Pheromone synthesis. Part 245: Synthesis and chromatographic analysis of the four stereoisomers of 4,8-dimethyldecanal, the male aggregation pheromone of the red flour beetle, Tribolium castaneum

Article abstract of DOI:10.1016/j.tet.2010.10.086

All four stereoisomers of 4,8-dimethyldecanal (1) were synthesized from the enantiomers of 2-methyl-1-butanol and citronellal. Enantioselective GC analysis enabled separation of (4R,8R)-1 and (4R,8S)-1 from a mixture of (4S,8R)-1 and (4S,8S)-1, when octakis-(2,3-di-O-methoxymethyl-6-O-tert-butyldimethylsilyl)- γ-cyclodextrin was employed as a chiral stationary phase. Complete separation of the four stereoisomers of 1 on reversed-phase HPLC at -54 °C was achieved after oxidation of 1 to the corresponding carboxylic acid 12 followed by its derivatization with (1R,2R)-2-(2,3-anthracenedicarboximido) cyclohexanol, and the natural 1 was found to be a mixture of all the four stereoisomers.

Full text of DOI:10.1016/j.tet.2010.10.086

Tetrahedron 67 (2011) 201e209
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pheromone synthesis. Part 245: Synthesis and chromatographic analysis
of the four stereoisomers of 4,8-dimethyldecanal, the male aggregation
pheromone of the red flour beetle, Tribolium castaneumq
,
Kazuaki Akasaka a, Shigeyuki Tamogami b, Richard W. Beeman c, Kenji Mori d
*
a Shokei Gakuin University, 4-10-1 Yurigaoka, Natori-shi, Miyagi 981-1295, Japan
b Technical Research Institute, T. Hasegawa Co., Ltd, 29-7 Kariyado, Nakahara-ku, Kawasaki-shi, Kanagawa 211-0022, Japan
c US Department of Agriculture, Agricultural Research Service, Center for Grain and Animal Health Research, 1515 College Avenue, Manhattan, KS 66502, USA
d Photosensitive Materials Research Center, Toyo Gosei Co., Ltd, 4-2-1 Wakahagi, Inzai-shi, Chiba 270-1609, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 October 2010
Received in revised form 26 October 2010
Accepted 27 October 2010
Available online 2 November 2010
All four stereoisomers of 4,8-dimethyldecanal (1) were synthesized from the enantiomers of 2-methyl-1-
butanol and citronellal. Enantioselective GC analysis enabled separation of (4R,8R)-1 and (4R,8S)-1 from
a
mixture of (4S,8R)-1 and (4S,8S)-1, when octakis-(2,3-di-O-methoxymethyl-6-O-tert-butyldime-
thylsilyl)- -cyclodextrin was employed as a chiral stationary phase. Complete separation of the four
g
stereoisomers of 1 on reversed-phase HPLC at ꢀ54 ꢁC was achieved after oxidation of 1 to the corre-
sponding carboxylic acid 12 followed by its derivatization with (1R,2R)-2-(2,3-anthracenedicarboximido)
cyclohexanol, and the natural 1 was found to be a mixture of all the four stereoisomers.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
4,8-Dimethyldecanal
GC, Enantiomer separation
HPLC, Diastereomer separation
Pheromone
Tribolium castaneum
Tribolure
1. Introduction
and found it to be less active than the natural pheromone.4 Later, in
1987, the trivial name ‘tribolure’ was given to 1, when it was found
Does an organism produce a single enantiomer of a chiral semi-
ochemical or a mixture of stereoisomers? It is an interesting but
difficult question to answer, because powerful separation technol-
ogies are required to analyze the stereoisomeric composition of
a scarce natural product. We recently made the unexpected dis-
covery that the male aggregation pheromone of the red flour beetle
[Tribolium castaneum (Herbst). COLEOPTERA: Tenebrionidae] is
a mixture of all four stereoisomers of 4,8-dimethyldecanal (1, Fig.1).
The present paper describes our chemical works underlying that
discovery, that is, the synthesis and chromatographic analysis of the
four stereoisomers of 1 to establish the conditions for their
separation.
alsotobetheaggregationpheromoneofTriboliumfreemani(Hinton).5
Enantioselective synthesis of all four stereoisomers of 1 was first
achieved in 1983 by Mori et al.6 Since then many different syn-
theses of the enantiomers or stereoisomeric mixtures of 1 have
been reported.7e9 Based on bioassay of the four stereoisomers of 1
on T. castaneum, Suzuki and Mori concluded that the natural tri-
bolure was (4R,8R)-1, because it was as active as the natural pher-
omone.10 Subsequently, a 4:1 mixture of (4R,8R)-1 and (4R,8S)-1
was found to be ten times more active than (4R,8R)-1 alone,
although (4R,8S)-1 itself was inactive at lower doses.11 That result
In 1980, Suzuki identified 4,8-dimethyldecanal (1) as the male-
producedaggregationpheromoneoftheredflourbeetle, T. castaneum
(Herbst), and the confused flour beetle, Tribolium confusum (Jacquelin
duVal).2,3 Hethensynthesized a mixture ofall four stereoisomers of 1,
CHO
1
CHO
CHO
q
(4R,8R)-1
For Part 244, see Ref. 1.
(4R,8S)-1
* Corresponding author. Tel.: þ81 3 3816 6889; fax: þ81 3 3813 1516; e-mail
address: kjk-mori@arion.ocn.ne.jp (K. Mori).
Fig. 1. 4,8-Dimethyldecanal (1), the male aggregation pheromone of T. castaneum.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.086

202
K. Akasaka et al. / Tetrahedron 67 (2011) 201e209
puzzled us, and in 1987 Suzuki et al. speculated that the aggrega-
tion pheromone of the three species (T. castaneum, T. confusum and
T. freemani) might be a mixture of (4R,8R)-1 (main active compo-
nent) and some other stereoisomers.5 Unfortunately it was im-
possible to verify that hypothesis in 1980s, because there was no
good method available at that time to analyze precisely the ste-
reoisomeric composition of the natural tribolure.
The scientific situation concerning optically active compounds
has changed dramatically since then. Both synthetic and analytical
techniques to prepare and evaluate enantiopure compounds have
made remarkable progress. Thus, enantioselective synthesis of the
stereoisomers of 1 (by K.M.) was a relatively easy task, and their
separation was feasible by chromatographic means such as enan-
tioselective GC (by S.T.) or reversed-phase HPLC after derivatization
(by K.A.). On the basis of these chemical studies described below,
biological experiments (by Y. Lu et al.) on these important pest
insects of stored products were conducted subsequently.
ref.12,13
ref.12,13
OH
Br
CO2H
(R)-2
(R)-3
(R)-5
3
1
,
2
1
f.
e
r
OTs
a
(R)-4
I
(R)-6
(S)-5
Br
OH
2. Results and discussion
(S)-3
I
2.1. Synthesis of the four stereoisomers of 1 and their
derivatization to provide analytical samples 12, 13, and 14
(S)-6
Scheme 2. Synthesis of the enantiomers of 5 and 6. Reagents: (a) NaI, DMF [70% for
(R)-6; 80% for (S)-6].
Scheme 1 shows our retrosynthetic analysis of 1. 4,8-Dime-
thyldecanal (1) can be prepared by cleaving the double bond of
OHC
Mg
( )-7
R
CHO
Br
MgBr
HO
1
A
THF
(
)-5
S
OH
OH
+
B
(3S,5 RS ,7R)-8
(R)-9
X
+
OHC
H
C
D
(citronellal)
H
+
+ (R)-9
Scheme 1. Retrosynthetic analysis of 4,8-dimethyldecanal (1).
