Enantioselective synthesis of the female sex pheromone of the pink hibiscus mealybug, Maconellicoccus hirsutus

Article abstract of DOI:10.1021/jf048198k

The pink hibiscus mealybug, Maconellicoccus hirsutus (Green), is an exotic insect pest and recently invaded Southern California and Florida. The female M. hirsutus releases the 2-methylbutanoate of a novel cyclobutanoid monoterpene alcohol (maconelliol) that together with lavandulyl 2-methylbutanoate constitutes the sex pheromone to attract males from a distance. Enantioselective syntheses of four different stereoisomers of the major component, maconelliyl 2-methylbutanoate 1, from α-pinene are reported. Absolute configurations of both naturally occurring maconelliyl 2-methylbutanoate 1 and the minor component, lavandulyl 2-methylbutanoate 2, have been established. Comparison of the analytical data of naturally occurring compounds with those of optically active synthetic isomers proved that both esters show the (R)-configuration at the alcohol and the (S)-configuration at acid moieties.

Full text of DOI:10.1021/jf048198k

J. Agric. Food Chem. 2005, 53, 2451−2455 2451
Enantioselective Synthesis of the Female Sex Pheromone of
the Pink Hibiscus Mealybug, Maconellicoccus hirsutus
AIJUN ZHANG* AND JUNYING NIE
Chemicals Affecting Insect Behavior Laboratory, Agricultural Research Service, U.S. Department of
Agriculture, Beltsville Agriculture Research CentersWest, Beltsville, Maryland 20705
The pink hibiscus mealybug, Maconellicoccus hirsutus (Green), is an exotic insect pest and recently
invaded Southern California and Florida. The female M. hirsutus releases the 2-methylbutanoate of
a novel cyclobutanoid monoterpene alcohol (maconelliol) that together with lavandulyl 2-methylbu-
tanoate constitutes the sex pheromone to attract males from a distance. Enantioselective syntheses
of four different stereoisomers of the major component, maconelliyl 2-methylbutanoate 1, from R-pinene
are reported. Absolute configurations of both naturally occurring maconelliyl 2-methylbutanoate 1
and the minor component, lavandulyl 2-methylbutanoate 2, have been established. Comparison of
the analytical data of naturally occurring compounds with those of optically active synthetic isomers
proved that both esters show the (R)-configuration at the alcohol and the (S)-configuration at acid
moieties.
KEYWORDS: Sex pheromone; Maconellicoccus hirsutus; (R)-maconelliyl (S)-2-methylbutanoate; (R)-
lavandulyl (S)-2-methylbutanoate; enantioselective synthesis
1
INTRODUCTION
relative to the residual solvent for H (C6H6 at δ 7.20 and CHCl3 at
7.25 ppm) or to the central peak of solvent 13C signal (C6D6 at 128.5
and CDCl3 at 77.0 ppm). Low-resolution electron impact (EI) gas
chromatography-mass spectrometry (GC-MS) was conducted on a
Hewlett-Packard (HP) 6890 GC coupled to a HP 5973 Mass Selective
Detector using a 60 m × 0.25 mm i.d., 0.25 µm film thickness DB-
WAXETR capillary column (J&W Scientific Inc., Folsom, CA) with
helium as the carrier gas (50 °C for 2 min and then programmed to
230 °C at 15 °C/min and held for 15 min). High-resolution EI-MS
(HREIMS) was measured on a Shimadzu GC-17A GC coupled to a
JEOL JMS-SX102A mass spectrometer using a 15 m × 0.25 mm i.d.,
0.25 µm film thickness OV-5 capillary column (Ohio Valley Specialty
Chemical, Marietta, OH) with helium as the carrier gas (50 °C and
then programmed to 200 °C at 15 °C/min and held for 15 min). A 70
eV electron beam was employed for sample ionization. Enantiomeric
excess (ee) data were obtained on a HP 6890 GC equipped with a 30
m × 0.25 mm i.d., 0.25 µm film thickness â-DEX 120 capillary column
(Supelco, Inc., Bellefonte, PA) in the split mode (100:1) with hydrogen
as the carrier gas (55 cm/s, 90 or 100 °C isothermal). Optical rotation
was measured on a Perkin-Elmer 241 Polarimeter at 24 °C. Melting
points were determined on a hot stage and are uncorrected. All reactions
were performed under a nitrogen atmosphere with magnetic stirring
unless otherwise indicated. All chemicals were obtained from Aldrich
Chemical Co., and solvents were obtained from EM Science. Flash
column chromatography was carried out on silica gel 60 (EM Science,
230-400 mesh), and solvents were evaporated using a Bu¨chi RE 111
rotary evaporator.
