Synthesis of Pheromones: Highlights from 2002-2004

Current Organic Chemistry, 2009, 13, 299-338 299
Synthesis of Pheromones: Highlights from 2002-2004
P. H. G. Zarbin 1,* , J. A. F. P. Villar 1 , I. Marchi 1 , J. Bergmann 2 and A. R. M. Oliveira 1
1 Departamento de Química, Universidade Federal do Paraná, CP 19081, 81531-990, Curitiba-PR, Brazil
2 Instituto de Química, Pontificia Universidad Católica de Valparaíso, Avenida Brasil 2950, Valparaíso, Chile
Abstract: This review summarizes the synthesis of pheromones published in the triennium 2002-2004. The syntheses of a
total of 66 pheromone compounds (65 from insects, 1 from a crustacean species), belonging to 9 different structural categories,
are presented in schemes. New methodologies, but also well-known reactions have been employed to achieve the
(in many cases stereoselective) synthesis of the compounds.
1. INTRODUCTION
Since its very beginnings in the mid 19th century, organic
chemistry has made advances unimaginable to the
early pioneers of the field. Among the experimental key
techniques contributing to these advances are chromatography,
which made possible the separation of complex mixtures,
and spectroscopic (UV, IR, NMR) and mass spectrometric
methods, giving organic chemists powerful tools for
the structure determination of organic compounds. This, in
turn, stimulated research in organic synthesis, as products
and by-products of reactions could be easily isolated and
characterized. As once stated by Meinwald, “Organic chemistry
blossomed into a self-contained, inward-looking science,
bringing order and understanding to the synthesis and
reactions of millions of compounds” [1]. This order and understanding
allowed the development of countless reactions
of carbon-carbon bond formation or modification of functional
groups, applicable to all classes of organic molecules,
which would later eventually be modified or improved, e.g.
in terms of scope, yields, reaction conditions, or stereochemical
selectivities. Research in chemical communication
has been profiting from these decade-lasting and ongoing
efforts, as the synthesis of pheromones is of great importance
in the process of identifying these chemical messengers.
Moreover, a sort of mutualism has been evolving, as many
new synthetic methods have been developped with the explicit
aim to improve the synthetic route towards a pheromone.
Pheromones are compounds which are produced and liberated
by an individual, provocing a behavioural or physiological
response in another individual of the same species.
As pheromones are usually produced in minute amounts,
thus preventing crystallographic or extensive NMR experiments,
their independent synthesis is required to confirm the
identification and to establish the absolute configuration in
case of chiral compounds. Furthermore, chemical synthesis
of pheromones provides the amounts necessary for the
evaluation of their biological activity in the laboratory or in
the field.
*Address correspondence to this author at the Departamento de Química,
Universidade Federal do Paraná, CP 19081, 81531-990, Curitiba-PR, Brazil;
Tel: +55 41 33613174; Fax: +55 41 33613186;
E-mail: pzarbin@quimica.ufpr.br
The chemical structures of pheromones identified so far
are diverse and their complexity ranges from simple n-
alkanes to highly complex molecules bearing (multiple) cyclic
substructures, double or triple bonds, heteroatoms,
and/or (multiple) stereogenic centers. In many cases, only
one stereoisomer or a defined mixture of stereoisomers is
biologically active, while the unnatural isomers or a different
ratio of isomers may be inactive or even inhibit the response
to the natural compounds. Against this background, methods
are required which lead in high yields and with high stereoselectivity
to the desired compounds. Pheromone syntheses
published over the last few decades have been reviewed repeatedly.
The most comprehensive reviews are probably
those written by Mori in 1981 and 1992 [2, 3]. Other accounts,
relating pheromone synthesis to specific topics [4-6]
and a partial, nevertheless impressive update [7] were published
by the same author. Most recently, and reflecting a
growing branch in organic synthesis, the application of biocatalysis
to the synthesis of pheromones has been reviewed
[8].
In this article, we review the syntheses of pheromones
published in the triennium 2002-2004. The aim is to provide
a comprehensive overview of the syntheses, and we sincerely
apologize to the authors of those articles which may
have escaped our attention. The presentation of the syntheses
is done according to the compound class of the respective
target compound, adopting the style established by Mori [3].
2. SYNTHESIS OF ALKANES AS PHEROMONES
2.1. 5,9-Dimethylpentadecane (1)
The coffee leaf miner, Leucoptera coffeella, is an economically
important pest of coffee trees in Brazil. It has been
demonstrated by Francke and co-workers [9] that the main
component of the female-produced sex pheromone of this
species is 5,9-dimethylpentadecane (1), however, the stereochemistry
of the natural pheromone remains unknown.
Moreira and Corrêa [10] described an enantioselective
synthesis of three stereoisomers of 1, from commercial
isopulegol and synthetic neo-isopulegol [11, 12] (Scheme 1).
Zarbin et al. [13] described a straightforward synthesis of
racemic 1 employing an unsymmetrical double Wittig olefination
as the key reaction to build the carbon skeleton of the
1385-2728/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

300 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
OH
1) B 2 H 6
2) H 2 O 2 , NaOH,
THF, 0 °C, 84%
H
OH
OH
1) NaH, BnBr, THF, 83%
2) PCC, CH 2 Cl 2 , 93%
3) m-CPBA/NaHCO 3 , 75%
H
O
O
(-)- isopulegol
OBn
1) MeOH, H + (cat), 93%
2) TsCl, Py, 72%
OTs
n-BuMgBr, Li 2 CuCl 4
3) LiAIH 4 , THF
4) TsCl, Py, 93%
OBn
THF, -78 o C, 90%
OBn
1) H 2 , Pd/C, MeOH, 73%
n-PrMgBr, Li 2 CuCl 4
2) MsCl, Py, CH 2 Cl 2 , 91%
THF, -78 o C, 90%
OMs
(5S,9S) - 1
From
(+)-neoisopulegol
similarly
OTs
n-BuMgBr,
Li 2 CuCl 4
OBn
OBn
(5R,9S) - 1
EtMgBr,
Li 2 CuCl 4
OBn
Scheme 1.
(5S,9R) - 1
Br
Br
1) 1.1 equiv n-BuLi, - 90 o C
2) 1 equiv 2-octanone, - 90 o C to rt.
2.1 equiv PPh 3 , DMF, 92%
3) 1.1 equiv n-BuLi, -90 o C
4) 1 equiv 2-hexanone, -90 o C to rt., 64%
H 2 , Pd/C,
BrPh 3 P
PPh 3 Br
Scheme 2.
hexane, 93%
1 54% overall yield
molecule. The bis-phosphonium salt obtained from 1,3-
dibromopropane and triphenylphosphine, was reacted consecutively
with the ketones 2-octanone and 2-hexanone, affording
the asymmetric diene, which was readily hydrogenated
over Pd/C, furnishing 1 in 54% overall yield (Scheme
2). Synthetic 1 showed high biological activity when tested
in field experiments.
2.2. (S)-9-Methylnonadecane (2) and meso-13,23-
dimethylpentatriacontane (3)
(S)-9-Methylnonadecane (2) is a sex pheromone component
of the cotton leafworm Alabama argillacea [14], and
meso-13,23-dimethylpentatriacontane (3), is the sex pheromone
of the tse tse fly Glossina pallidipes [14].

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 301
H
O
H
O
H
H
H
H
Ref. [16]
H
HO
CBr 4 , PPh 3 , CH 2 Cl 2 , 78%
H
Br
O
1) m-CPBA, MgSO 4 , CH 2 Cl 2
OH
O
1) NaOEt, NaBH 4 , EtOH, 77%
2) PTSA, EtOH, 59% overall
H
Br
2) H 2 , Pd/C, EtOAc, 83%
HO
A
O
O
1) PCC, CH 2 Cl 2 , 78%
2) [C 7 H 15 PPh 3 ] + I - , n-BuLi,
THF, -78 o C, 98%
O
O
1) DIBAL-H, toluene, -78 o C, 86%
2) [C 2 H 5 PPh 3 ] + I - , n-BuLi, THF,
-78 o C, 92%
3) H 2 , Pd/C, EtOAc, 95%
( ) 8 ( ) 6
2
A
1) PCC, CH 2 Cl 2 , 78%
2) [C 9 H 19 PPh 3 ] + I - , n-BuLi,
THF, -78 o C, 89%
3) DIBAL-H, toluene, -78 o C, 80%
B
O
A
1) TBDPSCl, imidazole,
DMAP, DMF, 81%
2) DIBAL-H, toluene, -78 o C, 80%
3) [C 6 H 13 PPh 3 ] + I - , n-BuLi,
THF, -78 o C, 89%
( ) 7 ( ) 4
TBDPSO
( ) 3
1) TBAF, THF, 94%
2) I 2 , PPh 3 , imidazole, CH 3 CN,
Et 2 O, 0 o C to rt. 87%
3) PPh 3 , toluene, reflux, 80%
IPh 3 P
1) n-BuLi, THF, B, -78 o C
( ) 4
2) H 2 , Pd/C, 99%
( ) 10
( ) 10
3
Scheme 3.
Lamers et al. [15] reported the synthesis of these two
pheromones starting from the readily available (+)-
aromadendrene via the chiral intermediate A [16] (Scheme
3).
2.3. 7,11-Dimethylheptadecane (4)
The hydrocarbons 7-methylheptadecane and 7,11-
dimethylheptadecane (4) have been identified as constituents
of the female-produced sex pheromone of the spring hemlock
looper (Lambdina athasaria) and the pitch pine looper
(L. pellucidaria) [17, 18]. Subsequently, bioassays confirmed
that (S)-7-methylheptadecane and meso-4, that is
(7S,11R), are the bioactive stereoisomers [19]. Chow et al.
[20] described the synthesis of a mixture of all isomers of 4
in 6 steps, starting from hepta-1,6-diene. Pure (R,R)-4 was
synthesized by hydrolytic kinetic resolution of the bisepoxide
obtained from hepta-1,6-diene using 1.4 % equiv. of
[(R,R)-(salen)Co(III)(OAc)]-Z complex (Fig. 1), followed by
a Grignard reaction and methylation (Scheme 4).
3. SYNTHESIS OF ALKENES AS PHEROMONES
3.1. (6Z,9Z)-Heneicosa-6,9-diene (5), (3Z,6Z,9Z)-
heneicosa-3,6,9-triene (6), and heneicosane (7)
(6Z,9Z)-Heneicosa-6,9-diene (5), (3Z,6Z,9Z)-heneicosa-
3,6,9-triene (6), and heneicosane (7), have been identified as

302 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
m-CPBA, CH 2 Cl 2
1) n-C 5 H 11 MgBr, CuI,
O O O
O
Et 2 O
1) MeMgI, Et 2 O
2) DMSO
( ) 5 ( ) 5
2) Jones Reagent.
( ) 4 H 2 , Pd/C
( ) 5
( ) 5
( ) 5
racemic and meso-4
O
O
1) (R,R)-Z, H 2 O
O
+
HO
O
OH
+
O
OH
OH
OH
OH
O
O
1) n-C 5 H 11 MgBr, CuI
OMs
OMs
Me 2 CuLi,
Scheme 4.
2) MsCl, Et 3 N
( ) 5 ( ) 5
( ) 5 ( ) 5
Et 2 O
(R,R)-4
t Bu
H
N
H
H 2 O
N
Co
OAc O
t Bu
t Bu
H
N
H
H 2 O
N
Co
OAc O
t Bu
Fig. (1).
t Bu O t Bu
(R,R)-Z
t Bu O t Bu
(S,S)-Z
R
O
OH
SOCl 2 , 50 o C
benzene, 24h
R
O
Cl
O
NH
CHCl 3 , Py, 16h
R
O
N
O
1) n-C 3 H 7 MgCl, CeCl 3 ,
THF, -78 o C, 1.5 h
2) 10% AcOH
R
O
TsNH-NH 2
EtOH, rt., 24h
TsHN
R
N
( ) 4 ( ) 7
( ) 4
( ) 16
1) DIBAL-H, CH 2 Cl 2
0 o C, 30 min
2) 3N NaOH
5
6
7
Scheme 5.
pheromone components of Achaea janata, a destructive oligophagus
insect for castor crops, especially when young
crops are attacked.
Badioli et al. [21] described the synthesis of these three
hydrocarbons from linoleic, linolenic, and stearic acid, respectively,
by addition of organocerium reagents to the corresponding
morpholine amides. The resulting propyl ketones
were reduced via their tosylhydrazones (Scheme 5).
3.2. (9E,11Z)-Hexadeca-9,11-dienal (8)
(9E,11Z)-Hexadeca-9,11-dienal (8) has been identified as
a female-produced sex pheromone of the pecan nut casebearer
(Acrobasis nuxvorella) [22].