O
MgBr
(R)-7
Scheme 3. Synthesis of (3S,5RS,7R)-8 by Grignard reaction.
alkene A, which is obtained by deoxygenation of alcohol B. Cou-
pling of C with D (citronellal) gives B. In the 1980s only (S)-C and
(R)-D were commercially available, and therefore the present
strategy could be used only for the preparation of (4S,8S)-1 or
a mixture of stereoisomers.4 At present, both the enantiomers of C
as well as D are available. Accordingly, the strategy is applicable to
the synthesis of all four stereoisomers of 1.
Scheme 2 summarizes the synthesis of the enantiomers of 2-
methylbutyl bromide (5) and iodide (6). The starting acid (R)-2 was
supplied by T. Hasegawa Co.,12,13 while alcohol (S)-3 was com-
mercially available. These starting materials were converted to the
enantiomers of 5 and 6 by standard methods.12,13
The next step was the addition of a Grignard reagent prepared
from (S)-5 and magnesium in THF to (R)-citronellal (7). This
reaction turned out to be problematic. After chromatographic pu-
rification of the product, the more polar fractions were combined
and distilled, which was expected to yield (3S,5RS,7R)-8 (Scheme
3). However, the product obtained in 40e50% yield based on (S)-5
was an almost 1:1 mixture of the desired 8 and (R)-citronellol (9),
which was generated by reduction of (R)-7 with the Grignard
reagent as shown in Scheme 3.
unwanted reduction product.14e16 Accordingly, 2-methylbutyl
iodide (6) in diethyl ether was treated with 2 equiv of tert-butyl-
lithium in pentane at ꢀ78 ꢁC to effect transmetallation (Scheme 4).
Addition of the resulting organolithium reagent to (S)-citronellal
(7) took place without event to give the desired (3R,5RS,7S)-8 in
75% yield after chromatographic purification and distillation.
In order to remove the hydroxyl group of 8, it was first mesy-
lated to give mesylate (3R,5RS,7S)-9. Subsequent reduction of 9
with lithium aluminum hydride gave crude (6R,10R)-10 (84%
purity) in 70% yield after distillation. Epoxidation of (6R,10R)-10
with m-chloroperbenzoic acid (MCPBA) afforded epoxide
(3RS,6R,10R)-11 (Mþ¼226) as a stereoisomeric mixture at C-3
contaminated with two unidentified impurities (2.1% and 2.2%,
respectively, both with Mþ¼240). Finally, treatment of 11 with
periodic acid dihydrate in THF and diethyl ether gave (4R,8R)-4,8-
27
dimethyldecanal (1, 92% purity), [
a
]
ꢀ7.34 (c 4.11, CHCl3), in 50%
D
yield after chromatographic purification and distillation. Its IR, 1H
and 13C NMR, and MS data were identical with those reported
previously.2,6e8 The overall yield of (4R,8R)-1 was 25% based on (R)-
6 (five steps). Its enantiomeric purity was considered as 97% ee at C-
4 and >99% ee at C-8, respectively, reflecting the purity of (R)-2
To circumvent the problem, we turned our attention to the use
of 2-methylbutyllithium instead of the Grignard reagent. Alkyl-
lithium is known to give the desired product without yielding the
(>99% ee) and that of (S)-7 (97% ee). Similarly, (4R,8S)-1, [
a
]
25 þ10.1
D

K. Akasaka et al. / Tetrahedron 67 (2011) 201e209
203
OR6
OHC
O
OR6
O
a
( )-7
S
2
O
O
O
O
R O
I
Li
O
R6O
R3
R3O
R2
(
R
)-6
R2O
OR3
O
O
R3O
OR2
OR
c
OR6
O
OR3
O
R2O
O
(6R,10R)-10
R6O
(3R,5RS,7S)-8 R = H
(3R,5RS,7S)-9 R = Ms
R3O
b
O
R3
OR2
R2
O
O
O
O
OR6
O
R6O
d
e
β-Cyclodextrin
R2 = R3 = R6 = H
O
(3RS ,6R,10R)-11
R
R
2 = R3 = CH2OMe
MOMTBDMSBCD
ACTBDMSBCD
DMPBCD
6 = SiMe2t-Bu
CHO
CHO
CHO
R2 = R3 = Ac
(4R,8R)-1
(4R,8S)-1
(4S,8S)-1
R6 = SiMe2t-Bu
R2 = R6 = Me
R3 = n-C5H11
CHO
(4 ,8 )-1
S
R
OR6
O
Scheme 4. Synthesis of (4R,8R)-1. Reagents; (a) t-BuLi, pentane, Et2O; then (S)-7 (75%);
(b) MsCl, C5H5N, CH2Cl2 (quant.); (c) LiAlH4, THF (70%); (d) MCPBA, CH2Cl2 (96%); (e)
HIO4$2H2O, THF, Et2O (50%).
OR6
O
O
R2O O
O
R3
R3O
25
O
(c 4.11, CHCl3), (4S,8R)-1, [
a]
ꢀ9.06 (c 4.12, CHCl3), and (4S,8S)-1,
OR2
R2O
R3O
D
R6O
O
OR6
25
[
a]
þ7.20 (c 4.17, CHCl3) were synthesized. All the stereoisomers
D
of 1 could thus be secured in >1 g quantities sufficient for bioassay.
In order to determine the best conditions for chromatographic
separation of the four stereoisomers of 1 or its derivatives, several
derivatives of 1 were prepared by sacrificing a small portion of 1. As
shown in Scheme 5, Jones oxidation of 1 gave 4,8-dimethyldecanoic
acid (12). Reduction of 1 with lithium aluminum hydride afforded
4,8-dimethyl-1-decanol (13), and acetylation of 13 yielded 4,8-
dimethyldecyl acetate (14). These were used in the analytical
studies as described below.
OR3
O
O
R2O
OR2
O
R3O
O
OR3
R6O
OR6
R2O
O
O
OR2
O
R3O
OR3
O
R2
O
O
R6O
O
OR6
γ-Cyclodextrin
R2 = R3 = R6 = H
a
CHO
CO2H
R2 = R3 = CH2OMe
1
12
MOMTBDMSGCD
BUTBDMSGCD
R6 = SiMe2t-Bu
b
R2 = R3 = n-Bu
R
6 = SiMe2t-Bu
c
OAc
R
2 = R3 = CO(CH2)2Me
OH
TBDMSGCD
Butyryl
R6 = SiMe2t-Bu
14
13
Scheme 5. Conversion of 1 to 12, 13, and 14. Reagents: (a) Jones CrO3, Me2CO (75%e
quant.); (b) LiAlH4, Et2O (85e90%); (c) Ac2O, C5H5N (88e93%).
R2 = R6 = Me
R3 = COCF3
DMTFAGCD
2.2. Partial separation of the four stereoisomers of 1 and 13
by enantioselective GC
Chiramix® = DMPBCD + DMTFAGCD
GC17 and LC18 are known to be powerful analytical tools in
pheromone science. Their application to enantiomer separation of
pheromones was reviewed recently.19
Fig. 2. Structures of cyclodextrin-based chiral stationary phases used in the present
work. Partial separation of 1 was observed with MOMTBDMSGCD and DMTFAGCD.
Separation of the four stereoisomers of 1, 13, and 14 was ex-
amined on eight different chiral stationary phases including
ChiramixÒ20 based on cyclodextrins as shown in Fig. 2. All of them
failed to separate the stereoisomers of the acetate 14.
