Pheromone synthesis. Part 243: Synthesis and biological evaluation of (3R,13R,1′S)-1′-ethyl-2′-methylpropyl 3,13-dimethylpentadecanoate, the major component of the sex pheromone of Paulownia bagworm, Clania variegata, and its stereoisomers

Article abstract of DOI:10.1016/j.tet.2010.02.028

All of the four stereoisomers of (1′S)-1′-ethyl-2′-methylpropyl 3,13-dimethylpentadecanoate, the major component of the female sex pheromone of Clania variegata, were synthesized by employing olefin cross metathesis as the key reaction and starting from (R)- or (S)-2-methyl-1-butanol, (R)- or (S)-citronellal, and (S)-2-methyl-3-pentanol. Their bioassay revealed the (3R,13R,1′S)-isomer as the bioactive one, whose more efficient synthesis was achieved in two different ways by employing Wittig reaction as the key step.

Full text of DOI:10.1016/j.tet.2010.02.028

Tetrahedron 66 (2010) 2642–2653
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pheromone synthesis. Part 243: Synthesis and biological evaluation of
(3R,13R,10S)-10-ethyl-20-methylpropyl 3,13-dimethylpentadecanoate, the major
component of the sex pheromone of Paulownia bagworm, Clania variegata,
and its stereoisomersq
,
b
,
b
c
,
d
d
Kenji Mori a , Takuya Tashiro , Boguang Zhao , David M. Suckling , Ashraf M. El-Sayed
*
*
a Photosensitive Materials Research Center, Toyo Gosei Co., Ltd, Wakahagi 4-2-1, Inba-mura, Inba-gun, Chiba 270-1609, Japan
b Glycosphingolipid Synthesis Group, Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology, Hirosawa 2-1, Wako-shi, Saitama 351-0198, Japan
c Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, China
d The New Zealand Institute for Plant & Food Research Ltd, Canterbury Research Center, Lincoln 7608, New Zealand
a r t i c l e i n f o
a b s t r a c t
All of the four stereoisomers of (10S)-10-ethyl-20-methylpropyl 3,13-dimethylpentadecanoate, the major
component of the female sex pheromone of Clania variegata, were synthesized by employing olefin cross
metathesis as the key reaction and starting from (R)- or (S)-2-methyl-1-butanol, (R)- or (S)-citronellal,
and (S)-2-methyl-3-pentanol. Their bioassay revealed the (3R,13R,10S)-isomer as the bioactive one, whose
more efficient synthesis was achieved in two different ways by employing Wittig reaction as the key step.
Ó 2010 Elsevier Ltd. All rights reserved.
Article history:
Received 20 January 2010
Received in revised form 3 February 2010
Accepted 4 February 2010
Available online 8 February 2010
Keywords:
Clania variegata
3,13-Dimethylpentadecanoic acid
2-Methyl-3-pentanol
Olefin cross metathesis
Pheromone
1. Introduction
remaining stereogenic centers of the carboxylic part of 1, however,
remained unknown.
The Paulownia bagworm, Clania variegata Snell (Lepidoptera:
Psychidae), is an economically important pest, and occurs in Asian
countries such as China, India, Indonesia, Japan, Korea, Thailand,
and Vietnam. The larvae feed on the foliage and young shoots of
many plant species, including the Bishop wood (Bischofia javanica
Blume) and the Princess tree (Paulownia tomentosa Thunb) causing
serious damage to the growth and reduced timber yields. In addi-
tion, it causes significant defoliation of pine trees, Pinus spp., in
naturally regenerating forests. It has only one generation per year in
China, and the duration of adult activity is only two weeks.
The major component of its female-produced sex pheromone
was reported to be 10-ethyl-20-methylpropyl 3,13-dimethylpenta-
decanoate (1, Fig. 1) by Gries et al.2 in 2006. As to the absolute
configuration of the pheromone 1, they assigned S configuration to
the alcohol part by synthesis of both (10R)- and (10S)-1 followed by
their field bioassay in China.2 The absolute configuration of the two
O
13 (CH2)9
3
O
1'
(3R,13R,1'S)-1
Figure 1. Structure of the major component of the sex pheromone of Clania variegata.
In continuation of our long-term studies on the absolute
configuration of pheromones,3 we became interested in clarifying
the stereochemistry of the naturally occurring 1. We therefore
synthesized all of the four stereoisomers of (10S)-1 by means of
olefin cross metathesis, which was reported as a preliminary
communication in 2009.4 The four isomers of (10S)-1 were
bioassayed in China, and only a single isomer (3R,13R,10S)-1 was
shown to be highly bioactive.
This paper describes in detail our metathesis-mediated
synthesis of the four stereoisomers of (10S)-1 together with two
additional syntheses of (3R,13R,10S)-1 by means of Wittig reaction.
The new syntheses were more efficient than the metathesis-
mediated one. As to the synthesis of (S)-2-methyl-3-pentanol, the
q
For Part 242, see Ref. 1.
* Corresponding authors. Tel.: þ81 3 3816 6889; fax: þ81 3 3813 1516 (K. M.);
e-mail addresses: kjk-mori@arion.ocn.ne.jp, zhbg596@126.com.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.028

K. Mori et al. / Tetrahedron 66 (2010) 2642–2653
2643
alcohol part of 1, we will report both the details of the previous
syntheses4 and a new synthesis based on organozinc chemistry.
Details of the bioassay in China will also be recorded.
based on (R)-5. GC–MS analysis of the product revealed it to be
a 91.2:8.8 mixture of (R)-8 and (3R,6R)-9. The latter must have been
generated in the course of the preparation of the Grignard reagent.
Similarly, commercially available (S)-3 (Tokyo Kasei) afforded crude
(S)-8 as a 93:7 mixture of (S)-8 and (3S,6S)-9. The contaminating
hydrocarbon 9 could be removed after olefin metathesis. The en-
antiomeric purity of (R)-8 was >98.0% ee, while that of (S)-8 was
99.0% ee as determined by their GC analysis using CHIRAMIXÒ8 as
the chiral stationary phase. The overall yield of (R)-8 was 32% based
on (R)-2 (four steps), and that of (S)-8 was 22% based on (S)-3
(three steps).
2. Results and discussion
2.1. Metathesis-mediated synthesis of the four
stereoisomers of (10S)-1
Since the absolute configuration of the natural pheromone was
unknown at the outset of this work, we chose olefin cross me-
tathesis as the key reaction to provide all the four isomers of (10S)-1
quickly without complication. Our synthesis is totally different
from a synthesis reported by Wei et al. in the patent literature.5
Scheme 1 shows our retrosynthetic analysis of (3R,13R,10S)-1.
The ester 1 can be dissected to 1-acetoxy-3,13-dimethyl-6-penta-
decene moiety A and the alcohol moiety B. The olefinic acetate A
would be synthesized by cross metathesis of C with D, the two
a
c
OR
CO2H
(R)-2
(R)-3 R = H
(R)-4 R = Ts
b
d
+
Br
metathesis partners. The optically active olefin
C would be
RO
prepared from (R)-2-methylbutanoic acid (E) and 5-hexen-1-ol (F).
Another metathesis partner D would be obtained from (R)-citro-
nellal (G), and the alcohol part B must be obtainable via asymmetric
synthesis.
6 R = H
7 R = Ts
(R)-5
b
+
O
(R)-8 (= C)
Similarly
(3R,6R)-9
(CH2)9
O
(3R,13R,1'S)-1
OH
(S)-3
(S)-8
HO
OAc
ref. 9
A [= (3R,6EZ,13R)-13]
B [= (S)-20]
CHO
CHO
OR
PCy3
Ru
PCy3
Cl
Cl
(R)-10
(R)-11 R = H
(R)-12 R = Ac (= D)
e
Ph
Similarly
Grubbs I
OAc
(S)-10
(S)-12
OAc
Scheme 2. Synthesis of the metathesis partners 8 and 12. Reagents: (a) LiAlH4, Et2O;
(b) TsCl, C5H5N (51% for 7); (c) LiBr, DMF [78% based on (R)-2, three steps]; (d) (i) (R)-5,
Mg, THF; (ii) 7, THF, Li2CuCl4 [42% based on (R)-5 or 66% based on 7]; (e) Ac2O, DMAP,
C5H5N (82%).
C [= (R)-8]
D [= (R)-12]
The other partners of metathesis reaction, (R)- and (S)-12, were
prepared by acetylation of (R)- and (S)-11. These alcohols (R)- and
(S)-11, respectively, were synthesized from the enantiomers of
citronellal (10, Takasago International Corporation, both 97% ee),
and employed as the intermediates in the synthesis of the phero-
mone of an Okinawan moth, Lyclene dharma dharma.9 Their enan-
tiomeric purities were 97.2% ee for both (R)- and (S)-12 by their GC
analysis using octakis-(2,3-di-O-methoxymethyl-6-O-tert-butyldi-
CHO
HO
CO2H
E [= (R)-2]
F (= 6)
G [= (R)-10]
Scheme 1. Retrosynthetic analysis of (3R,13R,10S)-1.
Synthesis of the metathesis partners, (R)-8 (¼C) and (R)-12
(¼D), is summarized in Scheme 2. The starting material for (R)-8
was (R)-2-methylbutanoic acid (2, T. Hasegawa Co., >99.0% ee),
which was obtained by treatment of (ꢀ)-2 with Pseudomonas sp.
TH-252-1.6 Reduction of (R)-2 with lithium aluminum hydride gave
alcohol (R)-3, whose tosylate (R)-4 was treated with lithium bro-
mide in DMF to furnish (R)-2-methylbutyl bromide (5). The
Grignard reagent prepared from (R)-5 and magnesium in THF was
coupled with tosylate 7 (obtained by tosylation of commercially
available 6) in the presence of dilithium tetrachlorocuprate at ꢁ65
to ꢁ50 ꢂC under the Schlosser conditions7 to give (R)-8 in 42% yield
methylsilyl)-g
-cyclodextrin as the chiral stationary phase.9 The
overall yield of (R)-12 was 46% based on (R)-10 (seven steps), and
that of (S)-12 was 45% based on (S)-10 (seven steps).
Scheme 3 shows the synthesis of the key acid (3R,13R)-17 via the
crucial step of olefin cross metathesis.10–14 Some applications of
cross metathesis to pheromone synthesis have been reported by us
and others.1,9,14–16 Because (R)-8 could be prepared in fewer steps
(four) than (R)-12 (seven steps), 3 equiv of (R)-8 was mixed with
1 equiv of (R)-12 in dichloromethane. In the presence of 5 mol %
[based on (R)-12] of Grubbs’ first generation catalyst, the mixture