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 303
O
OH
H
MeC(OEt) 3 , H +
O
OEt
basic Alumina,
benzene
O
OEt
1) LiAlH 4 , Et 2 O, 0 o C
2) Ac 2 O, Py
OAc
1) BrMg(CH 2 ) 7 OTHP, CuI
2) PTSA, MeOH
(E,Z:E,E 2:1)
OH
1) tetracyanoetylene, THF
2) P 2 O 5 , DMSO, then Et 3 N
8
O
H
H
1) n-BuLi, Et 2O
2) acrolein
OH
MeC(OEt) 3 , H +
O
OEt
1) LiAlH 4 , Et 2 O, 0 o C
2) TsCl, Et 3 N
OTs
1) BrMg(CH 2 ) 5 OTHP, CuI, -78 o C
2) PTSA, MeOH
3) recrystallization
OH
1) Zn, C 2 H 4 Br 2 , LiCuBr 2
2) P 2 O 5 , DMSO, then Et 3 N
O
H
>99% E
8
Scheme 6.
HO
Br
1) Ref. [25]
2) 2-propyne-1-ol/LiNH 2 , fl. NH 3
THPO
OH
1) LiAlH 4 , Et 2 O, rt.
2) (COCl) 2 , DMSO
3) Et 3 N, CH 2 Cl 2 , -78 o C
THPO
O
H
Separation of (E,E)-isomer by
[n-BuPPh3] + Br -
NaHMDS, THF, -20 o C
1) PTSA, MeOH, rt.
THPO
H
Diels-Alder reaction with
tetracyanoethylene
2) (COCl) 2 , DMSO
3) Et 3 N, CH 2 Cl 2 , -78 o C
O
Scheme 7.
9
Two alternative syntheses were described by Passaro and
Webster [23]. The key steps in both sequences is an orthoester
Claisen rearrangement (Scheme 6).
3.3. (8E,10Z)-8,10-Tetradecadienal (9)
Francke et al. described the synthesis of (8E,10Z)-8,10-
tetradecadienal (9), the female produced sex pheromone of
the horse-chestnut leafminer (Cameraria ohridella) [24].
The synthesis of 9 was carried out in 30% overall yield,
starting from 7-bromoheptanol. The (8E) configuration was
achieved by stereoselective reduction of an acetylene, while
the (10Z) configuration results from a stereoselective Wittig
reaction (Scheme 7).
4. SYNTHESIS OF EPOXY PHEROMONES
4.1. (6Z,9Z,11S,12S)-trans-11,12-Epoxyheneicosa-6,9-
diene (10) (Posticlure)
Wakamura et al. [26] identified posticlure [(6Z,9Z,
11S,12S)-trans-11,12-epoxyheneicosa-6,9-diene, 10] as the
female-produced pheromone of the tussock moth Orgyia
postica. Fernandes and Kumar [27] described a highly enantioselective
synthesis of (+)- and (-)-posticlure employing
the Sharpless asymmetric dihydroxylation of olefin A or the
regio- and stereoselective mono-dihydroxylation of the trans
olefin bond of the (Z,Z,E)-triene B to obtain the enantiomerically
pure diols C and D, which were transformed into (+)-

304 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
OH
O
O
H
(DHQ) 2 -PHAL or (DHQD) 2 -PHAL, ( ) 8 OEt
OsO
O
4 , MeSO 2 NH 2 , K 3 Fe(CN) 6 ,
OH
Ph 3 P=CHCO 2 Et,
K 2 CO 3 , t-BuOH/H 2 O [1:1],
or
THF, rt., 12 h, 86% ( ) 8 OEt
OH O
A
24 h, 0 o C, 94%
( ) 4
( ) 8 OEt
OH
1) 2,2-DMP, (CH 3 ) 2 CO,
O
1) (COCl) 2 , DMSO, CH 2 Cl 2 ,
O
PTSA, rt., 8 h, 99%
( ) 8 OH Et 3 N, -78 o to -60 o C
( )8
( ) 8 OEt
( ) 8
( ) 4
O
O
2) LiAlH 4 , Et 2 O,
2) [(Z)-C 5 H 11 CH=CHCH 2 CH 2 P + Ph 3 ]I - ,
0 o C to rt., overnight, 97%
n-BuLi, THF, -80 o C, 8 h, 76%
3N HCl, MeOH, rt., 12 h, 90%
OH
OH
( ) 8 or ( ) 8
( ) 4
OH
OH
C
D
O
1) DIBAL-H, Et 2 O, 0 o C, 0.5 h, 90%
A
2) PCC, CH 2 Cl 2 , rt., 8 h
B
3) [(Z)-C 5 H 11 CH=CHCH 2 CH 2 P + Ph 3 ]I - ,
LiHMDS, THF, -80 o C, 8 h, 74%
(DHQ) 2 -PHAL, OsO 4 , MeSO 2 NH 2 ,
K 3 Fe(CN) 6 , K 2 CO 3 , t-BuOH/H 2 O [1:1],
( ) 4
( ) 4
OH
B
10 h, 0 o C, 78%
( ) 8
OH
C
(DHQD) 2 -PHAL, OsO 4 , MeSO 2 NH 2 ,
K 3 Fe(CN) 6 , K 2 CO 3 , t-BuOH/H 2 O [1:1],
OH
B
10 h, 0 o C, 79%
OH
D
C or D
( ) 8
(+) - 10
1) CH 3 C(OMe) 3 , PTSA (cat),
CH 2 Cl 2 , rt, 30 min
( )8
OAc
( ) 8
( ) 8
( )4
+
( ) 4
( ) 4
Br
2) CH 3 COBr, CH 2 Cl 2 , rt., 4 h
Br
OAc
Scheme 8.
K 2 CO 3 , MeOH, rt., 4 h,
86 - 88% overall
H
H
( )
( )
4 or
4
( ) H
( ) 8 H
8
O
O
(-) - 10
and (-)-10 via the respective acetoxybromides in a one-pot
reaction (Scheme 8).
4.2. (3Z)-cis-6,7-cis-9,10-Diepoxyheneicos-3-ene (11) (leucomalure)
Gries et al. identified leucomalure [(3Z)-cis-6,7-cis-9,10-
diepoxyheneicos-3-ene, 11] as the major component of the
female-produced sex pheromone of the Satin moth, Leucoma
salicis [28]. Muto and Mori [29] employed the lipase PS-
C(Amano)-catalyzed asymmetric acetylation of (±)-4-(tertbutyldiphenylsilyloxy)-cis-2,3-epoxybutan-1-ol,
which afforded
the (2R,3S)-epoxy alcohol A and the (2S,3R)-
epoxyacetate B as optically active building blocks to prepare
all isomers of 11 (Scheme 9).

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 305
HO
OH
1) NaH, TBDPSCl, THF, 92%
TBDPSO
O
OH
Lipase PS-C,
CH 2 =CHOAc, Et 2 O
2) m-CPBA, CH 2 Cl 2 , 94%
TBDPSO
O
OH
+
TBDPSO
O
OAc
(2R,3S)-A
49%, 99.5% e.e.
(2S,3R)-B
48%, 98.1% e.e.
K 2 CO 3 , MeOH, 99%
TBDPSO
O
OH
(2S,3R)-A
98.1% e.e.
TBDPSO
O
OH
n-BuLi, Tf 2 O; then
THF, HMPA, 77%
Me(H 2 C) 10 C CLi
TBDPSO
O
( ) 10
(2R,3S)-A
1) H 2 , Pd/CaCO - 3 Pb + 2 , cyclohexane
2) m-CPBA, CH 2 Cl 2 ; then MPLC
separation.
1) TBAF, THF, 81%
2) n-BuLi, Tf 2 O; then
THF, HMPA, 77%
Et
O O
TBDPSO
(2S,3R,5R,6S)-C
( ) 10
( ) 10
( ) 10
O O
O O
TBDPSO
+ TBDPSO
( ) 10
(2S,3R,5S,6R)-C 23%
(2S,3R,5R,6S)-C 58%
Me(H 2 C) 10 C CLi
O O
H 2 , Pd/CaCO - 3 Pb + 2 ,
O O
cyclohexane
Et
( ) 10
Et
( ) 10
(3Z,6S,7R,9S,10R)-11
Similarly
O O
(3Z,6S,7R,9R,10S)-11
O O
TBDPSO
O
OH
Similarly
Et
(3Z,6R,7S,9R,10S)-11
( ) 10
(2S,3R)-A
O
O
Et
( ) 10
Scheme 9.
All four isomers of 11 have also been synthesized by
Wimalaratne and Slessor, using D-xylose as the optically
pure starting material [30]. The epoxy alcohol A was transformed
to chain-elongated epoxy alcohols B and C, respectively,
which were subsequently epoxidized by the method
of Sharpless and finally alkenylated to give the pure isomers
of 11 (Scheme 10).
(3Z,6R,7S,9S,10R)-11
4.3. (6Z)-cis-9,10-Epoxyheneicos-6-ene (12) and (6Z)-cis-
9,10-epoxyeicos-6-ene (13)
The pure enantiomers of epoxide A used in Mori’s synthesis
of 11 [29] (Scheme 9) were also the key intermediates
for the synthesis of the enantiomers of (6Z)-cis-9,10-
epoxyheneicos-6-ene (12) and (6Z)-cis-9,10-epoxyeicos-6-
ene (13) [31] (Scheme 11).

306 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
HO
HO
O
OH
OH
1) EtSH/H +
2) acetone/I 2
3) t-BuOK
O
O
OH
SEt
SEt
1) LiAlH 4
2) TBDMSCl .
3) HgO/BF 3 Et 2 O
O
O
OH
CHO
O
O
OTBDMS
CHO
1) [Me(CH 2 ) 8 PPh 3 ] + Br -
2) H 2 , Pd/C,
3) TFA, aq. THF
HO
OH
OH
1) TsCl
( ) 10
OH
2) K 2 CO 3
O
( )10
A
A
1) TBDMSCl
2) TBDMSOCH 2 CC - Li + ,
BF 3 .Et 2 O
3) TsCl
OTBDMS
TBDMSO
1) TsCl
2)TBDMSOCH 2 CC - Li + ,
BF 3 . Et 2 O
3)K 2 CO 3
O
TBDMSO
OTs
( ) 10
( ) 10
O
O
OH
HO
( ) 10 ( ) 10
B
1) TBAF
1) TBAF
2) P
2) P 2 -Ni, H 2 -Ni, H 2
2
B
C
1) (+)-(L)-DET
1) (-)-(D)-DET
2) TsCl
2) TsCl
3) (C 4 H 7 ) 2 CuLi
3) (C 4 H 7 ) 2 CuLi
O
O
O
O
( ) 10 Et
( )10
(Z)-3-(6S,7R,9S,10R)-11
(Z)-3-(6R,7S,9S,10R)-11
C
Et
1) (+)-(L)-DET
2) TsCl
3) (C 4 H 7 ) 2 CuLi
1) (-)-(D)-DET
2) TsCl
3) (C 4 H 7 ) 2 CuLi
O
O
O
O
Et
( ) 10 Et
( ) 10
(Z)-3-(6R,7S,9R,10S)-11
(Z)-3-(6S,7R,9R,10S)-11
Scheme 10.
5. SYNTHESIS OF NON-ISOPRENOIDAL PHERO-
MONE ALCOHOLS AND THEIR ESTERS
5.1. 2-Methyl-4-octanol (14)
2-Methyl-4-octanol (14) has been described as a component
of the aggregation pheromones of several weevil species
[32, 33]. Baraldi et al. [34] reported the enantioselective
synthesis of (R)- and (S)-14 starting from isovaleryl chloride.
The key step of this synthetic route is the asymmetric reduction
of ethyl 5-methyl-3-oxohexanoate with Saccharomyces
cerevisiae to the corresponding hydroxyester (S)-A in
high enantiomeric excess (Scheme 12). The (S) isomer was

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 307
TBDPSO
O
OH
n-BuLi, Tf 2 O
TBDPSO
O
OTf
LiC
C(CH 2 ) 4 Me, THF
A
HMPA, 74% overall
TBDPSO
TsO
O
O
( ) 4 Similarly
O
H 1) TBAF, THF, 99%
2 , Pd/CaCO 3 -Pb
+ 2
TBDPSO
( ) 4
cyclohexane, quant.
2) TsCl, Py, 77%
O
(n-C 10 H 21 ) 2 CuLi, Et 2 O, 80%
( ) 10 ( ) 4
(9S,10R)-12
( ) 4
(n-C
O
9 H 19 ) 2 CuLi, Et 2 O, 80%
TBDPSO
O
OH
( ) 9 ( ) 4
O
(9S,10R)-13
( ) 10 ( ) 4
(9R,10S)-12
A
O
( ) 9 ( ) 4
Scheme 11.
(9R,10S)-13
O
LiCH 2 CO 2 Et, 85%
Cl
1) p-NO 2 C 6 H 6 CO 2 H
Ph 3 P, DEAD
OH
O
CO 2 Et
CO 2 Et
S. cerevisiae
allyl alcohol
50%, 99% e.e.
OH
(S) - A
CO 2 Et
2) NaOH, EtOH
70%, 99% e.e.
(R) - A
(R) - A or (S) - A
1) LiAlH 4 , THF, 85%
OH
or
OH
2) TsCl, Et 3 N, 80%
3) EtMgBr,
(R) - 14
(S) - 14
Scheme 12.
Li 2 CuCl 4 , 70%
prepared in five steps and 20% overall yield, while the (R)
enantiomer was obtained in six steps and 14% overall yield.
The key step of the synthesis of (R)-14 described by
Dhotare et al. [35] is the K-selectride reduction of the intermediate
ketone A obtained from D-mannitol. The reduction
proceeded with absolute syn selectivity (Scheme 13).
D-mannitol was also used by Zarbin et al. [36] to obtain
(S)-14 by a new and higly enantioselective approach, involving
the known (R)-glyceraldehyde acetonide A as key intermediate
(8.8% overall yield) (Scheme 14).
5.2. 4-Methylheptan-3-ol (15)
(3S,4S)-4-Methylheptan-3-ol [(3S,4S)-15] is the major
component of the aggregation pheromone of the bark beetles
Scolytus scolytus and S. multistriatus [37-40]. Recently,
(3S,4S)-15 was tentatively identified as the main component
of the aggregation pheromone of the almond bark beetle,
Scolytus amygdali, along with (3S,4S)-4-methyl-3-hexanol,
which functions as a synergist. Substitution of the pure
(3S,4S) isomer with racemic 4-methyl-3-heptanol in field
tests resulted in a lower trap catch of beetles in the field,
indicating the possibility that one or more of the unnatural
stereoisomers has an inhibitory effect [41].
Zada et al. [42] described the synthesis of all four
stereoisomers of 15. Key steps included preparation of enantiomerically
pure (R)- and (S)-4-methyl-3-heptanone (A) by
the SAMP/RAMP method, reduction to the corresponding
alcohols, and stereospecific transesterification with vinyl
acetate by lipase AK catalysis (Scheme 15). In field tests,