Fortunately, two g-cyclodextrin-based stationary phases were
effective in partially separating the stereoisomers of 1 and 13. A
mixture of (4R,8R)- and (4R,8S)-4,8-dimethyl-1-decanol (13) could

204
K. Akasaka et al. / Tetrahedron 67 (2011) 201e209
be separated from a mixture of (4S,8R)- and (4S,8S)-13, employing
CO2H
O
octakis-(2,3-di-O-methoxymethyl-6-O-tert-butyldimethylsilyl)-
g
g
-
13
cyclodextrin21 or octakis-(2,6-di-O-methyl-3-O-trifluoroacetyl)-
-
N
cyclodextrin.22
EDC, DMAP
toluene, MeCN
O
A mixture of the stereoisomers of tribolure (1) showed three
peaks when it was analyzed over octakis-(2,3-di-O-methoxymethyl-
(1R,2R)-15
O
6-O-tert-butyldimethylsilyl)-
identified as (4R,8R)-1, (4R,8S)-1, and a mixture of (4S,8R)-1 and
(4S,8S)-1. When octakis-(2,6-di-O-methyl-3-O-trifluoroacetyl)-
cyclodextrin was used as the stationary phase, a mixture of (4R,8R)-
and (4R,8S)-1 could be separated from a mixture of (4S,8R)- and
(4S,8S)-1. Gas chromatograms showing the partial separation of the
four stereoisomers of 1 are illustrated in Fig. 3.
g-cyclodextrin. The three peaks were
CO
O
g-
N
O
(1R,2R)-16
OH
O
12
N
EDC, DMAP
toluene, MeCN
O
(1R,2R)-17
4'
CO
8'
O
O
1
2
N
O
(1 ,2 )-18
R
R
OAc
(CH2)12
Me(CH2)4
(CH2)9Me
New World screwworm fly pheromone
OH
H
H
O
(CH2)9Me
HO
HO
OH
O
HN
O
(CH2)9Me
O
H
H
OH
plakoside A
Fig. 4. Structures of chiral and fluorescent derivatizing reagents, (1R,2R)-2-(anthra-
cene-2,3-dicarboximido)cyclohexanecarboxylic acid (15) and (1R,2R)-2-(anthracene-
2,3-dicarboximido)cyclohexanol (17). Their applications in determination of stereo-
chemistry are also illustrated.
Fig. 3. GC separation of the stereoisomers of 4,8-dimethyldecanal (1) on (a) 10%
DMTFAGCD (two peaks) and (b) 50% MOMTBDMSGCD (three peaks). For conditions,
see Experimental.
reagent 15 was employed to determine the enantiomeric purity of
the New World screwworm fly pheromone,27 while 17 was used in
the determination of the absolute configuration of a marine natural
product, plakoside A.28
It was concluded that complete GC separation of the four ste-
reoisomers of 1 could not be realized by the stationary phases so far
examined. Nevertheless, GC proved to be a simple method for the
preliminary analysis of the natural pheromone without any
derivatization.
Derivatization of alcohol 13 with the fluorescent reagent
(1R,2R)-15 in the presence of 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide hydrochloride (EDC), and 4-dimethylaminopyridine
(DMAP) in toluene and acetonitrile afforded 16, whose four ste-
reoisomers were eluted as three broad peaks upon HPLC analysis,
indicating that complete separation could not be achieved.
Fortunately, derivatization of acid 12 with the reagent (1R,2R)-
17 gave satisfactory results. The four stereoisomers of the resulting
derivative (1R,2R)-18 could not be separated by the C-30 column at
40 ꢁC, but they were completely separable by the ODS second
column kept at ꢀ54 ꢁC as shown in Fig. 5. Assignment of the each
peak was made possible by comparing its retention time (tR) with
that of the authentic stereoisomer of (1R,2R)-18. The LCeLC system
using these two columns was very effective to remove interfering
substances and also to reduce the time for analysis of the natural
samples. Accordingly, the OhruieAkasaka method of analysis was
2.3. Complete separation of the four stereoisomers of 12 by
OhruieAkasaka’s derivatization-reversed phase HPLC method
Ohrui and Akasaka recentlydeveloped a powerful method for the
determination of enantiomeric purityat a remote stereogenic center
far separated from functional groups.23e25 They designed optically
active and fluorescent derivatizing reagents including (1R,2R)- and
(1S,2S)-2-(anthracene-2,3-dicarboximido)cyclohexanecarboxylic
acid (15, Fig. 4; commerciallyavailable fromTokyo Kasei: TCI-A1657)
and (1R,2R)- and (1S,2S)-2-(anthracene-2,3-dicarboximido)cyclo-
hexanol (17).25,26 Due to the fluorescent nature of the reagents,
detection of the derivatives is possible at 10ꢀ15 mol levels. The

K. Akasaka et al. / Tetrahedron 67 (2011) 201e209
205
4. Experimental
4.1. General
Boiling points are uncorrected values. Refractive indices (nD)
were measured on an Atago DMT-1 refractometer. Optical rotations
were measured on a Jasco P-1020 polarimeter. IR spectra were
measured on a Jasco FT/IR-410 spectrometer. 1H NMR spectra
(400 MHz, TMS at
spectra (100 MHz, CDCl3 at
recorded on a Jeol JNM-AL 400 spectrometer. GCeMS were mea-
sured on Agilent Technologies 5975 inert XL. HRMS were recorded
on Jeol JMS-SX 102 A. Column chromatography was carried out on
Merck Kieselgel 60 Art 1.07734.
d
¼0.00 as internal standard) and 13C NMR
d
¼77.0 as internal standard) were
4.2. 2-Methylbutyl iodide (6)
4.2.1. (R)-Isomer. A solution of (R)-2-methylbutyl tosylate (4, 41.0 g,
169 mmol) in DMF (200 mL) was stirred and heated with NaI (60 g,
400 mmol) at 60 ꢁC for 1 h. The mixture was diluted with water, and
the heavy iodide layer was separated. The aqueous layer was
extracted with pentane. The iodide and the extract were combined,
washed with water and brine, dried (MgSO4), and concentrated
through a Vigreux column at atmospheric pressure. The residue was
distilled to give 24.8 g (70%) of (R)-6. Bp 144e146 ꢁC; nD22¼1.4942;
26
[a
]
ꢀ5.32 (c 4.87, pentane); nmax (film): 2960 (s), 1456 (m), 1379
D
(m), 1194 (s); dH (CDCl3): 0.89 (3H, t, J 7.2, CH2CH3), 0.98 (3H, d,
J 7.2, CHCH3), 1.20e1.32 (1H, m), 1.35e1.45 (2H, m), 3.15e3.25 (2H,
m); GCeMS [column: HP-5MS, 5% phenylmethylsiloxane,
30 mꢂ0.25 mm i.d.; press: 48.7 kPa; temp: 40e230 ꢁC (þ5 ꢁC/min)]:
tR 3.47 (2.3%, 2-methylbutyl chloride), 7.35 min [97.3%, (R)-6]. MS of
(R)-6 (70 eV, EI): m/z 198 (21) [Mþ, C5H11I],169 (4),127 (5), 71 (100),
55 (17), 43 (71), 39 (32). HRMS calcd for C5H11I: 197.9905, found:
197.9907.
4.2.2. (S)-Isomer. In the same manner, (S)-4 (57.3 g, 237 mmol)
27
yielded 37.8 g (89%) of (S)-6, Bp 145e146 ꢁC; nD21¼1.4962; [
a
]
D
þ5.30 (c 4.88, pentane); GC [under the same conditions for (R)-6]:
tR 7.36 min [98.3%, (S)-6]. Its IR, 1H NMR, and mass spectra were
identical to those of (R)-6. HRMS calcd for C5H11I: 197.9905, found:
197.9910.
