Concise synthesis of (3 Z)-dodecen-12-olide, pheromone component of the emerald ash borer

Article abstract of DOI:10.1080/00397911.2014.881497

Emerald ash borer (EAB), Agrilus planipennis Fairmaire, is an invasive insect that has killed millions of ash trees in Canada and the USA. (3Z)-Dodecen-12-olide is a known female-produced pheromone of this insect, and a concise, three-step synthesis of a

Full text of DOI:10.1080/00397911.2014.881497

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Concise Synthesis of (3Z)-Dodecen-12-
olide, Pheromone Component of the
Emerald Ash Borer
P. D. Mayo a , P. J. Silk a , D. I. MaGee b & J. McConaghy a
a Natural Resources Canada, Canadian Forest Service–Atlantic
Forestry Centre , Fredericton , New Brunswick , Canada
b Deparment of Chemistry , University of New Brunswick ,
Fredericton , New Brunswick , Canada
Accepted author version posted online: 03 Apr 2014.Published
online: 29 May 2014.
To cite this article: P. D. Mayo , P. J. Silk , D. I. MaGee & J. McConaghy (2014) Concise Synthesis of
(3Z)-Dodecen-12-olide, Pheromone Component of the Emerald Ash Borer, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:13, 1957-1969,
DOI: 10.1080/00397911.2014.881497
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Synthetic Communications1, 44: 1957–1969, 2014
Copyright # Crown Copyright
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.881497
CONCISE SYNTHESIS OF (3Z)-DODECEN-12-OLIDE,
PHEROMONE COMPONENT OF THE EMERALD
ASH BORER
P. D. Mayo,1 P. J. Silk,1 D. I. MaGee,2 and J. McConaghy1
1Natural Resources Canada, Canadian Forest Service–Atlantic Forestry
Centre, Fredericton, New Brunswick, Canada
2Deparment of Chemistry, University of New Brunswick, 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 Canada and the USA. (3Z)-Dodecen-12-olide is a
known female-produced pheromone of this insect, and a concise, three-step synthesis of a
2:1 blend of (3Z)-dodecen-12-olide and (3E)-dodecen-12-olide starting from commercially
available (2-carboxyethyl)triphenylphosphonium bromide and 10-bromo-1-decene is
described. The key steps in this synthesis are a lithium-salt-free Wittig reaction and an
intramolecular SN2 esterification. Both of these macrocyclic lactones are behaviorally
active toward EAB, and the 2:1 blend whose synthesis is described here has the potential
to be a detection agent, mating disruptor, or mass trapping agent, which could be used in
the control of EAB.
Keywords (3E)-Dodecen-12-olide; (3Z)-dodecen-12-olide; emerald ash borer; mating
disruption; pheromone
INTRODUCTION
The emerald ash borer (EAB, Agrilus planipennis Fairmaire) is an invasive
palearctic species that has killed millions of ash trees (Fraxinus spp. L.) (Oleaceae)
in North America.[1–3] Early detection of EAB infestations is difficult because visual
signs appear only after trees have been heavily infested for years.[1,4] Previous work
has shown that adult EABs respond to volatiles from girdled ash,[5] ash leaves,[4,6,7]
and Manuka and Phoebe oils,[8,9] indicating that plant semiochemicals may provide
Received November 8, 2013.
Address correspondence to P. J. Silk, Natural Resources Canada, Canadian Forest Service–
Atlantic Forestry Centre, Fredericton, NB, Canada, E3B 5P7. E-mail: Peter.Silk@NRCan-RNCan.gc.ca
1957

