Synthesis of syn-4,6-dimethyldodecanal, the male sex pheromone and trail-following pheromone of two species of the termite Zootermopsis

Article abstract of DOI:10.1080/14786419.2010.535152

Recently, we reported that syn-4,6-dimethyldodecanal is the male sex pheromone and the trail-following pheromone of the Termopsidae Zootermopsis nevadensis and Zootermopsis angusticollis. In this article, we describe the syntheses of the mixture of the fo

Full text of DOI:10.1080/14786419.2010.535152

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Synthesis of syn-4,6-
dimethyldodecanal, the male sex
pheromone and trail-following
pheromone of two species of the
termite Zootermopsis
J. Ghostin a , C. Bordereau b & J.C. Braekman a
a Department of Organic Chemistry, CP 160/06 , Faculty of
Sciences, University of Brussels , 50 Avenue F. Roosevelt, 1050
Brussels, Belgium
b CNRS-UMR 5548 ‘Developpement et Communication Chimique
Chez les Insectes’ , University of Burgundy , 6 Boulevard Gabriel,
21000 Dijon, France
Published online: 07 Mar 2011.
To cite this article: J. Ghostin , C. Bordereau & J.C. Braekman (2011) Synthesis of syn-4,6-
dimethyldodecanal, the male sex pheromone and trail-following pheromone of two species of the
termite Zootermopsis , Natural Product Research: Formerly Natural Product Letters, 25:5, 560-568,
DOI: 10.1080/14786419.2010.535152
To link to this article: http://dx.doi.org/10.1080/14786419.2010.535152
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Natural Product Research
Vol. 25, No. 5, March 2011, 560–568
Synthesis of syn-4,6-dimethyldodecanal, the male sex pheromone and
trail-following pheromone of two species of the termite Zootermopsis
a
J. Ghostin , C. Bordereau and J.C. Braekman
b
a
*
aDepartment of Organic Chemistry, CP 160/06, Faculty of Sciences, University of Brussels,
50 Avenue F. Roosevelt, 1050 Brussels, Belgium; CNRS-UMR 5548 ‘Developpement et
b
Communication Chimique Chez les Insectes’, University of Burgundy, 6 Boulevard Gabriel,
21000 Dijon, France
(Received 19 May 2010; final version received 13 October 2010)
Recently, we reported that syn-4,6-dimethyldodecanal is the male sex
pheromone and the trail-following pheromone of the Termopsidae
Zootermopsis nevadensis and Zootermopsis angusticollis. In this article, we
describe the syntheses of the mixture of the four stereoisomers of 4,6-
dimethyldodecanal using a synthetic pathway where the key step is a Wittig
reaction between methyl 4-methyl-5-oxo-pentanoate and 1-methylheptyl-
triphenylphosphonium iodide, and of (ꢀ)-syn-4,6-dimethyldodecanal start-
ing from 3,5-dimethyl-2-cyclohexen-1-one. Direct GC–MS comparison of
these synthetic samples with the natural pheromone allowed its unambig-
uous identification.
Keywords: syn-4,6-dimethyldodecanal; pheromone; termite; Zootermopsis
nevadensis; Zootermopsis angusticollis
1. Introduction
For reproduction at the time of dispersal flight and to maintain their social structure,
termites use sophisticated chemical communication, including the production of sex
pheromones to recruit sexual partners and trail-following pheromones to orientate
individuals while foraging outside the nest. Sex pheromones are secreted by the
sternal gland and/or by the tergal glands, depending on the species (Bordereau &
Pasteels, 2010), whereas trail-following pheromones are secreted by the sternal gland
in all species (Quennedey, Sillam-Dusses, Robert & Bordereau, 2008). Despite the
fact that the existence of such pheromones has been known for about 50 years, the
number of chemically identified pheromones remains low (Bordereau & Pasteels,
2010). But recently, in the context of an evolutionary study of the strategies of
chemical communication in termites, Bordereau et al. (2010) demonstrated that syn-
4,6-dimethyldodecanal was the male sex pheromone as well as the trail-following
pheromone of two Termopsidae termites, Zootermopsis nevadensis and Zootermopsis
angusticollis. This identification resulted from direct comparison of GC–MS data
of the natural pheromone with a synthetic mixture of the four stereoisomers of
*Corresponding author. Email: braekman@ulb.ac.be
ISSN 1478–6419 print/ISSN 1029–2349 online
ß 2011 Taylor & Francis
DOI: 10.1080/14786419.2010.535152
http://www.informaworld.com

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561
4,6-dimethyldodecanal and with synthetic (ꢀ)-syn-4,6-dimethyldodecanal. In this
article, the syntheses of these two reference samples are described.
