Synthesis of Pheromones: Highlights from 2005 ... - IngentaConnect

Current Organic Chemistry, 2009, 13, 683-719 683
Synthesis of Pheromones: Highlights from 2005-2007
J. Bergmann 1 , J.A.F.P. Villar 2 , M.F. Flores 1 and P.H.G. Zarbin 3,*
1 Instituto de Química, Pontificia Universidad Católica de Valparaíso, Avenida Brasil 2950, Valparaíso, Chile
2 Campus Centro-Oeste Dona Lindu, Universidade Federal de São João Del Rei, 35501-296, Divinópolis- MG, Brazil
3 Departamento de Química, Universidade Federal do Paraná, CP 19081, 81531-990, Curitiba-PR, Brazil
Abstract: The synthesis of insect pheromones published in the period 2005-2007 is reviewed. A total of 66 compounds
from different insect orders and belonging to different structural classes were included.
1. INTRODUCTION
Pheromones are naturally occurring chemicals which are
produced and released by an organism in order to transmit
information to another individual of the same specie. So far,
the use of pheromones has been documented for many species
belonging to different taxa, with the insects clearly
standing out in terms of number of species studied. This is
probably due to several factors, including the relatively simple
behavior of insects (facilitating the design of bioassays),
their occurrence in great numbers (easy access to material),
and their importance as pests in agriculture.
The study of insect pheromones is a fascinating research
field. The prospect of unraveling the molecular basis of
chemical communication as well as the possibility of developing
environmentally benign methods of pest control is
driving many research activities. In this context, pheromones
need to be synthesized for two reasons. First, to provide
authentic reference material needed for unambiguous identification
of the natural compound by comparing their analytical
data. Second, to provide the material necessary for the
evaluation of their effect on insect behavior in laboratory
bioassays or under natural conditions in the field. In many
cases, insect pheromones were found to occur as pure or as
defined mixtures of stereoisomers, so synthetic routes have
to be developed, which lead with high selectivity to the desired
geometric and/or absolute configuration. The synthesis
of insect pheromones has been reviewed in a number of articles.
Mori provided comprehensive overviews in 1981 and
1992 [1, 2] with a partial update in 2004 [3] and also published
articles relating pheromone synthesis to specific topics
[4-6]. The application of biocatalysis to pheromone synthesis
has also been reviewed recently [7].
The present article is a follow-up of our summary of
pheromone syntheses published from 2002-2004 [8]. Here,
we review the most recent advances in the synthesis of
pheromones published in the triennium 2005-2007.
* Address correspondence to this author at the Departamento de Química,
Universidade Federal do Paraná, CP 19081, 81531-990, Curitiba-PR, Brazil;
Fax: +55 41 3361 3186; E-mail: pzarbin@quimica.ufpr.br
2. SYNTHESIS OF ALKANES AS PHEROMONES
2.1. meso-7,11-Dimethylheptadecane (1)
The branched alkanes meso-7,11-dimethylheptadecane
(1) and (S)-7-methylheptadecane constitute the female sex
pheromones of the spring hemlock looper Lambdina
athasaria and of the pitch pine looper L. pellucidaria [9, 10].
Nagano et al. [11] presented a stereoselective synthesis
of 1. Starting from ethyl bromomethacrylate (A), they prepared
diethyl 4-benzyloxy-2,6-dimethyleneheptanedioate
(B), which was used in a diastereoselective chelationcontrolled
radical reaction with pentyl iodide in the key step
(Scheme 1). Use of 6 equivalents of the Lewis acid
MgBr 2·OEt 2 and low temperatures turned out to be crucial
for the high diastereoselectivity of the reaction.
2.2. 5,9-Dimethylpentadecane (2) and 5,9-dimethylhexadecane
(3)
5,9-Dimethylpentadecane (2) and 5,9-dimethylhexadecane
(3) are components of the sex pheromone of the coffee
leaf miner Leucoptera coffeella [12].
Racemic mixtures of both compounds were synthesized
starting from citronellol by Doan et al. [13], using a sequence
of ultrasound-assisted tosylation and alkylation reactions
(Scheme 2). The overall yield was above 50 % over six
steps in both cases, and the use of ultrasound shortened considerably
the reaction times as compared to conventional
procedures.
3. SYNTHESIS OF ALKENES AS PHEROMONES
3.1. (Z,Z)-5,25-Hentriacontadiene (4) and (Z,Z)-5,27-
tritriacontadiene (5)
(Z,Z)-5,25-Hentriacontadiene (4) and (Z,Z)-5,27-tritriacontadiene
(5), have been identified as the major sex pheromone
components from female cuticular extracts of Drosophila
ananassae and D. pallidosa, respectively. The authors
indicate that the major sex pheromone compounds are key
factors in male recognition between D. ananassae and D.
pallidosa, and that morphological differences are less important
[14, 15].
1385-2728/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

684 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.
EtO 2 C
A
Br
1) H 2 C=O, H 2 O/EtOH (1:1), 79%
2) PCC, AcONa, CH 2 Cl 2
EtO 2 C
O
OH
1) A, Zn, aq NH 4 Cl, 54%
2) BnOC(=NH)CCl 3 , TfOH
cyclohexane/CH 2 Cl 2 (2:1), 70%
EtO 2 C
OBn
B
CO 2 Et
n-C 5 H 11 I, n-Bu 3 SnH, Et 3 B,
6 equiv. MgBr 2 OEt 2 ,
CH 2 Cl 2 , -60 o C, 59%
4
( )
EtO 2 C
OBn
4
( )
CO 2 Et
1) DIBAL-H, CH 2 Cl 2 , 96%
HO
OH
OH
1) MsCl, Py, CH 2 Cl 2 , 96%
2) H 2 , Pd/C, EtOH, 100%
.
( )
5
( )
5
2) LiAlH 4 , Et 2 O, 88%
Scheme 1.
1
OH
TsCl, Py, CHCl 3 ,
OTs
RMgBr, Li 2 CuCl 4 ,
( )
n
ultrasound, 80 - 92%
THF, -78 o C, ultrasound
R = n - C 4 H 9
R = n - C 5 H 11
n = 4 or 5
1) perphthalic acid
2) HIO 4 , THF
H
O
1) NaBH 4 , MeOH,
( )
n 2) TsCl, Py, CHCl 3 ,
TsO
ultrasound
n = 4 or 5 n = 4 or 5
( )
n
Scheme 2.
2-hexylMgBr, Li 2 CuCl 4 ,
THF, -78 o C, ultrasound
( )
3
n = 4, (2)
n = 5, (3)
( )
n
Br OH
( )
n
n = 8
n = 10
1) PhSO 2 Me, n-BuLi,
THF/HMPA
(n = 8, 97%; n = 10, 88%)
2) DMSO, (COCl) 2 , Et 3 N,
CH 2 Cl 2 (n = 8, quant; n = 10, 99%)
PhO 2 S
O
( )
n
8
n = 10
H
[CH 3 (CH 2 ) 5 PPh 3 ] + Br - , KHMDS,
THF/HMPA (n = 8, 92%; n = 10, 99%)
Scheme 3.
PhO 2 S
1) n-BuLi, A, THF/HMPA
(n = 8, 70%; n = 10, 88%)
( ) ( ) ( )
n 4
2) SmI 3
2 , THF/HMPA
( )
n
( )
4
(n = 18, 74%; n = 20, 76%)
n = 8
n = 10
OH Br 2 , Ph 3 P, Py,
Br
( ) ( ) ( ) ( )
3 10
3 10
CH 2 Cl 2 , 96%
A
Morita et al. [16] described a synthesis of these two
compounds employing Wittig olefination followed by a sulfone
coupling (Scheme 3).
n = 18 (4)
n = 20 (5)
3.2. 9-Methylgermacrene-B (6)
The structure of the sex pheromone produced by the
males of the sandfly Lutzomyia longipalpis, from the Lap-

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 685
Geranium macrorrhizum
essential oil
(Zdravets oil)
recrystallisation
from EtOH
O
LDA, MeI, HMPA
-78 o C, 54%
O
LiAlH 4
OH
Ac 2 O, DMAP,
OAc
Py, 93% (2 steps)
n-BuLi, CS 2 , MeI Li, HNEt 2 , -10 o C,
10% on 1g scale
CS 2 Me
O
Bu 3 SnH, BEt 3 , O 2 ,
35% on 1g scale
over 2 steps
Scheme 4.
6
O
LiAlH 4 , THF,
0 o C to rt.
OH
( )
8
TsCl, Py,
( )
OTs
8
OCH 3
7
Me 2 CuLi,
CH 2 Cl 2 , 0 o C
THF, 0 o C
Scheme 5.
inha Cave (Minas Gerais State) region of Brazil, has been
proposed as the novel homosesquiterpene 9-methylgermacrene-B
[17]. The structure and absolute configuration
was defined as (S) by comparing analytical data and biological
activity of the synthetic enantiomers with the natural
product [18].
Hooper et al. [19] described a synthesis of 6 starting from
germacrone, which is the main component of the essential oil
of the cranesbill Geranium macrorrhizum (Zdravets oil) and
was obtained in pure form by recrystallization. Subsequent
methylation and deoxygenation afforded the racemic pheromone
over 4 steps (Scheme 4).
3.3. (3Z,6Z,9Z)-3,6,9-Nonadecatriene (7)
(3Z,6Z,9Z)-3,6,9-Nonadecatriene is the pheromone of a
number of geometrid and noctuid moths, for example it has
been identified in the autumn gum moth Mnesampela privata
[20].
The use of butylated hydroxytoluene as an antioxidant to
prevent loss of product was the key factor in the short synthesis
presented by Davies et al. [21]. Methyl linoleate (either
enriched from linseed oil or pure) was reduced to the
alcohol, which was converted to the tosylate. Reaction with
lithium dimethyl cuprate afforded 7 without C19 contaminants
in 65 % (starting from enriched methyl linoleate) and
85 % (starting from pure methyl linoleate) yield, respectively
(Scheme 5). All steps were carried out in the presence of 1 %
the antioxidant, which was carried through the synthesis and
assured an improved yield as compared to previous methods.
4. SYNTHESIS OF EPOXY PHEROMONES
4.1. (3Z,6Z,9S,10R)-9,10-Epoxy-1,3,6-heneicosatriene (8)
and (3Z,6Z,9S,10R)-9,10-epoxy-3,6-heneicosadiene (9)
(3Z,6Z)-9,10-Epoxy-1,3,6-heneicosatriene (8) and (3Z,
6Z)-9,10-epoxy-3,6-heneicosadiene (9) were identified in the
sex pheromone gland of the arctiid moth, Hyphantria cunea.
Of the synthesized enantiomers, the (9S,10R) alkenes were
biologically active, while the (9R,10S) forms were inactive
[22].
Diacrisia obliqua is a polyphagous insect attacking many
crops, particularly oil seed crops in India and Bangladesh
[23]. Persoons et al. showed that the pheromone of D. obliqua
is a five component blend consisting of 8, 9, (9Z,12Z)-
octadecadienal, (9Z,12Z,15Z)-octadecatrienal and (3Z,6Z,
9Z)-heneicosatriene [24].
Che and Zhang [25] described an enantioselective synthesis
of 8 utilizing a coupling reaction between a 1,4-diyne
and the chiral epoxy tosylate A (Scheme 6).

686 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.
HO
( )
10
4Å MS, D-(-)-DCHT, Ti(O-i-Pr) 4 ,
TBHP, CH 2 Cl 2 , -20 oC
HO
( )
10
+
HO
O
( )
10
1) m-CPBA, CH 2 Cl 2 , rt., 24 h
2) (i) TsCl, powdered KOH, Et 2 O,
-5 o C to 0 o C, 3 h
(ii) flash chromatography employed
to separate diastereoisomer
1) AcOH, PPh 3 , DIAD, THF, rt., 24 h
2) K 2 CO 3 , CH 3 OH, 0 o C, 1 h. D-(-)-DCHT,
dicyclohexyl D-(-)-tartrate; TBHP, tert-butyl
hydroperoxide; DIAD, diisopropyl
azodicarboxylate.
O
O
TsO
( )
10
(2S,3S)-A
3) (i) TsCl, powered KOH, Et 2 O,
-5 o C to 0 o C, 3 h
(ii) flash chromatography employed
to separate diastereoisomer
HO
( )
10
OTHP
1) n-BuLi, -78 o C, 20 min
2) BF 3
. Et 2 O, -78 o C, 10 min
3) (2S,3S)-A, -78 o C, 3h
HO
OTHP
1) PTSA, CH 3 OH, rt., 5 h
TsO
( )
10
2) K 2 CO 3 , CH 3 OH, rt., 30 min
O
Scheme 6.
( )
10
OH
1) H 2 , Pd-CaCO 3 , quinoline, CH 3 OH, rt.
2) (i) MsCl, Et 3 N, CH 2 Cl 2 , 0 o C to rt. , 1 h
(ii) LiBr, NaHCO 3 , THF, 8 h.
3) K 2 CO 3 , CH 3 OH, rt., 48 h.
O
8
Nakanishi and Mori [26] described a new and more practical
synthesis of 8 and 9 to furnish these compounds in a
suitable quantity (Scheme 7). The synthesis of both pheromones
was performed employing the chiral epoxide A obtained
in 84-87% e.e. from lipase-catalyzed asymmetric acetylation
of the racemic epoxide in the key step. (2S,3R)-A
was converted to the triflate and alkylated with diynes D
(synthesis of 8) and E (synthesis of 9), respectively. The
resulting epoxy diynes were further transformed to 8 and 9,
respectively, including Lindlar semihydrogenation and a
final alkylation step.
4.2. (7R,8S)-(+)-7,8-Epoxy-2-methyloctadecane (10) (disparlure)
Disparlure (2-methyl-7,8-epoxyoctadecane, 10) is the
single sex attractant pheromone emitted by the female gypsy
moth, Lymantria (Porthetria) dispar [27]. Iwaki et al. [28]
established the configuration of natural 10 to be (7R,8S) by
synthesis, and also observed that this isomer is attractive
while the enantiomer results in an inhibitory response.
Koumbis and Chronopoulos [29] described a short route
to obtain both enantiomers of disparlure, starting from isopropylidene
D- and L-erythrose (both available in multigram
quantities from D- and L-arabinose), respectively, which
were subjected to two Wittig olefinations. The saturated acetonide
obtained after hydrogenation with Raney-Ni was
transformed to the epoxide via the diol (Scheme 8).
An enantiodivergent route to both enantiomers of disparlure
was developed by Prasad and Anbarasan [30]. The common
precursor for both enantiomers was the homoallylic
alcohol A, obtained in 5 steps from the bis-Weinreb amide of
L-tartaric acid. The hydroxy group of A was either protected
as tosylate (synthesis of (-)-10) or as tert-butyldimethylsilyl
ether (synthesis of (+)-10). Building up of the carbon skeleton
by cross metathesis reactions and subsequent partial deprotection
and cyclization furnished the enantiomers in a
high overall yield (Scheme 9).
4.3. (6Z,9Z,11S,12S)-trans-11,12-Epoxy-6,9-heneicosadiene
(11) (posticlure)
Posticlure [(6Z,9Z,11S,12S)-trans-11,12-epoxy-6,9-
heneicosadiene (11)] is the pheromone of the tussock moth
Orgyia postica, a pest of mango and litchi trees in Japan
[31]. A multigram synthesis of the trans-epoxide pheromone,
starting from diethyl L-tartrate was carried out by
Fernandes [32], employing Wittig olefinations and the
stereoselective conversion of an intermediate diol to the epoxide
(Scheme 10).

