Synthesis of the Female Sex Pheromone of the Citrus Mealybug, Planococcus citri

Article abstract of DOI:10.1021/jf035301h

The citrus mealybug, Planococcus citri (Risso) is a common pest in the Southern U. S. and the Mediterranean. Two alternative syntheses of the female sex pheromone, (1R)-(+)-cis-2,2-dimethyl-3-isopropenyl-cyclobutane methanol acetate, have been developed. Key transformations include an allylic oxidation of (1R)-(+)-α-pinene to (+)-R-verbenone, oxidative decarboxylation using RuCl₃-NalO₄, and methylenation with Zn/CH ₂Br₂/TiCl₄.

Full text of DOI:10.1021/jf035301h

2896 J. Agric. Food Chem. 2004, 52, 2896−2899
Synthesis of the Female Sex Pheromone of the Citrus
Mealybug, Planococcus citri
†
LINDA C. PASSARO AND FRANCIS X. WEBSTER*,‡
Center for Bio/Molecular Science and Engineering, Naval Research Laboratory,
Washington, D.C. 20375 and Department of Chemistry, SUNY College of Environmental Science and
Forestry, Syracuse, NY 13210
The citrus mealybug, Planococcus citri (Risso) is a common pest in the Southern U. S. and the
Mediterranean. Two alternative syntheses of the female sex pheromone, (1R)-(+)-cis-2,2-dimethyl-
3-isopropenyl-cyclobutane methanol acetate, have been developed. Key transformations include an
allylic oxidation of (1R)-(+)-R-pinene to (+)-R-verbenone, oxidative decarboxylation using RuCl3-
NaIO4, and methylenation with Zn/CH2Br2/TiCl4.
KEYWORDS: (+)-cis-Planococcyl acetate; synthesis; pheromones; olefination; oxidation
INTRODUCTION
Scheme 1
The citrus mealybug, Planococcus citri (Risso), is a major
pest to coffee, citrus, and cocoa in both the southern U. S. and
the Mediterranean. Citrus mealybugs inflict damage by sucking
out plant sap and then excreting honeydew, which allows mold
to grow. Their toxic saliva can cause further growth distortions
and early leaf droppage. Without control, infested plants usually
die (1, 2).
Citrus mealybugs often congregate in crevices and cracks.
As a result, pesticide treatment is often ineffective in controlling
the citrus mealybug. Interest in alternative pest control strategies
resulted in the identification of the female-produced sex
pheromone as (1R)-(+)-cis-2,2-dimethyl-3-isopropenyl-cyclobu-
tane methanol acetate ((+)-cis-planococcyl acetate, (1) by Bierl-
Leonhardt et al. in 1981 (3). Field tests indicated that the
optically pure (+)-cis-isomer (1, [R]313025 +168°) was 10-fold
more attractive to males than either the (+)-trans-isomer or the
(a) RuCl3-NaIO , CH CN/CCl4/H O; (b) (CH ) SiCH MgCl; (c) Ac2O; (d)
4
3
2
3 3
2
LiAlH , Et2O; (e) Ac2O, pyr; (f) RuCl3-NaIO , t-BuOH/H O; (g) Zn/CH Br2/TiCl4.
4
4
2
2
25
(-)-cis-isomer ([R]3130 - 130°) (3). Since its identification,
there have been numerous syntheses of 1 (4-8). Previous
methods involved either photolytic rearrangement or oxidative
decarboxylation as the key step. We have developed two
alternative pathways for the synthesis of 1 starting from either
(+)-trans-verbenol (2) or (+)-R-verbenone (3) (Scheme 1).
oven-dried glassware under a N2(g) atmosphere. Solvents were
evaporated using a Bu¨chi R-124 rotary evaporator unless otherwise
indicated. All starting materials and reagents were obtained from Aldrich
Chemical Co.