2644
K. Mori et al. / Tetrahedron 66 (2010) 2642–2653
was stirred and heated under reflux for 6 h under argon. Chro-
matographic purification of the product first gave (3R,9EZ,16R)-14
[50% yield based on (R)-8], and then the desired (3R,6EZ,13R)-13
contaminated with (3R,6EZ,10R)-15 in 88% yield based on (R)-12.
a
c
b
OH
O
( )-18
19
a
+
OAc
+
(R)-8
(R)-12
OH
OH
O
(R)-18
(S)-20
21
(96% ee)
(95% ee)
b, c
OAc
e
d
B
(3R,6EZ,13R)-13 (E/Z = 5:1)
+
+
®
(R)-Alpine-Borane
OBz
OAc
(3R,6EZ,16R)-14
(3R,9EZ,10R)-15
(R)-22
(S)-23
Scheme 4. Synthesis of the alcohol (S)-20. Reagents: (a) Jones CrO3, acetone (73%); (b)
(R)-Alpine-BoraneÒ (47%); (c) H2, 10% Pd–C, pentane (83%); (d) BzCl, DMAP, C5H5N; (e)
Ac2O, C5H5N.
AcO
OAc
4-(dimethylamino)pyridine (DMAP, 1.5 equiv) in dichloromethane
23
to give (3R,13R,10S)-1 in 84% yield as an oil, [
a
]
ꢁ5.38 (c 1.30,
D
CHCl3). Its 1H and 13C NMR data were in good accord with those
d
published for (3RS,13RS,10S)-1.2 Similarly, we synthesized
CO2H
(CH2)9
(3R,13R)-16
OH
(CH2)9
(3R,13R)-17
23
23
(3R,13S,10S)-1, [
(c 1.31, CHCl3), and (3S,13S,10S)-1, [
a]
þ1.63 (c 1.32, CHCl3), (3S,13R,10S)-1, [
a
]
ꢁ10.8
D
D
23
a
]
ꢁ3.42 (c 1.20, CHCl3). The
D
spectral data of these four isomers of 1 were virtually in-
distinguishable. The overall yield of (3R,13R,10S)-1 was 13% based on
(R)-10 (12 steps).
Scheme 3. Synthesis of the acid (3R,13R)-17. Reagents: (a) Grubbs I [ca. 5 mol % based
on (R)-12], (R)-8/(R)-12¼ca. 3:1 in CH2Cl2, reflux, 6 h [88% based on (R)-12]; (b) NaOH,
MeOH, aq THF, reflux, 1 h (97%); (c) H2, 10% Pd–C, EtOH; then SiO2 chromatog. (58%);
(d) Jones CrO3, acetone (75%).
O
a
Since complete removal of 15 from 13 was difficult, the crude
(3R,6EZ,13R)-13 was subjected to alkaline hydrolysis and hydroge-
nation over 10% palladium/charcoal. Subsequent chromatographic
purification gave (3R,13R)-16 in 53% yield based on the crude
(3R,13R)-13 (two steps). Oxidation of (3R,13R)-16 with Jones chromic
acid afforded the desired acid (3R,13R)-17 in 75% yield. The overall
yield of (3R,13R)-17 was 35% based on (R)-12 (four steps). Other ste-
reoisomers of the acid 17 could be synthesized in the same manner.
The next task was the synthesis of (S)-2-methyl-3-pentanol (20).
Gries et al. previously prepared (S)-20 by kinetic resolution of (ꢀ)-
4-methyl-1-penten-3-ol by means of Sharpless asymmetric epoxi-
dation.2 As shown in Scheme 4, we synthesized (S)-20 by asym-
metric reduction of 4-methyl-1-pentyn-3-one (19) to (R)-18 with
Brown0s (R)-Alpine-BoraneÒ17 as the key step. Commercially avail-
able (ꢀ)-4-methyl-1-pentyn-3-ol (18) was oxidized with Jones
chromic acid to give ketone 19. This was reduced with (R)-Alpine-
BoraneÒ to give highly volatile (R)-18 in 47% yield. The enantiomeric
purity of (R)-18 was estimated as 96% ee by HPLC analysis of the
corresponding benzoate (R)-22, employing ChiralcelÒ OJ-H as the
chiral stationary phase. Hydrogenation of (R)-18 over 10% palladium/
charcoal in pentane afforded a 2:1 mixture of (S)-20 and 21. The
ketone 21 must have been produced via 4-methyl-1-penten-3-one
generated by palladium-catalyzed isomerization of 18. A similar
CO2H
(CH2)9
(CH2)9
(3R,13R,1'S)-1
O
(3R,13R)-17
Similarly
+
+
+
(3R,13S,1'S)-1
(3S,13R,1'S)-1
(3S,13S,1'S)-1
OAc
OAc
OAc
(S)-8
(R)-8
(S)-8
(R)-12
(S)-12
(S)-12
Scheme 5. Synthesis of the target esters 1. Reagents: (a) (S)-20, EDC, DMAP, CH2Cl2
[84% based on (3R,13R)-17].
2.2. Evaluation of pheromone activity of the four
stereoisomers of (10S)-1 by field experiment
isomerization–hydrogenation has been observed in the past.1 After
The four steroisomers of (10S)-1 were tested for the attraction of
male C. variegata in the forest of Platanus hispanica Muench. in
Yantai, Shandong Province, China, in June 2009.
As shown in Figure 2, the number of male C. variegata captured
in traps was affected by the stereochemistry of (10S)-1. Significantly
more males were captured in traps baited with (3R,13R,10S)-1 than
any other stereoisomer tested. An average of 43 males per trap
were captured in traps baited with (3R,13R,10S)-1 over a 12-day
period. Significantly fewer males (2.2 per trap) were captured in
traps baited with (3R,13S,10S)-1, while no male was captured in
25
chromatographic purification, highly volatile (S)-20; [
a
]
ꢁ20.1 (c
D
23
1.16, EtOH) {Ref. 18: [
a
]
ꢁ16.9 (c 0.39, EtOH)}, could be secured in
D
16% yield. Its enantiomeric purity was estimated as 95.0% ee by GC
analysis of the corresponding acetate 23. More efficient synthesis of
(S)-20 was later developed as described in Section 2.3.
The final step as depicted in Scheme 5 was the esterification of
the four stereoisomers of acid 17 with (S)-20. 1-Ethyl-3-(3-dime-
thylaminopropyl)carbodiimide hydrochloride (EDC, 1.5 equiv) was
added to a solution of (3R,13R)-17 (1 equiv), (S)-20 (1.1 equiv), and

K. Mori et al. / Tetrahedron 66 (2010) 2642–2653
2645
70
60
50
40
30
20
10
0
OH
a
H [= (3R,6EZ,13R)-30]
OHC
OAc
PPh3
b
I
J [= (R)-29]
c
c
c
T
T
T
T
T
Scheme 6. Retrosynthetic analysis of H [¼(3R,6EZ,13R)-30].
b
+
Br
RO
a
Cl
24 R = H
(R)-5
Stereoisomers of 1
25 R = Ts
Figure 2. Mean catch ꢀ standard error per trap over 12-day period of male Paulownia
bagworm, Clania variegata, in traps baited with one of the four possible stereoisomers
e
(100 m
g) of (10S)-10-ethyl-20-methylpropyl 3,13-dimethylpentadecanoate (1). Letters on
+
X
OHC
OAc
columns indicate significant differences (P<0.05).
(R)-26 X = Cl
(R)-27 X = I
ref.9
c
d
(R)-29
traps baited with either (3S,13R,10S)- or (3S,13S,10S)-1 or in blank
traps. The number of males captured in traps baited with
(3R,13R,10S)-1 was sufficient to provide large and statistically sig-
nificant differences between treatments. Unfortunately, because of
the very short flight period of this insect (less than two weeks), it
was neither possible to conduct additional experiments nor to in-
vestigate the behavioral activity of the other three stereoisomers of
(10S)-1 on male attraction.
The results obtained from this single field experiment provide
conclusive evidence that (3R,13R,10S)-1 is the active isomer among
the four stereoisomers of (10S)-1 tested. This strongly suggests that
(3R,13R,10S)-1 is the major component of the sex pheromone of
C. variegata. On the other hand, the attraction of a much smaller
number of males to traps baited with (3R,13S,10S)-1 could be due to
the same configuration at C-3 of the acid part. Similarly, the lack of
response to (3S,13R,10S)- or (3S,13S,10S)-1 might indicate that chi-
rality at C-3 of 1 is more important for the pheromone activity than
that at C-13 of 1.
(R)-28 X = P+Ph3I–
f
OH
(3R,6EZ,13R)-30
g
CO2H
(CH2)9
OH
(CH2)9
(3R,13R)-17
(3R,13R)-16
O
O
h
(CH2)9
(3R,13R,1'S)-1
The increase in catch in this study where the pure (3R,13R,10S)-1
was used, compared with the moderate catch in the previous study
by Gries et al.,2 could be due to difference in the population density
in the two studies, or could more likely be due to one of the three
other stereoisomers of (10S)-1 having an inhibitory effect. To ad-
dress this point, further field trapping experiments are required to
elucidate the biological activity of the three other isomers of (10S)-1.
O
i
N
OHC
31
OH
OH
(S)-20
(–)-MIB
Scheme 7. Synthesis of (3R,6EZ,13R)-30 by Wittig reaction and its conversion to the
pheromone. Reagents: (a) TsCl, DMAP, C5H5N (96%); (b) (i) (R)-5, Mg, THF; (ii) 25, THF,
Li2CuCl4 (71%); (c) NaI, DMF, Me2CO (89%); (d) Ph3P, toluene, heat (quant.); (e) (i) (R)-
28, n-BuLi, THF; then (R)-29; (ii) NaOH, aq MeOH [43%, (E/Z¼1:1.7)]; (f) H2, 10% Pd–C,
EtOAc (95%); (g) Jones CrO3, acetone (94%); (h) (S)-20, EDC, DMAP, CH2Cl2 (84%); (i)
Et2Zn, (ꢁ)-MIB, toluene (45%).
2.3. Wittig olefination-mediated synthesis of (3R,13R)-
3,13-dimethylpentadecanoic acid (17) and its conversion
to the pheromone
THF generated the Wittig reagent I. This was slowly added to a stir-
red and cooled solution of (R)-299 in THF. The product was treated
with sodium hydroxide in aqueous methanol to give (3R,13R)-30 in
43% yield based on (R)-29. The alkenol 30 was obtained as an E/Z-
mixture (E/Z¼1:1.7) as revealed by its GC–MS analysis. Hydrogena-
tion of (3R,6EZ,13R)-30 over 10% palladium/charcoal afforded
(3R,13R)-16, which was oxidized with Jones chromic acid to give
(3R,13R)-17. The overall yield of (3R,13R)-17 was 19% based on (R)-2
(nine steps).
Determination of the absolute configuration of the bioactive iso-
mer of 1 as 3R,13R,10S prompted us to develop a more efficient syn-
thesis of (3R,13R,10S)-1. AsshowninScheme6, ourfirstattempt wasto
prepare H [¼(3R,13R)-30] by Wittig reaction. Obvious bond discon-
nection of H demanded Wittig reagent I and aldehyde J as its pre-
cursors. ThissyntheticplanwasexecutedassummarizedinScheme 7.
(R)-2-Methylbutyl bromide (5) served as the starting material for
the Wittig reagent I. For the chain-extension of (R)-5, commercially
available 5-chloro-1-pentanol (24) was tosylated to give 25, which
was coupled with the Grignard reagent prepared from (R)-5 under
the Schlosser conditions.7 The resulting chloride (R)-26 was treated
with sodium iodide in acetone to give iodide (R)-27. Treatment of
(R)-27 with triphenylphosphine in hot toluene afforded phospho-
nium salt (R)-28. Addition of n-butyllithium to a solution of (R)-28 in
Esterification of
a gram-quantity of (3R,13R)-17 to give
(3R,13R,10S)-1 demanded the supply of a gram-quantity of (S)-20.
Accordingly, we prepared (S)-20 (96.8% ee as analyzed by the
enantioselective GC of its acetate) in 45% yield by the addition of
diethylzinc to isobutyraldehyde (31) in the presence of 2.5 mol % of
(2S)-(ꢁ)-3-exo-(morpholino)isoborneol [(ꢁ)-MIB],19 which was