Fig. 5. HPLC separation of the stereoisomers of (1R,2R)-18. (a) Elution from the
C30 column. Eluent: MeOH; Flow rate: 0.3 mL/min; Column temp: 40 ꢁC. (b) Separa-
tion on the ODS column. Eluent: MeOH/MeCN/THF/hexane¼220:200:80:4; Flow rate:
0.4 mL/min; Column temp: ꢀ54 ꢁC. (c) Separation by LCeLC system with the C30 and
the ODS columns.
4.3. 3,7,11-Trimethyl-10-dodecen-5-ol (8)
4.3.1. (3R,5RS,7S)-Isomer. A solution of t-BuLi in pentane (1.6 M,
35 mL, 56 mmol) was added dropwise to a stirred and cooled so-
lution of (R)-6 (5.54 g, 28 mmol) in dry Et2O (50 mL) at ꢀ78 ꢁC
under argon. The mixture was stirred for 10 min at ꢀ78 ꢁC, and then
for 10 min at room temperature. The solution was cooled again at
ꢀ78 ꢁC, and a solution of (S)-7 (3.85 g, 25 mmol) in dry Et2O (10 mL)
was added dropwise to the stirred mixture at ꢀ78 ꢁC. The dry ice-
acetone bath was removed, and the mixture was stirred for 1.5 h. It
was then quenched with ice, dil HCl and NH4Cl solution. The
mixture was extracted with Et2O. The Et2O solution was washed
with NaHCO3 solution and brine, dried (MgSO4), and concentrated
in vacuo. The residue (5.50 g) was chromatographed over SiO2
(50 g). Elution with hexane/EtOAc (9:1) gave 5.29 g of crude 8,
used to determine the stereoisomeric composition of the naturally
occurring 1 of T. castaneum.
3. Conclusion
The four stereoisomers of 4,8-dimethyldecanal (tribolure, 1)
were synthesized. They could be separated partially by enantiose-
lective GC, and completely by reversed-phase HPLC after de-
rivatization to (1R,2R)-18 employing OhruieAkasaka’s reagent
(1R,2R)-17. Established separation methods were used to determine
the stereoisomeric composition of naturally occurring tribolure.
The most important result of the analysis was the fact that the
natural tribolure of T. castaneum was a mixture of (4R,8R)-, (4R,8S)-,
(4S,8R)-, and (4S,8S)-1 in a ratio of about 4:4:1:1 (Y. Lu et al.
manuscript in preparation). In the course of the biosynthesis of
tribolure by T. castaneum, the configuration at C-8 is not at all
controlled, while that at C-4 is controlled partially to give a 4:1 ratio
of (4R)- and (4S)-isomers. Details of the above analytical results as
well as the stereochemistryepheromone activity relationships will
be the subject of another paper.
which was distilled to give 4.22 g (75%) of pure (3R,5RS,7S)-8. Bp
24
110e116 ꢁC/3 Torr; n2D1¼1.4585; [
a
]
ꢀ6.89 (c 4.11, hexane); nmax
D
(film): 3327 (m, OeH), 2962 (s), 2924 (s), 1460 (m), 1377 (m), 1059
(m); dH (CDCl3): 0.86e0.93 (9H, m, CH3), 1.08e1.22 (3H, m),
1.22e1.32 (2H, m), 1.32e1.50 (3H, m), 1.50e1.70 (3H, m), 1.61 (3H, s,
C]CCH3), 1.68 (3H, s, C]CCH3), 1.90e2.10 (2H, m), 3.79 (1H, m,
CHOH), 5.10 (1H, t-like C]CH); GCeMS [column: HP-5S, 5% phe-
nylmethylsiloxane, 30 mꢂ0.25 mm i.d.; press: 60.7 kPa; temp:
70e230 ꢁC (þ10 ꢁC/min)]: tR 13.09 [51.0%, (3R,5R or S,7S)-8],

206
K. Akasaka et al. / Tetrahedron 67 (2011) 201e209
13.23 min [45.8%, (3R,5S or R,7S)-8]. These two isomers showed the
same MS (70 eV, EI): m/z 226 (0.7) [Mþ, C15H30O], 208 (1), 197 (4),
152 (7), 141 (40), 123 (23), 109 (61), 95 (48), 82 (100), 81 (57), 69
(61), 55 (34), 41 (44). HRMS calcd for C15H30O: 226.2297, found:
226.2301.
room temperature for 1 h. It was then treated with ice and dil
HCl. The mixture was extracted with hexane. The hexane solution
was washed with water, NaHCO3 solution and brine, dried
(MgSO4), and concentrated in vacuo. The residue was distilled to
give 2.53 g (70%) of (6R,10R)-10. Bp 93e96 ꢁC/3 Torr; nD21¼1.4462;
27
[
a
]
ꢀ5.20 (c 4.16, hexane); nmax (film): 2962 (s), 2925 (s), 2873
D
4.3.2. (3S,5RS,7S)-Isomer. In the same manner, 5.54 g (28 mmol) of
(S)-6 and 3.80 g (24.7 mmol) of (S)-7 afforded 4.73 g (84%)
(s), 2729 (w), 1462 (m), 1377 (m), 825 (w); dH (CDCl3): 0.80e0.90
(9H, m, CH3), 1.00e1.20 (4H, m), 1.20e1.50 (7H, m), 1.57 (1H), 1.61
(3H, s, C]CCH3), 1.68 (3H, s, C]CCH3), 1.86e2.05 (2H, m), 5.10
(1H, t-like, C]CH); GCeMS [under the same conditions as for
(3R,5RS,7S)-8]: tR 10.84 (8.7%, unidentified, Mþ 208), 10.87 (7.3%,
unidentified, Mþ 208), 11.17 min [84.0%, (6R,10R)-10]. MS of
(6R,10R)-10 (70 eV, EI): m/z 210 (33) [Mþ, C15H30], 140 (7), 126
(17), 125 (15), 111 (28), 97 (19), 83 (32), 70 (71), 69 (100), 57 (48),
56 (40), 55 (37), 41(47). HRMS calcd for C15H30: 210.2348, found:
210.2344.
25
of (3S,5RS,7S)-8. Bp 129e132 ꢁC/6 Torr; nD24¼1.4580; [
a]
þ12.1 (c
D
4.39, hexane). Its IR, 1H NMR, and mass spectra were virtually
identical to those of (3R,5RS,7S)-8. GC [under the same conditions
as for (3R,5RS,7S)-8]: tR 13.12 [44.3%, (3S,5R or S,7S)-8], 13.22 min
[52,4%, (3S,5S or R,7S)-8]. HRMS calcd for C15H30O: 226.2297, found:
226.2299.
4.3.3. (3R,5RS,7R)-Isomer. In the same manner, 5.54 g (28 mmol) of
(R)-6 and 3.85 g (25 mmol) of (R)-7 yielded 4.32 g (77%) of
25
(3R,5RS,7R)-8. Bp 123e126 ꢁC/5 Torr; nD22¼1.4582; [
a]
ꢀ11.4 (c
4.5.2. (6R,10S)-Isomer. In the same manner, 6.60 g (ca. 21 mmol) of
(3S,5RS,7S)-9 gave 3.44 g (72%) of (6R,10S)-10. Bp 102e106 ꢁC/5 Torr;
D
4.10, hexane). Its IR, 1H NMR, and mass spectra were identical with
those of (3S,5RS,7S)-8. GC [under the same conditions as for
(3R,5RS,7S)-8]: tR 13.12 [46.4%, (3R,5R or S,7R)-8], 13.22 min [50.7%,
(3R,5S or R,7R)-8]. HRMS calcd for C15H30O: 226.2297, found:
226.2308.
