Synthesis of (3E)-dodecen-12-olide, a potential pheromone component of the emerald ash borer

Article abstract of DOI:10.1080/00397911.2011.634083

Emerald ash borer (EAB), Agrilus planipennis Fairmaire, is an invasive insect that has killed millions of ash trees in the USA and Canada. A concise synthesis of a potential EAB pheromone component, (3E)-dodecen-12-olide, using highly stereoselective Julia-Kocienski olefination as the key step, is reported. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2011.634083

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Synthesis of (3E)-Dodecen-12-olide, a
Potential Pheromone Component of the
Emerald Ash Borer
D. I. MaGee a , P. D. Mayo b , P. J. Silk b & B. Beattie a
a Department of Chemistry, University of New Brunswick,
Fredericton, New Brunswick, Canada
b Canadian Forestry Service–Atlantic, Fredericton, New Brunswick,
Canada
Accepted author version posted online: 06 Jun 2012.Version of
record first published: 05 Mar 2013.
To cite this article: D. I. MaGee , P. D. Mayo , P. J. Silk & B. Beattie (2013): Synthesis of (3E)-
Dodecen-12-olide, a Potential Pheromone Component of the Emerald Ash Borer, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:10, 1368-1377
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Synthetic Communications1, 43: 1368–1377, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.634083
SYNTHESIS OF (3E)-DODECEN-12-OLIDE, A
POTENTIAL PHEROMONE COMPONENT OF THE
EMERALD ASH BORER
D. I. MaGee,1 P. D. Mayo,2 P. J. Silk,2 and B. Beattie1
1Department of Chemistry, University of New Brunswick, Fredericton,
New Brunswick, Canada
2Canadian Forestry Service–Atlantic, Fredericton, New Brunswick, Canada
GRAPHICAL ABSTRACT
Abstract Emerald ash borer (EAB), Agrilus planipennis Fairmaire, is an invasive insect
that has killed millions of ash trees in the USA and Canada. A concise synthesis of a
potential EAB pheromone component, (3E)-dodecen-12-olide, using highly stereoselective
Julia–Kocienski olefination as the key step, is reported.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords (3E)-Dodecen-12-olide; (3Z)-dodecen-12-olide; emerald ash borer; Julia–
Kocienski olefination
INTRODUCTION
The emerald ash borer (EAB) is an invasive palearctic species that has killed
millions of ash trees (Fraxinus spp. L.) (Oleaceae) in North America.[1] Early detec-
tion of EAB infestations is difficult because visual signs appear only after trees have
been heavily infested for several years.[2] Previous work has shown that adult EABs
respond to volatiles from girdled ash,[1] ash leaves,[2–4] and Manuka and Phoebe
oils,[5,6] indicating that plant semiochemicals may provide a means for monitoring
Received October 3, 2011.
Address correspondence to D. I. MaGee, Department of Chemistry, P. O. Box 4400, University of
New Brunswick, Fredericton, NB, Canada E3B 5A3. E-mail: dmagee@unb.ca
1368

SYNTHESIS OF (3E)-DODECEN-12-OLIDE
1369
Figure 1. (3Z)- (1) and (3E)-dodecen-12-olide, (2), two macrocyclic lactones found to provide EAD
response in the emerald ash borer.
EABs. Sensory deprivation experiments suggested the presence of a short-range
volatile cue emitted by females[7] and Bartelt et al.[8] discovered an antennally active,
predominantly female-produced, macrocyclic lactone, (3Z)-dodecen-12-olide 1,
although no behavioral activity was reported.