2646
K. Mori et al. / Tetrahedron 66 (2010) 2642–2653
prepared by the method of Chen et al.20 By using (S)-20 thus pre-
pared, 4.12 g of (3R,13R,10S)-1 could be synthesized from (3R,13R)-
17 in 16% overall yield based on (R)-2 (10 steps).
(R)-Citronellal (10) was oxidized with pyridinium dichromate
(PDC) in DMF to give (R)-citronellic acid (32) in 87% yield.21 (S)-2-
Methyl-3-pentanol (20) was prepared by asymmetric ethylation of
isobutyraldehyde (31) with diethylzinc in the presence of (ꢁ)-MIB.
After the work-up, a solution of (S)-20 in hexane, toluene, and
diethyl ether was used directly for the esterification of 32, because
isolation of (S)-20 caused its substantial loss due to its high vola-
tility. Accordingly, (R)-citronellic acid (32) and DMAP were dis-
solved into the above solution of (S)-20, to which was added EDC.
This simplified version of esterification of (R)-32 with (S)-20
afforded (3R,10S)-33 in 74% yield. Epoxidation of 33 with m-chlor-
operbenzoic acid (MCPBA) furnished epoxy ester 34 quantitatively.
Treatment of 34 with periodic acid dihydrate gave the desired aldo
ester (3R,10S)-35 in 82% yield.
2.4. Wittig olefination-mediated synthesis of (3R,6EZ,13R,10S)-
10-ethyl-20-methylpropyl 3,13-dimethyl-6-pentadecenoate (36)
and its conversion to the pheromone
The most efficient synthesis of the pheromone (3R,13R,10S)-1 was
finally achieved, basing on the retrosynthetic analysis as shown in
Scheme 8. It is obvious that hydrogenation of K [¼(3R,6EZ,13R,10S)-
36] affords (3R,13R,10S)-1. Wittig reaction between the ylide I and
aldo ester L [¼(3R,10S)-35] could give K in a single step. This simple
idea was put into practice as shown in Scheme 9.
Wittig reaction of 35 with the ylide derived from (R)-28 afforded
(3R,6EZ,13R,10S)-36 in 47% yield. Finally, hydrogenation of 36 over
10% palladium/charcoal furnished (3R,13R,10S)-1 in 96% yield. The
overall yield of this process was 22% based on (R)-2 (eight steps) or
24% based on (R)-10 (six steps). This final route to the pheromone
was highly convergent and efficient. However, as to the consump-
tion of the chiral alcohol part (S)-20, this route is less economical
than the second route involving the final esterification step.
O
O
K [= (3R,6EZ,13R,1'S)-36]
3. Conclusion
O
We synthesized all of the four stereoisomers of (10S)-10-ethyl-20-
methylpropyl 3,13-dimethylpentadecanoate (1), the major
component of the sex pheromone of C. variegata. Olefin cross me-
tathesis was shown to be a useful reaction in pheromone synthesis,
particularly when a set of stereoisomers must be prepared quickly.
The four stereoisomers of 1 were tested for attraction of male
C. variegata in China to show (3R,13R,10S)-1 as the highly bioactive
one, which must be the naturally occurring 1. Two syntheses of
(3R,13R,10S)-1 were achieved via Wittig olefination to provide more
efficient preparative methods for the pheromone component.
The Paulownia bagworm, C. variegata, is not only an economi-
cally important insect in China and India, but also is potentially an
invasive species in other parts of the world where the host tree is
highly valued. Accordingly, the determination of the absolute
configuration of the main sex pheromone component as
(3R,13R,10S)-1 will enable not only monitoring and control of this
insect in its native habitats but also detection and delimitation in
any newly invaded habitat.
OHC
O
PPh3
I
L [= (3R,1'S)-35]
Scheme 8. Retrosynthetic analysis of K [¼(3R,6EZ,13R,10S)-36].
ref.21
CHO
(R)-10
a
+
CO2H
HO
(S)-20
(R)-32
O
O
O
b
O
O
4. Experimental
4.1. General
(3R,1'S)-33
(3R,1'S)-34
O
c
d
e
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 or P-1010 polarimeter. IR spectra
were measured on a Jasco FT/IR-410 or 460 plus spectrometer. 1H
+
OHC
O
P+Ph3I–
(R)-28
(3R,1'S)-35
NMR spectra (400 MHz or 500 MHz, TMS at
d
¼0.00 as internal
standard) and 13C NMR spectra (100 MHz or 126 MHz, CDCl3 at
O
d
¼77.0 as internal standard) were recorded on a Jeol JNM-AL 400 or
O
Varian VNMRS-500 spectrometer. GC were recorded on a Shimadzu
GC-2014 or an Agilent 7890 gas chromatograph. GC–MS were
measured on an Agilent Technologies 5975 inert XL. HPLC was
recorded on a Hitachi L-7110. HRMS were recorded on a Jeol JMS-
SX102A. Column chromatography was carried out on Merck
Kieselgel 60 Art 1.07734.
(3R,6EZ,13R,1'S)-36
O
(CH2)9
O
(3R,13R,1'S)-1
4.2. 2-Methylbutyl bromide 5
Scheme 9. Synthesis of (3R,6EZ,13R,10S)-36 by Wittig reaction and its conversion to the
pheromone. Reagents: (a) EDC, DMAP, Et2O, toluene, hexane [74% based on (R)-32]; (b)
MCPBA, CH2Cl2 (quant.); (c) HIO4$2H2O, THF, Et2O (82%); (d) (R)-28, n-BuLi, THF; then
(3R,10S)-35 (47%); (e) H2, 10% Pd–C, EtOAc (96%).
4.2.1. (R)-Isomer. A solution of (R)-2 (T. Hasegawa Co., >99.9% ee,
13.0 g, 127 mmol) in dry Et2O (20 mL) was added dropwise to an

K. Mori et al. / Tetrahedron 66 (2010) 2642–2653
2647
ice-cooled and stirred suspension of LiAlH4 (5.4 g, 128 mmol) in
dry Et2O (100 mL). The mixture was stirred for 1 h at 0–5 ꢂC. The
excess LiAlH4 was destroyed by slowly adding water. The mixture
was then acidified with ice and dil HCl, and extracted with Et2O.
The extract was successively washed with saturated NaHCO3
solution and brine, dried (MgSO4), and concentrated at atmo-
spheric pressure to give crude (R)-3 (11.8 g, quant) as an oil; nmax
(film): 3348 (OH, s), 1047 (s), 1016 (m); dH (CDCl3): 0.912 (3H, t, J
7.2, CH2CH3), 0.915 (3H, d, J 6.4, CHCH3), 1.19–1.25 (1H, m), 1.40–
1.60 (2H, m), 3.40–3.55 (2H, m, CH2OH). Powdered TsCl (30.0 g,
158 mmol) was added portionwise to an ice-cooled and stirred
solution of (R)-3 (11.8 g, 127 mmol) in dry pyridine (60 mL) at 0–
5 ꢂC. The mixture was stirred for 2 h at 0–5 ꢂC. It was then poured
into ice-water, and extracted with Et2O. The extract was suc-
cessively washed with dil. HCl, saturated NaHCO3 solution and
brine, dried (MgSO4), and concentrated in vacuo to give (R)-4
(29.2 g, 95%) as an oil; nmax (film): 1599 (w, arom. C]C), 1360
(m), 1176 (s), 964 (m); dH(CDCl3): 0.83 (3H, t, J 7.6, CH2CH3), 0.87
(3H, d, J 6.8, CHCH3), 1.10–1.22 (1H, m), 1.32–1.45 (1H, m), 1.65–
1.75 (1H, m), 2.45 (3H, s, arom. CH3), 7.34 (2H, d, J 8.8, arom. H),
7.78 (2H, d, J 8.8, arom. H). Powdered LiBr (20 g, 230 mmol) was
added to a solution of (R)-4 (29.2 g, 121 mmol) in dry DMF
(70 mL) with shaking. The mixture became homogenous after
exothermic reaction. It was then stirred and heated at 60 ꢂC for
1.5 h. After cooling, the mixture was diluted with ice and water,
and the heavy oil was separated. The aqueous layer was extracted
with a small amount of pentane. The combined organic solution
was washed with water and brine, dried (MgSO4), and concen-
trated at atmospheric pressure. The residue was distilled to give
(3 mL, 0.3 mmol) was added to the mixture through a syringe,
and the stirred mixture was left to stand overnight to bring it to
the room temperature. The mixture was then added to ice-cooled
NH4Cl solution and extracted with a small amount of pentane.
The pentane extract was washed with water and brine, dried
(MgSO4), and concentrated at atmospheric pressure. The residue
was distilled to give (R)-8 [4.61 g, 42% based on (R)-5 or 66%
based on 7] as a colorless oil, bp 94–96 ꢂC/48 Torr; nD22¼1.4263;
27
[
a
]
ꢁ11.0 (c 3.40, pentane); nmax (film): 3078 (w), 2927 (s), 1641
D
(m), 1462 (m), 1377 (m), 991 (m), 908 (s); dH (CDCl3): 0.80–0.90
(6H, m, CH3ꢃ2), 1.05–1.18 (2H, m), 1.20–1.42 (9H, m), 2.04 (2H, q-
like, J 7.2), 4.90–5.04 (2H, m, C]CH2), 5.75–5.87 (1H, m, CH]C);
GC–MS
[Column:
HP-5MS,
5%
phenylmethylsiloxane,
30 mꢃ0.25 mm i.d.; carrier gas: He; press: 52.8 kPa; tempera-
ture: 50–160 ꢂC (þ10 ꢂC/min) ꢁ220 ꢂC (þ4 ꢂC/min)]: tR 6.07 min
[8.8%, (3R,6R)-9], 8.16 min [91.2%, (R)-8]; MS of (3R,6R)-9 (70 eV,
EI): m/z: 142 (5) [Mþ, C10H22], 113 (32), 112 (12), 85 (10), 71 (82),
57 (100), 56 (28), 43 (36), 41 (32); MS of (R)-8 (70 eV, EI): m/z:
154 (1) [Mþ, C11H22], 125 (34), 97 (20), 83 (68), 70 (100), 69 (65),
57 (45), 55 (67), 41 (53). Enantioselective GC: [instrument: Agi-
lent 7890 GC; column: CHIRAMIXÒ 30 mꢃ0.25 mm i.d.; column
temperature: 40–180 ꢂC (þ0.7 ꢂC/min); carrier gas: He, 0.7 mL/
min]: tR 42 min [>99.0%, (R)-8], 47 min [<1.0%, (S)-8]. Enantio-
meric purity of (R)-8 was >98.0% ee. HRMS calcd for C11H22
:
154.1722, found: 154.1722.
4.4.2. (S)-Isomer. In the same manner as described above, (S)-5
(18.2 g, 120 mmol), Mg (3.1 g, 130 mmol), and 7 (15.2 g, 60 mmol)
afforded (S)-8 [5.21 g, 28% based on (S)-5 or 56% based on 7] as
26
14.9 g [78% based on (R)-2, three steps] of (R)-5 as a colorless oil,
a colorless oil, bp 110–115 ꢂC/65 Torr; nD22¼1.4263; [
a]
þ10.6 (c
D
26
bp 117–119 ꢂC (atm press); n2D2¼1.4434; [
a
]
ꢁ3.72 (c 6.56,
3.50, pentane); GC–MS [same conditions as described for (R)-8]: tR
6.07 min [7.0%, (3S,6S)-9], 8.17 min [93%, (S)-8]. Its spectral data
were identical with those of (R)-8. Enantioselective GC: [same
conditions as described for (R)-8]: tR 42 min [0.5%, (R)-8], 47 min
[99.5%, (S)-8]. Enantiomeric purity of (S)-8 was 99.0% ee. HRMS
calcd for C11H22: 154.1722, found: 154.1722.
D
pentane); nmax (film): 2964 (s), 2931 (m), 2875 (m), 1460 (m),
1381 (m), 1230 (m), 650 (m); dH (CDCl3): 0.91 (3H, t, J 7.2,
CH2CH3), 1.01 (3H, d, J 7.2, CHCH3), 1.20–1.35 (1H, m), 1.40–1.55
(1H, m), 1.65–1.76 (1H, m), 3.30–3.45 (2H, m).
4.2.2. (S)-Isomer. In the same manner as described above (S)-3
[Tokyo Kasei (TCI), 28.4 g, 322 mmol] yielded, via (S)-4, 38.0 g (78%,
25
two steps) of (S)-5, bp 117–119 ꢂC (atm press); nD22¼1.4440; [
a
]
4.5. 3-Methyl-6-heptenyl acetate 12
D
þ3.74 (c 4.76, pentane). Its spectral data were identical with those
of (R)-5.
4.5.1. (R)-Isomer. Acetic anhydride (15 mL, 16.2 g, 159 mmol) and
DMAP (10 mg) were added to a stirred and ice-cooled solution of
(R)-11 (7.7 g, 60 mmol) in dry pyridine (30 mL). The mixture was
left to stand overnight in a refrigerator. It was then poured into ice-
water, and extracted with Et2O. The organic extract was washed
with dil HCl, saturated NaHCO3 solution and brine, dried (MgSO4),
and concentrated in vacuo. The residue was distilled to give (R)-12
4.3. 5-Hexenyl p-toluenesulfonate 7
p-Toluenesulfonyl chloride (44.0 g, 231 mmol) was added por-
tionwise to a stirred and ice-cooled solution of 6 (21.5 g, 215 mmol)
in dry pyridine (100 mL). After stirring for 1 h, the mixture was left
to stand 3 days in a refrigerator. Subsequent work-up as described
for (R)-4 gave 7 (26.6 g, 51%) as a colorless oil; nmax (film): 3076 (m),
1641 (m), 1599 (m), 1360 (s), 1176 (s), 937 (s); dH (CDCl3): 1.38–1.46
(2H, m), 1.60–1.70 (2H, m), 1.95–2.05 (2H, m), 2.45 (3H, s), 4.03 (2H,
t, J 7.2, CH2OTs), 7.34 (2H, d, J 8.4, arom. H), 7.88 (2H, d, J 8.4, arom.
H). The low yield might have been due to the too long storage of the
reaction mixture in the refrigerator. This was used for the next step
without further purification.
(8.4 g, 82%) as a colorless oil, bp 130–134 ꢂC/80 Torr; nD25¼1.4314;
26
[a
]
þ1.53 (c 3.41, Et2O); nmax (film): 3078 (w), 1743 (s, C]O), 1641
D
(m, C]C), 1367 (m), 1240 (s), 1051 (m), 910 (m); dH(CDCl3): 0.92
(3H, d, J 6.0, CHCH3), 1.20–1.30 (1H, m), 1.38–1.50 (2H, m), 1.52–1.62
(1H, m), 1.63–1.70 (1H, m), 2.04 (3H, s, COCH3), 1.99–2.14 (2H, m),
4.04–4.16 (2H, m, CH2OAc), 4.92–5.04 (2H, m), 5.74–5.86 (1H, m).
Enantioselective GC: [instrument: Agilent 7890 GC; column:
octakis-(2,3-di-O-methoxymethyl-6-O-tert-butyldimethylsilyl)-g-
cyclodextrin (MOMTB DMSGCD) 30 mꢃ0.25 mm i.d.; column
temperature: 40–180 ꢂC (þ0.7 ꢂC/min); carrier gas: He, 0.7 mL/
min]: tR 77 min [98.6%, (R)-12], 78 min [1.4%, (S)-12]. The enantio-
meric purity of (R)-12 was 97.2% ee. HRMS calcd for C10H18O2:
170.1307, found: 170.1305.
4.4. 8-Methyl-1-decene 8
4.4.1. (R)-Isomer. A Grignard reagent was prepared from (R)-5
(10.7 g, 71 mmol) and Mg (2.0 g, 80 mmol) in dry THF (70 mL)
under Ar. A trace amount of I2 was used as an initiator, and
stirring and heating were continued for 30 min after the initial
exothermic reaction caused by the dropwise addition of (R)-5 in
THF subsided. The Grignard reagent was added through a syringe
to a stirred and cooled solution of 7 (11.4 g, 45 mmol) in dry THF
(60 mL) at ꢁ65 to ꢁ50 ꢂC under Ar. Then 0.1 M Li2CuCl4 in THF
4.5.2. (S)-Isomer. In the same manner as described for (R)-12, (S)-
11 (5.0 g, 39 mmol) yielded 5.8 g (87%) of (S)-12, bp 122–125 ꢂC/
25
66 Torr; n2D5¼1.4312; [
a
]
ꢁ1.36 (c 3.12, Et2O). Its spectral data were
D
identical with those of (R)-12. Enantioselective GC: [same condi-
tions as described for (R)-12]: tR 77 min [1.4%, (R)-12], 78 min