1958
P. D. MAYO ET AL.
a means for monitoring EAB. To this end, our laboratory has been researching the
pheromone chemistry of the EAB, in the hope that a synthetic pheromone could be
combined with a kairomone (a host-plant-produced semiochemical) as a tool for
detection, trapping, or mating disruption. Our starting point was the work of Bartelt
and coworkers, who first published the antennally active, predominantly female-
produced macrocyclic lactone 1 ((3Z)-dodecen-12-olide, Z-lactone, Scheme 1) as
a female-produced pheromone of EAB in 2007.[10]
Gas chromatography=electroantennographic detection (GC=EAD) studies in
our laboratory have shown that the excised antennae of EABs respond to both 1
and its E-isomer, (3E)-dodecen-12-olide 2 (E-lactone, Scheme 1). This is a technique
wherein the excised head of an insect is affixed to 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 electrophy-
siological responses of the antennae are correlated with the peaks from the
FID.[11] To synthesize 1, we have modified[2] and extensively used a benchmark syn-
thesis first published by Boden in 1993[12] (see Scheme 2). This synthesis gave 1 in
ꢀ97% stereochemical purity and 38% yield over eight steps. We have also previously
published a synthesis of 2 (also in ꢀ97% stereochemical purity) in 16% yield over six
steps.[1] The response of EAB antennae to both isomers of dodecen-12-olide was
noticed as a result of ꢀ3% of the E-isomer 2 being intrinsic to the synthesis of the
Z-isomer 1.[12] Extensive study in our laboratory and in the field has confirmed that
1 is emitted by female A. planipennis, confirming the work of Bartelt et al.,[10] and
also that 1 was found to increase mean catch of males on green prism sticky traps
when combined with the green leaf volatile, (3Z)-hexenol (relative to the green leaf
volatile alone), when the traps are deployed in the tree canopy.[2] For this reason, 1
could prove very useful as a mating disruption agent of EAB, provided large quan-
tities could be produced and an efficient method of delivery of 1 in the field could be
devised. The role of 2 in EAB semiochemistry is less clear, however; our own
research has shown that it is not significantly different from 1 in terms of its attract-
iveness toward male EAB in trap capture when both are combined with
(3Z)-hexenol, and in fact, 2 is more attractive than 1 toward male EAB in Y-tube
olfactometer tests.[2]
The Boden synthesis, with several modifications, was used extensively in our
laboratory to make small amounts (up to 8 g) of ꢀ97% stereochemically pure 1
Scheme 1. (3Z)-Dodecen-12-olide 1 and (3E)-dodecen-12-olide 2.

SYNTHESIS OF (3Z)-DODECEN-12-OLIDE
1959
Scheme 2. Synthesis of 1 in 38% overall yield and ꢀ97% stereochemical purity (Boden’s method with
modifications). (a) TBSCl, imidazole, DMF, rt, quantitative; (b) (i) O3, Sudan III, CH2Cl2, ꢁ78 ꢂC, (ii)
PPh3, ꢁ78 ꢂC–rt, 82%; (c) (i) NaHMDS (sodium hexamethyldisilylamide) þ 6, 0ꢂC–rt, (ii) 5þ ylide, ꢁ99 ꢂC–
rt, 90%; (d) TBAF, THF, rt, 84%: (e) TsOH, H2O, THF, reflux; (f) NaClO2, H2NSO3H, 1-methylcyclohexene,
0ꢂC–rt, 70% over two steps; (g) DEAD, PPh3, PhCH3, RT, 88%.
(see Scheme 2).[2,12] The modifications were the addition of a tert-butyldimethylsilyl
(TBS) protecting group at the beginning of the synthesis (step a), which greatly
improved the yield of the Wittig step (step c). The major advantage of this synthesis
is that all the steps are high yielding (between 80 and 100%), and 1 is obtained in very
high stereochemical purity. The major drawback of this synthesis is that it requires
eight steps. Also, the last step, which is a Mitsunobu ring closure (g), requires high
dilution, uses expensive reagents [DEAD (diethylazodicarboxylate)], and can only be
done on a small scale. These only become drawbacks when more than a relatively
small amount of 1 is needed; for an extensive EAB mating disruption study con-
ceived in our laboratory, approximately 20 g of 1 was needed. Consequently, we
relate our efforts in the formalization of a concise, convenient, and user-friendly syn-
thesis of 1, which is not as labor intensive as Boden’s synthesis. Our criteria were that
the synthesis contain a minimum number of steps, have relatively good yields, and be
easy to carry out in the laboratory.
Also, it was felt that the rate-limiting step in Boden’s synthesis of 1 was the
macrocyclization (g). As previously mentioned, an intramolecular macrocyclization
poses difficulties as, no matter the method employed, the intermolecular reaction
would compete to give a dimer, making high dilution necessary. The Mitsunobu
esterification as reported by Justus and Steglich[13] was used by Boden[12] to close