2. Results and discussion
To synthesise a mixture of the four possible stereoisomers [(ꢀ)-syn (1) and (ꢀ)-anti
(2)] of 4,6-dimethyldodecanal, we followed the pathway reported in Scheme 1. The
key step of this synthesis is a Wittig reaction of methyl 4-methyl-5-oxo-pentanoate
(3) and 1-methylheptyltriphenylphosphonium iodide (4). Aldehyde ester 3 was
prepared from propanal according to the procedure described by M. Oikawa,
T. Oikawa, & Ichihara (1995) while the Wittig salt 4 was synthesised from
commercial 1-heptyltriphenylphosphonium bromide (5) (Bondinell, Di Mari,
Frydman, Matsumoto, & Rapoport, 1968). Numerous assays were carried out to
study the influence of different parameters – such as temperature, proportion of
reactants, time of reaction – on the results of the Wittig reaction. The best yield in
ester 6 (48%) was obtained when the phosphonium salt 4 was treated without
purification with 0.95 eq of BuLi for 2 h at room temperature, with addition of 2.8 eq
of 3 at ꢁ78ꢂC and stirring of the mixture for 1 h at ꢁ78ꢂC and 16 h at room
temperature. The GC and 1H-NMR data of the isolated product indicated that it is a
mixture of two diastereoisomers (E and Z) in proportions 36/64.
Successive reduction of the double bond (H2, Pd/C in MeOH, yield 98%) and
of the ester group (LAH/Et2O, yield 94%), followed by Swern oxidation of the
generated primary alcohol, yielded a mixture of two racemic aldehydes, 1 and 2
(yield 93%). To avoid rapid oxidation of the aldehyde into the corresponding acid, it
is important to preserve the freshly purified mixture in hexane. GC–MS co-injection
O
O
i
ii
H
N
H
OMe
O
3
+ Br-
PPh3
+ I -
PPh3
iii
4
5
O
O
v
iv
vi
3
+ 4
OMe
OMe
6
7
O
vii
7
H
OH
1 syn
2 anti
8
Scheme 1. Synthesis of the mixture of the four stereoisomers of 4,6-dimethyldodecanal.
Reagents, conditions and yields: (i) piperidine, K2CO3, RT, 19 h; (ii) (a) methyl acrylate,
CH3CN, reflux, 24 h, (b) acetic acid/water, reflux, 21 h, 66%; (iii) (a) BuLi, THF, RT, 2 h, (b)
CH3I, RT, 1 h, 80%; (iv) (a) BuLi, THF, RT, 2 h, (b) 3, ꢁ78ꢂC, 1 h (c) RT, 16 h, 48%; (v) H2,
Pd/C, CH3OH, RT, 18 h, 98%; (vi) LAH, Et2O, RT, 12 h, 94%; (vii) (a) DMSO, (COCl)2,
CH2Cl2, ꢁ78ꢂC, 20 min, (b) 8, 1 h, ꢁ78ꢂC (c) Et3N, RT, 2 h, 93%.

562
J. Ghostin et al.
O
O
OSiMe3
O
ii
iii
i
11
10
9
12
O
OH
v
iv
O
O
Me
12
O
14
13
OMs
vii
ix
HO
NC
vi
O
14
16
Me
16
18
O
15
viii
MsO
17
O
x
H
18
1 syn
Scheme 2. Synthesis of (ꢀ)-syn-4,6-dimethyldodecanal. Reagents, conditions and yields:
(i) H2, Pd/C, C6H6, RT, 24 h, 97%; (ii) Me3SiCl, NaI, Et3N, CH3CN, RT, 4 h, 90%; (iii) (a)
LiNH2/NH3, THF, ꢁ41ꢂC, 2 h, (b) 1-iodopentane, THF, ꢁ41ꢂC, 7 h, 49%; (iv) m-CPBA,
TFA, CH2Cl2, 0ꢂC then RT, 16 h, 94%; (v) MeONa, MeOH, 0ꢂC, 4 h, 82%; (vi) MsCl, Et3N,
CH2Cl2, 0ꢂC, 4 h, 98%; (vii) LAH, Et2O, reflux, 16 h, 62%; (viii) MsCl, Et3N, CH2Cl2, 0ꢂC,
4 h, 98%; (ix) NaCN, DMF, 95ꢂC, 24 h, 68%; (x) DIBAL, hexane, ꢁ78ꢂC, 3 h, 97%.