308 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
D-Mannitol
O O
OH
Steps
A
1) n-BuMgBr, THF
K-selectride,
2) TFA, H 2 O, CH 2 Cl 2 OBn
2) NaH, DMSO,
O O
O O
THF, -78 o C
CHO
O
2) PCC, CH 2 Cl 2
1) NaH, BnBr, THF
OH
HO
1) NaIO 4 , aq. MeCN
[Me 2 CHPPh + 3 ]Br - , THF
H 2 , Pd/C, EtOH
OH
Scheme 13.
OBn
(R) - 14
HO
OH OH
OH OH
OH
MeO OMe
1) SnCl 2 , , 55%
2) NaIO 4 , NaHCO 3 , CH 2 Cl 2 , 61%
O
O
A
O
H
1) [n-C 3 H 7 PPh 3 + Br] - ,
n-BuLi, THF, 88%
2) H 2 , Pd/CaCO 3 , hexane, 81%
O
O
1) acidic DowexÆ W 50 ,
H 2 O, 79%
TsO
OH
i-C 3 H 7 MgBr,
OH
2) TsCl, Py, 60%
CuI, THF, 78%
(S)-14
Scheme 14.
8.8% overall yield; 99.5% e.e.
O
Ref. 43
LiAlH 4 , Et 2 O, 25 o C
Lipase AK, vinyl acetate
O
(S) - A
OH
+
KOH, MeOH
OH
(3S,4S)-15
OAc
OH
(3R,4S)-15
Similarly
OH
(3R,4R)-15
Scheme 15.
O
(R) - A
OH
(3S,4R)-15
only (3S,4S)-15 attracted beetles in combination with the
synergist (3S,4S)-4-methyl-3-hexanol, whereas the (3R,4S)
and (3R,4R) isomers were inhibitory.
5.3. (2S,3R)-3-Methylpentadecan-2-ol (16)
Larsson et al. [44] described the synthesis of (2S,3R)-3-
methylpentadecan-2-ol [(2S,3R)-16], a putative pheromone
precursor isolated from some pine sawflies of the genus Gilpinia.
The enantiomers of 2-methyl-3-(phenylsulfanyl)propanal
[(S)-A or (R)-A] were prepared from readily available
(S)- and (R)-3-hydroxy-2-methylpropanoic acid methyl ester
and were reacted with dimethylzinc to give the isomers
(2S,3S)-B or (2R,3R)-B, respectively, both of high d.e. and
e.e. These products were further purified by lipase catalysed

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 309
HO
O
OMe
1) (PhS) 2 , (n-Bu) 3 P, DMF,
0 o C, rt., 95%
PhS
OH
1) DMSO, oxalyl chloride, -78 o C
2) DIPEA, CH 2 Cl 2 , -78 o C
PhS
O
H
2) LiAlH 4 , THF, 96%
3) extractive workup with KH 2 PO 4
(R)-A or (S)-A
CH 2 Cl 2 , -78 o C,
TiCl 4 (1.0 equiv),
PhS
OH
+
PhS
OH
+
PhS
OH
+
PhS
OH
10 min, Me 2 Zn (1.0 equiv)
75% 2 steps
(2S,3S)-B (2R,3S)-B (2R,3R)-B (2S,3R)-B
From (S) - A 91,5% 7% 1.4% 0.1%
From (R) - A 2.9% 0.2% 92% 4.9%
Mixture of the
stereoisomers
of B obtained
from (S)-A
CAL-B 9%
OH
PhS
>1000/1 d.r.
1) TBDMSCl, DMF, imidazole, 99%
2) m-CPBA, CH 2 Cl 2 , 88%
O 2 SPh
OTBDMS
>99.9% e.e.
1) THF, DMPU, -40 o C, n-BuLi (2.1 equiv),
up to 0 o C, cool to -40 o C
90% yield
PhSO 2
OTBDMS
2) 1-Iodoundecane (1.2 equiv),
THF, up to 20 o C (96%)
1) 10% Na/Hg, MeOH, Na 2 HPO 4 , rt., 94%
OH
2) i) TBAF, THF, reflux
ii) acetylchloride, Py, CH 2 Cl 2 , 84%
3) i) Raney Ni, EtOH, H 2. ii) KOH/MeOH, rt., 82%
16
Scheme 16.
acylation to give the enantiomerically and diastereomerically
highly pure enantiomers (>99% d.e., >99.9% e.e.). Pure
(2S,3S)-B was transformed to (2S,3R)-16 in 54% yield over
eight steps (Scheme 16).
5.4. 3-Methylpentadecan-2-ol (16), 3,7-dimethyltridecan-
2-ol (17), 3,7,11-trimethyltridecan-2-ol (18), 3,7,9-
trimethyltridecan-2-ol (19), and 3,7-dimethyltetradecan-
2-ol (20)
Hedenström et al. [45] reported the synthesis of precursors
of the sex pheromones of females of pine sawfly species
[46-49]. The key reaction sequence in the syntheses was the
ring opening of either cis- or racemic trans-2,3-epoxybutane
using a higher order cyanocuprate as nucleophile, obtained
from iodides or chlorides E – I, followed by a highly efficient
lipase catalysed stereoselective acylation of the resulting
3-methylalkan-2-ols (Scheme 17).
5.5. (2S,3R,7RS)-3,7-Dimethyltridec-2-yl acetate (21) and
propanoate (22)
3,7-Dimethyltridec-2-yl acetate (21) and propanoate (22)
are sex attractants of the sawfly Diprion pini [48].
Bekish et al. [50] described a synthesis of a mixture of
the diastereomers (2S,3R,7S)- and (2S,3R,7R)-21, as well as
(2S,3R,7S)- and (2S,3R,7R)-22 by cyclopropanation of the
ethoxycarbonyl group in O-THP protected ethyl (S)-lactate
with ethylmagnesium bromide in the presence of titanium(IV)
isopropoxide, and subsequent C2–C3 ring opening
of the resulting cyclopropanol (Scheme 18). The resulting
(S) configured bromoalkenol A (stereoisomeric purity 98%)
was chain-elongated and hydrogenated. The (3R) configuration
was established by esterification with phthalic anhydride
followed by salt formation with pure (S)-1-phenylethylamine
and several recrystallisations of this salt to give the alcohol
with 92 % e.e. at C-3.

310 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
O
1) t-BuLi, THF
2) 1-iodohexane
O
1) (Ph 3 P) 2 NiCl 2 , benzene
2) MeMgBr
3) add 2-hexyl-4,5-dihydrofuran,
80 o C 5 h
OH
Pd/C, H 2 MeOH
OH
A
R
OH
R = 1-hexyl S or R
R = 2-hexyl
PPh 3 , Br 2 , CH 2 Cl 2
R
Br
1) Na(s), EtOH
2) CH 2 (CO 2 Et) 2
3) KOH, EtOH
4) 180 - 200 o C
R
O
OH
R = 1-(3-methylpentyl)
LiAlH 4 , Et 2 O
R
OH
B R = 1-hexyl S or R
C R = 2-hexyl
D R = 1-(3-methylpentyl)
A, B, C, or D
PPh 3 , CCl 4 or
PPh 3 , I 2 , imidazole,
THF/MeCN
1) Li, hexane
R
X
R'
2) add to MeCu(CN)Li,
Et 2 O, -78 o C
3) add cis- or racemic
trans-epoxybutane
E R = 1-pentyl, R' = CH 3 , X = I
F R = 1-hexyl, R' = CH 3 , X = I, S or R
G R = 2-hexyl, R' = CH 3 , X = Cl or I
H R = 1-(3-methylpentyl), R' = CH 3 , X = I
and I - 1-Chlorododecane
OCOR''
R
OH
lipase, vinyl ester,
heptane, 3 Å.
*
R
*
R'
threo-(2R,3R) or erythro-(2R,3S) esters
R'' = Me, Pr, or Bu
R'
threo or erythro 16-20
+
OH
17 R = 1-pentyl, R' = CH 3 ,
18 R = 1-hexyl, R' = CH 3 , S or R
19 R = 2-hexyl, R' = CH 3 ,
20 R = 1-(3-methylpentyl), R' = CH 3 ,
*
R
*
R'
threo-(2S,3S) or erythro-(2S,3R)
16 R = 1-heptyl, R' = H
Scheme 17.
5.6. 3,7-Dimethyltridec-2-yl propanoate (23)
Dandapani et al. described a synthesis of all 16 stereoisomers
of 3,7-dimethyltridec-2-yl propanoate (23), the sex
pheromone of the pine sawfly Microdiprion pallipes, by a
fluorous mixture-synthesis approach [51]. Each of the four
stereoisomers of 2-methyl-1,3-butanediol was marked separately
with a different fluorine-containing group, then the
quasi isomers were mixed and subjected to reactions, and
finally demixed by fluorous silica chromatography, making
use of the different fluorine tag of each isomer. In the first
step of the reaction sequence, each of the cuasi isomer in the
mixture M-1 was reduced, partially oxidized, then the mixture
was split and each part chain-elongated using the chiral
building block (S)-E or (R)-E. Each mixture obtained [M-2
(R) and M-2 (S)] was split again and chain-elongated sepa-

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 311
OH
CO 2 Et
1) DHP, PPTS (5 mol %),
CH 2 Cl 2 , 89%
2) EtMgBr, Ti(Oi-Pr) 4 ,
Et 2 O/THF
OTHP
OH
1) MsCl, Et 3 N, Et 2 O.
2) MgBr 2 , CHCl 3 /Et 2 O
59% (3 steps)
OH
A
Br
1) DHP, PPTS (5 mol %), CH 2 Cl 2 , 96%
OTHP
1) MeOH, PPTS (5 mol %.), 95%
2) 3-methylnonylmagnesium bromide,
CuI (5 mol %), 91%
.
2) NaBH 4 , NiCl 2 .6H 2 O, MeOH, 86%
OH
1) phthalic anhydride, Et 3 N, benzene
OH
CH 3 COCl or C 2 H 5 COCl,
Et 3 N, Et 2 O, 85 - 90%
OR
2) (S)-(-)-1-phenylethylamine, acetone
3) four recrystallizations from acetone
4) KOH, MeOH, 33% overall yield
Scheme 18.
(2S, 3R, 7RS)-21 R=COMe
(2S, 3R, 7RS)-22 R=COEt
rately with the same reagent (S)-E or (R)-E, giving rise to
four mixtures M-3. After hydrogenation, each mixture was
separated by HPLC and the fluorine-containing group was
removed to give the target compounds (Scheme 19).
5.7. (R)-2-Methyl-4-octanol (14), (R)- and (S)-3-octanol
(24), (R)-2-dodecanol (25), and (R)-2-methyl-4-heptanol
(26)
(R)-3-Octanol [(R)-24] is the sex attractant pheromone of
the ant Myrmica scabrinodis [52] while (S)-24 is an alarm
pheromone found in the ants Crematogaster castanea and C.
liengmei [53, 54]. (R)-2-Dodecanol (25) is a component of
the hind leg tibial gland secretion of worker ants of C. auberti
[55]. (R)-2-Methyl-4-heptanol (26) and (R)-2-methyl-4-
octanol (14) were identified as the male-produced aggregation
pheromones of the West Indian sugarcane weevils
Metamasius hemipterus [32, 56]. Scheme 20 shows the synthesis
of the optically active insect pheromones 14 and 24-26
described by Cho and Kim, starting from enantiomerically
pure -hydroxy sulfides [57]. The -hydroxy sulfides were
OH
OH
1) TMSCl, ET 3 N
C 6 H 4 -p-O(CH 2 ) 3 Rf
2) TMSOTf,
O
O
Rf(CH 2 ) 3 OC 6 H 6 CHO (A-D),
4 isomers
3) Mix in equimolar amts
A: Rf = C 4 F 9 (S,S)
B: Rf = C 6 F 13 (R,S)
C: Rf = C 7 F 15 (S,R)
M-1 (4 quasi isomers)
M-1
1) DIBAL-H
2) Dess -
Martin
periodinane
(S) - E
NaHMDS
(R) - E
NaHMDS
O F PAB
D: Rf = C 8 F 17 (R,R)
OTBS
M-2 (R), 90%
O F PAB
OTBS
M-2 (S), 89%
Ph
N
N
N N
Ph
N
N
N N
O
S
O
O
S
O
(S) - E
(R) - E
OTBS
OTBS