1960
P. D. MAYO ET AL.
the ring and generate 1 (Scheme 2, step g) and was used successfully by us, albeit on a
relatively small scale. We felt that, if possible, a simple, atom-efficient method such
as an intramolecular SN2 reaction would be ideal to close the ring for our purposes.
Intermolecular reaction, and hence dilution, would still be an issue; however, we felt
that the simplicity of the reaction and the inexpensive reagents for an SN2 reaction
would counter this. Two other routes to form 1 were studied first, however, and are
described here.
RESULTS AND DISCUSSION
The use of ring-closing olefin metathesis (RCOM) would seem to be an ideal
method for the synthesis of 1 in only 2 steps (Scheme 3). Diene 12 was easily
obtained by Steglich esterification[14] of 3-butenoic acid 11 and 9-decen-1-ol 3 with
dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). However,
under all conditions attempted (CH2Cl2 or tetrahydrofuran [THF] as solvent, tem-
peratures from 0 to 65 ꢂC), and with all catalysts used (see Fig. 1),[15,16] subjection
of 12 to RCOM gave a complicated, inseparable mixture of products in which 1
was only a minor component.
It is possible that the electron-withdrawing carbonyl group in diene 12 is too
close to the olefin for Ru-catalyzed RCOM to occur without competing side reac-
tions. It was noted that in all cases studied for this reaction, dimers such as 13
and 14 formed a significant amount (ꢀ40%) of the mass balance in the mixture of
products. It was our belief that dimerization, trimerization, and oligomerization in
general were too energetically favorable in the Ru-catalyzed RCOM of this system,
leading to catalyst fouling and excessive side reactions. Insulation of the ester func-
tionality from the alkenes by at least three methylene groups seems necessary for
RCOM to proceed successfully.[17]
As RCOM was impractical for both large-scale and small-scale synthesis of
1, a route that employed the Wittig step as the macrocyclization was attempted
Scheme 3. (a) DCC, DMAP, CH2Cl2, rt, quantitative; (b) [Ru], conditions; see Fig. 1.

SYNTHESIS OF (3Z)-DODECEN-12-OLIDE
1961
Figure 1. Grubbs’ first-generation ruthenium catalyst 15, Grubbs’ second-generation ruthenium catalyst
16, Hoveyda–Grubbs’ first-generation ruthenium catalyst 17, Hoveyda–Grubbs’ second-generation
ruthenium catalyst 18, and dichloro(3-methyl-2-butenylidene)bis(tricyclohexylphosphine)ruthenium (II) 19.
(unsuccessfully) and is outlined in Scheme 4. The DCC and DMAP coupling of 20
and 3 gave iodide 21 in only 8% yield (most of 3 was converted into 22b). Regardless
of the poor yield, ozonolysis of 21 with reductive workup gave 23 in 75% yield. The
Wittig salt 24 was presumably formed by refluxing 23 with PPh3 in THF for 10 days
(as monitored by thin-layer chromatography, TLC); then the reaction mixture was
cooled to ꢁ78 ꢂC and NaHMDS (sodium hexamethyldisilylamide) was added. After
warming to rt and stirring for 16 h, neither Z-lactone 1 or E-lactone 2 were isolated.
Assuming successful formation of 24, only removal of Ha by NaHMDS would give
rise to the desired ylide, which in turn could react intramolecularly with the aldehyde
Scheme 4. (a) DCC, DMAP, CH2Cl2, rt, 8% yield of 21, the major by-product being 22b, whose yield was
not determined; (b) (i) O3, Sudan III, CH2Cl2, ꢁ78 ꢂC (ii) PPh3, ꢁ78 ꢂC–rt, 75%; (c) PPh3, THF, reflux;
(d) NaHMDS, ꢁ78 ꢂC–rt, one pot; no product 1 was obtained.

