Synthesis and bioassay of the eight analogues of the ch503 male pheromone (3-acetoxy-11,19-octacosadien-1-ol) of the Drosophila Melanogaster fruit fly

Article abstract of DOI:10.1271/bbb.130383

Eight analogues of (3R,11Z,19Z)-CH503 (3-acetoxy- 11,19-octacosadien-1-ol), the anti-aphrodisiac pheromone of male Drosophila melanogaster, were synthesized for a bioassay. These were the enantiomers of 3-acetoxy- 11,19-octacosadiyn-1-ol (1), 3-acetoxyoctacosan-1-ol (2), (Z)-3-acetoxy-11- octacosen-1-ol (3), and (Z)-3-acetoxy- 19-octacosen-1-ol (4). None of them were pheromonally active, indicating that the two double bonds at C-11 and C-19 were necessary for bioactivity.

Full text of DOI:10.1271/bbb.130383

Biosci. Biotechnol. Biochem., 77 (9), 1931–1938, 2013
Synthesis and Bioassay of the Eight Analogues of the CH503 Male Pheromone
*
(3-Acetoxy-11,19-octacosadien-1-ol) of the Drosophila melanogaster Fruit Fly
y
1;
Yasumasa SHIKICHI,1 Shruti SHANKAR,2;3 Joanne Y. YEW,2;3 and Kenji MORI
1Photosensitive Materials Research Center, Toyo Gosei Co., Ltd., 4-2-1 Wakahagi, Inzai, Chiba 270-1609, Japan
2Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, Singapore 117604, Singapore
3Department of Biological Sciences, 14 Science Drive 4, National University of Singapore,
Singapore 117546, Singapore
Received May 10, 2013; Accepted June 2, 2013; Online Publication, September 7, 2013
[doi:10.1271/bbb.130383]
Eight analogues of (3R,11Z,19Z)-CH503 (3-acetoxy-
11,19-octacosadien-1-ol), the anti-aphrodisiac phero-
mone of male Drosophila melanogaster, were synthesized
for a bioassay. These were the enantiomers of 3-acetoxy-
11,19-octacosadiyn-1-ol (1), 3-acetoxyoctacosan-1-ol (2),
(Z)-3-acetoxy-11-octacosen-1-ol (3), and (Z)-3-acetoxy-
19-octacosen-1-ol (4). None of them were pheromonally
active, indicating that the two double bonds at C-11 and
C-19 were necessary for bioactivity.
OH
OH
n-C8H17
OAc
OAc
(3R,11Z,19Z)-CH503
natural pheromone with weak bioactivity
n-C8H17
(3S,11Z,19Z)-CH503
unnatural enantiomer with stronger bioactivity
Key words: 3-acetoxy-11,19-octacosadiyn-1-ol; 3-ace-
toxyoctacosan-1-ol; 3-acetoxy-11 or 19-
octacosen-1-ol; Drosophila melanogaster;
pheromone
OH
OAc
n-C8H17
n-C8H17
1
In 2009, Yew et al. isolated a new pheromone named
CH503 from the male fruit fly, Drosophila melanogaster,
and identified it as 3-acetoxy-11,19-octacosadien-1-ol.
The CH503 pheromone is transferred from males to
females during mating, remains on the surface of
females for at least 10 d, and inhibits courtship as an
anti-aphrodisiac.2) Since it has been well established that
bioactivity depended on the correct stereochemistry of a
pheromone,3,4) we decided to determine the olefin
geometry and absolute configuration at C-3 of CH503.
In 2010, we synthesized the enantiomers of
(11Z,19Z)-CH503 (Fig. 1), and found (3S,11Z,19Z)-
CH503 to be bioactive, while (3R,11Z,19Z)-CH503
was only slightly bioactive at the equivalent dose.5)
We therefore thought that (3S,11Z,19Z)-CH503 might
be the naturally occurring pheromone.5) The remaining
six stereoisomers of CH503 were subsequently synthe-
sized in 2012.6) Complete separation of the eight
stereoisomers of CH503 by reversed-phase HPLC at
ꢀ20 ꢁC was achieved after their esterification with
(1R,2R)-2-(2,3-anthracenedicarboximido)cyclohexane-
carboxylic acid, and natural CH503 was found to be
(3R,11Z,19Z)-CH503.6) Curiously, regardless of the
geometry of the two double bonds, all (S)-stereoisomers
of CH503 were also bioactive. It was therefore difficult
to determine the stereostructure of natural CH503 on the
basis of bioassay data alone.
OH
OAc
2
n-C8H17
n-C8H17
OH
OH
OAc
3
OAc
4
Fig. 1. Structures of (3R,11Z,19Z)-CH503, the Anti-Aphrodisiac
Pheromone of the Male Fruit Fly (Drosophila melanogaster), and
Its Analogues.
group and the acetoxy group at C-3 of CH503 seemed
necessary for the interaction with its receptor, we
planned to modify the two double bonds at C-11 and
C-19. Accordingly, the four pairs of enantiomers of the
analogues of CH503 were synthesized: (i) 3-acetoxy-
11,19-octacosadiyn-1-ol (1) to examine whether two
triple bonds could substitute for the two double bonds,
(ii) 3-acetoxyoctacosan-1-ol (2) to see whether fully
saturated compound 2 was bioactive or not, (iii) (Z)-3-
acetoxy-11-octacosen-1-ol (3) to examine the role of
the double bond at C-19, and (iv) (Z)-3-acetoxy-19-
octacosen-1-ol (4) to clarify whether the double bond at
C-11 was indispensable for bioactivity or not.
Our next concern was to clarify the structural
requirement for anti-aphrodisiac activity against male
Drosophila melanogaster. Since the terminal hydroxy
This paper reports the synthesis of the enantiomers of
1–4, starting from the known intermediates employed in
our previous synthesis of the stereoisomers of CH503.5,6)
*
y
Pheromone Synthesis, Part 254, see Ref. 1 for Part 253.
To whom correspondence should be addressed. Fax: +81-3-3813-1516; E-mail: kjk-mori@arion.ocn.ne.jp

1932
Y. SHIKICHI et al.
OPMB
OPMB
a
OR
n-C8H17
(CH2)6I
+
OTBS
n-C8H17
6
(R)-7 R = TBS
(R)-8 R = H
(R)-9 R = Ac
(R)-5
b
c
OH
d
OAc
n-C8H17
(R)-1
Similarly
OH
OPMB
OAc
n-C8H17
OTBS
(S)-1
(S)-5
OPMB
OH
e
n-C8H17
OAc
OAc
OAc
n-C8H17
(R)-2
(S)-2
(R)-9
(S)-9
Similarly
OPMB
OH
n-C8H17
OAc
n-C8H17
Scheme 1. Synthesis of the Enantiomers of 1 and 2.
Reagents: (a) n-BuLi, THF, HMPA [91% for (R)-7; 85% for (S)-7]; (b) TBAF, THF [76% for (R)-8; 77% for (S)-8]; (c) Ac2O, DMAP, C5H5N
[96% for (R)-9; 92% for (S)-9]; (d) DDQ, CH2Cl2, H2O [80% for (R)-1; 79% for (S)-1]; (e) H2, Pd–C, EtOAc [68% for (R)-2; 83% for (S)-2].
A bioassay of the eight new analogues [(R)- and (S)-1–4]
of CH503 revealed none of them to be pheromonally
active.
(R)-13 upon mesylation. Reduction of (R)-13 with
lithium aluminum hydride in THF removed the mesy-
loxy group to afford (R)-14 in a 43% yield, together with
a 45% yield of desilylated product (R)-15. The TBS
protective group of (R)-14 was then removed with
TBAF to yield an additional amount of (R)-15. The
triple bond at C-11 of (R)-15 was subjected to semi-
hydrogenation over Lindlar’s palladium catalyst in the
presence of quinoline to give (3R,11Z)-16 which was
acetylated to furnish (3R,11Z)-17. Finally, the PMB
protective group of 17 was removed by treatingt with
DDQ in wet dichloromethane to give desired monoene
analogue (3R,11Z)-3, mp 34–36 ꢁC. The overall yield of
(3R,11Z)-3 was 43% based on (3R,19Z)-10 (eight steps).
Similarly, (3S,11Z)-3 was synthesized from (3S,19E)-10
in a 45% overall yield.
Synthesis of the enantiomers of 3-acetoxy-19-oc-
tacosen-1-ol (4) is summarized in Scheme 3. Known
alkyne (R)-56) was alkylated with the 6-iodo-1-hexanol
tetrahydropyranyl (THP) ether, employing n-butyllithi-
um in THF/HMPA as the base to furnish (R)-18. This
was hydrogenated over palladium-charcoal to give (R)-
19, which was treated with p-toluenesulfonic acid
(TsOH) in methanol to remove both the THP and TBS
protective group, affording diol (R)-20. Selective tosy-
lation of (R)-20 with 1 eq. of p-toluenesulfonyl chloride
(TsCl) gave crude (R)-21. This was subjected to the
Finkelstein reaction with sodium iodide in DMF to
furnish iodide (R)-22, mp 58–59 ꢁC, in a 29% yield
based on (R)-20 with 59% recovery of (R)-20. Alkyla-
tion of 1-decyne with (R)-22 was achieved by using
n-butyllithium in THF/HMPA as the base to give (R)-23
in a 75% yield. Lindlar hydrogenation of (R)-23
Results and Discussion
The upper part of Scheme 1 summarizes the synthesis
of the enantiomers of 3-acetoxy-11,19-octacosadiyn-
1-ol (1). Known alkyne (R)-56) was alkylated with
known iodide 6,5) employing n-butyllithium as the
base in THF/HMPA to give (R)-7. Removal of the
t-butyldimethylsilyl (TBS) group of (R)-7 with
tetra(n-butyl)ammonium fluoride (TBAF) in THF
afforded alcohol (R)-8 which was acetylated to give
acetate (R)-9 in a 73% yield (two steps). Finally,
treatment of (R)-9 with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) in wet dichloromethane furnished
desired diyne analogue (R)-1 as a colorless oil in a 53%
overall yield based on (R)-5 (four steps). Similarly, oily
(S)-1 was prepared from (S)-5 in a 48% overall yield.