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 687
HO
OH
1) NaH, TBSCl, THF
2) m-CPBA, CH 2 Cl 2 , 81% (2 steps)
TBSO
O
OH
Lipase PS-C,
CH 2 =CHOAc, Et 2 O, 3 h
TBSO
O
OH
+
TBSO
O
OAc
(2R,3S)-A
47%, 81% e.e.
(2S,3R)-B
49%, 84-87% e.e.
1) K 2 CO 3 , MeOH, quant.
TBSO
O
OH
1) EtMgBr, Cu 2 Cl 2
(2S,3R)-A
OH
CH
CCH 2 Br, THF, 55%
2) TMSCl, Et 3 N, DMAP,
CH 2 Cl 2 , 93%
D
OTMS
(2R,3S)-A
1) n-BuLi, Tf 2 O, THF/HMPA, -78 o C
2) n-BuLi, D, THF, -78 o C
3) K 2 CO 3 , MeOH
[3 steps, 73% (average 60%)]
O
OTBS
OH
1) H 2 , Lindlar Pd-CaCO 3 -Pb 2 + ,
cyclohexane, cyclohexene, 83%
2) CBr 4 , PPh 3 , CH 2 Cl 2 , 96%
O
OTBS
Br
1) t-BuOK, 18-crown-6,
hexane, 77%
2) TBAF, THF, 90%
O
OH
1) TsCl, Py
2) (n-C 10 H 21 ) 2 CuLi,
Et 2 O (65%, 2 steps)
O
8
EtMgBr, Cu 2 Cl 2
CH
CCH 2 Br, THF, 55%
E
(2R,3S)-A
1) n-BuLi, Tf 2 O, THF/HMPA, -78 o C
2) n-BuLi, E, THF, -78 o C (67%, 2 steps)
O
1) H 2 , Lindlar Pd-CaCO 3 -Pb 2 + ,
cyclohexane, 77%
2) TBAF, THF, 96%
OTBS
O
Scheme 7.
OH
1) TsCl, Py
2) (n-C 10 H 21 ) 2 CuLi,
Et 2 O (62%, 2 steps)
O
9
5. SYNTHESIS OF NON-ISOPRENOIDAL PHERO-
MONE ALCOHOLS AND THEIR ESTERS
5.1. (2S,3S,7S)-3,7-Dimethylpentadecan-2-ol (12) and
(2S,3S,7S)-3,7-dimethylpentadec-2-yl acetate (13)
Since the pioneering work of Coppel, Jewett and coworkers
[33, 34], it is known that the sex pheromones of
several species of pine sawflies are esters that share a common
alcohol moiety, namely 3,7-dimethylpentadecan-2-ol
(12). Neodiprion lecontei and N. sertifer produce the acetate
13 as the major component of their pheromones, whereas
Diprion similis uses the propionate [33]. Later studies revealed
that the (2S,3S,7S) stereoisomers showed the highest
activity for all Neodiprion species [35, 36].

688 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.
O
O
O
OH
[CH 3 (CH 2 ) 8 Ph 3 P] + Br - , n-BuLi,
THF, 0 o C to rt., 95%
HO
O
O
( )
7
1) (COCl) 2 , DMSO,
CH 2 Cl 2 then Et 3 N, -55 o C to rt.
2) [(CH 3 ) 2 CH(CH 2 ) 3 Ph 3 P + ]Br - ,
n-BuLi, THF, 0 o C to rt., 91% (2 steps)
( )
2
O
O
( ) 7
1) H 2 , Raney-Ni, MeOH, rt., 98%
2) 37% HCl, THF/H 2 O (2:1), rt., 98%
HO
HO
1) CH 3 C(OEt) 3 , PPTS, toluene, 110 o C
2) TMSCl, CH 2 Cl 2 , rt.
3) 1 N KOH in MeOH,
THF, 0 o C to rt., 90%
O
(+)-10
O
OH
Similarly
O
O
O
Scheme 8.
OH
A
OBn
9
( )
TsCl, DMAP,
CH 2 Cl 2 , rt., 5 h, 87%
OTs
OBn
9
( )
(-)-10
4-methyl-1-pentene,
Grubbs 2nd gen. catalyst (5 mol%),
CH 2 Cl 2 , reflux 6 h, 92%
OTs
OBn
9
( )
H 2 , Pd/C, MeOH,
rt., 3 h, 90%
OTs
OH
9
( )
K 2 CO 3 , MeOH,
rt., 1 h, 89%
O
(-)-10
OH
( ) 9
OBn
A
TBDMSOTf, Py,
CH 2 Cl 2 , 0 o C, 1 h, 98%
OTBDMS
( ) 9
OBn
4-methyl-1-pentene,
Grubbs 2nd gen. catalyst (5 mol%),
CH 2 Cl 2 , reflux 8 h
OTBDMS
9
( )
OBn
H 2 , Pd/C, MeOH,
rt., 3 h, 81%
OTBDMS
9
( )
OH
TsCl, DMAP, CH 2 Cl 2
rt., 8 h, 90%
OTBDMS
9
( )
OTs
TBAF, THF, rt.,
10 h, 89%
O
Scheme 9.
(+)-10
Bekish et al. [37] reported a stereoselective synthesis of
alcohol 12 and acetate 13 based on the creation of methyl
branches in the carbon chain using the transformation of
carboxylic esters into 2-substituted allyl halides via sulfonates
of tertiary cyclopropanols (Scheme 11).
5.2. 7-Methyloctyl 5-methylhexanoate (14), 7-methyloctyl
octanoate (15), 7-methyloctyl 7-methyloctanoate (16), and
7-methyloctyl (Z)-4-decenoate (17)
7-Methyloctyl 5-methylhexanoate (14), 7-methyloctyl
octanoate (15), 7-methyloctyl 7-methyloctanoate (16), 7-

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 689
HO
CO 2 Et
(CH 3 ) 2 C(OCH 3 ) 2 , PTSA,
O
CO 2 Et
1) LiAlH 4 , THF, reflux, 4 h.
HO
CO 2 Et
benzene, reflux, 8 h, quant.
O
CO 2 Et
2) NaH, DMF, -15 o C, 30 min,
BnBr, 1 h, rt., 82%
O
O
A
OH
OBn
1) (COCl) 2 , DMSO, -78 o C, 30 min, rt., 1h
2) [n-C 7 H 15 CH 2 PPh 3 ] + Br - , n-BuLi, rt., 30 min
-80 o C, aldehyde "from A", 2 h, rt.,
overnight, 80%
O
O
B
( )
6
OBn
4N HCl, MeOH
rt., 8 h, 93%
HO
HO
( )
6
OBn
1) CH 3 C(OCH 3 ) 3 , PTSA, CH 2 Cl 2 , rt., 30 min
2) CH 3 COBr, CH 2 Cl 2 , rt., 1.5 h
3) K 2 CO 3 , MeOH, rt., 2.5 h, 90% overall
( )
6
O
H
H
OBn
Scheme 10.
B
Pd(OH) 2 /C 20%, H 2 (80 psi)
MeOH/EtOAc (1:5), rt.,
12 h, 94%
( )
6
OTHP
O
O
CO 2 Et
O
H
1) Zn, CuCl, 1,2-dibromoethane,
ClCO 2 Et, reflux
2) MeOH, THF, HCl, reflux
3) Et 3 N, reflux. (74%, 3 steps)
1) morpholine, 100 o C, 24 h
2) recrystallization
H
(-)-11
Pd(OH) 2 /C (20%),
H 2 (80 psi),
MeOH/EtOAc, rt.,
12 h, 95%
( )
8
( )
4
1) CH 3 C(OCH 3 ) 3 , PTSA, CH 2 Cl 2 ,
rt., 20 min
2) CH 3 COBr, CH 2 Cl 2 , rt., 1.5 h
3) K 2 CO 3 , MeOH, rt., 2.5 h, 89%
1) DHP, PPTS, CH 2 Cl 2 , reflux
2) EtMgBr, Ti(O-i-Pr) 4 , Et 2 O/THF
OH
( )
4
( )
6
O
O
N
O
cis/trans = 99:1
O
H
C
D
( )
8
OH
O
H
O
O
H
OH
4 N HCl, MeOH,
rt., 8 h, 92%
( )
6
H
(-)-11
OH
OTHP
O
1) PCC, NaHCO 3 , CH 2 Cl 2 , 0 o C, 4 h
2) [(Z)-n-C 5 H 11 CH=CHCH 2 CH 2 PPh 3 ] + I - ,
n-BuLi, rt., 30 min, -80 o C,
aldehyde "from C" , 1 h, rt., overnight, 77%
1) (COCl) 2 , DMSO, -78 o C, "20 min, B", 45 min,
Et 3 N, -78 o C, 30 min, rt., 1 h
2) [(Z)-n-C 5 H 11 CH=CHCH 2 CH 2 PPh 3 ] + I - , n-BuLi,
r.t., 30 min, -80 o C, aldehyde "from D", 1 h, rt.
overnight, 79%
HO
HO
( )
8
( )
4
1) MsCl, Et 3 N, Et 2 O
NaBH 4 , NiCl 2 ,
B(OH) 3 , H 2 O, 98%
1) DHP, PPTS, CH 2 Cl 2
2) MgBr 2 , Et 2 O/CHCl 3 , reflux
(57%, 4 steps)
2) (2R)-2-methyldecyllithium,
Et 2 O/THF, -78 o C
( )
4
O O
A
cis/trans = 10:1
OTHP
OTHP
O
Br
( )
7
Scheme 11.
1) N 2 H 4 , KOH, triethylene
glycol, 180 - 210 o C
2) MeOH, PPTS, reflux
OH
12
( )
7
CH 3 COCl, Et 3 N, Et 2 O
OCOCH 3
13
( )
7

