Synthesis of chiral alkenyl epoxides: The sex pheromone of the elm spanworm Ennomus subsignaria (Hübner) (Lepidoptera: Geometridae)

Article abstract of DOI:10.1016/j.tet.2011.05.015

The identification of the sex pheromone of the elm spanworm Ennomos subsignaria (Hübner), as the chiral alkenyl epoxide (6Z)-cis-9,10-epoxy- nonadecene has been accomplished. Both enantiomers of (6Z)-cis-9,10-epoxy- nonadecene have been synthesized via two routes. The key steps in the first route were to prepare both threo-epoxy tosylates and then to perform an alkylative rearrangement of these intermediates to obtain the target molecules. An alternative enantioenriched synthesis that took advantage of the Sharpless dihydroxylation reaction was developed so that a common starting material could be used to access both enantiomers. A field study and GC/EAD testing indicated that Z6-cis-9S,10R-epoxy-nonadecene was the sex pheromone of the elm spanworm E. subsignaria (Hübner).

Full text of DOI:10.1016/j.tet.2011.05.015

Tetrahedron 67 (2011) 5329e5338
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of chiral alkenyl epoxides: the sex pheromone of the elm spanworm
€
Ennomus subsignaria (Hubner) (Lepidoptera: Geometridae)
,
b
a,
David I. MaGee a , Peter J. Silk , Junping Wu b, Peter D. Mayo b, Krista Ryall c
*
a Department of Chemistry, University of New Brunswick, PO Box 4400, Fredericton, N.B., Canada E3B 5A3
b Canadian Forestry Service-Atlantic Forestry Centre, Natural Resources Canada, PO Box 4000, Fredericton, N.B., Canada E3B 5P7
c Natural Resources Canada, Great Lakes Forestry Centre, 1219 Queen Street East, Sault Ste Marie, ON, Canada P6A 2E5
a r t i c l e i n f o
a b s t r a c t
Article history:
€
The identification of the sex pheromone of the elm spanworm Ennomos subsignaria (Hubner), as the
chiral alkenyl epoxide (6Z)-cis-9,10-epoxy-nonadecene has been accomplished. Both enantiomers of
(6Z)-cis-9,10-epoxy-nonadecene have been synthesized via two routes. The key steps in the first route
were to prepare both threo-epoxy tosylates and then to perform an alkylative rearrangement of these
intermediates to obtain the target molecules. An alternative enantioenriched synthesis that took ad-
vantage of the Sharpless dihydroxylation reaction was developed so that a common starting material
could be used to access both enantiomers. A field study and GC/EAD testing indicated that Z6-cis-9S,10R-
Received 24 January 2011
Received in revised form 4 May 2011
Accepted 5 May 2011
Available online 12 May 2011
Keywords:
Sex pheromone
Elm spanworm
Alkylative rearrangement
Asymmetric synthesis
Enantioenriched epoxides
Sharpless asymmetric dihydroxylation
€
epoxy-nonadecene was the sex pheromone of the elm spanworm E. subsignaria (Hubner).
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
component blends of unsaturated hydrocarbons and/or epoxides
with enantiospecificity often found to be critical to bioactivity and
The elm spanworm, Ennomos subsignaria (Hubner), occurs
across Canada and the eastern United States and, most recently, has
appeared at damaging levels in Newfoundland (NL). Its common
name is misleading because it is a general feeder on a wide range of
deciduous trees, mostly hickory (Caryra), ash (Fraxinus), oak
(Quercus), red maple (Acer rubrum), elm (Ulmus), basswood (Tilia),
beech (Fagus) and horse-chestnut (Aesculus) species.1,2 Larvae pu-
pate on the leaves after about 30 days in netlike cocoons. Snow-
white adults emerge from late July to August and lay eggs in
clutches that over-winter on the underside of twigs. This insect can
be a destructive forest pest particularly in the southern Appala-
chians where severe outbreaks have occurred.3,4
Recently, relationships between egg or larval density and end-
of-season defoliation were established,5 but a means of detecting
and predicting outbreaks earlier would be very useful and a trap-
ping system involving the sex pheromone would have improved
detection sensitivity and sampling efficiency.
for species isolation.8 Most insect pheromones are volatile and
usually obtained in extremely small quantities, ranging from sev-
€
eral ng to several mg, thus it is often difficult to unequivocally de-
termine their structure. Our objective was then to identify the sex
pheromone of E. subsignaria as a tool for further study of its ecology
and phenology, and for detection and delimitation surveys. If suc-
cessful, then it is expected that the sex pheromone may then be
useful for controlling future outbreaks using mating disruption or
mass trapping techniques.
In 1973, Granett reported that female elm spanworm adults
release a male-attracting pheromone,10 but he did not report the
structure of the pheromone. In the Geometridae, it is common for
their pheromones to be oxygenated hydrocarbons, usually mono-
epoxides, with carbon chain lengths from C-17 to C-21.7 We have
recently reported the identification of the sex pheromone of the
elm spanworm6 using GC/MS (gas chromatography-mass spec-
trometry), GC/EAD (gas chromatography-electroantennographic
detection) and field trapping. Our results indicated that the EAD-
active compound was (6Z)-cis-9,10-epoxy-nonadecene 1, Fig. 1.
The retention time, elution order and the EI-mass spectra of the
compounds in the extracts were identical to those produced from
authentic racemic synthetic compounds, obtained by nonselective
m-CPBA oxidation of (6Z,9Z)-nonadeca-6,9-diene, and confirmed
Sex pheromones or attractants have been identified for >120
geometrids but none have been published for the genus
Ennomos.7e9 The pheromones usually consist of single or multi-
* Corresponding author. E-mail address: dmagee@unb.ca (D.I. MaGee).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.015

5330
D.I. MaGee et al. / Tetrahedron 67 (2011) 5329e5338
by hydrogenation and functional group manipulation. Aldehyde 3
is easily accessed from -dimethyl tartrate, 4. For generation of the
enantiomer a similar route could be followed from alcohol 5 to
epoxide 1(9R,10S). Generation of 5 could be accomplished by
stereoselective reduction of ketone 6 followed by epoxide forma-
tion. Finally, 6 is easily arrived at from the 1,2: 5,6-diacetonide of
O
1
H
H
L
Fig. 1. Structure of the elm spanworm E. subsignaria female sex pheromone.
D-mannitol, 7.
An alternative to this approach uses the Sharpless asymmetric
against data previously reported by Millar in 2000.7 Since it has
been shown that insect chemoreception can be highly enantiose-
lective and poor enantiomeric purity can present a problem when
studying biological activities, the preparation of chiral epoxides in
high enantiomeric purity may be crucial for developing a monitor-
ing tool for this insect. Therefore, the goal became to synthesize
both enantiomers of the cis-epoxides of (6Z)-9,10-epoxy-non-
adecene in as highly stereoefficient manner as possible.
dihydroxylation reaction, Scheme 2.10,18 Use of the commercially
available AD-mix
b would generate the threo-diol 9. Conversion
of this diol to epoxides 8 and 10 sets the stage for producing the
two enantiomers of the alkene/epoxide by taking advantage of
chemistry learned from the alkylative rearrangement route. The
advantage of this route is clearly the ability of being able to use
a common starting material 9; however, there was a concern as to
how enantio-efficient the Sharpless AD would be.
2. Proposed synthetic routes
3. Results and discussion
Examination of the literature revealed several strategies for the
synthesis of epoxides in enantiomerically enriched or enantio-
merically pure forms.7,10e16 Given this background it appeared that
there were two approaches that would satisfy our requirement for
high enantioselectivtiy. Using a ‘chiral pool’ approach, we could
rely on the ‘alkylative rearrangement’ strategy first outlined by Bell
and Ciaccio.17 In their studies they showed that threo- and erythro-
1,2-epoxy-3-alkanols could efficiently be generated from such
readily available natural sources as tartaric acid, sugars, etc. Con-
sequently, a retrosynthetic analysis evolved as shown in Scheme 1.
Treating epoxide 2 with 1-heptyne followed by reduction to the
Z-alkene, enantiomer 1(9S,10R) would be generated. Epoxide 2
could be arrived at from aldehyde 3 via a Wittig reaction followed
As outlined in Scheme 1, the synthesis of threo-(2S,3S)-epoxy
alcohol 2 was initiated by the employment of commercially avail-
able
L-(þ)-dimethyl tartrate as a chiral template. To begin,
L-
(þ)-dimethyl tartrate 4 was treated with acetone, triethylortho-
formate and 6 M HCl in DMF at room temperature for 72 h to gen-
erate the acetonide, Scheme 3. Conversion of the acetonide to diol 13
proceeded uneventfully by treatment with LAH inTHF at 0 ꢀC. While
numerous methods have been developed for the selective pro-
tection of unsymmetric diols, for example, protection of a primary
alcohol in the presence of a secondary alcohol, the selective
monoprotection of symmetric diols still presents a problem.19 Re-
cently, McDougal and co-workers20 devised a simple method for the
selective mono-silylation of symmetrical primary diols. Importantly
O
H
O
O
OH
OH
HO
H
H
O
C9H19
C5H11
CHO
C9H19
MeO2C
CO2Me
OTBS
1(9S,10R)
4
2
3
O
H
H
OH
C9H19
O
H
O
O
O
HO
O
C9H19
C5H11
O
C9H19
O
1(9R,10S)
6
5
7
OH
O
Scheme 1. Retrosynthetic analysis for the synthesis of the two enantiomers of (6Z)-cis-9,10-epoxy-nonadecene using the alkylative rearrangement strategy.
Scheme 2. Retrosynthetic analysis for the synthesis of the two enantiomers of (6Z)-cis-9,10-epoxy-nonadecene using the Sharpless AD reaction.

D.I. MaGee et al. / Tetrahedron 67 (2011) 5329e5338
5331
Scheme 3. Synthesis of (6Z)-cis-9S,10R-epoxy-nonadecene. Reagents and conditions: (a) CH3COCH3, CH(OC2H5)3, 6 M HCl in DMF, rt, 72 h, 88%; (b) LAH, THF, 0 ꢀC, 1 h, 80%; (c)
TBSCl, NaH, THF, rt, 3 h, 85%; (d) (COCl)2, DMSO, Et3N, CH2Cl2, ꢁ78 ꢀC, 99%; (e) CH3(CH2)7PPh3
þ
Brꢁ, n-BuLi, THF, ꢁ78 ꢀC to rt, 16 h, 73%; (f) TBAF, THF, 1 h, 86%; (g) cat. 30% Pd/C, H2,
MeOH, 93%. (h) TsCl, pyridine, 0 ꢀCe5 ꢀC, 72 h, 94%; (i) 1% methanolic HCl, 5 h, 82%; (j) K2CO3, MeOH, 0 ꢀCdrt, 1 h, 83%; (k) TsCl, KOH, Et2O, 2.5 h, 81%; (l) 1-heptyne, n-BuLi,
BF3$Et2O, ꢁ78 ꢀC, THF; (m) K2CO3, MeOH, 0 ꢀC to rt, 1 h, 78% over two steps; (n) cat. 5% Pd/CaCO3 poisoned with lead, C9H7N, H2, 2 h, 93%.
this method makes efficient use of both the diol and protecting
reagent.
presence of a small amount of quinoline produced cis-epoxide 1
(9S,10R). While the sequence was lengthy (14 steps) it did allow for
the synthesis of the presumed pheromone with high optical purity
(>93.4%) and an overall yield of 13%.