Synthesis of the enantiomers of 3-acetoxyoctacosan-
1-ol (2) is shown in the lower part of Scheme 1.
Hydrogenation of (R)-9 over palladium-charcoal gave
(R)-2, mp 68–69 ꢁC, in a 68% yield with concomitant
removal of the p-methoxybenzyl (PMB) protective
group. Similarly, (S)-9 furnished (S)-2 in an 83% yield.
Scheme 2 shows the synthesis of the enantiomers of
(Z)-3-acetoxy-11-octacosen-1-ol (3). Known enyne
(3R,19Z)-106) was oxidized with m-chloroperbenzoic
acid (MCPBA) to give epoxide 11 as a diastereomeric
mixture. This was reduced with lithium aluminum
hydride to furnish a regioisomeric mixture of alcohol
(R)-12 which gave a mixture of corresponding mesylate

Synthesis and Bioassay of Analogs of the CH503 Pheromone
1933
OPMB
OPMB
a
n-C8H17
n-C8H17
OTBS
OTBS
O
(3R,19RS,20RS)-11
(3R,19Z)-10
OH
OPMB
c
b
n-C8H17
OTBS
OPMB
(R)-12
OPMB
OMs
d
n-C8H17
OR
n-C8H17
OTBS
(R)-13
(R)-14 R = TBS
(R)-15 R = H
e
n-C8H17
OPMB
f
OR
(3R,11Z)-16 R = H
(3R,11Z)-17 R = Ac
g
h
n-C8H17
OH
(3R,11Z)-3
OAc
Similarly:
OPMB
n-C8H17
OH
n-C8H17
OTBS
(3S,11Z)-3
OAc
(3S,19E)-10
Scheme 2. Synthesis of the Enantiomers of 3.
Reagents: (a) MCPBA CH2Cl2 [99% for crude (3R,19RS,20RS)-11; 99% for crude (3S,19RS,20RS)-11]; (b) LiAlH4, Et2O, reflux [79% for
(R)-12; 84% for (S)-12]; (c) MsCl, C5H5N [91% for (R)-13; 92% for (S)-13]; (d) LiAlH4, THF, reflux [43% for (R)-14 and 45% for (R)-15; 42%
for (S)-14 and 44% for (S)-15]; (e) TBAF, THF, reflux [94% for (R)-15 and 91% for (S)-15]; (f) H2, Lindlar’s Pd cat., quinoline, cyclohexane
[88% for (3R,11Z)-16 and 95% for (3S,11Z)-16]; (g) Ac2O, C5H5N [96% for (3R,11Z)-17 and 95% for (3S,11Z)-17]; (h) DDQ, CH2Cl2, H2O
[86% for (3R,11Z)-3 and 84% for (3S,11Z)-3].
OPMB
OPMB
a
b
THPO(CH2)6
OPMB
OTBS
OTBS
(R)-18
(R)-5
OPMB
c
THPO
RO
OTBS
OH
(R)-19
(R)-20 R = H
(R)-21 R = Ts
d
OPMB
OPMB
e
f
I
n-C8H17
OH
OH
(R)-23
(R)-22
g
n-C8H17
OPMB
OR
(3R,19Z)-24 R = H
(3R,19Z)-25 R = Ac
h
n-C8H17
OH
i
OAc
(3R,19Z)-4
Similarly:
OPMB
n-C8H17
OH
OTBS
OAc
(3S,19Z)-4
(S)-5
Scheme 3. Synthesis of the Enantiomers of 4.
Reagents: (a) THPO(CH2)6I, n-BuLi, THF, HMPA [83% for (R)-18 and 83% for (S)-18]; (b) H2, Pd–C, EtOAc [91% for (R)-19 and 92% for
(S)-19]; (c) TsOH, MeOH [76% for (R)-20 and 76% for (S)-20]; (d) TsCl, C5H5N; (e) NaI, DMF [29%, 2 steps for (R)-22; 34%, 2 steps for (S)-
22]; (f) 1-decyne [4.5 eq. for (R)-23 and 3.0 eq. for (S)-23], n-BuLi [4.2 eq. for (R)-23 and 2.8 eq. for (S)-23], THF, HMPA [75% for (R)-23 and
54% for (S)-23]; (g) H2, Lindlar’s Pd cat., quinoline, cyclohexane [83% for (3R,19Z)-24 and 82% for (3S,19Z)-24]; (h) Ac2O, C5H5N [89% for
(3R,19Z)-25 and 97% for (3S,11Z)-25]; (i) DDQ, CH2Cl2, H2O [89% for (3R,19Z)-4 and 88% for (3S,19Z)-4].

1934
Y. SHIKICHI et al.
Table 1. The Analogues of (3R,11Z,19Z)-CH503 and (3S,11Z,19Z)-
CH503 Were Tested in a Courtship Assay at Respective Doses of
2667 ng/fly and 83 ng/fly, Respectively
XL instrument (Agilent Technologies, CA, USA), and HRMS data
were recorded on a 6530 Accurate Mass Q-TOF LC/MS instrument
(Agilent Technologies, CA, USA). Column chromatography was
carried out on Kieselgel 60 Art. 1.07734 (Merck, Darmstadt,
Germany).
Concentration
(ng/fly)
Courtship
percentagea,b
Compound
3-t-Butyldimethylsilyloxy-11,19-octacosadiyn-1-ol PMB ether (7).
(i) (R)-Isomer. In the same manner as that previously described,5)
known (R)-5 (1.01 g, 2.33 mmol)6) and 7-hexadecynyl iodide (6,
896 mg, 2.57 mmol)5) gave 1.39 g (91%) of (R)-7 as a colorless oil,
Chloroform (control)
Hexane (control)
(R)-1
0
0
100% (n ¼ 18)
95% (n ¼ 38)
100% (n ¼ 18)
100% (n ¼ 15)
100% (n ¼ 16)
94% (n ¼ 18)
83% (n ¼ 18)
82% (n ¼ 17)
89% (n ¼ 18)
94% (n ¼ 16)
2667
83
(S)-1
(R)-2
22
nD 1.4872; ½ꢁꢂD ꢀ5:71 (c 4.09, hexane); IR ꢂmax (film) cmꢀ1: 2930
(s), 2856 (s), 1613 (m, arom. C=C), 1586 (w), 1514 (s), 1464 (m), 1249
(s), 1098 (m), 1040 (m), 836 (m), 774 (m); 1H-NMR ꢀH (CDCl3): 0.03
(3H, s, CH3Si), 0.04 (3H, s, CH3Si), 0.84–0.94 (12H, m), 1.18–1.54
(33H, m), 1.63–1.80 (2H, m), 2.07–2.24 (8H, br, 4 ꢃ CꢄCCH2), 3.50
(2H, t, J ¼ 6:8 Hz), 3.80 (3H, s, OCH3), 4.36–4.46 (2H, m, OCH2Ar),
6.87 (2H, d, J ¼ 8:6 Hz, arom. H), 7.25 (2H, d, J ¼ 8:6 Hz, arom. H).
HRMS of (R)-7 [ESI ionization, positive polarity, 150 V fragmentor,
N2 (50 psi) nebulizer, N2 (10 L/min, 350 ꢁC) drying gas, 3500 V
capillary current, 0.01 M HCO2H aq./MeCN (10/90) eluent]: calcd. for
C42H73O3Si [ðM þ HÞþ], 653.5323; found, 653.5322.
23
2667
83
(S)-2
(3R,11Z)-3
(3S,11Z)-3
(3R,19Z)-4
(3S,19Z)-4
2667
83
2667
83
aThe sample size for each experimental trial is indicated; no significant
difference in courtship percentage was found between the control and
experimental conditions.
bAt the time of these bioassays, (3S,11Z,19Z)-CH503 was also assayed on a
nearly weekly basis, which showing 40–50% courtship suppression at a dose
of 83 ng/fly.
(ii) (S)-Isomer. Similarly, (S)-5 (1.01 g, 2.33 mmol) gave 1.29 g
22
23
(85%) of (S)-7 as a colorless oil, nD 1.4869; ½ꢁꢂD þ5:66 (c 4.16,
hexane). Its IR and 1H-NMR spectra were identical to those of (R)-7.
HRMS of (S)-7: calcd. for C42H73O3Si [ðM þ HÞþ], 653.5323; found,
653.5322.
afforded (3R,19Z)-24, whose acetylation gave (3R,19Z)-
25. Finally, its PMB protective group was removed to
furnish another monoene analogue, (3R,19Z)-4, mp 27–
28 ꢁC. The overall yield of (3R,19Z)-4 was 8% based on
(R)-5 (nine steps). Similarly, (3S,19Z)-4 was prepared
from (S)-5 in a 7% overall yield.