312 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
Scheme 19. Contd….
M-2 (R)
1) TBAF
2) Dess -
Martin
periodinane
(S) - E
NaHMDS
(R) - E
NaHMDS
O F PAB
M-3 (R,R), 75%
O F PAB
M-3 (R,S), 75%
OTBS
OTBS
1) TBAF
2) Dess-Martin
periodinane
3) CH 2 =PPh 3
4) NH=NH
O F PAB
M-4 (R,R), 77%
O F PAB
M-4 (R,S), 77%
(S) - E
O F PAB
O F PAB
M-2 (S)
1) TBAF
NaHMDS
M-3 (S,R), 80%
OTBS
M-4 (S,R), 77%
2) Dess -
Martin
periodinane
(R) - E
NaHMDS
O F PAB
OTBS
O F PAB
M-3 (S,S), 80%
O
M-4 (S,S), 77%
M-4 (R,R)
1) HPLC separation
O
2) Pd/C, H 2 , 97%
3) EtCOCl (8 equiv.)
Then PS-trisamine (97%)
23 - 4 individual isomers
M-4 (R,S)
M-4 (S,R)
M-4 (S,S)
Scheme 19.
Similarly
23 - 12 individual isomers
prepared by enantioselective reduction of the corresponding
-keto sulfides, catalyzed by oxazaborolidine (R)- or (S)-X
with 74 – 81% e.e. Recrystallization of the acylated -
hydroxy sulfides in appropriate solvents increased the enantiomeric
purity to 96 – 99% e.e. The sulfides were deacylated,
oxidized to the sulfoxides, alkylated if necessary, and
reduced with Raney-Ni to furnish the target compounds.
5.8. (-)-(2R,6Z)-Undec-6-en-2-ol (27) (nostrenol)
Nostrenol [(2R,6Z)-undec-6-en-2-ol, 27] was identified
from thoracic glands of the ant-lion species Euroleon nostras
and Grocus bore [58]. Chow and Kitching [59] described the
synthesis of this and other insect pheromones (sections 5.9.,
5.11., 5.12., and 6.4.) by hydrolytic kinetic resolution (HKR)
of functionalised epoxides, using (salen)Co(OAc) complexes
(R,R)-Z and (S,S)-Z (Fig. 1), providing enantiomerically
enriched epoxides and diols. The synthesis of 27 started from
undec-1-en-6-yne (A), which was epoxidised with m-
chloroperbenzoic acid in dichloromethane [59]. HKR of the
resulting epoxide furnished the (S)-epoxide B and diol C.
(S)-B was further transformed to 27 (Scheme 21)
5.9. (-)-(R)- and (+)-(S)-10-Methyldodecyl acetate (28)
(R)- and (S)-10-Methyldodecyl acetate (28) are components
of the pheromone of the lesser tea tortrix moth, Adoxophes
spp. [60, 61]. Chow and Kitching [59] described the
synthesis of both enantiomers. Benzyl ether A was epoxidized
with m-CPBA and the enantiomers of the resulting
epoxide B were kinetically resolved by stirring with 0.5
mol% of (R,R)-Z and 0.55 mol equiv. of H 2 O at room temperature
(22°C) for ca. 24 h, giving (R)-epoxide B and (S)-
diol C, which were straightforwardly converted to (R)-28
and (S)-28, respectively (Scheme 22).
5.10. 6-Acetoxy-19-methylnonacosane (29) and 7-acetoxy-
15-methylnonacosane (30)
In 1993, Pomonis et al. reported the identification of sixteen
compounds in a pheromonally active HPLC fraction
extracted from the females of the screw-worm fly Cochliomyia
hominivorax [62]. In 2002, Furukawa et al. synthesized
five possible pheromone candidates [63], and a bioassay of
these five compounds showed activity for 6-acetoxy-19-

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 313
R
Ar
O
R = n-C 5 H 11
R = i-Bu
R = n-C 10 H 21
O
R
A R = n-C 5 H 11 , 96% e.e.
B R = i-Bu, 98% e.e.
R
O
OH
S-p-tolyl
N
(S) - X
S-p-tolyl
B
O
S-p-tolyl
H
Me
O
D R = n-C 5 H 11 , 96% e.e.
E R = i-Bu, 98% e.e.
(R) or (S)-MeCBS (X, 0.1 equiv.)
N-ethyl-N-isopropylanilineborane
complex (Y, 1.0 equiv.),
THF, 25 o C 98 - 99%
Ph
Et
Ph
N
Ph
Pr-i
BH 3
(Y)
1) 2N, NaOH,
MeOH, rt., 98 - 99%
2) m-CPBA, CH 2 Cl 2 ,
rt. 95%
n-BuLi(2.8 eq.), R' I,
THF, -78 o - 20 o C, 72 - 93%
OH
Ar
R = n-C 5 H 11 , 74% e.e.
R = i -Bu, 81% e.e.
R = n-C 10 H 21 , 79% e.e.
O
R
R
O
OH
OH O
S-p-tolyl
R
D R = n-C 5 H 11 , 96% e.e.
E R = i-Bu, 98% e.e.
F R = n-C 10 H 21 , 79% e.e.
S-p-tolyl
OH O
S-p-tolyl
R
R'
G R = n-C 5 H 11 , R' = Me
H R = i-Bu, R' = Et
I R = i-Bu, R' = n-Pr
OH
S-p-tolyl
2N, NaOH,
MeOH, rt.
Ar
3,5-(NO 2 ) 2 C 6 H 3 COCl,
TMEDA, CH 2 Cl 2 , 97 - 99%
A R = n-C 5 H 11 , 74% e.e.
B R = i -Bu, 81% e.e.
C R = n-C 10 H 21 , 79% e.e.
Ar
O
R
O
R
O
C
recrystallization
C'
O
m-CPBA, CH 2 Cl 2 ,
rt. 95%.
O
S-p-tolyl
O
S-p-tolyl
C' R = n-C 10 H 21
A, 96% e.e.
B, 98% e.e.
C', 99% e.e.
G
ent-G
H
I
Raney Ni, MeOH,
rt., 89 - 92%
(R)-24
OH
(R)-26
OH
(S)-24
OH
(R)-14
F
Scheme 20.
methylnonacosane (29) and 7-acetoxy-15-methylnonacosane
(30).
Mori et al. described a synthesis of all possible stereoisomers
of 29 [64] and 30 [65]. Starting from the enantiomers
of citronellal and oct-1-yn-3-ol, all four stereoisomers of 29
(R)-25
(Scheme 23) were synthesized with high stereochemical purities
(more than 90% e.e. at C-6; about 97% e.e. at C-19).
The stereoisomers of 30 (Scheme 24) were obtained
starting with the pure enantiomers of citronellal. The (R) and
(S) configuration, respectively, was carried through to C-15,

314 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
( ) 3 m-CPBA, CH 2 Cl 2
( ) 3
A
O
0.5% equiv. (S,S)-Z,
0.55 equiv. H 2 O
( ) 3 ( )
O
3
+
OH
OH
B
C
B
NaBH4, EtOH
( ) 3
OH
1) DHP, H +
2) Ti(Oi-Pr) 4 , i-PrMgBr,
Et 2 O then H 2 O
3) MeOH, H +
( ) 3
27
OH
Scheme 21.
B
C
) 7
OH
1) m-CPBA, CH 2 Cl 2
O
OBn
( ) 7 OBn HO
( ) 7 OBn
1) Me 2 CuLi, Et 2 O, 0 o C
( 1) O 3 , Me 2 S
)7 OBn
( OAc
+
A
2) 0.5% equiv (R,R)-Z,
B
C
0.55 equiv. H 2 O, rt. 24 h
( ) 7 OBn
( ) 7 OBn
2) MsCl, Et 3 N,
2) K 2 CO 3 , MeOH
(R)-28
3) Me 2 CuLi, Et 2 O, 0 o C
3) Ac 2 O, Py
1) MsCl, Et 3 N
OH
1) MsCl, Et 3 N
2) K 2 CO 3 , MeOH
2) Me 2 CuLi, Et 2 O, 0 o C
3) Me 2 CuLi, Et 2 O, 0 o C
( ) 7 ( ) 7
1) H 2 , Pd/C
OAc
2) Ac 2 O, Py
(S)-28
Scheme 22.
while a lipase-catalyzed asymmetric acetylation defined the
absolute configuration at C-7.
5.11. (2S,11S)-2,11-Diacetoxytridecane (31) and (2S,12S)-
2,12-diacetoxytridecane (32)
(2S,11S)-2,11-Diacetoxytridecane (31) and (2S,12S)-
2,12-diacetoxytridecane (32) are two of the three active
components identified by coupled gas chromatography–
electroantennography of extracts from the pheromone glands
of female pea midges (Contarinia pisi) which are serious
pests of commercial peas [67]. The key step in the synthesis
of diester 31 was the HKR of a stereoisomeric mixture of the
diepoxide A affording the epoxi-diol (2R,11S)-B, which was
transformed to (2S,11S)-31 [59] (Scheme 25).
Similarly, HKR of a stereoisomeric mixture of diepoxide
C afforded pure (2R,12R)-C, which was transformed to
(2S,12S)-32 [59] (Scheme 26).
5.12. (1R,7R)-1,7-Dimethylnonyl propanoate (33)
Various isomers of 1,7-dimethylnonyl propanoate (33)
exhibit attractancy for males of corn rootworms, with the
western corn rootworm (Diabrotica virgifera virgifera) and
the northern corn rootworm (D. barberi) responding strongly
to the (1R,7R)-isomer [68]. The synthesis of this isomer is
shown in Scheme 27. The racemic bisepoxide A obtained by
m-CPBA epoxidation of 1,8-nonadiene was treated with
1.0% equiv. of (R,R)-Z and 0.8 equiv. of H 2 O, providing a
mixture of the (S,S)-bisepoxide, the (S,S)-epoxydiol B and
the (S,S)-tetraol. After column chromatography, epoxydiol B

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 315
OHC
Ref. [66]
OTs
1) THPO(CH 2 ) 7 MgBr,
Li 2 CuCl 4 , THF
OH
1) TsCl, Py
( ) 9 ( ) 10
(6R,19S)-29
2) NaI, DMF (77%, 2 steps)
( ) 9
( ) 4
I
( ) 9 ( ) 10
(S)-A
2) PTSA, MeOH (69%, 2 steps)
( ) 9 ( )
Similarly
OHC
I
10
( ) 4
then (S)-A 68%
(R)-A
OH
2.2 eq. n-BuLi, THF/HMPA,
(S)-B
1) H 2 , PtO 2 , EtOAc
(15 min at rt. 85%)
2) Ac 2 O, DMAP, Py,
CH 2 Cl 2 (98%)
(R)-A
(R)-A
(S)-A
+
+
+
(S)-B
(R)-B
(R)-B
( ) 9 ( ) 10
OAc
( ) 9 ( ) 12 ( ) 4
(6S,19S)-29
OAc
( ) 9 ( ) 12 ( ) 4
( ) 9 ( ) 12
(6S,19R)-29
OAc
( ) 4
(6R,19R)-29
OAc
( ) 9 ( ) 12 ( ) 4
OH
Scheme 23.
was transformed to (1R,7R)-33 in nine steps [59] (Scheme
27).
6. SYNTHESIS OF NON-ISOPRENOIDAL ALDE-
HYDES, KETONES, ACIDS, AND ESTERS AS
PHEROMONES
6.1. (R)-4-Methylnonan-1-ol (34) and (4R,8RS)-4,8-
dimethyldecanal (35)
(R)-4-Methylnonan-1-ol (34) was identified as a sex attractant
of the yellow mealworm Tenebrio molitor by Tanaka
[69, 70] et al. In 1980, Suzuki identified 4,8-dimethyldecanal
(35) as the aggregation pheromone of the red flour beetle
(Tribolium castaneum) and of the confused beetle (Tribolium
confusum), notorious pests of various stored products [71,
72] Mori and co-workers [73, 74] established the absolute
configuration of natural 35 as (4R,8R). Suzuki et al. [75]
later found that a 8:2 mixture of the isomers (4R,8R)- and
(4R,8S) was about 10 times more active than (4R,8R)-35
alone.
Ismuratov and co-workers [76] described a synthesis of
34 and 35 starting from (S)-3,7-dimethyl-1,6-octadiene. The
hydroxyketone B, obtained by ozonolysis of the unsaturated
ketone A followed by reductive workup, was either transformed
to (R)-34 or (4R,8RS)-35 (Scheme 28).
6.2. (E)-2-(4-Methyl-3-pentenylidene)butanedial (36) (acaridial)
-Acaridial [(E)-2-(4-methyl-3-pentenylidene)butanedial,
36] is known as the sex pheromone [78] and aggregation
pheromone [79] of Caloglyphus polyphyllae and as the alarm
pheromone [80] of Tyrophagus longior.
Shimizu et al. [81] described the synthesis of 36 in five
steps from 1,2,4-butanetriol with 19 % overall yield (Scheme
29). Z-selective Wittig reaction allowed the preparation of