trans-(R)-Verbenol (2). (1R)-(+)-R-Pinene (91% + ee/GLC, 7.42
g, 54.5 mmol) was dissolved in benzene and heated to 65-70 °C. Lead
(IV) tetraacetate (26.5 g, 59.8 mmol, 1.1 eq) was added over 15 min,
and the mixture was allowed to stir 1.5 h further. The reaction mixture
was filtered and the filtrate was washed with H2O (2×), brine, dried
(Na2SO4), filtered, and evaporated. The residue was dissolved in glacial
AcOH (35 mL, 0.609 mol, 11 eq) and allowed to stand (35 min). The
solution was diluted with H2O and extracted with hexane (2×). The
combined extracts were washed with H2O, 5% aq NaHCO3, brine, dried
(Na2SO4), filtered, and evaporated to yield crude acetate. The residue
was distilled under high vacuum (0.05 mmHg) to afford verbenol acetate
(bp 65-67 °C).
METHODS AND MATERIALS
General. All bps are uncorrected. NMR (1H and 13C) were obtained
using a Bruker Avance 300 MHz with CDCl3. GC/FID sample analysis
was carried out on an HP 6890 instrument equipped with a 30-m DB-5
column. Samples were heated from 50 °C (1 min) to 280 °C (10 min)
at a rate of 8°/min. Optical rotations were measured using a Jasco DIP-
1000 digital polarimeter. All synthetic procedures were carried out with
* To whom correspondence should be addressed. Email: fwebster@
mailbox.syr.edu.
The acetate collected was dissolved in MeOH (10 mL) with 20%
aq KOH (10 mL) and placed in the refrigerator (2 days). The mixture
was diluted with H2O and extracted with Et2O (2×). The combined
† Naval Research Laboratory.
‡ SUNY College of Environmental Science and Forestry.
10.1021/jf035301h CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/22/2004

Sex Pheromone of the Citrus Mealybug
J. Agric. Food Chem., Vol. 52, No. 10, 2004 2897
organics were washed with H2O and brine, dried (Na2SO4), filtered,
and evaporated to give trans-(R)-verbenol 2 (4.54 g, 29.9 mmol, yield
55% for both steps), whose 1H NMR spectrum was in accordance with
anhydride was added dropwise (3.5 mL, 37.1 mL, 3.5 equiv). Once a
precipitate formed, the mixture was warmed to room temperature (1.5
h). The reaction was quenched with H2O (20 mL) and then separated.
The aqueous layer was extracted with Et2O (2×), and the combined
organics were washed with brine, dried (Na2SO4), filtered, and
evaporated. The residue was taken up in Et2O and washed with aq
Na2CO3 (3×). The combined aqueous layers were acidified with 1 N
HCl (pH 2) and extracted with Et2O (2×). The extracts were washed
with brine, dried (Na2SO4), filtered, and evaporated to yield isopropenyl
acid 5 (0.532 g, 3.17 mmol, yield 30%). The residue was immediately
reduced with LiAlH4 to prevent epimerization (see below).
(+)-(1R)-cis-2,2-Dimethyl-3-isopropenyl-cyclobutanecarboxylic
Acid (5) using Zn/CH2Br2/TiCl4. Activated zinc (12) (24.9 g, 381
mmol, 10.9 equiv) was suspended in anhydrous THF (150 mL) with
dibromomethane (10 mL, 142.5 mmol, 4.1 equiv). The reaction mixture
was cooled to -45 °C and TiCl4 (12 mL, 109 mmol, 3.1 equiv) was
added dropwise. When the formation of yellow smoke had subsided,
the mixture was warmed to 0 °C and maintained with good stirring for
2 days. Anhydrous CH2Cl2 (40 mL) was added followed by dropwise
addition of ketoacid 4 (5.97 g, 35.1 mmol) in CH2Cl2 (35 mL). The
mixture was stirred (0.5 h) and then warmed to room temperature (3
h). Hexane (100 mL) was added with 1.5 N HCl (slow initially, total
140 mL). The mixture was stirred for 0.5 h and then separated. The
aqueous layer was extracted with hexane (2×), and the combined
extracts were dried (Na2SO4), filtered, and evaporated. The residue was
immediately reduced with LiAlH4 to prevent epimerization (see below).
literature data collected at a lower field strength (9). [R]22 +110.3°
D
(CHCl3, c ) 12.9). 1H NMR (300 MHz, CDCl3, 25 °C): δ ) 0.86 [s,
3H, C(6)-CH3], 1.32 [s, 3H, C(6)-CH3], 1.71 [s, 3H, C(2)-CH3],
1.94-2.29 [m, 4H], 4.25 [s, 1H, C(4)-H], 5.33 [s, 1H, C(3)-H]. 13
C
NMR (300 MHz, CDCl3, 25 °C): δ ) 20.8, 23.0, 27.0, 29.1, 47.5,
48.2, 48.5, 70.8, 119.2, 149.2.