With this report as a guide, diol 13 was treated with TBSCl in the
presence of 1 equiv of NaH to give mono-silyl alcohol in an ex-
ceptional 85% yield. It is believed that the success of this reaction
lies in the relative insolubility of the mono-sodium salt of 13, thus
effectively removing any excess base. In addition, it is believed that
as the reaction proceeds, silylation of the small amount of alkoxide,
that is, in solution is faster than proton transfer between the alk-
oxide and product alcohol.
The synthesis of threo-(2R,3R)-epoxy alcohol 5 began with
1,2:5,6-di-O-isopropylidene- -mannitol 7 as the chiral template,
D
Scheme 4. Oxidative cleavage of 7 with sodium metaperiodate25
afforded the sensitive (R)-glyceraldehyde acetonide in 78% yield.
Immediate Grignard addition of nonylmagnesium bromide to this
aldehyde afforded a mixture of erythro and threo alcohols, de-
termined to be 6:1 by GC analysis. It should be noted that although
the diastereomeric ratio was acceptable it was the undesired ste-
reoisomer that was produced in excess. To reverse this, the mixture
of alcohols was oxidized under Swern conditions to smoothly gen-
erate ketone 6. Reduction of the ketone with L-Selectride produced
alcohol 16 as a threo to erythro ratio of 8:1. In this nucleophilic ad-
dition reaction, the process does not proceed via a chelate-con-
trolled26 addition, but rather appears to follow a normal Felkin
model.27 The inhibition of chelate-controlled addition may be
a consequence of several factors, including: (a) a significant ring
strain which develops in the derived chelate structure, (b) a de-
pressed donor ability of the acetonide oxygen, relative to an ether
oxygen, due to an inductive electron withdrawal, and (c) steric in-
hibition to chelate formation due to non-bonded interactions be-
tween the metal ligands and the acetonide methyl group.
Oxidation of the alcohol to the corresponding aldehyde under
Swern conditions21 generated aldehyde 3 in near quantitative yield.
Wittig coupling of
3 with the ylide derived from 1-octyl-
triphenylphosphonium bromide gave predominantly the Z-alkene.
The Z/E ratio was determined by GC to be 30:1, however, this was
inconsequential since the olefin was going to be reduced. To fully
complete incorporation of one half of the molecule the E/Z mixture
of alkenes was treated with TBAF, to remove the silyl protecting
group, followed by catalytic hydrogenation to give alcohol 14.
With one half of the target pheromone now constructed, the
stage was set to incorporate the remaining 7-carbon chain. This
began by tosylation of the primary alcohol followed by acid-
catalyzed deacetalization to liberate the protected alcohols.
Ensuing treatment of the diol with potassium carbonate afforded
threo-(2S,3S)-1,2-epoxy-3-dodecanol 2. At this point the optical
purity was assessed to be 93.4% ee as determined by chiral GC after
making the derivative of compound 2 using (S)-(ꢁ)-2-acetoxy-
propionyl chloride.22
To set the final stage for introduction of the 7-carbon chain, the
alcohol was converted to its tosylate by treatment with TsCl in the
presence of KOH in Et2O.23 It should be noted that an acceptable
yield of tosylate was only accomplished by using this non-
traditional method. When the more standard protocol was used
(pyridine, TsCl, CH2Cl2, 0 ꢀCdrt, 72 h) only low yields (<20%) and
complex reaction mixtures were obtained. The tosylate was treated
with 1-lithio-1-heptyne and boron trifluoride etherate,24 to gen-
erate alkynyl alcohol 15. Although this compound was reasonably
stable, no attempts were made to purify it, rather it was directly
subjected to epoxide formation by simply treating with potassium
carbonate in methanol for a brief period of time. Finally, partial
catalytic hydrogenation of the alkyne using Lindlar’s catalyst in the
With the proper stereochemistry now firmly installed, acid-
catalyzed deactalization of 16 gave threo-(2R,3R)-1,2,3-dodecane-
triol in 78%. Selective monotosylation of the primary alcohol by
reaction with 1 equiv of TsCl in pyridine at 0e5 ꢀC afforded the
tosylate in a disappointing 40% yield. Regardless, subsequent
treatment of this compound with anhydrous potassium carbonate
in anhydrous MeOH yielded threo-(2R,3R)-l,2-epoxy-3-dodecanol 5.
The optical purity of 5 was measured using the same method as
described for 2 and was found to have an ee greater than 99%.
Completion of the synthesis proceeded as previous described,
namely: (1) conversion of 5 to its tosylate, (2) treatment of the
tosylate with heptynyl lithium and boron triflouride etherate to give
17, (3) epoxide formation via K2CO3 in methanol, and (4) partial
reduction of the alkyne using Lindlar’s catalyst. The synthesis of the
1 (9R,10S) stereoisomer was accomplished in 11 steps with an
overall yield of 2.4% and with exceptional stereochemical purity.

5332
D.I. MaGee et al. / Tetrahedron 67 (2011) 5329e5338
O
OH
O
O
a) NaIO4, CH2Cl2, 78%
b) CH3(CH2)8MgBr, 71%
e) 1N HCl, 78%
f) TsCl, py, 40%
C9H19
O
O
C9H19
O
c) Swern Ox, 91%
d) L-Selectride, 71%
HO
5
HO
O
g) K2CO3, MeOH, 71%
HO
7
16
h) TsCl, KOH,
74%
i) 1-heptyne, nBuLi
H11C5
OH
O
j) K2CO3, MeOH, 46%
over 2 steps
H
H
C9H19
H11C5
C9H19
k) H2, Lindlar's cat., 90%
17
OTos
1(9R, 10S)
Scheme 4. Synthesis of (6Z)-cis-9R,10S-epoxy-nonadecene. Reagents and conditions: (a) NaIO4, NaHCO3, CH2Cl2, rt, 2 h, 78%; (b) CH3(CH2)8MgþBrꢁ, Et2O, 0 ꢀC, 3 h, 0e5 ꢀC,
overnight, 71%; (c) (COCl)2, DMSO, Et3N, CH2Cl2, ꢁ78 ꢀC; 91%; (d) L-Selectride, THF, ꢁ78 ꢀC to rt, overnight, 71%; (e) 1 N HCl, THF, 6 h, 78%; (f) TsCl, pyridine, 0 ꢀCe8 ꢀC, 72 h, 40%; (g)
K2CO3, MeOH, 0 ꢀC to rt, 1 h, 71%; (h) TsCl, KOH, Et2O, 0 ꢀC, 2.5 h, 74%; (i) 1-heptyne, BuLi, BF3$Et2O, THF, ꢁ78 ꢀC; (j) K2CO3, MeOH, 0 ꢀC to rt, 1 h, 46% over two steps; (k) cat. 5% Pd/
CaCO3 poisoned with lead, C9H7N, H2, 2 h, 90%.
With sufficient material made to allow for field studies, atten-
tion was focused on trying to streamline the route. The reasons for
this were twofold: firstly, different starting materials were required
for the synthesis of the two enantiomers, this was inefficient and
unacceptable if the chemistry learned from this project was to be
applied to other pheromone syntheses. Secondly, larger quantities
of material were going to be required for more extensive field
studies, or perhaps for commercial application, therefore efficien-
cies needed to be found.
With this in mind a second synthetic route involving Sharpless
AD28,29 chemistry was developed. To begin, Scheme 5, decanal 12
was subjected to HornereWadswotheEmmons reaction with trie-
thylphosphonoacetate to furnish the trans-olefin 11 exclusively
after silica gel chromatography. Olefin 11 was treated with AD-mix-
b30 (Aldrich) to give diol 9 in 81% yield. Attempts were made to
reduce 9 with LAH to generate the triol, however, this reaction was
somewhat capricious. Therefore conversion of diol 9 to its aceto-
nide followed by reduction with LAH smoothly furnished alcohol 18
in excellent yield. Since 18 was enantiomeric to 14, optical rotation
allowed for an initial assessment of the ee (99%).
Continuing with the synthesis, alcohol 18 was converted to its
tosylate, hydrolyzed to the diol and as expected, when treated with
K2CO3 in MeOH, epoxy alcohol 5 was efficiently generated. The
optical purity was then measured by chiral GC using the same
method as for 2 and was determined to be 99%. Alcohol 5 was seen
as the lynchpin that would allow for the production of both pher-
omone enantiomers.
In order to generate 1 (9S,10R), alcohol 5 was first converted to
its TBS-silyl ether via the agency of TBSCl in DMF in the presence of
imidazole to give epoxide 8. Treatment of 8 with 1-lithio-1-heptyne
and boron triflouride etherate generated the secondary alcohol in
61% yield. This was then converted to a mesylate, which when
subjected to desilylation with TBAF in anhydrous THF followed by
partial catalytic hydrogenation to generate the targeted epoxide 1
(9S,10R). As compared to our previous route, this approach allowed
for the synthesis to be accomplished in 2 less steps (12 vs 14),
comparable overall yield (12.8% vs 13%) and higher enantiopurity
(99% vs 93.4%).
To complete the study, Scheme 6, transformation of alcohol 5
into tosylate 10 proceeded uneventfully. Opening of the epoxide
a) (EtO)2POCH2CO2Et, NaH, 95%
b) AD-mix 81%
c) 2,2-dimethoxypropane, H+, 87%
e) TsCl, KOH, 89%
f) 4N HCl, MeOH, 89%
g) K2CO3, MeOH, 84%
O
O
OH
O
C9H19
C9H19
H
C9H19
O
d) LAH, THF, 97%
18
5
12
OH
h) TBSCl, 88%
OTBS
O
i) 1-heptyne, nBuLi, 61%
j) MsCl, TEA, 70%
k) TBAF, THF, 85%
H
H
C9H19
C9H19
O
H11C5
1(9S, 10R)
8
l) H2, Lindlar's cat, 93%
Scheme 5. Synthesis of 6Z-cis-9S,10R-epoxy-nonadecene. Reagents and conditions: (a) triethyl phosponoacetate, NaH, THF, reflux, 1 h, 95%; (b) AD-mix-b, t-BuOH, H2O, rt, Na2SO3,
CH3SO2NH2, 81%; (c) 2,2-dimethoxypropane, p-TSA, CH2Cl2, 87%; (d) LAH, THF, 0 ꢀC, 1 h, 97%; (e) TsCl, KOH, Et2O, 0 ꢀC, 2 h, 89%; (f) 4 N HCl, MeOH, 8 h, 89%; (g) K2CO3, MeOH, 0 ꢀC to
rt, 1 h, 84%; (h) TBSCl, DMF, imidazole, rt, 16 h, 58%; (i) 1-heptyne, BuLi, BF3$Et2O, THF ꢁ78 ꢀC, 61%; (j) MsCl, Et3N, CH2Cl2, 4e8 ꢀC, 72 h, 70%; (k) TBAF, THF, rt, 1 h, 85%; (l) cat. 5% Pd/
CaCO3 poisoned with lead, C9H7N, H2, 2 h, 93%.