25
1
n2D4¼1.4462; [
a]
D
þ11.9 (c 4.56, hexane). Its IR, H NMR, and mass
spectra were virtually identical to those of (6R,10R)-10. GC [under the
same conditions as for (6R,10R)-10]: tR 10.85 (6.7%), 10.88 (7.4%),
11.17 min [85.9%, (6R,10S)-10]. HRMS calcd for C15H30: 210.2348,
found: 210.2345.
4.3.4. (3S,5RS,7R)-Isomer. In the same manner, 5.54 g (28 mmol) of
(S)-6 and 3.80 g (24.7 mmol) of (R)-7 afforded 4.84 g (86%) of
4.5.3. (6S,10R)-Isomer. In the same manner, 4.25 g (ca. 19 mmol) of
(3S,5RS,7R)-8. Bp 121e123 ꢁC/5 Torr; nD22¼1.4582; [
a]
D
26 þ6.60 (c 4.31,
(3R,5RS,7R)-9 furnished 2.98 g (75%) of (6S,10R)-10. Bp 100e103 ꢁC/4
25
hexane). Its IR,1H NMR, and mass spectrawere identical with those of
(3R,5RS,7S)-8. GC [under the same conditions as for (3R,5RS,7S)-8]: tR
13.09 [51.1%, (3R,5R or S,7S)-8], 13.23 min [48.9%, (3R,5S or R,7S)-8].
HRMS calcd for C15H30O: 226.2297, found: 226.2293.
Torr; n2D1¼1.4468; [
a]
ꢀ12.0 (c 4.39, hexane). Its IR, 1H NMR, and
D
mass spectra were identical with those of (6R,10S)-10. GC [under the
same conditions as for (6R,10R)-10]: tR 10.85 (7.8%), 10.88 (8.2%),
11.17 min [84.0%, (6S,10R)-10]. HRMS calcd for C15H30: 210.2348,
found: 210.2345.
4.4. Methanesulfonate (9) of 3,7,11-trimethyl-10-dodecen-5-ol
4.5.4. (6S,10S)-Isomer. In the same manner, 4.75 g (ca. 21 mmol) of
(3S,5RS,7R)-9 afforded 3.89 g (82%) of (6S,10S)-10. Bp 105e108 ꢁC/6
4.4.1. (3R,5RS,7S)-Isomer. A solution of MsCl (2.30 g, 20 mmol) in
dry CH2Cl2 (10 mL) was added dropwise to a stirred and ice-cooled
solution of (3R,5RS,7S)-8 (3.87 g, 17 mmol) in dry pyridine (15 mL).
The mixture was stirred for 5 h at 0e5 ꢁC. It was then quenched by
pouring into ice-water. The mixture was extracted with Et2O. The
extract was washed with dil HCl, NaHCO3 solution and brine, dried
(MgSO4), and concentrated in vacuo to give 4.87 g (quant.) of
(3R,5RS,7S)-9, nmax (film): 2962 (s), 2927 (s), 1462 (m), 1336 (s), 899
(s); dH(CDCl3): 0.87e0.97 (9H, m, CH3), 1.10e1.25 (2H, m), 1.25e1.55
(4H, m), 1.55e1.65 (4H, m), 1.61 (3H, s, C]CCH3), 1.68 (3H, s, C]
CCH3), 1.71e1.81 (1H, m), 1.90e2.10 (2H, m), 2.99 (3H, s, CH3SO2),
4.82e4.95 (1H, m), 5.05e5.15 (1H, m). This was employed in the
next step without further characterization.
Torr; n2D4¼1.4456; [
a]
28 þ5.29 (c 4.38, hexane). Its IR, 1H NMR, and
D
mass spectra were identical with those of (6R,10R)-10. GC [under
the same conditions as for (6R,10R)-10]: tR 10.84 (6.2%), 10.87
(5.4%), 11.17 min [88.4%, (6S,10S)-10]. HRMS calcd for C15H30
:
210.2348, found: 210.2352.
4.6. 2,3-Epoxy-2,6,10-trimethyldodecane (11)
4.6.1. (3RS,6R,10R)-Isomer. MCPBA (65% purity, 4.0 g, 15 mmol) was
added portionwise to a stirred and ice-cooled solution of (6R,10R)-
10 (2.50 g, 12 mmol) in dry CH2Cl2 (50 mL) at 5e10 ꢁC. The mixture
was stirred for 1 h at 0e5 ꢁC, and then diluted with Et2O. The
solution was successively washed with Na2CO3 solution containing
a small amount of Na2S2O3 and brine, dried (MgSO4), and concen-
trated in vacuo to give 2.58 g (96%) of (3RS,6R,10R)-11, nmax (film):
2960 (s), 2925 (s), 2873 (s), 1462 (m), 1377 (m), 1327 (w), 1250 (w),
1122 (m), 897 (w), 872 (w); dH (CDCl3): 0.80e0.90 (9H, m, CH3),
0.86e1.10 (2H, m), 1.10e1.20 (2H, m), 1.23e1.40 (5H, m), 1.28 (3H, s,
CH3), 1.31 (3H, s, CH3), 1.40e1.50 (2H, m), 1.50e1.60 (2H, m),
1.60e1.68 (1H, br. s), 2.70 (1H, t-like, J 6.0, epoxide H); GCeMS
[under the same conditions as for (3R,5RS,7S)-8]: tR 13.13 [46.1%,
(3R or S,6R,10R)-11], 13.23 [49.4%, (3S or R, 6R,10R)-11], 13.78 (2.1%,
unidentified, Mþ 240), 13.89 min (2.2%, unidentified, Mþ 240). MS
of the two isomers of (3R,10R)-11 was identical with each other
(70 eV, EI): m/z 226 (1) [Mþ, C15H30O], 197 (6), 152 (9), 141 (44),
123 (24), 109 (64), 95 (50), 82 (100), 81 (58), 69 (58), 55 (33), 41
(42). This was employed in the next step without further
characterization.
4.4.2. (3S,5RS,7S)-Isomer. In the same manner, 4.80 g (21 mmol) of
(3S,5RS,7S)-8 afforded 6.65 g (quant.) of (3S,5RS,7S)-9. Its IR and 1H
NMR spectra were virtually identical to those of (3R,5RS,7S)-9.
4.4.3. (3R,5RS,7R)-Isomer. In the same manner, 4.30 g (19 mmol) of
(3R,5RS,7R)-8 afforded 5.80 g (quant.) of (3R,5RS,7R)-9. Its IR and 1H
NMR spectra were identical with those of (3S,5RS,7S)-9.
4.4.4. (3S,5RS,7R)-Isomer. In the same manner, 4.80 g (21 mmol) of
(3S,5RS,7R)-8 yielded 6.38 g (quant.) of (3S,5RS,7R)-9. Its IR and 1H
NMR spectra were identical with those of (3R,5RS,7S)-9.
