Synthesis of disparlure analogues, using resolution on microcrystalline cellulose triacetate-I

Article abstract of DOI:10.1016/j.tetasy.2005.10.031

The gypsy moth, Lymantria dispar, uses a chiral epoxide, (+)-(7R,8S)-2-methyl-7,8-epoxyoctadecane, (+)-disparlure, as its main sex attractant. The moths can detect both enantiomers of disparlure and respond differently to each one. In an effort to understand the structure-activity relationships of the gypsy moth olfactory system, we prepared the analogues of (+)- and (-)-disparlure. The key intermediate in route to the analogues was 2-epoxytridecan-1-ol. Herein we report the resolution of 2-epoxytridecan-1-yl esters on microcrystalline cellulose triacetate and the synthesis of 5-oxa and (5Z)-ene analogues of (+)- and (-)-disparlure. An effort to make 5-aza analogues resulted in the formation of anti-5-(1-hydroxy-1-undecyl)-3-(3-methylbutyl) oxazolidin-2-one. The analogues were tested for their electroantennogram responses and for their ability to bind to pheromone-binding protein 1 (PBP1). We found that the 5-oxa analogues gave strong responses and that the antenna and the PBP1 no longer distinguish the enantiomers of the 5-oxa analogues. The analogues all bound the PBP1 with similar affinity to (-)-disparlure.

Full text of DOI:10.1016/j.tetasy.2005.10.031

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3773–3784
Synthesis of disparlure analogues, using resolution
on microcrystalline cellulose triacetate-I
James A. H. Inkster,a Ivy Ling,b Nicolette S. Honson,b Lo¨ıc Jacquet,c
Regine Griesd and Erika Plettnerb,*
aTRIUMF, 4004 Wesbrook Mall, Vancouver, B.C., Canada V6T 2A3
bDepartment of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, B.C., Canada V5A 1S6
cCamfil-Farr France, 77/81 Bld de la Re´publique, 92257 La Garenne Colombes Cedex, France
dDepartment of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, B.C., Canada V5A 1S6
Received 18 June 2005; accepted 18 October 2005
Abstract—The gypsy moth, Lymantria dispar, uses a chiral epoxide, (+)-(7R,8S)-2-methyl-7,8-epoxyoctadecane, (+)-disparlure, as
its main sex attractant. The moths can detect both enantiomers of disparlure and respond differently to each one. In an effort to
understand the structure–activity relationships of the gypsy moth olfactory system, we prepared the analogues of (+)- and (ꢀ)-dis-
parlure. The key intermediate in route to the analogues was 2-epoxytridecan-1-ol. Herein we report the resolution of 2-epoxytri-
decan-1-yl esters on microcrystalline cellulose triacetate and the synthesis of 5-oxa and (5Z)-ene analogues of (+)- and
(ꢀ)-disparlure. An effort to make 5-aza analogues resulted in the formation of anti-5-(1-hydroxy-1-undecyl)-3-(3-methylbutyl)oxa-
zolidin-2-one. The analogues were tested for their electroantennogram responses and for their ability to bind to pheromone-binding
protein 1 (PBP1). We found that the 5-oxa analogues gave strong responses and that the antenna and the PBP1 no longer distinguish
the enantiomers of the 5-oxa analogues. The analogues all bound the PBP1 with similar affinity to (ꢀ)-disparlure.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
O
The main component of the gypsy moth, Lymantria
dispar, sex attractant pheromone is (+)-(7R,8S)-epoxy
2-methyloctadecane [(+)-disparlure], (+)-1.1–3 This com-
pound is required for upwind flight of male moths to the
pheromone-emitting females. The enantiomer (ꢀ)-1 is
neither attractive nor repellent by itself, but when pre-
sented simultaneously with (+)-1, it cancels upwind
flight behavior in the males.4 Studies on the olfactory
mechanisms of these moths have revealed that there
are distinct neurons, housed in separate populations of
sensory hairs, that respond to one of the two disparlure
enantiomers.2 Furthermore, the two pheromone-binding
proteins (PBPs) of the gypsy moth bind both enantio-
mers, although PBP1 prefers to bind (ꢀ)-1, while
PBP2 prefers to bind (+)-1.5
O
C10H21
C10H21
(+)-1
(-)-1
dihydroxylation.9 Compound (+)-1 has also been pre-
pared from L-(+)-tartaric acid,10,11 (ꢀ)-2-deoxy-D-
ribose,12 (S)-(+)-glutamic acid,13 and tri-O-acetyl-
D-galactal.14 Chiral auxiliaries have also been used in
several syntheses.6,7,9,15,16 The resolutions of key inter-
mediates have also been reported, for example, pig
pancreatic lipase has been used to resolve 1,4-diacet-
oxy-cis-2,3-epoxybutane;17 Amano PS lipase has been
used to resolve (syn)-ethyl-3-chloro-2-hydroxytridecano-
ate;18 cis-4-bromo-2,3-epoxybutyl-(1S)-10-camphorsul-
fonate diastereomers have been resolved by fractional
crystallization and are now available commercially,19
and b-hydroxysulfide intermediates have been resolved
as (R)-1-(1-naphthyl)ethyl isocyanate derived carba-
mates.20 We chose to resolve cis-2,3-epoxytridecan-1-yl
p-bromobenzoate 2c on microcrystalline cellulose triace-
tate I (MCTA-I). Herein, we report the synthesis of both
Disparlure enantiomers have been synthesized individu-
ally by asymmetric epoxidation6–8 or asymmetric
*
Corresponding author. Tel.: +1 604 291 3586; fax: +1 604 291
3765; e-mail: plettner@sfu.ca
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.10.031