Further studies involving gas chromatography = electroantennographic detection
(GC=EAD) in our laboratory have shown that the excised antennae of EABs respond
to both 1 and its E-isomer, (3E)-dodecen-12-olide (2) (Fig. 1). GC=EAD is a technique
wherein the excised head of an insect is affixed in an electrolytic gel and the eluent from
a gas chromatograph column is split and passed through a flame-ionization detector
(FID) and over the antennal preparation simultaneously. The electrophysiological
responses of the antennae are correlated with the peaks from the FID.[9] The response
of EAB antennae to both isomers of dodecen-12-olide was noticed as a result of ꢀ3%
of the E-isomer being intrinsic to the synthesis of the Z-isomer.[10]
Given the potential severity of this pest, much effort is being expended to ident-
ify efficient early-detection systems. As a result, our laboratory became involved in a
study to investigate the EAB attractiveness of the two lactone isomers, 1 and 2, as
well as the possible synergistic effects of these isomers with plant-derived kairo-
mones.[11] However, before beginning any field studies, efficient syntheses of the
two lactone isomers had to be developed. While several syntheses of Z-lactone 1 have
been reported,[8,10,12–19] many require numerous steps, have one or several low-
yielding steps, or require harsh or special reagents. However, with a slight
modification of the Boden procedure, Z-lactone 1 was synthesized with excellent
stereopurity (ca. 97%) and acceptable overall yield (7 steps, 38%).[20] E-Lactone 2
on the other hand, has only one reported synthesis in extremely poor yield (6%)
and poor stereoselectivity (unspecified).[21] Therefore, if we were to investigate the
ability of this lactone to attract EABs in the field studies that were planned, we
needed to develop an efficient and stereochemically pure syntheses of 2 that would
produce useful quantities (100s mg to g). Our results are presented herein.
RESULTS AND DISCUSSION
Retrosynthetic analysis was based upon the route used to make the Z-isomer
with the exception of using the Schlosser modification for the Wittig reaction to
generate the desired E-stereochemistry (Fig. 2).

1370
D. I. MAGEE ET AL.
Figure 2. Retrosynthetic analysis for the synthesis of 2.
Thus, ethylvinyl ether (EVE) protection of alkenol 3 followed by ozonolysis
with reductive workup proceeded smoothly to give 4 (Scheme 1). The choice of
the EVE protecting group was crucial because it was envisaged that the alcohol
would be liberated only at a late stage in the synthesis; namely after the masked
b-c-unsaturated acid was installed. Immediate treatment of the aldehyde 4 with
the known Wittig salt 5[22] using the Schlosser modification[23] to give alkene acetal
6 proved disappointing, the E-selectivity of the reaction being very capricious, with
80% stereochemical purity being the best result out of a dozen attempts at the reac-
tion.
With the failure of the Schlosser-modified Wittig reaction, an alternative route
was sought. A number of years ago we investigated the utility of the Ramberg–
Backlund reaction for the construction of macroheterocycles that contained an
alkene.[24] It was found that under the appropriate conditions good yields and stereo-
selectivity could be routinely obtained. Pertinent to this study a trans-13-membered
macrocyclic azacycle was efficiently generated using this method in a 96:4 trans=cis
ratio. With this in mind we developed three potential routes that would allow us to
explore whether this could be used to make the targeted lactone 2 (Scheme 2).
Our first strategy was to react 8-bromo-1-octanol with chloro propionyl
chloride to efficiently generate dihalo-ester 8. Following our published procedure,[24]
Scheme 1. Synthesis of aldehyde 4 and olefination using the Schlosser modification of the Wittig reaction.
Reagents and conditions: (a) ethylvinyl ether, PPTS, CH2Cl2, rt, 0.25 h, 98%; (b) O3, Sudan III, CH2Cl2,
ꢁ78 ꢂC, 1.25 h; (c) PPh3, ꢁ78 ꢂC–rt, 1 h, 93%; (d) 5, 2 equiv. PhLi, ꢁ70 ꢂC, then ethereal HCl, ꢁ30 ꢂC, then
KOtBu in tBuOH, ꢁ30 ꢂC–rt, 47%.

SYNTHESIS OF (3E)-DODECEN-12-OLIDE
1371
Scheme 2. Attempted synthesis of macrocyclic lactone 11 using the Ramburg–Backlund reaction.
