A short and efficient synthesis of (+)-disparlure and its enantiomer

Article abstract of DOI:10.1016/j.tetlet.2005.04.081

A short and highly efficient approach was applied for the total synthesis of the gypsy moth sex pheromone (+)-disparlure and its enantiomer from isopropylidene D- and L-erythrose, using a common strategy.

Full text of DOI:10.1016/j.tetlet.2005.04.081

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4353–4355
A short and efficient synthesis of (+)-disparlure and its enantiomer
Alexandros E. Koumbis* and Demetrios D. Chronopoulos
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece
Received 10 March 2005; revised 10 April 2005; accepted 20 April 2005
Available online 5 May 2005
Abstract—A short and highly efficient approach was applied for the total synthesis of the gypsy moth sex pheromone (+)-disparlure
and its enantiomer from isopropylidene D- and L-erythrose, using a common strategy.
Ó 2005 Elsevier Ltd. All rights reserved.
(7R,8S)-(+)-7,8-Epoxy-2-methyloctadecane
1,
also
ones utilize an asymmetric epoxidation reaction5f
(resembling a possible biosynthetic pathway6) or dihydr-
oxylation,5j as the key step for the construction of the
two asymmetric centers present in the natural product.
Other routes employ chiral stannanes,5b enantiopure
sulfoxides,7 asymmetric chloroallylboration5c or the
use of enzymatic procedures.5h,8 Chiral pool approaches
have been very popular, as well, using mainly carbohy-
drates,5g,9 L-glutamic acid,10 and L-tartaric acid11 as
the starting materials of choice. Relatively less work
has been directed towards the preparation of the unnat-
ural (À)-enantiomer.12 The syntheses of analogues,13
trans-isomers5k and labeled compounds,14 have also
been reported. In general, the use of asymmetric reac-
tions, although often very simple, always have the draw-
back of producing material which is contaminated with
the (À)-enantiomer, even in small quantities. On the
other hand, the chiral auxiliary and chiral pool schemes
were often rather costly and lengthy.
known as (+)-disparlure, is the single sex attractant
pheromone emitted by the female gypsy moth, Lyman-
tria (Porthetria) dispar1 (Fig. 1). The gypsy moth is a
seriously harmful pest affecting a variety of forest,
shade, and orchard trees in Europe and North America.
For this reason, numerous syntheses of (+)-disparlure
have been reported so far, in order to use the synthetic
material in field tests aimed at population monitoring.
Initial efforts produced racemic disparlure.1,2 However,
epoxide 1 is required to be nearly enantiopure to elicit
male attraction since its enantiomer, (À)-disparlure 2,
has an opposite effect on the male population.3 The need
for enantiopure material led several groups to address
this problem.4,5 Among the different solutions proposed
to prepare enantiopure (+)-disparlure the most common
In continuation of our natural product synthesis pro-
gram, employing acetonides of D- and L-erythroses as
starting materials,15 we wish to report here a new, short,
and very efficient approach for the synthesis of both
enantiomers of disparlure.
R
S
O
1
The common strategy for the target compounds
(Scheme 1) involves the construction of an epoxide ring
at a late stage from the appropriately protected diols 4,
bearing the correct cis-stereochemistry in each case. The
required aliphatic C7 and C10 chains were planned to be
introduced by successive Wittig olefinations and double
alkene reduction, leading finally back to protected eryth-
roses 6. It thus became obvious, that the stereochemistry
of 6 could be directly transferred to the target epoxides
3.
S
R
O
2
Figure 1. Structures of (+)-disparlure 1 and (À)-disparlure 2.
Keywords: Disparlure; Erythrose; Wittig olefination; Epoxide.
*
Corresponding author. Tel.: +30 2310 997839; fax: +30 2310
997679; e-mail: akoumbis@chem.auth.gr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.081