of the synthetic mixture and the sternal secretion of Z. nevadensis and Z. angusticollis
indicated that the natural pheromone had a linear retention index (LRI on DB-wax
and HP5 columns) and mass spectral data identical to that of the synthetic aldehyde
having the smaller LRI (Bordereau et al., 2010). We were not able to separate the
two diastereoisomers 1 and 2. Thus, to attribute the GC peaks to the syn and anti
diastereoisomers, we decided to synthesise (ꢀ)-syn-4,6-dimethyldodecanal (1)
starting from commercial 3,5-dimethyl-2-cyclohexen-1-one (9), following the path-
way described in Scheme 2.
Hydrogenation of 9 using the procedure of Sugimura and Uchida (2005)
furnished 97% yield syn-3,5-dimethylcyclohexanone (10). Treatment of the latter
with trimethylsilyl iodide generated in situ from the corresponding chloride led to the
trimethylsilyl enol ether 11 (Cazeau, Duboudin, Moulines, Babot, & Dunogues,
1987, yield 90%). Alkylation of 11 was achieved readily in tetrahydrofuran (THF)
with pentyl iodide (yield 49%) using lithium amide in liquid ammonia (Binkley &
Heathcock, 1975; Patterson & Fried, 1974). Assignment of the anti stereochemistry
in 12 of the pentyl chain and the adjacent methyl group was based on the coupling
constant between H-2 and H-3 (J ¼ 12 Hz) that is consistent with the presence of
axial protons. Such stereochemistry is compatible with an attack of the carbocation
from the less hindered side of the molecule. On Baeyer–Villiger oxidation, ketone 12
was converted into lactone 13 in 94% yield. As expected, the reaction proceeded with
retention of configuration at the migrating carbon atom and with migration of
carbon atom C-7 due to its better ability to accommodate a partial positive charge in
the transition state than C-3. Hydrolysis of the lactone group (yield 82%) followed
by mesylation of the generated secondary alcohol provided the methyl ester 15 (yield
98%). LAH reduction of 15 afforded 16 (yield 62%). Subsequently, the hydroxyl

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563
group of 16 was replaced by a nitrile group via mesylate 17 (yield 83%). Finally,
reduction of the nitrile group with diisobutylaluminum hydride in hexane afforded
the target aldehyde 1 in 97% yield.
3. Experimental
EI–MS were performed with a Fisons VG Micromass Autospec instrument (70 eV).
1
In all cases, peak intensities are expressed as % relative to the base peak. The H-
NMR spectra were recorded in CDCl3 at 300 MHz with a Bruker Avance TM 300
and are reported in ppm from internal TMS on the ꢀ scale. Data are reported as
follows: chemical shift [multiplicity (s, singlet; d, doublet; dd, double doublet; ddd,
double double doublet; t, triplet; dt, double triplet; tt, triple triplet; q, quartet; m,
multiplet), coupling constants in Hertz, integration]. The 13C-NMR spectra were
recorded in CDCl3 at 75.4 MHz with a Bruker Avance TM 300 instrument. The IR
spectra were recorded with a Bruker IFS 25 instrument as thin films on a NaCl disk.
Thin-layer chromatography analyses were performed with 0.25 mm Polygram silica
gel SILG/UV254 pre-coated plates (Macherey-Nagel). Chromatographies were
performed on silica gel columns (MN Kieselgel 60, 0.04–0.063 mm) using the flash
technique.
3.1. Methyl 4-methyl-5-oxo-pentanoate (3)
Compound 3 was obtained using the procedure described by Oikawa et al. (1995).
3.2. 1-Methylheptyltriphenylphosphonium iodide (4)
Butyllithium in hexane (3.5 mL, 1.4 mol Lꢁ1, 4.9 mmol) was added dropwise to a
suspension of 1-heptyltriphenylphosphonium bromide (5, 2 g, 4.5 mmol) in dry THF
(13 mL). The solution was stirred at room temperature. After 2 h, iodomethane
(2 mL, 32 mmol) was added and the solution stirred for 1 h at room temperature. The
excess of iodomethane was evaporated in vacuo to yield crude 4 (1.8 g, 3.58 mmol,
80%) as a brown oil.