Reagents and conditions: (a) chloropropionyl chloride, CH2Cl2, rt, 24 h, 91%; (b) Na2S, EtOH, reflux,
36 h; (c) KSAc, NaI, CH3CN, reflux, 16 h, 93%; (d) chloropropionly chloride, CH2Cl2, rt, 16 h, 91%; (e)
NaOH, MeOH, rt, 30 min then reflux 16 h; (f) KSAc, NaI, CH3CN, reflux, 16 h, 93%; (g) NaOH, MeOH,
0.5 h, rt, then add 3-chloro-1,1-diethoxyproprionaldehyde, NaI (cat), reflux, 24 h, 59%; (h) pTSA, THF,
H2O, 2 h, reflux, 80%; i) NH2SO3H, NaClO2, 1-methylcyclohexene, CH2Cl2, 0 ꢂC–rt, 30 min; and (j)
PPh3, DEAD, C6H3CH3, 24 h.
dihalide 8 was subjected to Na2S in refluxing aqueous ethanol and although the
starting material was completely consumed, unfortunately no macrocylic lactone
was observed. From the two compounds that were isolated, infrared (IR) and 13C
NMR clearly showed that a carbonyl functionality was not present in either one
1
of them. From H NMR, one of the fractions isolated from SiO2 chromatography
appeared to be 8-mercapto-1-octanol contaminated with its disulfide, while the other
fraction appeared to be a mixture of 8-bromo-1-octanol, 8-chloro-1-octanol and
8-ethoxy-1-octanol in roughly equal proportions. Lowering the temperature or alter-
ing the time had no effect on the outcome of the reaction.
To probe whether the ester hydrolysis was a direct result of Na2S addition, we
altered the route. In our second attempt, alcohol 8 was treated with potassium thioa-
cetate in dimethylformamide (DMF) first, followed by addition of chloro propionyl
chloride to efficiently generate thioacetate 9. It was hoped that we could selectively
hydrolyze the thioacetate and that the generated thiolate would then cyclize intramo-
lecularly to produce 11. To this end, treatment of 9 with NaOH in methanol for
30 min followed by heating at reflux overnight completely consumed the starting
material, but once again none of 11 could be isolated. In fact, the major fraction iso-
1
lated from SiO2 chromatography was shown by H NMR to be identical to one of
the fractions obtained when 8 was treated with Na2S, namely 8-mercapto-1-octanol
and its disulfide.
Results from the first two routes suggested that the macrocycle could not be
formed via a thiolate substitution; therefore this led to a third route. First, alcohol
8 was thioacetylated with NaSAc as we had done before, and then treatment with
NaOH in ethanol for 30min followed by addition of 3-chloro-1,1-diethylacetal cleanly
provided alcohol 10. Hydrolysis of the acetal with aqueous acid generated the alde-
hyde, but all attempts to oxidize the acid failed to give any identifiable products.
With all attempts to form lactone 11 being unsuccessful, we were forced to
explore other alternatives. Although there are numerous methods known to make

1372
D. I. MAGEE ET AL.
alkenes, few (nonstabilized) are highly stereospecific, a criteria that was of para-
mount importance for this project. Recently there has been much interest in the
Julia–Kocienski reaction as a method to generate E-alkenes, and many improve-
ments have been made such that excellent stereoselectivity can now be routinely
obtained.[25,26] Therefore, we decided to investigate whether this would solve our
problem.
Consequently, phenyltetrazole (PT) sulfone 15 was synthesized by deprotonat-
ing 1-phenyl-1H-tetrazole-5-thiol 13 with sodium hydride and coupling it with com-
mercially available 12 to give thioether 14 (Scheme 3). Oxidation of this thioether
using molybdenum[27] and H2O2 cleanly furnished the PT sulfone 15 in 73% yield.
Attempts to use other oxidizing agents such as meta-chloroperbenzoic acid
(mCPBA),[28] oxone,[29] or camphor sulfonyl oxaziridine[30] gave either inferior yields
or complete destruction of the starting material. Subjecting aldehyde 4 to the Julia–
Kocienski olefination using PT sulfone 15 and potassium (bistrimethylsilyl) amide
(KHMDS) as base generated olefin 16 in 60% yield and ca. 97% E stereochemistry,
as determined by GC.
With the carbon backbone in place, what remained was functional group
manipulation and macrocyclization. To this end, acid-catalyzed hydrolysis of the
two acetals of 16 smoothly gave hydroxyaldehyde 17, which upon immediate Lindg-
ren oxidation[31] gave hydroxyacid 18 in 60% overall yield. Finally, as reported by
Boden,[5] macrocyclic lactonization using the modified Mitsunobu method[32,33] gave
(3E)-dodecen-12-olide 2 in excellent yield, 80%. The structure and stereochemical
purity (>97%) of this compound was determined by extensive NMR and GC analysis.
