Synthesis of the enantiomers of 21-methyl-7-hentriacontanone and a stereoisomeric mixture of 5-acetoxy-19-methylnonacosane, candidates for the female sex pheromone of the screwworm fly, Cochliomyia hominivorax

Article abstract of DOI:10.1271/bbb.67.2224

The enantiomers of 21-methyl-7-hentriacontanone (1), which might show weak bioactivity as the female sex pheromone of the screwworm fly (Cochliomyia hominivorax), were synthesized by starting from the enantiomers of citronellal. (±)-Citronellol was converted to a racemic and diastereomeric mixture of 5-acetoxy-19-methylnonacosane (2), which was considered to be a candidate for the female sex pheromone of C. hominivorax. Synthetic 2 exhibited no pheromone activity against male C. hominivorax.

Full text of DOI:10.1271/bbb.67.2224

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Synthesis of the Enantiomers of 21-Methyl-7-
hentriacontanone and a Stereoisomeric Mixture of 5-
Acetoxy-19-methylnonacosane, Candidates for the
Female Sex Pheromone of the Screwworm Fly…
Kenji MORIa
a Insect Pheromone and Traps Division, Fuji Flavor Co., Ltd.Midorigaoka 3-5-8, Hamura-
City, Tokyo 205-8503, Japan
Published online: 22 May 2014.
To cite this article: Kenji MORI (2003) Synthesis of the Enantiomers of 21-Methyl-7-hentriacontanone and a Stereoisomeric
Mixture of 5-Acetoxy-19-methylnonacosane, Candidates for the Female Sex Pheromone of the Screwworm Fly…,
Bioscience, Biotechnology, and Biochemistry, 67:10, 2224-2231, DOI: 10.1271/bbb.67.2224
To link to this article: http://dx.doi.org/10.1271/bbb.67.2224
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Biosci. Biotechnol. Biochem., 67 (10), 2224–2231, 2003
Synthesis of the Enantiomers of 21-Methyl-7-hentriacontanone and a
Stereoisomeric Mixture of 5-Acetoxy-19-methylnonacosane, Candidates for
the Female Sex Pheromone of the Screwworm Fly, Cochliomyia hominivorax
*
†
Kenji MORI
Insect Pheromone and Traps Division, Fuji Flavor Co., Ltd., Midorigaoka 3-5-8, Hamura-City,
Tokyo 205-8503, Japan
Received May 28, 2003; Accepted June 23, 2003
The enantiomers of 21-methyl-7-hentriacontanone
(1), which might show weak bioactivity as the female
sex pheromone of the screwworm ‰y (Cochliomyia
hominivorax ), were synthesized by starting from the
identiˆcation of sixteen compounds in a pheromonal-
ly active HPLC fraction extracted from the females.1)
Unfortunately, they were unable to identify the
compound(s) responsible for the pheromone activity,
because no bioactivity could be observed in peaks
trapped either by GC or by recombination of the
trapped capillary GC peaks, presumably due to ther-
mal decomposition in the course of GC separation.
Carlson then requested us to synthesize the ˆve
±
enantiomers of citronellal. ( )-Citronellol was convert-
ed to a racemic and diastereomeric mixture of 5-
acetoxy-19-methylnonacosane (2), which was consi-
dered to be a candidate for the female sex pheromone of
C. hominivorax. Synthetic 2 exhibited no pheromone
activity against male C. hominivorax.
compounds, (
±
)-1, 3, 4, 5 and 6, (Fig. 1) out of the
sixteen candidates reported by Pomonis.1) These ˆve
compounds have been synthesized as stereoisomeric
mixtures2) and bioassayed in the United States.3) The
result was very encouraging to reveal the strong
pheromone activity of 6-acetoxy-19-methylnonaco-
Key words: Cochliomyia hominivorax ; methyl-bran-
ched ketone; methyl-branched secondary
acetate; pheromone; screwworm ‰y
The New World screwworm ‰y (Cochliomyia
hominivorax ) is a troublesome pest to livestock in
Central and South America. In order to eradicate this
‰y, a sterile male release program was successfully
executed in that region. Possible incompatibility of
the sex pheromones in released ‰ies versus wild ‰ies,
however, may cause problems to render the program
unsuccessful. Accordingly, in 2001, Carlson at the
United States Department of Agriculture started
his endeavors to clarify the pheromone system of
sane (3) against male C. hominivorax at 1–6 mg,
causing copulatory response.3) 7-Acetoxy-15-methyl-
nonacosane (6) was also active but less potent.
Although 7-acetoxy-19-methylnonacosane (4) and
8-acetoxy-19-methylnonacosane (5) were devoid of
pheromone activity, 21-methyl-7-hentriacontanone
(1) did not seem to be inert, seeming to be very slight-
ly active (Carlson, D. A. personal communication
dated March 11, 2002). We therefore thought that
the enantiomers of 1 should be synthesized to clarify
the matter. Another synthetic target suggested by
Carlson was 5-acetoxy-19-methylnonacosane (2).
This isomer of 3 is one of Pomonis's sixteen com-
C. hominivorax
.
Pomonis et al. were the ˆrst to study the phero-
mone of C. hominivorax, and reported in 1993 the
Fig. 1. Structures of Components 1–6 of the Female Sex Pheromone of the Screwworm Fly, Cochliomyia hominivorax
.
*
Pheromone Synthesis, Part 222. For Part 221, see Masuda, Y., Fujita, K., and Mori, K., Biosci. Biotechnol. Biochem., 67, 1744–1750
(2003).
†
To whom correspondence should be addressed. Fax:
＋
81-42-555-7920