1H-NMR: ꢀ 7.80–7.70 (m, 15H), 4.92 (m, 1H), 1.89–1.65 (m, 4H), 1.37 (dd,
J ¼ 19.7, 6.8 Hz, 3H), 1.24–1.05 (m, 6H) and 0.82 (t, J ¼ 6.8 Hz, 3H). 13C-NMR:
ꢀ 134.9, 134.9, 134.2, 134.0, 130.7, 130.5, 118.4, 117.3 (aromatic C), 31.5, 30.5, 29.5,
26.8, 22.6 (C-3, C-4, C-5, C-6, C-7), 26.1 (C-2), 14.1 (C-8) and 13.5 (C-1).
3.3. (E Y Z)-Methyl 4,6-dimethyldodec-5-enoate (6)
A suspension of crude 4 in dry THF (13 mL) was added to butyllithium in hexane
(2.4 mL, 1.4 mol Lꢁ1, 3.4 mmol) and the resulting red solution was stirred at room
temperature for 2 h. Subsequently, methyl 4-methyl-5-oxo-pentanoate (3, 1.44 g,
9.97 mmol) dissolved in dry THF (2 mL) was added at ꢁ78ꢂC. The mixture was
stirred 1 h at ꢁ78ꢂC and 16 h at room temperature. Pentane was added and the
precipitate eliminated by filtration. The residue obtained after evaporation of the
solvent was flash-chromatographed on silica gel (pentane/Et2O, 99 : 1). This afforded
6 (526 mg, 2.19 mmol, 48%) as a colourless oil.

564
J. Ghostin et al.
1H-NMR: ꢀ 4.83 (d, J ¼ 9.5 Hz, 1H), 3.66 (s, 3H), 2.34–2.22 (m, 3H), 1.94 (m,
2H), 1.65 (d, J ¼ 1.2 Hz, H3C-6 E or Z), 1.56 (d, J ¼ 1.2 Hz, H3C-6 E or Z), 1.30–1.26
(m, 10H), 0.93 (d, J ¼ 6.6 Hz, H3C-4) and 0.88 (t, J ¼ 6.7 Hz, 3H). 13C-NMR: ꢀ 174.6
(CO), 135.4, 135.2 (C-6 E and Z), 130.6, 129.9 (C-5 E and Z), 51.5 (OCH3), 32.8, 32.4
(C-3 E and Z), 32.3, 32.2 (C-2 E and Z), 32.0 (C-4), 39.8, 31.9, 31.8, 29.5, 29.0, 28.3,
28.0, 22.8 (C-7, C-8, C-9, C-10, C-11), 23.5, 21.7, 21.4, 16.2 (H3C-4 and H3C-6 E and
Z) and 14.2 (C-12). IR: 2927, 1742 cmꢁ1. EIMS m/z: 240 (52) [M]þ, 209 (32)
[M ꢁ OCH3]þ, 166 (41), 155 (79), 123 (75), 109 (78), 97 (86), 83 (90), 69 (100)
and 55 (95).
3.4. (syn Y anti)-Methyl 4,6-dimethyldodecanoate (7)
A solution of methyl 4,6-dimethyldodec-5-enoate (6) (127 mg, 0.53 mmol) in
methanol (3 mL) was hydrogenated over Pd/C (10%, 40 mg) under H2 atmosphere
at room temperature. After 18 h, the solvent was evaporated in vacuo and the solid
residue was purified by flash-chromatography on silica gel (hexane/Et2O, 98 : 2) to
give the saturated ester 7 (126 mg, 0.52 mmol, 98%).
1H-NMR: ꢀ 3.66 (s, 3H), 2.34–2.26 (m, 2H), 1.69–1.03 (m, 16H) and 0.90–0.80
(m, 9H). 13C-NMR: ꢀ 174.7 (C-1), 51.5 (OCH3), 44.9, 44.5 (C-5), 38.0, 37.0, 32.9,
32.1, 32.0, 31.9, 31.8, 29.8, 29.7, 27.1, 27.0, 22.8 (C-2, C-3, C-7, C-8, C-9, C-10, C-
11), 30.0, 30.1, 29.9, 29.8 (C-4 and C-6), 20.2, 20.0, 19.6, 19.2 (H3C-4 and H3C-6) and
14.2 (C-12). IR: 2956, 1744 cmꢁ1. EIMS m/z: 242 (15) [M]þ, 211 (22) [M ꢁ OCH3]þ,
87 (100) [C4H7O2]þ and 74 (51) [C3H6O2]þ.
3.5. (syn Y anti) 4,6-Dimethyldodecan-1-ol (8)
A suspension of LAH (160 mg, 4.21 mmol) in anhydrous diethyl ether (2 mL) was
added at 0ꢂC to 7 (116.8 mg, 0.48 mmol) dissolved in anhydrous diethyl ether (3 mL).
