New approach to the synthesis of 9-oxo-2E-decenoic acid, a multifunctional pheromone of queen honeybee, from the telomer of butadiene and water

Article abstract of DOI:10.1007/s10600-011-0060-9

A new approach was proposed for the synthesis of 9-oxo-2E-decenoic acid, a multifunctional pheromone of queen honeybee (Apis mellifera L.), starting from the available telomer of butadiene and water (2E,7-octadien-1-ol) using in the key steps partial ozonolysis of the corresponding carbonyl compound, selective oxidation of the conjugated aldehyde into a carboxylic acid, and alkylation of acetoacetic ester to introduce the oxo group.

Full text of DOI:10.1007/s10600-011-0060-9

Chemistry of Natural Compounds, Vol. 47, No. 5, November, 2011 [Russian original No. 5, September-October, 2011]
NEW APPROACH TO THE SYNTHESIS OF 9-OXO-2E-DECENOIC
ACID, A MULTIFUNCTIONAL PHEROMONE OF QUEEN HONEYBEE,
FROM THE TELOMER OF BUTADIENE AND WATER
1
*
1
1
G. Yu. Ishmuratov, V. A. Vydrina, G. V. Nasibullina,
UDC 542.947.5:547.313
1
1
2
M. P. Yakovleva, R. R. Muslukhov, and G. A. Tolstikov
A new approach was proposed for the synthesis of 9-oxo-2E-decenoic acid, a multifunctional pheromone of
queen honeybee (Apis mellifera L.), starting from the available telomer of butadiene and water
(
2E,7-octadien-1-ol) using in the key steps partial ozonolysis of the corresponding carbonyl compound,
selective oxidation of the conjugated aldehyde into a carboxylic acid, and alkylation of acetoacetic ester to
introduce the oxo group.
Keywords: 2E,7-octadien-1-ol, 2E,7-octadienal, ozonolytic cleavage, 9-oxo-2E-decenoic acid, synthesis.
9
-Oxo-2E-decenoic acid (1) was identified as an important component in the honeybee (Apis mellifera L.) queen
substance. It regulates the behavior and vital activity of the bee family. Furthermore, according to our research [1], it exhibits
significant pharmacological properties such as antibacterial (for infections caused by Staphylococcus aureus, Proteus,
Escherichia coli, Pseudomonas aeruginosa) and anti-inflammatory (for formalin, protein, and lidocaine inflammation models),
acts as a wound-healing accelerator for flap wounds and thermal burns, an antidote, and an immunomodulator. Several
approaches to the synthesis of 1 exist. They differ by the methods of introducing the oxo- and ꢀ,ꢁ-unsaturated carboxylic acid
[
2].
Herein we propose a new approach to the synthesis of the biologically active keto acid 1 starting from the available
telomer of butadiene and water (2) [3] that involves conversion of the allyl alcohol in the substrate into a conjugated acid and
introduction of the oxo group using acetoacetic ester.
The carbon skeleton of the starting diene alcohol 2 had to be shortened by one C atom in order to carry out the
synthetic scheme. This was accomplished by partial ozonolysis of the carbonyl compound corresponding to it, 2E,7-octadienal
(
3), and selective protection of the intermediate dialdehyde 4. For this, we were guided by the known reduced reactivity of
conjugated aldehydes for ozone [4] and in reactions that form acetals [5].
a
b, c
d
OH
O
O
O
8
0%
82%
90%
2
3
4
O
OMe
O
O
e - g
0%
h
MeO
O
HO
OH
OH
5
32%
5
6
1
a. PCC, CH Cl ; b. O , c-C H , MeOH; c. PPh ; d. MeOH, NH Cl; e. H O –AgNO (cat.), MeCN; f. HCl, H O, MeOH; g. NaOH,
2
2
3
6
12
3
4
2
2
3
2
NaBH , MeOH, then HCl; h. i) CH NH , Et O (82%); ii) PBr , Py, PhH (85%); iii) CH C(O)CH CO Et, EtONa, EtOH, then NaOH, H O,
4
2
2
2
3
3
2
2
2
then H SO (46%)
2
4
Scheme 1
) Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, 450054, Ufa,
1
fax: (3472) 35 60 66, e-mail: insect@anrb.ru; 2) N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian
Branch, Russian Academy of Sciences, Russia, 630090, Novosibirsk, Prosp. Akad. Lavrentꢂeva, 9. Translated from Khimiya
Prirodnykh Soedinenii, No. 5, September–October, 2011, pp. 693–695. Original article submitted March 28, 2011.
0
009-3130/11/4705-0789 ©2011 Springer Science+Business Media, Inc.
789