OH
OTos
O
H
H
a) TsCl, KOH,
74%
b) 1-heptyne, nBuLi, 61%
C9H19
C9H19
10
O
O
H11C5
C9H19
c) K2CO3, MeOH, 86%
d) H2 Lindlar's cat, 93%
1(9R, 10S)
5
Scheme 6. Synthesis of 6Z-cis-9R,10S-epoxy-nonadecene. Reagents and conditions: (a) TsCl, KOH, Et2O, 0 ꢀC, 2.5 h, 74%; (b) 1-heptyne, BuLi, BF3$Et2O, THF ꢁ78 ꢀC, 61%; (c) K2CO3,
MeOH, 0 ꢀCdrt, 1 h, 86%; (d) cat. 5% Pd/CaCO3 poisoned with lead, C9H7N, H2, 2 h, 93%.

D.I. MaGee et al. / Tetrahedron 67 (2011) 5329e5338
5333
with heptynyl lithium as previously, followed by epoxide formation
and partial catalytic reduction of the alkyne led to the formation of
1 (9R,10S). When compared to the route beginning from mannitol,
this approach was of equal length (11 steps), much better overall
yield (15.6% vs 2.4%) and comparable enantiopurity (99%).
From these studies it is clear that the Sharpless AD route pro-
vides an advantage for the synthesis of these types of alkene/ep-
oxides. For one enantiomer the overall yield was improved by 6½
fold, while for the other enantiomer yields were comparable but
the overall synthetic sequence was two steps shorter, which in itself
is an advantage. Also, the Sharpless AD technology provided superb
optical purities for both enantiomers achieving levels that were not
obtained using the ‘chiral pool’ approach. It should be noted that
our route used commercially available AD-mix, which is only
suitable for small-scale reactions. However, Sharpless28,29 has
provided a ‘recipe’ that allows for convenient preparation of a large
amount of this reagent that has allowed for the facile production of
several 100se1000s of mmol of these compounds to be efficiently
generated.
mass spectrometer (Xevo QToF). Samples were introduced into the
mass spectrometer using a commercially available Atmospheric
Solids Analysis Probe (ASAP). Infrared spectra were recorded on
a PerkineElmer 727B infrared spectrometer using KBr discs. Optical
rotations were recorded on a PerkineElmer 341 spectrometer using
the 589 sodium line. Melting points were measured on a Gallenkamp
melting point apparatus and all melting points are uncorrected.
5.1.1. Preparation of (4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-dime-
thane. To a round bottom flask were successively introduced
(þ)-dimethyl
L
-tartate 4 (25 g, 141 mmol), acetone (38 mL), trie-
thylorthoformate (32 mL) and 6 M HCl solution of dime-
thylformamide (0.75 mL). The mixture was stirred for 72 h at room
temperature and then alkalinized with triethylamine. The mixture
was concentrated in vacuo and the residue was diluted with Et2O
(200 mL) and then washed with water (2ꢂ30 mL) and dried over
MgSO4. The solvent was removed in vacuo to afford 27 g of (4R,5R)-
2,2-dimethyl-1,3-dioxolane-4,5-dimethane31 (88%) as a colourless
oil, which was of sufficient purity to be used directly in the next
reaction. 1H NMR (CDCl3): 4.83 (s, 2H), 3.85 (s, 6H), 1.52 (s, 6H). 13
d C
4. Conclusions
NMR (CDCl3): d
170.3, 114.1, 77.2, 53.0, 26.5. IR (KBr) cmꢁ1: 2957
(CH), 1762 (C]O), 1483, 1375. MS mþ/z: 203 (Mꢁ15), 175, 159, 141,
D20
]
The synthesis of the two enantiomers of the suspected phero-
mone of the elm spanworm was accomplished. Both enantiomers
of (6Z)-cis-9,10-epoxy-nonadecene have been synthesized via two
routes. The key steps in the first route were to prepare both threo-
epoxy tosylates and then to perform an alkylative rearrangement of
these intermediates to obtain the target molecules. An alternative
enantioenriched synthesis that took advantage of the Sharpless
dihydroxylation reaction was developed so that a common starting
material could be used to access both enantiomers. This has
allowed for the facile production of several 100se1000s of mmol of
these compounds to be efficiently generated, thus making it pos-
sible for the possible use of this chiral epoxide as a pest control
reagent in pheromone traps or as an early detection monitor for
this insect pest. This could lead to an environmental-friendly pest
management system for the insect.
133, 117, 101, 85, 73, 59. [
a
ꢁ43.3 (c 2.1, CH2Cl2).
5.1.2. Preparation of (4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-dime-
thanol (13). To a round bottom flask was put (4R,5R)-2,2-di-
methyl-1,3-dioxolane-4,5-dimethane (22.8 g, 0.1 mol) and THF
(100 mL). The solution was cooled to 0 ꢀC and LAH (8.0 g, 0.2 mol)
was added portion-wise over 15 min. After complete addition the
reaction mixture was stirred for 1 h. The reaction was quenched by
successive addition of water (8 mL), 15% NaOH (8 mL) and water
(24 mL) again. After stirring for 10 min the mixture was filtered
through Celite and then dried over MgSO4. The solvent was re-
moved in vacuo to afford 13.5 g (80%) of diol (4S,5S)-2,2-dimethyl
1,3-dioxolane-4,5-dimethanol32 13 as a yellow oil after purification
by silica gel chromatography using 1:4 hexanes: ethyl acetate (v/v)
as eluent. 1H NMR (CDCl3):
(br s, 2H), 1.43 (s, 6H). 13C NMR (CDCl3):
(KBr) cmꢁ1: 3399 (OH), 2987 (CH), 2936, 1458. MS mþ/z: 147
(Mꢁ15), 131, 113, 100, 85, 69, 59, 43. [ ꢁ4.7 (c 1.5, CH2Cl2).
d
3.97 (m, 2H), 3.70e3.76 (m, 4H), 2.96
109.3, 78.3, 62.1, 27.0. IR
d
5. General experimental procedures
5.1. General
a]
D20
5.1.3. Preparation of (2S,3S)-2,3-O-isopropylidene-1,2,3,4-butanete-
trol tert-butyldimethylsilyl ether. To a round bottom flask were
added NaH (60% wt dispersion in mineral oil, 3.3 g, 83.6 mmol) and
THF (150 mL). Diol 13 (13.5 g, 83.6 mmol) in THF (20 mL) was then
added drop-wise over 5 min. After complete addition, the reaction
mixture was stirred for 1 h then treated with tert-butyldime-
thylsilyl chloride (12.6 g, 83.6 mmol). After stirring for 3 h the re-
action was diluted with water and ether and the layers separated.
The organic layer was washed with brine and dried over MgSO4.
The solvent was removed in vacuo to afford 19.7 g (85%) of (2S,3S)-
2,3-O-isopropylidene-1,2,3,4-butanetetrol tert-butyldimethylsilyl
ether33 as a colourless oil after purification by silica gel chroma-
tography using 2:1 hexane: ethyl acetate (v/v) as eluent. 1H NMR
Unless otherwise indicated, all non-aqueous reactions were
conducted in oven-dried glassware and under an argon atmo-
sphere. 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 was performed using
SILICYCLE TLC plates, pre-coated 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 230e420 mesh
silica gel 60 from Fisher. Preparative thin-layer chromatography
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.
(CDCl3):
d
3.99 (dt, 1H, J¼7.7, 4.6 Hz), 3.91e3.63 (m, 5H), 2.36 (dd,
1H, J¼7.5, 4.5 Hz), 1.42 (s, 3H), 1.40 (s, 3H), 0.90 (s, 9H), 0.09 (s, 6H).
13C NMR (CDCl3):
d 109.3, 80.3, 78.3, 63.9, 62.9, 27.2, 27.0, 26.0, 18.5,
ꢁ5.3 (two signals). IR (KBr) cmꢁ1: 3451 (OH), 2929 (CH), 1468, 1378.
D20
NMR spectra were recorded on a Varian Innova 300 MHz spec-
trometer. All spectra were recorded in CDCl3 containing TMS as an
internal standard or in deuterated DMSO with chemical shifts
MS mþ/z: 261 (MꢁCH3), 219, 161, 131, 117, 75, 59, 43. [
a
]
þ10.9 (c
2.1, CH2Cl2).
reported inparts per milloin (
Agilent 6890 N (GC) and 5973 N (MS) model GC/MS or Hew-
lettePackard 5890 Series (GC) and HewlettePackard 5971 Series
(MS) model GC/MS. High resolution mass spectra were acquired on
a Waters Xevo QToF hybrid quadrupole orthogonal time-of-flight
d
). GC/MS spectrawere measured on an
5.1.4. Preparation of (2S,3S)-2,3-O-isopropylidene-2,3,4-trihydrox-
ybutanal tert-butyldimethylsilyl ether (3). To a round bottom flask
were added CH2Cl2 (100 mL) and oxalyl chloride (6.3 mL,
72.3 mmol). The solution was cooled to ꢁ78 ꢀC and anhydrous
DMSO (10.3 mL, 144.6 mmol) was added drop-wise over 5 min.
P

5334
D.I. MaGee et al. / Tetrahedron 67 (2011) 5329e5338
After stirring at this temperature for 15 min a solution of (2S,3S)-
2,3-O-isopropylidene-1,2,3,4-butanetetrol tert-butyldimethylsilyl
ether (18.1 g, 65.7 mmol) in CH2Cl2 (30 mL) was added over 15 min.
The resulting mixture was stirred for 1 h at ꢁ78 ꢀC and then trie-
thylamine (46 mL, 329 mmol) was added and the cooling bath was
removed. After stirring for 5 min the reaction mixture was diluted
with H2O and extracted with ether (3ꢂ100 mL). The combined
organic phase was washed with water, brine, dried over MgSO4,
filtered and the solvent removed in vacuo to afford 18.0 g (99%)
of crude (2S,3S)-2,3-O-isopropylidene-2,3,4-trihydroxybutanal
tert-butyldimethylsilyl ether33 3 as a pale yellow oil. 1H NMR
and the bottle was flushed with hydrogen, and the contents were
placed under H2 pressure (50 psi) and shaken for 16 h. The solution
was then filtered through a pad of Celite and rinsed with ether. The
solvent was removed in vacuo to yield 1.3 g (93%) of (2S,3S)-2,3-O-
isopropylidene-l,2,3-dodecantriol34 14 as a colourless oil, which
was of sufficient purity for use in the next reaction. 1H NMR
(CDCl3):
d
3.94e3.72 (m, 3H), 3.62 (m, 1H), 1.86 (dd, 1H, J¼7.5,
5.1 Hz), 1.56 (m, 6H), 1.44 (d, 6H, J¼3.2 Hz), 1.29 (br s, 14H), 0.90 (t,
3H, J¼6.6 Hz,). 13C NMR (CDCl3):
d 108.6, 81.6, 77.0, 73.9, 72.6, 64.8,
62.2, 33.6, 33.1, 31.9, 29.7, 27.2, 25.8, 22.7, 14.1. IR (KBr) cmꢁ1: 3409
(OH), 2925 (CH), 1643, 1467. MS mþ/z: 243 (MꢁCH3), 227, 123, 109,
95, 81, 59. HRMS (mþþH) calcd for C15H31O3 259.2274, found
(CDCl3):
d
9.78 (dd, 1H, J¼1.6, 0.8 Hz), 4.33 (dm, 1H, J¼7.2 Hz), 4.13
D20
(m, 1H), 3.82 (d, 2H, J¼4.5), 1.49 (s, 3H), 1.42 (s, 3H), 0.91 (s, 9H),
259.2273. [
a
]
ꢁ3.8 (c 1.6, CH2Cl2).