Scheme 3. Synthesis of lactone 2 using the Julia–Kocienski reaction. Reagents and conditions: (a) NaH,
DMF, NaI, 0–60 ꢂC, 2 h, 76%; (b) (NH4)6Mo2O24 ꢃ 4H2O, H2O2, EtOH, 24 h, 73%; (c) KHMDS, DME,
ꢁ55 ꢂC, 1 h, then add 4, ꢁ55 ꢂC–rt, 1.5 h, 60%; (d) pTSA, wet THF, D, 1 h; (e) NH2SO3H, NaClO2,
1-methylcyclohexene, CH2Cl2, 0 ꢂC–rt, 30 min, 60% over 2 steps; (f) PPh3, DEAD, C6H3CH3, 24 h, 80%.

SYNTHESIS OF (3E)-DODECEN-12-OLIDE
1373
CONCLUSION
In conclusion, the 3E-lactone [(3E)-dodecen-12-olide] (2) synthesis was success-
fully accomplished in six steps with an overall yield of 16%. The key steps were the
Julia–Kocienski olefination of aldehyde 4 with sulfone 15 to install the E-alkene and
macrocyclization using a modified Mitsunobu reaction. With convenient syntheses
of lactones 1 and 2 available, extensive field testing is now under way.
EXPERIMENTAL
Unless otherwise indicated, all nonaqueous reactions were conducted in oven-
dried glassware under an argon atmosphere. Air-sensitive reagents were transferred
via syringe through rubber septa. Reagents were purchased from commercial suppli-
ers and directly used without further purification. Analytical thin-layer chromato-
graphy (TLC) was performed using Silicycle TLC plates, precoated with 0.25 mm
of UV254 silica gel. Visualization was done by dipping the TLC plate in potassium
permanganate solution or phosphomolybdic acid = ethanol solution followed by
baking on a hot plate. Flash column chromatography was performed using a glass
column filled with 230 to 420-mesh silica gel 60 from Fisher. Preparative TLC was
carried out on 1 mm Silicycle silica-gel plates. Reagent-grade solvents were used
without further purification. All compounds purified by SiO2 chromatography were
greater than 98% purity as determined by GC and=or NMR.
NMR spectra were recorded on Varian Innova 300-MHz or Unity 400-MHz
spectrometers. All spectra were recorded in CDCl3 containing tetramethylsilane
(TMS) as an internal standard or in deuterated dimethylsulfoxide (DMSO) with
chemical shifts reported in parts per million (ppm) (d). Synthetic samples and puri-
fied extracts were analyzed by gas chromatography = mass spectrometry (GC=MS)
on a Hewlett-Packard 5890 GC and a 5971 mass selective detector in the electron
impact (EI, 70 eV) mode as described by Silk et al. (2007). IR spectra were recorded
on a Perkin-Elmer 727B IR spectrometer using KBr discs.
Sulfide 14[34]
1-Phenyl-1H-tetrazole-5-thiol (12) (2.0 g, 11.3 mmol) and DMF (30 mL) were
added to a round-bottomed flask. The solution was cooled to 0 ꢂC, and NaH was
added (508 mg, 60 w=w % in mineral oil, 12.7 mmol) to give the anion. The solution
was briefly warmed to 60 ꢂC and then cooled to 0 ꢂC again. 3-Chloropropionalde-
hyde diethylacetal 13 (1.9 mL, 11.3 mmol) and NaI (0.42 g, 2.8 mmol) were added,
and the solution was warmed to 60 ꢂC for 2 h. The reaction was then cooled to rt,
quenched with water (30 mL), and extracted with 1:9 CH2Cl2=hexanes (30 mL ꢄ 4).