4.5. 2,6,10-Trimethyl-2-dodecene (10)
4.5.1. (6R,10R)-Isomer. A solution of the mesylate (3R,5RS,7S)-9
(4.85 g, ca. 17 mmol) in dry THF (10 mL) was added dropwise to
a stirred and ice-cooled suspension of LiAlH4 (0.80 g, 21 mmol) in
dry THF (40 mL). The mixture was stirred at 60 ꢁC for 2 h, and at
4.6.2. (3RS,6R,10S)-Isomer. In the same manner, 2.57 g (11.9 mmol)
of (6R,10S)-10 afforded 2.70 g (quant.) of (6RS,6R,10S)-11. Its IR, 1H

K. Akasaka et al. / Tetrahedron 67 (2011) 201e209
207
NMR, and mass spectra were virtually identical to those of
(3RS,6R,10R)-11.
solution (10 mLꢂ3). The alkaline solution was acidified with dil HCl,
and extracted with Et2O. The extract was washed with brine, dried
(MgSO4), and concentrated in vacuo to give 138 mg (75%) of
(4R,8R)-12, nmax (film): 3500e3000 (m, br), 2927 (s), 2675 (m, br),
1711 (s, C]O), 1462 (m), 1414 (m), 1379 (m), 1284 (m), 941 (m, br);
dH (CDCl3): 0.80e0.92 (9H, m, CH3), 1.00e1.16 (3H, m), 1.16e1.40
(6H, m), 1.40e1.50 (2H, m), 1.62e1.74 (1H, m), 2.28e2.42 (2H, m);
GCeMS [under the same conditions as for (3R,5RS,7S)-8]: tR 12.37
[96.0%, (4R,8R)-12], 12.75 min (2.1%, unidentified, Mþ226). MS of
(4R,8R)-12 (70 eV, EI): m/z 200 (1) [Mþ, C12H24O2], 171 (6), 153 (11),
143 (48),141 (26),111 (15),101 (19), 99 (16), 97 (15), 85 (57), 83 (32),
73 (100), 72 (60), 70 (42), 57 (63), 55 (55), 43 (36), 41 (42).
4.6.3. (3RS,6S,10R)-Isomer. In the same manner, 3.31 g (15.8 mmol)
of (6S,10R)-10 furnished 3.25 g (91%) of (3RS,6S,10R)-11. Its IR, 1H
NMR, and mass spectra were identical with those of (3RS,6R,10S)-11.
4.6.4. (3RS,6S,10S)-Isomer. In the same manner, 3.80 g (18.1 mmol)
of (6S,10S)-10 gave 4.14 g (quant.) of (3RS,6S,10S)-11. Its spectral
data were identical with other stereoisomers.
4.7. 4,8-Dimethyldecanal (1)
4.7.1. (4R,8R)-Isomer. A solution of (3RS,6R,10R)-11 (2.50 g, 11.1
mmol) in Et2O (10 mL) was added dropwise to a stirred and ice-
cooled solution of HIO4$2H2O (3.42 g, 15 mmol) in THF (40 mL) at
0e5 ꢁC. The mixture was stirred for 20 min at 0e5 ꢁC, diluted with
water, and extracted with Et2O. The Et2O solution was successively
washed with water, NaHCO3 solution containing a small amount of
Na2S2O3 and brine, dried (MgSO4), and concentrated in vacuo. The
residue was chromatographed over SiO2 (20 g). Elution with hexane
and hexane/EtOAc (10:1) gave 1.43 g of crude (4R,8R)-1, which was
distilled to give 1.12 g (50%), of (4R,8R)-1. Bp 93e96 ꢁC/4 Torr;
4.8.2. (4R,8S)-Isomer. In the same manner, (4R,8S)-1 (156 mg,
0.8 mmol) gave 170 mg (quant.) of (4R,8S)-12. Its IR, 1H NMR, and
mass spectra were virtually identical to those of (4R,8R)-12. GC
[under the same conditions as for (4R,8R)-12]: tR 12.32 [90.4%,
(4R,8S)-12].
4.8.3. (4S,8R)-Isomer. In the same manner (4S,8R)-1 (227 mg,
1.2 mmol) afforded 218 mg (88%) of (4S,8R)-12. Its IR, 1H NMR, and
mass spectra were identical with those of (4R,8S)-12. GC [under the
same conditions as for (4R,8R)-12]: tR 12.33 [92.5%, (4S,8R)-12].
n2D4¼1.4370; [
a]
D
27 ꢀ7.34 (c 4.11, CHCl3); nmax (film): 2958 (s), 2927 (s),
2873 (s), 2713 (w, O¼C-H), 1728 (s, C]O), 1462 (m), 1379 (m), 1136
(w), 1014 (w); dH(CDCl3): 0.80e0.93 (9H, m, CH3), 1.00e1.18 (3H, m),
1.18e1.38 (6H, m), 1.38e1.50 (2H, m), 1.62e1.72 (1H, m), 2.35e2.50
(2H, m), 9.77 (1H, t-like, CHO); dC(CDCl3): 11.4, 19.3, 19.4, 24.4, 28.9,
29.5, 32.4, 34.4, 36.9, 37.1, 41.7, 202.8 (C]O); GCeMS [under the
same conditions as for (3R,6RS,7S)-8]. tR 10.17 [92.2%, (4R,8R)-1],
12.91 min (7.8%, unidentified, Mþ 226). MS of (4R,8R)-1 (70 eV, EI):
m/z 183 (<1)[Mþꢀ1], 140 (22), 137 (13), 125 (11),111 (36), 95 (53), 85
(60), 81 (51), 71 (62), 70 (93), 69 (73), 57 (100), 56 (62), 55 (71), 43
(56), 41 (69). HRMS calcd for C12H24O: 184.1827, found: 184.1824.
4.8.4. (4S,8S)-Isomer. In the same manner, (4S,8S)-1 (263 mg,
1.4 mmol) furnished 275 mg (96%) of (4S,8S)-12. Its IR, 1H NMR, and
mass spectra were identical with those of (4R,8R)-12. GC [under the
same conditions as for (4R,8R)-12]: tR 12.34 [97.1%, (4S,8S)-12].
4.9. 4,8-Dimethyl-1-decanol (13)
4.9.1. (4R,8R)-Isomer. A solution of (4R,8R)-1 (395 mg, 2.1 mmol) in
dry Et2O (5 mL) was added to a stirred and ice-cooled suspension of
LiAlH4 (76 mg, 2 mmol) in dry Et2O (5 mL). After stirring for 30 min,
the mixture was worked up by acidification and Et2O extraction to
give 339 mg (85%) of (4R,8R)-13, nmax (film): 3332 (m, OeH), 2927
(s), 1462 (m), 1377 (m), 1059 (m), 899 (w); dH (CDCl3): 0.80e0.93
(9H, m, CH3), 1.02e1.20 (4H, m), 1.20e1.45 (8H, m), 1.45e1.65 (3H,
m), 3.63 (2H, t, J 6.8); GCeMS [under the same conditions as for
(3R,5RS,7S)-8]: tR 11.02 [85.5%, (4R,8R)-13], 13.19 min (8.43%, un-
identified, Mþ 226). MS of (4R,8R)-13 (70 eV, EI): m/z 185 (<1)
[Mþꢀ1],140 (26),125 (17),111 (26), 97 (29), 84 (42), 83 (41), 70 (74),
69 (100), 57 (47), 56 (38), 55 (57), 43 (30), 41 (51).
4.7.2. (4R,8S)-Isomer. In the same manner, 2.65 g (11.7 mmol) of
(3RS,6R,10S)-11 gave 1.49 g (68%) of (4R,8S)-1. Bp 100e106 ꢁC/6 Torr;
n2D1¼1.4380; [
a
]
25 þ10.1 (c 4.22, CHCl3). Its IR, 1H and 13C NMR, and
D
mass spectrawere virtually identical tothose of (4R,8R)-1. GC [under
the same conditions as for (4R,8R)-1]: tR 10.16 [95.3%, (4R,8S)-1],
12.91 min (4.7%, unidentified, Mþ 226). HRMS calcd for C12H24O:
184.1827, found: 184.1817.