0.093 (s, 3H), 0.091 (s, 3H). 13C NMR (CDCl3):
d 201.8, 111.3, 79.8,
66.2, 26.6, 25.1. IR (KBr) cmꢁ1: 2987 (CH), 1735 (C]O), 1457, 1373.
MS mþ/z: 259 (MꢁCH3), 245, 217, 199, 187, 171, 159, 145, 129, 117,
5.1.8. Preparation of (2S,3S)-2,3-O-isopropylidene-L-(tosyloxy)-2,3-
dodecanediol. Into a round bottom flask were put (2S,3S)-2,3-O-
isopropylidene-l,2,3-dodecantriol 14 (0.34 g, 5.19 mmol), pyridine
(10 mL) and then the solution was cooled to 0 ꢀC. TsCl (0.99 g,
5.19 mmol) was added portion-wise over 15 min. The resulting
mixture was stored for 72 h in a fridge (4e8 ꢀC) and then diluted
with ice water (10 mL). The solution was extracted with ether
(3ꢂ25 mL) and the combined organic phase was washed with
water, dried over MgSO4, filtered and the solvent evaporated to
D20
101, 85, 75, 59, 43. [
a
]
þ3.3 (c 1.0, CH2Cl2).
5.1.5. Preparation of (4E) and (4Z)-(2S,3S)-2,3-O-isopropylidene-4-
dodecene-1,2,3-triol tert-butyldimethylsilyl ether. To a round bottom
flask were put 1-octyltriphenylphospnonium bromide (13.4 g,
53.0 mmol) and THF (100 mL). The solution was cooled to ꢁ78 ꢀC
and n-BuLi (24 mL, 2.5 M, 59.8 mmol) was added drop-wise over
10 min, after complete addition, stirring was continued at this
temperature for 30 min. Then crude aldehyde 3 (12.8 g, 46.9 mmol)
was added drop-wise and the reaction mixture was allowed to
warm slowly to room temperature and stirred overnight. Anhy-
drous MeOH (15 mL) was then added to quench the reaction and
the resulting mixture was concentrated in vacuo. The residue was
purified by silica gel chromatography (10:1 hexane/ethyl acetate, v/
v) to afford 12.7 g (73%) of (4E) and (4Z)-(2S,3S)-2,3-O-iso-
propylidene-4-dodecene-1,2,3-triol tert-butyldimethylsilyl ether as
yield 2.0 g of (2S,3S)-2,3-O-isopropylidene-L-(tosyloxy)-2,3-dodec-
anediol (94%) as a pale yellow oil after purification by silica gel
chromatography with 5:1 hexanes/ethyl acetate (v/v) as eluent. 1H
NMR (CDCl3):
d
7.81 (dt, 2H J¼8.3, 1.7 Hz), 7.39 (dd, 2H, J¼7.9,
1.0 Hz), 4.11 (m, 2H), 3.80 (m, 3H), 2.48 (s, 3H), 1.38 (s, 3H), 1.32 (s,
3H), 1.29 (br s, 16H), 0.91 (t, 3H, J¼7.0 Hz). 13C NMR (CDCl3):
d 144.0,
131.8, 128.9 (two signals), 127.1 (two signals), 108.3, 76.1, 75.6, 68.2,
62.8, 32.1, 30.9, 28.5, 28.3, 26.3, 25.7, 24.9, 21.7, 20.7, 16.9, 13.1. IR
(KBr) cmꢁ1: 2927 (CH), 2855, 1598 (C]C), 1369, 1190, 1907, 983,
815, 555. HRMS (mþþH) calcd for C22H37O5S 413.2362, found
a clear, yellowish oil. 1H NMR (CDCl3):
d 5.66 (m, 1H), 5.39 (m, 1H),
D20
4.78 (m, 1H), 3.79 (m, 1H), 3.69e3.62 (m, 2H), 2.03e2.13 (br m, 2H),
1.44 (s, 3H), 1.43 (s, 3H), 1.24e1.34 (m, 10H), 0.98e0.74 (m, 12H),
413.2365. [
a]
ꢁ22.9 (c 1.8, CH2Cl2).
0.08 (s, 3H), 0.07 (s, 3H). 13C NMR (CDCl3):
d
136.4,126.6,108.9, 82.0,
5.1.9. Preparation
of
(2S,3S)-1-tosyloxy-2,3-dodecanediol. To
73.0, 61.7, 32.0, 29.9, 29.4, 28.0, 27.5, 27.2, 26.10 (two signals), 22.9,
18.6, 14.3, ꢁ5.9, ꢁ5.3. IR (KBr) cmꢁ1: 2928 (CH), 1462, 1379. MS mþ/
z: 355 (MꢁCH3), 325, 297, 255, 225, 196, 173, 157, 143, 117, 89, 75, 57,
43. HRMS (mþþH) calcd for C21H23O3Si 371.2982, found 371.2984.
a round bottom flask were put (2S,3S)-2,3-O-isopropylidene-L-
(tosyloxy)-2,3-dodecanediol (1.0 g, 2.5 mmol) and 1% methanolic
HCl (20 mL). The mixture was stirred for 5 h at room temperature,
diluted with water (100 mL) and extracted with ether. The com-
bined organic phase was washed with water, dried over MgSO4,
filtered and solvent evaporated, to afford 0.8 g of (2S,3S)-1-tosy-
loxy-2,3-dodecanediol (82%) as a white solid after purification by
silica gel chromatography with 3:1 hexane/ethyl acetate (v/v) as
D20
[
a]
ꢁ6.1 (c 1.3, CH2Cl2).
5.1.6. Preparation of (4E)- and (4Z)-(2S,3S)-2,3-O-isopropylidene-4-
dodecene-1,2,3-triol. Into a round bottom flask were added (4E) and
(4Z)-(2S,3S)-2,3-O-isopropylidene-4-dodecene-1,2,3-triol
tert-
eluent. 1H NMR (CDCl3):
d
7.83 (dt, 2H, J¼8.3, 1.8 Hz), 7.35 (dd, 2H,
butyldimethylsilyl ether (15.3 g, 41.3 mmol) and THF (100 mL) fol-
lowed by drop-wise addition of TBAF (123.8 mL, 123.4 mmol). After
stirring for 1 h the reaction mixture was diluted with ether and
washed with 1 M HCl, water, brine, dried over MgSO4, filtered and
the solvent evaporated to yield 9.1 g of (4E)- and (4Z)-(2S,3S)-2,3-
O-isopropylidene-4-dodecene-1,2,3-triol (86%) as a colourless oil
after purification by silica gel chromatography with 3:1 hexanes/
J¼8.6, 0.7 Hz), 4.12 (m, 2H), 3.74 (m, 1H), 3.61 (m, 1H), 2.48 (s, 3H),
1.29 (br s, 18H, 2OH), 0.90 (t, 3H, J¼6.9 Hz). 13C NMR (CDCl3):
d
145.2, 132.6, 130.0 (two signals), 128.0 (two signals), 77.2, 71.5,
71.4, 70.8, 33.5, 31.9, 30.9, 29.53 (two signals), 29.5, 29.3, 25.5, 22.7,
21.7, 14.1. IR (KBr) cmꢁ1: 3439, 3280 (OH), 2918 (CH), 1599 (C]C),
1353, 962. HRMS (mþþH) calcd for C19H33O5S 373.2049, found
373.2049. [
a
ꢁ9.9 (c 1.1, CH2Cl2). Mp: 73.9e75.9 ꢀC.
D20
]
ethyl acetate (v/v) as eluent. 1H NMR (CDCl3):
d 5.73 (m, 1H), 5.40
(m, 1H), 4.74 (t, 1H, J¼8.6 Hz), 3.86 (m, 1H), 3.76 (m, 1H), 3.58 (m,
5.1.10. Preparation of (2S,3S)-l,2-epoxy-3-dodecanol (2). Into
a round bottom flask were placed (2S,3S)-1-tosyloxy-2,3-dodeca-
nediol (0.75 g, 2.02 mmol) and MeOH (20 mL). This solution was
cooled to 0 ꢀC and anhydrous K2CO3 (0.55 g, 4.04 mmol) was added
and the reaction mixture was allowed to slowly warm to room
temperature and stir for 1 h. The mixture was then diluted with an
equal volume of water and extracted with ether (3ꢂ25 mL). The
combined organic phase was washed with water, dried over
MgSO4, filtered and solvent evaporated to afford 0.34 g of (2S,3S)-
l,2-epoxy-3-dodecanol35 2 (83%) after purification by silica gel
chromatography with 3:1 hexane/ethyl acetate (v/v) as eluent. 1H
1H), 2.22e2.06 (br m, 2H), 1.84 (m, 1H), 1.47 (s, 6H), 1.20 (s, 10H),
0.90 (t, 3H, J¼6.8 Hz). 13C NMR (CDCl3):
d 137.0, 126.1, 109.3, 81.6,
72.8, 60.9, 32.0, 29.9, 29.4, 29.36, 27.9, 27.5, 27.2, 22.9, 14.3. IR (KBr)
cmꢁ1: 3451 (OH), 2927 (CH),1380. MS mþ/z: 256 (Mþ), 241,196, 181,
167, 155, 137, 121, 107, 97, 83, 67, 59, 43. HRMS (mþþH) calcd for
C15H29O3 257.2117, found 257.2117. [
a
]
ꢁ7.6 (c 2.8, CH2Cl2).
D20
5.1.7. Preparation of (2S,3S)-2,3-O-isopropylidene-l,2,3-dodecantriol
(14). (4E)- and (4Z)-(2S,3S)-2,3-O-Isopropylidene-4-dodecene-
1,2,3-triol (1.4 g, 5.4 mmol) was taken up in anhydrous methanol
(30 mL) and transferred to a Parr hydrogenation bottle. To this was
added a catalytic amount of palladium (30% wt on activated carbon)
NMR (CDCl3):
d
3.46 (br m, 1H), 3.00 (m, 1H), 2.85 (dd, 1H, J¼5.0,
4.4 Hz), 2.75 (dd, 1H, J¼4.9, 2.8 Hz), 1.63 (m, 2H), 1.39 (br s, 14H),

D.I. MaGee et al. / Tetrahedron 67 (2011) 5329e5338
5335
0.89 (t, 3H, J¼6.5 Hz). 13C NMR (CDCl3):
d
71.7, 55.5, 45.2, 34.4, 31.9,
1.30e1.22 (m, 20H), 0.863 (t, 3H, J¼6.6 Hz), 0.86 (t, 3H, J¼6.1 Hz). 13
C
29.6, 29.5 (two signals), 29.3, 25.3, 22.7, 14.1. IR (KBr) cmꢁ1: 3413
NMR (CDCl3):
d
132.7, 123.8, 57.2, 56.6, 31.9, 31.5, 29.6 (two signals),
(OH), 2924 (CH). MS mþ/z: 157, 139, 111, 97, 88, 83, 74, 69, 55, 41.