(+)-R-Verbenone (3). (1R)-(+)-R-Pinene (91% + ee/GLC, 25.0 g,
183.7 mmol) was dissolved in acetone (590 mL) with H2O (80 mL).
N-Hydroxyphthalimide (33.0 g, 202 mmol, 1.1 eq.) was added and
allowed to dissolve. Chromium trioxide was added every 3 h (3 portions
of 18.7 g, 561.3 mmol, 3.1 equiv) and allowed to stir overnight. The
mixture was partitioned between hexane and 1 N HCl then separated.
The aqueous layer was extracted with hexane (3 × 110 mL), and the
combined organics were washed with saturated aqueous NaHCO3 (2×),
brine, dried (Na2SO4), filtered, and evaporated to yield crude 3. The
residue was distilled under vacuum (1.4 mmHg) with a dry ice/acetone
cooled collection flask to afford pure 3 (9.90 g, bp 78-82 °C, 66.0
mmol, yield 36%) whose NMR spectra (1H and 13C) were in accordance
with literature data collected at a lower field strength (10). [R]22
D
+180.1° (CHCl3, c ) 78.7). 1H NMR (300 MHz, CDCl3, 25 °C): δ )
0.95 [s, 3H, C(6)-CH3], 1.44 (s, 3H, C(6)-CH3], 1.96 [d, 3H, 4JH,H
)
3
1.6 Hz, C(2)-CH3], 2.02 [d, 1H, JH,H ) 9.1 Hz, C(7)-H], 2.37 [td,
1H, 3JH,H ) 5.8 Hz, 2JH,H ) 1.4 Hz, C(7)-H], 2.58 [dt, 1H, 3JH,H ) 6.0
3
3
3
Hz, JH,H 1.7 Hz, C(5)-H], 2.75 [dt, 1H, JH,H ) 9.1 Hz, JH,H ) 5.5
Hz, C(1)-H], 5.67 [m, 1H, C(3)-H]. 13C NMR (300 MHz, CDCl3, 25
°C): δ ) 21.9, 23.4, 26.4, 40.7, 49.5, 53.9, 57.4, 121.0, 170.0, 203.8.
(+)-(1R)-cis-2,2-Dimethyl-3-isopropenyl-cyclobutane Methanol
Acetate (1). Lithium aluminum hydride (1.04 g, 27.4 mmol, 0.92 equiv)
was suspended in anhydrous Et2O (220 mL) and cooled to 0 °C.
Isopropenyl acid 5 (5.0 g, 29.8 mmol) in Et2O (30 mL) was added
dropwise, and the mixture was allowed to stir (1.5 h). Excess LiAlH4
was destroyed (13), and the mixture was then warmed to room
temperature overnight. The reaction mixture was vacuum filtered and
the filtrate was dried (Na2SO4), filtered, and evaporated. The residue
was added to a solution of Ac2O (7 mL) and pyridine (32 mL) at 0 °C.