1962
P. D. MAYO ET AL.
and give lactone 1 or 2. There are still two other protons (Hb and Hc) in 24 that are
acidic enough to be removed by NaHMDS; removal of either of these would not lead
to the desired product 1. It is likely that this is, in fact, what occurred.
Although attempts to form the macrocycle via intramolecular Wittig reaction
were unsuccessful, attention was still focused on a Wittig reaction to build the back-
bone of 1. To this end, Wittig salt 25a was prepared from commercially available
3-iodopropionic acid 20 and triphenylphosphine (Scheme 5). This was accomplished
by refluxing 20 and PPh3 in various solvents until TLC showed complete consumption
of starting materials (see Table 1). The formation of the Wittig salt 25a was slow, and
also, subsequent Wittig reaction in the same pot using NaHMDS as the base and alde-
hyde 26a proved capricious, sometimes giving poor yield or no product (27a) at all (see
Table 1; also see experimental for a general procedure).
However, the commercial availability of (2-carboxyethyl)triphenylphospho-
nium bromide 25b (Scheme 5) rendered Wittig salt synthesis unnecessary and led
to much improved yield and ease of reaction in the Wittig step to give 27a, b, or
c. Indeed, the use of 25b has been reported previously in the synthesis of Ferrulac-
tone II[18] [(S, Z)-dodec-3-en-11-olide, 28, Scheme 5] in a Wittig reaction similar to
that employed by us (Scheme 5). As THF gave the best Z-selectivity in the product
Scheme 5. (a) PPh3, solvent, reflux (see Table 1); (b) (i) NaHMDS, one pot, 0 ꢂC–rt; (ii) 26a, ꢁ78 ꢂC–rt;
see Table 1 for yield and Z=E ratio of product 27a; (c) (i) NaHMDS, THF, 0 ꢂC–rt; (ii) 26a, 26b, or 26c,
ꢁ78 ꢂC–rt; 70% yield for 27a, 67% for 27b, 61% for 27c.

SYNTHESIS OF (3Z)-DODECEN-12-OLIDE
1963
Table 1. Wittig reaction of 25a (generated in situ from 20 and PPh3 in the specified solvent) with
NaHMDS as base and with aldehyde 26a to give bromoacid 27a; see Scheme 5
Entry
Solvent
Yield (%) of 27a
Z=E ratio
Time required for formation of 25a
1
2
3
4
5
Toluene
1,2-DMEa
THF
35
16
30
0
1:1.6
1:4
24 h
4 d
4 d
3 d
3 d
1.6:1
n=a
n=a
Benzene
EtOHb
0
aSee Experimental section for in situ formation of 25a and subsequent Wittig reaction in 1,2-DME.
bEtOH was removed in vacuo after formation of 25a was complete, and THF was added as the solvent
for the subsequent Wittig reaction.
27a when the Wittig salt 25a was synthesized in situ (Table 1, entry 3), this solvent
was used in subsequent Wittig reactions with commercially available 25b. For
aldehydes 26a, b, and c, yields of 70%, 67%, and 61%, respectively, were obtained
for the Wittig reaction using 25b as the Wittig salt, THF as the solvent, and
NaHMDS as the base (Scheme 5). A straightforward intramolecular SN2 reaction
of 27a using potassium carbonate (K2CO3) as base, potassium iodide (KI) as promoter,
and refluxing acetone as solvent yielded a 2:1 mixture of 1:2 in good yield (82%,
Scheme 6). A small amount (ca. 10%) of dimer 13 was formed as expected by inter-
molecular SN2 reaction between two molecules of 27a followed by an intramolecular
SN2 reaction of the dimer.
Iodoaldehyde 26b could be used in the Wittig step to give iodoacid 27b
(Scheme 5), which cyclized in the same fashion as 27a to a mixture of 1 and 2 in simi-
lar yield (72%) and Z=E selectivity (2:1), but without the KI promoter (Scheme 6).
Dimer 13 was formed in ca. 10% of the overall yield whether 27a or b was cyclized.
Acetal 27c could also be obtained in a Wittig reaction employing Wittig
salt 25b and aldehyde 26c in similar yield (61%) and Z=E (2:1) selectivity to acids
27a and b (Scheme 5). The hydroxyl group of 27c can then be unmasked with hydro-
chloric acid in wet THF (quantitative yield) to give 10, and the Mitsunobu
conditions as reported by Boden et al.,[12] using diisopropylazodicarboxylate
Scheme 6. (a) K2CO3, KI (only for 27a), acetone, reflux; 82% yield of 1 þ 2 for 27a; 72% for 27b.