The pink hibiscus mealybug, Maconellicoccus hirsutus
(Green) (Homoptera: Pseudococcidae), is an exotic insect pest
(1) to more than 200 agricultural and vegetable crops, forest
trees, and ornamental plants (2-5) and recently invaded
Southern California (6) and Florida (4). The sex pheromone of
the M. hirsutus contains a novel cyclobutanoid monoterpene
derivative (7). This compound, together with lavandulyl 2-meth-
ylbutanoate 2, constitutes the female sex pheromone of the pink
hibiscus mealybug. The structure of maconelliyl 2-methylbu-
tanoate has been proposed as 1 (7). The cyclobutane carbon
skeleton with a methylethylidene group on the ring (“maconel-
liane”) has not previously been reported although the Plano-
coccus alcohol isolated from the citrus mealybug is structurally
close (8). An incompletely characterized ester of lavandulol with
2-methylbutanoic acid has been described by others (9, 10), but
the optically active esters have not previously been described.
We now report the synthesis of 1, as well as 2, thereby
confirming their structures, establishing their absolute configura-
tions, and providing material for field biological testing (11).
(1R,3S)-(-)-3-(1-Hydroxy-1-methylethyl)-2,2-dimethylcyclobu-
tanecarboxylic Acid (3a). To a solution of 11.0 g (0.065 mol) of
pinononic acid in 200 mL of tetrahydrofuran (THF) was added dropwise
65 mL (0.195 mol) of methylmagnesium chloride (3.0 M THF). The
reaction mixture was refluxed for 2 h on an 80 °C oil bath, then cooled,
and treated with 50 g of ice water and 25 mL of concentrated HCl.
The aqueous layer was separated and extracted with ether. The
combined organic solutions were extracted with 1 N Na2CO3. After
the solution was washed with ether, the Na2CO3 solution was acidified
MATERIALS AND METHODS
General. NMR spectra were recorded in C6D6 or CDCl3 solution
on a Bruker QE Plus spectrometer at 300 MHz for 1H and 75 MHz for
13C, respectively. The chemical shifts are expressed in ppm (δ scale)
* To whom correspondence should be addressed. Tel: +1-301-504-5223.
Fax: +1-301-504-6580. E-mail: zhanga@ba.ars.usda.gov.
10.1021/jf048198k This article not subject to U.S. Copyright. Published 2005 by the American Chemical Society
Published on Web 03/02/2005

2452 J. Agric. Food Chem., Vol. 53, No. 7, 2005
Zhang and Nie
with concentrated HCl and extracted again with ether. The combined
extracts were washed with brine, dried over MgSO4, and concentrated
to give 10.5 g of white semisolid. Recrystallization of the crude product
(1:8 ) ethyl acetate:hexanes) gave 8.37 g (44 mmol) of pure 3a in
67% yield. Optical purity: 80% ee; mp 98-99 °C; [R]D24 -5.0 (c 0.1,
MeOH). 1H NMR (CDCl3): δ 1.10 (3H, s), 1.17 (3H, s), 1.22 (3H, s),
1.28 (3H, s), 1.8-2.0 (4H, bm), 2.1-2.4 (2H, m). 13C NMR (CDCl3):
δ 176.26, 71.68, 51.88, 45.76, 44.39, 31.75, 29.06, 27.50, 19.71, 18.10.
EI-MS m/z (%): 168 [M - H2O] (3), 153 (21,) 128 (22), 123 (21),
110 (12), 101 (37), 99 (67), 83 (44), 71 (45), 69 (52), 59 (100), 56
(45), 43 (40).
(100), 67 (23), 55 (14), 41 (20). HREIMS: obsd, 154.1362; calcd for
C10H18O (M+), 154.1358.