3774
J. A. H. Inkster et al. / Tetrahedron: Asymmetry 16 (2005) 3773–3784
enantiomers of several disparlure analogues, using ester
2c resolved on MCTA-I. We also report the electrophys-
iological and pheromone-binding protein 1 (PBP1) bind-
ing activity of the analogues.
mobenzoates separated with near-baseline resolution,
and the pooled fractions of each enantiomer had none
of the opposite enantiomer detectable by the GC method.
From the specific rotation and the MTPA ester of
alcohol (ꢀ)-3, the ee of its precursor, ester (+)-2c, must
have been P97%. Ester (ꢀ)-2c had a similarly high ee,
as could be inferred from the MTPA ester of alcohol
(+)-3 and the similar rotations of opposite sign obtained
for ethers (ꢀ)-5 and (+)-5, and epoxides (ꢀ)-7 and
(+)-7, obtained from (ꢀ)-3 and (+)-3, respectively
(Scheme 1).
2. Results and discussion
2.1. Resolution on MCTA-I
MCTA-I is a widely used, economical chiral stationary
phase for both analytical and preparative separa-
tions.21–23 Structure–activity relationships have been
undertaken with derivatives of trans-2-phenyl-1-cyclo-
hexanols, glycerol, 1-phenyl-2-propanol, 3-phenyl-1,2-
propanediol (chromatographed as the 1,3-dioxanes),
1,2- and 1,3-diols, 2,3-epoxypropan-1-ol (oxyranyl-
methanol), 4-hydroxy-cyclopent-2-enone,23 and c- and
d-lactones.22 A variety of compounds with aryl moieties
have also been separated.24 Apart from a pyranyl diol,25
1-fluorenyl-1-ethanol and 10-ethyl-20,20,20-trifluoroethyl-
anthracene,26 alcohols generally do not separate readily
on MCTA-I, although the corresponding benzoate es-
ters have been found to separate cleanly.21,23 Within
one series of aryl-containing compounds, a relationship
was seen with respect to the electronic and/or steric
character of the substituent on the aryl moiety. Amongst
the benzoate esters, p-chloro and p-bromo esters often
ranked highly in their separation and resolution factors.
Usually within a series, the elution order of the enantio-
mers remained constant across the series.23 Both shape
and electronic interactions appear to govern the extent
to which enantiomers separate on MCTA-I.23,24,27
2.2. Synthesis of disparlure and the analogues
Ester 2c could be readily saponified, without significant
Payne rearrangement.28,29 Alcohol 3 was then converted
to ether 5 by deprotonation of the alcohol with NaH,
followed by reaction with the primary alkyl bromide
to furnish the ether. Similar conditions have been used
previously to alkylate 2,3-epoxy primary alcohols in
high yield.29 Alcohol 3 was also converted to aldehyde
6. Aldehyde 6 was sufficiently stable to be purified by
flash chromatography, but it could not be stored for
extended periods of time. Thus, intermediate 6 was
reacted immediately in the next step, either via a Wittig
reaction to give 7 or a reductive amination to afford 8.
During purification of compound 8 by flash chromato-
graphy, oxazolidinone 9 was formed by absorption of
CO2 from air (Scheme 2). Compound 9 accumulated
as a white solid in the fractions. A similar reaction with
CO2 has been reported for allylamines reacted with I2
under a CO2 atmosphere.30 The approach used here
gave epoxy alcohols (+)-3 and (ꢀ)-3 in high enantio-
1
Our results with esters 2a,b, and 2c are consistent with
these previous studies, with the enantiomers of the p-
bromobenzoate separating best and the enantiomers of
the acetate separating least (Table 1), with the (ꢀ)-enan-
tiomer eluting first always. Alcohol 3 was retained, but
did not separate on MCTA-I (Table 1). The p-bro-
meric purity (P97% ee). Furthermore, H NMR data
of the MTPA esters 4a and 4b of alcohols (ꢀ)-3 and
(+)-3, respectively, were consistent with previously
reported data,8 while the specific rotations of (ꢀ)-3,
(+)-7, and (ꢀ)-7 are in accordance with previously
reported values.6,8,14
Table 1. Separation of esters 2a–c and alcohol 3 on MCTA-I
Compound
Columna
Temperature (ꢁC)
Solvent
Flow (mL/min)
0.1
Retention times (h)
Rb
ac
2a
Medium
30
Ethanol–water 9:1
3.5
3.8
4.7
5.3
6.3
9.5
11
0.2
1.1
2b
2c
3
Medium
Medium
Medium
Large
30
30
20
50
50
50
Ethanol–water 9:1
Ethanol–water 9:1
Hexane–ether 4:1
Ethanol–water 9:1
Ethanol–water 9:1
Ethanol–water 9:1
0.1
0.1
0.1
1.0
0.5
0.5
0.7
1.0
0.6
1.1
1.1
1.0
1.1
1.5
1.2
1.3
1.2
1.3
13
2c
2c
2c
6.5
8.4
13.8
16.8
14.3
18.3
Large
Large
a See text; the medium-sized column was used to separate 10–30 mg, and the large column was used to separate typically 100–200 mg of racemic
material.
b Resolution (R), estimated as = separation between peaks/(1.7 · average peak width at half height).21
c Separation factor a ꢁ retention time (late)/retention time (early).21 Strictly, the separation factor a is the ratio of the retention factors, k = (t ꢀ to)/
to, where t is the retention time of the compound and to is the retention time of an unretained substrance. However, we do not know any substance
that is completely unretained on MCTA-I.38

J. A. H. Inkster et al. / Tetrahedron: Asymmetry 16 (2005) 3773–3784
3775
C10H21
HO
i, ii
ii
O
O
OH
C10H21
O
Br
MCTA-I
O
R
O
O
O
baseline
separation:
2c
C10H21
C10H21
(+)-2c
3
2 a: R = CH3
b: R = phenyl
c:R= p-bromo
phenyl
MCTA-I
(poor separation)
iii
O
Ph
iv
O
OH
O
OMe
O
CF3
C10H21
C10H21
(-)-3
4
racemic-6
vi
R' =
v
viii
O
R'
R'
+
N
H
N
H
O
O
H
O
O
O
C10H21
C10H21
C10H21
cis-8
C10H21
(-)-6
(-)-5
vii
O
O
R'
R'
N
O
N
O
+
O
HO
HO
C10H21
C10H21
(-)-7
C10H21
anti-9
Scheme 1. Synthesis of disparlure analogues from ester 2c, resolved on a column of microcrystalline cellulose triacetate I (MCTA-I). Reagents and
conditions: (i) the appropriate acyl chloride, pyridine, CH2Cl2, DMAP; (ii) m-CPBA; (iii) 1 M KOH in EtOH; (iv) MTPA-Cl, pyridine, CCl4; (v) (1)
NaH in DMF, (2) (CH3)2CH(CH2)2Br; (vi) PCC, CH2Cl2; (vii) (1) (Ph)3P(CH2)3CH(CH3)2, THF, n-BuLi; (2) 6; (viii) (1) (CH3)2CH(CH2)2NH2,
CH2Cl2, molecular sieves; (2) NaBH4, MeOH.
H+
R
R
R
HO
H
O
O
O C O
R'
O
N
N
N R'
O
R'
H+
O
-O
Scheme 2. Possible mechanism of oxazolidinone 9 formation by reaction of 8 with CO2.
2.3. Physiological and biochemical assays
sensory hairs located between the reference and record-
ing electrodes.31 The dose–response for (ꢀ)-5 [the ether
analogue of (+)-1] was slightly lower overall than the
dose–response for (+)-1 (Fig. 2). This response pattern
can also be seen in the saturation study (Table 3), where
(ꢀ)-5 gave smaller responses than (+)-1 with respect to
depolarization, hyperpolarization and recovery time
(all P < 0.05, t-test). The analogue of (ꢀ)-1, (+)-5,
The analogues were tested by GC-electroantenno-
graphic detection (GC-EAD); the only compounds that
gave a signal were ether analogues (ꢀ)-5 and (+)-5
(Table 2). The dose–responses for the analogues were
obtained from electroantennogram (EAG) recordings
(Fig. 1). EAG traces reveal the summed responses from

