Novel synthesis of Planococcus citri pheromone

Article abstract of DOI:10.1007/s10600-006-0082-x

An effective method was proposed for synthesizing (+)-cis-1R-acetoxymethyl- 3-isopropenyl-2,2-dimethylcyclobutane, a pheromone of the citrus mealybug, based on ozonolysis of verbenone that led in one step to the key synthon 1R,3S-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid. 2006 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10600-006-0082-x

Chemistry of Natural Compounds, Vol. 42, No. 2, 2006
NOVEL SYNTHESIS OF
PHEROMONE
Planococcus citri
O. S. Kukovinets,1,2 T. I. Zvereva,1 V. G. Kasradze,2
F. Z. Galin,1,2 L. L. Frolova,3 A. V. Kuchin,3
L. V. Spirikhin,2 and M. I. Abdullin2
UDC 632.936.2+547.573
R
An effective method was proposed for synthesizing (+)-cis-1 -acetoxymethyl-3-isopropenyl-2,2-
dimethylcyclobutane, a pheromone of the citrus mealybug, based on ozonolysis of verbenone that led in one
R S
step to the key synthon 1 ,3 -3-acetyl-2,2-dimethylcyclobutanecarboxylic acid.
Key words: pheromone, citrus mealybug, olefination, ozonolysis.
Populations of the dangerous grape and citrus pest
Risso(citrus mealybug) can be reliablycontrolled
Planococcus citri
by using traps containing a pheromone of this pest identified as (+)- -1 -acetoxymethyl-3-isopropenyl-2,2-
cis R
dimethylcyclobutane (1) [1]. Several synthetic pathways to it have been described [1-6], the most efficient of which is a method
based on selective transformations ofα-pinene [3]. Chain shortening steps at the first C atom that conclude with transformation
of the ozonolysis product of β-pinene (ketoaldehyde) into the enolacetate and its subsequent ozonolytic cleavage substantially
decrease the yield of the sex pheromone 1.
We propose a novel method for synthesizing 1 that is based on ozonolysis of verbenone (2) in CH CN or CH Cl .
3
2
2
O
O
−
+
CH N
1. O
2
2
4
2
CH P Ph Br
3
3
3
COOH
COOMe
1
3
2. Me S
2
Et O
2
BuLi
2
3
O
2
3
4
O
COOMe
1. DIBAH
O
2. Ac O/Py
2
5
1
1R,3S-3-Acetyl-2,2-dimethylcyclobutanecarboxylic acid (3) was produced from verbenone 2 in 83% yield by reacting
it with an excess of ozone (~2 mmol) in CH CN at -40°C. Simultaneously with cleavage of the double bond of 2, the side chain
3
undergoes oxidative dehydration, which we noted for ozonolysis of other α,β-unsaturated ketones [7]. Formation of 3 by
-1
ozonolysis of verbenone was proved by the presence in the IR spectrum of the isolated crystalline product of bands at 1715 cm
(C=O) and 1695 and 2400-3600 (COOH). The PMR spectrum of 3 contained three singlets for methyls (0.95 and 1.45 ppm,
1
3
gem-dimethyl; 2.05, acetyl) and an AB system of protons on C and C of the ring, each of which was split by magnetically
nonequivalent H atoms of the methylene. The methylene protons resonated as a doublet of doublets at 1.90 and 2.60 ppm.
The methyl ester of 4 was prepared by treatment of 3 with diazomethane in diethylether. Compound 4 was converted
bymethylidenetriphenylphosphoranetotheolefinicmethyl ester (1R,3S)-3-isopropenyl-2,2-dimethylcyclobutanecarboxylicacid
(5), hydride reduction of which and subsequent acetylation of the resulting alcohol gave 1.
1)Bashkir StateUniversity, 450014,Ufa, 14, Mingazheva, 100, e-mail:PMSV@bsu.bashedu.ru; 2) InstituteofOrganic
Chemistry, Urals Scientific Center, Russian AcademyofSciences, 450054, Ufa, 54, pr. Oktyabrya, 71; 3) Institute ofChemistry,
Komi Scientific Center, Urals Division, Russian Academy of Sciences, 167982, Syktyvkar, Komi, Pervomaiskaya, 48.
Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 179-180, March-April, 2006. Original article submitted November
22, 2005.
0009-3130/06/4202-0216 ©2006 Springer Science+Business Media, Inc.
216