29.5, 29.3, 29.3, 27.8, 27.4, 26.6, 26.2, 22.7, 22.6, 14.1, 14.0. IR (NaCl)
[
a]
ꢁ4.74 (c 1.3, CH2Cl2).
cmꢁ1: 2925 (CH),1467. MS mþ/z: 280, 251, 237, 223, 209, 195, 183, 169,
D20
155, 139, 124, 110, 95, 81, 69, 55. HRMS (mþþH) calcd for C19H36
O
D20
a]
5.1.11. Preparation of (2S,3S)-l,2-epoxy-3-(tosyloxy)dodecane. To
a round bottom flask were put (2S,3S)-l,2-epoxy-3-dodecanol 2
(0.34 g, 1.68 mmol), Et2O (10 mL) and TsCl (0.48 g, 2.52 mmol). The
solution was cooled to ꢁ5 ꢀC and freshly powdered KOH (1.41 g)
was added portion-wise over 15 min. After complete addition, the
resulting mixture was stirred for 2.5 h at 0 ꢀC and then ice water
(10 mL) was added. The solution was extracted with ether
(3ꢂ25 mL) and the combined organic phase was washed with
water, dried over MgSO4, filtered and solvent evaporated to yield
0.48 g of (2S,3S)-l,2-epoxy-3-(tosyloxy)dodecane36 (81%) as a tan
coloured solid after purification by silica gel chromatography with
281.2846, found 281.2846. [
þ3.1 (c 1.1, CH2Cl2).
5.1.14. Preparation of (R)-glyceraldehyde acetonide. To a round
bottom flask were placed 1,2:5,6-di-O-isopropylidine- -mannitol 7
D
(5.0 g, 19.2 mmol), CH2Cl2 (20 mL) and saturated aqueous sodium
bicarbonate (2 mL). The flask was put in a water bath and then
sodium metaperiodate (8.2 g, 38.4 mmol) was added portion-wise
over 10 min. The resulting mixture was stirred for 2 h and then
MgSO4 (2.5 g) was added. The reaction mixture was stirred for
another 20 min and the slurry was vacuum-filtered through a glass
frit filter. The filter cake was removed and transferred back into
a flask, then CH2Cl2 (25 mL) was added, stirred for 10 min and then
the slurry was vacuum-filtered again. The filtrates were combined
and dried over MgSO4 and then concentrated in vacuo to afford
3.9 g (78%) of crude (R)-glyceraldehyde acetonide25 as a colourless
3:1 hexane/ethyl acetate (v/v) as eluent. 1H NMR (CDCl3):
d 7.82 (d,
2H, J¼8.3 Hz), 7.33 (d, 2H, J¼8.0 Hz), 4.34 (m, 1H), 3.05 (m, 1H), 2.79
(t, 1H, J¼4.2 Hz), 2.63 (dd, 1H, J¼4.8, 2.6 Hz), 2.45 (s, 3H), 1.70 (m,
2H), 1.23 (br s, 14H), 0.89 (t, 3H, J¼6.6 Hz). 13C NMR (CDCl3):
d 144.6,
134.3, 129.9, 127.9, 83.4, 52.7, 44.8, 31.86, 31.83, 29.4, 19.3, 29.26,
oil. 1H NMR (CDCl3):
d
9.75 (dd, 1H, J¼1.9, 0.4 Hz), 4.41 (ddd, 1H,
29.2, 24.8, 22.7, 21.7, 14.1. IR (KBr) cmꢁ1: 2924 (CH), 1596 (C]C),
J¼7.3, 4.8, 1.9 Hz), 4.23e4.10 (ABMX, 2H), 1.51 (m, 3H), 1.44 (t, 3H,
1531 (SO). [
a
]
þ5.2 (c 1.0, CH2Cl2). Mp: 60.5e62.1 ꢀC.
J¼0.7 Hz). 13C NMR (CDCl3):
d 201.8, 111.3, 79.8, 66.2, 26.6, 25.1. IR
D20
(NaCl) cmꢁ1: 2987 (CH), 1735 (C]O), 1457, 1373. MS mþ/z: 31
D20
5.1.12. Preparation
of
(9S,10R)-9,10-epoxy-nonadec-6-yne. In
(Mþ1), 115, 101, 85, 73, 59, 55. [
a
]
þ42.2 (c 0.55, CH2Cl2).
a round bottom flask cooled to ꢁ78 ꢀC were put 1-heptyne (1.0 g,
3.0 mmol) and THF (20 mL) followed by drop-wise addition of n-
BuLi (5.6 mL, 1.6 M, 9.0 mmol). The resulting mixture was stirred
for 30 min and then BF3$Et2O (1.1 mL, 9.0 mmol) was added followed
30 min later by (2S,3S)-l,2-epoxy-3-(tosyloxy)dodecane (1.1 g,
3.0 mmol) in THF (5 mL). The reaction mixture was stirred for 1 h at
ꢁ78 ꢀC and was then quenched with saturated aqueous NH4Cl. The
solution was extracted with ether (3ꢂ25 mL) and the combined or-
ganic phase was washed with water, dried over MgSO4, filtered and
solvent evaporated to afford 1.5 g of crude 15. This crude product,15,
(1.5 g, 3.4 mmol) was dissolved in anhydrous MeOH (15 mL) and
cooled to 0 ꢀC at which time anhydrous K2CO3 (0.9 g, 6.7 mmol) was
added. The reaction mixture was then slowly warmed to room
temperature and stirred for 1 h. An equal volume of water was then
added and the solution was extracted with ether (3ꢂ25 mL) and the
combined organic phase was washed with water, dried over MgSO4,
filtered and solvent evaporated to afford 0.7 g of (9S,10R)-9,10-epoxy-
nonadec-6-yne (78%) as a colourless oil after purification by silica gel
chromatography using 8:1 hexane/ethyl acetate (v/v) as eluent. 1H
5.1.15. Preparation of (2R,3R)- and (2R,3S)-l,2-O-isopropylidene-
1,2,3-dodecanetriol. To a round bottom flask cooled to 0 ꢀC were put
(R)-glyceraldehyde acetonide (4.0 g, 30.8 mmol) and Et2O (10 mL).
To this was added nonylmagnesium bromide (38.6 mL, 38.6 mmol,
1 M in diethylether) drop-wise over 15 min. After complete addi-
tion the reaction mixture was stirred for 3 h at 0 ꢀC and then placed
in a refrigerator overnight. Saturated aqueous NH4Cl was added to
destroy excess Grignard reagent and Et2O (100 mL) was then added.
The layers were separated and the organic phase was washed with
water, brine, dried over MgSO4, filtered and solvent evaporated to
afford 5.7 g of (2R,3R)- and (2R,3S)-l,2-O-isopropylidene-1,2,3-
dodecanetriol38 (71%) after purification by silica gel chromatogra-
phy using 3:1 hexane/ethyl acetate (v/v) as eluent. GC analysis
indicated a 6:1 mixture of erythro to threo alcohols. 1H NMR
(CDCl3):
d
4.09e3.90 (m, 2H), 3.80 (m, 1H), 3.67 (t, 1H, J¼6.6 Hz),
1.96 (s, 1H), 1.46 (m, 3H), 1.39 (m, 3H), 1.60e1.25 (br m, 16H), 0.90 (t,
3H, J¼6.6 Hz). 13C NMR (CDCl3):
d 109.3 (108.9), 79.2 (78.7), 72.3
(70.6), 66.1 (64.5), 33.7 (32.6), 31.9, 29.6 (29.6), 29.5 (two signals),
(29.5), (29.45), 29.3 (29.3), 26.6 (26.5), (25.8), 25.5, 25.3, 22.6, 14.1.
IR (NaCl) cmꢁ1: 3434 (OH), 2925 (CH), 1467, 1370. MS mþ/z: 243
(MꢁCH3), 215, 201, 183, 155, 138, 123, 116, 109, 101, 83, 73, 59, 43.
NMR (CDCl3):
d
3.14 (m, 1H), 2.97 (ddd, 1H, J¼5.7, 5.7, 4.4 Hz), 2.59
(dm, 1H, J¼17.0, 2.8 Hz), 2.52e2.13 (m, 3H), 1.57e1.44 (m, 4H),
1.43e1.24 (m, 18H), 0.92 (t, 3H, J¼7.0 Hz), 0.91 (t, 1H, J¼6.8 Hz). 13C
NMR (CDCl3): d 82.5, 74.8, 57.1, 55.5, 31.9, 31.1, 29.6, 29.5 (twosignals),
29.3, 28.6, 27.6, 26.5, 22.7, 22.2, 18.8, 18.7, 14.1, 14.0. IR (NaCl) cmꢁ1
:
5.1.16. Preparation of (2R)-l,2-O-isopropylidene-1,2-dihydroxy-3-do-
decanone (6). To a round bottom flask cooled to ꢁ78 ꢀC were put
CH2Cl2 (30 mL) and oxalyl chloride (2.7 mL, 21.3 mmol). To this was
added anhydrous DMSO (3.3 mL, 42.6 mmol) in CH2Cl2 (5 mL)
drop-wise over 5 min. After stirring at 78 ꢀC for 15 min, a solution
of (2R,3R)- and (2R,3S)-l,2-O-isopropylidene-1,2,3-dodecanetriol
(5.0 g, 19.4 mmol) in CH2Cl2 (10 mL) was added drop-wise over
5 min. The solution was stirred at this temperature for 30 min and
then triethylamine (13.6 mL, 97.0 mmol) was added, the cold bath
was removed and after stirring for 5 min the reaction mixture was
diluted with H2O and extracted with ether (3ꢂ100 mL). The com-
bined organic phase was washed with water, brine, dried over
MgSO4, filtered and the solvent removed in vacuo to afford to
produce 4.5 g (91%) of (2R)-l,2-O-isopropylidene-1,2-dihydroxy-3-
dodecanone38 6 as a colourless oil after purification by silica gel
chromatography using 3:1 hexane/ethyl acetate (v/v) as eluent. 1H
2926 (CH), 1467. MS mþ/z: 277 (Mꢁ1), 263, 249, 235, 221, 207, 193,
179, 165, 151, 137, 123, 109, 95, 81, 67, 55. HRMS (mþþH) calcd for
C19H35O 279.2688, found 279.2689. [
a]
D20
þ30.3 (c 4.5, CH2Cl2).