(S)-(+)-Maconelliol (6b). Optical purity: 70% ee; [R]D24 +22.0 (c
0.1, MeOH).
[(R)-2,2-Dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-
2-Methylbutanoate [(R)-Maconelliyl (S)-2-Methylbutanoate] (1a).
To a solution of 2.2 mL (20.1 mmol) of (S)-(+)-2-methylbutanoic acid
{Aldrich, 99% ee, [R]D24 +24.0 (c 0.1, MeOH)} in 15 mL of benzene
was treated with 2.2 mL (25.2 mmol) of oxalyl chloride and 10 µL of
dimethyl formamide (DMF). After 1.5 h at room temperature, the
benzene and excess oxalyl chloride were removed followed by the
addition of another 15 mL portion of benzene. The acid chloride residue
was dissolved in 15 mL of benzene, and then, a solution of 1.65 g
(10.7 mmol) of 6a and 1.8 mL (22.2 mmol) of pyridine in 15 mL of
benzene was added dropwise. After it was stirred at room temperature
for 1 h, the solvent was removed. The residue was treated with 20 mL
of water and extracted with ether. The organic solution was washed
with water, 1 N hydrochloric acid, 1 N aqueous sodium bicarbonate,
and brine, dried over sodium sulfate, and concentrated to afford yellow
oil. Pure 1a (2.0 g, 79% yield) was obtained by chromatography (silica
(1R,5S)-(+)-4,4,6,6-Tetramethyl-3-oxabicyclo[3.1.1]heptan-2-
one (4a). To a solution of 2.66 g (14.28 mmol) of alcohol 3a in 15 mL
of pyridine was added dropwise 1.40 mL (15.00 mmol) of phosphorus
oxychloride at ice-water cooling. The mixture was stirred at room
temperature for 24 h, poured onto 75 g of ice, and extracted with ether.
The ether extracts were washed with water, 2 N hydrochloric acid,
then water, saturated aqueous solution of sodium hydrogen carbonate,
and brine. After it was dried over sodium sulfate, the solvent was
removed, and the residue was purified by chromatography (30/70, ethyl
acetate/hexanes) to afford 1.8 g (10.71 mmol) of pure lactone 4a in
24
gel, 2% of ethyl acetate in hexanes). Optical purity: 99% ee; [R]D
-0.79 (c 2.03, MeOH). 1H NMR (C6D6): δ 0.84 (3H, t, J ) 7.19 Hz),
1.08 (3H, d, J ) 6.82 Hz), 1.12 (3H, s), 1.24 (3H, s), 1.36 (1H, m),
1.40 (3H, bs), 1.51 (3H, t, J ) 1.89 Hz), 1.67 (2H, m), 2.05 (1H, m),
2.17 (1H, m), 2.27 (1H, m), 2.48 (1H, ddt, J ) 14.75, 8.79, 1.52 Hz),
4.15 (2H, d, J ) 7.57 Hz). 13C NMR (C6D6): δ 175.76, 137.48, 122.55,
65.30, 44.43, 41.39, 39.71, 28.62, 27.79, 27.13, 21.17, 19.60, 18.64,
16.85, 11.80. EI-MS m/z (%): 238 [M]+ (2), 136 (29), 121 (100), 107
(12), 93 (20), 81 (26), 67 (5), 57 (16), 41 (10). HREIMS: obsd,
238.1929; calcd for C15H26O2 (M+), 238.1933.
24
1
75% yield. Optical purity: 80% ee; [R]D +5.0 (c 0.1, MeOH). H
NMR (CDCl3): δ 1.14 (3H, s), 1.37 (3H, s), 1.38 (3H, s), 1.49 (3H,
s), 1.81 (1H, d, J ) 10.59 Hz), 2.10 (1H, dd, J ) 6.05, 5.67 Hz), 2.48
(1H, ddd, J ) 10.59, 5.67, 5.30 Hz), 2.63 (1H, dd, J ) 6.05, 5.30 Hz).
13C NMR (CDCl3): δ 175.04, 82.44, 50.34, 50.01, 40.91, 29.11, 26.11,
25.81, 25.27, 25.25. EI-MS m/z (%): 153 (26), 125 (20), 110 (40),
109 (55), 95 (100), 83 (27), 69 (72), 68 (78), 67 (60), 55 (42), 43 (35),
41 (38). HREIMS: obsd, 153.0911; calcd for C9H13O2 (M+ - CH3),
153.0916.