The combined organic layers were washed with water (30 mL) and brine (40 mL)
and dried (MgSO4). Column chromatography (2:3 EtOAc=hexanes) yielded sulfide
14[34] as a colorless, transparent liquid (2.7 g, 8.6 mmol, 76%). Rf ¼ 0.59 (2:1
1
hexanes=EtOAc). H NMR (CDCl3, 400 MHz): d 7.53–7.59 (m, 5H), 4.64 (t, 1H,
J ¼ 5.5 Hz), 3.64–3.71 (m, 2H), 3.43–3.56 (m, 4H), 2.14–2.19 (m, 2H), 1.21 (t, 6H,
J ¼ 7.0 Hz). 13C NMR (CDCl3, 100 MHz): d 154.3, 133.7, 130.1, 129.8, 123.8,
101.3, 61.7, 33.2, 28.7, 15.3. IR (KBr windows) cmꢁ1: 3062 (m), 2976 (s), 2930 (s),

1374
D. I. MAGEE ET AL.
2880 (s), 2363 (w), 2333 (w), 2217 (w), 1737 (s), 1597 (s), 1501 (s), 1443 (s), 1387 (s),
1348 (s), 1278 (s), 1243 (s), 1125 (s), 1063 (s). MS (CI) major peaks: 292, 293, 295,
296, 297, 303, 304, 309 (base peak). HRMS (mþ þ H) calcd. for C13H21N5O2S
311.1418, found 311.1418.
PT Sulfone 15
A round-bottomed flask was charged with sulfide 14 (0.31 g, 1.0 mmol) and
ethanol (30 mL), and the solution was cooled to 0 ꢂC. Then (NH4)6Mo2O24 ꢃ 4H2O
(0.12 g, 0.1 mmol) in 30% H2O2 (1.0 mL, 1.0 mmol) was added, and the reaction mix-
ture was allowed to slowly warm to room temperature and stir overnight. Water
(200 mL) and CH2Cl2 (25 mL) were added, and the layers were separated. The aque-
ous phase was extracted with CH2Cl2 (2 ꢄ 25 mL), and the combined organic phases
were dried (MgSO4) and concentrated by rotary evaporation. Column chromato-
graphy (EtOAc=Hexanes 1:2) yielded the sulfone 15 as a clear, colorless liquid
(0.25 g, 0.73 mmol, 73%). Rf ¼ 0.27 (1:6 EtOAc=hexanes). 1H NMR (CDCl3,
400 MHz): d 7.55–7.69 (m, 5H), 4.68 (t, 1H, J ¼ 5.1 Hz), 3.83 (AA0XX0, 2H), 3.67
(pentet, 2H, J ¼ 8.4 Hz), 3.52 (pentet, 2H, J ¼ 7.0 Hz), 2.26 (m, 2H), 1.21, (t, 6H,
J ¼ 7.2 Hz). 13C NMR (CDCl3, 100 MHz): d 153.4, 133.1, 131.5, 129.7, 125.2,
100.2, 62.3, 51.8, 26.8, 15.2. IR (KBr windows) cmꢁ1: 3066 (m), 2977 (s), 2933 (s),
1733 (s, br), 1596 (m), 1575 (w), 1498 (s), 1438 (m), 1343 (s), 1237 (m), 1152 (s),
1061 (s). MS (EI) major peaks: 47, 57, 65, 75, 85 (base peak), 103, 118, 157, 165,
195, 267, 283, 311. HRMS (mþ þ H) calcd. for C14H21N4O4S 341.1285, found
341.1284.
trans-Alkene 16
A round-bottomed flask was charged with PT sulfone 15 (4.2 g, 12.4 mmol),
dimethoxyethane (DME) (100 mL) and cooled to ꢁ55 ꢂC. Potassium bis(trimethylsi-
lyl)amide (0.5 M in toluene, 24.8 mL, 12.4 mmol) was added dropwise over 10 min,
and the reaction was stirred at ꢁ55 ꢂC for a further 1 h. Aldehyde 4 (2.9 g,
12.1 mmol) was then added neat at ꢁ55 ꢂC via syringe, and the syringe was rinsed
with THF (2 ꢄ 2 mL). The reaction was stirred at this temperature for a further
1 h and then allowed to warm to room temperature over 1.5 h. The reaction was
quenched with water (70 mL), the layers were separated, the aqueous layer was
extracted with Et2O (3 ꢄ 50 mL), and the combined organic layers were washed with
brine (50 mL) and dried (MgSO4). Column chromatography (1:4 EtOAc=hexanes)
yielded the product 16 (2.6 g, 60%) as a clear, colorless liquid. Rf ¼ 0.66 (6:1
1
hexanes=EtOAc). H NMR (CDCl3, 400 MHz): d 5.32–5.55 (m, 2H), 4.68 (q, 1H,
J ¼ 5.3 Hz), 4.47 (t, 1H, J ¼ 5.9 Hz), 3.36–3.70 (m, 8H), 2.32 (ABMX, 2H), 1.98
(ABMXY, 2H), 1.52–1.58 (m, 2H), 1.29–1.39 (m, 10H), 1.30 (d, 3H, J ¼ 5.4 Hz),
1.204 (t, 3H, J ¼ 7.0 Hz), 1.201 (t, 6H, J ¼ 7.1 Hz). 13C NMR (CDCl3, 100 MHz):
d 133.5, 124.6, 102.8, 99.5, 65.3, 61.0 (2 signals), 60.6, 37.3, 32.7, 29.9, 29.5 (2 sig-
nals), 29.4, 29.1, 26.3, 19.9, 15.3 (3 signals). IR (KBr windows) cmꢁ1: 2975 (s),
2929 (s), 1569 (w), 1444 (w), 1373 (m), 1342 (m), 1129 (s), 1061 (s). MS (EI) major
peaks: 103 (base peak), 121, 163, 181, 207, 225, 253, 283, 299, 329, 343. HRMS
(mþ þ H) calcd. for C20H41O4 345.3006, found 345.3010.