5.1.13. Preparation of (6Z)-cis-9S,10R-epoxy-nonadecene (1(9S,10R)).
(9S,10R)-9,10-Epoxy-nonadec-6-yne (0.78 g, 2.81 mmol) was taken
up in anhydrous hexane (20 mL) and transferred to a Parr hydroge-
nation bottle. Lindlar’s catalyst (5% palladium on CaCO3 poisoned
with lead, 84 mg) and quinoline (28 mg) were then added and the
bottle was flushed with hydrogen and the contents were placed un-
der hydrogen pressure (50 psi) and shaken for 1 h. The solution was
then filtered through a pad of Celite and the pad was washed with
Et2O. The solvent was removed in vacuo to yield 0.73 g (93%) of (6Z)-
cis-9S,10R-epoxy-nonadecene37 1 (9S,10R) as a colourless oil after
purification by silica gel chromatography using 8:1 hexane/ethyl ac-
etate (v/v) as eluent. 1H NMR (CDCl3):
(m, 2H), 2.32 (m, 1H), 2.18 (m, 1H), 2.06e1.99 (m, 2H), 1.50 (m, 2H),
d
5.54e5.34 (m, 2H), 2.90e2.87
NMR (CDCl3): d 4.39 (m, 1H), 4.29 (m, 2H), 2.58e2.78 (m, 8H), 1.25
(br s, 14H), 0.90 (t, 3H, J¼6.7 Hz). 13C NMR (CDCl3):
d 211.0, 110.9,

5336
D.I. MaGee et al. / Tetrahedron 67 (2011) 5329e5338
80.3, 66.5, 38.6, 31.9, 29.5, 29.4, 29.3, 29.2, 26.0, 25.0, 22.9, 22.7,14.1.
(0.7 g, 1.9 mmol) and MeOH (10 mL). This solution was cooled to
0 ꢀC and anhydrous K2CO3 (0.5 g, 3.8 mmol) was added and the
reaction mixture was allowed to slowly warm to room temperature
and stir for 1 h. The mixture was then diluted with an equal volume
of water and extracted with Et2O (3ꢂ25 mL). The combined organic
phase was washed with water, dried over MgSO4, filtered and sol-
vent evaporated to afford 0.3 g of (2R,3R)-l,2-epoxy-3-dodecanol 5
(71%) as a colourless oil after purification by silica gel chromatog-
raphy with 3:1 hexane/ethyl acetate (v/v) as eluent. This material
was spectroscopically and chromatographically identical to its en-
antiomer 237. HRMS (mþþH) calcd for C12H25O2 201.1855, found
IR (NaCl) cmꢁ1: 2929 (CH), 1718 (C]O), 1458, 1373. MS mþ/z: 241
(MꢁCH3), 211, 155, 141, 101, 93, 83, 73, 65, 55, 43. [
a
]
þ22.7 (c 1.1,
D20
CH2Cl2).
5.1.17. Preparation of (2R,3R)-l,2-O-isopropylidene-1,2,3-dodecane-
triol (16). To a round bottom flask were put (2R)-l,2-O-iso-
propylidene-1,2-dihydroxy-3-dodecanone 6 (4.8 g, 18.8 mmol) and
THF (30 mL). The solution was cooled to ꢁ78 ꢀC and L-Selectride
(28.0 mL, 28.0 mmol, 1 M in THF) was added drop-wise over
25 min. After complete addition the mixture was slowly warmed to
room temperature and stirred overnight. Then 3 M NaOH (29 mL)
and 30% H2O2 (25 mL) were successively added while maintaining
the temperature below 50 ꢀC. The resulting mixture was stirred for
6 h at 35 ꢀC and then Et2O (100 mL) was added. The layers were
separated and the organic phase was washed with water, brine,
dried over MgSO4, filtered and solvent evaporated to afford 4.2 g of
a mixture of diastereomeric alcohols (the threo/erythro ratio was
estimated as approximately 8:1 by comparison of GC/MS peak
areas), which after silica gel chromatography using 5:1 hexane/
ethyl acetate (v/v) as eluent gave (2R,3R)-l,2-O-isopropylidene-
1,2,3-dodecanetriol38 16 as a clear, yellow oil (71%). 1H NMR
D20
201.1852. [
a]
þ3.8 (c 1.3, CH2Cl2).
5.1.21. Preparation of (2R,3R)-l,2-epoxy-3-(tosyloxy)dodecane. To
a round bottom flask were put (2R,3R)-l,2-epoxy-3-dodecanol 5
(0.2 g, 1.0 mmol), Et2O (10 mL) and TsCl (0.3 g, 1.5 mmol). The so-
lution was cooled to ꢁ5 ꢀC and freshly powdered KOH (0.8 g) was
added portion-wise over 15 min. After complete addition, the
resulting mixture was stirred for 2.5 h at 0 ꢀC and then ice water
(10 mL) was added. The solution was extracted with Et2O
(3ꢂ25 mL) and the combined organic phase was washed with
water, dried over MgSO4, filtered and solvent evaporated to yield
0.3 g of (2R,3R)-l,2-epoxy-3-(tosyloxy)dodecane (74%) as a tan
coloured solid after purification by silica gel chromatography with
3:1 hexane/ethyl acetate (v/v) as eluent. This material was spec-
troscopically and chromatographically identical to its enantiomer
(2S,3S)-l,2-epoxy-3-(tosyloxy)dodecane. HRMS (mþþH) calcd for
(CDCl3): d 4.07e3.97 (m, 2H), 3.75 (m, 1H), 3.50 (m, 1H), 2.15 (d, 1H,
J¼5.2 Hz),1.46 (s, 3H),1.39 (s, 3H), 1.62e1.26 (br m,16H), 0.90 (t, 3H,
J¼7.0 Hz). 13C NMR (CDCl3):
d 109.3, 79.2, 72.3, 66.1, 62.9, 33.7, 31.9,
29.6, 29.5, 29.3, 26.6, 25.5, 25.3, 22.6, 14.1. IR (NaCl) cmꢁ1: 3477
(OH), 2925 (CH), 1467, 1371. MS mþ/z: 243 (MꢁCH3), 215, 201, 183,
D20
D20
155, 138, 123, 116, 109, 101, 83, 73, 59, 43. [
a]
þ0.9 (c 1.1, CH2Cl2).
C19H31O4S 355.1944, found 355.1940. [
a]
ꢁ6.0 (c 0.72, CH2Cl2).
5.1.18. Preparation of (2R,3R)-l,2-3-dodecanetriol. Into
a
round
5.1.22. Preparation of (9R,10S)-9,10-epoxy-nonadec-6-yne. In a round
bottom flask cooled to ꢁ78 ꢀC were put 1-heptyne (0.17 g,
1.78 mmol) and THF (20 mL) followed by drop-wise addition of n-
BuLi (1.01 mL, 1.6 M, 1.62 mmol). The resulting mixture was stir-
red for 30 min and then BF3$Et2O (0.21 mL, 1.62 mmol) was added
followed 30 min later by (2R,3R)-l,2-epoxy-3-(tosyloxy)dodecane
(1.90 g, 0.54 mmol) in THF (5 mL). The reaction mixture was
stirred for 1 h at ꢁ78 ꢀC and was then quenched with saturated
aqueous NH4Cl. The solution was extracted with Et2O (3ꢂ25 mL)
and the combined organic phase was washed with water, dried
over MgSO4, filtered and solvent evaporated to afford 0.27 g of
crude 17 as a brown oil. The crude alcohol 17 (0.27 g, 0.61 mmol),
anhydrous MeOH (5 mL) and anhydrous K2CO3 (0.17 g, 1.21 mmol)
were stirred together for 1 h to afford 0.08 g of epoxide 37 (46%)
as a colourless oil after purification by silica gel chromatography
using 8:1 hexane/ethyl acetate (v/v) as eluent. This material was
spectroscopically and chromatographically identical to its enan-
bottomed flask were put (2R,3R)-l,2-O-isopropylidene-1,2,3-
dodecanetriol 16 (3.2 g,12.4 mmol), THF (60 mL)and 1 N HCl(60 mL).
The mixture was stirred for 6 h at room temperature and then neu-
tralized with saturated NaHCO3. Et2O (100 mL) was added and the
layers were separated. The organic phase was washed with water,
brine, dried over MgSO4, filtered, and solvent evaporated to afford
2.1 g of (2R,3R)-l,2,3-dodecanetriol36 (78%) as an off white solid after
purification by silica gel chromatography using 1:2 hexanes/ethyl
acetate (v/v) as eluent. 1H NMR (DMSO):
d 4.34 (m, 1H), 4.25 (d, 1H,
J¼5.4 Hz), 4.06 (d, 1H, J¼6.3 Hz), 3.42e3.24 (m, 4H), 1.42e1.20 (m,
16H), 0.86 (t, 3H, J¼6.6 Hz). 13C NMR (DMSO):
d 74.5, 70.9, 63.3, 33.2,
31.9, 29.7, 29.6, 29.5, 29.2, 26.1, 22.6, 14.4. IR (NaCl) cmꢁ1: 3286 (OH),
þ10.9 (c 1.1, MeOH). Mp: 63.4e64.4 ꢀC.
D20
2917 (CH), 1467. [a]
5.1.19. Preparation of (2R,3R)- -(tosyloxy)-2,3-dodecanediol. Into
L
a round bottom flask were put (2R,3R)-l,2,3-dodecanetriol (1.0 g,
4.6 mmol) and pyridine (5 mL). The solution was cooled to 0 ꢀC and
TsCl (0.9 g, 4.6 mmol) was added portion-wise over 15 min. After
complete addition the resulting mixture was stored for 72 h in
a fridge (4e8 ꢀC) and then diluted with ice water (10 mL). The so-
lution was extracted with Et2O (3ꢂ25 mL) and the combined or-
ganic phase was washed with water, dried over MgSO4, filtered and
D20
tiomer (9S,10R)-9,10-epoxy-nonadec-6-yne. [
CH2Cl2).
a
]
ꢁ28.8 (c 1.0,
5.1.23. Preparation of (6Z)-cis-9R,10S-epoxy-nonadecene (1(9R,10S)).
(9R,10S)-9,10-Epoxy-nonadec-6-yne (0.1 g, 0.4 mmol) was taken up
in hexane (20 mL) and transferred to a Parr hydrogenation bottle.
Lindlar’s catalyst (5% palladium on CaCO3 poisoned with lead,
12 mg) and quinoline (4 mg) were then added and the bottle was
flushed with hydrogen and the contents were placed under hy-
drogen pressure (50 psi) and shaken for 1 h. The solution was then
filtered through a pad of Celite and the pad was washed with Et2O.
The solvent was removed in vacuo to yield 0.09 g (6Z)-cis-9R,10S-
epoxy-nonadecene37 1(9R,10S) (90%) as a colourless oil after pu-
rification by silica gel chromatography using 8:1 hexane/ethyl
acetate (v/v) as eluent. This material was spectroscopically and
the solvent evaporated to yield 0.7 g of (2R,3R)-L-(tosyloxy)-2,3-
dodecanediol (40%) as a tan coloured solid after purification by
silica gel chromatography using 1:1 hexanes/ethyl acetate (v/v) as
eluent. 1H NMR (CDCl3):
d
7.83 (dt, 2H, J¼8.3, 1.8 Hz), 7.35 (dd, 2H,
J¼8.6, 0.7 Hz), 4.11 (ABX, 2H), 3.72 (m,1H), 3.60 (m, 1H), 2.47 (s, 3H),
2.38 (b, 1H), 1.92 (b, 1H), 1.56e1.20 (br s, 16H), 0.89 (t, 3H, J¼6.5 Hz).