316 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
( ) 13 ( ) 13
( ) 7
( ) 3
( ) 5
)
1) LiAlH 4 , Et 2 O, 96%
1) Me(CH 2 ) 11 MgBr, Li 2 CuCl 4 , THF
OHC
TsO
2) TsCl, Py
2) OsO 4 , NMO, tert-BuOH, Me 2 CO,
H 2 O, 3 d., rt. then Na 2 SO 4 , 94% (3 Steps)
OH 1) HIO 4.2 H 2 O, THF, (quant.)
( ) 5
OTHP
1) MsCl, CH 2 Cl 2 , Py
EtOH, 39 % (3 Steps)
O
LiC CTMS, THF, 86%
OTHP
( ) 13 ( ) 8
( ) 13 ( ) 7 H
2) PCC, NaOAc, MS 4Å,
OH
2) THPO(CH 2 ) 5 MgBr, THF, 64%
OH
2) LiAlH 4 , THF
1) PTSA, THF,
( ) 13 ( ) 7
CH 2 =CHOAc,
(3R,11R)
TMS
(3R,11R)-D
CH 2 Cl 2 , 72%
OAc
OH
K 2 CO 3 , MeOH
( ) 13 ( ) 7
TMS
OH
OH
(i-Pr) 2 O, 14 d., rt.
(3RS,11R)-C
( ) 13 ( ) K 7
2 CO 3 , MeOH
( ) 13 ( ) 7
OH
Lipase PS-D,
( ) 13 ( ) 7
99.5% e.e. 92.5% e.e.
Similarly
( ) 13 ( ) Similarly
7
OHC
97.5% e.e. 79% e.e.
(3S,11R) TMS
98% e.e. 98.5% e.e.
(3S,11R)-D
OH
OH
( ) 13
( ) 13 ( ) 7
TMS
(3R,11S)-D
(3RS,11S)-C
OH
(3R,11R)-D
( ) 13 ( ) 7
98% e.e. 94% e.e.
(3S,11S)-D
1) TBSCl, imidazole, DMF, 76%
OH
1) H 2 , PtO 2 , EtOAc, 15 min, rt.
2) n-BuLi, n-BuI, THF, HMPA, 75%
2) TBAF, THF, 92% (2 steps)
( ) 13 ( ) 7 ( )5
( ) 13 ( ) 7
OH
Ac 2 O, DMAP,
CH 2 Cl 2 , Py, 83%
OAc
(3S,11R)-D
( ) 13 ( ) 7 ( 5
98.5% e.e. 91% e.e.
(7S,15R)-30
OAc
Similarly
(3R,11S)-D
( ) 13 ( ) 7 ( ) 5
98% e.e. 97% e.e.
(7R,15R)-30
OAc
Similarly
(3S,11S)-D
( ) 13 ( ) 7 ( ) 5
98% e.e. 83% e.e.
(7S,15S)-30
OAc
Similarly
98% e.e. 96% e.e.
Scheme 24.
(7R,15S)-30

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 317
Scheme 25.
Br
1) Allyl MgBr, THF
Br
O
( )6 ( ) 6 ( ) 6
1.0% equiv. (S,S)-Z
O 0.6 equiv. H 2 O
2) m-CPBA, CH 2 Cl 2
O
O
OH
OH OH
O
+
OH + HO
( ) 6 OH
OR
1) LiAlH 4 , Et 2 O
OAc OAc
O
( ) 6 ( ) 6
(2R,11S)-B
( ) 6 O
A
(2R,11S)-B
1) 2,2-DMP, H +
OR
O
1) MeOH, H +
2) MeMgBr, CuI, Et 2 O, 0 o C
2) MsCl, Et 3 N
3) Ph 3 P, p-chlorobenzoic
(R = p-ClPhCO)
3) K 2 CO 3 , MeOH
acid, DEAD, THF
2) Ac 2 O, Py
(2S,11S)-31
O
( ) 7
C
(2R,12R)-C
1.0% equiv. (R,R)-Z
O
0.6 equiv. H 2 O
1) NaBH 4 , EtOH
2) Ac 2 O, Py
OH
OAc
OH
+
O
(
(2R,12R)-C
HO
OH +
O
) 7 O
OAc
OH
OH
(2S,12S)-32
Scheme 26.
O
( ) 3 ( ) 3
1.0% equiv.
m-CPBA, CH 2 Cl 2 O
O (R,R)-Z, 0.8 equiv. H 2 O
OH
OH OH
O O
( ) 3 ( ) 3 OH HO
( ) 3 OH
+
+
B
B
2,2-DMP, H +
O
O
1) Me 2 CuLi, Et 2 O, 0 o C
( ) 3 O
( ) 3
2) MsCl, Et 3 N
( ) 3
O
O
3) Me 2 CuLi, Et 2 O, 0 o C
1) MeOH, H +
2) MsCl, Et 3 N
3) K 2 CO 3 , MeOH
O
1) NaBH 4 , EtOH
2) (EtCO) 2 O, Py
( ) 3
33
OCOEt
Scheme 27.
the geometric isomer, (Z)-36 (-(Z)-acaridial), which was
detected as a trace component in the secretion of C. polyphyllae,
together with the (E)-configured hydroxy aldehyde
B.
6.3. (R)-10-Methyl-2-tridecanone (37)
10-Methyl-2-tridecanone (37) is the sex pheromone of
the southern corn rootworm (Diabrotica undecimpunctata
howardi), and biological evaluation of the enantiomers indi-

318 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
O
A
O
LiI
Ref. [77]
AcCH 2 CO 2 Et
Br
NaH
DMF
CO 2 Et
N 2 H 4 , H 2 O
1) O
O
3
KOH
OH
34
2) NaBH(OAc) 3 B
OH
B
MeCH=PPh 3
OH
H 2 , Pd/C
OH
PCC
O
Scheme 28.
35
H
HO
A
OH
TBSCl, DMAP,
OH Et 3 N, CH 2 Cl 2
P + Ph 3 Br -
OTBS
OTBS
n-BuLi, Et 2 O
P + Ph 3 Br -
NaHMDS, THF
TBSO
TBAF, THF
OTBS
OTBS
OH
PDC, CH 2 Cl 2
OTBS
TBSO
OH
Dess-Martin periodinane,
CH 2 Cl 2
OH
H O
PDC, CH 2 Cl 2
OH
H
B
1) TBAF, THF
2) Dess-Martin periodinane,
O
CH 2 Cl 2
O
A
H O
(E)-36
O
H
OTBS
O
H
Scheme 29.
(Z)-36
O
1) EtMgBr, CuI
1) n-BuLi, THF, -78 o C
( ) 7 OBn ( )7 OBn
( ) 7
(R)-37
O
B
2) MsCl, Et 3 N
3) Me 2 CuLi, Et 2 O, 0 o C
2) PdCl 2 , CuCl, DMF/H 2 O, O 2
Scheme 30.
cated that the (R) enantiomer was preferred by males [82].
The epoxide (R)-B from scheme 22 was converted to (R)-37
in five steps (Scheme 30).
Another synthesis took a similar approach as shown in
scheme 3, starting from (+)-aromadendrene [16] (Scheme
31).
6.4. (6R,12R)-6,12-Dimethylpentadecan-2-one (38)
(6R,12R)-6,12-Dimethylpentadecan-2-one (38) is the female
produced sex pheromone of the banded cucumber beetle
(Diabrotica balteata), the larvae of which are serious
pests of crops such as cucurbits and sweet potatoes [83].

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 319
H
Ref. 16
H O
CBr 4 , PPh 3 , CH 2 Cl 2 , 78%
H O
H
H
H
H
OH
O
H
Br
1) m-CPBA, MgSO 4 , CH 2 Cl 2
OH
OEt
1) NaOEt, NaBH 4 , EtOH, 77%
2) PTSA, EtOH, 59% overall
H
Br
2) H 2 , Pd/C, EtOAc, 83%
HO
OEt
1) TsCl, Py, 79%
I
A
O
2) LiAlH 4 , THF, 95%
3) I 2 , PPh 3 , imidazole, CH 2 Cl 2 , 91%
1) allylMgCl, THF, 83%
2) PdCl 2 , CuCl, O 2 , DMF
(wet) (100%).
37
O
Scheme 31.
1.0% equiv.
( ) 3 m-CPBA, CH 2 Cl 2
O
O
( ) 3
(R,R)-Z, 0.8 equiv.
H 2 O
OH
OH OH
O
( O O
)3 ( ) 3 OH HO
( ) 3 OH
+
+
B
O
1) EtMgBr, CuI, Et 2 O, 0 o C
DMP, H + O
B
( ) 3 O
( ) 3
( ) 2
2) MsCl, Et 3 N
C
3) Me 2 CuLi, Et 2 O, 0 o C
1) MeOH, H +
O
( ) 3 1) H 2 C=CH(CH 2 ) 2 MgBr, CuI, Et 2 O, 0 o C
( ) 2
2) MsCl, Et 3 N
2) MsCl, Et 3 N
3) K 2 CO 3 , MeOH
3) Me 2 CuLi, Et 2 O, 0 o C
( ) 3 1) PdCl 2 , CuCl,
( ) ( ) 3
2
( ) 2
O
O
O
Scheme 32.
DMF/H 2 O, O 2
38
Chow and Kitching [59] described the synthesis of (6R,12R)-
38 from epoxy-acetonide C (Scheme 32).
6.5. (6Z,8E)-Heneicosa-6,8-dien-11-one (39) and (Z)-6-
heneicosen-11-one (40)
(6Z,8E)-Heneicosa-6,8-dien-11-one (39) and (6Z)-
heneicos-6-en-11-one (40) are sex pheromone components
of the Douglas-fir tussock moth (Orgyia pseudotsugata)
[84]. Addionally, 39 has been identified as a major sex
pheromone component of O. vetusta [85] and was also found
in the painted apple moth (Teia anartoides) [86].
Jury et al. [87] reported the synthesis of 39 in seven steps
from 1,2-epoxydodecane in an overall yield of 25% (Scheme
33). (E)-Vinyl iodide B was obtained as a single stereoisomer
in good yield by the hydrozirconation–iodination of
acetylene A with Schwartz’s reagent and freshly sublimed

320 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
1) LiC CH:H 2 NCH 2 CH 2 NH 2
OTBS 1) Cp 2 ZrHCl, benzene, rt.,
OTBS
O DMSO, rt., 86%
( ) 9
( )
dark, 48 h
9
( ) 9
2) TBDMSCl, imidazole,
A
2) I 2 , 65%
B
DMF, 0 o C, 97%
OTBS
( )
1-heptyne, PdCl 4
1) Ni(OA ) 2 .4H 2 O, NaBH 4 , EtOH, 0 o 2 (CH 3 CN) 2 ,
C
( ) 9
CuI, piperidine, rt., quant.
C
2) H 2 NCH 2 CH 2 NH 2 , H 2 , rt., 69%
O
OTBS
1) TBAF, CH 2 Cl 2 , rt., 78%
( ) 9
( ) 4
( ) 9 ( ) 4
2) PCC, K 2 CO 3 , rt., CH 2 Cl 2 , 87%
39
I
Scheme 33.
MeO 2 C
O
( ) 9
1) NaBH 4 , THF, 74%
2) TBDMSC , imidazo e,
DMF, 98%
MeO 2 C
OTBDMS
( ) 9
1) DIBAL-H, to uene, 94%
2) PPh 3 = CHCO 2 Me,
to uene, 96%
MeO 2 C
OTBDMS
( ) 9
1) DIBAL-H, to uene, 94%
2) MnO 2 , CH 2 C 2 , 96%
OHC
OTBDMS
( ) 9
1) CBr 4 , Ph 3 P, CH 2 C 2 , 88%
2) Pd(PPh 3 ) 3 , (n-Bu) 2 SnH,
benzene, quant.
OTBDMS
1) n-C 5 H 11 MgBr,
NiC 2 , Et 2 O, 86%
OH
Br
( ) 9
2) TBAF, THF, quant.
( ) 9
Dess-Martin periodinane,
CH 2 C 2 , 79%
O
( ) 9
39
Scheme 34.
iodine. The (E,Z)-diene system was obtained in good yield
by the partial reduction of C in the presence of catalytic P2-
Ni under a hydrogen atmosphere.
Muto and Mori [31] described the synthesis of 39, employing
a Wittig reaction for the formation of the (8E) double
bond, while the conjugated (6Z) double bond was established
by Uenishi’s procedure (CBr 4 , PPh 3 ) [88] (Scheme
34).
Comeskey et al. [89] described the stereospecific synthesis
of all four isomers of 39, using the Suzuki coupling of
vinylic boronic acids A and C and vinylic iodide intermediates
B and D (Scheme 35).
Muto and Mori [31] described the synthesis of (Z)-6-
heneicosen-11-one (40), starting from 2-dodecanone in three
steps and 65% overall yield (Scheme 36).
6.6. (4S,6S,7S)-7-Hydroxy-4,6-dimethyl-3-nonanone (41)
(Serricornin)
Serricornin [(4S,6S,7S)-7-hydroxy-4,6-dimethyl-3-
nonanone), (4S,6S,7S)-41] is the sex pheromone produced by
female cigarette beetle, Lasioderma serricorne.[90-95]. Zlokazov
and Veselovsky [96] developed a synthesis of 41 starting
from (4S,5E)-4-methylhept-5-enenitrile [97] (Scheme
37).
6.7. (4R,6S,7R)-7-Hydroxy-4,6-dimethyl-3-nonanone (41)
and (3R,5S,6R)-6-hydroxy-3,5-dimethyl-2-octanone (42)
In 1999, Francke et al. found a stereoisomer of serricornin
as a pheromone component of the beetle Dinoderus
bifoveolatus [98]. The synthesis of (4R,6S,7R)-41 and
(3R,5S,6R)-6-hydroxy-3,5-dimethyl-2-nonanone (42) and