3776
J. A. H. Inkster et al. / Tetrahedron: Asymmetry 16 (2005) 3773–3784
Table 2. GC-electroantennogram detector (GC-EAD) responses
where the downstream response of pheromone olfactory
neurons would be impaired by the perception of the
compound. The latter mechanism is utilized by insects
in recognition of pheromone blends from other related
species.32,33 Adaptation should manifest itself in EAG
experiments, in which the analogue and pheromone
(+)-1 are passed in an alternating fashion over an ant-
enna. If inhibition is successful, then one expects
decreased depolarization, decreased hyperpolarization
and increased recovery times for both (+)-1 and the test
compound. None of the analogues tested caused signif-
icant decreases in depolarization and hyperpolarization.
Furthermore none of the analogues caused a significant
increase in recovery times (Table 3, all P > 0.05, t-test).
Thus, none of the compounds tested were a potential
olfactory inhibitor at the peripheral level, even though
the compounds bind to the pheromone-binding protein
(see below). The second form of olfactory inhibition,
at the level of the brain, should manifest itself in behav-
ioral and field tests. Such inhibition requires that the test
compound be detected by the insect. Ethers (+)-5 and
(ꢀ)-5 are good candidates for this type of olfactory inhi-
bition, because they give significant EAG responses by
themselves (Fig. 2, Table 3). These two compounds will
be tested further in future experiments.
Compounda
Responseb
(+)-Disparlure 1
(ꢀ)-Disparlure 1
(ꢀ)-Ether 5
++++
+++
++
(+)-Ether 5
+
(ꢀ)-(5Z)-Ene 7
None
None
None
None
None
(+)-(5Z)-Ene 7
(
)-Oxazolidinone 9
(ꢀ)-3
(+)-3
a 100 ng of each compound was injected.
b Ô+Õ Indicate that a GC-EAD peak was observed at the correct
retention time. The number of Ô+Õ indicates the relative magnitude of
the response. At least four injections were done for each compound.
showed a similar dose–response to (ꢀ)-1 (Fig. 2), which
was weaker than the response towards (+)-1 (Table 3,
depolarization, hyperpolarization, and recovery time,
all P < 0.05, t-test) and not significantly different from
the response to (ꢀ)-5 (Table 3, depolarization, hyperpo-
larization, and recovery time, all P > 0.05, t-test). Thus,
the introduction of the oxygen atom at the 5-position of
the pheromone structure lowered the ability of the moth
antenna to distinguish between the enantiomers of
compound 5, compared to the biologically active
compounds (+)-1 and (ꢀ)-1 (Fig. 2, Table 3). The
(5Z)-alkene analogues (ꢀ)-7 and (+)-7 gave no GC-
EAD response and the EAG responses did not differ
from hexane controls. Thus, (ꢀ)-7 and (+)-7 were not
investigated further. Racemic oxazolidinone 9 showed
no significant increase in the response to increasing the
dose (Fig. 2). General odorants gave much weaker
responses than epoxides 1, ethers 5, or oxazolidinone
9 (Fig. 2).
The pheromone-binding proteins (PBPs) in the sensillar
lymph are the first components of the insect olfactory
system that interact with the pheromone.34 We screened
analogues that showed EAG activity for their ability to
bind PBP1. We used a fluorescent probe displacement
assay, that can quickly give a ranking of kinetic affinity
of a PBP for various ligands.35 PBP1 bound the fluores-
cent probe with good affinity (1.5 lM) while PBP2 did
not bind the probe. PBP1 is the more discriminatory
of the two PBPs, and binds preferentially (ꢀ)-1.5 Inter-
estingly, PBP1 binds (ꢀ)-5 and (+)-5 with nearly the
same affinity as (ꢀ)-1 (Table 4). The affinity of PBP1
for (+)-1 was much weaker than for (ꢀ)-1, consistent
with what is known about this PBP from equilibrium
binding assays.5 Oxazolidinone 9 also bound to PBP1,
with approximately the same affinity as (7Z) 2-methyl-
We hoped to find compounds that interfered with phero-
mone signaling in one or more insect species. Such inter-
ference could occur on two levels: (1) the peripheral
level, where the compound would interfere with one
(or more) molecular process(es) in the antenna of the
insect and cause adaptation, or (2) the level of the brain,
Figure 1. Electroantennogram (EAG) experiment. The four peaks in each group correspond to 1, 10, 100, and 1000 ng of the odorant applied to a
filter paper and delivered to the antenna in a puff of air. The first odorant in this case was (ꢀ)-5, the second was (ꢀ)-1 and the third was (+)-1. The
duration of the air puffs is indicated by the bars at the top.

J. A. H. Inkster et al. / Tetrahedron: Asymmetry 16 (2005) 3773–3784
Depolarization Hyperpolarization
3777
Recovery time
30
20
10
0
9
6
3
0
6
5
4
3
2
1
0
-1
0
1
2
3
-1
0
1
2
3
-1
0
1
2
3
log (dose)
log (dose)
log (dose)
16
12
8
4
6
5
4
3
2
1
0
3
2
1
0
4
0
-1
0
1
2
3
-1
0
1
2
3
-1
0
1
2
3
log (dose)
log (dose)
log (dose)
0.3
4.0
3.0
2.0
1.0
0.0
3.0
2.0
1.0
0.0
0.2
0.1
0.0
0
1
0
1
2
3
0
1
2
3
2
3
log (dose)
log (dose)
log (dose)
Figure 2. Dose–responses for (+)-1, (ꢀ)-1, (ꢀ)-5, (+)-5, racemic 9, and three general odorants (camphor, geraniol, and menthol). Row 1: diamonds
(+)-1, squares (ꢀ)-1; Row 2: diamonds (ꢀ)-5, squares (+)-5, triangles 9; Row 3: circles camphor, diamonds geraniol, crosses menthol. Mean S.E.
for compounds (+)- and (ꢀ)-1, (+)- and (ꢀ)-5, and 9 (n = 5–12) and mean range for the general odorants (n = 3).
octadec-7-ene, the parent hydrocarbon of epoxides (+)-1
and (ꢀ)-136 and also a weak odorant in the gypsy moth.4
points are uncorrected. Optical rotations were obtained
on a Perkin–Elmer Polarimeter 340 thermostatted to
20 ꢁC, using the sodium D line. Routine gas chromato-
graphy and GC-EAD was done on a HP 5890A gas
chromatograph, fitted with a split/splitless injector, a
flame ionization detector (FID) and a DB-5 column
(30 m · 0.25 mm i.d., film thickness 0.25 lm). The GC
was operated in the splitless mode, using the following
temperature program: 100 ꢁC (5 min), 10ꢁ/min to
200 ꢁC (4 min), 50ꢁ/min to 250 ꢁC (20 min). Chiral ana-
lytical GC was performed on a Varian 3400 GC with a
3. Conclusions
We have used MCTA-I chiral resolution of a racemic
ester to prepare enantiomerically pure cis-(2,3)-epoxy-
tridecan-1-ol, 3. This alcohol was converted to various
analogues of disparlure. Amongst these analogs, the 5-
oxa forms of disparlure, (ꢀ)-5 and (+)-5, had the highest
electroantennogram activity and bound to the phero-
mone-binding protein 1 (PBP1). None of the analogues
caused adaptation of isolated gypsy moth antennae.
split/splitless injector,
a FID and a CycloSil-B
(30m · 0.25 mm i.d., film thickness 0.25 lm, JW Scien-
tific, Folsom CA) column. The GC was operated at
170 ꢁC isothermally, at 20 psi head pressure. Quantities
of (+)-1 and of (ꢀ)-1, prepared by hydrogenation of
(ꢀ)-7 and (+)-7, were too small to obtain specific rota-
tions. We used commercial (+)-1 (Aldrich) for EAG
studies. The (ꢀ)-1 for the EAG studies was obtained
from Dr. G. Gries (S.F.U.).
4. Experimental
4.1. General
Solvents were distilled prior to use: THF was distilled
over Na/benzophenone, ethyl acetate, and hexane were
distilled in glass with a 40 cm long Vigreaux column
prior to use. Thin-layer chromatography (TLC) was
run on plates with aluminum backing and fluorescein
as a fluorescent indicator (Merck). Most compounds
were visible under UV light on these TLC plates, but
for confirmation, plates were also stained with either
phosphomolybdic acid or anisaldehyde stain. NMR
spectra were obtained on a Brucker 400 MHz instru-
ment with the CHCl3 band as a reference. Melting
4.2. Synthesis of cis-2,3-epoxytridecan-1-yl p-bromo-
benzoate, 2c
4.2.1. Propargyl alcohol tetrahydropyranyl ether. Neat
dihydropyran (7.51 g, 11.2 mol) was placed in a round-
bottomed flask and cooled to 0 ꢁC. A small crystal of
TsOH catalyst was added; when the crystal was nearly
dissolved, propargyl alcohol (5.00 g, 11.2 mol) was
added and the solution was left to stir for 2 12 h. The
reaction was quenched with 10% NaHCO3 solution