13C NMR (CDCl3):
d 145.2, 132.6, 130.0, 128.0, 77.2, 71.5, 71.4, 70.8,
33.5, 31.9, 30.9, 29.53 (two signals), 29.5, 29.3, 25.5, 22.7, 21.7, 14.1.
IR (NaCl) cmꢁ1: 3439 (OH), 2918 (CH), 1599 (C]C). HRMS (mþþH)
calcd for C19H33O5S 373.2049, found 373.2049. [
a
]
D20
þ10.2 (c 1.2,
chromatographically identical to its enantiomer 1 (9S,10R). [
ꢁ3.5 (c 1.0, CH2Cl2).
a]
D20
CH2Cl2). Mp: 75.6e77.0 ꢀC.
5.1.20. Preparation of (2R,3R)-l,2-epoxy-3-dodecanol (5). To a round
bottom flask were placed (2R,3R)-1-tosyloxy-2,3-dodecanediol
5.1.24. Preparation of ethyl (E)-dodec-2-enoate (11). To a round
bottom flask cooled to 0 ꢀC were put NaH (1.14 g, 28.5 mmol, 60% in

D.I. MaGee et al. / Tetrahedron 67 (2011) 5329e5338
5337
mineral oil) and THF (50 mL) followed by drop-wise addition of
triethylphosphonoacetate (5.6 mL, 28.2 mmol). After stirring for
10 min at 0 ꢀC decanal 12 (4.0 g, 25.6 mmol) in THF (10 mL) was
added drop-wise. The reaction mixture was allowed to warm to
room temperature and then heated at reflux for 1 h. The solution
was cooled and diluted with distilled water and ethyl acetate
(1:1, 50 mL), the layers were separated and the aqueous layer was
extracted with ethyl acetate (2ꢂ30 mL). The combined organic
layer was washed with 1 M NaOH, H2O and brine, dried over
MgSO4 and the solvent was removed to afford 5.5 g (95%) of ethyl
(E)-dodec-2-enoate39 11 as a colourless oil after purification by
silica gel chromatography using 20:1 hexane/ethyl acetate (v/v)
0.66 mmol) was added. After complete addition the reaction mix-
ture was stirred for 1 h. The reaction was quenched by successive
addition of water (0.3 mL), 15% NaOH (0.3 mL) and water (0.9 mL)
again. After stirring for 0.5 h the mixture was filtered through Celite
and then dried over MgSO4. The solvent was removed in vacuo to
yield 0.17 g (97%) of (2R,3R)-2,3-O-isopropylidene-1,2,3-dodeca-
netriol40 18 as a colourless oil, which was of sufficient purity to be
used directly for the next reaction. This material was spectro-
scopically and chromatographically identical to its enantiomer 14.
D20
[a
]
þ14.9 (c 1.0, CH2Cl2).
5.1.28. Preparation of (2R,3R)-2,3-O-isopropylidene-1-(tosyloxy)-
2,3-dodecanediol. To a round bottom flask were put (2R,3R)-2,3-O-
isopropylidene-1,2,3-dodectriol 18 (0.32 g, 1.16 mmol), Et2O
(10 mL) and TsCl (0.33 g, 1.74 mmol). The solution was cooled to
ꢁ5 ꢀC and freshly powdered KOH (1.0 g) was added portion-wise
over 15 min. After complete addition, the resulting mixture was
stirred for 2.5 h at 0 ꢀC and then ice water (10 mL) was added. The
solution was extracted with ether (3ꢂ25 mL) and the combined
organic phase was washed with water, dried over MgSO4, filtered
and solvent evaporated to give (2R,3R)-2,3-O-isopropylidene-1-
(tosyloxy)-2,3-dodecanediol (89%) as a tan coloured oil after silica
gel chromatography using 3:1 hexane/ethyl acetate (v/v) as eluent.
This material was spectroscopically and chromatographically
identical to its enantiomer (2S,3S)-2,3-O-isopropylidene-1-(tosy-
as eluent. 1H NMR (CDCl3):
d
6.96 (dt, 1H, J¼15.7, 7.0 Hz), 5.84 (dt,
1H, J¼15.7, 1.6 Hz), 4.18 (q, 2H, J¼7.1 Hz), 2.29 (dtd, 2H, J¼7.0, 7.0,
1.5 Hz), 1.45 (m, 2H), 1.28 (t, 3H, J¼7.1 Hz), 1.30e1.26 (m, 12H),
0.88 (t, 3H, J¼6.5 Hz). 13C NMR (CDCl3):
d 166.8, 149.5, 121.2, 60.1,
32.2, 31.8, 29.5, 29.4, 29.3, 29.1, 28.0, 22.7, 14.3, 14.1. IR (NaCl)
cmꢁ1: 2927 (CH), 1724 (C]O), 1265, 1181. MS mþ/z: 227 (Mþ1),
197, 181, 169, 162, 155, 144, 138, 127, 115, 109, 101, 95, 88, 81, 73,
67, 61, 55.
5.1.25. Preparation of ethyl (2S,3R)-2,3-dihydroxydodecanoate
(9). In a round bottom flask were placed tert-butyl alcohol (25 mL),
H2O (25 mL) and AD-mix-
temperature until all the AD-mix-
b
(0.7 g). The solution was stirred at room
had dissolved and then meth-
b
D20
loxy)-2,3-dodecanediol. [
a
]
þ9.7 (c 1.1, CH2Cl2).
anesulfonamide (0.5 mg, 5.0 mmol) and ethyl (E)-dodec-2-enoate
11 (1.1 g, 5.0 mmol) were added. The reaction mixture was stirred at
room temperature until TLC showed complete consumption of
starting material, Na2SO3 (7.5 g) was then added and stirring con-
tinued for another 45 min. The reaction mixture was extracted with
ethyl acetate (3ꢂ50 mL) and the combined organic layer was
washed with 2 N KOH, dried over MgSO4, filtered and the solvent
was removed to afford 1.1 g (81%) of ethyl (2S,3R)-2,3-dihydrox-
ydodecanoate39 9 as a pale yellow oil after purification by silica gel
chromatography using 2:1 hexane/ethyl acetate (v/v) as eluent. 1H
5.1.29. Preparation of (2R,3R)-1,2-epoxy-3-dodecanol tert-butyldi-
methylsilyl ether (8). In a round bottom flask were placed (2R,3R)-
l,2-epoxy-3-dodecanol
5 (0.2 g, 1.0 mmol), imidazole (0.1 g,
1.5 mmol) and DMF (3 mL). To this solution was then added TBSCl
(0.2 g, 1.1 mmol). The reaction mixture was stirred 16 h at room
temperature and quenched by addition of H2O (8 mL). The reaction
mixture was extracted with Et2O (3ꢂ10 mL) and the combined
extracts were washed with water, brine and dried over MgSO4. The
solvent was removed to afford 0.3 g of (2R,3R)-1,2-epoxy-3-
dodecanol tert-butyldimethylsilyl ether 8 (88%) as a colourless oil
after silica gel chromatography using 5:1 hexane/ethyl acetate (v/v)
NMR (CDCl3):
d
4.32 (q, 2H, J¼7.1 Hz), 4.10 (dd, 1H, J¼5.2, 2.1 Hz),
3.90 (m, 1H), 3.04 (d, 1H, J¼5.2 Hz), 1.86 (d, 1H, J¼9.2 Hz), 1.68e1.57
(m, 2H), 1.38e1.28 (m, 14H), 1.35 (t, 3H, J¼7.1 Hz), 0.91 (t, 3H,
as eluent. 1H NMR (CDCl3):
2.56 (m, 1H), 1.58e1.42 (s, 14H), 0.94e0.86 (m, 12H), 0.13 (s, 3H),
0.08 (s, 3H). 13C NMR (CDCl3):
74.6, 56.0, 44.9, 34.7, 31.9, 29.6, 29.5,
d 3.27 (m,1H), 2.93 (m,1H), 2.79 (m,1H),
J¼6.5 Hz). 13C NMR (CDCl3):
d 174.1, 73.0, 72.5, 62.2, 33.9, 31.9,
29.53, 29.5 (two signals), 29.3, 25.7, 22.7, 14.2, 14.1. IR (NaCl) cmꢁ1
:
d
D20
3374 (OH), 2915 (CH), 1713 (C]O), 1292, 1106. [
a]
þ9.8 (c 1.1,
29.3, 25.9 (two signals), 25.3, 22.7, 18.2, 14.1, ꢁ4.4, ꢁ5.0. IR (NaCl)
cmꢁ1: 2927 (CH), 1102, 837. MS mþ/z: 299, 271, 253, 227, 187, 157,
143, 131, 115, 101, 75, 67, 59. HRMS (mþþH) calcd for C18H39O2Si
CH2Cl2). Mp: 53.4e55.1 ꢀC.
5.1.26. Preparation of ethyl (2S,3R)-2,3-O-isopropylidene-dodeca-
ncarboxylate. To a round bottom flask were put ethyl (2S,3R)-2,3-
D20
]
D20
315.2719, found 315.2719. [
1.2, CH2Cl2).
a
ꢁ9.5 (c 1.0, CH2Cl2). [
a]
þ6.8 (c
dihydroxydodecanoate
9 (0.75 g, 2.88 mmol), CH2Cl2 (50 mL),
p-TSA (50 mg) and 2,2-dimethoxypropane (0.45 g, 4.32 mmol). The
reaction mixture was stirred overnight at room temperature and
then solid NaHCO3 (0.5 g) was added and the reaction mixture was
stirred for an additional 30 min. The reaction mixture was filtered
through a pad of neutral alumina and the filtrate concentrated to
afford 0.75 g of ethyl (2S,3R)-2,3-O-isopropylidene-dodeca-
ncarboxylate40 (87%) as a colourless oil after silica gel chromatog-
raphy using 10:1 hexane/ethyl acetate (v/v) as eluent. 1H NMR
5.1.30. Preparation of (9S,10R)-9-hydroxy-10-tert-butyldimethylsily-
loxynonadec-6-yne. In a round bottom flask cooled to ꢁ78 ꢀC were
put 1-heptyne (0.18 g, 1.91 mmol) and THF (20 mL) followed by
drop-wise addition of n-BuLi (1.10 mL, 1.6 M, 1.74 mmol). The
resulting mixture was stirred for 30 min and then BF3$Et2O
(0.21 mL, 1.74 mmol) was added followed 30 min later by (2R,3R)-
1,2-epoxy-3-dodecanol tert-butyldimethylsilyl ether
8 (0.18 g,
0.58 mmol) in THF (5 mL). The reaction mixture was stirred for 1 h
at ꢁ78 ꢀC and was then quenched with saturated aqueous NH4Cl.
