlet.2003.10.183

An expeditious three-step synthesis of a mixture of stereoisomers of 5,9-dimethylpentadecane 1, the sexual pheromone of the coffee leaf miner Leucoptera coffeella, is described. The route employs an unsymmetrical double Wittig olefination to build the carbon skeleton of the molecule, as the key reaction. The bis-phosphonium salt 3, derived from 1,3-dibromopropane 2, reacted 'one-pot' with the ketones 2-octanone and 2-hexanone, affording the asymmetric diene 4. This was readily hydrogenated over Pd/C, furnishing pheromone 1 in 54% overall yield. Synthetic 1 showed high biological activity when tested in field experiments.

Full text of DOI:10.1016/j.tetlet.2003.10.183

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 239–241
Unsymmetrical double Wittig olefination on the syntheses
of insect pheromones. Part 1: Synthesis of 5,9-dimethylpentadecane,
the sexual pheromone of Leucoptera coffeella
Paulo H. G. Zarbin,a,* Jefferson L. Princival,a Eraldo R. de Lima,b Alcindo A. dos Santos,a
Bianca G. Ambrogiob and Alfredo R. M. de Oliveiraa
aDepartamento de Quꢀımica, Universidade Federal do Paranaꢀ, CP 19081, CEP 81531-990 Curitiba-PR, Brazil
bDepartamento de Biologia Animal, Universidade Federal de Vißcosa, CEP 36571-000 Vißcosa-MG, Brazil
Received 17 October 2003; revised 28 October 2003; accepted 30 October 2003
Abstract—An expeditious three-step synthesis ofa mixture ofstereoisomers of5,9-dimethylpentadecane 1, the sexual pheromone of
the coffee leafminer Leucoptera coffeella, is described. The route employs an unsymmetrical double Wittig olefination to build the
carbon skeleton ofthe molecule, as the key reaction. The bis-phosphonium salt 3, derived from 1,3-dibromopropane 2, reacted Ôone-
potÕ with the ketones 2-octanone and 2-hexanone, affording the asymmetric diene 4. This was readily hydrogenated over Pd/C,
furnishing pheromone 1 in 54% overall yield. Synthetic 1 showed high biological activity when tested in field experiments.
Ó 2003 Elsevier Ltd. All rights reserved.
Natural products with a 1,5-dimethyl branched pattern
are commonly isolated from a large variety of sources.1
As an example, several insect pheromones2 and insect
cuticular hydrocarbons3 have been described with this
structural characteristic. The compound 5,9-dimethyl-
pentadecane 1 (Fig. 1) was identified by Francke et al.4
as the sexual pheromone ofthe coffee leafminer Leu-
coptera coffeella. This species is one ofthe most
important pests on coffee in Brazil, and is also found in
other countries in South America.5
Recently, a total synthesis ofall ofthe ofur possible
stereoisomers of 1 was published by Kuwahara et al.8
The absolute configuration ofthe natural pheromone
still remains to be determined. One ofus (E.R.L.)
9
observed that the (5S,9S) isomer of 1 elicited higher
antennal response in EAD experiments when compared
with the other three possible isomers. However, in field
experiments, traps baited with pure isomers were poor
attractive. The insects were equally attracted only to a
binary mixture ofthe (5 S,9S) and (5R,9S) isomers, and
to a stereoisomeric mixture of 1.9
Few examples ofracemic or stereoselective syntheses of
compound 1 have been described in the literature.4;6;7
Here we report an expeditious three-step synthesis ofa
mixture ofstereoisomers of5,9-dimethylpentadecane 1,
employing an unsymmetrical double Wittig olefination
as the key reaction (see Scheme 1), and the biological
activity ofthis synthetic pheromone in field experiments.
1
Figure 1.
The bis-phosphonium salt 3 was readily synthesized in
large scale from 1,3-dibromopropane 2 in DMF10 (the
precipitation ofthe mono salt is observed when a less
polar solvent is employed) and can be stored indefi-
nitely. The asymmetric diene 4 was obtained one-pot
through addition of1.0 equiv of2-octanone to the
monoylide 5, generated from symmetric bifunctional
salt 3, followed by the addition of1.0 equiv of2-hexanone
Keywords: Pheromone; Synthesis; 5,9-Dimethylpentadecane; Leucop-
tera coffeella; Double Wittig reaction; 7,11-Dimethylheptadecane;
7-Methylheptadecane; Cuticular hydrocarbons.
* Corresponding author. Tel.: +55-41-361-3174; fax: +55-41-361-3186;
e-mail: pzarbin@quimica.ufpr.br
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.183