690 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.
BnO
OH
(COCl) 2 /DMSO/Et 3 N
CH 2 Cl 2
BnO
H
O
[(CH 3 ) 2 CHCH 2 PPh 3 ] + Br -
BuLi/THF
BnO
O
H 2 , Pd/C
HO
A
Py /Et 2 O, H 3 C(CH 2 ) 6 COCl
O
15
A
Jones
acetone
HO
O
(COCl) 2 /CH 2 Cl 2 , A/Py
O
16
O
OH
Jones
acetone
O
OH
(COCl) 2 /CH 2 Cl 2 ,
A/Py
O
O
14
OH
Jones, acetone,
(COCl) 2 /CH 2 Cl 2 , A/py
O
O
Scheme 12.
methyloctyl (Z)-4-decenoate (17) were identified by Tolasch
et al. as components of the sex pheromone produced by females
of the click beetle Elater ferrugineus [38]. The same
authors described a simple synthesis to obtain all four compounds.
The alcohol moiety A common to all esters was obtained
in four steps from 1,5-pentanediol, involving monoprotection,
partial oxidation, Wittig olefination and hydrogenation
reactions. The acid moieties were either commercially
available or synthesized from the corresponding alcohols
by Jones oxidation (Scheme 12).
5.3. (2S,10S)-2,10-Diacetoxyundecane (18)
(2S,10S)-2,10-Diacetoxyundecane (18) constitutes, together
with (2S,9S)-2,9-diacetoxyundecane and (S)-2-
acetoxyundecane, the sex pheromone of the swede midge
Contarinia nasturtii [39].
A novel approach for a remote asymmetric induction to
obtain 1,9-anti diols was presented by Cahill et al. [40]. The
diastereoselective synthesis of the furanyl spiroacetal A allowed
the preparation of spiroacetal fluit fly pheromones B
and C, which were used in the synthesis of the diastereomerically
pure mixture of (R,R) and (S,S) isomers of 1,9-anti
diol D by transacetalisation. Kinetic resolution of (±)-D using
Candida antarctica lipase B afforded the (R,R)-diacetate
and the (S,S)-diol, which was converted to 18 with acetic
anhydride (Scheme 13).
5.4. (2S,7S)-2,7-Dibutyroxynonane (19)
The orange wheat blossom midge Sitodiplosis mosellana
is a worldwide pest of wheat crops. The sex pheromone has
been identified as (2S,7S)-2,7-dibutyroxynonane (19) [41],
and a mixture of isomers is effective in monitoring the pest.
17
The stereoselective synthesis of (2S,7S)-19 was achieved
by Hooper et al. [42] using a diastereoselective ring closure
metathesis reaction of the mixed silaketal A in the key step
(Scheme 14). The other stereogenic center had been defined
by the use of (S)-5-hexen-2-ol during preparation of A.
5.5. (4E,7Z)-4,7-Tridecadienyl acetate (20)
(4E,7Z)-4,7-Tridecadienyl acetate (20) is a component of
the pheromone of the potato moth Phthorimaea opercucella
[43].
Starting from acrolein, Vakhidov and Musina [44] obtained
the allylic alcohol A by Grignard reation. The key
step was a stereoselective Claisen rearrangement of A with
triethylorthoacetate in the presence of propanoic acid. Oxidation
of the resulting hydroxy ester and stereoselective Wittig
reaction completed the carbon chain and was followed by
reduction and acetylation to obtain 20 in high purity
(Scheme 15).
5.6. (4E,6Z,10Z)-4,6,10-Hexadecatrien-1-ol (21)
(4E,6Z,10Z)-4,6,10-Hexadecatrien-1-ol (21) is the one of
five components of the pheromone bouquet of the cocoa pod
borer Conopomorpha cramerella [45].
Pereira and Cabezas [46] described a new method of
preparation of 1,5-diynes, by reaction of 1,3-dilithiopropyne
and propargylic chlorides. Two methodologies were used for
the synthesis of endiyne C. In the first, the authors coupled
the lithiated 1,5-dialkyne A with the vinylic iodide obtained
from alkyne B by hydroboration and reaction with iodine.
Alternatively, the vinylic bromide obtained from B by
hidrozirconation and reaction with NBS, was coupled to A
using Sonogashira’s palladium cross coupling reaction
(Scheme 16).

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 691
OTMS
O
+
O
O
1) n-BuLi, THF, -78 o C to 0 o C
2) H 2 , Pd/C, EtOAc, rt.
3) TBAF, CH 2 Cl 2 , rt.
4) PTSA, H 2 O, CH 2 Cl 2 , rt.
A
O
O
RuCl 3 , NaIO 4 ,
H 2 O-MeCN-CH 2 Cl 2
O
O
MeI, K 2 CO 3 ,
O
NaBH 4 , t-BuOH,
O
O
DMF, 70 o C
O
MeOH, reflux
O
O
OH
O
OMe
HO
B
C
ethanedithiol, BF 3
. Et 2 O
CH 2 Cl 2 , rt., 94%
OH
S
S
OH
OH
TsCl, Et 3 N, CH 2 Cl 2 ,
0 o C, 89%
OH
S
S
OH
OTs
NaBH 4 , DMSO,
80 o C, 87%
O
O
ethanedithiol, BF 3
. Et 2 O
CH 2 Cl 2 , rt., 71%
OH
S
S
OH
Raney-Ni, EtOH,
reflux, 90%
OH
(+/-)
OH
C (obtained from B in two steps)
D
polyacrylamide-bound Novozym 435
OH
(S,S)-D
OH
Ac 2 O, DMAP,
10 equiv vinyl acetate, toluene,
rt., 18 h, 50%
+
CH 2 Cl 2 , rt., quant.
OAc
OAc
OAc
(R,R)-19
OAc
(S,S)-19
Scheme 13.
TfO
Si
OTf
THF, Py, DMAP,
0 o C, cool to -78 o C,
(S)-5-hexen-2-ol, warm to rt.,
1,4-pentadien-3-ol
O
Si
O
Grubbs' catalyst, CH 2 Cl 2
40 o C, 70 %
O
Si
O
1) 10 equiv TBAF, 4 Å mol sieves,
reflux 18 h, 78%
2) H 2 , PtO 2 , MeOH, 83%
3) butyric anhydride, Py, 85%
A
O
O
O
Scheme 14.
19
O

692 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.
O
H
THPO
81%
MgBr
THPO
A
OH
1) triethylorthoacetate,
propionic acid, 138 o C
2) PTSA, rt., 56%
HO
COOEt
pyridinium chromate,
CHCl 3 , 62%
O
H
COOEt
[hexyl-PPh 3 ] + Br - ,
t-BuOK, 64%
COOEt
OAc
Scheme 15.
20
Br
n-BuLi, TMEDA
Li
Li
n-BuLi
H
H
H
H
Cl
81%
A
HO
A
TBDMSCl
99%
TBDMSO
B
Cp 2 Zr(H)Cl,
NBS, 79%
TBDMSO
Pd(PPh 3 ) 4 , A,
Br
n-BuLi
Et 2 NH, CuI, 94%
Sia 2 BH, I 2 ,
NaOH/H 2 O 2 , 86%
TBDMSO
Li
1) Sia 2 BH, HOAc, 60%
2) Bu 4 NF, 99%
C
Scheme 16.
HO
21
6. SYNTHESIS OF NON-ISOPRENOIDAL ALDE-
HYDES, KETONES, ACIDS, AND ESTERS AS
PHEROMONES
6.1. 4,8-Dimethyldecanal (22)
The aggregation pheromone of the stored foodstuffs pests
Tribolium castaneum and T. confusum was isolated and identified
by Suzuki as 4,8-dimethyldecanal (22) [47, 48]. Mori
and co-workers [49] developed the first total synthesis of all
of the four possible isomers of 22, establishing the absolute
configuration of the natural pheromone as (4R,8R)-22. Later,
bioassays showed that a 8:2 mixture of the isomers (4R,8R)
and (4R,8S) was about 10 times more active than (4R,8R)
alone [50].
Zarbin et al. [51] described a synthesis of (4R,8R)- and
(4S,8R)-22, coupling the Grignard reagent obtained from
(R)-2-methyl-1-bromobutane A and the tosylate of (R)- and
(S)-citronellol, respectively (Scheme 17), followed by ozonolysis
of the double bond of the resulting alkene. The key
intermediate A was obtained optically pure in five steps from
methyl (S)-3-hydroxy-2-methylpropionate [52, 53].
Another methodology was described by Kameda and Nagano
[54]. Starting from (R)-2,3-O-isopropylideneglyceraldehyde,
they obtained 22 in 11 steps and 7% overall yield

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 693
HO
O
OMe
[53]
THPO
PPh 3 , Br 2 ,
CH 2 Cl 2 , 75%
Br
(R)-A
*
OH
TsCl, Py, 0 o C
OTs
(R)-A, Mg, THF,
(R)-citronellol; 97% e.e.
(S)-citronellol; 67% e.e.
CHCl 3 , 86%
Li 2 CuCl 4 , 82%
*
O 3 , CH 2 Cl 2 ,
DMS, 83%
O
*
Scheme 17.
(4R,8R)-22 (58% overall yield; 96% e.e.)
(4S,8R)-22 (66% e.e.)
O
O
O
H
+
Br
CO 2 Et
1) Zn, THF, aq NH 4 Cl
2) BnBr, Ag 2 O, toluene
O
O
OBn
CO 2 Et
+
O
O
OBn
CO 2 Et
A
2.8:1
Recrystallisation,
26% from A
O
O
OBn
CO 2 Et
CO 2 Et
I
.
n-Bu 3 SnH, Et 3 B,
MgBr 2 OEt 2 , CH 2 Cl 2
O
O
OBn
CO 2 Et
CO 2 Et
1) LiAlH 4 , Et 2 O
OBn
1) H 2 , Pd/C, EtOH
2) TsCl, Py, CH 2 Cl 2
3) LiAlH 4 , Et 2 O
O
O
2) PhOC(=S)Cl, Py, CH 2 Cl 2
3) n-Bu 3 SnH, AIBN,
toluene, 85 o C
O
O
1) HCl, THF/H 2 O (1:1);
H
2) NaIO 4 , aq. CH 3 CN.
O
(4R,8R)-22
Scheme 18.
(Scheme 18). The key step in the synthesis was the highly
diastereoselective chelation-controlled radical reaction of
ethyl (4S,5R)-4-benzyloxy-5,6-(isopropylidenedioxy)-2-methylenehexanoate
with ethyl (R)-5-iodo-3-methylpentanoate
performed in the presence of 7 equivalents of MgBr 2 OEt 2 .
6.2. (E)-4-Oxo-2-hexenal (23), (E)-4-oxo-2-octenal (24),
and (E)-4-oxo-2-decenal (25)
Defensive secretions of stink bugs (Heteroptera: Pentatomidae)
are characterized by the presence of (E)-4-oxo-2-
alkenals with chain lenghts of 6, 8, and 10 carbon atoms [55,
56]. More recently, these compounds also have been identified
as pheromone components of nymphal [57] and adult
bugs [56, 58].
Moreira and Millar [59] described a simple one step syntheses
of (E)-4-oxo-2-hexenal (23) and (E)-4-oxo-2-octenal
(24) from commercially available 2-ethyl- and 2-butylfurans
respectively, and a two step synthesis of (E)-4-oxo-2-decenal
(25) (Scheme 19).
6.3. 3,11-Dimethylnonacosan-2-one (26)
In 1974, Nishida et al. [60] isolated and identified 3,11-
dimethyl-2-nonacosanone (26) as the major component of
the female-produced contact sex pheromone of the German
cockroach, Blattella germanica.
Ahn et al. [61] described a simple synthesis of 26, starting
from 1,8-octanediol. The key steps are the alkylation of
the methyl ketone A (obtained from methylation of 8-
bromooctanoic acid) to yield bromoalcohol B, and coupling
of B with the anion of the commercially available ethyl 2-
methylacetoacetate. The final decarboxylation step yielded
26 (Scheme 20).

694 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.
O
n-BuLi, THF,
1-iodohexane, 89,8%
Commercially
available
O
O
O
( )
4
( )
2
NBS, Py
THF/acetone/H 2 O, 48%
O
( )
H
4
O
4-oxo-(E)-2-decenal (23)
O
( )
H
2
O
4-oxo-(E)-2-octenal (24)
O
Scheme 19.
HO
O
H
4-oxo-(E)-2-hexenal (25)
1) HBr (48% aq)/benzene,
O
O
reflux, 18 h, 72%
CH 3 Li, THF,
( ) OH
( ) Br
( )
6 2) Jones reagent, acetone,
HO 5
5
-78 o C to 0 o C, 1 h, 64%
0 o A
C to rt., 1 h, 80%
Br
( )
16
OH
1) PBr 3 /Et 2 O, reflux, 2 h, 95%
2) Li/Et 2 O, rt., 30 min
A
( ) Li
( )
16
Et 16 HO
2 O, 0 o C, 3h, 60%
B
( )
6
Br
B
1) Et 3 SiH, BF 3
. Et 2 O/CH 2 Cl 2 ,
0 o C, 2 h, 95%
2) ethyl-2-methyl acetoacetate,
K 2 CO 3 , KI/acetone, reflux, 20 h, 93%
( )
16
( )
7
O
CO 2 Et
15% NaOH, (n-Bu) 4 NOH
THF, rt., 2 h, 73%
O
( )
16
Scheme 20.
H
O
O
26
n-C 5 H 11 MgBr
( )
4
OH
O
1) t-BuLi
2) 1-iododecane
3) H+
O
9 ( )
O
( )
4
(endo:exo 7:3)
Scheme 21.
AcCl, NaI, AcOH
( )
8
O
27 (E:Z 7:3)
( )
4
6.4. (Z)-6-Heneicosen-11-one (27)
(Z)-6-Heneicosen-11-one (27) was first reported in 1975
as the pheromone of the Douglas-fir tussock moth Orgyia
pseudotsugata [62]. It has also been found that a 60:40 (E/Z)
mixture of 27 was considerably more active than pure (Z)-27
[63].
Shin et al. [64] developed a selective method for the
transformation of 6,8-dioxabicyclo[3.2.1]octanes to ,enones
by Lewis acid-induced C–O bond cleavage. The use
of AcCl–NaI was crucial for the selectivity of the reaction.
The method was applied to the synthesis of 27, employing 5-
decyl-7-pentyl-6,8-dioxabicyclo[3.2.1]octane, which was
prepared by the reaction of the dimer of acrolein with n-
pentylmagnesium bromide, with subsequent alkylation and
cyclization steps (Scheme 21).
6.5. (4S,6S,7S)-7-Hydroxy-4,6-dimethyl-3-nonanone (28)
(serricornin)
Serricornin [(4S,6S,7S)-7-hydroxy-4,6-dimethyl-3-nonanone,
(4S,6S,7S)-28] is the sex pheromone produced by females
of the cigarette beetle, Lasioderma serricorne [65-69].