11,19-Octacosadiyne-1,3-diol 1-PMB ether (8).
(i) (R)-Isomer. In the same manner as that previously described,6)
(R)-7 (1.37 g, 2.10 mmol) gave 863 mg (76%) of (R)-8 as a colorless
25
solid. Mp 36 ꢁC; ½ꢁꢂD þ6:04 (c 4.11, hexane); IR ꢂmax (film) cmꢀ1
:
To determine whether any of the synthesized ana-
logues was biologically active as a male anti-aphrodis-
iac, a standardized courtship assay was used to deter-
mine whether male Drosophila courtship behavior was
suppressed in the presence of a female fly perfumed with
each of the analogues. Each analogue was tested at the
same dose that was found to be sufficient for the
bioactivity of (3R,11Z,19Z)-CH503 (2667 ng/fly) or
(3S,11Z,19Z)-CH503 (83 ng/fly). In all cases, no sig-
nificant suppression of male courtship behavior was
apparent (Table 1).
3505 (s, O–H), 2930 (s), 2849 (s), 1613 (m, arom. C=C), 1586 (w),
1518 (m), 1462 (s), 1252 (s), 1092 (m), 1032 (m), 813 (m); 1H-NMR
ꢀH (CDCl3): 0.88 (3H, t, J ¼ 6:8 Hz), 1.21–1.55 (32H, m), 1.68–1.75
(2H, m), 2.08–2.18 (8H, br, 4 ꢃ CꢄCCH2), 2.89 (1H, d, J ¼ 3:2 Hz),
3.58–3.64 (1H, m), 3.66–3.73 (1H, m), 3.74–3.84 (1H, br), 3.80 (3H, s,
OCH3), 4.45 (2H, s, OCH2Ar), 6.88 (2H, d, J ¼ 8:6 Hz, arom. H), 7.25
(2H, d, J ¼ 8:6 Hz, arom. H). HRMS of (R)-8 [same conditions as
those for 7]: calcd. for C36H59O3 [ðM þ HÞþ], 539.4459; found,
539.4459.
(ii) (S)-Isomer. Similarly, (S)-7 (1.26 g, 1.93 mmol) gave 804 mg
24
(77%) of (S)-8 as a colorless solid. Mp 35–36 ꢁC; ½ꢁꢂD ꢀ5:97 (c 4.14,
hexane). Its IR and 1H-NMR spectra were identical to those of (R)-8.
HRMS of (S)-8: calcd. for C36H59O3 [ðM þ HÞþ], 539.4459; found,
539.4458.
Conclusion
3-Acetoxy-11,19-octacosadiyn-1-ol PMB ether (9).
(i) (R)-Isomer. In the same manner as that previously described,5)
(R)-8 (812 mg, 1.51 mmol) gave 836 mg (96%) of (R)-9 as a colorless
The enantiomers of 3-acetoxy-11,19-octacosadiyn-
1-ol (1), 3-acetoxyoctacosan-1-ol (2), (Z)-3-acetoxy-
11-octacosen-1-ol (3), and (Z)-3-acetoxy-19-octacosen-
1-ol (4) were synthesized, and their function as a male
anti-aphrodisiac tested by using a courtship assay.
Unlike CH503 [(3R,11Z,19Z)-3-acetoxy-11,19-octaco-
sadien-1-ol], none of the analogues was pheromonally
active as an anti-aphrodisiac against male Drosophila
melanogaster. Accordingly, the two double bonds at
C-11 and C-19 of CH503 were found indispensable for
its bioactivity.
25
23
oil, nD 1.4926; ½ꢁꢂD ꢀ13:3 (c 4.03, hexane); IR ꢂmax (film) cmꢀ1
:
2930 (s), 2856 (s), 1737 (s, C=O), 1613 (m), 1586 (w), 1514 (s), 1465
(m), 1371 (m), 1246 (s), 1097 (m), 1038 (m), 822 (m); 1H-NMR ꢀH
(CDCl3): 0.88 (3H, t, J ¼ 6:8 Hz), 1.14–1.66 (32H, m), 1.77–1.92 (2H,
m), 2.00 (3H, s, COCH3), 2.07–2.26 (8H, br, 4 ꢃ CꢄCCH2), 3.39–3.55
(2H, m), 3.80 (3H, s, OCH3), 4.40 (2H, s, OCH2Ar), 4.97–5.11 (1H,
m), 6.87 (2H, d, J ¼ 8:4 Hz, arom. H), 7.25 (2H, d, J ¼ 8:4 Hz, arom.
H). HRMS of (R)-9 [same conditions as those for 7]: calcd. for
C
38H61O4 [ðM þ HÞþ], 581.4564; found, 581.4568.
(ii) (S)-Isomer. Similarly, (S)-8 (654 mg, 1.21 mmol) gave 647 mg
22
23
(92%) of (S)-9 as a colorless oil, nD 1.4925; ½ꢁꢂD þ13:7 (c 4.03,
hexane). Its IR and 1H-NMR spectra were identical to those of (R)-9.
HRMS of (S)-9: calcd. for C38H61O4 [ðM þ HÞþ], 581.4564; found,
581.4563.
Experimental
All boiling point (bp) data are uncorrected values. Refractive
indices (nD) were measured with a DR-M2 refractometer (Atago,
Tokyo, Japan). Melting points were measured with an EXSTAR DSC
6220 instrument (SII, Chiba, Japan), and optical rotation values were
measured with a P-1020 polarimeter (Jasco, Tokyo, Japan). IR spectra
were measured with an FT/IR-410 spectrometer (Jasco, Tokyo, Japan),
and 1H-NMR spectra (400 MHz, TMS at ꢀ ¼ 0:00 as an internal
standard) and 13C-NMR spectra (100 MHz, CDCl3 at ꢀ ¼ 77:0 as an
internal standard) were recorded with a JNM-AL 400 spectrometer
(Jeol, Tokyo, Japan). GC-MS data were measured with a 5975 Inert
3-Acetoxy-11,19-octacosadiyn-1-ol (1).
(i) (R)-Isomer. In the same manner as that previously described,5)
(R)-9 (328 mg, 0.565 mmol) gave 208 mg (80%) of (R)-1 as a colorless
20
23
oil which solidified in a refrigerator, nD 1.4732; ½ꢁꢂD ꢀ7:71 (c 1.14,
hexane); IR ꢂmax (film) cmꢀ1: 3453 (br, O–H), 2930 (s), 2856 (s), 1738
(s, C=O), 1464 (m), 1373 (m), 1245 (s, C–O), 1056 (m), 1023 (m), 724
(w); 1H-NMR ꢀH (CDCl3): 0.88 (3H, t, J ¼ 6:8 Hz), 1.18–1.53 (31H,
m), 1.53–1.71 (2H, m), 1.79–1.89 (1H, m), 2.09 (3H, s, COCH3), 2.09–
2.20 (8H, br, 4 ꢃ CꢄCCH2), 2.33–2.39 (1H, br), 3.48–3.58 (1H, m,

Synthesis and Bioassay of Analogs of the CH503 Pheromone
1935
CHHOH), 3.59–3.68 (1H, m, CHHOH), 4.98–5.06 (1H, m, CHOAc);
13C-NMR ꢀC (CDCl3): 14.1, 18.7, 18.8, 21.1, 22.7, 25.5, 28.39, 28.40,
28.8, 28.9, 29.04, 29.07, 29.13, 29.14, 29.18, 29.24, 29.3, 31.9, 34.6,
37.5, 58.6, 71.6, 80.10, 80.18, 80.19, 80.3, 172.1; GC-MS [HP-5MS
5% phenylmethylsiloxane column, 30 m ꢃ 0:25 mm i.d., 52.7 kPa
pressure; 50–325 ꢁC temperature (+15 ꢁC/min)], tR 24.43 min
(96.9%). MS of (R)-1 (70 eV, EI) m=z: 460 (0.4) [Mþ, C30H52O3],
417 (1), 361 (2), 343 (2), 329 (2), 315 (4), 301 (6), 287 (6), 273 (9), 259
(18), 245 (26), 231 (9), 215 (6), 201 (8), 187 (14), 175 (25), 161 (44),
147 (53), 133 (49), 119 (47), 105 (57),95 (69), 93 (70), 91 (72), 81
(94), 67 (100), 55 (72), 43 (86). HRMS of (R)-1 [same conditions as
those for 7]: calcd. for C30H53O3 [ðM þ HÞþ], 461.3989; found,
461.3986.
2.09–2.18 (4H, m, 2 ꢃ CꢄCCH2), 2.62–2.67 (2H, m), 3.50 (2H, t,
J ¼ 6:8 Hz, CH2OAr), 3.76–3.84 (1H, br), 3.80 (3H, s, OCH3), 4.37–
4.45 (2H, m, ArCH2), 6.87 (2H, d, J ¼ 8:4 Hz, arom. H), 7.25 (2H, d,
J ¼ 8:4 Hz, arom. H). Its IR spectrum was indistinguishable from that
of (3R,19RS,20RS)-11.
3-t-Butyldimethylsilyloxy-11-octacosyne-1,19-diol 1-PMB ether and
3-t-butyldimethylsilyloxy-11-octacosyne-1,20-diol 1-PMB ether (12).