SYNTHESIS OF (3E)-DODECEN-12-OLIDE
1375
trans-Acid 18
A round-bottomed flask was charged with diethylacetal 16 (1.4 g, 4.13 mmol)
and THF (50 mL) and heated to reflux. p-Toluenesulfonic acid (1.1 mL, 0.1 M in
H2O, 0.11 mmol) was then added and the reaction was stirred at reflux for 1 h. After
cooling to rt, water (40 mL) was then added, and the reaction mixture was extracted
with Et2O (4 ꢄ 40 mL). The combined organic layers were washed with water (40 mL,
this washing was kept for the next step) and brine (40 mL) and dried (MgSO4).
Removal of the solvent in vacuo yielded the intermediate hydroxyaldehyde 17 as a
clear, colorless liquid. Rf ¼ 0.32 (1:2 EtOAc=hexanes). This was used in the next step
without further purification. 1H NMR (CDCl3, 400 MHz): d 9.66 (t, 1H, J ¼ 2.1 Hz),
5.62 (m, 1H), 5.47 (m, 1H), 3.65 (t, 2H, J ¼ 5.8 Hz), 3.12 (dd, 2H, J ¼ 3.9, 1.9 Hz),
2.43 (t, 1H, J ¼ 7.3 Hz), 2.06 (m, 2H), 1.57 (m, 2H), 1.26–1.41 (m, 10H). 13C
NMR (CDCl3, 100 MHz): d 200.5, 137.0, 119.1, 63.0, 47.3, 32.8, 32.7, 29.40,
29.36, 29.1, 29.0, 25.7. IR (KBr windows) cmꢁ1: 3391 (br, m), 2926 (s), 2854 (s),
1725 (m), 1686 (w), 1464 (m), 1429 (w), 1386 (m), 1343 (w), 1112 (m), 1055 (m).
MS (EI) major peaks: 41, 55 (base peak), 67, 81, 95, 109, 123, 133, 142,152, 162,
180, 198.
The crude hydroxyaldehyde 17 was immediately taken up in CH2Cl2 (30 mL)
and water (40 mL, the wash from the prior workup), 1-methyl-1-cyclohexene
(2.0 mL, 17 mmol) was added, and the reaction mixture was cooled to 0 ꢂC.
NH2SO3H (6.0 mL, 1.0 M in H2O, 6.0 mmol) and then NaClO2 (18.0 mL, 1.0 M in
H2O, 18.0 mmol) were added and the reaction was stirred at 0 ꢂC for 30 min and then
at rt for 30 min. The layers were then separated, and the aqueous phase was extracted
with CH2Cl2 (3 ꢄ 30 mL). The organic layers were combined and the solvent was
removed in vacuo. The crude product was then taken up in Et2O (50 mL) and
extracted with 0.5 M aqueous Na2CO3 (4 ꢄ 30 mL). The combined Na2CO3 extrac-
tions were washed with Et2O (30 mL) and acidified with 30 mL of concentrated
HCl. The aqueous suspension was then extracted with Et2O (4 ꢄ 50 mL), and the
combined ether extractions were washed with 2 M HCl (50 mL), water (50 mL),
and brine (50 mL) and dried (MgSO4). Removal of the solvent in vacuo yielded
the hydroxyacid 18 as a white solid (0.53 g, 2.48 mmol, 60% yield over two steps).