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 695
O
S
+
H
O
O
S
O
wet
DMSO
H N N
N N N
H H
O OH
O O
S
S
75% (> 98% e.e.)
Li s Bu 3 BH, THF,
-78 o C, 83%
OH
OH
O
O
1) Et 3 SiOTf, 2,6-lutidine,
CH 2 Cl 2 , 0 o C, 97%
OSiEt 3
O
O
1) Raney-Ni, EtOH, reflux, 82%
S
S
2) NaH, CS 2 , MeI, 93%
3) Bu 3 SnH, AIBN, PhMe,
110 o C, 91-97%
S
S
2) HOAc, CH 2 Cl 2
OH
O
AcCl, DMAP,
OAc
O
CH 2 Cl 2 (72% 2 Steps)
28
29
Scheme 22.
O
O
K 2 CO 3 , MeI
Acetone, 95%
O
O OH O OH O
Table 1
30 A
(4S,5R)-30 B
OH
O
OH
O
Scheme 23.
30 C
(4S,5S)-30 D
Ward et al. [70] described a synthesis of serricornin in 7
steps and 31% overall yield, employing an enantioselective
direct aldol reaction with a chiral tetrazole catalyst derived
from L-proline in the key step. The keto group of the aldol
adduct was stereoselectively reduced using Li(sec-Bu) 3 BH,
and the resulting diol A was monosilylated and submitted to
Barton-McCombie deoxygenation followed by desulfurization
and deprotection to afford 28, which was isolated and
characterized as the acetate 29 (Scheme 22).
6.6. 5-Hydroxy-4-methyl-3-heptanone (30) (sitophilure)
Sitophilure (5-hydroxy-4-methyl-3-heptanone, 30) was
identified in 1984 by Phillips et al. [71, 72] as the maleproduced
aggregation pheromone of the rice weevil, Sitophilus
oryzae and of the maize weevil, Sitophilus zeamais. The
synthesis of the four possible stereoisomers of 30 followed
by indoor bioassays, revealed the (4S,5R) isomer to be the
active form of the pheromone [73, 74].
Kalaitzakis et al. [75] described a chemoenzymatic synthesis
of sitophilure in two steps and an overall yield of 81%,
starting from commercially available 3,5-heptanedione
(Scheme 23). The key step of this synthesis relies on the
stereoselective reduction of the chemically synthesized precursor
of (+)-sitophilure, 4-methyl-3,5-heptanedione, by isolated
NADPH-dependent ketoreductases (KRED) (Table 1).
The absolute stereochemistry of products 30 B and 30 D was
determined by the use of chiral derivatizing agents.
6.7. 1-Ethylpropyl 3-hydroxy-2-methylpentanoate (31)
(sitophilate)
Sitophilate (1-ethylpropyl 2-methyl-3-hydroxypentanoate,
31) was identified by Phillips et al. [76] as the maleproduced
aggregation pheromone of the granary weevil Sitophilus
granarius. Bioassays employing all of the synthetic
isomers revealed (2S,3R)-31 to be the natural pheromone
[77].
Kalaitzakis et al. [78] worked out a chemoenzymatic synthesis
using a ketoreductase (KRED) for the selective reduction
of -ketoester A. Of over 100 enzymes tested, the
KRED-A1B gave the best selectivity towards the desired
(2S,3R) configuration. The diastereomeric purity of sitophilate
was improved either by chromatographic separation after
transesterification (Scheme 24, pathway 1) or by use of an
enzymatic hydrolysis of the resulting -hydroxyester B
(pathway 2) and subsequent esterification with 3-bromopentane.
Gil et al. [79] described a two-step synthesis of 31 employing
the condensation of the dianion of propanoic acid
and propanal, and subsequent esterification with 3-pentanol
(Scheme 25). Different bases, reaction conditions and chiral

696 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.
Table 1.
Substrate
KRED
Diastereomeric Ratio % (30)
A B C D
Conversion
(time)
U/mg
Product
101 3 - 6 91 100% (6h) 0.042
114 8 4 - 88 90% (24h) 0.042
115 4 - 4 92 100% (6h) 0.016
O
O
118 4 - - 96 93% (24h) 0.069
OH
O
119 99 100% (12h) 0.204
123 20 - - 80 100% (6h) 0.032
128 3 - 1 96 100% (3h) 0.180
130 6 - - 94 100% (16h) 0.046
A1A 98 20% (24h) 0.058
A1B - 97 3 - 100% (40min) 0.184
A1C - 98 2 - 100% (1h) 0.168
A1D - 97 3 - 100% (1h) 0.131
O
O
K 2 CO 3 , MeI,
O
O
O
acetone, reflux, 99%
O
pathway 1:
A
KRED-EXP-A1B,
NADPH, pH 8.0,
0 o C (12 h),
25 o C (12 h), 90%
A
OH O
O
90% d.e., >99% e.e.
1) NaOH, MeOH/H 2 O, (1:1)
2) 3-bromopentane, DMF, 50 o C,
chromatography, 65%
98% d.e. >99% e.e.
OH
31
O
O
pathway 2:
KOH, 3-bromopentane, DMF
50 o C, 80%, 99% d.e., >99% e.e.
A
KRED-EXP-A1B,
NADPH, pH 6.9
25 o C, 95%
OH
O
O
ICR-112, 25 o C, 83%
OH
O
OH
Scheme 24.
B
82% d.e., >99% e.e.
98% d.e., >99%e.e.
O
OH
Base
OLi
OLi
H
O
OH
O
OH
+
OH
O
OH
OH
H +
OH
O
OH
O
O
+
O
Scheme 25.
31

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 697
O
H
(CH 3 ) 2 NH HCl, 37% formaldehyde,
70 o C, 24 h, 88%
O
H
NaBH 4 , 5% NaHCO 3
MeOH, 5 o C, 1 h, 90%
OH
CH 3 C(OC 2 H 5 ) 3 , propanoic acid,
138 o C, 5 h, 76%
COOEt
H 2 , 10% Pd/C,
EtOH, 3 h, 92%
COOEt
KOH/EtOH/H 2 O
reflux 2.5 h, 95%
COOH
Scheme 26.
33
32
A
A
Ac 2 O, Py, DMAP,
rt., 100%
m-CPBA, CH 2 Cl 2 ,
NaHCO 3 , rt., 82-85%
O O OH O OH O
L-proline (30 mol %),
H +
( ) ( )
CHCl
+ 9
3 , 24 h, 80%
9
A
B
OAc O
85:15. 96% e.e. syn
m-CPBA, CH 2 Cl 2 ,
( )
9
NaHCO 3 , rt., 82-85%
OAc
O O
( )
9
OH
O O Ac 2 O, Py, DMAP,
( )
9
rt., 100%
(-)-(5R,6S)-34
Scheme 27.
amines as bases were tested, but only a modest diastereoselectivity
and a modest degree of asymmetric induction was
obtained.
6.8. 4-Methyloctanoic acid (32)
4-Methyloctanoic acid (32) and its ethyl ester (33) are
aggregation pheromones of Oryctes rhinoceros beetles, pests
of coconut and date palm crops in Southeast Asia and North
Africa [80-82].
A five-step synthesis with high overall yield was developed
by Ragoussis et al. [83]. The key step is a Claisen orthoester
rearrangement of the intermediate formed by reaction
of 2-methylene-1-hexanol and triethylorthoacetate, resulting
in chain elongation and completion of the carbon
skeleton (Scheme 26).
7. SYNTHESIS OF LACTONES AS PHEROMONES
7.1. (5R,6S)-6-Acetoxyhexadecan-5-olide (34)
The major component of the oviposition attractant
pheromone of the mosquito Culex pipiens fatigans was identified
by Laurence and Pickett [84] in 1982 as erythro-6-
acetoxy-5-hexadecanolide (34). The absolute configuration
was established as (-)-(5R,6S) by comparative chromatography
of the 6-trifluoroacetoxy derivatives of the natural
pheromone and of the synthetic (–)-(5R,6S) and (+)-(5S,6R)
enantiomers [85].
Sun et al. [86] described a synthesis of (5R,6S)-34 employing
a L-proline-catalyzed asymmetric aldol reaction in
the key step, giving diastereomeric intermediates A and B in
a 85:15 ratio. A was obtained in 96% e.e., but it was not
stated if or how the diastereomers were separated. Transformation
of A by Baeyer-Villiger oxidation followed by acetylation
(or the inverse sequence) yielded 34 (Scheme 27).
In a similar approach, Ikishima et al. [87] obtained the
aldol adducts B and C (75:25) by L-proline-catalyzed aldol
condensation between 1,3-dithiane A and cyclopentanone.
Adduct B was obtained in 83% e.e. and separated from C by
chromatography. Desulfurization of B followed by Baeyer-
Villiger oxidation and acetylation yielded 34 (Scheme 28).
Dhotare et al. [88] reported the synthesis of (5R,6S)-34
by a stereoselective addition of n-decyllithium to (R)-2,3-
cyclohexylideneglyceraldehyde A in the key step. The adduct
was straightforwardly converted to 34 in 8 steps
(Scheme 29).
The stereoselective synthesis developed by Prasad and
Anbarasan [89] started from the bis-Weinreb amide of L-
tartaric acid which was converted to the benzyloxy aldehyde
A. Allylation of A and acetalisation of the resulting homoallylic
alcohol with acrolein diethyl acetal afforded key intermediate
B, which was subjected to a ring closure metathesis
reaction. Mitsunobu inversion and a final lactol oxidation are
further key steps in this synthesis (Scheme 30).

698 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.
O
COOEt
LDA (2 eq.) THF, -78 o C
C 7 H 15 Br, 0 o C, 1 h, 60%
O
( )
7
O
COOEt
1) HS(CH 2 ) 3 SH, BF 3 OEt 2 ,
AcOH, rt. 3 h, 98%
2) DIBAL-H, CH 2 Cl 2 ,
-78 o C, 30 min, 99%
S
( )
7
S
O
H
30 mol % L-proline
13 o C, 20 h, 85% B/C 75:25
O
OH
S
S
O OH S S
+
( ) ( )
7
7
A
B (83% e.e.)
C (90% e.e.)
Scheme 28.
O OH
1) m-CPBA, NaHCO 3 ,
OAc
Raney Ni (W-4),
CH 2 Cl 2 , rt., 9 h, 90%
O O
B ( )
( )
AcOEt, rt., 1 h, 62%
7 2) Ac 2 O, DMAP, Py,
7
rt. 4 h, 100%
34
O
A
O
O
H
A) n-decyllithium, hexane,
- 40 o C to rt., 75%
or B) n-decyllithium, Et 2 O,
- 40 to 0 o C, 78%
O
O
O O
+
( ) 9
( ) 9
OH
Method A: syn/anti 7:93
Method B: syn/anti 5:95
OH
1) TBDPSCl, imidazole, rt.
2) CF 3 CO 2 H, H 2 O,
0 o C, 91% (2 steps)
HO
OH
9
( )
1) TsCl, Py, 0 o C
O
( ) 9
1) 3-butenyl-MgBr, CuBr,
- 40 o C to rt., 77%
OTBDPS
2) K 2 CO 3 , MeOH, rt.,
89% (2 steps)
OTBDPS
2) O 3 , MeOH, NaOH,
-15 o C, 77%
O
Scheme 29.
O
H
9 1) TBAF, THF, rt., 69%
( ) ( )
9
O O
2) Ac 2 O, Py, 0 to -10 o C, 79%.
H
OTBDPS
OAc
34
7.2. (4R,9Z)-Octadec-9-en-4-olide (35)
In 2001 Cossé et al. [90] isolated and identified (Z)-
octadec-9-en-4-olide (35) as a female-specific and antennally
active compound from the female currant stem girdler, Janus
integer, a pest of red currant in North America. The absolute
configuration has been established as (R) by synthesis [91]
and bioassays [92].
Mori [93] described a synthesis of 35 in a gram quantities
using a Sharpless asymmetric dihydroxylation obtaining the
chiral diol A, which was converted to epoxide B presenting
87% e.e. Jacobsen hydrolytic kinetic resolution improved the
optical purity to 96% e.e. Meyer’s oxazoline alkylation
method [94, 95] was adopted to convert (R)-B to (R)-
octadec-9-yn-4-olide, which was partially hydrogenated to
yield 35 (Scheme 31).
A stereoselective synthesis of 35 was presented by
Sabitha et al. [96]. Base-induced ring opening of the chiral
epoxy chloride A and subsequent treatment with butyl bromide,
gave the acetylenic diol B, which was subjected to a
zipper isomerization by treatment with 1,3-diaminopropane
and sodium amide in the key step (Scheme 32). The resulting
terminal alkyne was chain elongated and transformed to 35
in 4 further steps.
Another sequence, using similiar intermediates, was presented
by the same author [97] (Scheme 33). The chiral epoxy
chloride A was prepared in several steps, including a
Sharpless asymmetric epoxidation. The resulting alkynol B
was methoxycarbonylated at the triple bond after protection
of the hydroxyl group, while the other extreme was subjected
to deprotection, oxidation, and stereoselective Wittig reaction
resulting in chain-elongation; followed by the final deprotection
and cyclization steps.