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P. H. G. Zarbin et al. / Tetrahedron Letters 45 (2004) 239–241
Br
Br
2
a
BrPh3P
PPh3Br
3
b
4
c
1
Scheme 1. Synthesis ofthe pheromone 1. Reagents and conditions:
(a) 2.1 equiv PPh3, DMF, 92%; (b) (i) 1.1 equiv n-BuLi, )90 °C, (ii)
1 equiv 2-octanone, )90 °C to room temperature, (iii) 1.1 equiv n-BuLi,
)90 °C, (iv) 1 equiv 2-hexanone, )90 °C to room temperature, 64%;
(c) Pd/C, hexane, H2 (30 psi), 93%.
Figure 2. (A) GC profile ofthe stereoisomeric mixture ofthe dienes.
Products ratio 4/4a/4b ꢀ 1.0:0.028:0.070; (B) GC profile ofthe satu-
rated hydrocarbons.
A sequential double-Wittig reaction was previously
described by Pohnert et al.14 and Pohnert and Boland15
on the synthesis ofhomoconjugated trienes as volicitin,
1.1 equiv.
PPh3
BrPh3P
PPh3Br
BrPh3P
n-BuLi
3
5
16
a potent elicitor ofplant volatile biosynthesis,
and
geometrid moth pheromones. In that case, the authors
reacted the carbonyl compounds with a bis(ylide) gen-
1.0 equiv.
1.1 equiv.
BrPh3P
6
2-octanone
n-BuLi
erated rfom the addition of2.2 equiv ofKN(SiMe
)
2
3
(allowing to ensure a (Z)-configuration ofthe resulting
double bonds17) to an unsaturated symmetric bifunc-
tional Wittig salt. However, in our modified experi-
ments,11 we detected that by reacting the first carbonyl
compound (ketones or aldehydes) with a monoylide, as
structure 5, and further generating the new reactive
ylide, as structure 7, the formation of symmetric cou-
pling products could be suppressed in almost 20%.
Ph3P
1.0 equiv.
2-hexanone
4
7
Scheme 2.
to the new monoylide 7, derived from intermediate 6 (see
Scheme 2). Under optimized reaction conditions,11 the
formation of the symmetrical by-products 4a and 4b was
less than 10% ofthe product mixture (Fig. 2A). Since the
target molecule ofthe present work is a saturated
compound, no efforts were made in order to control the
geometry ofthe double bonds. In this reaction, both
ylides 5 and 7 were generated employing 1.1 equiv of n-
BuLi as base, at )90 °C. Finally, a routine hydrogena-
tion over Pd/C ofdienes afforded pheromone 1 as a
mixture ofstereoisomers, in 54% overall yield. The ratio
ofthe hydrogenated by-products 1a and 1b was the
same as detected to the dienes (Fig. 2B).
We suppose that the formation of one phosphorane at a
time is possible due to the stability ofanions under
different temperature, that is, after addition of the first
equivalent of n-BuLi at )90 °C, statistical mixture ofthe
bisphosphorane and monophosphorane must be
formed. However, when the reaction reached room
temperature, keep stirring for an additional time, the
bis(ylide) must be converted to the monoylide by
reacting with the remaining bis-Wittig salt. This
hypothesis is supported on the fact that when the car-
bonyl sources were added to the phosphoranes that were
not previously heated, ꢀ45% ofthe symmetric coupling
dienes 4a and 4b were obtained.
We employed successfully the same approach on the
synthesis oftwo others saturated hydrocarbons identi-
fied as components ofthe female sex pheromone ofthe
spring hemlock looper Lambdina athasaria12 the 7,11-
dimethylheptadecane 1b and 7-methylheptadecane 8.13
Symmetric 1b could be easily prepared in excellent yields
(65%) using only 2-octanone to react with the ylides 5
and 7, while the single methyl branched compound 8
was obtained in 49% overall yield employing 2-octanone
and heptanal13 as carbonyl sources.
Field experiments were run on coffee plantations in
ß
Vicosa MG, Brazil, to test the biological activity of
synthetic 1. Rubber septa (8 mm OD, white rubber,
Aldrich) were loaded with 0.5 mg ofsynthetic 1 and with
a
racemic pheromone provided by Fuji Flavors
(Japan).18 Delta traps (10/treatment) were positioned
randomly 30 m apart from each other in the field. Traps
were placed at 0.1 m above the ground. Moths trapped