1964
P. D. MAYO ET AL.
Scheme 7. (a) HCl, H2O, THF, rt, quantitative; (b) DIAD, PPh3, PhCH3, rt, 84% yield of 1 þ 2.
(DIAD) instead of DEAD, readily forms the lactone as a mixture of Z and E isomers
1 and 2 (84% combined yield) as well as a small amount of the dimer 13 (ca. 5%,
Scheme 7).
Aldehydes 26a, b, and c are readily prepared in two steps from commercially
available 9-decen-1-ol 3 (see Scheme 8; the yields of 22a, b, and c were 100%,
100%, and 98%, respectively, and the yields for the ozonolysis of 22a into 26a, 22b
into 26b, and 22c into 26c were 100%, 92%, and 93%, respectively). The commercial
availability of 22a makes 26a obtainable in only one step.
The success of the intramolecular SN2 reaction in the conversion of 27a or b
into a mixture of 1 and 2 (82% and 72% yields, respectively) could be due to the fact
that the leaving group (bromide or iodide ion) is on an sp3 carbon, and the negatively
charged carboxylate acts as the nucleophile. This is similar to Mitsunobu conditions
in that, under Mitsunobu conditions, the hydroxyl on the terminal sp3 carbon of 10
is converted into a leaving group (in the case of the Mitsunobu reaction, triphenyl-
phosphine oxide), and the carboxylic acid on the other terminus of the molecule
acts as the nucleophile. This is in contrast to more typical Steglich conditions for
Scheme 8. (a) CBr4, PPh3, CH2Cl2, 0 ꢂC, quantitative; (b) I2, PPh3, imidazole, 1:3 CH3CN–Et2O,
rt, quantitative; (c) ethyl vinyl ether, PPTS, CH2Cl2, rt, 98%; (d) (i) O3, Sudan III, CH2Cl2, ꢁ78 ꢂC,
(ii) PPh3, ꢁ78 ꢂC–rt, quantitative yield for 26a, 92% for 26b, 93% for 26c.

SYNTHESIS OF (3Z)-DODECEN-12-OLIDE
1965
esterification of a hydroxyacid (DCC, DMAP)[13,14] in which the carboxyl group is
activated, and the hydroxyl on the other end of the molecule acts as the nucleophile.
In conclusion, a user-friendly, concise, three-step synthesis of a 2:1 mixture of
Z=E lactones 1 and 2 was developed in an overall yield of 57% from commercially
available 25b [(2-carboxyethyl)triphenylphosphonium bromide] and commercially
available 10-bromo-1-decene 22a. The key steps in this synthesis are a Wittig
reaction to form the 12-carbon backbone of 1 and an intramolecular SN2 reaction
to close the ring. The major drawback of this synthesis is that 1 and 2 are synthesized
as an inseparable, 2:1 mixture; however, as previously mentioned, 2 has attractive-
ness comparable to 1 for male EAB, and so the mixture of 1 and 2 could conceivably
disrupt EAB mating as effectively as pure 1. Field tests of the efficacy of this mixture
for the mating disruption of EAB are pending.
EXPERIMENTAL
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 suppliers and directly used
without further purification. Analytical thin-layer chromatography (TLC) was
performed using Whatman TLC plates, precoated with 0.25 mm of UV254 silica
gel on aluminum backing. Visualization was done by dipping the TLC plate in
potassium permanganate solution, followed by baking on a hot plate. Flash column
chromatography was performed using a glass column filled with 230- to 400-mesh
Silia Flash F60 silica gel from Silicycle unless otherwise specified. Reagent-grade
solvents were used without further purification. All compounds purified by SiO2
chromatography were greater than 98% pure as determined by GC=MS and=or
NMR. Synthetic compounds were characterized by GC=MS on an Agilent 6890
GC and an Agilent 5973 mass selective detector in the electron impact (unit resolution,
EI, 70eV) mode. For all analyses, we employed a temperature program of 70ꢂC for
2 min and then increased the temperature in increments of 10ꢂC=min until the oven
temperature reached 220 ꢂC, which was then maintained for 25min. A Zebron ZB-
5MS Inferno capillary GC column (Phenomenex, Torrance, CA; 30m, 0.25mm id,
0.25-mm film) was used for all analyses. NMR spectroscopy (1H and 13C) was carried
out on a Varian Unity 400-MHz spectrometer or a Varian Innova 300-MHz spec-
trometer in CDCl3, with tetramethylsilane (TMS) as internal standard, with chemical
shifts reported in parts per million (ppm) (d). Infrared (IR) spectra were recorded
on a Varian 640-IR FT-IR spectrometer. High-resolution mass spectra (HRMS) were
obtained at Dalchem Mass Spectrometry Laboratory in Halifax, NS, Canada.
Synthesis of 25a
A round-bottomed flask was charged with iodoacid 20 (5.12 g, 25.6 mmol),
1,2-dimethoxyethane (DME, 60.0 mL), and triphenylphosphine (6.74 g, 25.7 mmol).
The reaction mixture was heated at reflux for 4 d. Thin-layer chromatography (TLC)
was used to monitor the reaction’s progress. Upon completion, the mixture of Wittig
salt 25a in DME was used directly in the subsequent Wittig step to make 27a.