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 699
OEt
H
O
OBn
A
( )
9
SnBu 3
HO
( )
9
OBn
OEt
PPTS, benzene
reflux, 3 h, 62%
EtO
O
B
OBn
( )
9
Grubbs 1st gen, cat. (5 mol%)
toluene, 60 o C, 8 h, 86%
EtO
O
OBn
( )
9
H 2 , 10% Pd/C,
MeOH, 3 h, 99%
EtO
O
OH
( )
9
1) DIAD, PNBA, PPh 3 , THF
0 o C, rt., 6 h
2) K 2 CO 3 , MeOH, rt., 2 h
86% (two steps)
EtO
O
( )
9
OH
Ac 2 O, Et 3 N
DMAP, CH 2 Cl 2
rt., 2.5 h, 94%
EtO
O
( )
9
OAc
1) 3M HCl-THF, rt., 3.5 h
2) PCC, NaOAc, Celite
CH 2 Cl 2 , rt., 2.5 h
72% for two steps
O
O
34
( )
9
OAc
Scheme 30.
OH
1) TsCl, Py
2) NaI, DMF, 92% (2 steps)
I
1) n-C 8 H 17 C CH, n-BuLi, THF, 71 %
2) AD-mix , t-BuOH, H 2 O, 0-5 o C, 6 h,
then rt. overnight
( )
7
(R)-A
OH
recrystallization from hexane
[1x(84%) for (R)-A of 75% e.e;
2x(60%) for (R)-A of 87% e.e.*;
5x(20%) for (R)-A of 98% e.e.]
OH
MeC(OMe) 3 ,
PPTS, CH 2 Cl 2
* Used in the next step
7
O
O
OMe
AcBr,
CH 2 Cl 2
7
Br
OAc
K 2 CO 3 , MeOH,
87% (3 steps)
O
Jacobsen's (R,R)-salen
cobalt catalyst, 0.4 equiv.
( )
7
H 2 O, THF, 72%
( )
7
(R)-B (87% e.e.)
(R)-B (96% e.e.)
O
1) 2,4,4-trimethyl-2-oxazoline,
n-BuLi, THF, -78 o C to rt.
O
O
H 2 , Lindlar Pd-CaCO 3 -Pb 2+ ,
O
O
2) dil. HCl, THF, 60 o C,
30 min (58%, 2 steps)
( )
7
hexane, -5 to 0 o C, 94 %
( )
7
35
Scheme 31.
7.3. (S)-5-Hexadecanolide (36)
(S)-5-Hexadecanolide (36) was isolated from mandibular
glands of the queens of the oriental hornet, Vespa orientalis
[98] where it functions as a pheromone to stimulate the
workers to construct queen cells.
Sabitha et al. [99, 100] described two similar approaches
to the synthesis of this pheromone. In both syntheses the key
step was the base-induced opening of a chiral epoxide by
lithium amide in liquid ammonia at -78 °C, and subsequent
treatment with 1-bromononane to give the chiral alkynols A
and B, which finally were converted to 36 (Scheme 34).
7.4. (R)-4-Dodecanolide (37)
(R)-4-Dodecanolide (37) is a defensive secretion isolated
from the pygidial glands of rove beetles, Bledius mandibularis
and Bledius spectabilis [101].
The synthesis of Sabitha et al. [99] started with the chiral
propargylic alcohol A [102], which was methoxycarbony-

700 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.
THPO
O
Cl
1) Li/Liq NH 3 , Fe(NO 3 ) 3 , -78 o C, THF, 2 h
THPO
OH
A
2) n-C 4 H 9 Br, THF, 4 h, 70%
B
1) NaNH 2 , 1,3-diaminopropane
60 o C, 6 h, 60%
2) MOMCl, Hunigís base, CH 2 Cl 2 ,
0 o C to rt., 2 h, 85%
THPO
OMOM
1) n-BuLi, n-C 8 H 17 Br
THF, -78 o C, 2 h, 70%
2) PPTS, MeOH, 12 h, rt., 72%
HO
OMOM
1) IBX, DMSO,CH 2 Cl 2 ,
rt., 2 h, 80%
O
OMOM
( )
7
2) NaClO 2 , NaH 2 PO 4 2H 2 O,
aq. DMSO, rt., 1 h, 74%
OH
( )
7
1) PTSA, MeOH, 12 h, 80%
2) H 2 , Lindlar catalyst,
quinoline, EtOAc, 2 h, 90%
O
O
C 8 H 17
35
Scheme 32.
THPO
Br
+
OH
Li/liq. NH 3 , Fe(NO 3 ) 3 ,
THF, 6 h, 70%
THPO
OH
LiAlH 4 , THF,
0 o C to rt., 3 h, 90%
THPO
OH
(-)-DET, Ti(O-i-Pr) 4 , cumenehydroperoxide,
MS 4 Å, CH 2 Cl 2 , -24 o C, 6 h, 83
THPO
O
OH
PPh 3 , NaHCO 3 , CCl 4 ,
reflux, 4 h, 80%
THPO
A
O
Cl
Li/liq. NH 3 , Fe(NO 3 ) 3 ,
THF, 6 h, 70%
THPO
OH
1) MOMCl, Hunig's base,
0 o C to rt., 2 h, 90%
THPO
OMOM
B
2) n-BuLi, methylchloroformate,
THF, -78 o C, 30 min, 73%
COOMe
1) Pd/C, H 2 , MeOH, 6 h, 70%
2) IBX, DMSO, CH 2 Cl 2 ,
rt., 2 h, 75%
O
H
O
OMOM
COOMe
1) [C 9 H 19 PPh 3 ] + Br - , THF-HMPA,
n-BuLi, -78 o C to rt., 75%
2) PTSA, MeOH, 12 h, 80%
O
( )
7
Scheme 33.
35
lated after protection. Hydrogenation and deprotection gave
directly 37 (Scheme 35).
7.5. (4R,5Z)-5-Tetradecen-4-olide (38) (japonilure)
(R)-Japonilure [(4R,5Z)-5-tetradecen-4-olide, (38)] is the
female-produced pheromone of the Japanese beetle Popillia
japonica [103].
The synthesis of 38 presented by Sabitha et al. [97] involved
the preparation of the chiral epoxy chloride A (by
stereoselective reduction of a triple bond and asymmetric
Sharpless epoxidation), which was subjected to a baseinduced
ring opening followed by treatment with 1-
bromooctane in a one-pot reaction to give alkynol B with the
carbon skeleton already established. B was further transformed
to 38 in five steps (Scheme 36).

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 701
THPO
( )
8
THPO
OBn
O
Cl
O
Li/liq NH 3 , Fe(NO 3 ) 3 (cat.),
Me(CH 2 ) 8 Br, dry THF, 70%
CO 2 Et
OH
H 2 , 10% Pd/C (cat.),
EtOH, 12 h, 70%.
1) Ph 3 P, NaHCO 3 , CCl 4 ,
reflux, 4 h, 80%
2) Li/liq NH 3 , Fe(NO 3 ) 3 (cat.),
THF, C 9 H 19 Br, 8 h, 60%
( )
8
( )
9
36
OH
A
O
( )
8
O
OTHP
OH
B
1) NaH, BnBr, THF,
0 o C to rt., 98%
2) PPTS, MeOH, rt., 96%
3) (COCl) 2 , DMSO, Et 3 N,
Ph 3 P=CHCO 2 Et, CH 2 Cl 2 ,
-78 o C, 70%
OTHP
1) MOMCl, i-Pr 2 NEt,
0 o C to rt., 2 h, 98%
2) H 2 , 10% Pd/C, EtOH,
rt., 6 h, 80%
( )
10
OMOM
OH
1) IBX, DMSO, CH 2 Cl 2 ,
rt., 2 h, 77%
2) NaClO 2 , NaH 2 PO 4 , aq DMSO,
rt., 1 h, 71%;
3) PTSA, MeOH, rt., 12 h, 80%.
( )
9
36
O
O
Scheme 34.
OH
1) MOMCl, i-Pr 2 NEt, CH 2 Cl 2 ,
0 o C to r.t., 2 h, 90%
OMOM
A
2) n-BuLi in hexane, ClCO 2 Me,
THF, -78 o C, 30 min, 90%
O
OMe
1) H 2 , Pd/C, EtOAc, 4 h, 90%
2) PTSA, MeOH, rt., 12 h, 80%
37
O
O
Scheme 35.
HO
OTHP
(-)-DET, Ti(O-i-Pr) 4 ,
cumenehydroperoxide,
MS 4 Å, CH 2 Cl 2 , -24 o C, 4 h, 77%
HO
O
OTHP
PPh 3 , NaHCO 3 , CCl 4 ,
reflux, 4 h, 79%
Cl
O
A
OTHP
1) Li/Liq NH 3 , Fe(NO 3 ) 3 ,
-78 o C, THF, 2 h
2) n-C 8 H 17 Br, THF, 70%
( )
7
OH
B
OTHP
1) TBDMSCl, imidazole,
CH 2 Cl 2 , 0 o C to rt., 83%
2) recrystallized PPTS, MeOH,
rt., 2 h, 63%
( )
7
OTBDMS
OH
1) Dess-Martin periodinane,
CH 2 Cl 2 , 0 o C to rt., 2 h, 85%
2) NaClO 2 , NaH 2 PO 4 H 2 O,
DMSO, 0 o C to rt., 80%
( )
7
OTBDMS
COOH
PTSA, MeOH, rt.,3 h, 85%
O
O
Lindlar catalyst, H 2 , quinoline,
O
O
EtOAc, 2 h, 85%
38
Scheme 36.

702 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.
OH
1) EtMgBr, CuI
2) Prenyl-Br, 93%
OH
LiAlH 4 , 89%
OH
(-)-DIPT, Ti(O-i-Pr) 4 , TBHP,
MS 4 Å, 75%
A
O
OH
Me 2 CuLi, 84%
B
OH
OH
+
OH
OH
elimination of 1,2-diol,
by reaction with NaIO 4
Scheme 37.
O
HO
O
(R)-(-)-Pinononic acid
from (R)-(+)--pinene
O
HO
B
1) TsCl, Et 3 N, DMAP
2) NaCN, NaI, 75%
1) MeLi/ether, 1.0 e.q.,
THF, -20 o C, 15 min
2) MeMgCl/THF, 1.6 e.q.,
-10 o C, 30 min, rt., 1 h, 89%
LiAlH 4 , Et 2 O, rt.,
overnight, 88%
HO
HO
O
OH
OH
CN
1) NaOH
2) H 2 SO 4 , 86%
1) POCl 3 , Py, rt., 24 h, 75%
2) PTSA, benzene, reflux,
24 h, 78%
39
O
O
(S)-(+)-pinononic acid
from (S)-(-)-verbenone
Similarly
(R)-A (78% e.e.)
(S)-A (70% e.e.)
(S)-(+) or
(R)-(-)-2-methylbutyric acid
(COCl) 2 , DMF/benzene
rt., 1.5 h, 79%
O
O
O
O
O
O
O
O
(R,S)-40
(R,R)-40
(S,S)-40
(S,R)-40
O
O
HO
O
O
(R)-B
(R,S)-41
O
(R,R)-41
O
HO
O
O
Scheme 38.
(S)-B
(S,S)-41
7.6. (3S,4R)-3,7-Dimethyl-6-octen-4-olide (39) (eldanolide)
Eldanolide [(3S,4R)-3,7-dimethyl-6-octen-4-olide, (39)]
is a male-produced monoterpenoid sex attractant for the African
sugarcane stem borer Eldana sacharina [104].
The synthesis of 39 presented by Kong et al. [105] involved
the preparation of the chiral epoxy alcohol A (93.4%
e.e.) in 4 steps from propargyl alcohol, including a Sharpless
epoxidation (Scheme 37). Methylation of the epoxide provided
a mixture of a 1,2- and a 1,3-diol B, which was resolved
by cleavage of the 1,2-diol by reaction with NaIO 4
(R,S)-41
and subsequent chromatography, providing pure B. Chain
elongation by reaction with cyanide, hydrolysis and lactonization
finally provided 39 in 22 % overall yield.
8. SYNTHESIS OF ISOPRENOIDS AS PHEROMONES
8.1. Synthesis of Isoprenoidal Pheromone Alcohols and
their Esters as Pheromones
8.1.1. Maconelliyl 2-methylbutanoate (40) and lavandulyl
2-methylbutanoate (41)
Maconelliyl 2-methylbutanoate (40) and lavandulyl 2-
methylbutanoate (41) have been identified as constituents of