2648
K. Mori et al. / Tetrahedron 66 (2010) 2642–2653
[98.6%, (S)-12]. The enantiomeric purity of (S)-12 was 97.2% ee.
HRMS calcd for C10H18O2: 170.1307, found: 170.1299.
36.6, 37.0, 39.8, 61.0, 61.1, 129.5 and 129.9 [(Z)-isomer], 130.0 and
130.4 [(E)-isomer] (Z/E¼1:4).
4.6. 3,13-Dimethyl-6-pentadecenyl acetate 13
4.7.2. (3R,6EZ,13S)-Isomer. In the same manner as described for
(3R,6EZ,13R)-30, (3R,6EZ,13S)-13 (780 mg, 2.5 mmol) was treated
with NaOH (0.5 g) to give crude (3R,6EZ,13S)-30 (608 mg, 96%). Its
spectral data were identical with those of (3R,6EZ,13R)-isomer.
4.6.1. (3R,6EZ,13R)-Isomer. Grubbs’ first generation catalyst
(Grubbs I, 92.8 mg, 0.11 mmol) was added to a solution of (R)-8
(1.611 g, 10.5 mmol) and (R)-12 (567 mg, 3.3 mmol) in dry CH2Cl2
(5 mL). The wine red solution was stirred and heated under reflux
under Ar for 3 h. Then an additional amount of Grubbs I catalyst
(30.0 mg, 0.04 mmol) was added, and the stirring was continued
for another 3 h, when the evolution of ethylene ceased. The mixture
was left to stand for 3 d, and concentrated in vacuo. The residue was
chromatographed over SiO2 (15 g). Elution with hexane gave
(3R,9EZ,16R)-14 [1.19 g; nmax (film): 2923 (s), 1462 (s), 1377 (m), 966
(s)], and further elution with hexane/EtOAc (15:1) gave 866 mg
[88% based on (R)-12] of crude (3R,6EZ,13R)-13 contaminated with
a small amount of (3R,6EZ,10R)-15. This crude product was used for
the next step without further purification, because diol resulting
from 15 can be separated from the desired (3R,13R)-16 by chro-
matography. Properties of crude (3R,6EZ,13R)-13: nmax (film): 1743
(s, C]O), 1462 (m), 1365 (m), 1238 (s), 1053 (m), 968 (m); dH
(CDCl3): 0.70–0.94 (9H, m, CH3ꢃ3), 1.00–1.50 (12H, m), 1.50–1.70
(2H, m), 1.92–2.10 (2H, m), 2.04 (3H, s, COCH3), 4.03–4.15 (2H, m,
CH2OAc), 5.32–5.45 (2H, m, CH]CH); dC (CDCl3): 11.4, 14.1, 19.3,
21.0, 22.6, 24.6, 26.9, 27.2, 29.3, 29.5, 29.6, 31.6, 32.6, 34.3, 35.4, 36.5,
36.9, 62.9, 129.3 and 129.9 [(Z)-isomer], 129.8 and 130.4 [(E)-iso-
mer] (Z/E¼1:4), 171.0; GC–MS [column: HP-5MS, 5% phenyl-
methylsiloxane, 30 mꢃ0.25 mm i.d.; carrier gas, He: press:
60.7 kPa; 70–230 ꢂC (þ10 ꢂC/min)]: tR 17.74 min [16.3%, (Z)-13],
17.88 min [83.7%, (E)-13]; MS of these two peaks were almost
identical; MS of (3R,6E,13R)-13 (70 eV, EI): m/z: 296 [Mþ, C19H36O2],
236 (8, MþꢁAcOH), 221 (5), 137 (7), 123 (12), 109 (37), 95 (35), 81
(100), 67 (30), 55 (28), 43 (42).
4.7.3. (3S,6EZ,13R)-Isomer. In the manner as described for
(3R,6EZ,13R)-30, (3S,6EZ,13R)-13 (780 mg, 2.5 mmol) was treated
with NaOH (0.6 g) to give crude (3S,6EZ,13R)-30 (510 mg, 82%). Its
spectral properties were identical with those of (3R,6EZ,13R)-
isomer.
4.7.4. (3S,6EZ,13S)-Isomer. In the same manner as described for
(3R,6EZ,13R)-30, (3S,6EZ,13S)-13 (742 mg, 2.4 mmol) was treated
with NaOH (0.5 g) to give crude (3S,6EZ,13S)-30 (570 mg, 94%). Its
spectral data were identical with those of (3R,6EZ,13R)-isomer.
4.8. 3,13-Dimethyl-1-pentadecanol 16
4.8.1. (3R,13R)-Isomer. To a solution of (3R,6EZ,13R)-3,13-dimethyl-
6-pentadecen-1-ol (30, 680 mg, 2.7 mmol) in 99% EtOH (15 mL)
was added 10% Pd–C (200 mg). The suspension was stirred under
H2 atmosphere for 1 h at room temperature. The mixture was fil-
tered through Celite, and the Celite was washed with Et2O. The
organic filtrate was concentrated in vacuo, and the residue was
chromatographed over SiO2 (5 g). Elution with hexane/EtOAc (3:1)
25
gave 391 mg (58%) of (3R,13R)-16; n2D2¼1.4514; [
a
]
D
ꢁ2.12 (c 2.64,
hexane); nmax (film): 3334 (s, OH), 1057 (m, C–O), 721 (w); dH
(CDCl3): 0.80–0.92 (9H, m, CH3ꢃ3), 1.02–1.19 (3H, m), 1.20–1.41
(20H, m), 1.50–1.70 (2H, m), 3.61–3.72 (2H, m). HRMS (FAB) calcd
for C17H36ONa: 279.2664, found: 279.2664.
4.8.2. (3R,13S)-Isomer. In the same manner as described for
(3R,13R)-16, (3R,6EZ,13S)-30 (590 mg, 2.3 mmol) in 99% EtOH
(10 mL) was hydrogenated over 10% Pd–C (200 mg) to give 483 mg
4.6.2. (3R,6EZ,13S)-Isomer. In the same manner as described for
(3R,6EZ,13R)-13, (S)-8 (1.561 g, 10 mmol) and (R)-12 (522 mg,
3.1 mmol) were treated with Grubbs I catlyst (95 mg, 0.12 mmol) to
give 780 mg [86% based on (R)-12] of (3R,6EZ,13S)-13. Its spectral
data were identical with those of (3R,6E,13R)-13.
(82%) of (3R,13S)-16 after chromatography over SiO2 (5 g);
25
n2D2¼1.4514; [
a]
þ7.99 (c 3.26, hexane). Its spectral data were
D
identical with those reported for (3R,13R)-16. HRMS (FAB) calcd for
C17H36ONa: 279.2664, found: 279.2666.
4.6.3. (3S,6EZ,13R)-Isomer. In the same manner as described for
(3R,6EZ,13R)-13, (R)-8 (1.563 g, 10 mmol) and (S)-12 (537 mg,
4.8.3. (3S,13R)-Isomer. In the same manner as described for
(3R,13R)-16, (3S,6EZ,13R)-30 (510 mg, 2.0 mmol) in 99% EtOH
(10 mL) was hydrogenated over 10% Pd–C (200 mg) to give 403 mg
3.2 mmol) were treated with Grubbs
I catalyst (119.7 mg
0.15 mmol) to give (3S,6EZ,13R)-13 [827 mg, 88% based on (S)-12].
Its spectral data were identical with those of (3R,6EZ,13R)-13.
(79%) of (3S,13R)-16 after chromatography over SiO2 (5 g);
25
n2D2¼1.4512; [
a
]
D
ꢁ8.46 (c 3.07, hexane). Its spectral data were
4.6.4. (3S,6EZ,13S)-Isomer. In the same manner as described for
(3R,6EZ,13R)-13, (S)-8 (1.570 g, 10.2 mmol) and (S)-12 (517 mg,
3.0 mmol) were treated with Grubbs I catalyst (116 mg, 0.14 mmol)
to give (3S,6EZ,13S)-13 [790 mg, 88% based on (S)-12]. Its spectral
properties were identical with those of (3R,6EZ,13R)-13.
identical with those reported for (3R,13R)-16, HRMS (FAB) calcd for
C17H36ONa: 279.2664, found: 279.2663.
4.8.4. (3S,13S)-Isomer. In the same manner as described for
(3R,13R)-16, (3S,6EZ,13S)-30 (550 mg, 2.2 mmol) in 99% EtOH
(10 mL) was hydrogenated over 10% Pd–C (200 mg) to give 355 mg
4.7. 3,13-Dimethyl-6-pentadecen-1-ol 30
(65%) of (3S,13S)-16 after chromatography over SiO2 (5 g);
25
n2D2¼1.4512; [
a
]
þ1.65 (c 1.89, hexane). Its spectral data were
D
4.7.1. (3R,6EZ,13R)-Isomer. A solution of (3R,6EZ,13R)-13 (866 mg,
2.7 mmol) in THF (5 mL) was added to a solution of NaOH (0.6 g,
15 mmol) in H2O (2 mL) and MeOH (5 mL). The mixture was stirred
and heated under reflux for 1 h. It was then concentrated in vacuo,
diluted with water, and extracted with hexane. The extract was
washed with water and brine, dried (MgSO4), and concentrated in
vacuo to give 680 mg (97%) of crude (3R,6EZ,13R)-30 as an oil; nmax
(film): 3330 (s, OH), 1059 (m), 966 (m); dH (CDCl3): 0.80–0.92 (9H,
m, CH3ꢃ3), 1.00–1.15 (2H, m), 1.18–1.45 (12H, m), 1.52–1.66 (3H, m),
1.90–2.10 (4H, m), 3.61–3.74 (2H, m), 5.30–5.44 (2H, m); dC (CDCl3):
11.4, 19.2, 19.5, 24.6, 26.93, 26.96, 29.0, 29.47, 29.49, 30.0, 32.6, 34.3,
identical with those reported for (3R,13R)-16. HRMS (FAB) calcd for
C17H36ONa: 279.2664, found: 279.2668.
4.9. 3,13-Dimethylpentadecanoic acid 17
4.9.1. (3R,13R)-Isomer. Jones chromic acid (2.67 M, 27.3 mL,
72.9 mmol) was added dropwise to an ice-cooled and stirred so-
lution of (3R,13R)-16 (3.75 g, 14.6 mmol) in acetone (300 mL) at
0 ꢂC. The mixture was stirred for 3 h at room temperature, and then
cooled to 0 ꢂC. The reaction was quenched with i-PrOH (6.5 mL) at
0 ꢂC. The resulting mixture was stirred for 1 h at room temperature.