[(R)-2,2-Dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (R)-
2-Methylbutanoate [(R)-Maconelliyl (R)-2-Methylbutanoate] (1b).
(R)-(-)-2,2-Dimethyl-3-(1-methylethylidene)cyclobutane-
carboxylic Acid (5a). A solution of 3.68 g (21.9 mmol) of 4a in 60
mL of benzene with 416 mg (2.19 mmol) of p-toluenesulfonic acid
monohydrate was heated in an oil bath at 100-110 °C for 24 h. A
mini Dean-Stark trap was used for azeotropic distillation. Benzene
was evaporated on a rotary evaporator, and the residue was treated
with 2 N aqueous Na2CO3 solution. The basic aqueous solution was
washed with ether, then acidified to pH 2 with hydrochloric acid, and
again extracted with ether. The combined ether extracts were washed
with water and brine, dried, and concentrated to give 2.87 g (17.1 mmol,
78% yield) of 5a as colorless oil after chromatography (silica gel, eluted
with 20-25% of ethyl acetate in hexanes). Optical purity: 79% ee
24
(R)-(-)-2-Methylbutyric acid (13) {99% ee, [R]D -24.0 (c 0.1,
24
1
MeOH)}. Optical purity: 99% ee; [R]D -24.0 (c 0.1, MeOH). H
NMR (C6D6): δ 0.84 (3H, t, J ) 7.51 Hz), 1.08 (3H, d, J ) 7.01 Hz),
1.12 (3H, s), 1.23 (3H, s), 1.33 (1H, m), 1.40 (3H, bs), 1.51 (3H, t, J
) 2.00 Hz), 1.67 (2H, m), 2.05 (1H, m), 2.17 (1H, m), 2.26 (1H, m),
2.48 (1H, ddt, J ) 14.77, 9.01, 1.50 Hz), 4.15 (2H, m). 13C NMR
(C6D6): δ 175.74, 137.47, 122.55, 65.28, 44.41, 41.38, 39.75, 28.61,
27.80, 27.09, 27.18, 19.60, 18.63, 16.88, 11.80. MS (EI): m/z 238 [M]+
(2), 136 (27), 121 (100), 107 (11), 93 (19), 81 (27), 67 (5), 57 (19), 41
(12).
[(S)-2,2-Dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-
2-Methylbutanoate [(S)-Maconelliyl (S)-2-Methylbutanoate] (1c).
24
1
(after methylation); [R]D -22.0 (c 0.1, MeOH). H NMR (CDCl3):
δ 1.19 (3H, s), 1.37 (3H, s), 1.48 (3H, s), 1.58 (3H, s), 2.55 (1H, m),
2.81 (2H, m). 13C NMR (C6D6): δ 183.49, 135.57, 123.27, 47.47, 45.09,
28.15, 25.94, 22.09, 19.51, 18.52. EI-MS m/z (%): 168 [M]+ (38),
153 (38), 135 (8), 125 (21), 123 (27), 107 (59), 93 (29), 81 (100), 67
(30), 53 (16), 41 (25). HREIMS: obsd, 168.1152; calcd for C10H16O2
(M+), 168.1150.
24
Optical purity: 97% ee; [R]D +16.0 (c 0.1, MeOH).
[(S)-2,2-Dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (R)-
2-Methylbutanoate [(S)-Maconelliyl (R)-2-Methylbutanoate] (1d).
24
Optical purity: 99% ee; [R]D -0.2 (c 2.03, MeOH).