1966
P. D. MAYO ET AL.
Synthesis of 27a via 25a
Compound 25a (25.6 mmol) in DME was cooled to 0 ꢂC, and sodium hexam-
ethyldisilylamide (NaHMDS, 60.0 mL, 1.0 M in THF, 60.0 mmol) was added drop-
wise over 6 min. The reaction mixture was stirred at 0 ꢂC for 30 min, warmed to rt,
stirred for 75 min, and then cooled to ꢁ78 ꢂC. Aldehyde 26a (3.89 g, 17.6 mmol) in
THF (2 mL) was added via syringe with rinsing (2 ꢃ 2.0 mL THF). The reaction
was allowed to warm to rt over 1 h and stirred at rt for 20 h. Saturated aqueous
NH4Cl (100 mL) was added, the layers were separated, and the aqueous layer was
extracted with diethyl ether (3 ꢃ 80 mL). The combined organic layers were washed
with brine (100 mL) and dried (MgSO4). Column chromatography on silica gel (80%
EtOAc=hexanes as eluent) yielded bromoacid 27a (1:4 Z=E) as a colorless, trans-
parent liquid (730 mg, 2.64 mmol, 15%).
Synthesis of 27a via Commercially Available 25b
A round-bottomed flask was charged with 25b (5.07 g, 12.2 mmol) and THF
(60 mL) and cooled to 0 ꢂC. NaHMDS (25.0 mL, 1.0 M in THF, 25.0 mmol) was
added dropwise over 5 min. The reaction was stirred at 0 ꢂC for 1 h, warmed to rt,
and stirred for 2 h. After cooling to ꢁ78 ꢂC, aldehyde 26a (2.63 g, 11.9 mmol) in
THF (3.0 mL) was added via syringe with rinsing (2 ꢃ 3.0 mL THF). The reaction
was allowed to warm to rt over 1 h and then stirred for 17 h. Saturated aqueous
NH4Cl (100 mL) was added, the layers were separated, and the aqueous layer was
extracted with diethyl ether (3 ꢃ 40 mL). The combined organic layers were washed
with brine (100 mL) and dried (MgSO4). Column chromatography on silica gel
(EtOAc as eluent) yielded bromoacid 27a (2:1 Z=E) as a colorless, transparent liquid
(2.30 g, 8.30 mmol, 70%). Rf ¼ 0.27 (1:2 EtOAc=hexanes). 1H NMR (CDCl3,
300 MHz): d 5.59 (m, 2H), 3.44 (t, 2H, J ¼ 6.8 Hz), 3.16 (d, 1.34H, J ¼ 6.2 Hz),
3.10 (d, 0.66H, J ¼ 6.0 Hz), 2.06 (m, 2H), 1.88 (p, 2H, J ¼ 6.9 Hz), 1.32–1.47 (m,
10H), OH proton not seen. 13C NMR (CDCl3, 100 MHz): d 177.9, 177.8, 135.4,
134.0, 120.8, 120.0, 34.02, 33.99, 32.79, 32.78, 32.4 (two signals), 29.23, 29.21,
29.16, 29.1, 29.00, 28.96, 28.7 (two signals), 28.1 (two signals), 27.3 (two signals).
IR (neat, cmꢁ1): 2926 (br, s), 2854 (m), 1709 (s), 1462 (w), 1434 (m), 1292 (w),
1250 (s), 1218 (m), 1180 (w), 1089 (w), 1045 (m). HRMS for 27a: Calc. for
C12H12017Ag79BrO2: 382.9770. Found: 382.9754. Difference: 4.18 ppm.
Ring Closure of 27a
A round-bottomed flask was charged with 27a (1.06 g, 3.83 mmol), acetone
(500 mL), K2CO3 (640 mg, 4.63 mmol), and KI (1.10 g, 6.63 mmol). The reaction
mixture was heated to reflux for 4 d, and then cooled to rt. After ꢀ90% of the solvent
was removed in vacuo, H2O (40 mL) was added, and the mixture was extracted with
hexanes (6 ꢃ 30 mL). The combined extractions were washed with brine (100 mL)
and dried (MgSO4). Column chromatography with a Buchi 660 fraction collector
on silica gel (25 g) with a solvent gradient of 0 to 7% EtOAc=hexanes over 20 min
and then removal of the solvent in vacuo yielded lactones 1 and 2 in a 2:1 ratio as
an inseparable mixture, and a small amount of the dimer 13 (ꢀ10% of the total
yield). The mixture of 1 and 2 was a colorless, transparent liquid (619 mg, 3.16 mmol,