Table 3. EAG data for alternating stimuli of (+)-1 and various test compoundsa
Test compound
Measurement
nb
Response to first stimulus
Size of subsequent responses, relative to the response to
the first stimulusc (%)
Size of test compound
response relative to the
response to (+)-1d (%)
(+)-1
Compound
Second
Compound
95 10
Third
Compound
(+)-1
(+)-1
First
Second
Third
Clean air
(ꢀ)-1
(ꢀ)-5
(+)-5
9
Depolarization (mV)
Depolarization (mV)
Depolarization (mV)
Depolarization (mV)
Depolarization (mV)
6
4
13
12
5
19.7 4.1
22.0 2.3
24.9 2.7
27.8 2.7
10.9 0.5
5.7 1.5
7.3 0.9
9.7 1.0
10.8 0.9
3.0 0.2
102
95
2
3
1
2
4
105 10
105
9
7
6
7
7
23
33
39
40
28
5
1
1
2
1
22
38
40
39
30
5
2
2
2
4
25
36
40
37
23
6
2
2
2
2
110
98
96
9
3
7
95
93
97
4
2
3
3
105
95
89
95
97
101
110 18
102
82
Clean air
(ꢀ)-1
(ꢀ)-5
(+)-5
9
Hyperpolarization (mV)
Hyperpolarization (mV)
Hyperpolarization (mV)
Hyperpolarization (mV)
Hyperpolarization (mV)
6
4
13
12
5
6.3 1.9
7.7 0.9
8.5 1.0
9.7 1.1
5.3 0.1
2.6 0.2
3.9 0.3
3.6 0.3
2.8 0.4
2.0 0.1
113 15
99 23
128 27
97 25
69 14
103 11
118 22
40 13
32
39
39
36
33
9
2
4
4
2
30
35
43
34
38
7
7
3
5
3
106
109
108
106
3
6
3
3
82
99
3
9
100
103
101
104
8
6
5
0
52
47
31
38
4
6
4
1
144 22
93
6
102
8
Clean air
(ꢀ)-1
(ꢀ)-5
(+)-5
9
Recovery time (s)
Recovery time (s)
Recovery time (s)
Recovery time (s)
Recovery time (s)
6
4
13
12
5
7.9 1.2
9.3 0.8
9.9 0.9
9.8 0.8
7.3 0.5
7.3 1.1
8.0 0.8
7.0 0.8
6.2 0.8
6.3 0.6
103
105
103
104
8
6
9
9
83 17
108 13
75 10
89 31
93 13
102 11
111 19
73 23
55 14
69 10
69 10
51 15
82 10
76 12
76 10
94 19
83
97
9
9
88
92
93
5
8
8
86
69
62
86
9
6
6
8
115 29
92
61
76
8
3
103 11
6
77 23
a Pheromone (+)-1 and the test compound were passed over the antenna in 2.5 s puffs, alternating between (+)-1 and the test compound, three times. Between puffs the antenna was allowed to recover to
the resting potential. The first stimulus of a series was always with (+)-1. The dose of both compounds was 1 lg, delivered on a filter paper in a cartridge.
b Data shown is the mean S.E. for n replicates.
c Determined relative to the first stimulus of either (+)-1 or the test compound.
d Determined for the first, second and third pairs of (+)-1 and test compound stimuli.

J. A. H. Inkster et al. / Tetrahedron: Asymmetry 16 (2005) 3773–3784
Table 4. PBP1 binding with various ligandsa
3779
(0.6 g, 3 mmol) was added, and the reaction stirred for
3 h 20 min. The reaction was quenched with aqueous
Na2CO3, adjusted to pH 10, diluted with ethyl acetate
(60 mL), washed twice with aqueous Na2CO3 (pH 10).
The aqueous portion was back-extracted twice, and the
organic portion pooled, washed with brine (30 mL),
dried over Na2SO4, and concentrated. Flash-chromato-
graphy on silica gel (10:1 hexane–ethyl acetate) yielded
the title compound (3.90 g, 96% yield), as a yellow oil.
The reaction was also achieved by H2 reduction on
Pd/C poisoned with quinoline, yielding a mixture of
Z- (ꢂ80%) and E-isomers. Purification of the alkenol
on a silica column containing 5% silver nitrate (93:6:1
Ligand
IC50 (nM)
Emission maximum
(nm)
(+)-Disparlure (+)-1
(ꢀ)-Disparlure (ꢀ)-1
(ꢀ)-Epoxy ether (ꢀ)-5
(+)-Epoxy ether (+)-5
100
4.7
8.5
13.2
22.6
260
212
168
26.4
389
380
381
381
380
381
381
382
381
(
)-Oxazolidinone 9
Geraniol
Menthol
(1R)-(+)-Camphor
(7Z)-2-Methyloctadec-7-ene
a Determined with a 1-NPN competitive displacement assay.
1
hexane–ether–toluene) yielded >96% Z-compound. H
NMR (400 MHz, CDCl3): Z-isomer d 0.88 (t, J =
7.4 Hz, 3H), 1.25 (br s, 14H), 1.35 (m, 2H), 1.54 (br,
OH), 2.06 (dt, J = 7.4, 7.0 Hz, 2H), 4.19 (d, J =
6.6 Hz, 2H), 5.57 (m, 2H).
(20 mL), diluted with ether (90 mL), and washed twice
with 10% NaHCO3 (20 mL). The aqueous portion was
back-extracted and the organic layers combined, washed
once with brine (10 mL), dried over Na2SO4, and puri-
fied by flash-chromatography on a silica column (1:1
hexane–ether) to give 12.24 g of the title compound (98%
4.2.4. (2Z)-Tridecen-1-yl p-bromobenzoate. Into a dry
round-bottomed flask containing pyridine (25 mL),
(2Z)-tridecen-1-ol (1.3012 g, 6.56 mmol) was added, fol-