(i) (3R,19RS)- and (3R,20RS)-Isomer. (3R,19RS,20RS)-11
(496 mg, 0.739 mmol) in dry Et2O (9 mL) was treated with LiAlH4
(121 mg, 3.19 mmol) under reflux for 1.5 h to give 496 mg of a crude
mixture. This mixture was chromatographed over SiO2 (15 g). Elution
with hexane/EtOAc ¼ 10:1 gave 395 mg (79%) of a mixture of
(3R,19RS)- and (3R,20RS)-12 as an oil. IR ꢂmax (film) cmꢀ1: 3375 (s,
OH), 2927 (s), 2854 (s), 1613 (m), 1586 (w), 1514 (m), 1464 (m), 1249
(m), 1099 (m, C–O), 1040 (m), 836 (m), 774 (m); 1H-NMR ꢀH
(CDCl3): 0.029 (3H, s, CH3Si), 0.034 (3H, s, CH3Si), 0.84–0.93 (12H,
m), 1.20–1.54 (39H, m), 1.65–1.80 (2H, m), 2.09–2.17 (4H, m,
2 ꢃ CꢄCCH2), 3.50 (2H, t, J ¼ 6:8 Hz, CH2OAr), 3.53–3.61 (1H, br),
3.74–3.84 (1H, br), 3.80 (3H, s, OCH3), 4.37–4.45 (2H, m, ArCH2),
6.87 (2H, d, J ¼ 8:4 Hz, arom. H), 7.25 (2H, d, J ¼ 8:4 Hz, arom. H).
(ii) (3S,19RS)- and (3S,20RS)-Isomer. Similarly, (3S,19RS,20RS)-
11 (484 mg, 0.721 mmol) gave 409 mg (84%) of a mixture of (3S,19RS)-
and (3S,20RS)-12 as an oil. Its IR and 1H-NMR spectra were identical to
those of the mixture of (3R,19RS)- and (3R,20RS)-12.
(ii) (S)-Isomer. Similarly, (S)-9 (301 mg, 0.518 mmol) gave
190 mg (79%) of (S)-1 as a colorless oil which solidified in a
23
23
refrigerator, nD 1.4741; ½ꢁꢂD þ7:51 (c 1.06, hexane). GC-MS [same
conditions as those for (R)-1]: tR 24.43 min (95.0%). Its spectral data
(IR, 1H- and 13C-NMR, and MS) were identical to those of (R)-1.
HRMS of (S)-1: calcd. for C30H53O3 [ðM þ HÞþ], 461.3989; found,
461.3989.
3-Acetoxyoctacosan-1-ol (2).
(i) (R)-Isomer. Palladium on charcoal (10%, 80 mg) was added to
a solution of (R)-9 (211 mg, 0.363 mmol) in EtOAc (8 mL). The
suspension was stirred under H2 (balloon) for 3 h at room temperature.
The mixture was then filtered through Celite, and the catalyst and
Celite were washed with Et2O. The filtrate and washings were
concentrated in vacuo. The residue (219 mg) was chromatographed
over SiO2 (20 g). Elution with hexane/EtOAc ¼ 10:1–5:1 gave
3-t-Butyldimethylsilyloxy-19-methanesulfonyloxy-11-octacosyn-1-ol
PMB ether and 3-t-butyldimethylsilyloxy-20-methanesulfonyloxy-11-
octacosyn-1-ol PMB ether (13).
22
115 mg (68%) of (R)-2 as a colorless solid. Mp 68–69 ꢁC; ½ꢁꢂD
(i) (3R,19RS)- and (3R,20RS)-Isomer. The mixture of (3R,19RS)-
and (3R,20RS)-12 (380 mg, 0.565 mmol) in dry C5H5N (5 mL) was
treated with methanesulfonyl chloride (0.31 mL, 4.0 mmol) at 0–5 ꢁC
to give 414 mg of a crude mixture. This mixture was chromatographed
over SiO2 (15 g). Elution with hexane/EtOAc ¼ 10:1 gave 384 mg
(91%) of a mixture of (3R,19RS)- and (3R,20RS)-13 as an oil. IR ꢂmax
(film) cmꢀ1: 2927 (s), 2855 (s), 1613 (m), 1586 (w), 1514 (m), 1464
(m), 1358 (m), 1249 (m), 1175 (m), 1098 (m, C–O), 1039 (m), 905 (m),
836 (m), 775 (m); 1H-NMR ꢀH (CDCl3): 0.029 (3H, s, CH3Si), 0.034
(3H, s, CH3Si), 0.84–0.92 (12H, m), 1.20–1.52 (34H, m), 1.62–1.80
(6H, m), 2.10–2.17 (4H, m, 2 ꢃ CꢄCCH2), 2.99 (3H, s, CH3SO2), 3.50
(2H, t, J ¼ 6:8 Hz, CH2OAr), 3.76–3.84 (1H, br), 3.80 (3H, s, OCH3),
4.37–4.45 (2H, m, ArCH2), 4.65–4.73 (1H, m, CHOMs), 6.87 (2H, d,
J ¼ 8:8 Hz, arom. H), 7.25 (2H, d, J ¼ 8:8 Hz, arom. H).
ꢀ8:05 (c 1.13, Et2O); IR ꢂmax (thin film) cmꢀ1: 3414 (br, O–H), 2916
(s), 2848 (s), 1736 (s, C=O), 1463 (m), 1375 (m), 1243 (s, C–O), 1051
(m), 1025 (m), 729 (m); 1H-NMR ꢀH (CDCl3): 0.88 (3H, t,
J ¼ 6:8 Hz), 1.20–1.37 (46H, br), 1.48–1.70 (3H, m), 1.79–1.88 (1H,
m), 2.09 (3H, s, COCH3), 2.30–2.36 (1H, m), 3.48–3.57 (1H, m,
CHHOH), 3.59–3.68 (1H, m, CHHOH), 4.98–5.06 (1H, m, CHOAc);
13C-NMR ꢀC (CDCl3): 14.1, 21.1, 22.7, 25.5, 29.37, 29.40, 29.52,
29.57, 29.65, 29.67, 29.69, 29.71, 31.9, 34.7, 37.5, 58.6, 71.62,172.1;
GC-MS [same conditions as those for (R)-1]: tR 24.23 min (95.0%).
MS of (R)-2 (70 eV, EI) m=z: 468 (0.1) [Mþ, C30H60O3], 450 (0.2)
[M–18], 425 (4), 390 (10), 379 (11), 362 (8), 348 (2), 334 (3), 320 (1),
306 (1), 292 (2), 278 (2), 264 (2), 250 (2), 236 (2), 222 (2), 207 (2), 194
(1), 180 (1), 166 (2), 152 (3), 137 (6), 117 (71), 97 (40), 88 (66), 82
(44), 71 (51), 57 (100), 43 (88). HRMS of (R)-2 [APCI ionization,
positive polarity, 6 mA corona current, N2 (35 psi) nebulizer, N2
(5 L/min, 350 ꢁC) drying gas, 350 ꢁC vaporizer, 3500 V capillary
current, 0.01 M HCO2H aq./MeOH (10/90) eluent]: calcd. for
C30H61O3 [ðM þ HÞþ], 469.4615; found, 469.4619.
(ii) (3S,19RS)- and (3S,20RS)-Isomer. Similarly, the mixture of
(3S,19RS)- and (3S,20RS)-12 (393 mg, 0.584 mmol) gave 402 mg
(92%) of a mixture of (3S,19RS)- and (3S,20RS)-13 as an oil. Its IR and
1H-NMR spectra were identical to those of the mixture of (3R,19RS)-
and (3R,20RS)-13.
(ii) (S)-Isomer. Similarly, (S)-9 (218 mg, 0.375 mmol) gave
24
146 mg (83%) of (S)-2 as a colorless solid. Mp 68–69 ꢁC; ½ꢁꢂD
3-t-Butyldimethylsilyloxy-11-octacosyn-1-ol PMB ether (14).
(i) (R)-Isomer. The mixture of (3R,19RS)- and (3R,20RS)-13
(381 mg, 0.507 mmol) in dry THF (5 mL) was treated with LiAlH4
(77 mg, 2.0 mmol) under reflux for 1.5 h to give 285 mg of a crude
mixture. This mixture was chromatographed over SiO2 (15 g). Elution
with hexane/EtOAc ¼ 10:1–5:1 gave 143 mg (43%) of (R)-14 as a
colorless oil and 123 mg (45%) of (R)-15 as a colorless solid.
þ8:70 (c 1.07, Et2O). GC-MS [same conditions as those for (R)-1]: tR
24.20 min (94.2%). Its spectral data (IR, 1H- and 13C-NMR, and MS)
were identical to those of (R)-2. HRMS of (S)-2: calcd. for C30H61O3
[ðM þ HÞþ], 469.4615; found, 469.4618.
3-t-Butyldimethylsilyloxy-19,20-epoxy-11-octacosyn-1-ol
ether (11).