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 321
catecholborane 70 o C, 55%
t 2 O, NaOH, I 2 , 53%
( ) 4
(E)-B
B(OH) 2
( ) 4
I
( ) 4
( ) 4
4
(E)-A
I
AgNO 3 , acetone, NBS, 46%
Br
B(OH) 2
HBBr 2 then KIPBH, 78%
( ) 4
t 2 O, THF, I 2 , 37%
( ) 4
(Z)-B
(E)-C + (E)-B
( ) 4
( )
2) Dess - Martin periodinane, 72%
9
OH
O lithium acetylide/ DA
OH
catecholborane 70 o C, 29%
( ) complex, DMSO, 82%
9
( ) 9
B(OH) 2
( ) 9
(Z)-A
( ) 9 I
t 2 O, THF, I 2 , 46%
OH
(E)-C
(Z)-D
1) Pd(PPh 3 ) 4 , NaO t, 36%
O
(E)-C + (Z)-B
( ) 9 ( )
2) Dess - Martin periodinane, 66%
(E,Z)-39
(E,E)-39
O
1) Pd(PPh 3 ) 4 , NaO t, 66%
(Z)-D + (Z)-A
1) Pd(PPh 3 ) 4 , NaO t, 8%
( ) 4
( ) 9
2) Dess - Martin periodinane, 78%
(Z,Z)-39
O
1) Pd(PPh 3 ) 4 , NaO t, 40%
(Z)-D + (E)-A
( ) 9
2) Dess - Martin periodinane, 64%
(Z,E)-39
( ) 4
O
( ) 4
Scheme 35.
O
O
NaH, CO(OMe) 2 ,
( ) 9
MeO 2 C
( ) 9
toluene, heat, 93%
(Z)-3-nonenyl iodide
K 2 CO 3 , MeCOEt, 83%
O
O
Scheme 36.
CO 2 Me
( ) 9
KOH, MeOH/H 2 O, 84%
40
( ) 9
their stereoisomers was performed by Masuda et al. [99].
The starting chiral building block A was obtained by lipase
AK-catalyzed asymmetric acetylation of meso-2,4-dimethyl-
1,5-pentanediol. Asymmetric acetylation with vinyl acetate
and lipase PS-D (Amano) furnished the acetate (2R,4S,5R)-B
and the alcohol (2R,4S,5S)-C, which were further transformed
to the target compounds (Scheme 38).
6.8. (E)-2,4-Dimethyl-2-hexenoic acid (43)
(E)-2,4-Dimethyl-2-hexenoic acid (43) is a caste-specific
substance present in the mandibular glands of male ants in
the genus Camponotus [100]. Fernandes et al. [101] described
a synthesis of 43 with high stereoselectivity and 39%
overall yield, by zinc-promoted reduction of the 2-(bromo-

322 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
I
I
CN
NaOH E,OH,
sealed ,ube, 200 + C
HO
O
1) NIS, DMF, 20 + C
2) )hr+ma,+graphy
O
O
+
O
O
A
3:2
4
4
Scheme 37.
1) n-Bu 3 SnH AIBN, benzene, 80 + C
2) (TMS) 2 NLi, THF HMPA,
-78 + C ,+ 10 + C, ,hen MeI, -78 + C
O
O
E,MgBr, THF, - 40 + C
OH
(4S,6S,7S)-41
O
O
O
O
HO
OH
CH 2 =CHOAc, lipase AK, 86%
HO
OAc
1)TB MSCl, imidazole, MF, 95%
A
2) K 2 CO 3 , MeOH, 96%
3) TPAP, NMO, CH 2 Cl 2
4) EtMgBr, THF, (2 steps, 73%)
TB MSO
TB MSO
CH 2 =CHOAc,
lipase PS-
(2R,4S,5R)-B, 27%
OAc
OH
TB MSO
(2R,4S,5S)-C, 64%
OH
EtMgBr, THF
O
OH
(2R,4S,5R)-B
1) TBAF, THF, %uant.
2) KOH, MeOH, 87%
3) TPAP, NMO, CH 2 Cl 2 , 79%
O
O
MeMgBr, THF
(4R,6S,7R)-41
O
OH
(3R,5S,6R)-42
EtMgBr, THF
1) TBAF, THF, 92%
O
OH
(2R,4S,5S)-C
2) TPAP, NMO, CH 2 Cl 2 , 78%
O
O
(4R,6S,7S)-41
MeMgBr, THF
Scheme 38.
O
(3R,5S,6S)-42
OH

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 323
O O
OH O
DABCO, 72%
H + OCH 3
OCH 3
A
O
O
OCH
1) Zn/A%OH, 88%
3
OH
HBr, H 2 SO 4 , 75%
Scheme 39.
O
B
O
Br
O
O
P
O
2) N OH, MeOH/H 2 O, 83%
1) (CH 3 ) 2 CH 2 I,
t-BuOK, DMSO
2) LiHMDS, CH 3 CHO,
O
O
43 39% ) / er ll yield
1) AD-mix-, H 2 O/t-BuOH, 0 o C
2) KOH, H 2 O/ tOH
HO
O
OH
OH
THF, -78 o C
MsCl, Py, 0 o C
O
O
OH
(S,S)-44
O
O
AD-mix-, H 2 O/t-BuOH, 0 o C
Similarly
O
O
OH
(R,R)-44
1) (CH 3 ) 2 CH 2 I,
O
O
O
P
O
O
t-BuOK, DMSO
2) PCl 5 , 75 o C
O
O
O
P
O
O
CF 3
CF 3
NaHMDS, 18-crown-6,
CH 3 CHO, THF, -78 o C
3) CF 3 CH 2 OH,
toluene, t 3 N
O
O
1) AD-mix-, H 2 O/t-BuOH, 0 o C
HO
O
OH
MsCl, Py, 0 o C
O
O
2) LiOH, H 2 O/i-PrOH
OH
OH
Scheme 40.
O
O
AD-mix-, H 2 O/t-BuOH, 0 o C
Similarly
O
O
OH
(R,R)-45
(S,S)-45
methyl) alkenoate B derived from the corresponding Baylis–
Hillman adduct A (Scheme 39).
7. SYNTHESIS OF LACTONES AS PHEROMONES
7.1. 2-Hydroxy-2-(1-methylethyl)-3-butanolide (44), 2-
ethyl-2-hydroxy-3-butanolide (45), 7-hydroxy-5-
dodecanolide (46)
Schulz and Nishida [102, 103] reported that males of the
giant white butterfly Idea leuconoe release a complex mixture
of compounds containing alkaloids, aromatics, terpenoids,
hydrocarbons, and lactones, during courtship.
The pure (S,S) and (R,R) enantiomers of the -lactones 2-
hydroxy-2-(1-methylethyl)-3-butanolide (44) and 2-ethyl-2-
hydroxy-3-butanolide (45) were synthesized based on a controlled
C-C coupling by a Horner-Wadsworth-Emmons approach,
followed by asymmetric dihydroxylation (Scheme
40). The absolute configuration of the natural lactones was
determined to be (S,S) by enantioselective gas chromatography
[104].

324 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
O
1) SnC 2 , N 2 CH 2 COOEt, CH 2 C 2
O O O
H
2) Mg(OEt) 2 , C CO(CH 2 ) 3 COOMe, Et 2 O
O
3) NaC , D, DMSO/H 2 O
1) H 2 , (R)-Ru-BINAP, MeOH
o( NaBH 4 , MeOH,
OH OH O
O
o(
OH OH O
O
O
O
PTSA, CHC 3
O
OH
(R,R) - 46
o(
O OH
O
rac - 46
1) PPh 3 , DEAD,
benzoic acid, CH 2 C 2
O
O
OH
2) NaOMe, MeOH
Scheme 41.
(R,S) - 46
SiMe 3 O
O
LDA, -78 o C, then
CH 3 CH 2 CHO, 3 h, 93%
SiMe 3 O
O
OH
1%HF aq., rt., 1.5 h, 96%
2%TBDPSCl, imidazole,
DMF, rt., 12 h, 94%
HO
O
OTBDPS
1%CAN, acetonitrile,
0 o C, 20 min, 92%
2%BH 3 THF, 0.
o C,
then rt., 4 h, 95%
HO
OTBDPS
1%MsCl, Et 3 N, 0 o C, 3h
2%NaI, acetone, reflux. 12 h
3%NaCN, DMSO, rt.,
12 h, 80% overall
NC
OTBDPS
1%NaOH, 2-methoxyethanol,
reflux, 21 h, then HCl, 90%
2%TBAF, THF, rt., 4 h, 86%
Scheme 42.
O
R%-47
O
The -lactone 7-hydroxy-5-dodecanolide (46) was synthesized
as a mixture of stereoisomers and as the pure (R,R)
isomer, the latter by enantioselective reduction of the methyl
dioxoalkanoate precursor employing Ru-BINAP catalyst.
The (R,S) isomer was obtained by Mitsunobu inversion of
the (R,R) isomer (Scheme 41). The natural product was
shown to be a mixture of all stereoisomers [104].
7.2. (R)-4-Hexanolide (47)
(R)-4-Hexanolide (47) was identified as a component of
the sex pheromone of females of the dermestid beetle Trogoderma
glabrum [105, 106].
Arceo et al. [107] described the synthesis of 47 with 45%
overall yield in high enantiomeric purity using a chiral auxiliary
derived from (S)-camphor (Scheme 42).
7.3. (4R,9Z)-Octadec-9-en-4-olide (48)
Cossé et al. [108] reported the occurrence of a femalespecific
compound from the currant stem girdler (Janus integer),
which they identified as the chiral lactone (Z)-octadec-
9-en-4-olide (48). The structure was proven by synthesis of
the racemic compound. Upon chiral GC analysis, only one
enantiomer was detected to be produced by the insects, but
the absolute configuration was not determined.

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 325
OH
HO
A, THF, 0 o C, then
NH 4 C , MeOH, ref ux
NH 2
HOOC
COOH
NaOMe,
anhydrous MeOH, rt.
A BrMg
C BrMg
DHP, CH 2 C 2
0,1N HC , rt.
HO
HONO
O
O
D
PDC, CH 2 C 2
H
OH
THPO
THPO
MgSO 4 , rt.
O
B
TPAP, NMO
( ) 7
O
( ) 7
O
OH
CH 2 C 2 , rt.
(±)-48
1) BH 3. Me 2 S
O O COOH
OTs
O O
2) TsC , TMPDA, 0 - 5 o C
C, THF, 0 o C
( ) 7
O
O O
(R)-48
( ) 7
( ) 7
( ) 6
( ) 7 ( ) 4
Scheme 43.
HO OH
Ref. 111
TBDPSO
O CH CLi . H 2 N(CH 2 ) 2 NH 2 ,
THF, 62%
( ) 5 H
OH
OAc
OH Lipase AH-S (Amano),
TBDPSO
TBDPSO
TBDPSO
CH 2 CHOAc,
( ) 5
+
( ) 5
( ) 5
(+)-A
OTBS
1) TBSCl, imidazole, DMF, 94%
OH
1) H 2 , PtO 2 , hexane, 89%
TBDPSO
( ) 5
HO
( ) 5
rac. - A
SiO 2 chromatography
(+)-A 29% yield, 96% e.e.
B
OH
TBDPSO
( ) 5
K 2 CO 3 , MeOH
(-)-A 24% yield (2 steps), 93% e.e.
HO
( ) 5 O
O
O
O
2) n-BuLi, ClCO 2 Me, THF, 94%
CO 2 Me 2) TBAF, THF
1) PCC, MS 4Å
1) KOH, MeOH, H 2 O
sieves, CH 2 Cl 2 , 68%
( ) 7 ( ) 4 O
O
2) dil. HCl (79%; 3 steps)
2) [Me(CH 2 ) 8 PPh + 3 ]Br - , NaHMDS,
(R)-48
hexane, THF, -100 o C, 68%
Similarly
(95.9% e.e., E/Z 1.6:98.4)
(-)-A
(S)-48
CO 2 Me
(94.9% e.e., E/Z 1.6:98.4)
Scheme 44.
James et al. [109] described the synthesis of racemic and
the pure enantiomers of 48 and determined the absolute configuration
of the natural compound to be (R). In the racemic
route, Grignard reagent A was added to aldehyde B, followed
by deprotection and selective oxidation of the primary
hydroxyl group with tetrapropylammonium perruthenate
(TPAP). (R)-48 was synthesized by addition of Grignard
reagent C to the chiral epoxide D prepared from (S)-(+)-
glutamic acid (Scheme 43).
Shibata and Mori [110] synthesized both enantiomers of
48. The key step was the lipase-catalyzed asymmetric acetylation
of a racemic mixture of the acetylenic alcohol A with
vinyl acetate and lipase AH-S, which furnished (+)-A (96%
e.e.) and the acetylated product B, which was hydrolyzed to
give (-)-A (93% e.e.). (+)-A and (-)-A were transformed to
(R)-48 and (S)-48, respectively (Scheme 44).