After stirring for 12 h at room temperature, the reaction was quenched with a
saturated aqueous solution of MgSO4 and the aqueous layer extracted with
dichloromethane. The organic fractions were combined, evaporated in vacuo and
purified by flash-chromatography (pentane/Et2O 8 : 2) to yield alcohol 8 (96 mg,
0.45 mmol, 94%) as a colourless oil.
1H-NMR: ꢀ 3.62 (t, J ¼ 6.7 Hz, 2H), 1.59–1.04 (m, 18H) and 0.90–0.80 (m, 9H).
13C-NMR: ꢀ 63.6, 63.5 (C-1), 45.2, 44.9 (C-5), 38.1, 37.0, 34.0, 32.9, 32.1, 30.5, 30.3,
29.9, 29.8, 27.1, 27.0, 22.8 (C-2, C-3, C-7, C-8, C-9, C-10, C-11), 30.2, 30.16, 30.1,
30.0 (C-4 and C-6), 20.4, 20.3, 19.6, 19.5 (H3C-4 and H3C-6) and 14.2 (C-12). IR:
3307, 2957 cmꢁ1. EIMS m/z: 196 (1) [M ꢁ H2O]þ, 181 (2), 168 (12), 153 (30), 112 (65),
111 (72), 110 (39), 97 (29), 83 (70), 69 (100), 57 (88).
3.6. (syn Y anti) 4,6-Dimethyldodecanal (1 Y 2)
Oxalylchloride (57 mL, 0.66 mmol) was added to dimethylsulphoxide (93 mL)
dissolved in CH2Cl2 (1 mL) at ꢁ78ꢂC. After 20 min, 8 (40 mg, 0.187 mmol) dissolved
in CH2Cl2 (1 mL) was added. The solution was stirred for 1 h at ꢁ78ꢂC. Then,
triethylamine (139 mL, 0.98 mmol) was added dropwise. The reaction mixture was
stirred for 2 h at room temperature, quenched with water and extracted with CH2Cl2.

Natural Product Research
565
The organic layers were combined, concentrated in vacuo and flash-chromato-
graphed on silica gel (pentane/Et2O, 95 : 5) to yield a mixture of 1 and 2 (37 mg,
0.174 mmol, 93%) as a colourless oil that presented two peaks in GC on two
different columns (DB-wax and HP5).
1H-NMR: ꢀ 9.77 (t, J ¼ 1.8 Hz, 1H), 2.45–2.40 (m, 2H), 1.62–0.96 (m, 16H) and
0.90–0.80 (m, 9H). 13C-NMR: ꢀ 203.2 (C-1), 44.9, 44.6 (C-5), 41.9, 41.7 (C-2), 38.0,
36.9, 32.1, 31.1, 29.9, 29.8, 28.8, 27.1, 27.0, 22.8 (C-3, C-7, C-8, C-9, C-10, C-11),
30.2, 30.1, 29.9, 29.8 (C-4 and C-6), 20.3, 20.1, 19.6, 19.3 (H3C-4 and H3C-6) and
14.2 (C-12). IR: 2957, 2714 and 1729 cmꢁ1. EIMS m/z: 168 (2), 153 (14), 127 (13), 112
(41), 109 (34), 97 (10), 83 (54), 71 (43), 69 (34), 67 (21), 57 (100), 55 (63), 43 (91), 41
(91) and 29 (57). This spectrum was identical to that of the natural pheromone.
3.7. syn-3,5-Dimethylcyclohexanone (10)
Compound 10 was obtained using the procedure described by Sugimura and
Uchida (2005).
3.8. (syn-3,5-Dimethylcyclohex-1-enyloxy) trimethylsilane (11)
To a solution of 10 (7.5 g, 59.5 mmol) in dry acetonitrile (16 mL) triethylamine
(31 mL), trimethylchlorosilane (11 mL, 86 mmol) and sodium iodide (12.5 g,
83.4 mmol) dissolved in acetonitrile (80 mL) were added successively. The reaction
mixture was stirred at room temperature. After 4 h, cold water (100 mL) was added
and the aqueous solution extracted with cold pentane. The organic layers were
combined and evaporated in vacuo to give 11 (10.66 g, 53.83 mmol, 90%) as a
brown oil.
1H-NMR: ꢀ 4.69 (bs, 1H), 2.28–2.23 (m, 1H), 1.99–1.93 (m, 1H), 1.75–1.59
(m, 3H), 0.95 (m, H3C-3 and H3C-5), 0.66 (m, 1H) and 0.17 (bs, OSiMe3).