The mixture was stirred (15 min) and then warmed to room temperature
overnight. The resulting solution was partitioned between H2O and
hexane then separated. The aqueous layer was extracted with hexane
(2×) and the combined organics were washed with 1 N HCl (3×),
brine, dried (Na2SO4), filtered, and evaporated to yield crude isopro-
penyl acetate 1 (4.20 g, 24.7 mmol, yield 83%). The crude residue
was distilled under vacuum (1.4 mmHg) to afford 1 (3.03 g, bp 83-
86 °C, yield from 4 44%) whose NMR spectra (1H and 13C) were in
(+)-(1R)-cis-2,2-Dimethyl-3-acetyl-cyclobutanecarboxylic Acid (4)
using CH3CN/CCl4/H2O. Verbenol 2 (4.54 g, 29.9 mmol) was
dissolved in a mixture of CH3CN (30 mL), CCl4 (60 mL), and H2O
(90 mL) and then cooled to 0 °C. Ruthenium chloride (0.148 g, 0.714
mmol, 0.024 equiv) was added, followed by portion-wise addition of
NaIO4 (55.0 g, 257.2 mmol, 8.60 equiv) over 0.5 h. The mixture was
stirred (5 h) and then vacuum filtered. The filtrate was separated, and
the aqueous layer was extracted with CCl4 (5×). Ethyl alcohol (95%,
2 mL) was added to the combined organics, dried (Na2SO4), filtered,
and decolorized with carbon. The solution was refiltered, evaporated,
and dissolved in Et2O. The ether solution was filtered through Celite
and evaporated to yield ketoacid 4 (1.79 g, 10.53 mmol, yield 35%)
whose NMR spectra (1H and 13C) were in accordance with literature
data collected at a lower field strength (11). 1H NMR (300 MHz, CDCl3,
25 °C): δ ) 0.95 [s, 3H, C(2)-CH3], 1.43 [s, 3H, C(2)-CH3], 1.89
[dt, 1H, 3JH,H ) 11.7 Hz, 3JH,H ) 7.8 Hz, C(4)-H], 2.05 [s, 3H, CH3-
accordance with literature data (5). [R]22 +17.2° (CHCl3, c ) 49.5).
D
1H NMR (300 MHz, CDCl3, 25 °C): δ ) 0.80 [s, 3H, C(2)-CH3],
1.18 [s, 3H, C(2)-CH3], 1.62 [m, 1H], 1.64 [s, 3H, isopropenyl CH3],
COO], 2.61 [m, 1H, C(4)-H], 2.81 [dd, 1H, 3JH,H ) 10.7 Hz, 3JH,H
)
3
3
8.0 Hz, C(3)-H], 2.89 [dd, 1H, 3JH,H ) 10.6 Hz, 3JH,H ) 7.7 Hz, C(1)-
H], 8.25-8.60 [bs, 1H, COOH]. 13C NMR (300 MHz, CDCl3, 25 °C):
δ ) 17.9, 18.7, 29.8, 30.2, 44.8, 44.9, 52.9, 177.7, 206.9.
1.88 [dt, 1H, JH,H ) 10.7 Hz, JH,H ) 7.6 Hz, C(4)-H], 2.01 [s, 3H,
CH3COO], 2.15 [m, 1H], 2.38 [m, 1H], 3.93 [dd, 1H, 2JH,H ) 11.1 Hz,
3JH,H ) 8.6 Hz, CH2OAc], 4.05 [dd, 1H, 2JH,H ) 11.1, 3JH,H ) 6.4 Hz,
CH2OAc), 4.55 [bs, 1H, isopropenyl vinylic], 4.79 [sextet, 1H, 2JH,H
)
(+)-(1R)-cis-2,2-Dimethyl-3-acetyl-cyclobutanecarboxylic Acid
(4) using Aqueous t-Butanol: Sodium metaperiodate (90.4 g, 422
mmol, 9 equiv) was suspended in aqueous t-BuOH (42%, 217 mL),
and (+)-R-verbenone (3, 7.04 g, 46.9 mmol) was added. The reaction
mixture was heated to 32 °C, and RuCl3 ‚ 3H2O was added (0.215 g,
1.04 mmol, 0.022 equiv). The mixture was stirred 2 h further, cooled
to 0 °C, diluted with Et2O (100 mL), and acidified using 6 N HCl (pH
2). After stirring (20 min), the milky mixture was vacuum filtered,
and the solids were washed with Et2O (2×). The combined organics
were washed with H2O and brine, dried (Na2SO4), and allowed to stand
in the refrigerator overnight. The solution was filtered and evaporated
to afford ketoacid 4 (7.50 g, 44.1 mmol, yield 94%) whose NMR spectra
(1H and 13C) were identical with those collected for the ketoacid 4
prepared using the alternative CH3CN/CCl4/H2O solvent system
described above.