4354
A. E. Koumbis, D. D. Chronopoulos / Tetrahedron Letters 46 (2005) 4353–4355
C7H15
C7H15
standard Swern oxidation conditions and the latter were
Epoxide
formation
O
O
employed, without isolation, in the second Wittig olefin-
ation with the unstable phosphonium ylide derived from
1-bromo-4-methylpentane.18
O
C10H21
C10H21
3
4
It is worth noting that at this stage dienes 10 and 16 were
an inseparable mixture of all four possible geometrical
isomers.19 However, there was no obvious reason to sep-
arate this mixture and identify its components since the
following reduction step afforded protected diols 11 and
17, respectively. These reductions were best performed
using Ra-Ni whereas Pd/C catalytic hydrogenations
proved to be too sluggish, yielding complicated mixtures
after prolonged times and incomplete reactions.
Reduction
Wittig
olefination
O
OH
O
O
C5H11
C8H17
O
O
Wittig
olefination
5
6
Scheme 1. Retrosynthetic analysis.
Having acetonides 11 and 17 in hand, we smoothly pre-
pared the corresponding diols 12 and 18 upon acidic
hydrolysis. Then, these diols were used to reach the de-
sired compounds using a well established procedure,5d,20
which involves a three-step sequence: successive treat-
ment with triethyl orthoacetate, TMSCl, and finally
KOH in THF. Pure epoxides 1 and 2 were obtained
after column chromatography on silica gel and were
found to have identical physical and spectroscopic
To investigate the feasibility of this retrosynthetic plan,
acetonides 7 and 13, both available in multigram quan-
tities from D- and L-arabinose,16 respectively, were ini-
tially subjected to a Wittig olefination upon treatment
with the unstable phosphonium ylide derived from non-
yl bromide, yielding a mixture of geometrical isomers 8
and 14, in each case (Schemes 2 and 3).17 These mixtures
were next used to prepare aldehydes 9 and 15 applying
O
HO
X
OH
(CH2)7CH3
(CH2)7CH3
ii
O
iv
i
O
O
O
O
O
O
O
11
7
8
9 X = O
iii
10 X = CH(CH2)2CH(CH3)2
v
HO
vi
O
HO
12
1
Scheme 2. Synthesis of (+)-disparlure 1. Reagents and conditions: (i) Ph3P+(CH2)8CH3BrÀ, n-BuLi, THF, 0 °C to room temperature, 95%; (ii)
(COCl)2, DMSO, CH2Cl2 then Et3N, À55 °C to room temperature; (iii) Ph3P+(CH2)3CH(CH3)2BrÀ, n-BuLi, THF, 0 °C to room temperature, 91%
overall from 8; (iv) H2, Ra-Ni, MeOH, room temperature, 98%; (v) 37% HCl, THF/H2O (2:1), room temperature, 98%; (vi) (a) CH3C(OEt)3, PPTS,
toluene, 110 °C; (b) TMSCl, CH2Cl2, room temperature; (c) 1 N KOH in MeOH, THF, 0 °C to room temperature, 90%.
O
HO
X
OH
(CH2)7CH3
iv
(CH2)7CH3
ii
O
O
i
O
O
O
O
O
O
17
13
14
15 X = O
iii
16 X = CH(CH2)2CH(CH3)2
v
HO
vi
O
HO
18
2
Scheme 3. Synthesis of (À)-disparlure 2. Reagents and conditions: (i) Ph3P+(CH2)8CH3BrÀ, n-BuLi, THF, 0 °C to room temperature, 97%; (ii)
(COCl)2, DMSO, CH2Cl2 then Et3N, À55 °C to room temperature; (iii) Ph3P+(CH2)3CH(CH3)2BrÀ, n-BuLi, THF, 0 °C to room temperature, 90%
overall from 14; (iv) H2, Ra-Ni, MeOH, room temperature, 96%; (v) 37% HCl, THF/H2O (2:1), room temperature, 99%; (vi) (a) CH3C(OEt)3, PPTS,
toluene, 110 °C; (b) TMSCl, CH2Cl2, room temperature; (c) 1 N KOH in MeOH, THF, 0 °C to room temperature, 88%.

A. E. Koumbis, D. D. Chronopoulos / Tetrahedron Letters 46 (2005) 4353–4355
4355
properties to those reported in the literature.5b {For 1:
[a]D +0.9 (c 1.1, CCl4), lit.5b [a]D +0.9 (c 1.1, CCl4);
for 2: [a]D À0.8 (c 1, CCl4), lit.5b [a]D À0.9 (c 0.21,
CCl4)}.
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Although, the general synthetic scheme described above
furnished in a straightforward way the desired (+)-dis-
parlure and its enantiomer in almost 75% overall yields
from D- and L-erythrose precursors we were also keen to
explore the possibility of performing the same sequence
of reactions with minimum isolation of the intermedi-
ates. Indeed, we were pleased to observe that similar re-
sults were obtained without isolation of any of the
intermediates before epoxide formation. Thus, steps
(i)–(iv) were repeated with simple filtration of the result-
ing reaction mixtures through a short pad of silica gel in
each case. This was enough to remove organic and inor-
ganic salts as well as polar phosphorus entities. Accord-
ing to this modified experimental procedure, which
demands only two chromatographic separations, (+)-
disparlure and its enantiomer were obtained in overall
yields of more than 70%.
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The work described in this article presents a short and
efficient synthetic approach toward the preparation of
(+)-disparlure 1 and its enantiomer 2 making use of
readily available, multigram quantities of D- and L-ery-
throse derived chirons and employing a common retro-
synthetic route. The overall yields for both targets are in
the range of 70–75% in a six-step sequence involving a
minimum number of purifications and relatively simple
and inexpensive procedures.
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1
determined from the H NMR spectra of their mixtures.
18. 1-Bromo-4-methylpentane is commercially available but
in our case we prepared it from the corresponding alcohol,
which is much cheaper.
1
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spectroscopy.
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