326 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
O
N
1) n-BuLi, THF, -78 o C
N
OH
H 3 O +
2)
HO H 92% O
85%
O
O
H
+
O
O
H
I
(S)-A (from ref. 115)
HO H
I
(R)-A (from ref. 115)
similarly
cis - (2R,5S)-49 trans - (2S,5S)-49
(cis/trans = 7:3)
78% overall from iodide (S)-A
O
O
O
O
H +
H
cis - (2S,5R)-49 trans -(2R,5R)-49
(cis/trans = 7:3)
80% overall from iodide (R)-A
O
N
n-BuLi, THF, -78 o C
85%
O
O
I
O
O
N
O
H + , MeOH
60%
H
HO
O
O
51% overall yield from iodide B
B (from ref. [116])
Ref. [117]
Scheme 45.
O
Ac 2 O, Py, DMAP, rt., 100%
A
m-CPBA, CH 2 Cl 2 ,
NaHCO 3 , r.t., 82 - 85%
A
H
( ) 9
OAc
O
O
50
O L-proline (20 mol%),
OH O
OH
+
CHCl 3 , 24 h, 80%
( ) 9
+
( ) 9
A
85 : 15
OAc O m-CPBA, CH 2 Cl 2 ,
96% e.e.
NaHCO 3 , rt., 82 - 85%
( ) 9
OH
O O Ac 2 O, Py, DMAP, rt., 100%
O
O
O
Scheme 46.
51
7.4. cis- and trans-2-Methyl-5-hexanolide (49) and (4R,
5Z)-tetradec-5-en-4-olide (50)
cis-2-Methyl-5-hexanolide (49) is a component of the
pheromone blend of the carpenter bee Xylocopa hirutissima
[112], while (4R,5Z)-tetradec-5-en-4-olide (50) is the sex
pheromone of the Japanese beetle, Popillia japonica [113].
Zarbin et al. [114] proposed a general approach to the synthesis
of chiral pheromone lactones using readily available
starting materials derived from 2-oxazolines. To show the
usefulness of this approach, the diastereoselective synthesis
of cis- and trans-49 and a formal synthesis of (4R,5Z)-50
were performed (Scheme 45).
7.5. (5R,6S)-6-Acetoxyhexadecane-5-olide (51)
Laurence and Pickett described for the first time a natural
mosquito oviposition attractant pheromone in 1982 [118]. A
synthesis of the compound, (5R,6S)-6-acetoxyhexadecane-5-

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 327
OH
O
OH
1) CrCO 3 , DMF/MeOH,
pH 7.0, BnBr, rt., 17 h, 84%
O
O
OBn
O
O
2) NaBH 4 , Et 2 O/MeOH,
-20 o C, 2h, 95%
O
(S)-A; 92% e.e.
3) PPL, Et 2 O, 30 o C, 24 h, 74%
1) Pd/C 10%, H 2 , 1 atm, 3 h, 95%
2) BH 3 .DMS, THF, rt., 2 h, 90%
3) PCC, CH 2 Cl 2 , rt., 2 h 90%
O
O
(S)- B
O
H
(S)-A
DIBAL-H, THF,
-78 o C, 2h, 71%
HO
O
(R)- C
O
OBn
( ) 6
PPh 3
(S)-B, THF, -100 o C, 1.5 h, 60%
O
O
(S) - 52
Z/E = 96:4; 27% overall yield; 92% e.e.
(R)-C, THF, -100 o C, 1.5 h, 55%
Scheme 47.
O
O
(R) - 52
Z/E = 96:4; 18% overall yield; 92% e.e.
isoprene
Br 2
Br
Br
DMPU
Br
+ vinylic isomers
Scheme 48.
1) In, NaI, DMF,
3-methylbutanal, 91%
2) NH 4 Cl/H 2 O
OH
53
olide (51) was carried out by Sun et al. [119], employing a
L-proline-catalyzed asymmetric aldol condensation between
cyclopentanone and undecanal, followed by oxidation and
acetylation (Scheme 46).
7.6. (Z)-Hexadeca-7,15-dien-4-olide (52)
(Z)-Hexadeca-7,15-dien-4-olide (52) was described by
Leal et al. [120] as the female sex pheromone of the yellowish
elongate chafer (Heptophylla picea). Clososki et al.
[121] described an enzymatic synthesis of (R)- and (S)-52. A
known lipase-catalysed enantiolactonization in the key step
afforded the common precursor (S)-A for both enantiomers
of the pheromone, in 92% e.e. (overall yield: 27% for (S) and
18% for (R)-isomer) (Scheme 47).
8. SYNTHESIS OF ISOPRENOIDS AS PHEROMONES
8.1. Synthesis of Isoprenoidal Alcohols As Pheromones
8.1.1. 2-Methyl-6-methyleneoct-7-en-4-ol (53) (ipsenol)
Ipsenol (2-methyl-6-methyleneoct-7-en-4-ol, 53) was
identified as the aggregation pheromone of the California
bark beetle (Ips paraconfusus) [122]. Ceschi et al. [123] described
a short synthesis of racemic 53 employing a selective
indium insertion on a mixture of 2-bromomethylbuta-1,3-
diene and its vinylic isomers, in good yields (Scheme 48).
8.1.2. (1R,3R)-(3-Isopropenyl-2,2-dimethylcyclobutyl)
methyl 3-methyl-3-butenoate (54)
(1R,3R)-(3-Isopropenyl-2,2-dimethylcyclobutyl)methyl
3-methyl-3-butenoate (54) has been identified as the sex
pheromone produced by virgin females of the mealybug
Pseudococcus cryptus [124].
Nakahata et al. [125] acetylated (+)--pinene with lead
acetate and cleaved the resulting acetate by ozonolysis. The
triol obtained by reductive workup was reacted with
trimethyl orthoformate, and subsequent treatment with acetic
acid yielded the alcohol A, which was esterified to give 54 in
43% overall yield (Scheme 49).
8.1.3. (1R,3R)-(3-Isopropenyl-2,2-dimethylcyclobutyl)
methyl acetate (55)
(1R,3R)-(3-Isopropenyl-2,2-dimethylcyclobutyl)methyl
acetate (55) has been identified as the female-produced sex
pheromone of the citrus mealybug (Planococcus citri) which

328 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
Pd(OAc) 4 ,
benzene, 75%
OAc
+
(95:5)
OAc
O 3 , MeOH, then
NaBH 4 , K 2 CO 3 , 72%
HO
OH
OH
DCC, DMAP,
1) HC(OMe) 3 , PPTS, THF
2) Ac 2 O, then NaOH (88% overall)
HO
CH 2 Cl 2 , 91%
OH
O
O
A
O
54
Scheme 49.
1) Pb(OAc) 4 , benzene
RuCl 3 - NaIO 4 ,
CH 3 CN/CCl 4 /H 2 O
COOH
2) MeOH, KOH, 55% (2 steps)
(+)--pinene
COOH
1) (CH 3 ) 3 SiCH 2 MgCl
OH
(+)-trans-verbenol - A
1) LiAlH 4 , Et 2 O
OAc
O
2) Ac 2 O
2) Ac 2 O, Py
55
Zn, CH 2 Br 2 , TiCl 4
1) LiAlH 4 , Et 2 O
RuCl 3 - NaIO 4 ,
acetone, N-hydroxyphthalimide,
t-BuOH/H 2 O
(+)--pinene
CrO 3 , 36%
O
(+)-R-verbenone - B
COOH
OAc
O
COOH
2) Ac 2 O, Py
55
Scheme 50.
is a major pest of coffee, citrus, and cocoa in both the southern
U. S. and the Mediterranean [126].
Pássaro and Webster described two alternative syntheses
of 55 [127]. Compound 55 was synthesized starting from
(+)-trans-verbenol A or (+)-(R)-verbenone B, obtained from
-pinene. The key step for both syntheses is the oxidative
decarboxylation using RuCl 3 -NaIO 4 (Scheme 50).
8.1.4. cis-2-(2-Isopropenyl-1-methylcyclobutyl)ethanol (56)
(grandisol)
Grandisol [cis-2-(2-isopropenyl-1-methylcyclobutyl)
ethanol, 56] is the major component of the male-produced
pheromone of the cotton boll weevil (Anthonomus grandis)
[128] and was also identified from other pests, like bark
weevils [129, 130] and bark beetles [131].
The synthesis of a mixture of grandisol and its diastereomer
fragranol was described by Bernard et al. [132]
and is shown in Scheme 51. Key step is the palladium(0)-
catalysed reduction of the 2-cyclobutylidenepropyl sulfonic
ester A (E:Z 30:70) by ammonium formate to furnish (±)-56
and (±)-fragranol in 70:30 ratio.
8.2. Synthesis of Isoprenoidal Aldehydes and Ketones as
Pheromones
8.2.1. (Z)-exo--Bergamotenal (57)
Alizadeh et al. [133] described the synthesis of a racemic
mixture of (Z)-exo--bergamotenal (57), a sex pheromone
component of the white-spotted spined bug Eysarcoris parvus,
from racemic exo--bergamotene by a five-step se-

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 329
SPh
H
+
O
OBn
n-BuLi
THF, 0 o C
SPh
OH
OBn
PTSA
benzene, , 98%
O
OBn
COOEt
P(O)OEt 2
CH 2 OTs
Pd(dba)2, PPh3,
1) NaH, TDA-1, THF,
OBn
CH3CN, HCOONH4
OBn
+
OBn
2) LiAlH 4
(70:30)
3) TsCl, DMAP, NEt
A
3
Li/NH 3
+
OH
OH
56 (70:30)
Scheme 51.
O
COCl
Ref. 134
1) N 2 H 4 , AcOH, EtOH
2) t-BuOK, DMSO
m-CPBA, aq.
O
H 5 IO 6 , H 2 O/THF
OHC
NaHCO 3 , CH 2 Cl 2
57
1) NaH, (o-Tolyl-O) 2 P(O)CH(CH 3 )CO 2 Et, THF
2) DIBAL - H, THF
3) MnO 2 , hexane
CHO
Scheme 52.
quence involving regioselective epoxidation and (Z)-
selective Wittig olefination reactions (Scheme 52).
8.2.2. Iridodial (58)
In 2004, Zhang et al. [135] identified iridodial [(1R,2S,
5R,8R)-(2-(1-formylethyl)-3-methylcyclopentanecarboxaldehyde,
58] as a male-produced male-aggregation pheromone
of Chrysopa oculata, the first pheromone identified from
lacewings.
Chauhan et al. [136] described the synthesis of
(1R,2S,5R,8R)-58 and of the diastereomers (1R,2S,5R,8S)-
58, (1S,2S,5R,8R)-58, and (1S,2S,5R,8S)-58 in five steps
from (4aS,7S,7aR) and (4aS,7S,7aS)-nepetalactones, which
have been isolated by chemical separation from catnip (Nepeta
cataria) oil [137] (Scheme 53).
8.2.3. 3,7-Dimethyl-2-oxooct-6-ene-1,3-diol (59)
Dickens et al. [138] identified 3,7-dimethyl-2-oxooct-6-
ene-1,3-diol (59) as the male-produced aggregation pheromone
from the Colorado potato beetle (Leptinotarsa decemlineata).
The absolute configuration of natural 59 was determined
to be (S) by syntheses of the racemate and both
enantiomers from geraniol and (R)- and (S)-linalool, respectively,
by Oliver et al. [139] (Scheme 54).
9. SYNTHESIS OF ACETALS AS PHEROMONES
9.1. 4-Hydroxy-1,7-dioxaspiro[5.5]undecane (60)
Baker and co-workers described the isolation and identification
of 4-hydroxy-1,7-dioxaspiro[5.5]undecane (60), a
minor component of the female-produced sex pheromone of
the olive fruit fly, Bactrocera oleae, establishing the most
favorable configuration as (4S,6S) [140, 141]. Hao and Forsyth
[142] described a short total synthesis of 60 employing
a double intramolecular hetero-Michael addition strategy,
applicable to spiroketal synthesis (Scheme 55).

330 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
O
O
NaHCO 3 (5%),
MeOH/H 2 O (95:5), rt.
COOCH 3
CHO
1) HOCH 2 CH 2 OH, toluene, cat.
TsOH, azeotropic dehydration
2) flash chromatography
COOCH 3
O
O
+
COOCH 3
O
O
A
B
A
1) DIBAL - H, toluene, -78 to 0 o C
2) PDC, dry CH 2 Cl 2 , rt.
CHO
O
O
THF, 2N HCl, rt.
CHO
CHO
Similarly
CHO
(1R,2S,5R,8R)-58
B
CHO
(1R,2S,5R,8S)-58
O
CHO
CHO
O
Similarly
CHO
CHO
Scheme 53.
(1S,2S,5R,8R)-58
(1S,2S,5R,8S)-58
OH
1) t-BuOOH, VO(acac) 2
O
OAc
2) Ac 2 O, Py
OH
geraniol
*
OH
t-BuOOH, VO(acac) 2
*
OH
O
1) HClO 4 , DMF
2) K 2 CO 3 , MeOH
*
OH
A: racemic
B: 3-(S)
C: 3-(R)
OH
(R)- and (S)-linalool
OH
OH
A: racemic
B: 3-(S)
C: 3-(R)
1)TBDPSCl, imidazole
2) Swern oxidation
*
O
OTBDPS
TBAF
*
O
OH
racemic 59
(S)-59
(R)-59
Scheme 54.