PMB
25
17
Properties of (R)-14: nD 1.4837; ½ꢁꢂD ꢀ5:90 (c 1.04, hexane); IR
ꢂmax (film) cmꢀ1: 2925 (s), 2854 (s), 1613 (m), 1586 (w), 1514 (m),
1464 (m), 1249 (m), 1098 (m, C–O), 1041 (m), 836 (m), 774 (m); 1H-
NMR ꢀH (CDCl3): 0.029 (3H, s, CH3Si), 0.034 (3H, s, CH3Si), 0.84–
0.93 (12H, m), 1.19–1.51 (40H, m), 1.65–1.80 (2H, m), 2.13 (4H, t,
J ¼ 7:2 Hz, 2 ꢃ CꢄCCH2), 3.50 (2H, t, J ¼ 6:8 Hz, CH2OAr), 3.76–
3.84 (1H, br), 3.80 (3H, s, OCH3), 4.37–4.45 (2H, m, ArCH2), 6.87
(2H, d, J ¼ 8:4 Hz, arom. H), 7.25 (2H, d, J ¼ 8:4 Hz, arom. H).
HRMS of (R)-14 [same conditions as those for 7]: calcd. for
(i) (3R,19RS,20RS)-Isomer. In the usual manner, known
(3R,19Z)-10 (509 mg, 0.777 mmol)6) in CH2Cl2 (5 mL) was treated
with MCPBA (69% purity, 215 mg, 0.858 mmol) to give 516 mg (99%)
of crude (3R,19RS,20RS)-11 as an oil. IR ꢂmax (film) cmꢀ1: 2927 (s),
2855 (s), 1613 (m), 1586 (w), 1514 (m), 1464 (m), 1249 (m), 1098 (m,
C–O), 1040 (m), 836 (m), 774 (m); 1H-NMR ꢀH (CDCl3): 0.029 (3H, s,
CH3Si), 0.034 (3H, s, CH3Si), 0.84–0.94 (12H, m), 1.20–1.56 (36H,
m), 1.64–1.80 (2H, m), 2.09–2.18 (4H, m, 2 ꢃ CꢄCCH2), 2.86–2.94
(2H, br), 3.50 (2H, t, J ¼ 6:8 Hz, CH2OAr), 3.76–3.84 (1H, br), 3.80
(3H, s, OCH3), 4.37–4.45 (2H, m, ArCH2), 6.87 (2H, d, J ¼ 8:4 Hz,
arom. H), 7.25 (2H, d, J ¼ 8:4 Hz, arom. H). This oil was employed for
the next step without further purification.
C
42H77O3Si [ðM þ HÞþ], 657.5636; found, 657.5640.
(ii) (S)-Isomer. Similarly, a mixture of (3S,19RS)- and (3S,20RS)-
14 (386 mg, 0.514 mmol) gave 142 mg (42%) of (S)-14 as a colorless
oil and 124 mg (44%) of (S)-15 as a colorless solid. Properties of (S)-
26
17
(ii) (3S,19RS,20RS)-Isomer. Similarly, known (3S,19E)-10 (507
mg, 0.774 mmol)6) gave 512 mg (99%) of crude (3S,19RS,20RS)-11 as
an oil. 1H-NMR ꢀH (CDCl3): 0.029 (3H, s, CH3Si), 0.034 (3H, s,
CH3Si), 0.84–0.94 (12H, m), 1.20–1.56 (36H, m), 1.64–1.80 (2H, m),
14: nD 1.4835; ½ꢁꢂD þ6:03 (c 0.935, hexane). Its IR and 1H-NMR
spectra were identical to those of (R)-14. HRMS of (S)-14: calcd. for
42H77O3Si [ðM þ HÞþ], 657.5636; found, 657.5632.
C

1936
11-Octacosyne-1,3-diol 1-PMB ether (15).
Y. SHIKICHI et al.
CHCl3); IR ꢂmax (thin film) cmꢀ1: 3460 (s, OH), 3004 (w), 2924 (s),
2853 (s), 1739 (s, C=O), 1465 (m), 1374 (m), 1244 (s, C–O), 1053
(m), 1025 (m), 955 (w), 721 (w); 1H-NMR ꢀH (CDCl3): 0.88 (3H, t,
J ¼ 6:8 Hz), 1.18–1.38 (38H, br), 1.47–1.70 (3H, m), 1.79–1.89 (1H,
m), 1.95–2.06 (4H, m, 2ꢃ ¼ CHCH2), 2.08 (3H, s, COCH3), 2.32–
2.40 (1H, br), 3.48–3.58 (1H, m, CHHOH), 3.59–3.68 (1H, m,
CHHOH), 4.98–5.06 (1H, m, CHOAc), 5.28–5.40 (2H, m, CH=CH);
13C-NMR ꢀC (CDCl3): 14.1, 21.1, 22.7, 25.5, 27.19, 27.24, 29.2, 29.35,
29.37, 29.42, 29.59, 29.67, 29.71, 29.73, 29.79, 31.9, 34.7, 37.5, 58.6,
71.6, 129.8, 130.0, 172.1; GC-MS [same conditions as those for 1]: tR
23.36 min (13.0%, broad, decomposition peak), 23.72 min (82.0%),
24.28 min (4.8%, broad, decomposition peak). The observed GC purity
of (3R,11Z)-3 was less than the reality due to thermal decomposition.
Its 1H-NMR spectrum guaranteed the high purity of the sample.
Similar decomposition was apparent with other mono-olefin samples
(3S,11Z)-3, (3R,19Z)-4, and (3S,19Z)-4. MS of (3R,11Z)-3 (70 eV, EI)
m=z: 448 (3) [M-18], 406 (3), 388 (6), 360 (2), 334 (2), 320 (2), 281
(7), 264 (2), 253 (2), 222 (2), 207 (23), 191 (4), 177 (4), 163 (9), 149
(22), 135 (33), 121 (27), 109 (32), 95 (60), 81 (67), 67 (58), 55 (67), 43
(100). HRMS of (3R,11Z)-3 [same conditions as those for 2]: calcd. for
(i) (R)-Isomer. (R)-14 (132 mg, 0.201 mmol) in dry THF (1 mL)
was treated with a solution of TBAF in THF (1.0 M, 0.6 mL, 0.6 mmol)
under reflux for 1.5 h to give 126 mg of a crude mixture. This mixture
was chromatographed over SiO2 (8 g). Elution with hexane/
EtOAc ¼ 5:1 gave 102 mg (94%) of (R)-15 as a colorless solid. Mp
24
50–51 ꢁC; ½ꢁꢂD þ7:15 (c 1.98, hexane); IR ꢂmax (thin film) cmꢀ1: 3508
(m, OH), 2919 (s), 2848 (s), 1613 (m), 1586 (w), 1517 (m), 1466 (m),
1250 (m), 1126 (w), 1091 (m, C–O), 1033 (m), 812 (w), 721 (m);
1H-NMR ꢀH (CDCl3): 0.88 (3H, t, J ¼ 6:8 Hz), 1.19–1.54 (40H, m),
1.68–1.76 (2H, m), 2.13 (4H, t, J ¼ 7:0 Hz, 2 ꢃ CꢄCCH2), 2.89 (1H,
d, J ¼ 2:9 Hz), 3.58–3.73 (2H, m, CH2OAr), 3.74–3.84 (1H, br), 3.80
(3H, s, OCH3), 4.45 (2H, s, ArCH2), 6.88 (2H, d, J ¼ 8:6 Hz, arom. H),
7.25 (2H, d, J ¼ 8:6 Hz, arom. H). HRMS of (R)-15 [same conditions
as those for 7]: calcd. for C36H63O3 [ðM þ HÞþ], 543.4772; found,
543.4773.
(ii) (S)-Isomer. Similarly, (S)-14 (132 mg, 0.201 mmol) gave
25
99 mg (91%) of (S)-15 as a colorless solid. Mp 50–51 ꢁC; ½ꢁꢂD
ꢀ7:11 (c 1.48, hexane). Its IR and 1H-NMR spectra were identical to
those of (R)-15. HRMS of (S)-15: calcd. for C36H63O3 [ðM þ HÞþ],
543.4772; found, 543.4777.
C
30H59O3 [ðM þ HÞþ], 467.4459; found, 467.4454.
(ii) (3S,11Z)-Isomer. Similarly, (3S,11Z)-17 (160 mg, 0.273
mmol) gave 107 mg (84%) of (3S,11Z)-3 as a colorless solid. Mp
(11Z)-11-Octacosene-1,3-diol 1-PMB ether (16).
20
34–36 ꢁC; ½ꢁꢂD þ8:59 (c 1.02, CHCl3). GC-MS [same conditions as
(i) (3R,11Z)-Isomer. Lindlar’s Pd catalyst on CaCO3 with Pb2þ
(Aldrich, 12 mg) and quinoline (24 mL) were added to a solution of
(R)-15 (220 mg, 0.405 mmol) in cyclohexane (2 mL). The mixture was
stirred for 5.5 h under an H2 atmosphere (gas cylinder, 1 atm) at room
temperature. The mixture was then filtered through Celite, and the
catalyst and Celite were washed with Et2O. The filtrate and washings
were diluted with Et2O, and successively washed with dil. HCl, water,
an NaHCO3 solution and brine, dried (MgSO4), and concentrated in
vacuo. The residue (222 mg) was chromatographed over SiO2 (15 g).
Elution with hexane/EtOAc ¼ 5:1 gave 194 mg (88%) of (3R,11Z)-16
those for (R)-1]: tR 23.34 min (9.2%, broad, decomposition peak),
23.72 min (83.1%), 24.29 min (6.7%, broad, decomposition peak). Its
spectral data (IR, 1H- and 13C-NMR, and MS) were identical to those
of (3R,11Z)-3. HRMS of (3S,11Z)-3: calcd. for C30H59O3 [ðM þ HÞþ],
467.4459; found, 467.4453.