13C-NMR: ꢀ 149.9 (C-1), 111.0 (C-2), 41.0 (C-4), 38.6 (C-6), 30.4, 29.8 (C-3 and C-5),
22.9, 22.2 (H3C-3 and H3C-5) and 0.5 (OSiMe3).
3.9. (2R*,3S*,5R*)-3,5-Dimethyl-2-pentylcyclohexanone (12)
Compound 11 (6.7 g, 33.83 mmol) dissolved in dry THF (110 mL) and lithium amide
(1.04 g, 45.31 mmol) were added to liquid ammonia (180 mL). After stirring for 2 h
at ꢁ41ꢂC, a solution of 1-iodopentane (15 mL) in THF (15 mL) was added and the
resulting mixture was stirred for 7 h. Then ammonium chloride was added and the
ammonia was allowed to evaporate. After addition of water and extraction with
ether, the organic layers were combined, dried over magnesium sulphate and
evaporated in vacuo. The solid residue was flash-chromatographed on silica gel
(hexane/AcOEt 97 : 3) to yield 12 (3.23 g, 16.47 mmol, 49%) as a colourless oil.
1H-NMR: ꢀ 2.33 (ddd, J ¼ 12, 3, 3 Hz, 1H), 2.03–1.14 (m, 14H), 1.05 (d,
J ¼ 6.4 Hz, H3C-3 or H3C-5, 3H), 0.99 (d, J ¼ 6.2 Hz, H3C-3 or H3C-5, 3H) and 0.87
(t, J ¼ 6.8 Hz, 3H). 13C-NMR: ꢀ 212.4 (C-1), 56.5 (C-2), 50.6 (C-6), 43.9 (C-4), 37.8,
33.8 (C-3 and C-5), 32.5, 27.2, 25.6, 22.7 (C-40, C-30, C-20, C-10), 22.6, 20.9 (H3C-3,
H3C-5) and 14.2 (C-50). EIMS m/z: 196 (7) [M]þ, 126 (60) [M ꢁ C5H10]þ, 111 (100)
[M ꢁ C5H10–CH3]þ.

566
J. Ghostin et al.
3.10. (4R*,6S*,7R*)-4,6-Dimethyl-7-pentyloxepan-2-one (13)
To a solution of 12 (1.962 g, 10.01 mmol) in dry CH2Cl2 (20 mL) m-chloroperbenzoic
acid (4.5 g, 26.07 mmol) was added. The suspension was cooled to 0ꢂC and
trifluoroacetic acid (380 mL, 5.11 mmol) was added dropwise. During this operation,
the reaction flask was protected from light. Subsequently, the solution was allowed
to warm to room temperature. After 16 h, the mixture was diluted with
dichloromethane (20 mL) and the organic layer was washed successively with a
10% aqueous solution of Na2SO3 (20 mL), a saturated aqueous solution of
potassium carbonate (10 mL) and water (20 mL). Finally, the organic layer was
evaporated in vacuo to give lactone 13 (1.99 g, 9.38 mmol, 94%).
1H-NMR: ꢀ 4.04 (ddd, J ¼ 8, 8, 3 Hz, 1H), 2.56–2.41 (m, 2H), 1.93–1.10 (m, 12H),
1.03 (d, J ¼ 6.6 Hz, 4-CH3 or 6-CH3, 3H), 0.91 (d, J ¼ 6.9 Hz, 4-CH3 or 6-CH3, 3H)
and 0.88 (t, J ¼ 6.9 Hz, 3H). 13C-NMR: ꢀ 175.1 (C-2), 84.4 (C-7), 48.0, 42.0 (C-3 and
C-5), 37.3, 30.1 (C-4 and C-6), 33.1, 31.8, 24.7, 22.7 (C-40, C-30, C-20, C-10), 24.3, 19.0
(H3C-4 and H3C-6), 14.2 (C-50). EIMS m/z: 213 (100) [M þ 1]þ, 195 (24), 112 (71)
and 97 (22).
3.11. (3R*,5S*,6R*) Methyl 6-hydroxy-3,5-dimethylundecanoate (14)
Under nitrogen atmosphere, Na pieces (175 mg, 7.61 mmol) were carefully added to
anhydrous methanol (7.2 mL). The resulting solution was added dropwise to a
solution of 13 (1.608 g, 7.58 mmol) in anhydrous methanol (7.1 mL) at 0ꢂC. The
reaction mixture was stirred for 4 h at 0ꢂC. Then, the reaction was quenched with a
saturated aqueous solution of NH4Cl (7 mL). The aqueous layer was extracted with
dichloromethane and the combined organic fractions were evaporated in vacuo to
give the methyl ester 14 (1.517 g, 6.22 mmol, 82%) as a clear, oily liquid.