lowed by p-bromobenzoyl chloride (1.5910 g,
7.25 mmol) and the reaction left to stir at room temper-
ature for 16 h. The reaction was quenched with 0.1 M
HCl (10 mL), diluted with ether (75 mL), and washed
twice with 0.1 M HCl (10 mL) and once with ice water
(10 mL). The aqueous portion was back-extracted and
the organic portions combined, washed once with brine
(10 mL), dried over MgSO4, and purified by flash-chro-
matography on silica gel (7:1 hexane–ether) to afford
2-tridecen-1-yl p-bromobenzoate (1.8678 g, 75% yield),
a colorless oil. GC–MS (EI): m/z (rel. abundance %)
353 (2%, M+ꢀC2H4), 351 (1%, M+ꢀC2H4), 301 (6%,
M+ꢀBr), 201 (21%), 203 (20%) 183 (95%, COC6H6Br+),
185 (100%, COC6H6Br+), 155 (10%), 157 (12%). IR
(KBr, cmꢀ1): 3078 (@C–Hstr.), 2926, 1723 (C@O),
1583, 1437, 1269, 1098, 703, 517 (C–Br). 1H NMR
(400 MHz, CDCl3): d 0.87 (t, J = 7.2 Hz, 3H), 1.24 (br
s, 14 H), 1.48 (m, 2H), 2.17 (dt, J = 6.5, 4.0 Hz, 2H),
4.85 (d, J = 5.5 Hz, 2H), 5.68 (m, 2H), 7.56 (br d,
J = 8 Hz, 2H), 7.90 (br d, J = 8 Hz, 2H).
1
yield). H NMR (400 MHz, CDCl3): d 1.47–1.68 (m,
4H), 1.69–1.78 (m, 1H) 1.78–1.85 (m, 1H) 2.41 (t,
J = 2.2 Hz, 1H), 3.54 (m, 1H), 3.84 (m, 1H), 4.23 (dd,
J = 15.8, 2.2 Hz, 1H), 4.30 (dd, J = 15.8, 2.6 Hz, 1H),
4.82 (t, J = 3.3 Hz, 1H).
4.2.2. 2-Tridecyn-1-ol tetrahydropyranyl ether. Pro-
tected propargyl alcohol (3.0816 g, 22.0 mmol) in THF
(10 mL) was placed into a dry three-necked round-bot-
tomed flask. The solution was stirred under argon at
ꢀ50 ꢁC (acetone/dry ice bath) for 5 min. Upon addition
of n-butyllithium (13 mL, 22.1 mmol, 1.7 M in pentane),
the solution turned orange. After 1 h, a solution of 1-
bromodecane (4.8134 g, 21.8 mmol) in HMPA (12 mL)
was added and the mixture allowed to warm to room
temperature. The reaction was stirred for 5 12 h. The
reaction was quenched with 0.5 M aqueous Na2CO3
(10 mL), diluted with ether (90 mL), and washed twice
with 10% aqueous Na2CO3 (10 mL). The aqueous por-
tion was back-extracted and the organic portions com-
bined, washed with brine (10 mL), dried over Na2SO4,
and purified by flash-chromatography (7:1 hexane–
ether) to afford the title compound (5.0449 g, 82% yield).
1H NMR (400 MHz, CDCl3): d 0.875 (t, J = 7.0 Hz,
3H), 1.12–1.45 (br s, 14H), 1.45–1.67 (m, 6H), 1.73 (m,
1H), 1.85 (m, 1H), 2.20 (tt, J = 7.0, 2.2 Hz, 2H),
>3.52 (m, 1H) 3.84 (m, 1H) 4.20 (dt, J = 15.1, 2.2 Hz,
1H), 4.29 (dt, J = 15.1, 2.2 Hz, 1H), 4.81 (t, J = 3.3 Hz,
1H).
4.2.5. Esters for MCTA-I separation
4.2.5.1. cis-2,3-Epoxytridecan-1-yl acetate, ( )-2a.
Racemic epoxy alcohol ( )-3 (70.3 mg, 0.33 mmol)
was dissolved in 2 mL of CH2Cl2 and 0.3 mL of
pyridine. To this solution, 30 mg (0.34 mmol) of acetyl
chloride was added, followed by a crystal of 4-N,N-dim-
ethylaminopyridine (DMAP). The reaction was stirred
for 1 h at room temperature. The organic solution was
washed with water and 0.1 M HCl, and the solution
then dried over Na2SO4. After purification on a small
column of silica gel (8:1 hexane–ether), 47 mg (50%) of
acetate 2a were obtained. GC–MS (EI): m/z (rel. abun-
dance %) 257 (10%, M+1), 197 (3%), 123 (3%), 115
(38%), 109 (8%), 97 (11%), 95 (17%), 83 (6%), 81 (7%),
67 (5%), 55 (21%), 43 (100%).
4.2.3. (2Z)-Tridecen-1-ol. To a round-bottomed flask
fitted with a balloon and rubber septum was added 2-
tridecyn-1-ol tetrahydropyranyl ether (5.6 g, 20 mmol)
in 20 mL distilled hexane. LindlarÕs catalyst (Pd,
5 wt % on CaCO3 poisoned with Pb, 0.1058 g) was
added, the flask filled with H2 and the reaction left to stir
under H2, until the balloon no longer deflated at an
appreciable rate. The product was filtered with hexane
through silica gel to remove the catalyst and then con-
centrated. A portion of hydrogenated material from a
trial reaction was added (5.78 g, 20.6 mmol total), and
the pooled product dissolved in MeOH (40 mL). TsOH
We compared the results obtained for various esterifica-
tions of epoxy alcohol 3 against esterification of (2Z)-
tridicen-1-ol followed by epoxidation of the ester, and
found that the latter procedure gave cleaner products.