The solution was extracted with ether (3ꢂ25 mL) and the combined
organic phase was washed with water, dried over MgSO4, filtered
and solvent evaporated to afford 0.14 g (61%) of (9S,10R)-9-hy-
droxy-10-tert-butyldimethylsilyloxynonadec-6-yne as a yellowish
oil after silica gel chromatography using 10:1 hexane/ethyl acetate
(CDCl3):
d
4.24 (qd, 2H, J¼7.2, 1.2 Hz), 4.13e4.08 (m, 2H), 1.82e1.62
(m, 2H), 1.46 (s, 3H), 1.44 (s, 3H), 1.36e1.24 (m, 14H), 1.29 (t, 3H,
J¼7.1 Hz), 0.88 (t, 3H, J¼6.5 Hz). 13C NMR (CDCl3):
d 171.0, 110.7,
79.3, 79.2, 61.3, 33.5, 31.9, 29.5 (two signals), 29.47, 29.3, 27.2, 25.7,
25.6, 22.7, 14.2, 14.1. IR (NaCl) cmꢁ1: 2926 (CH), 1761 (C]O), 1213,
D20
1100. [
a]
þ14.1 (c 1.1, CH2Cl2).
(v/v) as eluent. 1H NMR (CDCl3):
d 3.85 (m, 1H), 3.62 (m, 1H),
5.1.27. Preparation of (2R,3R)-2,3-O-isopropylidene-1,2,3-dodectriol
(18). To round bottom flask were put (2S,3R)-2,3-O-iso-
2.40e2.29 (m, 3H), 2.20e2.15 (m, 2H), 1.80e1.20 (m, 22H),
0.98e0.88 (m, 15H), 0.13 (s, 3H), 0.12 (s, 3H). 13C NMR (CDCl3):
a
propylidene-dodecancarboxylate (0.20 g, 0.66 mmol) and THF
d
82.4, 76.4, 72.7, 71.3, 33.8, 31.9, 31.1, 29.7, 29.6, 29.5, 29.3, 28.7,
(10 mL). The solution was cooled to 0 ꢀC and LAH (0.03 g,
25.9, 25.3, 24.6, 22.7, 22.2, 18.7, 18.1, 14.1, 14.0, ꢁ4.2, ꢁ4.7. IR (NaCl)

5338
D.I. MaGee et al. / Tetrahedron 67 (2011) 5329e5338
cmꢁ1: 3551 (OH), 2927 (CH). HRMS (mþþH) calcd for C25H50O2Si
Supplementary data
D20
431.3658, found 431.3655. [
a
]
ꢁ9.5 (c 1.0, CH2Cl2).
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.05.015.
5.1.31. Preparation of (9S,10R)-9-mesyloxy-10-tert-butyldimethylsi-
lyloxynonadec-6-yne. In a round bottom flask cooled to 0 to ꢁ10 ꢀC
were
put
(9S,10R)-9-hydroxy-10-tert-butyldimethylsilylox-
References and notes
ynonadec-6-yne (0.09 g, 0.23 mmol), dichloromethane (2 mL) and
triethylamine (0.05 mL, 0.35 mmol). To this solution was added
MsCl (0.02 mL, 0.25 mmol) and the resulting mixture was stored for
72 h in a fridge (4e8 ꢀC). It was then diluted with dichloromethane
(5 mL) and was washed with ice water (3 mL), 10% HCl solution,
saturated sodium bicarbonate solution and brine. The organic
phase was dried over MgSO4, filtered and the solvent evaporated to
yield 0.08 g of (9S,10R)-9-mesyloxy-10-tert-butyldimethylsilylox-
ynonadec-6-yne (70%) as a pale yellow oil after silica gel chroma-
tography using 5:1 hexane/ethyl acetate (v/v) as eluent. 1H NMR
1. Ciesla, W. M. Ann. Entomol. Soc. Am. 1965, 57, 591e596.
2. Johnson, W. T.; Lyon, H. H. Insects that Feed on Shrubs, 2nd ed.; Cornell
University Press: Ithaca, NY, 1988.
3. Fedde, G. F. J. For. 1964, 62, 102e106.
4. Morin, R. S.; Liebhold, A. M.; Gottschalk, K. N. J. Appl. For. 2004, 21, 31e39.
5. Fry, H. R. C.; Quiring, D. T.; Ryall, K. L.; Dixon, P. L. J. Econ. Entomol. 2008, 101,
822e828.
6. Ryall, K.; Silk, P. J.; Wu, J.; Mayo, P.; Lemay, M. A.; MaGee, D. Naturwissenschaften
2010, 97, 717e724.
7. Millar, J. G. Annu. Rev. Entomol. 2000, 45, 575e604.
8. Ando, T.; Inomata, S.; Yamamoto, M. Top. Curr. Chem. 2004, 239, 51e96.
9. El-Sayed, A. M. The pherobase: database of insect pheromones and semio-
chemicals, 2008. http://www.pherobase.com.
10. Granett, J. J. Econ. Entomol. 1973, 66, 808e809.
11. Mori, K. Tetrahedron 1974, 30, 3817e3820.
(CDCl3):
d 4.57 (m, 1H), 3.96 (m, 1H), 3.14 (s, 3H), 2.74 (dm, 1H,
J¼17.2 Hz), 2.52 (ddd, 1H, J¼17.0, 8.1, 2.3 Hz), 2.18e2.12 (m, 2H),
1.54e1.26 (m, 22H), 0.92 (m, 15H), 0.14 (s, 3H), 0.10 (s, 3H). 13C NMR
12. Rodin, J. O.; Silverstein, R. M.; Burkholder, W. E.; Gorman, J. E. Science 1969, 165,
904e906.
13. Tumlinson, J. H.; Klein, M. G.; Doolittle, R. E.; Ladd, T. L.; Proveaux, A. T. Science
(CDCl3):
d 82.9, 82.8, 75.7, 72.0, 38.5, 31.9, 31.4, 31.1, 29.6, 29.5 (two
signals), 29.3, 28.5, 25.8 (two signals), 25.4, 22.7, 22.2,19.9,18.7, 18.0,
14.1, 14.0, ꢁ4.54, ꢁ4.59. IR (NaCl) cmꢁ1: 2928 (CH), 1725, 1366, 1178.
HRMS (mþþH) calcd for C26H53O4SSi 489.3434, found 489.3434.
1977, 197, 789e792.
14. Talerico, R. L. Home and Garden Bull. 1978, 224, 1e23.
15. Iwaki, S.; Marumo, S.; Saito, T.; Yamada, M.; Karagiri, K. J. Am. Chem. Soc. 1974,
7842e7844.
16. Pougny, J. R.; Rollin, P. Tetrahedron Lett. 1987, 28, 2977e2978.
17. Bell, T. W.; Ciaccio, J. A. J. Org. Chem. 1993, 58, 5153e5162.
18. Rossiter, B. E.; Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 464e465.
19. Leznoff, C. C. Acc. Chem. Res. 1978, 11, 327e333.
5.1.32. Preparation
of
(9S,10R)-9,10-epoxy-nonadec-6-yne. In
a round bottom flask were put (9S,10R)-9-mesyloxy-10-tert-butyl-
dimethylsilyloxynonadec-6-yne (55 mg, 0.1 mmol) and THF (3 mL)
followed by drop-wise addition of TBAF (1 M soln in THF, 0.11 mL,
0.11 mmol). The reaction mixture was stirred for 1 h at room tem-
perature and was then quenched with saturated aqueous NH4Cl.
The solution was extracted with ether (3ꢂ5 mL) and the combined
organic phase was washed with water, dried over MgSO4, filtered
and solvent evaporated to afford 26 mg of (9S,10R)-9,10-epoxy-
nonadec-6-yne (85%) as a colourless oil after purification by silica
gel chromatography using 8:1 hexane/ethyl acetate (v/v) as eluent.
This material was identical in all respects to the material synthe-
20. McDougal, P. G.; Rico, J. G.; Oh, Y. I.; Condon, B. D. J. Org. Chem. 1986, 51,
3388e3390.
21. Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 2480e2482.
22. Doolittle, R. E.; Heath, R. R. J. Org. Chem. 1984, 49, 5041e5050.
23. Che, C.; Zhang, Z. N. Tetrahedron 2005, 61, 2187e2193.
24. Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391e394.
25. Schmidt, C. R.; Bryant, J. D. Org. Synth. 1993, 72, 6e13.
26. Adam, C. E.; Walker, F. J.; Sharpless, K. B. J. Org. Chem. 1985, 50, 422e424.
ꢀ
27. Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18, 2199e2204.
28. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crisoino, G. A.; Hartung, J.; Jeong,
K.; Kwong, H.; Morikawa, K.; Wang, Z.; Xu, D.; Zhang, X. J. Org. Chem. 1992, 57,
2768e2771.
29. Naidu, S. V.; Gupta, P.; Kumar, P. Tetrahedron 2007, 63, 7624e7633.
30. Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.; Hartung, J.; Kawanawi, Y.;
D20
sized from the previous route. [
a]
þ30 (c 2.6, CH2Cl2).
€
Lubben, D.; Manoury, E.; Ogino, Y.; Shibata, T.; Ukita, T. J. Org. Chem. 1991, 56,
4585e4588.
Acknowledgements
31. Kobayashi, Y.; Kokubo, Y.; Aisaka, T.; Saiga, T. A. Tetrahedron: Asymmetry 2008,
19, 2536e2541.
32. Mash, E. A.; Nelson, K. A.; Van Deusen, S.; Hemperly, S. B. Org. Synth. 1990, 68,
92e98.
33. Henry, N.; Robertson, M. N.; Marquez, R. Tetrahedron Lett. 2007, 48, 6088e6091.
34. Fernandes, R. A. Eur. J. Org. Chem. 2007, 5064e5070.
35. Danel, M.; Gagnaire, J.; Queneau, Y. J. Mol. Cat. A: Chem. 2002, 184, 131e138.
36. Zhang, Z. B.; Wang, A. M.; Wang, Y. X.; Liu, H. Q.; Lei, G. X.; Shi, M. Tetrahedron:
Asymmetry 1999, 10, 837e840.
37. Millar, J. G.; Giblin, M.; Barton, D.; Underhill, E. W. J. Chem. Ecol. 1991, 17,
911e929.
38. Ichimoto, I.; Machiya, K.; Kirihata, M.; Ueda, H. Agric. Biol. Chem. 1990, 54,
657e662.
We wish to thank the Natural Sciences and Engineering Re-
search Council of Canada (NSERC-Discovery grant), Natural Re-
sources Canada, Canadian Forest Service, and Ontario Natural
Resources through SERG International, and UNB for funding of this
project. We thank Gaetan LeClair, Matt Lemay, Andrea Sharpe,
Catherine Desjardins, Heidi Fry, Gilles Vautour and Larry Calhoun
for their technical assistance. We thank Jocelyn Millar (University of
California Riverside) and Ashot Khrimian (United States De-
partment of Agriculture) for the gift of several epoxide compounds
as analytical standards during the exploratory stage of this study.
All experiments reported here comply with the laws of Canada.
39. Schneekloth, J. S., Jr.; Sanders, J. L.; Hines, J.; Crews, C. M. Bioorg. Med. Chem. Lett.
2006, 16, 3855e3858.
40. Fernandez, R. A.; Kumar, P. Tetrahedron 2002, 58, 6686e6690.