1H-NMR: ꢀ 3.66 (s, 3H), 3.43 (m, 1H), 2.35–1.03 (m, 14H), 0.97 (d, J ¼ 6.3 Hz,
3H), 0.90 (d, J ¼ 6.6 Hz, 3H) and 0.89 (t, J ¼ 6.1 Hz, 3H). 13C-NMR: ꢀ 173.9 (C-1),
76.1 (C-6), 51.5 (OCH3), 40.9, 39.6 (C-2 and C-4), 36.4, 28.2 (C-3 and C-5), 33.3,
32.1, 25.9, 22.8 (C-7, C-8, C-9, C-10), 21.1, 16.1 (H3C-3 and H3C-5) and 14.2 (C-11).
IR: 3400, 2955 and 1741 cmꢁ1. EIMS m/z: 173 (11), 144 (21) and 101 (100).
3.12. (3R*,5S*,6R*) Methyl 3,5-dimethyl-6-(methanesulphonyloxy)
undecanoate (15)
To a solution of 14 (1.098 g, 4.5 mmol) in dichloromethane (24 mL) triethylamine
(3.8 mL, 27.03 mmol) and mesyl chloride (655 mL, 8.46 mmol) were added. The
mixture was stirred at 0ꢂC. After 4 h, aqueous NaHCO3 (1N, 20 mL) was added and
the resulting solution extracted with dichloromethane. The organic layers were
combined and evaporated in vacuo to give mesylate 15 (1.417 g, 4.4 mmol, 98%) as a
yellowish oil.
1H-NMR: ꢀ 4.63 (m, 1H), 3.66 (s, 3H), 3.01 (s, 3H), 2.33–1.03 (m, 14H), 0.99 (m,
6H) and 0.90 (t, J ¼ 6.6 Hz, 3H). 13C-NMR: ꢀ 173.4 (C-1), 87.6 (C-6), 51.5 (OCH3),
41.1, 39.6 (C-2 and C-4), 38.8 (H3C-SO3), 34.4, 27.8 (C-3 and C-5), 31.6, 29.5, 25.4,
22.6 (C-7, C-8, C-9, C-10), 20.6, 15.1 (H3C-3 and H3C-5) and 14.1 (C-11). IR: 2957,
1736, 1353, 1174, 909 cmꢁ1. EIMS m/z: 322 (3) [M]þ, 227 (100) [M ꢁ CH3SO3]þ, 219
(14), 195 (38), 179 (60) and 152 (92).

Natural Product Research
567
3.13. syn-3,5-Dimethylundecan-1-ol (16)
To a suspension of LAH (975 mg, 25.6 mmol) in anhydrous diethyl ether (10 mL) at
0ꢂC, a solution of 15 (1 g, 3.10 mmol) in anhydrous ether (10 mL) was added. The
mixture was refluxed for 16 h. Then, the solution was cooled to 0ꢂC before addition
of a saturated aqueous solution of MgSO4. The resulting aqueous layer was extracted
with dichloromethane. The combined organic fractions were evaporated in vacuo and
the oily residue was flash-chromatographed (hexane/AcOEt 9:1) to yield alcohol 16
(382 mg, 1.91 mmol, 62%) as an oil.
1H-NMR: ꢀ 3.69 (m, 2H), 1.66–0.93 (m, 16H) and 0.87 (m, 9H). 13C-NMR: ꢀ 61.3
(C-1), 45.4, 40.0, 36.9 (C-2, C-4, C-6), 30.1, 27.0 (C-3 and C-5), 32.1, 29.8, 27.0, 22.8
(C-7, C-8, C-9, C-10), 20.3 (H3C-3 and H3C-5) and 14.2 (C-11). IR: 3329, 2956 cmꢁ1
EIMS m/z: 153 (9), 126 (6), 111 (20), 97 (100), 91 (34) and 83 (27).
.
3.14. syn-3,5-Dimethyl-1-(methylsulphonyloxy)undecane (17)
To a solution of 16 (855 mg, 4.27 mmol) in dichloromethane (23 mL) triethylamine
(3.7 mL, 26.32 mmol) and mesyl chloride (620 mL, 8.01 mmol) were added at 0ꢂC.