3780
J. A. H. Inkster et al. / Tetrahedron: Asymmetry 16 (2005) 3773–3784
As a result, this method was adopted for esters 2b and
2c.
EM Science, Gibbstown NJ), equilibrated with distilled
ethanol–water (9:1). The column was jacketed and kept
at a constant temperature of 30 ꢁC using a recirculating
heater/pump (Haake E2). The flow rate was 0.1 mL/
min. Ester 2a did not separate significantly, while ester
2b showed moderate separation. Ester 2c was more
retained and eluted with baseline separation in two cases
and with only a small overlap in two other cases. As the
esters are not separated on the chiral GC column, sam-
ples of the representative fractions were hydrolyzed and
the resulting alcohol 3 analyzed by chiral GC (CycloSil
B). An attempt to separate alcohol 3 directly by chroma-
tography on MCTA-I was not successful.
4.2.5.2. cis-2,3-Epoxytridecan-1-yl benzoate ( )-
2b. (2Z)-Tridecen-1-ol (300 mg, 1.5 mmol) was reacted
with 333 mg (1.5 mmol) of benzoyl chloride, as
described above, to give 192 mg (0.5 mmol, 33%) of
1
the benzoate. H NMR (400 MHz, CDCl3): (major iso-
mer, Z, 93%) d 0.86 (t, J = 6.5 Hz, 3H), 1.25 (m, 14H),
1.40 (m, 2H), 2.16 (br q, J ꢂ 5 Hz, 1.9H), 4.86 (d,
J = 6.5 Hz, 1.9H), 5.68 (m, 1.9H), 7.4 (br t, J = 9 Hz,
2H), 7.55 (br t, J = 9 Hz, 1H), 8.02 (br d, J = 9 Hz,
2H). (minor isomer, E, 7%) same as Z, except: d 2.07
(m, 0.1H, H-4), 4.75 (d, J = 6.5 Hz, 0.1H, H-1), 5.88
(m, 0.1H, H-2 and H-3).
For preparative runs, a representative procedure was
given. Racemic epoxy ester 2c (0.1610 g) in 5 mL buta-
nol was injected onto a large column (ID = 2.5 cm,
length = 100 cm) of MCTA-I (as above). The solvent
was distilled ethanol–water (9:1), the flow rate was
0.5 mL/min and the temperature was 50 ꢁC. (2S,3R)-
(ꢀ)-2c (0.0546 g collected) eluted from 12:30 h to 15 h;
(2R,3S)-(+)-2c eluted from 15:30 h to 17:45 h (0.0822 g
collected). Samples of relevant column fractions were
transesterified for GC analysis of enantiomeric excess
prior to pooling. A representative procedure is as fol-
lows: a 20 lL sample was placed in an ampoule, fol-
lowed by 1 M KOH (10 lL) in ethanol. The ampoules
were sealed and vortexed, then left for 1 12 h. Then the
ampoule was opened and water (10 lL) was added,
followed by ethyl acetate (100 lL). The sample was sha-
ken for 30 s, the lower aqueous portion removed with a
syringe, and another 10 lL of water was added. After
two more washes, the ethyl acetate was transferred into
a dry ampoule containing a small amount of Na2SO4.
The ampoule was sealed and left for 1 h. The extract
was transferred to a fresh ampoule and concentrated
to ꢂ2 lL, using a water aspirator, prior to analysis.
Fractions that contained one enantiomer were pooled
(Z)-2-Tridecen-1-yl benzoate (47 mg, 0.16 mmol), dis-
solved in 2 mL of CH2Cl2, was added to m-CPBA
(32 mg, 0.16 mmol) in 2 mL of CH2Cl2. The mixture
was stirred at room temperature for 4.5 h, after which
the organic solution was washed with water, followed
by NaOH (1 M). The organic phase was dried and the
product was purified on silica gel (3:1 hexane–ether).
The small amount of trans epoxide, that formed from
the minor E isomer, readily separated from the major
cis epoxide during chromatography. After evaporation
of the solvent, 10 mg (0.04 mmol, 20%) of the pure cis
benzoate 2b was obtained. 1H NMR (400 MHz, CDCl3):
d 0.87 (t, J = Hz, 3H), 1.29 (m, 16H), 1.60 (m, 2H), 3.06
(m, J = 13.6 Hz, ꢂ5–6 Hz, 1H), 3.31 (m, J = 13.6 Hz,
ꢂ5–6 Hz, 1H), 4.30 (dd, J = 11 Hz, 6.5 Hz, 1H), 4.56
(dd, J = 11 Hz, 4.5 Hz, 1H), 7.46 (br t, J = 7.3 Hz, 2H),
7.58 (br t, J = 7.3 Hz, 1H), 8.08 (br d, J = 7.3 Hz, 2H).
4.2.5.3. cis-2,3-Epoxytridecan-1-yl p-bromobenzoate
( )-2c. In a dry round-bottomed flask containing
5 mL of CH2Cl2, pure (Z)-2-tridecen-1-yl p-bromo-
benzoate (0.1064 g, 0.279 mmol) was added, followed
by solid NaHCO3 (0.0611 g, 0.727 mmol). After the
addition of m-CPBA (0.0529 g, 0.306 mmol), the reac-
tion was left to stir for 2 h, after which another half
equivalent of m-CPBA was added, followed by another
half equivalent after 3 h. The reaction was left for 16 h.
The reaction was quenched with ice water (10 mL),
diluted with ether (60 mL), and washed three times (ice
water (10 mL), 10% Na2SO3 (10 mL), and 10% NaH-
CO3 (10 mL)). The aqueous portion was back-extracted
and the organic portions combined, washed once with
brine (10 mL), dried over MgSO4, and purified by
flash-chromatography (7:1 hexane–ethyl acetate) to
afford ( )-2c (0.1069, 96% yield), a white solid, mp:
48.5–49 ꢁC. 1H NMR (400 MHz, CDCl3): d 0.88 (t,
J = 7.0 Hz, 3H), 1.2–1.41 (br, 16H), 1.59 (m, 2H), 3.07
(m, 1H), 3.31 (dt, J = 7.0, 4.4 Hz, 1H), 4.28 (dd,
J = 12.1, 7.4 Hz, 1H), 4.57 (dd, J = 12.1, 4.4 Hz, 1H),
7.59 (d, J = 8.5, 2H), 7.94 (d, J = 8.5, 2H).
and the intermediate fractions, with both enantio-
20
mers, were recycled. (2R,3S)-(+)-2c: ½aꢃD ¼ þ9:4 (c
20
0.80, CHCl3). (2S,3R)-(ꢀ)-2c: ½aꢃD ¼ ꢀ9:3 (c 1.12,
CHCl3).
4.4. cis-2,3-Epoxytridecan-1-ol, 3
4.4.1. Racemic ( )-3 by direct epoxidation of (2Z)-
tridecen-1-ol. Racemic epoxy alcohol was obtained by
direct epoxidation of (2Z)-tridecen-1-ol. A typical pro-
cedure is as follows. m-CPBA (0.9718 g, 5.63 mmol)
was added in small portions over 2 h to a solution of
(Z)-tridecen-1-ol (0.5354 g, 2.70 mmol) in CH2Cl2
(14 mL) while the reaction was kept at 0 ꢁC. The reac-
tion was allowed to warm to room temperature over
another 2 h, then diluted with CH2Cl2, chilled, and
filtered. The product mixture was washed twice with
saturated aqueous Na2CO3, the aqueous portion back-
extracted, and the organic portions pooled and washed
with brine. Recrystallization from pentane afforded
( )-3 (0.5752 g, 99%).
4.3. Resolution on microcrystalline cellulose triacetate-I
(MCTA-I)
For trial runs, racemic epoxy esters 2a–c in 0.5 mL buta-
nol were injected onto a semi-preparative column
(ID = 0.9 cm, length = 60 cm) of MCTA-I (25–40 lm,
4.4.2. Alcohol 3 by transesterification of epoxy ester
2c. Epoxy ester ( )-2c (0.6058 g, 1.52 mmol) was dis-
solved in a solution of 1 M KOH in ethanol. After