Rf ¼ 0.16 (2:1 hexanes=EtOAc). 1H NMR (CDCl3, 400 MHz): d 5.49–5.16 (2H, sym-
metrical 12-line multiplet), 3.65 (2H, t, J ¼ 6.5 Hz), 3.06 (2H, d, J ¼ 6.5 Hz), 2.04 (2H,
dt, J ¼ 6.8, 6.8 Hz), 1.53–1.58 (2H, m), 1.16–1.40 (10H, m); 2 hydroxyl protons not
observed. 13C NMR (CDCl3, 100 MHz): d 176.9, 135.4, 121.1, 63.1, 37.7, 32.6, 32.3,
29.24, 29.17, 28.9, 28.7, 25.6. IR (KBr windows) cmꢁ1: 3445–3670 (v. b, s), 1712 (br,
s), 1463 (s), 1403 (s), 1271 (br, s), 1056 (s). MS (chemical ionization) major peaks: 82
(base peak), 123, 124, 179, 197, 215. HRMS (mþ þ H) calcd. for C12H23O3 215.1647,
found 215.1647.
(3E)-Dodecen-12-olide 2
A round-bottomed flask was charged with triphenylphosphine (2.10 g,
8.01 mmol) and toluene (500 mL), and then diisopropyl azodicarcarboxylate (DIAD)
(1.70 g, 8.41 mmol) was added with stirring. A solution of the trans-hydroxyacid 18
(0.34 g, 1.59 mmol) in toluene (100 mL) was added from a dropping funnel over 8 h at

1376
D. I. MAGEE ET AL.
room temperature. The reaction mixture was stirred for an additional 16 h at room
temperature; then the solvent was removed in vacuo and column chromatography of
the crude product mixture yielded the E-lactone 2[20] (0.25 g, 1.27 mmol, 80%) as a
1
transparent, colorless liquid. Rf ¼ 0.45 (13:1 hexanes=EtOAc). H NMR (CDCl3,
400 MHz): d 5.47–5.62 (10 line symmetrical multiplet, 2H), 4.12 (AA0XX0, 2H),
2.98 (d, 2H, J ¼ 7.0 Hz), 2.05 (m, 2H), 1.57 (m, 2H), 1.29–1.42 (m, 10H). 13C
NMR (CDCl3, 100 MHz): d 172.0, 135.4, 123.2, 64.5, 39.0, 31.4, 27.2, 26.34,
26.28, 25.7, 24.9, 23.6. IR (neat): cmꢁ1 3027 (w), 2928 (s), 2855 (s), 1733 (s), 1666
(w), 1457 (w), 1375 (w), 1348 (w), 1246 (s), 1143 (m), 1111 (m), 1039 (m). MS (EI)
major peaks: 41 (base peak), 54, 67, 81, 95, 109, 121, 136, 150, 168, 178, 196. HRMS
(mþ þ H) calcd. for C12H21O2 197.1542, found 197.1538.
SUPPLEMENTARY INFORMATION
Full experimental details for the syntheses of compounds 2–18 are available
1
online, including H and 13C spectra for all new compounds.
ACKNOWLEDGMENTS
We thank Sara Carmichael for technical assistance and the Canadian Forest
Service, University of New Brunswick, and National Science and Engineering
Research Council of Canada (NSERC) for funding this research. All experiments
reported here comply with the laws of Canada.
REFERENCES
1. Poland, T. M.; McCullough, D. G. J. For. 2006, 104, 118–124.
2. de Groot, P.; Biggs, W. D.; Lyons, D. B.; Scarr, T.; Czwerwinski, E.; Evans, H. J.;
Ingram, W.; Marchant, K. Natural Resources Canada Report, 2006, 16 pp.
3. Rodriguez-Saona, C.; Poland, T. M.; Miller, J. R.; Stelinski, L. L.; Grant, G. G.; de
Groot, P.; Buchan, L.; MacDonald, L. Chemoecology 2006, 16, 75–86.