(R)-2-Isopropenyl-5-methylhex-4-enyl (S)-2-Methylbutanoate [(R)-
Lavandulyl (S)-2-Methylbutanoate] (2a). Esterification of (R)-(-)-
24
[(R)-(-)-2,2-Dimethyl-3-(1-methylethylidene)cyclobutyl]-
methanol [(R)-(-)-Maconelliol] (6a). A solution of 2.1 g (12.5 mmol)
of 5a in 30 mL of dry ether was stirred under a nitrogen atmosphere
and cooled with an ice bath, while 713 mg (18.8 mmol) of lithium
aluminum hydride was added in portions. The mixture was then stirred
at room temperature overnight. To decompose excess hydride, 0.8 mL
of water was added dropwise at ice bath temperature and stirred for 15
min, followed by the addition of 0.8 mL of 10% aqueous sodium
hydroxide solution and stirring for another 15 min. After the ice bath
was removed, 2.4 mL of water was added and it was stirred for an
additional 30 min, and then, the solid was filtered off and washed with
ether. The combined ether solutions were dried over Na2SO4 and
concentrated to afford 2.0 g of clear oil. Pure compound 6a (1.7 g, 11
mmol, 88% yield) was obtained by chromatography (silica gel, eluted
with 15-20% of ethyl acetate in hexanes). Optical purity: 78% ee;
lavandulol {(86% ee, [R]D -9.6 (c 0.1, MeOH), prepared according
to the method described by Cardillo et al. (14)} with (S)-(+)-2-
methylbutanoic acid using the same procedures as compound 1a gave
24
75 mg (75% yield) of 2a as a clear oil. Optical purity: 99% ee; [R]D
1
+5.0 (c 0.1, MeOH). H NMR (C6D6): δ 0.83 (3H, t, J ) 7.29 Hz),
1.08 (3H, d, J ) 7.0 Hz), 1.35 (1H, m), 1.50 (3H, s), 1.59 (3H, t, J )
0.80 Hz), 1.61 (3H, d, J ) 1.13 Hz), 1.68 (1H, m), 2.06 (2H, m), 2.28
(1H, sextet, 6.85 Hz), 2.42 (1H, quintet, 7.00 Hz), 4.12 (2H, m), 4.79
(1H, m), 4.83 (1H, quintet, J ) 1.51 Hz), 5.11 (1H, t, quintet, J )
7.19, 1.52 Hz). 13C NMR (C6D6): δ 175.88, 146.31, 132.70, 122.00,
112.50, 66.68, 45.41, 41.22, 29.13, 26.00, 25.80, 20.00, 17.80, 16.50,
11.52. EI-MS m/z (%): 238 [M]+ (1), 169 (2), 156 (3), 136 (15), 121
(39), 107 (11), 93 (100), 85 (23), 80 (25), 69 (75), 57 (59), 41 (40).
HREIMS: obsd, 238.1934; calcd for C15H16O2 (M+), 238.1933.
(R)-2-Isopropenyl-5-methylhex-4-enyl (R)-2-Methylbutanoate [(R)-
Lavandulyl (R)-2-Methylbutanoate] (2b). Optical purity: 99% ee;
[R]D24 -11.0 (c 0.1, MeOH). 1H NMR (C6D6): δ 0.83 (3H, t, J ) 7.57
Hz), 1.08 (3H, d, J ) 7.19 Hz), 1.35 (1H, m), 1.50 (3H, s), 1.59 (3H,
q, J ) 0.76 Hz), 1.61 (3H, d, J ) 1.10 Hz), 1.69 (1H, m), 2.07 (2H,
m), 2.28 (1H, sextet, 6.81 Hz), 2.43 (1H, quintet, 7.00 Hz), 4.12 (2H,
m), 4.79 (1H, m), 4.83 (1H, m), 5.12 (1H, t, quintet, J ) 7.00, 1.51
24
1
[R]D -31.0 (c 0.1, MeOH). H NMR (CDCl3): δ 1.15 (3H, s), 1.25
(3H, s), 1.38 (1H, br), 1.44 (3H, bs), 1.56 (3H, bs), 2.08 (2H, m), 2.58
(1H, bm), 3.62 (1H, dd, J ) 17.0, 11.4 Hz), 3.75 (1H, dd, J ) 17.0,
11.3 Hz). 13C NMR (CDCl3): δ 179.85, 135.57, 123.27, 47.48, 45.09,
28.14, 25.93, 22.09, 19.51, 18.52. EI-MS m/z (%): 154 (17), 139 (18),
136 (13), 121 (59), 111 (14), 105 (12), 95 (34), 93 (28), 91 (15), 81

Sex Pheromone of the Pink Hibiscus Mealybug
J. Agric. Food Chem., Vol. 53, No. 7, 2005 2453
Scheme 1a
standard methods. To prevent decarboxylation during dehydra-
tion, 3a was first converted into its methyl ester using thionyl
chloride in absolute methanol (17, 18). Among many reported
dehydration catalysts and reagents, we felt that the best chance
of success for this transaction would involve use of a copper-
(II) triflate [Cu(OTf)2] catalyst (19). It was reported to dehydrate
a number of alcohols to olefins under mild conditions. Unfor-
tunately, treatment of 3a with 0.1 mol equiv of Cu(OTf)2 under
conditions previously reported gave no useful result, even after
extended periods of time at elevated temperatures.