J. A. H. Inkster et al. / Tetrahedron: Asymmetry 16 (2005) 3773–3784
3781
2 h, the reaction was quenched with ice, diluted with
130 mL ethyl acetate, and washed twice with water
(5 mL). The organic portions were pooled and washed
with brine, then concentrated and purified by flash-chro-
matography (4:1 hexane–ethyl acetate) to afford the title
compound epoxy alcohol ( )-3 (0.3040 g, 93% yield), a
white solid. Mp: 56–57 ꢁC. (lit. 59.5–60 ꢁC,18 61–
63 ꢁC,8 63 ꢁC14). Similar procedures were carried out
for the (ꢀ)- and (+)-epoxy alcohols, starting from enan-
tiomerically pure (2R,3S)-(+)-2c and (2S,3R)-(ꢀ)-2c,
respectively. Enantiomeric excess of the corresponding
epoxy alcohols (2R,3S)-(ꢀ)-3 and (2S,3R)-(+)-3 was
estimated at >97% by chiral GC and from the specific
rotation. Chiral GC (CycloSil B): (2S,3R)-(+)-3
15.191 min, (2R,3S)-(ꢀ)-3 15.399 min.
GC–MS (EI): m/z (rel. abundance %) 215 (1%, M++1),
197 (1%), 183 (1%), 111 (17%), 97 (70%), 83 (57%) 55
(100%). 1H NMR (400 MHz, CDCl3): d 0.88 (t,
J = 6.6 Hz, 3H), 1.16–1.38 (br s, 16H), 1.38–1.63 (m
3H), 3.03 (m, 1H), 3.15 (dt, J = 7.0, 4.0 Hz, 1H), 3.68
(ddd, J = 12.1, 7.0, 5.1 Hz, 1H), 3.86 (ddd, J = 12.1,
7.4, 4.0 Hz, 1H). (lit.18,8). 13C NMR (400 MHz, CDCl3):
oil, 1.7 mmol) was added, and an hour later 3-methyl-
1-bromobutane (0.5511 g, 3.64 mmol, Aldrich) in
DMF added dropwise to the alkoxide (total solvent
ꢂ35 mL DMF). The reaction was allowed to warm to
room temperature. After 15 h, the reaction was
quenched with ice water (5 mL), diluted with ether
(60 mL) and washed twice [ice water (5 mL), 10% NaH-
CO3 (10 mL)]. The combined organic portions were
back-extracted, concentrated and purified by flash-chro-
matography (2:1 hexane–ethyl acetate) to afford ( )-5
(0.2998 g, 62% yield), as a colorless oil. Chiral GC
(CycloSil B): (2R,3S)-(ꢀ)-7: 45.39 min, (2S,3R)-(+)-7:
45.93 min. GC–MS (EI): m/z (rel. abundance %) 285
(1%, M++1), 266 (5%, M+ꢀH2O), 227 (5%), 215
(20%), 197 (38%), 179 (14%), 137 (12%), 123 (25%),
111 (16%), 109 (27%), 97 (33%), 95 (27%), 81 (23%),
71 (100%). 1H NMR (400 MHz, CDCl3): d 0.88
(t, J = 7.1 Hz, 3H), 0.90 (dd, J = 6.8 Hz, 6H) 1.16–
1.38 (br s, 16H), 1.38–1.59 (m, 4H), 1.71 (m, 1H), 2.97
(m, 1H), 3.13 (dt, J = 6.2, 4.3 Hz, 1H), 3.41–3.52 (m,
2H), 3.56 (dt, J = 9.2, 6.8 Hz, 1H), 3.63 (dd, J =
11.1, 4.3, 2H). Anal. Calcd for C18H36O2 (284.48): C,
76.00; H, 12.76. Found: C, 75.84; H, 12.94. Similar pro-
cedures were carried out for the (+)- and (ꢀ)-epoxy
14.05, 22.64, 26.61, 27.93, 29.27, 29.37, 29.49, 31.84,
20
56.72, 57.29, 60.92. (lit.14). (2S,3R)-(+)-3: ½aꢃD ¼ þ7:9
ethers, starting from optically pure (2S,3R)-(+)-3 and
20
20
(2R,3S)-(ꢀ)-3, respectively. (2S,3R)-(+)-5: ½aꢃD ¼ þ1:2
20
(c 1.85, EtOHabs), ee 97% (lit. (2R,3S)-(ꢀ)-3: ½aꢃD
¼
20
ꢀ7:8 (c 1.0, EtOHabs),6 (2S, 3R)-(+)-3 ½aꢃD ¼ þ7:8 (c
(c 0.59, CHCl3). (2R,3S)-(ꢀ)-5: ½aꢃD ¼ ꢀ1:2 (c 0.18,
1.28,
EtOH),8
both
ee
95%,
(2R,3S)-(ꢀ)-3
CHCl3).
20
½aꢃD ¼ ꢀ7:95 (c 1.76, EtOH)14).
4.6. cis-(2,3)-Epoxytridecan-1-al, ( )-6
4.4.3. MTPA esters of (+)-3 and (ꢀ)-3, (20R,2S,3R)-4
and (20R,2R,3S)-4. Optically-active (+)-3 (10 mg) was
mixed with pyridine (300 lL) and 400 lL a-methoxy-
a-trifluoromethylphenylacetic chloride, (S)-MTPA-Cl,
in CCl4 (600 lL). The reaction mixture was left to stir
overnight, after which it was concentrated and purified
twice by flash-chromatography (2:1 hexane–ether, 7:1
hexane–ether). Identical steps were carried out with
Racemic epoxy alcohol ( )-3 (0.1866 g, 0.87 mmol) in
CH2Cl2 (32 mL) was cooled to 0 ꢁC and a suspension
of PCC (1.708 g, 7.92 mmol) in CH2Cl2 (3 mL) was
added dropwise. After 1 h, the reaction was brought to
room temperature. After 3 h 40 min, 3 mL hexane was
added to precipitate the solid, and the solution was
passed through a column of silica with ethyl acetate.
The solution was concentrated and immediately purified
by flash-chromatography (4:1 hexane–ethyl acetate) to
afford ( )-7 (0.1194 g, 65% yield), a yellow oil. 1H
NMR (100 MHz, CDCl3): d 0.90 (t, J = 6.6 Hz, 3H),
1.2–1.4 (br, 16H), 1.5–1.7 (m, 2H), 3.3 (t, J = 5.1 Hz,
1H), 3.4 (m, J = 5.1 Hz, 2H), 9.5 (d, J = 5.0 Hz,
1H).18,8
1
(ꢀ)-3. The 4.3–4.6 ppm region of the H NMR of the
MTPA ester of (+)-3, (20R,2S,3R)-4, and for the MTPA
ester of (ꢀ)-3, (20R,2R,3S)-4, was consistent with litera-
ture data.8
1H NMR (400 MHz, CDCl3): (20R,2S,3R)-4 d 0.88 (t,
J = 7.1 Hz, 3H), 1.1–1.38 (br s, 14H), 1.50 (m, 2H),
1.68 (m, 2H), 3.02 (m, 1H), 3.20 (dt, J = 7.1, 4.3 Hz,
1H), 3.58 (s, 3H), 4.38 (dd, J = 12.0, 6.8 Hz, 1H), 4.45
(dd, J = 12.0, 4.6 Hz, 1H), 7.37–7.44 (m, 3H), 7.49–
7.56 (m, 2H). (20R,2R,3S)-4 d 0.88 (t, J = 7.1, 3H),
1.1–1.38 (br s, 14H), 1.50 (m, 2H), 1.63 (m, 2H), 3.02
(m, 1H), 3.22 (dt, J = 6.8, 4.6 Hz, 1H), 3.88 (s,
3H), 4.34 (dd, J = 12.0, 6.8 Hz, 1H), 4.50 (dd,
J = 12.0, 4.6 Hz, 1H), 7.37–7.44 (m, 3H), 7.48–7.56
(m, 2H).
4.7. 4-Methylpentan-1-ol
Crushed magnesium turnings (5.9 g, 0.24 mol) were
added to a dry flask, then cooled under argon. Dry ether
(40 mL) was added, followed by a 20 mL aliquot of iso-
amyl bromide (30.1 g, 0.20 mol) in 60 mL ether. The
reaction was cooled to 0 ꢁC. One small flake of I2 was
added and the remainder of the alkyl halide solution
added dropwise over 20 min, during which time the
reaction became turbid gray. The reaction was gently
heated at reflux for 45 min, then cooled to room temper-
ature and dry paraformaldehyde (11.5 g, 0.38 mol) was
added and the reaction was left 4.5 h. The reaction
was quenched with 6 M HCl (100 mL), diluted with
ether (200 mL), and washed twice with 6 M HCl
(100 mL and 20 mL). The aqueous portion was back-
extracted and the organic portions combined, washed
4.5. cis-(2,3)-Epoxy-1-(3-methylbutoxy)-tridecane, ( )-5
A dry flask was charged with racemic epoxy alcohol ( )-
3 (0.3666 g, 1.71 mmol) in dry DMF. NaH (0.2147 g,
60% in mineral oil, 5.64 mmol) was washed twice with
hexane and added as a slurry in DMF, dropwise at
0 ꢁC, under argon. The reaction was stirred vigorously.
After 3 h, 1 equiv of NaH (68.4 mg, 60% in mineral