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 703
O
Lipase PS (Amano),
CH 2 =CHOAc, Et 2 O, 0 o C, 4 h
O
+
O
OH
OAc
10 - 16%, 98.8% e.e. (2S,3R)-A 11 - 22%, 98.6% e.e. (2R,3S)-B
OH
A
1) 60% HClO 4 , DMF, 0 o C to rt., 12 h
then K 2 CO 3 , MeOH, rt., 20 h, 77-92%
2) TBDPSCl, Et 3 N, DMAP,
CH 2 Cl 2 , rt., 24 h, 93-97%
OH
OH
OTBDPS
1) SO 3 Py, DMSO, Et 3 N,
CH 2 Cl 2 , 0 o C to rt., 24 h, 78-91%
2) TBAF, THF, 0 o C, 5 min, 65%-quant.
OH
OH
(S)-42
O
O
OH
Ac 2 O, DMAP, Py,
30 min, 86-92%
O
OAc
Similarly
OH
O
(R)-42
OH
Scheme 39.
the female-produced pheromone of the pink hibiscus mealybug,
Maconellicoccus hirsutus, which is an exotic insect pest
in Southern California and Florida [106].
Zhang and Nie [107] described an enantioselective synthesis
of all stereoisomers of these two compounds, starting
from (R)- and (S)-pinononic acids, which are easily prepared
from (R)--pinene and (S)-verbenone, respectively. Methylation,
elimination of water, and reduction of the carboxyl
group afforded (R)- and (S)-maconelliol (A), respectively.
Esterification of A was carried out with commercially available
(S)-2-methylbutyric acid and previously prepared (R)-2-
methylbutyric acid [108] to afford all four stereoisomers of
40. For the synthesis of all isomers of 41, (R)- and (S)-
lavandulol (B), prepared according to the method described
by Cardillo et al. [108], were esterified with (S)- and (R)-2-
methylbutyric acids (Scheme 38).
8.1.2. 3,7-Dimethyl-2-oxo-6-octene-1,3-diol (42)
Dickens et al. [109] identified 3,7-dimethyl-2-oxo-6-
octene-1,3-diol (42) as the male-produced aggregation
pheromone from the Colorado potato beetle (Leptinotarsa
decemlineata). The absolute configuration of natural 42 was
determined by Oliver et al. [110] to be (S) by synthesis of
the racemate and both enantiomers from geraniol and (R)-
and (S)-linalool, respectively.
Tashiro and Mori [111] described the synthesis of pure
enantiomers of 42 employing the lipase-catalysed enantioselective
acetylation of (±)-2,3-epoxynerol in the key step,
yielding acetate (2S,3R)-A (98.8% e.e.) and alcohol (2R,3S)-
B (98.6% e.e.). Ring opening under inversion of the configuration
at carbon 3 of A by treatment with HClO 4 in DMF at 0
°C and subsequent protection of the primary hydroxyl group
was followed by selective oxidation and deprotection to give
(S)-42. The enantiomer was obtained similarly starting with
alcohol B (Scheme 39).
8.1.3. (1S,4R)-4-Isopropyl-1-methyl-2-cyclohexen-1-ol (43)
(1S,4R)-4-Isopropyl-1-methyl-2-cyclohexen-1-ol (43) is
the aggregation pheromone of the ambrosia beetle Platypus
quercivorus, and the absolute configuration of the pheromone
was established as (1S,4R) [112, 113].
Mori [114] described a synthesis of the (1S,4R), (1R,4R),
and (1S,4S) isomers and of a racemic mixture of 43. In this
paper Mori mentioned that (1R*,4R*)-4-isopropyl-1-methyl-
2-cyclohexen-1-ol was detected as a minor component of the
frass volatiles of P. quercivorus. Synthesis of (1S,4R)-43
was performed by addition of methyl lithium to (R)-cryptone
(91.5–93% e.e.) obtained in six steps from (S)-perillyl alcohol.
The racemic pheromone was also prepared by methylation
of (±)-cryptone, prepared from (+)-nopinone. Both
(1R,4R)- and (1S,4S)-isomers (98% e.e.) of the pheromone
were synthesized from the enantiomers of dihydrolimonene
oxide (Scheme 40).
8.1.4. cis-2-(2-Isopropenyl-1-methylcyclobutyl)ethanol (44)
(grandisol)
Grandisol [cis-2-(2-isopropenyl-1-methylcyclobutyl)
ethanol, 44] has first been identified as a male-produced
pheromone from the boll weevil Anthonomus grandis [115],
and has since been found in other insect species [116-118].
Racemic grandisol, contaminated with 10% of the trans
diastereomer fragranol (45) was prepared by Bernard et al.
[119] via an efficient route starting from 2-(1-methyl-2-
phenylthioethyl)cyclobutanone (A), involving the 1,4-
addition of lithium dimethylcuprate to the cyclobutylidene
aldehyde B in the key step (Scheme 41).
Pure (1R,2S)-(-)-grandisol was prepared following a
similar sequence (Scheme 42). A more bulky substituent at
position 2 of the enantiopure cyclobutylidene aldehyde B
improved the diastereoselectivity of the copper-catalyzed

704 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.
OH
1) t-BuOOH, VO(acac) 2 ,
toluene, rt., 2.5 h, quant.
OTBS
O
H 2 , PtO 2 , hexane,
OTBS
O
2) TBSCl, imidazole,
DMF, quant.
EtOAc (1:1), quant.
(S)-Perillyl alcohol
1) Ph 2 Se 2 , NaH, THF,
HMPA, reflux, 3 h
O
MeLi, LiBr,
OH
2) TBAF, THF, rt.
3) NaIO 4 , THF, H 2 O, rt,
1.5 h, 28% (three steps)
Et 2 O, THF, 44%.
(R)-cryptone (91.5-93% e.e.)
(1S,4R)-43 (93.3% e.e.)
O
O
O
AlCl 3 , CH 2 Cl 2 ,
0 - 5 o C, 70 min, 89%
+
MeLi, LiBr, Et 2 O/ THF,
-40 o C to rt,
OH
OH
OH
10 - 15%
+
+
(±)-(S*,R*)-43
44%
(±)-(R*,R*)-43
10%
O
H 2 , PtO 2 ,
MeOH, 92%
O
O
A
+
O
B
Ph 2 Se 2 , NaBH 4 ,
EtOH, reflux, 2 h
OH
SePh
H
+
OH
SePh
+
H
SePh
44% after chromatography
H
From B
OH
30% H 2 O 2 , THF, Py,
rt. 1 h, 61%.
O
Similarly
OH
OH
(1S,4S)-43 (97.8 - 98.2% e.e.)
Scheme 40.
(1R,4R)-43 (98.3 - 98.7% e.e.) 25% overall yield
methylation key step. B (obtained from A by reduction and
partial oxidation) was used as the substrate, because direct
methylation of TBDMSOTf-activated A with Me 2 CuLi resulted
in lower diastereoselectivity.

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 705
O
COOMe
OH
TMPA/NaH,
DIBAL-H
PCC, CH 2 Cl 2
THF, reflux, 88%
THF -78 o C, 90%
0 o C, 90%
A
SPh
SPh
SPh
H
O
O
H
O
H
B
SPh
Me 2 CuLi
Et 2 O, - 78 o C, 98%
H
SPh
+
H
SPh
[120, 121]
OH
OH
Three steps, 75%
H
+
H
(±)-44
(±)-45
(cis/trans) = (90:10)
Scheme 41.
COOMe
O
H
O
H
H
O
DIBAL-H
THF, -78 o C, 88%
H
O
OH
PCC, CH 2 Cl 2
0 o C, 88%
H
O
Me 2 CuLi
Et 2 O, -78 o C, 97%
H
O
O
A
O
O
B
O
NaBH 4 , MeOH/THF 1:1
0 o C, 94%
H
O
OH
BzCl/DMAP
Et 3 N/CH 2 Cl 2 , 94%
H
O
OBz
TFA, MeOH/H 2 O
rt., 91%
H
OH
OBz
O
O
OH
DIAD/PPh 3
benzene, 91%
H
O
OBz
DIBAL-H
THF, -78 o C, 94%
H
OH
OH
[122]
H
OH
(1S,2S,2'S)-(cis)
(-)-44
Scheme 42.
8.1.5. 1-Acetoxymethyl-2,3,4,4-tetramethylcyclopentane
(46)
(1R*,2R*,3S*)-1-Acetoxymethyl-2,3,4,4-tetramethylcyclopentane
(46) is the female-produced sex pheromone of
the obscure mealybug Pseudococcus viburni [123].
The synthesis developped by Millar and Midland [124]
started with a polyphosphoric acid-catalyzed cyclization of
isobutyl methacrylate to obtain the ,-unsaturated cyclopentenone
A. 1,4-Addition of lithium dimethylcuprate to
A usually affords the trans isomer, but careful selection of
the reaction conditions (reaction at -40 ºC and quenching
with ethyl salicylate at -78 ºC) resulted in a 72:28 cis:trans
mixture of intermediate B. Conversion of the carbonyl group
to a methylene group and subsequent hydroboration yielded
alcohol C as a mixture of isomers, from which (1S*,2R*,
3S*)-C was isolated by column chromatography and
Kugelrohr distillation. Inversion of the stereogenic center at
carbon 1 and acetylation gave (1R*,2R*,3S*)-46, showing
90% isomeric purity (Scheme 43).

706 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.
O
O
polyphosphoric acid
O
Me 2 CuLi, ethyl salicylate
quench, -78 o C, 89%
O
100 o C, 34%
A
B
(cis:trans 72:28)
OH
O
H
Zn-CH 2 Br 2 -TiCl 4
BH 3 DMS, THF, 0 o C
aq. NaOH, H 2 O 2 , 75%
PDC, CH 2 Cl 2
81%
mainly (1S*, 2R*, 3S*)-C
O
H
OH
OAc
NaOMe, MeOH
NaBH 4 , EtOH
93%
AcCl, Py
CH 2 Cl 2 , 81%
Scheme 43.
(1S*, 2R*, 3S*)-46
O
O
O
+
PPh 3 Br
n-BuLi
THF, reflux
O
A
O
DIBAL-H
CH 2 Cl 2 , -78 o C
Scheme 44.
OH
Ac 2 O, Et 3 N
DMAP, CH 2 Cl 2
(Z)-47
O
O
+
(E)-47
O
O
8.1.6. 2-Isopropyl-5-methyl-2,4-hexadienyl acetate (47)
Ho et al. identified 2-isopropyl-5-methyl-2,4-hexadienyl
acetate (47) as the sex pheromone produced by females of
the passionvine mealybug Planococcus minor, and presented
a non-stereoselective synthesis of the compound [125].
Wittig reaction between ethyl 3-methyl-2-oxobutanoate
and the ylide of 3-methyl-but-2-enyltriphenylphosphonium
bromide yielded a mixture of the esters (E)- and (Z)-A,
which was transformed to a mixture of (E)- and (Z)-47 by
reduction and acetylation (Scheme 44). The stereoisomers
were separated by HPLC for assignment of the geometry of
the natural product, which turned out to be (E).
8.1.7. 2-Methyl-6-(4’-methylenebicyclo[3.1.0]hexyl)hept-2-
en-1-ol (48)
The aggregation pheromone of the stink bug Erysarcoris
lewisi has been proposed to be (E)-2-methyl-6-(4’-
methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol (48) [126].
Mori synthesized the (2E,6R)-, (2E,6S)-, (2Z,6R)-, and
(2Z,6S)-isomers of 48, starting from citronellal [127]. The
absolute configuration at carbon 6 was defined by the use of
(R)- or (S)-citronellal, respectively, while the geometry of
the double bond was established by stereoselective olefination
reactions. Citronellal was converted to diazoketone A in
7 steps, including methylenation and a Claisen orthoester
rearrangement as the key steps of this part of the synthesis
(Scheme 45). The -ketocarbene generated from A added
intramolacularly to the exo methylene double bond, establishing
the bicyclic structure in intermediate B. This reaction
cannot be controlled stereochemically and a mixture of two
diastereomers of B was obtained in each case. The double
bond of B was cleaved oxidatively to give aldehyde C,
which was converted to (E)-48 in 3 further steps with the
(E)-selective olefination of the formyl group with (carbethoxymethylidene)triphenylphosphorane
as the key step. To
obtain (Z)-48, the olefination of aldehyde C was carried out
employing Ando’s reagent ethyl 2-(di-o-tolylphosphono)
propanoate, which in turn was prepared in three steps from
triethyl orthophosphite and ethyl 2-bromopropanoate
(Scheme 45). Bioassays with the synthetic isomers suggested
the natural pheromone to show (2Z,6R) configuration.

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 707
CHO
37% CH 2 O, propanoic acid,
pyrrolidine, i-PrOH,
45 o C, 4 h, 90%
CHO
LiAlH 4 , Et 2 O,
91%
OH
1) MeC(OEt) 3 , propanoic acid,
140 o C, 1 h, 95%
2) KOH, EtOH, H 2 O, reflux, 2 h, 83%
CO 2 H
1) NaOEt, EtOH
2) (COCl) 2 , Py, hexane,
quant. (2 steps)
COCl
CH 2 N 2 , Et 2 O
quant.
A
COCHN 2
Cu, CuSO 4 ,
cyclohexane,
reflux, 1 h, 58%
O
B
OsO 4 , NaIO 4 , t-BuOH,
THF, H 2 O, quant
O
C
O
H
1) Ph 3 P=C(Me)CO 2 Et,
THF, CH 2 Cl 2 , 57%
2) [CH 3 PPh 3 ] + Br - ,
n-BuLi, THF, 96%
CO 2 Et
DIBAL-H, toluene
55%
(2E,6R)-48
OH
C
(o-MeC 6 H 4 O) 2 P(O)CHMeCO 2 Et,
NaH, THF, -78 o C to 5 o C, quant.
CO 2 Et
1) [CH 3 PPh 3 ] + Br - , n-BuLi, THF, 96%
2) DIBAL-H, toluene, 22%
OH
O
(2Z,6R)-48
CHO
Similarly
OH
or
OH
(2Z,6S)-48
(2E,6S)-48
(EtO) 3 P +
O
Cl 2 PCHCO 2 Et
Me
MeCHCO 2 Et
160 o C, 2 h
Br
60%
o-cresol, Et 3 N, CH 2 Cl 2 ,
0 o C - 5 o C, 30 min, rt., 1 h, 60%
O
(EtO) 2 PCHCO 2 Et
Me
Me
O
O P CHCO 2 Et
Me
2
PCl 5 , 75-80 o C
14 h, 67%
Scheme 45.
8.2 Synthesis of Isoprenoidal Aldehydes, Ketones and
Acids as Pheromones
8.2.1. (R)-1,1,5,8-Tetramethyl-1,2,3,4,5-pentahydrobenzo
[a][7]annulene (49) [(R)-ar-himachalene]
In 2001 Bartelt et al. [128] isolated and identified the
male-produced pheromone of the flea beetle Aphthona flava
as (S)-ar-himachalene (49). Mori [129] proposed the opposite
absolute configuration for the natural compound.
Mori [130, 131] described a synthesis of (R)-turmerone A
from (4-methylphenyl)acetic acid employing Evans’ asymmetric
alkylation in the key step. (R)-Turmerone was converted
to (R)-ar-himachalene according to Pandey and Dev’s
procedure [132] (Scheme 46). Interestingly, (R)-49 was dextrorotatory
in hexane, while levorotatory in chloroform.
8.2.2. (2E,4S)-2,4-Dimethylhex-2-enoic acid (50), 4,6-
dimethylnon-4-en-3-one [(S)-manicone, 51], 3,5-dimethyloct-3-en-2-one
[(S)-normanicone], 52, (1S)-1-methylbutyl-
(2E)-2-methylpent-2-enoate (dominicalure-I, 53) and (1S)-
1-methylbutyl (2E)-2,4-dimethylpent-2-enoate (dominicalure-II,
54)
(2E,4S)-2,4-Dimethylhex-2-enoic acid (50) is a castespecific
substance present in the mandibular glands of the
male carpenter ants in the genus Camponotus [133]. (S)-
Manicone (4,6-dimethylnon-4-en-3-one, 51) and (S)-