1.4 Hz, isopropenyl vinylic]. 13C NMR (300 MHz, CDCl3, 25 °C): δ
) 16.0, 20.9, 22.8, 23.0, 30.9, 39.8, 41.0, 48.9, 64.9, 109.4, 144.9,
170.9.
RESULTS AND DISCUSSION
Oxidative ring opening of verbenol 2 with loss of CO2 was
carried out with RuCl3-NaIO4 in a mixed solvent system (CH3-
CN/CCl4/H2O) to yield ketoacid 4 in 35% yield (11). In our
hands, the reaction was difficult to control on a larger scale (50
g) and resulted in decreased product yields due to the excessive
pressure released. In addition, isolation of 4 was challenging,
due to the difficulty in removing the residual ruthenium salts.
It was found that allowing the particulates to settle out overnight
made the workup easier. Methylenation of 4 using trimethyl-
silylmethylmagnesium chloride and acetic anhydride gave
olefinic acid 5 in 30% yield (14). An excess amount of Grignard
reagent (g2.8 equiv) was needed to complete the reaction, in
part, due to the presence of the acid functionality. Reduction
(+)-(1R)-cis-2,2-Dimethyl-3-isopropenyl-cyclobutanecarboxylic
Acid (5) using (CH3)3SiCH2SiCl. A trimethylsilylmethylmagnesium
chloride solution (30 mL, 1 M/Et2O, 30 mmol) was cooled to 0 °C,
and the ketoacid (4) solution (1.79 g, 10.53 mmol in 15 mL THF) was
added dropwise over 15 min. The reaction mixture was warmed to
room temperature for 1 h then cooled again to 0 °C, and acetic

2898 J. Agric. Food Chem., Vol. 52, No. 10, 2004
Passaro and Webster
expensive reagents (Pb(OAc)4), and required the use of benzene
Scheme 2
as a solvent, the use of verbenol 2 as a substrate was abandoned.
Work by Lardy and Padma indicated that (+)-R-verbenone
(3) could be produced from (+)-R-pinene, using chromium
trioxide and N-hydroxyphthalimide in aqueous acetone in 51%
yield (Scheme 2) (19). Compared with the oxidation of (+)-
R-pinene using Pb(OAc)4 to verbenol 2, the experimental
conditions to produce intermediate 3 were simple, the reagents
were cheap, and the procedure could be substantially scaled up.
The allylic oxidation of 6, when carried out using the described
conditions (19), afforded 3 in 36% yield after distillation.
(a) Pb(OAc)4, benzene; (b) KOH, MeOH; (c) CrO , N-hydroxyphthalimide.
3
of 5 with lithium aluminum hydride followed by acetylation
using acetic anhydride in pyridine afforded pheromone 1. The
overall yield of pheromone 1 from 2 was 2%. Due to the poor
yields obtained and the impracticality of scale-up, another route
to 1 was devised.
LITERATURE CITED
(1) Carlsen, P. H.; Odden, W. Synthesis of the female sex pheromone
of the citrus mealybug, Planococcus citri (Risso). Acta Chem.
ScandinaVica B. 1984, 38, 501.
An alternative ruthenium catalyzed oxidative ring opening
with concomitant decarboxylation using a different solvent
system (aqueous tert-butyl alcohol) and a different substrate
((+)-R-verbenone, 3) afforded ketoacid 4 in 94% yield (15).
Compared with the previous conditions above (1), the alternative
procedure was more easily carried out, and the isolation was
less cumbersome. Methylenation of 4 using a Zn/CH2Br2/TiCl4
procedure gave olefinic acid 5 (16, 17). It was found that 5 had
to be immediately taken on to the next step to avoid epimer-
ization. Although the need to move through to next step quickly
might have been inconvenient, the Zn/CH2Br2/TiCl4 methyl-
enation procedure was sizably more applicable to larger scale
preparations, unlike similar Wittig procedures, which often
require extensive chromatographic purification. Olefinic acid 5
that was kept in the refrigerator (2-3 days) epimerized to a
1:1 mixture of diastereomers. Subsequent reduction of 5 with
lithium aluminum hydride and acetylation with acetic anhydride
in pyridine afforded pheromone 1. Overall yield for the second
sequence was 42% from 3.