4.7.3. (4S,8R)-Isomer. In the same manner, 3.20 g (14.1 mmol) of
(3RS,6S,10R)-11 afforded1.57 g(63%)of(4S,8R)-1. Bp90e92ꢁC/3 Torr;
4.9.2. (4R,8S)-Isomer. In the same manner, (4R,8S)-1 (604 mg, 3.3
mmol) furnished 546 mg (90%) of (4R,8S)-13. Its IR, 1H NMR, and
mass spectra were virtually identical to those of (4R,8R)-13. GC
[under the same conditions as for (4R,8R)-13]: tR 11.01 [84.9%,
(4R,8S)-13]. 13.19 min (5.71%, unidentified, Mþ 226).
n2D5¼1.4376; [
a]
D
25 ꢀ9.06 (c 4.12, CHCl3). Its IR, 1H and 13C NMR, and
mass spectra were identical with those of (4R,8S)-1. GC [under the
same conditions as for (4R,8R)-1]: tR 10.17 [91.7%, (4S,8R)-1],
12.91 min (8.3%, unidentified, Mþ 226). HRMS calcd for C12H24O:
184.1827, found: 184.1848.
4.9.3. (4S,8R)-Isomer. In the same manner, (4S,8R)-1 (611 mg, 3.3
mmol) gave 556 mg (90%) of (4S,8R)-13. Its IR, 1H NMR, and mass
spectra were identical with those of (4R,5S)-13. GC [under the
same conditions as for (4R,8R)-13]: tR 11.01 [83.2%, (4S,8R)-13],
13.19 min (8.59%, unidentified, Mþ 226).
4.7.4. (4S,8S)-Isomer. In the same manner, 4.10 g (18.1 mmol) of
(3RS,6S,10S)-11 furnished 1.80 g (54%) of (4S,8S)-1. Bp 106e109oC/6
Torr; n2D4¼1.4368; [
a]
25 þ7.20 (c 4.17, CHCl3). Its IR, 1H and 13C NMR,
D
and mass spectra were identical with those of (4R,8R)-1. GC [under
the same conditions as for (4R,8R)-1]: tR 10.17 [94.4%, (4S,8S)-1],
12.91 min (5.6%, unidentified, Mþ 226). HRMS calcd for C12H24O:
184.1827, found: 184.1824.
4.9.4. (4S,8S)-Isomer. In the same manner, (4S,8S)-1 (618 mg, 3.4
mmol) afforded 541 mg (87%) of (4S,8S)-13. Its IR, 1H NMR, and
mass spectra were identical with those of (4R,8R)-13. GC [under the
same conditions as for (4R,8R)-13]: tR 11.02 [88.45%, (4S,8S)-13],
13.19 min (6.70%, unidentified, Mþ 226).
4.8. 4,8-Dimethyldecanoic acid (12)
4.8.1. (4R,8R)-Isomer. Jones chromic acid (0.5 mL, 2.4 mmol) was
added to a stirred and ice-cooled solution of (4R,8R)-1 (170 mg,
0.9 mmol) in acetone (3 mL). After 30 min, MeOH was added to
destroy excess CrO3. The mixture was diluted with water, and
extracted with Et2O. The Et2O solution was extracted with 5% NaOH
4.10. 4,8-Dimethyldecyl acetate (14)
4.10.1. (4R,8R)-Isomer. Acetic anhydride (1 mL, 10.6 mmol) was
added to an ice-cooled solution of (4R,8R)-13 (161 mg, 0.9 mmol) in

208
K. Akasaka et al. / Tetrahedron 67 (2011) 201e209
dry pyridine (2 mL). The mixture was left to stand overnight at
room temperature. Subsequent work-up gave 173 mg (88%) of
(4R,8R)-14, nmax (film): 2297 (s), 1743 (s, C]O), 1462 (m), 1365 (m),
1240 (s), 1038 (m); dH (CDCl3): 0.81e0.92 (9H, m, CH3), 1.02e1.20
(4H, m), 1.20e1.45 (8H, m), 1.52e1.70 (2H, m), 2.05 (3H, s), 4.04 (2H,
t, J 6.8); GCeMS [under the same conditions as for (3R,5RS,7S)-8]: tR
12.60 [86.2%, (4R,8R)-14], 14.20 min (7.2%, unidentified). MS of
(4R,8R)-14 [70 eV, EI]: m/z 229 (<1) [Mþþ1], 185 (3), 168 (7), 140
(53), 125 (25), 111 (42), 97 (53), 84 (58), 83 (67), 71 (53), 70 (90), 69
(100), 57 (58), 56 (43), 55 (63), 43 (100), 41 (50).
MOMTBDMSGCD): two peaks at 129.26 [(4R)-isomers] and 129.64
[(4S)-isomers] min.
4.13. Complete separation of the four stereoisomers
of (1R,2R)-18 by reversed-phase HPLC
4.13.1. Instruments for analytical HPLC. The HPLC pumps used were
Tosoh DP-8020 equipped with Rheodyne 7125 sample injector with
a 100 mL sample loop for the first separation and Jasco PU-980 for
the second separation, respectively. Tosoh PT-8000 was used for
column switching. The fluorescence detector was Jasco FP-920 with
a 16 mL flow cell. The integrator was Chromatocorder 21 (System
Instrument, Tokyo, Japan). Cryocool CC100-II was used to control
the second column temperature.
4.10.2. (4R,8S)-Isomer. In the same manner, (4R,8S)-13 (360 mg,
1.9 mmol) gave 386 mg (87%) of (4R,8S)-14. Its IR, 1H NMR, and
mass spectra were virtually identical to those of (4R,8R)-14. GC
[under the same conditions as for (4R,8R)-14]: tR 12.62 [78.9%,
(4R,8S)-14], 14.20 min (5.9%, unidentified).
4.13.2. Preparation of (1R,2R)-18. Excess amounts of the (1R,2R)-
reagent (17), DMAP, and EDC were added to a solution of acid 12 in
toluene/acetonitrile (1:1, v/v). The solution was stood for more than
1 h at room temperature. An aliquot was then loaded onto a silica
gel TLC (7 cm length, Silica gel 60 F254, Art-5554, Merck) and
developed with hexane/ethyl acetate (4:1, v/v). The target spot
detected by fluorescence was collected, packed in a Pasteur pipette,
and eluted with ethyl acetate/methanol (4:1, v/v). After evaporation
of the solvent with a nitrogen gas stream, the residual (1R,2R)-18
was dissolved in methanol and used for HPLC analysis.
4.10.3. (4S,8R)-Isomer. In the same manner, (4S,8R)-13 (327 mg,
1.8 mmol) gave 373 mg (93%) of (4S,8R)-14. Its IR, 1H NMR, and
mass spectra were identical with those of (4R,8S)-14. GC [under the
same conditions as for (4R,8R)-14]: tR 12.62 [79.1%, (4S,8R)-14],
14.20 min (8.2%, unidentified).
4.10.4. (4S,8S)-Isomer. In the same manner, (4S,8S)-13 (326 mg,
1.8 mmol) gave 361 mg (90%) of (4S,8S)-14. GC [under the same
conditions as for (4R,8R)-14]: tR 12.62 [86.6%, (4S,8S)-14], 14.20 min
(6.6%, unidentified).