708 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.
CO 2 H
1) SOCl 2 , C 6 H 6 , reflux, quant.
2) (S)-4-benzyl-2-oxazolidinone, n-BuLi,
THF, -78 o C, 30 min, then rt., 79%
Bn
O
N
O
O
1) NaHMDS, MeI, THF,
-78 o C, 3 h, then rt., 97%
2) LiAlH 4 , THF,
0 o C to rt., 69%
OH
1) TsCl, DMAP, Py,
0-5 o C, 2 h, 95%
CN
KOH, HO(CH 2 ) 2 OH, H 2 O,
2) NaCN, NaI, DMSO,
110 o C, 30 min, 78%
100 o C, 3 h, 91%
O
OH
1) MeNHOMe HCl, EDC, DMAP,
(i-Pr) 2 NEt, CH 2 Cl 2 , 0 o C, 4 d, 84%
2) Me 2 C=CHMgBr, THF,
-20 o C to rt., 2 h, 88%.
O
(R)-turmerone (A)
AlCl 3 , CS 2 , -40 to -20 o C, 1 h,
then reflux , 46 o C, 4 h, 40%
O
N 2 H 4 H 2 O, KOH, diethylene glycol,
200 - 210 o C, 3 h, 42%.
(R)-ar-himachalene (49)
[] D
23 = +3.8 o (hexane)
[] D
23 = -2.4 o (CHCl 3 )
Scheme 46.
CHO
50
O
+
OH
O
O
SOCl 2 , Benzene
DABCO, dioxane,
0 o C, 20 h
O
Cl
OH
A
O
OMe
Et 2 CuLi,
Et 2 O, -78 o C
Me 2 CuLi,
Et 2 O, -78 o C
1) NaBH 4 , CuCl 2 2H 2 O
MeOH, rt.
2) NaOH, MeOH/H 2 O
51
O
O
R
O
H
R = Et
R = iPr
+
O
O
DABCO
O
R
OH
R = Et (B)
R = iPr (B')
OMe
1) NaBH 4 , CuCl 2 2H 2 O
MeOH, rt.
2) NaOH, MeOH/H 2 O
O
R
52
R = Et
R = iPr
O
OH
Scheme 47.
1) SOCl 2
2) (+)-(2S)-pentan-2-ol
53
O
or
O
54
normanicone (3,5-dimethyl-oct-3-en-2-one, 52) are the mandibular-gland
alarm pheromone components of the ants in
the genus Manica [134, 135]. Dominicalure-I [(1S)-1-
Methylbutyl (2E)-2-methylpent-2-enoate, 53] and dominicalure-II
[(1S)-1-methylbutyl (2E)-2,4-dimethylpent-2-
enoate, 54] are the aggregation pheromones of the lesser
grain borer Rhyzopertha dominica [136].
Das et al. [137] described a synthesis of these pheromone
compounds employing Baylis–Hillman adducts. Compounds
50, 51 and 52 were obtained from Baylis-Hillman adduct A,
which was treated with sodium borohydride in the presence
of CuCl 2·2H 2 O in MeOH to give the corresponding (E)-2-
methyl-2-alkenoate, which was hydrolyzed yielding acid 50.
Transformation of 50 to the acid chloride and alkylation with
lithium diethylcuprate and lithium dimethylcuprate yielded
51 and 52, respectively. For the synthesis of 53 and 54, the
Baylis-Hillman adducts B and B’ were subjected to a similar
reaction sequence (Scheme 47).

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 709
CO 2 CH 3
OCH 3
1) n-BuLi, cyclohexane, , 15h
1) K, THF, NH 3 , t-BuOH, -68 o C
A
2) CO 2 , Et 2 O, -78 o C to rt.
3) MeOH, toluene, PTSA (cat.)
, 8h, 45% (3 steps)
2) LiBr (2.2 eq), allyl bromide, -68 o C to rt.
3) HCl (cat.), acetone, 4 o C, 5 min,
46% (3 steps)
CO 2 CH 3
O
Zn, allyl bromide,
OH
CO 2 CH 3
CO 2 CH 3
C (3 mol%), CH 2 Cl 2 ,
HO
1) LiAlH 4 , THF, rt. 20 h, 96%
2) MsCl, Et 3 N, CH 2 Cl 2 ,
-15 o C, 5 min
HO
OMs
KOH, 18-crown-6, benzene,
rt. 1.5 h, 74% (2 steps)
O
E
PhSSPh (2 mol%), hn (vis.),
O
1) LDA, THF, -78 o C
2) Me 2 N=CH 2 I, THF,
HMPA, -78 o C to rt.
O
benzene, 15 o C, 10 min
E 58% + F 38%
Scheme 48.
OCH 3
Periplanone C (55)
DMF, rt. 20 h, 89%
rt., 23 h, 81%
B
D
C =
(Cy 3 )P
Cl 2 Ru
(Cy 3 )P
Ph
F
3) MeI, rt., 2 h
4) NaOAc, H 2 O, Et 2 O, rt.,
1 h, 53% from F
8.2.3. (3Z,7E)-9-Isopropyl-2,6-dimethylene-3,7-cyclodecadien-1-one
(periplanone C, 55)
Periplanone C [(3Z,7E)-9-isopropyl-2,6-dimethylene-3,7-
cyclodecadien-1-one, 55] is one of at least four biologically
active components of the sex pheromone of the American
cockroach, Periplaneta americana [138-143].
The key steps of the synthesis of racemic 55 presented by
Matovic et al. [144] are a ring closure metathesis (RCM)
reaction, assuring the Z configuration of the newly formed
double bond in the bicyclic intermediate D, and subsequent
rupture of the central bond yielding E. The monocyclic precursor
B was obtained from the anisol derivative A and submitted
to RCM using Grubbs first generation catalyst (C) to
yield the bicyclic intermediate D. The rupture of the central
bond was achieved by Grob fragmentation under ionic conditions
and yielded the (Z,Z)-cyclodecadienone E, which
could be isomerized photochemically under radical conditions
to the (Z,E)-cyclodecadienone F. The lithium enolate of
F was aminomethylated with Eschenmoser’s reagent and 55
was obtained after spontaneous elimination of dimethylamine
(Scheme 48).
8.2.4. (E)- and (Z)-3-Methyl-4-heptenoic acid (56), and 3-
methyleneheptanoic acid (57)
The volatile sex pheromone released by females of the
cowpea weevil Callosobruchus maculatus has been identified
to be a mixture of (E)- and (Z)-3-methyl-2-heptenoic
acid, (E)- and (Z)-3-methyl-4-heptenoic acid (56), and 3-
methyleneheptanoic acid (57) [145].
The three latter compounds have been synthesized by
Yajima et al. [146]. 57 was prepared using Chong’s procedure
of alkylation of the dianion of 3-methyl-3-buten-1-ol,
followed by sequential Dess-Martin and Pinnick oxidations
to give the target molecule in a moderate yield but without
isomerization of the somewhat sensitive 3-exo methylene
double bond. For the synthesis of 56, the (E) and (Z) isomers
of the vinylic iodide 4-iodo-3-methyl-3-buten-1-ol were prepared
from 3-butyn-1-ol, respectively, and further transformed
via alkylation and oxidation to the desired products
(Scheme 49) [147, 148].
9. SYNTHESIS OF ACETALS AS PHEROMONES
9.1. (1S,3R,5R,7S)-1-Ethyl-3,5,7-trimethyl-2,8-dioxabicyclo[3.2.1]octane
[(+)-sordidin, 58] and (1S,3R,5R,7R)-1-
ethyl-3,5,7-trimethyl-2,8-dioxabicyclo[3.2.1]octane [(–)-7-
epi-sordidin, 59]
The banana weevil Cosmopolites sordidus is the most
devastating insect pest on banana plants worldwide [149].
The major compound of the male-produced aggregation
pheromone has been identified as (1S,3R,5R,7S)-1-ethyl-
3,5,7-trimethyl-2,8-dioxabicyclo[3.2.1]octane (58), which
was given the common name sordidin [150-152]. A minor
component of the volatile bouquet released by the weevil is

710 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.
OH
n-BuLi, TMEDA, n-C 3 H 7 Br
Et 2 O, -78 o C to 0 o C, 46%
OH
1) Dess-Martin periodinane,
CH 2 Cl 2 , rt.
2) NaClO 2 , NaH 2 PO 4 , 2-methyl-2-butene
THF, t-BuOH, H 2 O, 0 o C, 52%
COOH
57
OH
1) [147], 80%
2) TBSCl, Et 3 N, DMAP
CH 2 Cl 2 , 92%
I
OTBS
1) n-C 3 H 7 MgBr, PdCl 2 (dppf), Et 2 O
2) TBAF, THF, 73%
OH
1) Dess-Martin periodinane, CH 2 Cl 2
2) NaClO 2 , NaH 2 PO 4 , 2-methyl-2-butene
THF, t-BuOH, H 2 O, 0 o C, 47%
(E)-56
COOH
OH
1) Ref. 14, 60%,
2) TBSCl, Et 3 N, DMAP
CH 2 Cl 2 , quant.
I
OTBS
1) n-C 3 H 7 MgBr, PdCl 2 (dppf), Et 2 O
2) TBAF, THF, 84%
OH
1) Dess-Martin periodinane, CH 2 Cl 2
COOH
2) NaClO 2 , NaH 2 PO 4 , 2-methyl-2-butene
THF, t-BuOH, H 2 O, 0 o C, 49%
(Z)-56
Scheme 49.
(1S,3R,5R,7R)-7-epi-sordidin (59) [153]. Interestingly, the
enantiomer of the latter has been found in caddisflies [154].
An asymmetric synthesis of (1S,3R,5R,7S)-58 and
(1S,3R,5R,7R)-59 was performed by Enders et al. [155]. The
first two stereogenic centers were formed by three -
alkylations of the RAMP-hydrazone of 2,2-dimethyl-1,3-
dioxan-5-one A. The third stereogenic center was formed by
diastereoselective epoxide opening employing the azaenolate
of 3-pentanone SAEP-hydrazone in the key step
(Scheme 50). The mixture of the diastereomers was separated
by preparative gas chromatography, furnishing the pure
enantiomers with e.e. > 98%.
9.2. 1,5-Dimethyl-6,8-dioxabicyclo[3.2.1]octane (60)
(frontalin)
Frontalin (1,5-dimethyl-6,8-dioxabicyclo[3.2.1]octane,
60) was first isolated and identified as a component of the
aggregation pheromones of the southern pine beetle (Dendroctonus
frontalis) and of the western pine beetle (Dendroctonus
brevicomis) by Kinzer et al. [158]. By means of
bioassays with pure synthetic enantiomers, Mori [159, 160]
showed the absolute configuration of natural 60 to be
(1S,5R) in both species.
Prasad et al. [161] described an enantioselective formal
synthesis of frontalin employing the addition of Grignard
reagents to the bis-Weinreb amide A derived from L-(+)-
tartaric acid and to B as the key steps (Scheme 51).
Schuster et al. [163] described a stereoselective synthesis
of 60 by addition of an organo zinc reagent to an -keto ester
coupled to a chiral auxiliary. The synthesis was performed
either in solution (98 % e.e. for (+)-60) or with the -keto
ester-chiral auxiliary complex immobilized (86 % e.e.)
(Scheme 52).
9.3. exo-Brevicomin (61), 1’-hydroxy-exo-brevicomin (62)
and 2-hydroxy-exo-brevicomin (63)
exo-Brevicomin (61) and endo-brevicomin (exo- and
endo-7-ethyl-5-methyl-6,8-dioxabicyclo[3.2.1]octane) are
common components of the aggregation pheromone system
of several bark beetle species of the genera Dendroctonus
and Dryocoetes [160, 164-166]. Francke et al. [167] have
identified 1’-hydroxy-exo-brevicomin (62) and 2-hydroxyexo-brevicomin
(63) from the pine beetle Dendroctonus
ponderosae.
Prasad et al. [168-170] described a synthesis of 61, 62,
and 63 employing addition of Grignard reagents to the bis-
Weinreb amide A derived from L-(+)-tartaric acid and subsequent
stereoselective reduction of the keto function with L-
selectride or K-selectride as common steps (Schemes 53 –
55). 61 was synthesized from diol B by oxidative cleavage
with lead tetraacetate in benzene and subsequent stereoselective
alkylation of the resulting aldehyde to yield the corresponding
threo alcohol C as a single diastereomer. Wacker
oxidation of terminal olefin and simultaneous debenzylation
and intramolecular acetalization with Pd/C in MeOH and a
trace of 3 M HCl gave the compound 61 (Scheme 53). For
the synthesis of 62, TBDMS protected amide D was reduced
with sodium borohydride, tosylated, and reduced with super
hydride to obtain acetonide E. Wacker oxidation and cycliza-