After stirring for 4 h, an aqueous solution of NaHCO3 (1N) was added. The resulting
aqueous solution was extracted with dichloromethane. The organic layers were
combined and concentrated in vacuo to give mesylate 17 (1.17 g, 4.21 mmol, 98%)
as an oil.
1H-NMR: ꢀ 4.324.20 (m, 2H), 3.10 (s, 3H), 1.82–0.97 (m, 16H) and 0.88 (m, 9H).
13C-NMR: ꢀ 68.7 (C-1), 44.9 (C-4), 37.4 (H3C–SO3), 36.7, 35.9 (C-2 and C-6), 29.9,
26.9 (C-3 and C-5), 32.0, 29.7, 26.8, 22.7 (C-7, C-8, C-9, C-10), 20.2, 19.9 (H3C-3 and
H3C-5) and 14.2 (C-11). IR: 2957, 1355 and 1176 cmꢁ1. EIMS m/z: 153 (7), 126 (6),
111 (19), 97 (100), 83 (18), 69 (57) and 55 (90).
3.15. syn-4,6-Dimethyldodecanitrile (18)
To a solution of 17 (605 mg, 2.17 mmol) in dry DMF (8 mL) NaCN (1.075 g,
21.93 mmol) was added and the resulting mixture was stirred at 95ꢂC. After 24 h,
water (10 mL) was added and the solution extracted with ether. The combined
organic layers were evaporated in vacuo and flash-chromatographed on silica gel
(hexane/AcOEt, 9:1). This yielded 18 (310 mg, 1.48 mmol, 68%).
1H-NMR: ꢀ 2.40–2.24 (m, 2H), 1.82–0.94 (m, 16H) and 0.88 (m, 9H). 13C-NMR:
ꢀ 120.1 (C-1), 44.4 (C-5), 30.0, 29.4 (C-4 and C-6), 36.7, 32.2, 32.0, 29.7, 26.9, 22.7
(C-3, C-7, C-8, C-9, C-10, C-11), 20.2, 19.4 (H3C-4 and H3C-6), 14.9 (C-2) and 14.2
(C-12). IR: 2958, 2247 cmꢁ1. EIMS m/z: 210 (95) [M þ 1]þ, 194 (50), 180 (34), 166
(40), 152 (39), 138 (53), 125 (100), 83 (33) and 55 (62).
3.16. syn-4,6-Dimethyldodecanal (1)
A solution of diisobutylaluminum hydride in hexane (1.44 mL, 1 mol Lꢁ1) was added
dropwise to a solution of 18 (150 mg, 0.717 mmol) in anhydrous hexane (9 mL) at
ꢁ78ꢂC. The mixture was stirred. After 3 h, ethyl acetate (9 mL) and water (1 mL)
were added. The solution was brought to room temperature, diluted with hexane
(9 mL) and washed with HCl (0.5N, 2 mL). The mixture was then extracted three

568
J. Ghostin et al.
times with hexane and washed successively with HCl (0.5N, 9 mL) and with a
saturated aqueous solution of NaHCO3 (8 mL). The organic layers were combined,
.
evaporated in vacuo and flash-chromatographed on silica gel (hexane/Et2O, 95:5).
This yielded syn-4,6-dimethyldodecanal 1 (148 mg, 0.698 mmol, 97%) as a
colourless oil.
1H-NMR: ꢀ 9.77 (t, J ¼ 1.8 Hz, 1H), 2.46–2.38 (m, 2H), 1.69–0.92 (m, 16H) and
0.88 (m, 9H). 13C-NMR: ꢀ 203.2 (C-1), 44.9 (C-5), 41.7 (C-2), 30.1, 29.8 (C-4 and
C-6), 36.9, 32.1, 29.8, 28.8, 27.0, 22.8 (C-3, C-7, C-8, C-9, C-10, C-11), 20.3, 20.0
(H3C-4 and H3C-6) and 14.2 (C-12). IR: 2925, 2712, 1728 cmꢁ1. EIMS m/z: 168 (2),
153 (14), 127 (13), 112 (40), 109 (34), 97 (10), 83 (54), 71 (43), 69 (34), 57 (100), 55
(63), 43 (91), 41 (91) and 29 (57). This spectrum was identical to that of the natural
pheromone.
4. Conclusion
The LRI of the synthetic material indicated unambiguously that the natural
pheromone is the syn and not the anti diastereoisomer of 4,6-dimethyldodecanal.
This synthesis represents the first synthesis of the pure racemate of this termite
pheromone.
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