Therefore, more conventional dehydration catalysts were
deployed. Approaches were made by treating the methyl ester
of 3a with different reagents under the following conditions:
(a) 1.05 mol of POCl3 in pyridine at room temperature for 24
h (20); (b) 1.1 mol of p-TsCl with equal amounts of DMAP in
CH2Cl2 at room temperature for 6 h (21); and (c) 0.03 mol of
p-TsOH in benzene at 100-110 °C refluxing for 22 h (22-
24). In none of the cases could the desired compound be
obtained exclusively. In experiment (a), a mixture of isopropenyl
(56%) and methylethylidene compounds (44%) was obtained.
In (b), no dehydration product was isolated. In (c), about 90%
desired methylethylidene product was obtained but it still
contained 10% of the isopropenyl isomer as a byproduct. The
separation of these two isomers by column chromatography was
difficult, because of the similarity of chemical and physical
properties. From the above experiments, it was concluded that
it is impossible to prepare the required methylethylidene product
solely by the above methods.
Successful dehydration was ultimately realized through a key
intermediate 4. When the same experimental reagents and
conditions were conducted with free acid 3, lactone 4 was
obtained as a sole product in experiments (a) and (b). However,
experiment (c) still gave the same mixture as reacting with
methyl ester. Surprisingly, the lactone 4a was found to be easily
converted to the desired methylethylidene compound 5 exclu-
sively by the same reagent and conditions as described for
experiment (c); refluxing lactone 4 in benzene with a catalytic
amount of p-TsOH gave pure 5. Sole formation of the
methylethylidene compound 5 without its isopropenyl isomer
as a byproduct by the above dehydration process could be
confirmed by the absence of geminal olefinic resonance in the
1H NMR spectrum from δ 4.4-6.6 ppm.
a (a) MeLi/ether, 1.0 equiv, THF,
equiv, 10 C, 30 min, room temperature, 1 h; (c) POCl3/pyridine, room
temperature, 24 h; (d) p-TsOH/C6H6, reflux, 24 h; (e) LiAlH4/ether, room
temperature, overnight; (f) EtCHMECOOH, ClCOCOCl/DMF/C6H6, room
temperature, 1.5 h.
−20 °C, 15 min; (b) MeMgCl/THF, 1.6
−
°
Hz). 13C NMR (C6D6): δ 175.74, 145.22, 132.62, 122.38, 112.69, 65.50,
46.84, 41.41, 28.99, 27.08, 25.79, 19.87, 17.78, 16.91, 11.79. MS
(EI): m/z 238 [M]+ (1), 169 (2), 156 (4), 136 (17), 121 (42), 107 (11),
93 (100), 85 (22), 80 (25), 69 (72), 57 (53), 41 (35).
(S)-2-Isopropenyl-5-methylhex-4-enyl (S)-2-Methylbutanoate [(S)-
Lavandulyl (S)-2-Methylbutanoate] (2c). {(S)-(+)-lavandulol, 81%
24
ee, [R]D +10.0 (c 0.1, MeOH), prepared according to the method
described by Cardillo et al. (14)}. Optical purity: 98% ee; [R]D24 +10.0
(c 0.1, MeOH).
(S)-2-Isopropenyl-5-methylhex-4-enyl (R)-2-Methylbutanoate [(S)-
Lavandulyl (R)-2-Methylbutanoate] (2d). Optical purity: 99% ee;
24
[R]D -8.0 (c 0.1, MeOH).