SYNTHESIS OF (3Z)-DODECEN-12-OLIDE
1967
82%). Rf ¼ 0.27 (1:20 EtOAc=hexanes). For spectral data of 1 and 2, see Refs. 12 and
1, respectively.
Synthesis of 10
A round-bottomed flask was charged with 27c (2.14 g, 7.48 mmol), THF
(80 mL), and 2 M HCl (aqueous) (5.0 mL). After stirring at rt for 40 min, H2O
(20 mL) was added, and the mixture was extracted with diethyl ether (4 ꢃ 20 mL).
The combined extractions were washed with brine (100 mL) and dried (MgSO4) to
give hydroxyacid 10 (1.60 g, 7.48 mmol, 100%) as a white solid. See Refs. 12 and 1
for the spectral data of Z-10 and E-10, respectively. Compound 10 was used without
further purification in the Mitsunobu ring closure reported by Boden et al. in 1993
and MaGee et al. in 2013[12,1] to give a 2:1 mixture of 1 and 2 in 84% yield, as well as
ꢀ5% of the dimer 13.
Synthesis of 22a
A round-bottomed flask was charged with 9-decen-1-ol 3 (10.0 g, 64.1 mmol)
and CH2Cl2 (300 mL) and cooled to 0 ꢂC. Triphenylphospine (21.8 g, 83.1 mmol)
and CBr4 (27.6 g, 83.2 mmol) were added, and the mixture was allowed to warm
to rt over 1 h and stirred for 14 h. Column chromatography on silica gel with hexanes
as eluent, and then removal of the solvent in vacuo, yielded bromide 22a (14.0 g,
63.9 mmol, 100%) as a colorless, transparent liquid. Spectral data matched that of
the authentic commercially available sample.
Synthesis of 22b
A round-bottomed flask was charged with 9-decen-1-ol 3 (5.0 g, 32.1 mmol),
diethyl ether (133 mL), CH3CN (67 mL), imidazole (3.27 g, 48.1 mmol), triphenylpho-
sphine (10.1 g, 38.5 mmol), and iodine (13.0 g, 51.3 mmol). The reaction was stirred at
rt for 4 h. Then H2O (150 mL) was added, the layers were separated, and the aqueous
layer was extracted with diethyl ether (3 ꢃ 60 mL). The combined organic layers were
washed with brine (100 mL) and dried (MgSO4). Column chromatography on silica gel
with hexanes as eluent and then removal of the solvent in vacuo yielded iodide 22b
1
(8.50 g, 32.0 mmol, 100%) as a colorless, transparent liquid. Rf ¼ 0.66 (hexanes). H
NMR (CDCl3, 300 MHz): d 5.82 (m, 1H), 4.92–5.05 (m, 2H), 3.20 (t, 2H, J ¼ 7.0 Hz),
2.05 (m, 2H), 1.85 (p, 2H, J ¼ 7.0 Hz), 1.32–1.45 (m, 10H). 13C NMR (CDCl3,
100 MHz): d 138.9, 114.1, 33.7, 33.5, 30.4, 29.2, 28.9, 28.8, 28.4, 7.1. IR (neat, cmꢁ1):
3075 (w), 2924 (s), 2852 (s), 1823 (w), 1640 (m), 1461 (m), 1435 (m), 1267 (w), 1192
(m), 1168 (m). MS (EI, 70 eV) (main peaþks): m=z 55 (base peak), 69, 83, 97, 127, 141,
155, 169, 183, 196, 210, 224, 266 (M ). HRMS for 22b: calc. for C10H11907AgI:
372.9577. Found: 372.9571. Difference: 1.61ppm.
Synthesis of 22c
A round-bottomed flask was charged with 9-decen-1-ol 3 (1.76 g, 11.2 mmol),
CH2Cl2 (100 mL), ethyl vinyl ether (EVE) (2.0 mL, 20.9 mmol), and pyridinium
p-toluenesulfonate (276.3 mg, 1.10 mmol). The reaction mixture was stirred at rt