K. Mori et al. / Tetrahedron 66 (2010) 2642–2653
2649
It was then concentrated in vacuo. The residue was diluted with
water and extracted with EtOAc. The combined organic solution
was successively washed with water and brine, dried (MgSO4), and
concentrated in vacuo. The residue was chromatographed over SiO2
The freshly prepared (R)-Alpine-BoraneÒ (11.1 mL) was added to
19 (2.37 g, 24.7 mmol) at room temperature under Ar. The mixture
was stirred for 4 h at room temperature. The liberated a-pinene
was then evaporated in vacuo at 70 ꢂC. The residue was diluted
with Et2O, and cooled to 0 ꢂC. To this cooled mixture, 4 M aqueous
NaOH solution (10 mL) and 30% aqueous H2O2 solution (10 mL)
were successively added dropwise. After stirring for 1 h at 0 ꢂC, the
mixture was extracted with Et2O. The combined organic solution
was successively washed with saturated aqueous NaHCO3 solution
and brine, dried (MgSO4), and concentrated at atmospheric pres-
sure. The residue was purified by chromatography over SiO2 [40 g,
elution with pentane/Et2O (10:1)] followed by distillation to give
1.15 g (47%) of (R)-18 as a colorless oil, bp 119–121 ꢂC; nD24¼1.4357;
(100 g). Elution with hexane/EtOAc (50:1) gave 3.73 g (94%) of
24
(3R,13R)-17 as a colorless oil; n2D3¼1.4493; [
a]
ꢁ0.34 (c 1.39,
D
CHCl3); nmax (film): 3040 (br s, CO2H), 1710 (s, C]O), 1410 (m), 1300
(br m), 940 (br m); dH (500 MHz, CDCl3): 0.84 (3H, d, J 6.5), 0.85 (3H,
t, J 7.0, CH2CH3), 0.96 (3H, d, J 7.0),1.04–1.37 (21H, m),1.91–2.00 (1H,
m, 3-H), 2.14 (1H, dd, J 8.0, 15, 2-Ha), 2.35 (1H, dd, J 6.0, 15, 2-Hb),
11.44 (1H, br s, CO2H); dC (126 MHz, CDCl3): 11.4, 19.2, 19.7, 26.9,
27.1, 29.5, 29.62, 29.64, 29.706, 29.713, 30.0, 30.1, 34.4, 36.6, 36.7,
41.6, 179.8. HR-EIMS calcd for C17H34O2 [M]þ: 270.2559, found:
270.2562.
25
D
25
[
[
a
a
]
]
ꢁ0.96 (c 1.37, CHCl3); [
a
]
þ12.7 (c 1.23, dioxane), lit. Ref. 17
D
þ14.6 (c 2, dioxane) 91% ee; nmax (film): 3380 (br s, OH),
D
4.9.2. (3R,13S)-Isomer. In the same manner as described above,
3310 (s, C^CH), 2120 (w, C^C), 1030 (br s, C–O); dH (500 MHz,
CDCl3): 1.00 (3H, d, J 6.5, CH3), 1.02 (3H, d, J 6.5, CH3), 1.85–1.94 (1H,
m, 4-H), 1.99 (1H, br s, OH), 2.46 (1H, d, J 2.0, C^CH), 4.18 (1H, dd, J
2.0, 5.5, 3-H); dC (126 MHz, CDCl3): 17.3, 17.9, 34.3, 67.7, 73.6, 83.6.
HR-EIMS calcd for C6H9O [MꢁH]þ: 97.0653, found: 97.0655.
A portion of (R)-18 was converted to its benzoate (R)-22 for
determination of enantiomeric purity. HPLC (column: ChiralcelÒ
OJ-H, eluent: hexane/i-PrOH¼9:1, 0.5 mL/min; detection: 254 nm):
tR 10.96 min [98.0%, (R)-isomer], 11.91 min [2.0%, (S)-isomer], en-
antiomeric purity of (R)-18¼96.0% ee.
(3R,13S)-16 (303 mg, 1.18 mmol) was converted into 269 mg (84%)
24
of (3R,13S)-17 as a colorless oil, n2D5¼1.4484; [
a]
þ9.46 (c 1.36,
D
CHCl3); nmax (film): 3040 (br s, CO2H), 1710 (s, C]O), 1410 (m), 1295
(br m), 940 (br m); dH (500 MHz, CDCl3): 0.84 (3H, d, J 6.0), 0.85 (3H,
t, J 7.0, CH2CH3), 0.96 (3H, d, J 6.5), 1.04–1.37 (21H, m), 1.91–2.00
(1H, m, 3-H), 2.14 (1H, dd, J 8.0, 15, 2-Hb), 2.35 (1H, dd, J 6.0, 15, 2-
Ha), 11.38 (1H, br s, CO2H); dC (126 MHz, CDCl3): 11.4, 19.2, 19.7, 26.9,
27.1, 29.5, 29.62, 29.63, 29.70, 29.71, 30.0, 30.1, 34.4, 36.6, 36.7, 41.6,
179.7. These 1H and 13C NMR spectroscopic data are virtually
identical to those of (3R,13R)-17. HR-EIMS calcd for C17H34O2 [M]þ:
270.2559, found: 270.2552.
4.12. (S)-2-Methyl-3-pentanol (S)-20
4.9.3. (3S,13R)-Isomer. In the same manner as described above,
4.12.1. Hydrogenation of (R)-18. Palladium/charcoal (10%, Kawaken
Co., 357 mg) was added to a solution of (R)-18 (3.57 g, 36.4 mmol)
in pentane (20 mL). The suspension was stirred under H2 (balloon)
for 3 h at room temperature. The suspension was filtered through
a bed of Celite. The filtrate was concentrated in vacuo to give
a mixture of (S)-20 and 21 [3.09 g, 83%, (S)-20/21¼2:1] as a color-
less oil. The residue was purified by column chromatography on
SiO2 [40 g, elution with pentane/Et2O (10:1)] followed by distilla-
tion to give 610 mg (16%) of (S)-20 as a colorless oil, bp 104–106 ꢂC;
(3S,13R)-16 (328 mg, 1.28 mmol) was converted into 310 mg (90%)
24
of (3S,13R)-17 as a colorless oil; n2D3¼1.4488; [
a
]
ꢁ9.38 (c 1.28,
D
CHCl3). Its IR, 1H and 13C NMR spectra were identical with those of
(3R,13S)-17. HR-EIMS calcd for C17H34O2 [M]þ: 270.2559, found:
270.2547.
4.9.4. (3S,13S)-Isomer. In the same manner as described above,
(3S,13S)-16 (305 mg, 1.19 mmol) was converted into 267 mg (83%)
24
25
25
of (3S,13S)-17 as a colorless oil; n2D3¼1.4490; [
a
]
D
þ0.04 (c 1.12,
n2D4¼1.4180; [
a
]
ꢁ14.0 (c 1.10, CHCl3); [
a]
ꢁ20.1 (c 1.16, EtOH);
D
D
CHCl3). Its IR, 1H and 13C NMR spectra were identical with those of
(3R,13R)-17. HR-EIMS calcd for C17H34O2 [M]þ: 270.2559, found:
270.2559.
nmax (film): 3360 (br s, OH), 980 (br s); dH (500 MHz, CDCl3): 0.91
(3H, d, J 7.0, CH3), 0.92 (3H, d, J 7.0, CH3), 0.96 (3H, t, J 7.0, 5-CH3),
1.31 (1H, d, J 5.0, OH),1.40 (1H, ddq, J 7.0, 8.5,14, 4-Hb),1.54 (1H, ddt,
J 5.0, 7.0, 14, 4-Ha), 1.67 (1H, d-sept., J 5.0, 7.0, 2-H), 3.28 (1H, sext., J
5.0, 3-H); dC (126 MHz, CDCl3): 10.3, 17.1, 18.9, 26.9, 33.1, 78.2. HR-
EIMS calcd for C6H14O [M]þ: 102.1045, found: 102.1044. A portion
of (S)-20 was (24 mg) was converted to its acetate (S)-23 with Ac2O
in pyridine (12 h, at room temperature) for determination of en-
4.10. 4-Methyl-1-pentyn-3-one 19
Jones chromic acid (2.67 M, 74.2 mL, 198 mmol) was added
dropwise to an ice-cooled and stirred solution of (ꢀ)-18 (19.4 g,
198 mmol) in acetone (400 mL) at 0 ꢂC. The mixture was stirred for
4 h at room temperature, and then cooled to 0 ꢂC. The reaction was
quenched with Na2SO3 (13 g) at 0 ꢂC. The resulting mixture was
diluted with water and extracted with Et2O. The combined organic
solution was successively washed with water, a saturated aqueous
NaHCO3 solution, and brine, dried (Na2SO4), and concentrated at
atmospheric pressure. The residue was distilled to give 13.9 g (73%)
of 19 as a colorless oil, bp 104–109 ꢂC; nD24¼1.4179; nmax (film): 3260
(s, C^CH), 2090 (s, C^C) 1680 (br s, C]O), 1060 (br s); dH
(500 MHz, CDCl3): 1.21 (6H, d, J 7.0, CH3ꢃ2), 2.68 (1H, sept., J 7.0, 4-
H), 3.23 (1H, s, C^CH). HR-EIMS calcd for C6H8O [M]þ: 96.0575,
found: 96.0573.
antiomeric purity. GC analysis of (S)-23 [column: Cyclodex-bÒ
,
30 mꢃ0.25 mm i.d.; carrier gas: He, 100 kPa; temperature: 40 ꢂC
(1 min)þ1.0 ꢂC/min to 100 ꢂC]: tR 24.68 min [97.5%, (S)-23],
25.91 min [2.5%, (R)-23], enantiomeric purity of (S)-23¼95.0% ee.
4.12.2. Asymmetric alkylation. A solution of diethylzinc (1.0 M in
n-hexane, 100 mL, 100 mmol) was added dropwise to an ice-cooled
and stirred solution of (2S)-(ꢁ)-3-exo-(morpholino)isoborneol
[(ꢁ)-MIB, 598 mg, 2.50 mmol] and isobutyraldehyde (31, 4.56 mL,
50.0 mmol) in dry toluene (50 mL) under Ar at 0 ꢂC. The mixture
was stirred for 3 h at 0 ꢂC. The reaction was then quenched with
a saturated aqueous NH4Cl solution. The resulting mixture was
extracted with Et2O, and the combined organic solution was suc-
cessively washed with a 1 M aqueous HCl solution, water, a satu-
rated aqueous NaHCO3 solution and brine, dried (MgSO4), and
concentrated at atmospheric pressure. The residue was purified by
chromatography over SiO2 [80 g, elution with pentane/Et2O (10:1)]
4.11. (R)-4-Methyl-1-pentyn-3-ol (R)-18
(R)-Alpine-BoraneÒ was prepared as follows: (1R)-(þ)-
a-pinene
(Aldrich, 97% ee, 28.7 mL, 181 mmol) was added to 9-BBN (Aldrich,
solid dimer, 20.1 g, 165 mmol) under Ar. After stirring for 6 h at
65 ꢂC, the mixture was then cooled to room temperature.
followed by distillation to give 2.31 g (45%) of (S)-20 as a colorless
26
oil, bp 64–66 ꢂC/125 Torr; n2D3¼1.4157. [
a
]
ꢁ15.6 (c 1.86, CHCl3);
D
26
[a
]
ꢁ18.6 (c 1.10, EtOH). Its IR, 1H and 13C NMR spectra were
D