RESULTS AND DISCUSSION
Pinononic acid is a suitable intermediate for the preparation
of novel 1 because it can be easily obtained from R-pinene
through the intermediate verbenone and contains the required
cyclobutane skeleton and useful functional groups. Allylic
oxidation of (1R)-(+)-R-pinene (94% ee) at C4 using molecular
oxygen afforded (1R)-(+)-verbenone in moderate yield (15).
Subsequently, oxidative cleavage of double bond in verbenone
by using ruthenium trichloride/NaIO4 (16) resulted in the target
compound pinononic acid without epimerization.
Pursuing the synthesis of structure 1, the required methyl-
ethylidene group was introduced by treating pinononic acid with
a nucleophilic reagent to form the tertiary alcohol 3 and then
introduce the double bond upon dehydration. Reaction of
pinononic acid (94% ee) with 3 mol of Grignard reagent, CH3-
MgCl, in THF resulted in the formation of a crude semisolid,
which could be recrystallized from ethyl acetate and hexanes
to get pure 3a (80% ee). Partial loss of enantiomeric purity is
due to double epimerization during nucleophilic addition.
Conversion of pinononic acid to hydroxyacid 3 without epimer-
ization at both stereogenic centers was achieved later in a small-
scale reaction at different conditions. When the pinononic acid
(>96% ee) reacted with 1.0 equiv of MeLi at -20 °C, a THF
soluble carboxylate solution was formed. Following an addition
of 1.6 equiv of CH3MgCl, 3a was isolated in 89% yield with
virtually no change of chirality (96% ee) (Scheme 1).
The identity of lactone 4a was established on the basis of
observed 3JH-H values between axial methylene hydrogen H-7R
(δ 1.81, J7R,1 ) 0 Hz, J7R,5 ) 0 Hz) and vicinal H-1, H-5 (δ
2.63, J1,7R ) 0 Hz; δ 2.10, J5,7R ) 0 Hz). Through this analysis,
it was deduced that the dihedral angle between H-7R and two
vicinal protons, H-1and H-5, is about 90°; therefore, the coupling
constants are zero, and only a doublet resonance with Jgem is
observed (J7a,7â ) 10.59 Hz). This coupling pattern is similar
to that of bicyclic precursor, (1R)-(+)-verbenone, for which a
doublet resonance of axial geminal hydrogen H-7R is observed
at δ 2.06 ppm with Jgem ) 9.08 Hz (25) (1.76 ppm in C6D6)
4
(26). A long-range coupling with JH-H ) 6.05 Hz between
H-1 and H-5 is also observed because of the “W” configuration
in the molecule 4a.
With the geminal dimethyl tertiary alcohol 3a available, the
immediate aim of the present synthesis was to attempt dehydra-
tion of the alcohol to the desired methylethylidene product by

2454 J. Agric. Food Chem., Vol. 53, No. 7, 2005
Zhang and Nie
ACKNOWLEDGMENT
Scheme 2
We thank Dr. James Oliver of the Chemicals Affecting Insect
Behavior Laboratory for assistance with syntheses, Drs. Ashot
Khrimian and Jerome Klun of the Chemicals Affecting Insect
Behavior Laboratory and Jan Kochansky of the Bee Research
Laboratory for review of this paper, and Dr. Walter Schmidt
and Ms. Ute Klingebiel of the NMR facility for help in NMR
spectroscopy. Mention of trade names or commercial products
in this article is solely for the purpose of providing specific
information and does not imply recommendation or endorsement
by the U.S. Department of Agriculture.
LITERATURE CITED
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With methylethylidene compound 5 in hand, the remaining
steps were straightforward. The resulting acid 5a was treated
with LiAlH4 in ether (27, 28) to furnish the (R)-(-)-maconelliol
24
6a {[R]D -31.0 (c 0.1, MeOH)} in good yield, and its
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24
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(c 0.1, MeOH)}. The various spectral and GC data of synthetic
(R)-(-)-6a are in good agreement with those of the natural
product (7). Thus, we were able to determine the absolute
configuration of the naturally occurring maconelliol 6 to be R.
(S)-(+)-2-Methylbutyric acid was commercially available
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1
from the natural product on the basis of both H NMR spectra
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1
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Received for review October 28, 2004. Revised manuscript received
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