4.13.3. Separation by HPLC. The acid derivative (1R,2R)-18 was
separated at first on
a Develosil C30-UG-3 column (3 mm,,
15 cmꢂ4.6 mm i.d., Nomura Chemical Co., Aichi, Japan) eluted with
methanol at the rate of 0.3 mL/min and at 40 ꢁC. The eluate from the
first column between 15.6 min and 19.9 min was introduced onto
4.11. Stability of 4.8-dimethyldecanal (1) upon storage
4.11.1. Storage of neat (4R,8S)-1 at room temperature in the presence
of air. Neat (4R,8S)-1 was left to stand for a week in an open flask at
room temperature. The major part of the content was (4R,8S)-12 by
IR and MS comparisons. GCeMS [under the same conditions as for
(4R,8S)-12]: tR 10.16 [6.5%, (4R,8S)-1], 12.19 [89.1%, (4R,8S)-12],
12.91 min (4.4% unidentified, Mþ 226). The major component
showed a mass spectrum identical to that of 12.
the second column (Develosil ODS-HG-3, 3
mm,15 cmꢂ4.6 mm i.d.)
by valve device switching to remove interfering peaks and reduce
the time for analysis. The separation of the stereoisomers of (1R,2R)-
18 was performed by elution with a mixture of methanol/acetoni-
trile/THF/hexane (220/200/80/4, v/v/v/v) at a rate of 0.4 mL/min
at ꢀ54 ꢁC. The detection was carried out by monitoring the fluo-
rescence intensity at 462 nm (excitation at 298 nm). Since the
mixture of all authentic derivatives was eluted from the first column
between 16.0 min and 19.2 min as a broad single peak, the eluate
was introduced onto the second column with a slightly wide range.
tR of (1R,2R)-18: 67.3 (40R,8’S), 72.6 (40R,8’R), 82.9 (40S,8’R), 93.3
(40S,8’S) on the ODS column [see Fig. 5(b)] and 88.9 (4R0,80S), 94.4
(40R,8’R), 104.3 (40S,8’R), 114.9 (40S,8’S) on the LCeLC system [see
Fig. 5(c)], respectively.
4.11.2. Storage of neat (4R,8S)-1 in a refrigerator. Neat (4R,8S)-1 was
left to stand for a week in a refrigerator at 5 ꢁC. There was no ob-
servable change as checked by GCeMS.
4.11.3. Storage of a hexane solution of (4R,8S)-1 at room temper-
ature. A solution of (4R,8S)-1 in hexane was filled up into a small
vial, and left to stand for a week at room temperature. There was no
observable change as checked by GCeMS.
Acknowledgements
4.12. Partial separation of the four stereoisomers of 1 and 13
by enantioselective GC
We thank Mr. M. Kimura (President, Toyo Gosei Co., Ltd) and Dr.
A. Fujita (Director, Technical Research Institute, T. Hasegawa Co.,
Ltd) for their support. K.M. thanks Prof. H. Ohrui (Yokohama College
of Pharmacy) for discussion. Dr. T. Tashiro (RIKEN) kindly prepared
the Figures and Schemes. Mr. Y. Shikichi (Toyo Gosei Co., Ltd) is
thanked for NMR and GCeMS measurements. Our thanks are due to
Drs. T. Nakamura and Y. Hongo (both at RIKEN) for HRMS analysis.
Mention of trade names or commercial products in this publication
is solely for the purpose of providing specific information and does
not imply recommendation or endorsement by the U.S.
Department of Agriculture.
4.12.1. Instrument and conditions for enantioselective GC. Instru-
ment: Agilent 7890 gas chromatograph; column: eight cyclodex-
trin-based stationary phases were examined (see Fig. 2),
30 mꢂ0.25 mm i.d.; thickness of the stationary phase: 0.25
mm;
column temperature: 40e180 ꢁC (þ0.7 ꢁC/min); carrier gas: He,
0.7 mL/min; detector: FID; injection port temperature: 230 ꢁC;
detector temperature: 250 ꢁC.
4.12.2. Separation by enantioselective GC. (a) tR of the stereoiso-
mers of 1 (on 10% DMTFAGCD): 123.03 (4R,8R), 123.05 (4R,8S),
123.65 (4S,8R), 123.67 (4S,8S) min. (b) tR of the stereoisomers of 1
(on 50% MOMTBDMSGCD): 201.59 (4R,8R), 202.45 (4R,8S), 202.90
(4S,8S), 203.15 (4S,8R) min (see Fig. 3). (c) tR of the stereoisomers
of 13 (on 10% DMTFAGCD): two peaks at 122.96 [(4R)-isomers] and
123.64 min [(4S)-isomers] (d) tR of the stereoisomers of 13 (on 50%
References and notes
1. Mori, K.; Shikichi, Y.; Shankar, S.; Yew, J. Y. Tetrahedron 2010, 66, 7161e7168.
2. Suzuki, T. Agric. Biol. Chem. 1980, 44, 2519e2520.
3. Suzuki, T. Agric. Biol. Chem. 1981, 45, 1357e1363.
4. Suzuki, T. Agric. Biol. Chem. 1981, 45, 2641e2643.
5. Suzuki, T.; Nakakita, H.; Kuwahara, Y. Appl. Entomol. Zool 1987, 22, 340e347.

K. Akasaka et al. / Tetrahedron 67 (2011) 201e209
209
6. Mori, K.; Kuwahara, S.; Ueda, H. Tetrahedron 1983, 39, 2439e2444.
7. Mori, K.; Kato, M.; Kuwahara, S. Liebigs Ann. Chem. 1985, 861e865.
8. Mori, K.; Takikawa, H. Liebigs Ann. Chem. 1991, 497e500.
9. Mori, K. In The Total Synthesis of Natural Products; ApSimon, J., Ed.; Wiley: New
York, NY, 1992; Vol. 9, pp 141e148.
10. Suzuki, T.; Mori, K. Appl. Entomol. Zool 1983, 18, 134e136.
11. Suzuki, T.; Kozaki, J.; Sugawara, R. Appl. Entomol. Zool 1984, 19, 15e20.
12. Mori, K. Tetrahedron 2009, 65, 3900e3909.
19. Mori, K. In Methods in Chemical Ecology; Millar, J. G., Haynes, K. F., Eds.;
Chemical Methods; Kluwer: Norwell, 1998; Vol. 1, pp 295e338.
20. Tamogami, S.; Awano, K.; Amaike, M.; Takagi, Y.; Kitahara, T. Flavour Fragrance
J. 2001, 16, 349e352.
21. Takahisa, E.; Engel, K.-H. J. Chromatogr., A 2005, 1063, 181e192.
22. Bicchi, C.; Artuffo, G.; Pellegrino, G.; D’Amato, A.; Galli, A.; Galli, M. J. High
Resolut. Chromatogr. 1991, 14, 701e704.
23. Ohrui, H. Proc. Jpn. Acad., Ser. B 2007, 83, 127e135.
24. Imaizumi, K.; Terashima, H.; Akasaka, K.; Ohrui, H. Anal. Sci. 2003, 19,
1243e1249.
13. Mori, K.; Tashiro, T.; Zhao, B.; Suckling, D. M.; El-Sayed, A. M. Tetrahedron 2010,
66, 2642e2653.
14. Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404e5406.
15. Negishi, E.; Swanson, D. R.; Rousset, C. J. J. Org. Chem. 1990, 55, 5406e5409.
16. Mori, K. Tetrahedron: Asymmetry 2008, 19, 857e861.
17. Heath, R. R.; Dueben, B. D. In Methods in Chemical Ecology; Millar, J. G., Haynes,
K. F., Eds.; Chemical Methods; Kluwer: Norwell, 1998; Vol. 1, pp 85e126.
18. Millar, J. G. In Methods in Chemical Ecology; Millar, J. G., Haynes, K. F., Eds.;
Chemical Methods; Kluwer: Norwell, 1998; Vol. 1, pp 38e84.
25. Ohrui, H.; Terashima, H.; Imaizumi, K.; Akasaka, K. Proc. Jpn. Acad., Ser. B 2002,
78, 69e72.
26. Akasaka, K.; Ohrui, H. Biosci. Biotechnol. Biochem. 2004, 68, 153e158.
27. Mori, K.; Ohtaki, T.; Ohrui, H.; Berkebile, D. R.; Carlson, D. A. Eur. J. Org. Chem.
2004, 1089e1096.
28. Tashiro, T.; Akasaka, K.; Ohrui, H.; Fattorusso, E.; Mori, K. Eur. J. Org. Chem. 2002,
3659e3665.