4. Grant, G. G.; Ryall, K. L.; Lyons, D. B.; Abou-Zaid, M. M. J. Appl. Entomol. 2009, 134,
26–33.
5. Crook, D. J.; Krimian, A.; Francese, J.; Fraser, I.; Poland, T. M.; Sawyer, A. J.; Mastro,
V. Environ. Entomol. 2008, 37, 356–365.
6. Crook, D. J.; Mastro, V. C. J. Chem. Ecol. 2010, 36, 101–112.
7. Pureswaran, D. S.; Poland, T. M. J. Insect Behav. 2009,22, 205–216.
´
8. Bartelt, R.; Cosse, A. A.; Zilkowski, B. W.; Fraser, I. J. Chem. Ecol. 2007, 33, 1299–1302.
9. Cosse, A. A.; Bartelt, R. J. J. Chem. Ecol. 2000, 26, 1735–1748.
´
10. Boden, C. D. J.; Chambers, J.; Stevens, D. R. Synthesis 1993, 4, 411–420.
11. Crook, D. J.; Mastro, V. C. J. Chem. Ecol. 2010, 36, 101–112.
12. Vasil’ev, A. A.; Engman, L.; Merkubva, V. M. Russ. Chem. Bull., Int. Ed. 2000, 49,
1297–1300.
13. Abdukakharov, V. S.; Shakirzyanova, G. S.; Levkovich, M. G.; Abduvakhabov, A. A.
Chem. Nat. Cmps. 1997, 33, 93–96.
14. Ashmuratov, G. Y.; Ishmuratova, N. M.; Odinokov, V. N. Chem. Nat. Cmps. 1997, 33,
25–30.
15. Mori, K.; Tomioka, H. Liebig. Ann. Chem. 1992, 1011–1017.

SYNTHESIS OF (3E)-DODECEN-12-OLIDE
1377
16. Abdukakharov, V. S.; Kasymzhanova, N. M.; Shakiryanova, G. S.; Abduvakhabov, A.
A. Khim. Prirod. Soedi. 1990, 568–569.
17. Li, C.; Li, J.; Chan, T. K. Acta Chim. Sinica, Engl. Ed. 1989, 407–411.
18. Sakai, T.; Hamamoto, H.; Mori, K. Agric. Biol. Chem. 1986, 50, 1621–1627.
19. Millar, J. C.; Oehschlager, A. C.; Wong, J. W. J. Org. Chem. 1983, 48, 4404–4407.
´
20. Silk, P. J.; Ryall, K.; Mayo, P.; Lemay, M. A.; Grant, G.; Crook, D.; Cosse, A.; Fraser, I.;
Sweeney, J. D.; Lyons, D. B.; Pitt, D.; Scarr, T.; MaGee, D. Environ. Entom. 2011, 40,
904–916.
21. Litinas, K. E.; Salteris, B. E. J. Chem. Soc., Perkin Trans. 1, 1997, 2869–2872.
22. Viala, J.; Santelli, M. Synthesis 1988, 395–397.
23. Schlosser, M.; Christmann, K. F. Angew. Chem. Int. Ed. Engl. 1966, 5, 126.
24. MaGee, D. I.; Beck, E. J. J. Org. Chem. 2000, 65, 8367–8371.
25. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26–28.
26. A¨ıssa, C. Eur. J. Org. Chem. 2009, 1831–1844.
27. Al Dulayymi, J. R.; Bair, M. S.; Roberts, E.; Minnikin, D. E. Tetrahedron 2006, 62,
11867–11880.
28. Sanchez, I. P.; Turos, E. Tetrahedron: Asymmetry 2009, 20, 1646–1660.
29. Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 1287–1290.
30. Davis, F. A.; Billmers, J. M. J. Org. Chem. 1983, 48, 2672–2675.
31. Raghavan, S.; Rathore, R. Tetrahedron 2009, 10083–10092.
32. Kurihara, T.; Nakajima, Y.; Mitsunobu, O. Tetrahedron Lett. 1976, 2455–2458.
33. Justus, K.; Steglich, W. Tetrahedron Lett. 1991, 32, 5781–5784.
34. Lippmann, E.; Reifeferste, D. Zhur. Chem. 1975, 15, 146–147.