1968
P. D. MAYO ET AL.
for 16 h, water (50 mL) was added, the layers were separated, and the aqueous layer
was extracted with CH2Cl2 (2 ꢃ 40 mL). The combined organic layers were washed
with brine (50 mL) and dried (MgSO4). Column chromatography (20% EtOAc=hex-
anes) yielded 22c (2.50 g, 11.0 mmol, 98%) as a colorless, transparent liquid,
1
Rf ¼ 0.52 (1:9 EtOAc=hexanes). H NMR (CDCl3, 400 MHz): d 5.78 (m, 1H), 5.24
(m, 1H), 4.94 (m, 1H), 4.65 (q, 1H, J ¼ 5.3 Hz), 3.33–3.68 (m, 4H), 1.98–2.07 (m,
2H), 1.49–1.60 (m, 2H), 1.25–1.40 (m, 13H), 1.20 (t, 3H, J ¼ 7.0 Hz). 13C NMR
(CDCl3, 100 MHz): d 139.2, 114.2, 99.6, 65.3, 60.7, 33.9, 30.0, 29.51, 29.49, 29.1,
29.0, 26.3, 19.9, 15.4. IR (KBr windows) cmꢁ1: 3077 (m), 2976 (s), 2927 (s), 2847
(s), 1641 (s), 1459 (s), 1443 (s), 1380 (s), 1339 (s), 1270 (w), 1153 (br, s), 1052 (s).
MS (EI) major peaks: 55, 73 (base peak), 83, 97, 183, 213, 227 (Mþ ꢁ 1). HRMS
for 22c: Calc. for C14H28NaO2: 251.1982. Found: 251.1979. Difference: 1.19 ppm.
Synthesis of 26a
A round-bottomed flask was charged with 22a (10.0 g, 45.7 mmol), dichloro-
methane (200 mL), and Sudan III (50.0 mg) and then cooled to ꢁ78 ꢂC. Ozone
was bubbled through until the red color of the Sudan III was discharged. Then, oxy-
gen was bubbled through for 30 min at ꢁ78 ꢂC, triphenylphosphine (12.0 g,
45.7 mmol) was added, and the reaction was allowed to warm to rt over 1 h and then
stirred for 14 h at this temperature. The solvent was removed in vacuo. Column
chromatography on silica gel with 20% EtOAc=hexanes as eluent, then removal of
the solvent in vacuo, yielded bromoaldehyde 26a (10.2 g, 46.1 mmol, 100%) as a col-
orless, transparent liquid. Rf ¼ 0.27 (1:20 EtOAc=hexanes). 1H NMR (CDCl3,
300 MHz): d 9.67 (m, 1H), 3.32 (t, 2H, J ¼ 6.8 Hz), 2.34 (td, 2H, J ¼ 7.3, 1.8 Hz),
1.77 (p, 2H, J ¼ 6.7 Hz), 1.54 (m, 2H), 1.24–1.39 (m, 8H). 13C NMR (CDCl3,
100 MHz): d 202.4, 43.5, 33.7, 32.4, 28.8, 28.7, 28.2, 27.7, 21.6. IR (neat, cmꢁ1):
2928 (s), 2854 (s), 2719 (w), 1721 (s), 1462 (m), 1438 (m), 1409 (w), 1390 (w), 1250
(w), 1113 (m), 1027 (w). MS (EI, 70 eV) (main peaks): m=z 55 (base peak), 57, 67,
69, 81, 95, 97, 107, 109, 113, 123, 135, 357, 148, 150, 160, 162, 176, 178, 192, 194,
202, 204, 219 (Mþ– 1, 79Br), 221 (Mþ– 1, 81Br). HRMS for 26a: Calc. for
C9H7197BrNaO: 243.0355. Found: 243.0346. Difference: 3.70 ppm.
ACKNOWLEDGMENT
We thank Matt Brophy for technical assistance.
FUNDING
We are grateful to Natural Resources Canada and the Atlantic Innovation
Fund (AIF, Atlantic Canada Opportunities Agency) through SERG-I for funding
this research. All experiments reported here comply with the laws of Canada.
SUPPLEMENTAL MATERIAL
1
Full experimental details and H and 13C NMR spectra for this article can be
accessed on the publisher’s website.

SYNTHESIS OF (3Z)-DODECEN-12-OLIDE
1969
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