3782
J. A. H. Inkster et al. / Tetrahedron: Asymmetry 16 (2005) 3773–3784
with brine (10 mL), and dried over Na2SO4. The crude
product was vacuum-distilled (15 mmHg), collecting be-
tween 53 and 69 ꢁC, to afford 4-methylpentan-1-ol
(9.71 g, 48% yield), a colorless liquid. (Note: this com-
at ꢀ78 ꢁC for 3 h, after which it was left to warm to room
temperature overnight. The reaction was diluted with
ether (20 mL) and washed once with water (2 mL). The
aqueous portion was back-extracted once, and the
organic portions pooled, dried over MgSO4, concentrated.
GC and NMR analysis revealed that the product con-
tained 82% (Z) and 18% (E)-isomer. The isomers were
separated by flash-chromatography (5:1 hexane–ethyl
acetate) to afford (ꢀ)-(5Z)-7 (0.2370 g, 61% yield), a col-
orless oil. GC–MS (EI): m/z (rel. abundance %) 281 (5%,
M++1), 236 (14%), 169 (23%), 95 (100%). 1H NMR
(400 MHz, CDCl3): d 0.83–0.92 (m, 9H), 1.2–1.37 (br,
18H), 1.37–1.65 (m, 3H), 2.20 (m, H-4, 2H), 3.07 (m,
1H), 3.64 (ddd, J = 8.5, 4.4, 1.1 Hz, 1H), 5.19 (ddt,
J = 11.0, 8.5, 1.5 Hz, 1H), 5.75 (dtd, J = 11.0, 7.7,
1.1 Hz, 1H) (lit.8). 13C NMR (400 MHz, CDCl3): d
14.05, 22.41, 22.64, 25.72, 26.29, 27.54, 28.23, 29.28,
29.40, 29.51, 31.86, 38.68, 52.79, 58.60, 123.66, 137.51
1
pound has become available commercially). H NMR
(400 MHz, CDCl3): d 0.89 (d, J = 6.6 Hz, 6H), 1.18–
1.27 (m, 2H), 1.41 (br, OH), 1.5–1.62 (m, 3H), 3.63 (t,
J = 6.6 Hz, 2H).
4.8. 1-Bromo-4-methylpentane
Neat 4-methylpentan-1-ol (8.08 g, 79.1 mmol) was
placed in a round-bottomed flask fitted with a drying
tube and a NaOH trap. The reaction was cooled to
0 ꢁC and PBr3 (5.0 mL, 102 mmol) added dropwise with
stirring. After 15 min, the orange mixture was removed
from the ice bath and the reaction stirred for 25 h.
The reaction was quenched with ice water (10 mL),
diluted with ether (90 mL) and washed twice with water
(10 and 7.5 mL). The aqueous portion was back-
extracted and the organic portions combined, washed
once with brine (7.5 mL), dried over Na2SO4, and dis-
tilled, collecting between 161 and 165 ꢁC, to give 1-bromo-
4-methylpentane (6.67 g, 23% yield). 1H NMR
(400 MHz, CDCl3): d 0.89 (d, J = 6.6, i-(CH3)2, 6H),
d 1.30 (dt, J = 8.8, 7.0 Hz, H-3, 2H), 1.47–1.63 (m,
H-4, 1H), 1.86 (m, H-2, 2H), 3.39 (t, J = 6.6 Hz, H-1,
2H).
20
20
(lit.14). ½aꢃD ¼ ꢀ40:5 (c 0.82, CHCl3) (lit.14). ½aꢃD
¼
ꢀ39:5 (c 0.80, CHCl3). The same procedure was used
to synthesize ( )-7 and (+)-7, yielding compounds with
identical NMR spectra. Specific rotation of (+)-7:
20
½aꢃD ¼ þ43:8 (c 0.80, CHCl3).
4.11. (2,3)-Epoxy-1-(3-methyl-aminobutyl) tridecane
( )-8, and anti-5-(1-hydroxy-undecyl)-3-(3-methyl-
butyl)oxazolidin-2-one, ( )-9
A dry round-bottomed flask filled with activated molec-
ular sieves was flushed with argon and racemic epoxy
aldehyde 6 (0.2126 g, 1.00 mmol) dissolved in dry
CH2Cl2 (10 mL), added via cannula. 3-Methylbutan-1-
amine (0.0894 g, 1.03 mmol, Aldrich) in CH2Cl2
(2 mL) was added dropwise, and the mixture stirred
for 14 min. The reaction mixture was filtered to remove
the sieves and concentrated to give 0.2449 g crude epoxy
imine. The imine was dissolved in abs. MeOH (8 mL)
and NaBH4 (0.1033 g, 2.73 mmol) was added over
15 min, with stirring. After a total of 45 min, the reac-
tion was quenched with water (5 mL), diluted with ethyl
acetate (90 mL), and washed once with water (5 mL)
and twice with aqueous NaHCO3 buffer (pH 9, 5 mL).
The aqueous portions were back-extracted and the
organic portions pooled, washed with brine, and con-
centrated to give 0.2129 g of crude ( )-8. Flash-chroma-
tography on silica gel (5:1 CHCl3–MeOH) yielded epoxy
amine ( )-8 (0.1830 g, 64% yield) as a colorless oil.
Upon standing, 8 converted to anti-hydroxyoxazolidi-
none ( )-9, a white solid, which was recrystallized twice
from hexanes (0.1115 g, 53% yield), mp: 9 82.5–83 ꢁC.
GC–MS (EI): 8 m/z (rel. abundance %) 282 (6%,
M+ꢀ1), 266 (6%, M+ꢀOH), 224 (100%), 140 (38%),
112 (85%), 84 (46%); compound 9 m/z (rel. abundance
%) 327 (1%, M+), 279 (15%), 167 (44%), 149 (100%).
IR (KBr, cmꢀ1): 9 3356, 2959, 2923, 2851, 1713 (CO),
1470, 1347, 1280, 1208, 1141, 1079, 1007, 759, 718,
4.9. 4-Methylpentyl triphenylphosphonium bromide
Triphenylphosphine (0.4651 g, 1.77 mmol) in dry ben-
zene (3 mL) was refluxed under argon for 1 h. 1-Bro-
mo-4-methylpentane (0.1171 g, 0.79 mmol) was added
in benzene (2 mL) and the solution stirred at reflux for
8 h, after which the reaction was cooled to room temper-
ature and left stirring under argon for 16 h. The viscous
yellow-orange oil was transferred in CH2Cl2, concen-
trated, and washed three times in ether (previously dried
over MgSO4) to remove triphenylphosphine oxide. The
product was placed in hexane (2 mL) and gently heated
in a hot water bath, then the warm solvent was dec-
anted. The product, a pale orange solid, was dried under
vacuum to give the title compound (0.2374 g, 78% yield),
mp: 234.5–235.5 ꢁC. 1H NMR (400 MHz, CDCl3): d
0.763 (d, J = 6.4 Hz, 6H), 1.44–1.54 (m, 3H), 1.54–1.67
(m, 2H), 3.79 (m, 2H), 7.69 (m, 6H), 7.78 (m, 3H),
7.85 (m, 6H).
4.10. (ꢀ)-2-Methyl-(5Z,7R,8S)-epoxyoctadec-5-ene, (ꢀ)-
7
4-Methylpentyl triphenylphosphonium bromide (0.1195
g, 0.28 mmol) was placed in a dry three-necked flask
and heated gently for 40 min under vacuum. Dry THF
(2 mL) was added via cannula and the reaction put under
argon and brought to ꢀ78 ꢁC. A solution of n-butyl-
lithium (0.12 mL, 0.2 mmol, 1.6 M in hexane) was added
dropwise by syringe and the reaction was left to stir for
1 12 h, during which time the solution became dark
orange. Epoxy aldehyde (ꢀ)-6 (0.0293 g, 0.14 mmol) in
THF (2 mL) was added dropwise. The reaction was kept
626.
1H
NMR
(400 MHz,
CDCl3):
8
d
0.84–0.94 (m 9H), 1.18–1.38 (br s, 18H), 1.38–1.47 (m,
2H), 1.52 (m, 2H), 1.64 (m, 1H), 1.72–2.4 (br, NH),
2.64–2.76 (m, 2H), 2.96 (m, 1H), 3.12 (m, 1H). Com-
pound
9 d: 0.88 (t, J = 7.0 Hz, 3H), 0.93 (d,
J = 6.6 Hz, 6H), 1.12–1.35 (br s, 18H), 1.38–1.46 (m,
2H), 1.81–1.91 (m, 1H), 3.27 (m, 2H), 3.40 (m, 1H),

J. A. H. Inkster et al. / Tetrahedron: Asymmetry 16 (2005) 3773–3784
3783
3.50–3.59 (m, 2H), 4.38 (m, 1H). 13C NMR (400 MHz,
CDCl3): 9 157.51 (C@O), 75.37, 72.41, 46.12, 42.48,
35.94, 32.60, 31.87, 29.58, 29.52, 29.45, 29.30, 25.66,
25.41, 22.64, 22.36, 14.07. Anal. Calcd for C19H37NO2
9 (327.28): C, 69.68; H, 11.39; N, 4.28. Found: C,
69.79; H, 11.51; N, 4.13.
Corporation (Research Innovation Award RI 0519 to
E.P.).
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Acknowledgements
We thank Dr. K. N. Slessor, for a gift of (S)-MTPA-Cl,
Mrs. M. Tracey, for help with NMR, Mr. J. Belli, Ms.
M. Chatterton and Ms. R. Thorne, for technical
assistance, Dr. G. Gries, for permitting us to use his
EAG apparatus and for samples of (ꢀ)-1, and a
reviewer, for helpful comments. Funded by the Natural
Sciences and Engineering Research Council (NSERC)
of Canada (Grant RGPIN222923 to E.P.) and Research

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