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 331
O
OTBS
1) n-BuLi, TBSOCH 2 CH 2 CHO
2) MnO 2 , 75% (2 steps)
TBSO
OTBS
CSA, MeOH
O
1) NaBH 4 , MeOH
O
Scheme 55.
then benzene, 70%
O
O
2) PTSA, MeOH
82% (2 steps)
HO
60
O
(Z) or (E)
OH
1) MsCl, Py
2) LiBr, Acetone
Br
1) Mg, Et 2 O
2)
Br
(Z) or (E)
O
O
m-CPBA, CH 2 Cl 2
or
rac-cis- A
rac-trans- B
Mycobacterium
rac-cis- A
paraffinicum
NCIMB 10420
buffer pH 7.5, 83%
OH
OH
PdCl 2 , cat. CuCl 2
MeO(CH 2 ) 2 OMe
O
O
Mycobacterium
92% e.e.
(+)-exo - 61
rac-trans- B
paraffinicum
NCIMB 10420
buffer pH 7.5, 83%
OH
OH
PdCl 2 , cat. CuCl 2
MeO(CH 2 ) 2 OMe
O
O
92% e.e.
(-)-endo - 62
Scheme 56.
9.2. 7-Ethyl-5-methyl-6,8-dioxabicyclo[3.2.1]octane (61)
[exo-(61) and endo-brevicomin (62)]
exo-Brevicomin (61) and endo-brevicomin (62) are typical
components of the aggregation pheromone system of
several bark beetle species of the genera Dendroctonus and
Dryocoetes [143-146]. Mayer et al. [147] synthesized
(1R,5S,7R)-61 and (1S,5R,7R)-62, employing an enantioconvergent
biocatalytic hydrolysis of cis-configured 2,3-
disubstituted oxiranes by bacterial epoxide hydrolases
(Scheme 56).
9.3. (1R,5S,7R)-exo-Brevicomin (61), (1R,1’R,5’R,7’R)-
and (1S,1’R,5’R,7’R)-1-hydroxy-exo-brevicomin (63)
Francke et al. [148] have identified 1-hydroxy-exobrevicomin
(63) from the pine beetle Dendroctonus ponderosae.
Kumar and Rao [149] described a synthesis of
(1R,1’R,5’R,7’R)-63 and (1S,1’R,5’R,7’R)-63 and of
(1R,5S,7R)-61, starting from -picoline ((Scheme 57) (Table
1)).
9.4. 1,5-Dimethyl-6,8-dioxabicyclo[3.2.1octane (64) (frontalin)
Frontalin (1,5-dimethyl-6,8-dioxabicyclo[3.2.1]octane,
64) was first isolated by Kinzer [151], and is a component of
the aggregation pheromone of the southern pine beetle (Dendroctonus
frontalis), and of the western pine beetle, Dendroctonus
brevicomis. By means of bioassays with pure synthetic
enantiomers, Mori [145, 152] has shown that the absolute
configuration of natural 64 is (1S,5R). Chênevert and
Caron [153] described an enantioselective synthesis of
(1S,5R)-(–)-64 in 90% e.e. via enzymatic desymmetrization
of an achiral triol (Scheme 58).
A synthesis of racemic 64 was performed by Yang [154]
et al. Diene A was subjected to a double dihydroxylation
with catalytic osmium tetroxide and 4-methylmorpholine-Noxide
in MeCN–MeCOMe–H 2 O (1:1:1), generating tetraol
B. Subsequently, mono cleavage and acid-catalyzed intramolecular
acetalation led to 64. Use of AD-mix- in the

332 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
Ph 3 PCHCOCH 3 , CH 2 Cl 2 , 3 h
N
Na in liq. NH3.EtOH
N
H
4N HCl
O
A
O
H
(overall yield
for three steps 35%)
O
O
AD-mix-, t-BuOH/H 2 O,
1:1, 3 h, 0 o C
O
OH
O
PTSA (cat.),
CH 2 Cl 2 , 54% (2 steps)
OH
O
O
Table 1
O
O
+
O
O
O
OH
(1R,1'R,5'R,7'R)-63
OH
(1S,1'R,5'R,7'R)-63
A
Ph 3 PCHCOOEt, CH 2 Cl 2 30 min
(overall yield for three steps 25%)
O
O
OEt
AD-mix-, t-BuOH/H 2 O,
1:1, 3 h, 0 o C
O
OH
O
OEt
OH
PTSA (cat.),
CH 2 Cl 2 , 54% (2 steps)
O
O
OEt
LiCl, NaBH 4 ,
EtOH, THF, 77%
O
O
Ref. 150
O
O
Scheme 57.
O
OH
61
Table 1.
Solv.s and Temperature Yield (%) (1R,1’R,5’R,7’R)-(63) (1S,1’R,5’R,7’R)-(63)
Li AlH 4 THF, 0 o C 86 32 68
NaBH 4 MeOH, 0 o C 92 36 64
Zn(BH 4) 2 THF, 0 o C 84 25 75
K-Selectride Toluene, -78 o C 79 22 78
DIBAL-H THF, 0 o C 92 20 80
dihydroxylation step resulted in only poor enantioselectivity
(16% e.e.) (Scheme 59).
9.5. 1,3,8-Trimethyl-2,9-dioxabicyclo[3.3.1]non-7-ene (65)
In 2001, Nakashima [155] reported the identification of
1,3,8-trimethyl-2,9-dioxabicyclo[3.3.1]non-7-ene (65) from
the hexane extract of the brush organ located at the hind legs
of male swift moths Endoclita excrescens.
The absolute configuration was determined by synthesis
in a preliminary communication by Marukawa and Mori
[156]. The same authors reported the synthesis of the
(1R,3S,5S)- and (1S,3R,5R)-isomers, starting from the pure
enantiomers of ethyl 3-hydroxybutanoate [157] (Scheme 60).
9.6. (+)-Lineatin (66)
Lineatin [3,3,7-trimethyl-2,9-dioxatricyclo[3.3.1.0 4,7 ]nonane,
66] is the most important constituent of the aggregation
pheromone isolated from the frass of the female ambrosia
beetle Trypodendron lineatum, which is a deleterious pest
to coniferous forests in Europe and North America [158].
Alibés [159] et al. described a highly stereoselective
formal synthesis of (+)-lineatin in 14 steps and 14% overall
yield from the homochiral furanone A (Scheme 61). Key
steps of this synthetic approach feature the diastereoselective
construction of the cyclobutene derivative B by a photochemical
cycloaddition, and a regiocontrolled oxymercuration
reaction to form the dihydroxy compound C.
10. SYNTHESIS OF AN AMIDE AS PHEROMONE
10.1. (1’S,2R,2’S,3’R)-N-(1’-(Hydroxymethyl)-2’,3’-dihydroxytetradecyl)-2-hydroxy-21-methyldocosanamide
(67)
Asai et al. [162] reported in 2000 the ceramide (1’S,2R,
2’S,3’R)-N-(1’-(hydroxymethyl)-2’,3’-dihydroxytetradecyl)-
2-hydroxy-21-methyldocosanamide (67) to be the sex phero-

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 333
O
O O
MgBr
+ TBDPSO
OTBDPS
1) THF -78 o C
2) TBAF, THF
Pseudomonas sp. lipase,
O O
OH
vinyl acetate, benzene
OAc +
O O
(R)-A OH
1) TsCl, DMAP, Py,
O
2) PTSA, CH 2 Cl 2 , H 2 O.
(R)-A
OTs
LiEt 3 BH, THF,
O
reflux
TsCl, Et 3 N, DMAP, CH 2 Cl 2
PTSA,
OAc
OH
Et 2 O, H 2 O
O O
O
LiAlH 4 , THF
O O OH
OH
O O
OH
OH
OH
OAc
OAc
O
O
64
Scheme 58.
OsO 4 , NMO
MeCN/acetone/H 2 O
OH
OH
(1:1:1), 0°C, rt.
OH
OH
A
HCl, H 5 IO 6 , H 2 O,
O
B
Et 2 O, , 64%
64
O
O
1) AD-mix-, t-BuOH, H 2 O
(1:1), 0°C, rt.
O
Scheme 59.
A
2) HCl, H 5 IO 6 , H 2 O,
Et 2 O, , 55%
(-)-64 16% e.e.
OH
A
O
O
m-CPBA,CH 2 Cl 2 , 89%
1) NaBH 4 , CeCl 3.7 H 2 O,
MeOH, 94%
2) n-BuLi, CS 2 ,
MeI, THF, 98%
1) TBDMSCl, imidazole, DMF, 91%
2) DIBAL-H, CH 2 Cl 2 , 88%
3) 2,3-dimethylfuran, t-BuLi,
Et 2 O/HMPA
4) chromatography
O
O
OH
O
O
H
OCS 2 Me
O
OTBDMS
OH
(n-Bu) 3 SnH, AIBN,
toluene, 76%
OTBDMS
A 35% B 27%
48% HF aq.,
MeCN, 79%
+
O
O
O
O
(1R,3S,5S) - 65
O
OH
O
OTBDMS
Scheme 60.
OH
O
O
Similarly
O
O
(1S,3R,5R) - 65

334 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
PivO
O
A
O
(Z)-1,2-dichloroethylene, hn,
CH 3 CN, -15 o C, 89%
PivO
Cl
O
H
Cl
O
Zn, EtOH (80%),
MW, 105 o C
PivO
O
B
anti
O
H
PivO
76% d.e.
O
O
+
H
syn
B
1) MeLi, THF, -78 o C, 86%
2) PTSA, acetone, rt. 91%
O
O
OH
H
1) Hg(OAc) 2 , THF/H 2 O, rt.
2) NaBH 4 , NaOH, rt., 92%
O
O
OH
H
OH
C
1) NaH, BnBr, THF, rt., 79%
2) TFA, MeOH/H 2 O, rt., 94%
HO
OH
OH
H
OBn
1) TsCl, DMAP (cat.), Py, reflux, 84%
2) TCDI, THF, 70 o C, 90%
ImCSO
O
H
OBn
1) Bu 3 SnH, AIBN, toluene, 100 o C, 93%
2) H 2 , Pd/C, HOAc, rt. 98%.
O
H
OH
1) Dess-Martin periodinane, CH 2 Cl 2 , rt.
2) RuCl 3 , NaIO 4 , CCl 4 ,/H 2 O, rt. (81%, 2 steps)
O
O
H
O
Ref. [160, 161]
O
O
H
Scheme 61.
>99.5% e.e.
(+)-66
HO
1) (CH 3 ) 2 CH(CH 2 ) 2 MgBr,
Br Li 1) PTSA, EtOH, 97%
2 CuCl 4 , THF, 99%
( ) 11 THPO ( )19 HO 2 C ( ) 19
2) TsCl, Py, 89%
2) Jones' CrO 3 , acetone, 74%
3) THPO(CH 2 ) 6 MgBr,
Li 2 CuCl 4 , THF, 79%
1) Br 2 , P, , 84%
2) NaOH, H 2 O, 90%
CO 2 H
OH
1) CH 2 =CHOCOCH 3 ,
TBDMSO
Lipase PS, BHT, THF, 23%
( ) 18
CO 2 H ( ) 18
2) TBDMSCl, imidazole, DMF, 80%
A
(S) - Serine
Ref. [164,165]
O
NBoc
CHO
HC
C(CH 2 ) 9 CH 3 ,
n-BuLi, THF, 85%
O
NBoc
OH
( ) 9
1) Li, C 2 H 5 NH 2
OTBDMS
1) TsCl, Py, 90%
OTBDMS
2) TBDMSOTf, 2,6-lutidine,
CH 2 Cl 2 , 72% (2 steps)
TBDMSO
NH 2
( ) 9
TBDMSO
( ) 9
2) DMD, acetone, 68%
NHTs
3) DIBAL-H, toluene, 84%

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 4 335
Scheme 61 contd....
1) Na, naphthalene, DME
2) TBSOTf, 2,6-lutidine,
CH 2 Cl 2 , 81% (2 steps)
TBDMSO
OTBDMS
( ) 9
NH 2 OTBDMS
B
OH
A + B
1) EDC, HOBt, CH 2 Cl 2 , 55%
2) TBAF, THF, 71%
HO
HN
OH
OH
Scheme 62.
O
67
mone of the female hair crab, Erimacrus isenbeckii. Masuda
et al. [163] described a enantiodivergent synthesis, employing
12-bromododecan-1-ol for the synthesis of the acid moiety
A with a lipase-catalyzed resolution of hydroxy-acid in
the key step, and (S)-serine for the construction of the amine
moiety B, which were reacted to give the amide 67 (Scheme
62).
ACKNOWLEDGEMENTS
The Brazilian authors want to thank Capes, Fundação
Araucária and CNPq for financial support. JB thanks the
Dirección de Investigación of PUCV and Fondecyt for financial
support.
ABBREVIATIONS
Ac = acetyl
AIBN = azobisisobutyronitrile
BnBr = benzyl bromide
CAN = ceric ammonium nitrate
CSA = camphorsulfonic acid
DABCO = 1,4-diazabicyclo[2.2.2]octane
DEAD = diethyl azodicarboxylate
DET = diethyl tartrate
DHP = 3,4-dihydro-2H-pyran
(DHQ) 2 -PHAL = hydroquinine 1,4-phthalazinediyl
diether
DIBAL-H = diisobutylaluminium hydride
DIPEA = ethyldiisopropylamine
DMAP = 4-dimethylaminopyridine
DME = dimethoxyethane
2,2-DMP = 2,2-dimethoxypropane
DMF = N,N-dimethylformamide
DMPU = 1,3-dimethyltetrahydropyrimidin-
2(1H)-one
DMSO = dimethylsulfoxide
HMPA = hexamethylphosphoramide
HOBt = 1-hydroxybenzotriazole
HONO = gaseous nitrous acid
KIPBH = potassium tri-isopropoxyborohydride
LDA = lithium diisopropylamide
LiHMDS = lithium hexamethyldisilazide
m-CPBA = m-chloroperbenzoic acid
MeCBS = methyl oxazaborolidine
MsCl = methanesulfonyl chloride (mesyl
chloride)
NaHMDS = sodium hexamethyldisilazide
NIS = N-iodosuccinimide
NMO = N-methylmorpholine-N-oxide
PCC = pyridinium chlorochromate
PDC = pyridinium dichromate
PPh 3 = triphenyl phosphine
PPL = porcine pancreatic lipase
PPTS = pyridinium p-toluenesulfonate
PTSA = p-toluenesulfonic acid
Py = pyridine
SOCl 2 = thionyl chloride
TBAF = tetra-n-butylammonium fluoride
TBDMSCl = tert-butyldimethylsilyl chloride
TBDPSCl = tert-butyldiphenylchlorosilane
TCDI = 1,1'-thiocarbonyldiimidazole
TDA-1 = tris-(3,6-dioxaheptyl)amine
TFA = trifluoroacetic acid
THF = tetrahydrofurane
THP = tetrahydropyranyl
TMEDA = tetramethylethylenediamine
TMPDA = tetramethylpropylenediamine
TMSCl = trimethylsilyl chloride
TMSOTf = trimethylsilyl trifluoromethanesulfonate
TPAP = tetrapropylammonium perruthenate

336 Current Organic Chemistry, 2009, Vol. 13, No. 4 Zarbin et al.
TsCl = p-toluenesulfonyl chloride (tosyl
chloride)
TsNHNH 2 = p-toluenesulfonyl hydrazine
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