2650
K. Mori et al. / Tetrahedron 66 (2010) 2642–2653
identical with those of (S)-20 prepared by hydrogenation of (R)-18.
HR-EIMS calcd for C6H14O [M]þ: 102.1045, found: 102.1047. A por-
tion of (S)-20 (96 mg) was converted to its acetate with Ac2O in
pyridine (12 h, at room temperature) for determination of
enantiomeric purity. GC analysis of the acetate [same conditions as
described above]: tR 24.32 min [98.4%, (S)-23], 25.99 min [1.6%, (R)-
23]; enantiomeric purity of (S)-20¼96.8% ee.
7.0, CH3), 0.89 (6H, d, J 7.0, CH3ꢃ2), 0.94 (3H, d, J 7.0, CH3), 1.04–1.37
(21H, m), 1.48–1.62 (2H, m, 100-H2), 1.83 (1H, d-sept., J 5.0, 7.0, 20-H),
1.92–2.00 (1H, m, 3-H), 2.11 (1H, dd, J 8.0, 15, 2-Hb), 2.31 (1H, dd, J
6.0, 15, 2-Ha), 4.68 (1H, ddd, J 5.0, 5.0, 8.0, 10-H); dC (126 MHz,
CDCl3): 9.9, 11.4, 17.6, 18.6, 19.2, 19.8, 24.0, 26.9, 27.1, 29.5, 29.65,
29.71, 29.8, 30.0, 30.4, 30.8, 34.4, 36.6, 36.7, 42.3, 79.4, 173.3. These
1H and 13C NMR spectroscopic data are virtually identical to those
of (3R,13R,10S)-1. HRMS calcd for C17H33O [MꢁC6H13O]þ: 253.2531,
found: 253.2534.
4.13. 1-Ethyl-2-methylpropyl 3,13-dimethylpentadecanoate 1
4.13.1. (3R,13R,10S)-Isomer. EDC (3.95 g, 20.6 mmol) was added to
an ice-cooled and stirred solution of (3R,13R)-17 (3.72 g,
13.8 mmol), (S)-20 (1.55 g, 15.2 mmol), and DMAP (2.52 g,
20.6 mmol) in dry CH2Cl2 (70 mL) at 0 ꢂC. After stirring for 14 h at
room temperature, the mixture was poured into water, and
extracted with Et2O. The combined organic solution was succes-
sively washed with water, a saturated aqueous NaHCO3 solution
and brine, dried (MgSO4), and concentrated in vacuo. The residue
was chromatographed over SiO2 (80 g). Elution with hexane/EtOAc
4.14. 5-Chloropentyl tosylate 25
Tosyl chloride (19.0 g, 100 mmol) was added portionwise to
a stirred and ice-cooled solution of 24 (9.8 g, 80 mmol) and DMAP
(0.1 g) in dry pyridine (45 mL) at 0–5 ꢂC. The mixture was stirred at
0–5 ꢂC for 2 h, poured into ice-water, and extracted with Et2O. The
extract was successively washed with water, dil HCl, saturated
NaHCO3 solution and brine, dried (MgSO4), and concentrated in
vacuo to give 21.7 g (96%) of 25 as an oil. nmax (film): 1599 (m), 1360
(s), 1188 (s), 1176 (s); dH (CDCl3): 1.40–1.51 (2H, m), 1.60–1.75 (4H,
m), 2.45 (3H, s, ArCH3), 2.15 (2H, t, J 6.4, CH2Cl), 4.04 (2H, t, J 6.4,
CH2OTs), 7.35 (2H, d, J 8.4, arom. H), 7.79 (2H, d, J 8.4, arom. H). This
was employed in the next step without further purification.
(50:1) gave 4.12 g (84%) of (3R,13R,10S)-1 as a colorless oil.
23
n2D3¼1.4448; [
a]
ꢁ5.38 (c 1.30, CHCl3); nmax (film): 1735 (s, C]O),
D
1180 (m), 975 (m); dH (500 MHz, CDCl3): 0.84 (3H, d, J 7.0, CH3), 0.85
(3H, d, J 7.0, CH3), 0.87 (3H, t, J 7.0, CH3), 0.89 (6H, d, J 7.0, CH3ꢃ2),
0.94 (3H, d, J 7.0, CH3), 1.05–1.37 (21H, m), 1.48–1.62 (2H, m, 100-H2),
1.83 (1H, d-sept., J 5.0, 7.0, 20-H), 1.91–2.01 (1H, m, 3-H), 2.11 (1H,
dd, J 8.0, 15, 2-Hb), 2.31 (1H, dd, J 6.0, 15, 2-Ha), 4.68 (1H, ddd, J 5.0,
5.0, 8.0, 10-H); dC (126 MHz, CDCl3): 9.9, 11.4, 17.6, 18.6, 19.2, 19.7,
24.0, 26.9, 27.1, 29.5, 29.64, 29.65, 29.7, 29.8, 30.0, 30.4, 30.9, 34.4,
4.15. (R)-7-Methylnonyl chloride 26
A Grignard reagent was prepared in the conventional manner by
adding a solution of (R)-5 (14.9 g, 99 mmol) in dry THF (60 mL) to
a stirred suspension of Mg (2.6 g, 110 mmol) in dry THF (10 mL).
After the addition of 5 mL of the solution of (R)-5, the reaction was
initiated by the addition of a trace amount of I2 while refluxing. The
solution of (R)-5 was added dropwise to maintain the refluxing of
THF. The obtained Grignard reagent was cooled to room tempera-
ture, and added dropwise to a stirred and cooled solution of 25
(21.6 g, 78 mmol) in dry THF (60 mL) at ꢁ70 to ꢁ60 ꢂC under Ar.
Immediately after the addition, a solution of Li2CuCl4 in dry THF
(0.1 M, 3 mL, 0.3 mmol) was added, and the stirred mixture was left
to stand overnight under Ar with gradual warming to room tem-
perature. The mixture was quenched with ice and NH4Cl solution,
and extracted with hexane. The hexane solution was washed with
water and brine, dried (MgSO4), and concentrated in vacuo. The
36.6, 36.8, 42.3, 79.4, 173.3. HR-EIMS calcd for C17H33
O
[MꢁC6H13O]þ: 253.2531, found: 253.2529.
4.13.2. (3R,13S,10S)-Isomer. In the same manner as described above,
(3R,13S)-17 (86 mg) was converted into 105 mg (93%) of
23
(3R,13S,10S)-1 as a colorless oil; n2D3¼1.4439; [
a]
þ1.63 (c 1.32,
D
CHCl3); nmax (film): 1735 (s, C]O), 1180 (m), 975 (m); dH (500 MHz,
CDCl3): 0.84 (3H, d, J 7.0, CH3), 0.85 (3H, d, J 7.0, CH3), 0.87 (3H, t, J
7.0, CH3), 0.89 (6H, d, J 7.0, CH3ꢃ2), 0.94 (3H, d, J 7.0, CH3), 1.05–1.37
(21H, m), 1.48–1.62 (2H, m, 100-H2), 1.83 (1H, d-sept., J 5.0, 7.0, 20-H),
1.91–2.01 (1H, m, 3-H), 2.11 (1H, dd, J 8.0, 15, 2-Hb), 2.31 (1H, dd, J
6.0, 15, 2-Ha), 4.68 (1H, ddd, J 5.0, 5.0, 8.0, 10-H); dC (126 MHz,
CDCl3): 9.9, 11.4, 17.6, 18.6, 19.2, 19.7, 24.0, 26.9, 27.1, 29.5, 29.64,
29.65, 29.7, 29.8, 30.0, 30.4, 30.9, 34.4, 36.6, 36.8, 42.3, 79.4, 173.3.
These 1H and 13C NMR spectroscopic data are virtually identical to
those of (3R,13R,10S)-1. HR-EIMS calcd for C17H33O [MꢁC6H13O]þ:
253.2531, found: 253.2534.
residue was distilled to give (R)-26 (12.5 g, 71%) as a colorless oil, bp
26
73–75 ꢂC/4 Torr; n2D4¼1.4422; [
a
]
ꢁ8.05 (c 6.84, pentane); nmax
D
(film): 2958 (s), 2929 (s), 2856 (s), 1462 (m), 1377 (m), 727 (m), 656
(m); dH (CDCl3): 0.84 (3H, d, J 5.6, CHCH3), 0.86 (3H, t, J 7.2, CH2CH3),
1.05–1.20 (2H, m), 1.20–1.73 (7H, m), 1.38–1.46 (2H, m), 1.77 (2H,
m), 3.53 (2H, t, J 6.8, CH2Cl): dC (CDCl3): 11.4, 19.2, 26.9, 29.2, 29.5,
32.6, 34.3, 36.5, 45.1; GC–MS [column: HP-5MS, 5% phenyl-
methylsiloxane, 30 mꢃ0.25 mm i.d.; press: 60.7 kPa; temperature:
70–230 ꢂC (þ10 ꢂC/min)]: tR 4.31 min [2.1%, (3R,6R)-3,6-dimethyl-
octane], 6.95 min (7.8%, 1-bromo-5-chloropentane), 8.85 min
[85.8%, (R)-26]; MS of (R)-26 (70 eV, EI): m/z: 176 (<1) [Mþ,
C10H21Cl], 147 (33), 111 (34), 105 (21), 69 (84), 57 (100), 41 (50).
HRMS calcd for C10H21Cl: 176.1332, found: 176.1331.
4.13.3. (3S,13R,10S)-Isomer. In the same manner as described above,
(3S,13R)-17 (128 mg) was converted into 153 mg (91%) of
23
(3S,13R,10S)-1 as a colorless oil; n2D3¼1.4440; [
a
]
ꢁ10.8 (c 1.31,
D
CHCl3); nmax (film): 1735 (s, C]O), 1180 (m), 975 (m); dH (500 MHz,
CDCl3): 0.84 (3H, d, J 7.0, CH3), 0.85 (3H, d, J 7.0, CH3), 0.87 (3H, t, J
7.0, CH3), 0.89 (6H, d, J 7.0, CH3ꢃ2), 0.94 (3H, d, J 7.0, CH3), 1.05–1.37
(21H, m), 1.48–1.62 (2H, m, 100-H2), 1.83 (1H, d-sept., J 5.0, 7.0, 20-H),
1.92–2.00 (1H, m, 3-H), 2.11 (1H, dd, J 8.0, 15, 2-Hb), 2.31 (1H, dd, J
6.0, 15, 2-Ha), 4.68 (ddd, J 5.0, 5.0, 8.0, 10-H): dC (126 MHz, CDCl3):
9.9, 11.4, 17.6, 18.6, 19.2, 19.8, 24.0, 26.9, 27.1, 29.5, 29.65, 29.70, 29.8,
4.16. (R)-7-Methylnonyl iodide 27
30.0, 30.4, 30.8, 34.4, 36.6, 36.7, 42.3, 79.4, 173.3. These 1H and 13
C
NMR spectroscopic data are virtually identical to those of
(3R,13R,10S)-1. HR-EIMS calcd for C17H33O [MꢁC6H13O]þ: 253.2531,
found: 253.2533.
Sodium iodide (45.0 g, 300 mmol) was added to a solution of
(R)-26 (12.4 g, 70 mmol) and DMF (10 mL) in acetone (200 mL). The
mixture was stirred and heated under reflux for 10 h. The initial
solution soon became turbid, and NaCl precipitated. The mixture
was concentrated in vacuo, diluted with water, and extracted with
hexane. The hexane extract was washed with water and brine,
dried (MgSO4), and concentrated in vacuo. The residue was distilled
4.13.4. (3S,13S,10S)-Isomer. In the same manner as described above,
(3S,13S)-17 (113 mg) was converted into 139 mg (94%) of
23
(3S,13S,10S)-1 as a colorless oil; n2D3¼1.4451; [
a
]
D
ꢁ3.42 (c 1.20,
CHCl3); nmax (film): 1735 (s, C]O), 1180 (m), 975 (m); dH (500 MHz,
CDCl3): 0.84 (3H, d, J 7.0, CH3), 0.85 (3H, d, J 7.0, CH3), 0.87 (3H, t, J
to give 16.8 g (89%) of (R)-27 as a colorless oil, bp 96–98 ꢂC/5 Torr;
n2D2¼1.4958; [
a
]
ꢁ5.42 (c 7.94, hexane); nmax (film): 2958 (s), 2927
25
D