3-t-Butyldimethylsilyloxy-18-tetrahydropyranyloxy-11-octadecyn-1-
ol PMB ether (18).
(i) (R)-Isomer. In the same manner as that previously described,5)
(R)-5 (859 mg, 1.99 mmol)6) and 6-iodo-1-hexanol THP ether (748 mg,
27
as a colorless solid. Mp 40–41 ꢁC; ½ꢁꢂD þ7:41 (c 1.48, hexane); IR
ꢂmax (thin film) cmꢀ1: 3421 (s, OH), 3002 (m), 2924 (s), 2852 (s), 1613
(m), 1586 (w), 1514 (m), 1466 (m), 1248 (m), 1092 (m), 1038 (m), 821
(m), 720 (m); 1H-NMR ꢀH (CDCl3): 0.88 (3H, t, J ¼ 6:8 Hz), 1.20–
1.62 (40H, m), 1.68–1.76 (2H, m), 1.96–2.06 (4H, m, 2ꢃ ¼ CHCH2),
2.84–2.88 (1H, br), 3.57–3.72 (2H, m, CH2OAr), 3.74–3.83 (1H, br),
3.80 (3H, s, OCH3), 4.45 (2H, s, ArCH2), 5.28–5.38 (2H, m, CH=CH),
6.87 (2H, d, J ¼ 8:6 Hz, arom. H), 7.25 (2H, d, J ¼ 8:6 Hz, arom. H).
HRMS of (3R,11Z)-16 [same conditions as those for 7]: calcd. for
21
2.40 mmol) gave 1.01 g (83%) of (R)-18 as a colorless oil, nD 1.4919;
26
½ꢁꢂD ꢀ5:96 (c 4.17, hexane); IR ꢂmax (film) cmꢀ1: 2928 (s), 2855 (s),
1613 (m), 1586 (w), 1514 (m), 1464 (m), 1249 (m), 1119 (m), 1078
(m), 1036 (m), 836 (m), 774 (m); 1H-NMR ꢀH (CDCl3): 0.029 (3H, s,
CH3Si), 0.034 (3H, s, CH3Si), 0.87 (9H, s), 1.22–1.90 (28H, m), 2.09–
2.17 (4H, m, 2 ꢃ CꢄCCH2), 3.34–3.42 (1H, m), 3.46–3.54 (3H, m),
3.70–3.76 (1H, m), 3.76–3.83 (1H, br), 3.80 (3H, s, OCH3), 3.83–3.90
(1H, m), 4.36–4.46 (2H, m, ArCH2), 4.55–4.59 (1H, m), 6.87 (2H, d,
J ¼ 8:4 Hz, arom. H), 7.25 (2H, d, J ¼ 8:4 Hz, arom. H). HRMS of
(R)-18 [same conditions as those for 7]: calcd. for C37H65O5Si
[ðM þ HÞþ], 617.4596; found, 617.4596.
C
36H65O3 [ðM þ HÞþ], 545.4928; found, 545.4926.
(ii) (3S,11Z)-Isomer. Similarly, (S)-15 (110 mg, 0.203 mmol)
gave 105 mg (95%) of (3S,11Z)-16 as a colorless solid. Mp 40–
26
41 ꢁC; ½ꢁꢂD ꢀ7:07 (c 1.23, hexane). Its IR and 1H-NMR spectra were
(ii) (S)-Isomer. Similarly, (S)-5 (971 mg, 2.24 mmol) gave 1.14 g
23
19
identical to those of (3R,11Z)-16. HRMS of (3S,11Z)-16: calcd. for
C36H65O3 [ðM þ HÞþ], 545.4928; found, 545.4932.
(83%) of (S)-18 as a colorless oil, nD 1.4919; ½ꢁꢂD þ6:12 (c 4.05,
hexane). Its IR and 1H-NMR spectra were identical to those of (R)-18.
HRMS of (S)-18: calcd. for C37H65O5Si [ðM þ HÞþ], 617.4596; found,
617.4608.
3-Acetoxy-11-octacosyn-1-ol PMB ether (17).
(i) (3R,11Z)-Isomer. In the same manner as that previously
described,5) (3R,11Z)-16 (180 mg, 0.330 mmol) gave 187 mg (96%) of
3-t-Butyldimethylsilyloxy-18-tetrahydropyranyloxy-11-octadecan-1-
ol PMB ether (19).
27
18
(3R,11Z)-17 as a colorless oil, nD 1.4839; ½ꢁꢂD ꢀ13:2 (c 1.54,
hexane); IR ꢂmax (film) cmꢀ1: 3003 (m), 2925 (s), 2852 (s), 1738
(s, C=O), 1613 (m), 1586 (w), 1514 (m), 1465 (m), 1370 (m), 1245
(m), 1097 (m), 1038 (m), 957 (w), 821 (m), 722 (m); 1H-NMR ꢀH
(CDCl3): 0.88 (3H, t, J ¼ 6:8 Hz), 1.19–1.38 (38H, m), 1.49–1.58 (2H,
br), 1.79–1.87 (2H, m), 1.95–2.06 (4H, m, 2ꢃ ¼ CHCH2), 1.99 (3H, s,
COCH3), 3.40–3.51 (2H, m, CH2OAr), 3.80 (3H, s, OCH3), 4.40 (2H,
s, ArCH2), 4.97–5.05 (1H, m), 5.28–5.41 (2H, m, CH=CH), 6.87 (2H,
d, J ¼ 8:6 Hz, arom. H), 7.25 (2H, d, J ¼ 8:6 Hz, arom. H). HRMS of
(3R,11Z)-17 [same conditions as those for 2]: calcd. for C38H67O4
[ðM þ HÞþ], 587.5034; found, 587.5027.
(i) (R)-Isomer. In the same manner as that described for (R)-2,
(R)-18 (991 mg, 1.61 mmol) gave 910 mg (91%) of (R)-19 as a
18
colorless oil. The THP group remained intact in this step. nD 1.4841;
22
½ꢁꢂD ꢀ6:20 (c 4.17, hexane); IR ꢂmax (film) cmꢀ1: 2926 (s), 2853 (s),
1614 (m), 1586 (w), 1514 (m), 1464 (m), 1249 (m), 1119 (m), 1079
(m), 1037 (m), 836 (m), 774 (m); 1H-NMR ꢀH (CDCl3): 0.03 (3H, s,
CH3Si), 0.04 (3H, s, CH3Si), 0.87 (9H, s), 1.18–1.92 (36H, m), 3.34–
3.42 (1H, m), 3.46–3.54 (3H, m), 3.69–3.76 (1H, m), 3.76–3.83 (1H,
br), 3.80 (3H, s, OCH3), 3.83–3.91 (1H, m), 4.36–4.46 (2H, m,
ArCH2), 4.55–4.60 (1H, m), 6.87 (2H, d, J ¼ 8:4 Hz, arom. H), 7.25
(2H, d, J ¼ 8:4 Hz, arom. H). HRMS of (R)-19 [same conditions as
those for 2]: calcd. for C37H69O5Si [ðM þ HÞþ], 621.4909; found,
621.4911.
(ii) (3S,11Z)-Isomer.
Similarly,
(3S,11Z)-16
(174 mg,
0.319 mmol) gave 178 mg (95%) of (3S,11Z)-17 as a colorless oil,
27
19
nD 1.4841; ½ꢁꢂD þ13:4 (c 1.33, hexane). Its IR and 1H-NMR spectra
were identical to those of (3R,11Z)-17. HRMS of (3S,11Z)-17: calcd.
for C38H67O4 [ðM þ HÞþ], 587.5034; found, 587.5032.
(ii) (S)-Isomer. Similarly, (S)-18 (612 mg, 0.992 mmol) gave
27
18
565 mg (92%) of (S)-19 as a colorless oil, nD 1.4838; ½ꢁꢂD þ6:27
(c 4.02, hexane). Its IR and 1H-NMR spectra were identical to those of
(R)-19. HRMS of (S)-19: calcd. for C37H69O5Si [ðM þ HÞþ],
621.4909; found, 621.4903.
3-Acetoxy-11-octacosen-1-ol (3).
(i) (3R,11Z)-Isomer. In the same manner as that previously
described,5) (3R,11Z)-17 (162 mg, 0.276 mmol) gave 111 mg (86%) of
23
(3R,11Z)-3 as a colorless solid. Mp 34–36 ꢁC; ½ꢁꢂD ꢀ8:87 (c 1.03,

Synthesis and Bioassay of Analogs of the CH503 Pheromone
1937
1,3,18-Octadecanetriol 1-PMB ether (20).
(304 mg, 2.20 mmol, 4.5 eq.) in dry THF (2 mL) and HMPA (0.9 mL)
at ꢀ65–ꢀ40 ꢁC under Ar. The mixture was warmed to ꢀ10 ꢁC for
10 min, and then cooled again to ꢀ65 ꢁC. A solution of (R)-22 (260 mg,
0.488 mmol) in dry THF (2 mL) was added dropwise to the mixture at
ꢀ65 ꢁC, and the temperature was gradually raised to room temperature.
After stirring for 24 h at room temperature, the mixture was diluted
with water and extracted with EtOAc. The EtOAc solution was
successively washed with water and brine, dried (MgSO4), and
concentrated in vacuo. The residue (841 mg) was chromatographed
over SiO2 (20 g). Elution with hexane/EtOAc ¼ 5:1 gave 198 mg
(i) (R)-Isomer. p-Toluenesulfonic acid monohydrate (32 mg,
0.17 mmol) was added to a solution of (R)-19 (877 mg, 1.41 mmol)
in methanol (12 mL). The solution was stirred and heated under reflux
for 1.5 h, before being diluted with water and extracted with EtOAc.