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 711
OCH 3
OCH 3
OCH 3
N
N
O
O
[156, 157]
79% (2 steps)
N
N
O
O
1) t-BuLi, THF, - 78 o C
2) BOMCl, -100 o C to rt. 92%
N
N
O
O
OBn
A
d.e, e.e. > 96%
d.e, e.e. > 96%
1) O 3 , CH 2 Cl 2 , -78 o C, 79%
OH
OBn
1) i. NaH, THF, 0 o C
ii. CS 2 , MeI, 98%
OBn
2) NaBH 4 , MeOH, 0 o C, quant.
O
O
2) n-Bu 3 SnH, AIBN,
toluene, reflux, 98%
O
O
O
N
1) Ca/NH 3 , 97%
1) 3N HCl, H
OTs
2 O/MeOH,
rt. 87%
2) ) Et 3 N, DMAP,
O O
CH 2 Cl 2 , TsCl, rt. quant.
2) 2,6-lutidine, CH 2 Cl 2 ,
OTBS
N
TBSOTf, 0 o C, quant.
d.e, e.e. > 96%
3) NaH, THF, 0 o C, 99%
B
OCH 3
1) LiCl, LDA, THF, -78 o C,
1 h, then 0 o C, 10 min,
2) B, -78 o C to rt.,15 h
OCH 3
N
TBSO HO
3 N HCl, H 2 O/pentane,
rt., 6 d, 84%
O
O
+
O
O
d.r.
1.5 : 1.0
d.e. > 99% e.e. > 98%
(1S,3R,5R,7S)-(+)-sordidin (58)
d.e. > 97% e.e. > 98%
(1S,3R,5R,7R)-7-epi-(-)-sordidin (59)
Scheme 50.
Me OMe
N
O
O
O
Me N O
OMe
O
MgBr
( ) O
( )
3
3
THF, 0 o C, 1 h, 94% O ( )
3
O
MeMgBr, MgBr 2 , Et 2 O
CH 2 Cl 2 , -78 o C, 3.5 h, 74%
O
O
HO
( )
3
( )
3
OH
A
B
1) NaH, DMF, BnCl,
rt., 4h,
2) FeCl 3
. 6H 2 O, CH 2 Cl 2 ,
rt. 4 h, 40% (2 steps)
HO
HO
BnO
( )
3
( )
3
OBn
1) Pb(OAc) 4 , benzene,
rt. 1.5 h
2) NaBH 4 /MeOH,
0 o C, 1 h, 90% (2 steps)
BnO
OH
( )
3
[162]
O
60
O
Scheme 51.

712 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.
O
O
O
O
O
R
ZnCl
OH
O
O
O
O
R
R = Me or Wang resin
Solution Phase Synthesis 81% and 92% d.e.
R = Me or Wang resin
LiAlH 4 , THF
OH
OH
O 3 , CH 2 Cl 2
-78 o C
O
O
Scheme 52.
Solution Phase Synthesis 80%
Solid Phase Synthesis 50% 2 steps 86% e.e.
60
solution phase 99:1 (98% e.e.)
solid phase 93:7 (86% e.e.).
O
O
Me
Me
N
N O
A
OMe
O
OMe
1) NaH, DMF, BnBr,
0 o C to rt., 2 h, 97%
2) FeCl 3
. 6H 2 O, CH 2 Cl 2 ,
rt. 2 h, 89%
EtMgBr, MgBr 2 , CH 2 Cl 2 ,
MgBr
( )
3 (4 eq.)
THF, 0 o C, 1h, 96%
OH
HO
HO
B
O
O
OBn
( )
3
( )
3
OBn
O
O
( ) L-selectride (4 eq.)
3
( ) THF, -78 o C, 2.5 h, 94%
3
O
Pb(OAc) 4 , benzene,
H
rt., 1.5 h, 98%
OBn
OH
PdCl 2 , CuCl, O 2 , DMF/H 2 O,
O
O
OH
( )
3
( )
3
OH
-78 o C, 4.5 h, 78%
OBn
C
rt., 2.5 h, 85%
OBn
O
Scheme 53.
H 2 , 10% Pd/C, MeOH
3N HCl, rt., 2.5 h, 72%
O
O
61
tion yielded 62 (Scheme 54). For the synthesis of 63,
TBDMS protected amide F was reduced with DIBAL-H and
treated with phosphorus ylide to give the ,-unsaturated
ketone G. Hydrogenation over Pd/C and simultaneous
deprotection of the silyl ether and acetonide afford triol
H, which instantly ketalized to 63 (Scheme 55).
9.4. (±)-1,7-Dioxaspiro[5.5]undecane (64) and (2R*,6S*)-
2-methyl-1,7-dioxaspiro[5.5]undecane (65)
1,7-Dioxaspiro[5.5]undecane (64) has been identified as
the major component of the sex pheromone released by females
of the olive fruit fly Dacus oleae [171]. In bioassays,
(R)-64 was shown to be active against the males, whereas
(S)-64 was active against females [172]. 2-Methyl-1,7-
dioxaspiro[5.5]undecane (65) was identified as volatile component
of the cleptoparasite bee Epeolus cruciger [173].
Conway et al. [174] described a synthesis of these two spiroketal
compounds employing stereospecific Stille coupling
reactions of 2-metallo-dihydropyrans with suitable (Z)-1-
iodoalkenols and subsequent cyclisation (Scheme 56).
10. SYNTHESIS OF ALLENES AS PHEROMONES
10.1. Methyl (R,E)-tetradeca-2,4,5-trienoate (66)
Methyl (R,E)-(-)-tetradeca-2,4,5-trienoate (66) has been
of synthetic interest since Horler determined it to be a sex
attractant produced by the male bean weevil, Acanthoscelides
obtectus [175].

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 713
Me OMe
N
O
O
O
Me N O
OMe
MgBr
( )
3 (1.5 eq)
THF, -15 o C, 30 min, 92%
O
O
Me
O
N
3
O
OMe
1) L-selectride
THF, -78 o C, 2.5 h, 98%
2) TBDMSOTf, Py,
CH 2 Cl 2 , 0 o C to rt., 1 h, 98%
O
O
Me
OTBDMS
( )
3
O
N
OMe
1) NaBH 4 , MeOH,
0 o C to rt., 3 h, 95%
2) TsCl, DMAP, CH 2 Cl 2 ,
rt., 5 h, 92%
O
O
OTBDMS
( )
3
OTs
super hydride, THF,
rt. 2 h, 94%
O
O
E
OTBDMS
( )
3
D
PdCl 2 , CuCl, O 2 ,
DMF/H 2 O, rt., 6 h, 74%
O
O
Scheme 54.
62
OH
Me
N
OMe
O
OTBDMS
O
O
O
1) K-selectride
O
EtMgBr, THF,
THF, -78 o C, 25 min
O
O
O
O
O
-15 o C, 30 min, 88%
O
N
Me N 2) TBDMSCl, imidazole,
OMe
DMAP, DMF, 80 o C, 1.5 h,
N
Me OMe
68% (2 steps)
Me OMe
F
OTBDMS
OTBDMS
1) DIBAL-H, THF, -78 o C, 2h
O
H 2 , 10% Pd/C,
O
FeCl 3 6H 2 O, CH 2 Cl 2 ,
2)
O
O
rt. 1.5 h, quant. O
rt. 1.5 h, 87%
PPh 3
O
O
benzene, reflux, 4 h,
G
74% (2 steps)
OH OH O
( )
2
OH
H
O
O
63
OH
Scheme 55.
Ogasawara et al. [176] described an enantioselective synthesis
of this chiral allene using a palladium-catalyzed reaction
for the synthesis of the allene moiety in the key step.
Allene intermediate A was prepared by reaction of 3-bromo-
1,3-dodecadiene and dimethyl malonate. The use of
Pd(dba) 2 /(R)-segphos catalyst and 5 equivalents of malonate
were the best conditions in terms of both yield and asymmetric
induction (71% yield, 77% e.e.). Methanolic hydrolysis,
acidic decarboxylation and treatment with diazomethane
resulted in decarboxylation of A nearly without racemization.
A final desaturation step gave 66 in 76% e.e. (Scheme
57).

714 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.
HO
OTBDMS
1) (COCl) 2 , DMSO,
CH 2 Cl 2 , -78 o C, 92%
2) Ph 3 P=CHI, THF, -78 oC, 78%
3) CSA, MeOH, 20 o C, 15 h, 78%
H
H
I
OH
(Z : E = 6.4 : 1)
a) M = SnBu 3 ; (o-Tol) 3 P (10 mol%), Pd(OAc) 2 (5 mol%),
Et 3 N, CH 3 CN, 80 o C, 1.5 h, 33%, or
b) M = ZnCl; '(Ph 3 P) 2 Pd' (5 mol%), THF, 0 o C, 1 h, 71%, or
c) M = ZnCl; Pd(Ph 3 P) 4 (5 mol%), THF, 0 o C, 1 h, 72%
O
M
O
1) CSA, CH 2 Cl 2 , 20 oC, 82%
OH
O
64
2) H 2 , 5% Pd/C, EtOAc, 6 h, 93%
O
(Z : E = 6 : 1)
H
OH
O
OEt
TBDMSCl, DBU,
CH 2 Cl 2 , 20 o C, 99%
TBDMSO
O
OEt
1) DIBAL-H (1.6 equiv),
toluene, -78 o C,
2) citric acid, -78 o C, 88%
TBDMSO
A
O
H
DIBAL-H,
toluene, -78 -20 o C
TBDMSO
OH
(COCl) 2 , DMSO, -78 o C
OH
A
1) Ph 3 P=CHI, 73%
2) CSA, MeOH, 20 o C, 85%
HO I H H
(Z : E = 6.4 : 1)
O
ZnCl , Pd(PPh 3 ) 4 (5 mol%),
THF, 5 o C, 1 h, 48 -76 %
O
H
(Z : E = 6.4 : 1)
Scheme 56.
1) CSA, CH 2 Cl 2 , 20 o C, 66%
2) H 2 , 5%, Pd/C, EtOAc, 6 h, 74%
O
65
O
( )
7
+
Br
Pd(dba)2/(R)-segphos(10 mol%),
CsOt-Bu (1.0 eq), 71%
H
( )
7
H
COOMe
COOMe
1) KOH, H 2 O/MeOH
2) dil. H 2 SO 4 , 100 o C
3) CH 2 N 2 in Et 2 O
CH 2 (COOMe) 2 (5.0 eq)
A 77% e.e.
COOMe
1) LDA, THF, -78 o COOMe
H
C
H
2) PhSeBr
( )
7 H
( )
3) NaIO 4 , THF/H 2 O
7 H
76% e.e.
66 76% e.e.
O
O
O
PPh 2
PPh 2
Scheme 57.
O
(R)-segphos

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 715
ABBREVIATIONS
Ac = acetyl
AIBN = azobisisobutyronitrile
BnBr = benzyl bromide
BOMCl = benzyloxymethyl chloride
m-CPBA = m-chloroperbenzoic acid
CSA = camphorsulfonic acid
DABCO = 1,4-diazabicyclo[2.2.2]octane
DBU = diazabicyclo[5.4.0]undecene
DCHT = dicyclohexyl tartrate
DET = diethyl tartrate
DHP = 3,4-dihydro-2H-pyran
DIAD = diisopropyl azodicarboxylate
DIBAL-H = diisobutylaluminium hydride
DIPT = diisopropyl tartrate
DMAP = 4-dimethylaminopyridine
DMF = N,N-dimethylformamide
DMS = dimethylsulfide
DMSO = dimethylsulfoxide
EDC = 1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide
HMPA = hexamethylphosphoramide
IBX = 2-iodoxybenzoic acid
KHMDS = potassium hexamethyldisilazide
LDA = lithium diisopropylamide
MOMCl = methoxymethyl chloride
MsCl = methanesulfonyl chloride (mesyl
chloride)
NaHMDS = sodium hexamethyldisilazide
PCC = pyridinium chlorochromate
PDC = pyridinium dichromate
PNBA = p-nitrobenzoic acid
PPh3 = triphenyl phosphine
PPTS = pyridinium p-toluenesulfonate
PTSA = p-toluenesulfonic acid
Py = pyridine
TBAF = tetra-n-butylammonium fluoride
TBDMSCl = tert-butyldimethylsilyl chloride
TBDPSCl = tert-butyldiphenylchlorosilane
TBHP = tert-butyl hydroperoxide
TBSCl = tert-butyldimethylsilyl chloride
TBSOTf = tert-butyldimethylsilyl triflate
TFA = trifluoroacetic acid
THF = tetrahydrofurane
THP = tetrahydropyranyl
TMEDA = tetramethylethylenediamine
TMSCl = trimethylsilyl chloride
TsCl = p-toluenesulfonyl chloride (tosyl
chloride)
ACKNOWLEDGEMENTS
PHGZ thanks CNPq, CAPES and Fundação
Araucária/PR for financial support. JAFPV thanks CAPES
for a doctoral fellowship. JB thanks DII-PUCV and Fondecyt
(Chile) for financial support. MFF thanks Conicyt
(Chile) for a doctoral fellowship.
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