K. Mori et al. / Tetrahedron 66 (2010) 2642–2653
2651
(s), 2871 (s), 2854 (s), 1462 (m), 1377 (m), 1200 (m), 1171 (m); dH
4.20. (3R,13R)-3,13-Dimethyl-1-pentadecanol 16
(CDCl3): 0.84 (3H, d, J 6.0, CHCH3), 0.86 (3H, t, J 7.2, CH2CH3), 1.05–
1.20 (2H, m), 1.20–1.45 (9H, m), 1.74–1.90 (2H, m), 3.19 (2H, t, J 7.2,
CH2I); dC (CDCl3): 7.3, 11.4, 19.2, 26.8, 28.9, 29.4, 30.5, 33.5, 34.3,
36.4; GC–MS (same conditions as for (R)-26): tR 11.16 min (12.0%,
1,5-diiodopentane), 11.35 min [86.0%, (R)-27]; MS of (R)-27 (70 eV,
EI): m/z: 268 (4) [Mþ, C10H21I], 155 (15), 141 (16), 99 (15), 85 (73), 71
(63), 57 (100), 43 (46), 41 (39). HRMS calcd for C10H21I: 268.0688,
found: 268.0684.
Pd–C (10%, 0.5 g) was added to a solution of (3R,6EZ,13R)-30
(4.2 g, 16.5 mmol) in EtOAc (50 mL). The mixture was stirred under
H2 (balloon) for 1 h at room temperature, and filtered through
Celite. The Celite layer was washed with hexane. The combined
filtrate and washings were concentrated in vacuo to give 3.76 g
26
(95%) of (3R,13R)-16 as a colorless oil. n2D2¼1.4510; [
a
]
ꢁ2.73 (c
D
4.40, hexane); nmax (film): 3334 (br, OH), 2958 (s), 2925 (s), 2854 (s),
1464 (m), 1377 (m), 1059 (m), 721 (w); dH (CDCl3): 0.80–0.93 (9H,
m, CH3ꢃ3), 1.02–1.19 (3H, m), 1.20–1.45 (20H, m), 1.50–1.66 (2H, m),
3.61–3.72 (2H, m); dC (CDCl3): 11.5, 19.3, 19.7, 27.0, 27.2, 29.5, 29.73,
29.75, 29.77, 30.0, 30.06, 30.15, 34.4, 36.7, 37.2, 40.0, 61.2; GC–MS
[same conditions as for (R)-26]: tR 16.92 min (91.5%, 16); MS of
(3R,13R)-16 (70 eV, EI): m/z: 255 (<1) [Mþꢁ1, C17H35O], 210 (5), 181
(6), 153 (4), 139 (10), 125 (16), 111 (30), 97 (54), 83 (55), 70 (100), 69
(50), 57 (56), 56 (36), 55 (58), 43 (34), 41 (32). The spectral data of
the present 16 was identical to those of 16 prepared via the me-
tathesis route (Section 4.8.1).
4.17. (R)-7-Methylnonyltriphenylphosphonium iodide 28
A solution of (R)-27 [86% purity,13.5 g, 43 mmol (containing 12%
of 1,5-diiodopentane)] and triphenylphosphine (15.0 g, 57 mmol)
in dry toluene (50 mL) was stirred and heated under reflux under
Ar. After 10 min, the solution became turbid. Stirring and refluxing
was continued for 3.5 h, and the mixture was cooled to separate
into two layers. The lower layer solidified. Its recrystallization was
unsuccessful presumably due to the contamination of the
bisphosphonium salt resulting from 1,5-diiodopentane. The lower
layer was washed four times with dry benzene by stirring followed
by decantation to remove excess triphenylphosphine, and the
remaining lower layer of crude (R)-28 was used in the next step.
4.21. (R)-Citronellic acid 32
(R)-Citronellal (10, 21.0 g, 136 mmol) was oxidized with PDC as
26
reported previously21 to give 18.6 g (87%) of (R)-32. [
2.98, CHCl3).
a]
þ9.44 (c
D
4.18. (R)-6-Acetoxy-4-methylhexanal 29
This was obtained by the known method9 in 90% overall yield;
nmax (film): 2960 (m), 2931 (m), 2875 (m), 2725 (w, O]C–H), 1738
(vs, C]O), 1244 (s, C–O). This was used in the next step without
further purification.
4.22. (3R,10S)-1-Ethyl-2-methylpropyl citronellate 33
In the same manner as described in Section 4.12.2, 31 (4.56 mL,
50.0 mmol) in dry toluene (50 mL) was reacted with diethylzinc
(1.0 M solution in hexane, 100 mL, 100 mmol) in the presence of
(ꢁ)-MIB (598 mg, 2.50 mmol) at 0 ꢂC. After stirring for 3 h at 0 ꢂC,
the reaction was quenched with saturated aqueous NH4Cl solution
(50 mL). To this mixture, a 2 M aqueous HCl solution (120 mL,
240 mmol) was added slowly at 0 ꢂC. After stirring for 30 min at
room temperature, the mixture was diluted with Et2O. The organic
solution was washed twice with 2 M aqueous HCl solutions
(30 mLꢃ2). These acidic aqueous phases were combined. The or-
ganic solution was successively washed with water, a saturated
aqueous NaHCO3 solution and brine, dried (MgSO4), and filtered to
give a solution of crude (S)-20.
The combined acidic solution was made alkaline with a 4 M
aqueous NaOH solution, and extracted with Et2O. The combined
organic solution was washed with water and brine, dried (MgSO4),
and concentrated in vacuo. The residue was chromatographed over
SiO2 (20 g). Elution with hexane/EtOAc (4:1) gave 533 mg (89%) of
recovered (ꢁ)-MIB.
4.19. (3R,6EZ,13R)-3,13-Dimethyl-6-pentadecen-1-ol 30
A Wittig reagent was prepared by dropwise addition of n-BuLi in
hexane (1.6 M, 30.5 mL, 49 mmol) to a stirred and cooled solution
of (R)-28 [prepared from 13.5 g of (R)-27 (86% purity containing 12%
of 1,5-diiodopentane), ca. 43 mmol] in dry THF (50 mL) at ꢁ30 to
0 ꢂC under Ar. The resulting red solution was added dropwise to
a stirred and cooled solution of (R)-29 (7.0 g, 40 mmol) in dry THF
(50 mL) at ꢁ60 to ꢁ50 ꢂC under Ar. The red color soon disappeared,
and the stirred mixture was left to stand overnight with gradual
raise of the reaction temperature to room temperature. A solution
of NaOH (5 g, 120 mmol) in MeOH (40 mL) and water (20 mL) was
added, and the mixture was concentrated in vacuo. The residue was
partitioned between hexane and aqueous MeOH [MeOH/H2O¼2:1
(v/v)]. The hexane layer was separated, washed with aqueous
MeOH (MeOH/H2O¼2:1) containing 1 mL of 30% H2O2, which re-
moved a trace of Ph3P by oxidizing it to Ph3PO. Even a trace amount
of Ph3P in 30 inhibits its hydrogenation over Pd–C. The hexane
solution was washed with water and brine, dried (MgSO4), and
concentrated in vacuo. The residue was chromatographed over SiO2
(100 g) in hexane. Elution with hexane/EtOAc (3:1) gave 4.4 g (43%)
of (3R,6EZ,13R)-30 as a colorless oil. nmax (film): 3336 (br, OH), 2958
(s), 2873 (s), 2856 (s), 1462 (m), 1377 (m), 1057 (m), 966 (w); dH
(CDCl3): 0.84 (3H, d, J 7.6, CHCH3), 0.85 (3H, t, J 8.0, CH2CH3), 0.91
(3H, d, J 6.4, CHCH3), 1.04–1.18 (2H, m),1.18–1.50 (13H, m),1.52–1.68
(2H, m), 1.90–2.10 (4H, m), 3.60–3.74 (2H, m), 5.30–5.44 (2H, m); dC
(CDCl3): 11.4,19.2,19.5, 24.7, 26.93, 26.96, 27.2, 29.5, 29.6, 29.7, 32.6,
34.4, 36.6, 37.0, 37.1, 39.9, 61.1, 129.5 and 129.9 [(Z)-30], 130.0 and
130.4 [(E)-30; Z/E¼2:1]. GC–MS [same conditions as for (R)-26]: tR
16.69 min [60.5%, (Z)-30], 16.77 min [34.8%, (E)-30]; MS of (Z)- and
(E)-30 were identical (70 eV, EI): m/z: 254 (<1) [Mþ, C17H34O], 236
(3), 221 (3), 208 (3), 151 (4), 137 (7), 123 (11), 109 (33), 95 (39), 81
(100), 71 (39), 69 (37), 68 (38), 55 (46), 41 (33). The spectral data of
30 prepared by this route was virtually identical to those of 30
prepared by metathesis (Section 4.7.1).
To the obtained solution of crude (S)-20, (R)-citronellic acid (32,
8.50 g, 49.9 mmol) and DMAP (9.16 g, 75.0 mmol) were added. The
mixture was cooled to 0 ꢂC. EDC (14.5 g, 75.6 mmol) was added to
the mixture at 0 ꢂC. After stirring for 12 h at room temperature, the
mixture was poured into water, and extracted with EtOAc. The
combined organic solution was successively washed with water
and brine, dried (MgSO4), and concentrated in vacuo. The residue
was chromatographed over SiO2 [150 g, elution with hexane/EtOAc
(25:1)] followed by distillation to give 9.44 g (74% based on 32) of
33 as a colorless oil, bp 98–100 ꢂC/0.2 Torr; nD23¼1.4453; [
a
]
ꢁ2.55
22
D
(c 1.20, CHCl3); nmax (film): 1730 (s, C]O),1670 (w, C]C),1190 (br s,
C–O), 980 (br s); dH (500 MHz, CDCl3): 0.87 (3H, t, J 7.0, 200-H3), 0.89
(6H, d, J 7.0, 20-CH3ꢃ2), 0.96 (3H, d, J 7.0, 3-CH3), 1.19–1.27 (1H, m,
4-Ha), 1.34–1.41 (1H, m, 4-Hb), 1.48–1.60 (2H, m, 100-H2), 1.60 (3H, br
s, 7-CH3), 1.68 (3H, br s, 7-CH3), 1.79–1.87 (1H, m, 20-H), 1.93–2.07
(3H, m, 3-H, 5-H2), 2.12 (1H, dd, J 8.5,15, 2-Ha), 2.33 (1H, dd, J 6.0,15,
2-Hb), 4.69 (1H, ddd, J 5.0, 5.5, 8.0, 10-H), 5.09 (1H, t-quint., J 7.0, 1.5,
6-H); dC (126 MHz, CDCl3): 9.9, 17.6, 18.6, 19.6, 23.9, 25.4, 25.7, 30.0,