The EtOAc solution was successively washed with an NaHCO3
solution and brine, dried (MgSO4), and concentrated in vacuo. The
residue was recrystallized from hexane to give 455 mg (76%) of (R)-20
22
as a colorless solid. Mp 57–61 ꢁC; ½ꢁꢂD þ5:47 (c 0.448, CHCl3); IR
ꢂmax (thin film) cmꢀ1: 3312 (s, OH), 2916 (s), 2848 (s), 1609 (w), 1508
(m), 1465 (m), 1246 (m), 1075 (m), 1038 (w); 1H-NMR ꢀH (CDCl3):
1.18–1.68 (28H, m), 1.68–1.80 (2H, m), 2.23–2.45 (1H, br), 2.82–2.90
(1H, br), 3.58–3.74 (3H, m), 3.74–3.95 (2H, br), 3.80 (3H, s, OCH3),
4.45 (2H, s, ArCH2), 6.87 (2H, d, J ¼ 8:4 Hz, arom. H), 7.25 (2H, d,
J ¼ 8:4 Hz, arom. H). HRMS of (R)-20 [same conditions as those for
2]: calcd. for C26H47O4 [ðM þ HÞþ], 423.3469; found, 423.3473.
(ii) (S)-Isomer. Similarly, (S)-19 (946 mg, 1.52 mmol) gave
22
(75%) of (R)-23 as a colorless solid. Mp 52–53 ꢁC; ½ꢁꢂD þ5:47
(c 0.790, CHCl3); IR ꢂmax (thin film) cmꢀ1: 3507 (m, OH), 2918 (s),
2847 (s), 1613 (m), 1518 (m), 1466 (m), 1251 (m), 1129 (w), 1091 (m),
1033 (m), 812 (w), 721 (m); 1H-NMR ꢀH (CDCl3): 0.88 (3H, t,
J ¼ 6:8 Hz), 1.17–1.54 (40H, m), 1.67–1.76 (2H, m), 2.10–2.20 (4H,
m, 2 ꢃ C ꢄ CCH2), 2.91–2.96 (1H, br), 3.58–3.74 (2H, m, CH2OAr),
3.74–3.87 (1H, br), 3.81 (3H, s, OCH3), 4.46 (2H, s, ArCH2), 6.88 (2H,
d, J ¼ 8:4 Hz, arom. H), 7.25 (2H, d, J ¼ 8:4 Hz, arom. H). GC-MS
[same conditions as those for 1]: tR 48.13 min (95.2%). HRMS of (R)-
23 [same conditions as those for 7]: calcd. for C36H63O3 [ðM þ HÞþ],
543.4772; found, 543.4767.
25
487 mg (76%) of (S)-20 as a colorless solid. Mp 57–61 ꢁC; ½ꢁꢂD
ꢀ5:80 (c 1.05, CHCl3). Its IR and 1H-NMR spectra were identical to
those of (R)-20. HRMS of (S)-20: calcd. for C26H47O4 [ðM þ HÞþ],
423.3469; found, 423.3467.
(ii) (S)-Isomer. Similarly, (S)-22 (274 mg, 0.515 mmol), 1-decyne
(213 mg, 1.54 mmol, 3.0 eq.) and n-BuLi in hexane (1.6 M, 0.90 mL,
1.44 mmol, 2.8 eq.) gave 151 mg (54%) of (S)-23 as a colorless solid.
18-p-Toluenesulfonyloxy-1,3-octadecanediol 1-PMB ether (21).
(i) (R)-Isomer. Tosyl chloride (207 mg, 1.09 mmol) was added
portionwise to a solution of (R)-20 (449 mg, 1.06 mmol) in dry pyridine
(4.5 mL) at 0–5 ꢁC. The solution was stirred at 0–5 ꢁC for 5 h, before
being diluted with ice-cooled dil. HCl, and extracted with EtOAc. The
EtOAc solution was successively washed with water, a dil. CuSO4
solution, water, an NaHCO3 solution and brine, dried (MgSO4), and
concentrated in vacuo to give 675 mg (quant.) of crude (R)-21 as a
colorless solid. IR ꢂmax (thin film) cmꢀ1: 3463 (s, OH), 2916 (s), 2848
(s), 1613 (m), 1514 (m), 1469 (m), 1358 (m), 1249 (m), 1176 (m), 1098
(m), 1071 (m), 1033 (m); 1H-NMR ꢀH (CDCl3): 1.10–1.92 (30H, m),
2.45 (3H, s), 2.87–2.97 (1H, br), 3.58–3.74 (2H, m), 3.74–3.93 (1H,
br), 3.80 (3H, s, OCH3), 4.02 (2H, t, J ¼ 6:4 Hz, CH2OTs), 4.45 (2H, s,
ArCH2), 6.87 (2H, d, J ¼ 8:4 Hz, arom. H), 7.25 (2H, d, J ¼ 8:4 Hz,
arom. H), 7.34 (2H, d, J ¼ 8:4 Hz, arom. H), 7.79 (2H, d, J ¼ 8:4 Hz,
arom. H). This crude (R)-21 was employed for the next step without
further purification.
22
Mp 38–41 ꢁC; ½ꢁꢂD ꢀ6:08 (c 0.653, CHCl3). Its IR and 1H-NMR
spectra were indistinguishable with those of (R)-23. The low mp of this
stereoisomer was due to its slightly lower purity than that of the (R)-
isomer as determined by GC-MS. GC-MS [same conditions as those
for 1]: tR 48.04 min (82.6%). HRMS of (S)-23: calcd. for C36H63O3
[ðM þ HÞþ], 543.4772; found, 543.4771.
(19Z)-19-Octacosene-1,3-diol 1-PMB ether (24).
(i) (3R,19Z)-Isomer. In the same manner as that described for
(3R,11Z)-16, (R)-23 (150 mg, 0.276 mmol) gave 126 mg (83%) of
23
(3R,19Z)-24 as a colorless solid. Mp 45–46 ꢁC; ½ꢁꢂD þ5:42 (c 1.13,
CHCl3); IR ꢂmax (thin film) cmꢀ1: 3507 (s, OH), 3002 (m), 2918 (s),
2848 (s), 1613 (m), 1585 (w), 1519 (m), 1470 (m), 1251 (m), 1092 (m),
1033 (m), 817 (m), 718 (m); 1H-NMR ꢀH (CDCl3): 0.88 (3H, t,
J ¼ 6:8 Hz), 1.14–1.54 (40H, m), 1.68–1.77 (2H, m), 1.96–2.06 (4H,
m, 2ꢃ ¼ CHCH2), 2.86–2.92 (1H, br), 3.58–3.72 (2H, m, CH2OAr),
3.74–3.85 (1H, br), 3.80 (3H, s, OCH3), 4.45 (2H, s, ArCH2), 5.29–
5.39 (2H, m, CH=CH), 6.87 (2H, d, J ¼ 8:4 Hz, arom. H), 7.25 (2H, d,
J ¼ 8:4 Hz, arom. H). HRMS of (3R,19Z)-24 [same conditions as those
for 7]: calcd. for C36H65O3 [ðM þ HÞþ], 545.4928; found, 545.4917.
(ii) (3S,19Z)-Isomer. Similarly, (S)-23 (100 mg, 0.184 mmol)
gave 82 mg (82%) of (3S,19Z)-24 as a colorless solid. Mp 46–47 ꢁC;
(ii) (S)-Isomer. Similarly, (S)-20 (652 mg, 1.54 mmol) gave 1.05 g
(quant.) of crude (S)-21 as a colorless solid. Its IR and 1H-NMR
spectra were identical to those of (R)-21.
18-Iodo-1,3-octadecanediol 1-PMB ether (22).
(i) (R)-Isomer. Sodium iodide (407 mg, 2.72 mmol) was added to
a solution of crude (R)-21 (0.67 g, <1:06 mmol) in DMF (6 mL) at
room temperature. After the addition, the mixture was stirred and
heated at 50 ꢁC for 5 h, before being diluted with water and extracted
with EtOAc. The EtOAc solution was successively washed with a dil.
Na2S2O3 solution, an NaHCO3 solution and brine, dried (MgSO4), and
concentrated in vacuo. The residue (550 mg) was chromatographed
over SiO2 (15 g). Elution with hexane/EtOAc ¼ 5:1 gave 165 mg
(29%, 2 steps) of (R)-22 as a colorless solid. Further elution with
EtOAc recovered 266 mg (59%) of (R)-20. Properties of (R)-22: mp
21
½ꢁꢂD ꢀ6:03 (c 0.762, CHCl3). Its IR and 1H-NMR spectra were
identical to those of (3R,19Z)-24. HRMS of (3S,19Z)-24: calcd for
36H65O3 [ðM þ HÞþ], 545.4928; found, 545.4939.
C
(19Z)-3-Acetoxy-11-octacosen-1-ol PMB ether (25).