Further sequential work up of the resulting monosubstituted dialdehyde 5 by a reagent [30% H O –AgNO (cat.)] for
2
2
3
selective oxidation of conjugated aldehydes to the corresponding acids [6], dilute HCl (for removal of the acetal protection),
and NaBH produced the 2E-unsaturated hydroxy acid 6 that was converted by the known method [7] using alkylation of
4
acetoacetic ester in the key step into the target pheromone 1 in overall yield 8.8% calculated per starting telomer 2.
EXPERIMENTAL
IR spectra were recorded in thin layers on a Shimadzu IR Prestige-21 instrument. PMR spectra were obtained in
CDCl with TMS internal standard on a Bruker AM-100 spectrometer (operating frequency 100.13 MHz). Chromatographic
3
analysis was carried out on Chrom-5 [column length 1.2 m, stationary phase silicone SE-30 (5%) on Chromaton
N-AW-DMCS (0.16–0.20 mm), operating temperature 50–300°C] and Shimadzu GC-9A [quartz capillary column length
2
5 m, stationary phase OV-101, operating temperature 80–260°C] instruments with He carrier gas. Column chromatography
was performed over silica gel L (60–200 ꢃm, Lancaster, England). TLC analysis was carried out on Sorbfil plates (Krasnodar).
Solvents were dried by standard methods. Et O was distilled before use over diisobutylaluminum hydride.
2
2
E,7-Octadienal (3). A suspension of pyridinium chlorochromate (18.00 g, 83.5 mmol) in anhydrous CH Cl2
2
(
100 mL) was stirred (20°C, Ar), treated in one portion with a solution of 2 [2] (8.60 g, 68.3 mmol) in CH Cl (20 mL), stirred
2 2
for 1.5 h, diluted with anhydrous Et O (100 mL), and filtered through a layer of Al O (5 cm). The precipitate was washed
2
2 3
with anhydrous Et O (100 mL) and evaporated to afford 3 (6.76 g, 80%).
2
–
1
IR spectrum (ꢄ, cm ): 3085 (trans-CH=CH, CH=CH ), 2740 (CHO), 1700, 1645, 1000, 980, 920 .
2
PMR spectrum (ꢅ, ppm, J/Hz): 1.40–1.80 (2H, m, H-5), 1.85–2.60 (4H, m, H-4, H-6), 4.75–5.20 (2H, m, H-8),
5
.40–5.75 (1H, m, H-7), 6.00 (1H, dd, J = 16.2, 8.3, H-2), 6.8 (1H, dt, J = 16.2, 7.0, H-3), 9.43 (1H, d, J = 8.3, H-1).
2
E-Heptendial (4). An O –O mixture was passed at 30 L/h through a mixture of 3 (6.54 g, 52.7 mmol), anhydrous
3 2
MeOH (5.2 mL), and distilled cyclohexane (63 mL) at 5°C until 2.4 g (50 mmol) of O was absorbed (ozonator production
3
2
.4 g O /h). The reaction mixture was purged with Ar and treated with PPh (14.60 g, 55.6 mmol). The temperature was
3
3
increased to ambient. The mixture was stored for 10 h and evaporated. The solid was chromatographed (SiO , hexane:EtOAc,
2
1
:1) to afford 4 (5.50 g, 82%).
PMR spectrum (ꢅ, ppm, J/Hz): 1.71–2.70 (6H, m, H-4, H-5, H-6), 6.11 (1H, dd, J = 15.8, 7.5, H-2), 6.85 (1H, dt,
J = 15.8, 6.0, H-3), 9.53 (1H, d, J = 7.5, H-1), 9.81 (1H, t, J = 5.8, H-7) [8].
,7-Dimethoxy-2E-heptenal (5). A solution of 4 (5.50 g, 43.2 mmol) in anhydrous MeOH (50 mL) was treated with
dry NH Cl (0.5 g, 9.3 mmol), stirred for 24 h, and evaporated. The solid was treated with Et O (150 mL), washed successively
7
4
2
with saturated NaHCO and NaCl solutions, dried over Na SO , and evaporated to afford 5 (6.73 g, 90%).
3
2
4
–
1
IR spectrum (ꢄ, cm ): 2730 (CHO), 1685, 1160 (C–O), 1130, 1095, 1060, 1645 (trans-CH=CH), 980.
PMR spectrum (ꢅ, ppm, J/Hz): 1.55–1.77 (4H, m, H-4, H-5), 2.33–2.42 (2H, m, H-6), 3.33 (6H, s, OCH ), 4.38 (1H,
3
t, J = 5.2, H-7), 6.13 (1H, dd, J = 15.6, 7.9, H-2), 6.85 (1H, dt, J = 15.6, 6.7, H-3), 9.51 (1H, d, J = 7.9, H-1) [8, 9].
7
-Hydroxy-2E-heptenoic Acid (6). A solution of AgNO (0.64 g, 0.38 mmol) and 5 (6.50 g, 37.8 mmol) in MeCN
3
(
75 mL) was stirred, treated dropwise with H O (30%, 21.5 mL, 189.0 mmol), heated to 50°C, stored for 10 h, decomposed
2 2
by Na S O solution (20 mL, 10%) at 5°C, and extracted with CH Cl (3 ꢆ 150 mL). The organic layer was worked up with
2
2
3
2
2
saturated NaHCO solution (to pH 8–9). The aqueous layer was separated, acidified with HCl (conc.) (to pH ~2), and extracted
3
with Et O (3 ꢆ 150 mL). The extract was dried over Na SO and evaporated. The solid (5.30 g) was dissolved in MeOH
2
2
4
(
100 mL), stirred (Ar, 0°C), treated with HCl (15 mL, 10%), stirred for 5 h at room temperature, and evaporated. The solid was
diluted with H O (50 mL) and extracted with Et O (3 ꢆ 150 mL). The organic layer was washed with saturated NaCl solution,
2
2
dried over Na SO , and evaporated. The resulting solid (3.22 g) of aldehyde-acid was diluted with a mixture of
2
4
MeOH (250 mL) and NaOH solution (38.6 mL, 1N), cooled to 5°C, treated with NaBH (2.92 g, 76.8 mmol), stirred for 3 h at
4
room temperature, cooled to 5°C, acidified with HCl (10%, to pH 1), and extracted with EtOAc (3 ꢆ 150 mL). The organic
layer was washed with saturated NaCl solution, dried over Na SO , and evaporated to afford 6 (2.80 g, 50%). The IR and
2
4
PMR spectra of 6 were identical to those published [7].
-Oxo-2E-decenoic Acid (1). Hydroxy acid 6 (2.50 g, 17.4 mmol) produced [7] 1 (1.02 g, 32%), the IR and PMR
spectra of which were identical to those published [7].
9
790

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