2652
K. Mori et al. / Tetrahedron 66 (2010) 2642–2653
30.8, 36.8, 42.1, 79.4, 124.3, 131.4, 173.2. HR-EIMS calcd for C16H30O2
[M]þ: 254.2246, found: 254.2234.
concentrated in vacuo. The residue (2.24 g) was chromatographed
over SiO2 (30 g). Elution with hexane/EtOAc (10:1) gave
23
(3R,6EZ,13R,10S)-36 (1.15 g, 47%) as a colorless oil; n2D4¼1.4552; [
a]
D
4.23. (3R,6RS,10S)-10-Ethyl-20-methylpropyl 6,7-
epoxycitronellate 34
ꢁ8.67 (c 3.51, hexane); nmax (film): 2964 (s), 2927 (s), 2875 (m),
2856 (w), 1732 (s, C]O), 1462 (m), 1379 (m), 1200 (m), 1161 (m),
1128 (m), 974 (m); dH (CDCl3): 0.80–0.90 (9H, m, CH3ꢃ3), 0.89 [6H,
d, J 7.2, CH(CH3)2], 0.96 (3H, d, J 7.2, CHCH3), 1.04–1.18 (2H, m), 1.20–
1.48 (11H, m), 1.48–1.50 (2H, m), 1.78–1.88 (1H, m), 1.94–2.10 (5H,
m), 2.10–2.18 (1H, m), 2.30–2.38 (1H, m), 4.65–4.72 (1H, m), 5.30–
5.41 (2H, m); dC (CDCl3): 9.9, 11.4, 17.7, 18.6, 19.6, 19.8, 24.0, 24.7,
27.0, 27.3, 29.5, 29.7, 29.9, 30.1, 30.9, 34.4, 36.6, 36.8, 42.1, 79.4, 129.1
and 130.1 [(Z)-36], 129.5 and 129.6 [(E)-36; Z/E¼6:1], 172.9; GC–MS
[same condition as for (R)-26]: tR 18.32 min (5.2%, unidentified),
20.61 min [80.3%, (Z)-36], 20.80 min [13.1%, (E)-36]; MS of 36
(70 eV, EI) [Both (E)- and (Z)-36 showed identical MS.]: m/z: 352
(<1) [Mþ], 268 (12), 251 (50), 239 (11), 221 (9), 208 (21),137 (8),125
(9), 111 (10), 109 (10), 97 (15), 95 (15), 85 (100), 70 (44), 69 (34), 55
(27), 43 (50). HRMS calcd for C17H31O [C23H44O2ꢁC6H13O (alcohol
part)]: 251.2375, found: 251.2364.
MCPBA (65% purity, 2.5 g, ca. 10 mmol) was added portionwise
to a stirred and ice-cooled solution of (3R,10S)-33 (2.20 g, 8.7 mmol)
in dry CH2Cl2 (10 mL) at 0–5 ꢂC. The mixture was stirred for 30 min
at 0–5 ꢂC to generate the paste of m-chlorobenzoic acid. It was then
diluted with hexane, and filtered through a glass filter. The solid on
the filter was washed with hexane. The combined filtrate and
washings were washed with NaHCO3 solution and brine, dried
(MgSO4), and concentrated in vacuo. The residue was chromato-
graphed over SiO2 (20 g). Elution with hexane/EtOAc (10:1) gave
2.52 g (quant.) of 34 as a colorless oil; nmax (film): 2964 (s), 2933 (s),
2877 (m), 1730 (s, C]O), 1462 (m), 1288 (m), 1250 (m), 1205 (m),
1167 (m), 1124 (m), 976 (m); dH (CDCl3): 0.87 (3H, t, J 7.2, CH2CH3),
0.89 (6H, d, J 6.8, CH(CH3)2), 0.98 (3H, d, J 6.8, CHCH3), 1.27 (3H, s,
CH3), 1.31 (3H, s, CH3), 1.40–1.65 (6H, m), 1.78–1.88 (1H, m), 1.98–
2.08 (1H, m), 2.12–2.21 (1H, m), 2.30–2.38 (1H, m), 2.71 (1H, t-like, J
5.6, OCH), 4.66–4.74 (1H, m, O]C–O-CH). This was employed in the
next step without further purification.
4.26. (3R,13R,10S)-10-Ethyl-20-methylpropyl 3,13-
dimethylpentadecanoate 1
4.24. (3R,10S)-10-Ethyl-20-methylpropyl 3-methyl-6-
oxohexanoate 35
Pd–C (10%, 0.22 g) was added to a solution of (3R,6EZ,13R,10S)-36
(1.05 g, 3 mmol) in EtOAc (20 mL). The mixture was vigorously
stirred under H2 (balloon) for 1.5 h at room temperature. The
mixture was filtered through SiO2 (10 g) in hexane, and the column
was washed with hexane/EtOAc (5:1). The filtrate and washings
A solution of 34 (2.35 g, 8.7 mmol) in Et2O (10 mL) was added
dropwise to a stirred and ice-cooled solution of HIO4$2H2O (2.30 g,
10.1 mmol) in THF (15 mL). The mixture was stirred for 0.5 h at
0–5 ꢂC. HIO3 separated from the solution as white precipitates. The
mixture was diluted with water, and extracted with Et2O. The ex-
tract was successively washed with water, NaHCO3 solution, and
brine, dried (MgSO4), and concentrated in vacuo. The residue
(2.47 g) was chromatographed over SiO2 (20 g). Elution with hex-
were concentrated in vacuo to give (3R,13R,10S)-1 (1.01 g, 96%) as
25
a colorless oil; n2D4¼1.4478; [
a
]
ꢁ4.61 (c 2.52, CHCl3); nmax (film):
D
2964 (s), 2925 (s), 2875 (s), 2854 (s), 1734 (s, C]O), 1464 (m), 1379
(m), 1252 (m), 1180 (m), 1126 (m), 976 (m); dH (CDCl3): 0.80–0.90
(9H, m, CH3ꢃ3), 0.89 [6H, d, J 6.8, CH(CH3)2], 0.94 (3H, d, J 6.4,
CHCH3), 1.02–1.12 (2H, m), 1.13–1.40 (18H, m), 1.48–1.65 (3H, m),
1.78–1.88 (1H, m), 1.90–2.00 (1H, m), 2.08–2.15 (1H, m), 2.25–2.45
(1H, m), 4.64–4.70 (1H, m); dC (CDCl3): 9.97,11.5,17.7,18.7,19.3,19.8,
24.0, 27.0, 27.2, 29.5, 29.7, 29.76, 29.85, 30.1, 30.4, 30.9, 34.4, 36.7,
36.8, 42.3, 79.4, 173.2; GC–MS [same condition as for (R)-26]: tR
18.32 min (5.3%, unidentified), 21.04 min [92.5%,þ(3R,13R,10S)-1];
MS of (3R,13R,10S)-1 (70 eV, EI): m/z: 339 (<1) [M ꢁ15], 271 (17),
270 (29), 253 (53), 81 (95), 84 (100), 69 (35), 57 (34), 43 (39).
ane/EtOAc (10:1) gave 1.61 g (82%) of 35 as a colorless oil;
23
n2D4¼1.4398; [
a]
ꢁ3.73 (c 2.40, hexane); nmax (film): 2966 (s), 2935
D
(s), 2877 (s), 2823 (w), 2721 (w, O]C–H), 1728 (s, C]O), 1464 (m),
1383 (m), 1371 (m), 1255 (m), 1203 (m), 1165 (m), 1128 (m), 1099
(m), 976 (m); dH (CDCl3): 0.87 (3H, t, J 7.6, CH2CH3), 0.882 [3H, d, J
6.8, CH(CH3)CH3], 0.890 [3H, d, J 6.8, CH(CH3)CH3], 0.98 [3H, d, J 6.8,
CHCH3], 1.48–1.61 (3H, m), 1.68–1.78 (1H, m), 1.79–1.88 (1H, m),
1.95–2.06 (1H, m), 2.12–2.22 (1H, m), 2.30–2.36 (1H, m), 2.42–2.52
(2H, m), 4.66–4.71 (1H, m), 9.78 (1H, t, J 1.6, O]C–H); GC–MS [same
conditions as for (R)-26]: tR 12.70 min (86.3%, 35), 15.12 min (12.3%,
unidentified); MS of 35 (70 eV, EI): m/z: 213 (<1) [Mþꢁ15], 127
(100), 101 (10), 85 (24), 84 (22), 81 (47), 69 (20), 55 (14), 43 (26).
4.27. Field experiment
The four stereoisomers (3R,13R,10S)-, (3R,13S,10S)-, (3S,13R,10S)-,
and (3S,13S,10S)-1 were tested for the attraction of male C. variegata
in P. hispanica forests in Yantai, Shandong Province, China (121ꢂ590E.
37ꢂ280N) for 12-day period from the 1st of June to the 12th of June
2009, using a randomized complete block design. A red rubber
HRMS calcd for C7H11O2 [C13H24O3ꢁC6H13
O (alcohol part)]:
127.0759, found: 127.0743.
4.25. (3R,6EZ,13R,10S)-10-Ethyl-20-methylpropyl 3,13-dimethyl-
6-pentadecenoate 36
septum was loaded with 100
mg of each the four stereoisomers
dissolved in 200 L of hexane, and the solvent was allowed to
m
A Wittig reagent was prepared by the dropwise addition of n-
BuLi in hexane (1.6 M, 6.9 mL, 11 mmol) to a stirred and cooled
solution of (R)-28 [prepared from 2.8 g of (R)-27 (81% purity con-
taining 12% of 1,5-diiodopentane), ca. 10 mmol] in dry THF (10 mL)
at ꢁ30 to 0 ꢂC under Ar. The resulting red solution was added
dropwise to a stirred and cooled solution of (3R,10S)-35 (1.60 g,
7 mmol) in dry THF (10 mL) at ꢁ60 to ꢁ50 ꢂC under Ar. The stirred
mixture was left to stand overnight with gradual raise of the re-
action temperature to room temperature. The reaction was
quenched by adding MeOH (10 mL) and water (5 mL). H2O2 (30%,
1 mL) was added to the mixture to oxidize Ph3P to Ph3PO. The
mixture was then extracted with hexane. The extract was washed
with MeOH/H2O (2:1, 20 mL) and brine, dried (MgSO4), and
evaporate in a fume hood. The septa were stored at ꢁ20 ꢂC until
ready for use, except when shipped. Sticky traps were made from
open-ended 2 L milk cartons coated inside with Entomological Glue
(Huanxing Company, Guangdong Province, China), suspended from
trees 10 m above ground. Traps were placed in five rows with five
replications for each treatment at approximately 15–20 m spacing
between trapping stations and treatment rows. Septa were placed in
the center of the white sticky base lying on the sticky surface. Traps
baited with blank septa were used as negative controls. One of each
of the five treatments was randomly assigned to a trap tree within
each row of trees. Every day, except when it rained, the numbers of
moths captured were recorded and treatment positions were re-
randomized.

K. Mori et al. / Tetrahedron 66 (2010) 2642–2653
2653
4.27.1. Statistical analysis. The significance of the treatment effects
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K.M. thanks Mr. M. Kimura (President, Toyo Gosei Co., Ltd) for
his support. Our thanks are due to Mr. Y. Shikichi (Toyo Gosei Co.,
Ltd) for NMR and GC–MS measurements, and Dr. S. Tamogami (T.
Hasegawa Co.) for enantioselective GC analyses. We are grateful to
Professor T. Nakata (Tokyo University of Science) and Dr. T. Naka-
mura (RIKEN) for HRMS analyses, and Professor K. Manabe (RIKEN)
for his permission to use his GC apparatus. Both (R)- and (S)-cit-
ronellal were given by Takasago International Corporation, and (R)-
2-methylbutanoic acid was supplied by T. Hasegawa Co.
The biological work was partially supported by the New Zealand
Foundation for Research Science and Technology (CO2X0501, Better
Border Biosecurity; www.63nz.org), the State Forestry Adminis-
tration of China (No. 20070430), and the Natural Science Founda-
tion of China (No. 30872031). We thank Lee-Anne Manning and
Andrew Twiddle for technical assistance, and John Byers for com-
menting on the biological part of this paper.
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