(i) (3R,19Z)-Isomer. In the same manner as that previously
described,5) (3R,19Z)-24 (121 mg, 0.222 mmol) gave 116 mg (89%) of
20
17
(3R,19Z)-25 as a colorless oil, nD 1.4845; ½ꢁꢂD ꢀ9:47 (c 0.913,
CHCl3); IR ꢂmax (film) cmꢀ1: 3003 (m), 2925 (s), 2852 (s), 1739
(s, C=O), 1613 (m), 1586 (w), 1514 (m), 1465 (m), 1371 (m), 1245 (s),
1097 (m), 1038 (m), 957 (w), 821 (m), 721 (m); 1H-NMR ꢀH (CDCl3):
0.88 (3H, t, J ¼ 6:8 Hz), 1.19–1.44 (38H, m), 1.48–1.58 (2H, br),
1.79–1.88 (2H, m), 1.94–2.08 (4H, m, 2ꢃ ¼ CHCH2), 2.00 (3H, s,
COCH3), 3.40–3.51 (2H, m, CH2OAr), 3.80 (3H, s, OCH3), 4.40 (2H,
s, ArCH2), 4.97–5.06 (1H, m), 5.29–5.42 (2H, m, CH=CH), 6.87 (2H,
d, J ¼ 8:4 Hz, arom. H), 7.25 (2H, d, J ¼ 8:4 Hz, arom. H). HRMS of
(3R,19Z)-25 [same conditions as those for 2]: calcd. for C38H67O4
[ðM þ HÞþ], 587.5034; found, 587.5026.
24
58–59 ꢁC; ½ꢁꢂD þ5:50 (c 1.03, CHCl3); IR ꢂmax (thin film) cmꢀ1: 3456
(s, OH), 2915 (s), 2848 (s), 1612 (m), 1514 (m), 1469 (m), 1249 (m),
1167 (m), 1077 (m), 1025 (m); 1H-NMR ꢀH (CDCl3): 1.18–1.55 (26H,
m), 1.69–1.77 (2H, m), 1.77–1.87 (2H, m), 2.91 (1H, d, J ¼ 3:2 Hz),
3.19 (2H, t, J ¼ 7:2 Hz), 3.57–3.73 (2H, m), 3.73–3.88 (1H, br), 3.80
(3H, s, OCH3), 4.45 (2H, s, ArCH2), 6.87 (2H, d, J ¼ 8:4 Hz, arom. H),
7.25 (2H, d, J ¼ 8:4 Hz, arom. H). HRMS of (R)-22 [same conditions
as those for 7]: calcd. for C26H46IO3 [ðM þ HÞþ], 533.2486; found,
533.2484.
(ii) (S)-Isomer. Similarly, (S)-21 (1.0 g, <1:54 mmol) gave 283
mg (34%, 2 steps) of (S)-22 as a colorless solid and recovered 288 mg
(ii) (3S,19Z)-Isomer. Similarly, (3S,19Z)-24 (80 mg, 0.15 mmol)
24
20
17
(44%) of (S)-20. Properties of (S)-22: mp 57–59 ꢁC; ½ꢁꢂD ꢀ4:89
gave 83 mg (97%) of (3S,19Z)-25 as a colorless oil, nD 1.4846; ½ꢁꢂD
þ9:56 (c 0.831, CHCl3). Its IR and 1H-NMR spectra were identical to
those of (3R,19Z)-25. HRMS of (3S,19Z)-25: calcd. for C38H67O4
[ðM þ HÞþ], 587.5034; found, 587.5039.
(c 2.64, CHCl3). Its IR and 1H-NMR spectra were identical to those of
(R)-22. HRMS of (S)-22: calcd. for C26H46IO3 [ðM þ HÞþ], 533.2486;
found, 533.2487.
19-Octacosyne-1,3-diol 1-PMB ether (23).
(i) (R)-Isomer. A solution of n-BuLi in hexane (1.6 M, 1.28 mL,
2.05 mmol, 4.2 eq.) was added dropwise to a solution of 1-decyne
3-Acetoxy-19-octacosen-1-ol (4).
(i) (3R,19Z)-Isomer. In the same manner as that previously
described,5) (3R,19Z)-25 (104 mg, 0.177 mmol) gave 74 mg (89%) of

1938
Y. SHIKICHI et al.
21
(3R,19Z)-4 as a colorless solid. Mp 27–28 ꢁC; ½ꢁꢂD ꢀ8:63 (c 0.742,
CHCl3); IR ꢂmax (thin film) cmꢀ1: 3455 (s, OH), 3004 (w), 2924 (s),
2853 (s), 1739 (s, C=O), 1466 (m), 1374 (m), 1244 (s, C–O), 1054
(m), 1022 (m), 957 (w), 721 (w); 1H-NMR ꢀH (CDCl3): 0.89 (3H, t,
J ¼ 6:8 Hz), 1.18–1.42 (38H, br), 1.50–1.70 (3H, m), 1.80–1.89 (1H,
m), 1.96–2.06 (4H, m, 2ꢃ ¼ CHCH2), 2.09 (3H, s, COCH3), 2.32–
2.40 (1H, br), 3.48–3.58 (1H, m, CHHOH), 3.59–3.68 (1H, m,
CHHOH), 4.98–5.06 (1H, m, CHOAc), 5.32–5.42 (2H, m, CH=CH);
13C-NMR ꢀC (CDCl3): 14.07, 14.09, 21.09, 21.11, 21.20, 22.64, 22.66,
22.67, 25.43, 25.45, 25.46, 27.2, 29.29, 29.36, 29.50, 29.54, 29.65,
29.66, 29.74, 58.5, 71.6, 129.9, 172.2; GC-MS [same conditions as
those for 1]: tR 23.50 min (8.8%, broad, decomposition peak),
23.91 min (78.6%), 24.49 min (10.8%, broad, decomposition peak).
MS of (3R,19Z)-4 (70 eV, EI): m=z: 448 (3) [M-18], 406 (3), 388 (4),
360 (3), 331 (2), 289 (4), 275 (6), 261 (4), 247 (2), 222 (2), 207 (20),
193 (4), 179 (2), 166 (3), 151 (6), 135 (12), 117 (36), 95 (57), 83 (66),
69 (68), 55 (93), 43 (100). HRMS of (3R,19Z)-4 [same conditions as
those for 2]: calcd. for C30H59O3 [ðM þ HÞþ], 467.4459; found,
467.4458.
elsewhere.2,7) Briefly, for (R)-3-acetoxy-11,19-octacosadiyn-1-ol (1),
(R)-3-acetoxyoctacosan-1-ol (2), (R)-3-acetoxy-11-octacosen-1-ol (3),
and (R)-3-acetoxy-19-octacosen-1-ol (4), glass vials (Wheaton, USA)
were coated with 64 mg of the analogue diluted in 200 mL of hexane or
CHCl3, and the solvent was evaporated under a stream of N2. For (S)-
3-acetoxy-11,19-octacosadiyn-1-ol (1), (S)-3-acetoxyoctacosan-1-ol
(2), (S)-3-acetoxy-11-octacosen-1-ol (3), and (S)-3-acetoxy-19-oc-
tacosen-1-ol (4), 2 mg of the analogue was used to coat each glass
vial. Six live females were placed in each vial and gently vortexed for
three 20-s bouts with a 20-s pause between each bout. It has been
estimated that approximately 25% of the vial contents would be
transferred to the flies.7) Control flies were vortexed in a vial in which
hexane or chloroform had been placed and then evaporated. The heads
of perfumed flies were crushed immediately before the assay.
Acknowledgments
Our thanks are due to Mr. M. Kimura (President,
Toyo Gosei Co., Ltd.) and Mr. Y. Kimura (CEO, Toyo
Gosei Co., Ltd.) for their support. J. Y. Y. is supported
by the Singapore National Research Foundation
(RF001-363).
(ii) (3S,19Z)-Isomer. Similarly, (3S,19Z)-25 (75 mg, 0.13 mmol)
gave 53 mg (88%) of (3S,19Z)-4 as a colorless solid, mp 27–28 ꢁC;
22
½ꢁꢂD þ8:36 (c 0.505, CHCl3). GC-MS [same conditions as those for
(R)-1]: tR 23.50 min (15.0%, broad, decomposition peak), 23.89 min
(81.3%), 24.50 min (2.3%, broad, decomposition peak). Its spectral
data (IR, 1H- and 13C-NMR, and MS) were identical to those of
(3R,19Z)-4. HRMS of (3S,19Z)-4: calcd. for C30H59O3 [ðM þ HÞþ],
467.4459; found, 467.4466.
References
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2) Yew JY, Dreisewerd K, Luftmann H, Muthing J, Pohlenz G, and
¨
Fly stocks and husbandry. The CantonS flies used for the assay
¨
Kravitz EA, Curr. Biol., 19, 1245–1254 (2009).
3) Mori K, Bioorg. Med. Chem., 15, 7505–7523 (2007).
4) Mori K, Chirality, 23, 449–462 (2011).
were raised at 25 ꢁC on cornmeal agar food. Socially naıve flies aged
between 4–6 d were used for the assay.
5) Mori K, Shikichi Y, Shankar S, and Yew JY, Tetrahedron, 66,
7161–7168 (2010).
Courtship behavior assays with perfumed targets. Courtship assays
were performed in chambers of 10 mm diameter and 3 mm depth. One
male fly and one perfumed female target were placed in each chamber
and videotaped for 30 min. Wet filter paper was put into each chamber
to maintain humidity. The perfuming method has been described
6) Shikichi Y, Akasaka K, Tamogami S, Shankar S, Yew JY, and
Mori K, Tetrahedron, 68, 3750–3760 (2012).
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