EXPERIMENTAL
13
IR spectra were recorded on a UR-20 instrument as thin layers or in mineral oil. PMR and C NMR spectra were
recorded on a Bruker AM-300 spectrometer (working frequencies 300.13 and 75.25 MHz, respectively) in CDCl with TMS
3
internal standard. GC was performed on a Chrom-5 chromatograph using a column (1200 × 3 mm), stationary phase
Chromaton N-AW-DNICS (0.16-0.20 mm) + SE-30 (5%), working temperature 50-300°C (12 deg/min), and He carrier gas.
Verbenone (2) was prepared by liquid-phase oxidation of α-pinene as before [8].
(+)-1R,3S-3-Acetyl-2,2-dimethylcyclobutanecarboxylic Acid (3). An O /O mixture was passed through a solution
3
2
of 2 (0.5 g, 3.3 mmol) in absolute CH CN (5 mL) at -40°C until the starting ketone was completely consumed (TLC
3
monitoring). The reaction mixture was purged with argon, treated with Me S (0.5 mL), stirred for 2 h, treated with CHCl
2
3
(30 mL), washed with saturated NaCl solution, dried over MgSO , and filtered. Solvent was evaporated to produce 3 (0.46 g,
4
25
83%), mp 98-100°C, [α]
+28.5° (c 0.0106 g/mL, CHCl ), C H O .
3 9 14 3
IR spectrum (ν, cm ): 3600-2400 (COOH), 1715 (C=O), 1695.
D
-1
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 0.95 and 1.45 (6H, s, CH -2), 1.90 (1H, ddd, J
= J
4-3
= 8.0,
cis
cis
3
4-1
3
J
J
= 11.0, Z-CH-4), 2.05 (3H, s, CH CO), 2.60 (1H, ddd, J
= J
trans
4-3
= J
= 11.0, E-HC-4), 2.70 and 2.90 (2H, dd,
gem
trans
gem
3
4-1
= J
= 8.0, J
= J
3-4
= 11.0, HC-1 and HC-3), 11.30 (1H, s, COOH).
trans
cis
cis
trans
1-4
3-4
13
1-4
C NMR spectrum (75 MHz, CDCl ): 17.80 (CH CO, q), 18.59 and 29.78 (CH , q), 30.04 (CH , t), 44.77 (C-2, s),
3
3
3
2
45.18 (C-1, d), 52.75 (C-3, d), 177.45 (COOH, s), 207.33 (C=O, s).
Methyl Ester of (1R,3S)-cis-3-Acetyl-2,2-dimethyl-1-(methoxycarbonyl)cyclobutane (4). A solution of 3 (1 g,
5.88 mmol) in diethylether (20 mL) was treated over 40 min in portions with diazomethane in ether [prepared from KOH
solution (6 mL, 40%) and nitrosomethylurea (2 g, 19.42 mmol)] and stirred for 2 h on an ice bath. Solvent was evaporated to
20
produce 4 (1.06 g, 98%), [α]
+37.88° (c 0.00924 g/mL, CHCl ).
3
D
-1
IR spectrum (ν, cm ): 1710 (C=O), 1735 (COOCH ), 1190.
3
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 0.98 and 1.40 (6H, s, CH -2), 2.03 (3H, s, CH CO), 2.11 (1H, ddd,
3
3
3
J
= J = J
= 11.0, Z-CH-4), 2.53 (1H, ddd, J = J = 8.0, J
= 110, E-CH-4), 2.66 and 3.06 (2H, ddd, J = 7.0, 8.0,
gem
gem
4-1
4-3
4-1
4-3
11.0, H-1 and H-3), 3.63 (3H, s, OCH ).
3
Methyl Ester of (1R,3S)-3-Isopropenyl-2,2-dimethylcyclobutanecarboxylic Acid (5). Triphenylphosphonium
bromide (0.87 g, 2.46 mmol) in THF (13 mL) was treated dropwise with n-BuLi (3 mL, 1.3 M, 2.47 mmol) in hexane over
30 min at -75°C. The temperature was raised to -30°C. Ester 4 (1 g, 5.81 mmol) was added over 6 min. The reaction mixture
was held at -30°C for 1 h, at 25°C for 15 h, diluted with heptane, and filtered through a thin layer of silica gel. Solvent was
evporated to produce 5 (0.81 g) that was purified by chromatography (SiO , eluent petroleum ether:ethylacetate, 85:15, with
2
increasing content of the latter). Yield 88%, C H O .
11 18
2
-1
IR spectrum (ν, cm ): 3080 (C=CH ), 1740 (COCH ), 1650, 915.
2
3
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 0.86 and 1.08 (6H, s, CH ), 1.42 (1H, m, H-1), 1.57 (3H, s, CH C=),
3
3
3
2.15 (1H, m, H-3), 2.45 (2H, m, CH ), 4.85 (2H, br.s, =CH ), 3.65 (3H, s, OCH ).
2
2
3
(+)-cis-1R-Acetoxymethyl-3-isopropenyl-2,2-dimethylcyclobutane (1). A solution of 5 (0.25 g, 1.09 mmol) in
diethylether (10 mL) was treated at 0°C with a solution of diisobutylaluminum hydride (DIBAH, 0.5 mL, 70%) in toluene. The
reaction mixture was stirred for 1 h at 0°C, 15 h at 25°C, cooled to 5°C, and treated with water (0.5 mL). The organic layer
was separated, dried over MgSO , and evaporated to produce a compound (0.19 g) to which was added at 0-5°C Ac O
4
2
(1.72 g, 16.88 mmol) and dry pyridine (1.58 mL). The mixture was stirred for 2.5 h at 0°C, held for 12 h at 10°C, diluted with
CH Cl , washed successively with HCl (1 N) and saturated NaHCO solution, dried over MgSO , and filtered. Solvent was
2
2
3
4
evaporated to produce 1 (0.2 g, 85%), the constants and spectral properties of which were identical to those in the literature [1],
20
[α]
+7.11° (c 1.7101, CHCl ).
3
D
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