P. H. G. Zarbin et al. / Tetrahedron Letters 45 (2004) 239–241
241
3. Gibbs, A.; Pomonis, J. G. Comp. Biochem. Phys. B 1995,
112, 243–249.
a
a
20
15
10
5
ꢀ
€
4. Francke, W.; Toth, M.; Szocs, G.; Krieg, W.; Ernst, H.;
Buschmann, E. Z. Naturforsch 1988, 43C, 787–789.
5. Fragoso, D. B.; Guedes, R. N. C.; Picanco, M. C.;
Zambolim, L. B. Entomol. Res. 2002, 92, 203–212.
6. Liang, T.; Kuwahara, S.; Hasegawa, M.; Kodama, O.
Biosci. Biotech. Biochem. 2000, 64, 2474–2477.
ꢀ ꢀ
ꢀ
7. Poppe, L.; Novak, L.; Devenyi, J.; Szantay, C. Tetrahe-
dron Lett. 1991, 32, 2643–2646.
0
8. Kuwahara, S.; Liang, T.; Leal, W. S.; Ishikawa, J.;
Kodama, O. Biosci. Biotech. Biochem. 2000, 64, 2723–
2726.
Fuji Flavor
Synthetic 1
Source of pheromone
9. The manuscript describing a complete data set offield
experiments is now in progress and will appear elsewhere.
10. Friedrich, K.; Henning, H.-G. Chem. Ber. 1959, 92, 2756–
2760.
Figure 3. Number (mean SE) of L. coffeella males caught in Delta
traps baited with different pheromone sources during 7 weeks. The
amount ofcomponents loaded in each rubber septum was 0.5 mg (10
replicates).
11. Typical procedure for the double-Wittig reaction: To a
cold )90 °C (ethanol/liquid N2 cooling bath) suspension of
the bis-phosphonium salt (1.0 mmol) in THF (10 mL) was
added n-BuLi (1.1 mmol, 2.0 mol Lꢁ1 in hexane), and the
reaction mixture was allowed to warm to room temper-
ature, stirred for additional 30 min and re-cooled ()90 °C).
A solution ofthe first carbonyl component (1.0 mmol) in
THF (1.0 mL) was added dropwise, and the mixture was
allowed to reach room temperature, stirred for additional
30 min and re-cooled ()90 °C). The same protocol was
adopted to generate the second ylide (1.1 equiv n-BuLi)
and to the addition ofthe second carbonyl component
(1.0 equiv). Usual work-up and flash chromatography on
silica gel yielded the respective dienes.
were counted every week during 7 weeks. After each
counting, insects were removed. The lures were placed at
the bottom ofthe traps.
9
Male attraction was not significantly different among
the traps baited with our synthetic 1 and with the Fuji
Flavors pheromone (F1:133 ¼ 0:033; p ¼ 0:8554). The
means oftrap catch per week is represented in Figure 3.
In summary, we have straightforward synthesized a
stereoisomeric mixture ofhydrocarbons pheromones
and tested the biological activity of5,9-dimethylpenta-
decane 1. Field experiments revealed that the synthetic
pheromone, as appear in Figure 2B,19 was highly
attractive to males L. coffeella. We are now synthesizing
other insect pheromones employing this methodology,
including optically active molecules, and the results will
appear in due course.
12. Gries, R.; Gries, G.; Li, J.; Maier, C. T.; Lemmon, C. R.;
Slessor, K. N. J. Chem. Ecol. 1994, 20, 2501–2511.
13. The reactivity ofketones and aldehydes with the mono-
ylides under the reaction condition described above is
quite similar, and the ratio ofthe symmetric coupling
by-products
obtained
is
almost
the
same
8
14. Pohnert, G.; Koch, T.; Boland, W. Chem. Commun. 1999,
1087–1088.
15. Pohnert, G.; Boland, W. Eur. J. Org. Chem. 2000, 1821–
1826.
16. Alborn, H. T.; Turlings, T. C. J.; Jones, T. H.; Stenhagen,
G.; Loughrin, J. H.; Tumlinson, J. H. Science 1997, 276,
945–949.
Acknowledgements
This work was supported by the International Foun-
dation for Science (Sweden), Organization for Prohibi-
tion ofChemical Weapons (Netherlands), CNPq and
~
ꢀ
Fundaßcao Araucaria (Brazil) (grant to PHGZ).
17. Nicolaou, K. C.; Ramphal, J. Y.; Abe, Y. Synthesis 1989,
898–901.
18. This compound was proved as highly efficient in capturing
males ofcoffee leafminer in the field. The manuscript is in
preparation.
References and Notes
1. Herbert, R. B. The Biosynthesis of Secondary Metabolites.
2nd ed. Chapman & Hall: London, 1989.
2. Mori, K. In The Synthesis of Insect Pheromones; ApSi-
mon, J., Ed. The Total Synthesis ofNatural Products;
John Wiley & Sons: New York, 1992; Vol. 9.
19. It is quite difficult to separate the symmetrical products 1a
and 1b to the unsymmetrical 1 by conventional methods.
However, in the cases that the carbonyl sources differs in
more than four carbon atoms, a carefully distillation allow
the purification.