The structure of isopropenyl acetate 1 was verified using 1H
and 13C NMR. Optical rotation of 1 in CHCl3 was determined
to be +17.2° ([R]D, c ) 49.5, 22 °C) and was in accordance
with previously collected data (4-8). The enantiomeric excess
of the synthetic pheromone 1 is most likely ∼91%, because
the starting R-pinene was 91% + ee R-isomer. No diastereomers
were detected by either GC/FID or NMR analyses as a result
of epimerization at C-1 or C-3. Epimerization would have to
occur at both C-1 or C-3 to have any appreciable amount of
the opposite enantiomer. Comparison of our data to the literature
data is somewhat challenged by the inconsistency among the
sample concentrations. Pheromone 1 was highly attractive to
male mealybugs in the field (18).
(2) U. C. Pest Management Guidelines for Mealybugs on Citrus.
Citrus
mealybugs.
http://axp.ipm.ucdavis.edu/PMG/
r107300511.html. University of California, Davis, CA 95616,
2000.
(3) Bierl-Leonhardt, B. A.; Moreno, D. S.; Schwarz, M.; Fargerlund,
J.; Plimmer, J. R. Isolation, identification, and synthesis of the
sex pheromone of the citrus mealybug, Planococcus citri (Risso).
Tetrahedron Lett. 1981, 22, 389.
(4) Gaoni, Y. Conjugate addition of organocopper reagents to
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(Risso). Tetrahedron Lett. 1982, 23, 5215.
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(12) Zinc powder (200 mesh) activated by rinsing with 2% aq HCl
(2×), distilled H2O (2×), abs. EtOH (2×), and Et2O (2×).
Remaining solid dried at 200 °C under vacuum (15 mmHg)
overnight. See Fieser, L. F.; Fieser, M. Reagents for Organic
Synthesis; John Wiley & Sons: New York, 1967; Vol. 1, p 1276.
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Wiley & Sons: New York, 1967; Vol. 1, p 584.
Both (+)-trans-verbenol (2) and (+)-R-verbenone (3) are
commercially available, but only at steep prices and in small
quantities. There are numerous conditions reported in the
literature for the oxidation of (1R)-(+)-R-pinene (6) to either
(+)-trans-verbenol or R-verbenone, and (+)-R-pinene 6 is also
reasonably affordable and commercially available in large
amounts. We found it convenient to oxidize (1R)-(+)-R-pinene
(6) to trans-verbenyl acetate by using lead tetraacetate in
benzene (9) followed by saponification using aqueous KOH in
MeOH to give trans-verbenol (2) in 55% overall yield (Scheme
2). Of the few methods available to oxidize 6 to verbenol 2,
lead tetraacetate affords a single oxidation product, whereas the
other methods generate complicated product mixtures. Because
the oxidation reaction could not easily be scaled up, involved
(14) Rosini, G.; Geier, M.; Marotta, E.; Petrini, M.; Ballini, R.
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hept-3-en-6-ones and its utilization in stereoselective total

Sex Pheromone of the Citrus Mealybug
J. Agric. Food Chem., Vol. 52, No. 10, 2004 2899
synthesis of grandisol and lineatin via a versatile intermediate.
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(18) Personal communication from Gerhard Booysen on the Letaba
estate in South Africa. Our synthetic pheromone when compared
to pheromone supplied by Agrisens Co. caught nine times more
male mealybugs.
(19) Lardy, H. A.; Padma, M. Allylic oxidation of allylic compounds
using dicarboxylic acid imides and chromium-containing oxi-
dants. U.S. Patent WO9947485, 1999.
Received for review November 6, 2003. Revised manuscript received
March 11, 2004. Accepted March 17, 2004. This work was supported
in part by the Department of Chemistry at the SUNY College of
Environmental Science and Forestry, Syracuse, NY 13210 and IPM
Technologies, Portland, OR 97217.
JF035301H