Synthesis of Pheromone Candidates of the Screwworm Fly
2225
Scheme 1. Synthesis of the Enantiomers of 21-Methyl-7-hentriacontanone (1).
Reagents: (a) TsCl, C5H5N (quant.). (b) THPO(CH2)11MgBr, Li2CuCl4, THF. (c) TsOH, MeOH, THF (75
4A, NaOAc, CH2Cl2 (78 ). (e) Me(CH2)5MgBr, THF (89 ). (f) Jones CrO3, acetone (70 ).
z, 2 steps). (d) PCC, MS
z
z
z
pounds,1) and may also work as a pheromone compo-
nent. The present paper describes the synthesis of
until very recently. The enantiomeric purity (97z
e.e.) of the starting citronellal (7) was thought to be
preserved in ˆnal product 1, because there was no
step in the course of the synthesis to cause racemiza-
tion. In this particular case, the speciˆc rotation
(S)-1 and (R)-1, and also the synthesis of a racemic
and diastereomeric mixture of 2.
Synthesis of the Enantiomers of 21-Methyl-7-hen-
values of (R)- and (S)-1 were so small that they could
triacontanone (
1
)
not tell us anything about the purity of the enantiom-
ers of 1. Fortunately, however, Ohrui et al. have
developed an excellent method for estimating the
stereochemical purity of compounds with a methyl-
branched and long alkyl chain whose branching point
was located far from the functional groups.6) Ohrui's
method has recently been applied to the structural
elucidation of plakoside A, a marine galactosphin-
golipid.7) Professor Ohrui kindly estimated the enan-
tiomeric purity of the enantiomers of 11 and that of
Commercially available enantiomers of citronellal
(7, 97 e.e.; Takasago) were the most appropriate
starting materials for the synthesis of ( )- and ( )-1,
because conversion of 7 to tosylate 9 via alcohol 8
was already known (Scheme 1).4) Treatment of (
)-9
with 11-tetrahydropyranyl(THP)oxyundecylmag-
z
R
S
S
nesium bromide in the presence of dilithium
tetrachlorocuprate according to Schlosser5) aŠorded
(
S
)-10. Removal of the THP group of 10 with
uenesulfonic acid (TsOH) in methanol furnished
crystalline alcohol ( )-11. This was oxidized with
pyridinium chlorochromate (PCC) to give aldehyde
)-12. The Grignard reaction of ( )-12 with
hexylmagnesium bromide furnished alcohol (7RS
21 )-13 as a crystalline mixture of diastereomers.
Finally, alcohol 13 was oxidized with Jones chromic
acid to give ( )-21-methyl-7-hentriacontanone (1),
mp 42–43 C, [
yield of ( )-1 was 36
Similarly, ( )-citronellal (7) yielded (
p-tol-
(7RS, 21
S)- and (7RS, 21R )-13. Their stereochemical
S
purity values at the methyl-branching carbon was as
＝
＝
follows: (
(7RS, 21
96.7 e.e. As we expected, no racemization took
R
)-11 96.7
z
z
e.e.; (
S
)-11 97.1
z
e.e.;
(
S
S
R
)-13 96.6
＝
e.e.; and (7RS, 21
S
)-13
＝
,
z
S
place in the course of the synthesis. Application of
Ohrui's analytical method to our study of the
C. hominivorax pheromone will be thoroughly dis-
cussed in our forthcoming paper on the synthesis of
the four stereoisomers of 6-acetoxy-19-methyl-
nonacosane (3) (Mori, K., Ohrui, H., et al.: to be
submitted to Eur. J. Org. Chem.).
S
25
a
]
－
0.1 (
c
5.3, hexane). The overall
based on ( )-8 (6 steps).
)-1, mp 42–
9
D
S
z
S
R
S
21
＋
0.1 (c 4.4, hexane).
43
9
C, [
As to the enantiomeric purity of (
there had been no good method to estimate it directly
a
]
D
R
)- and (
S
)-1,
Very recently, Carlson et al. have repeated the
±
bioassay of ( )-1 against C. hominivorax males.

2226
K. MORI
Scheme 2. Synthesis of the Stereoisomeric Mixture of 5-Acetoxy-19-methylnonacosane (2).
Reagents: (a) OsO4, NMO, tert-BuOH, acetone, H2O (75 based on 14, steps). (b) HIO4
THPO(CH2)11MgBr, THF (90 ). (d) MsCl, C5H5N (quant.). (e) i) LiAlH4, THF; ii) dil HCl; iii) SiO2 chromatog; iv) recrystallization
(67 ). (f) PCC, MS 4A, NaOAc, CH2Cl2 (73.5 ). (g) Me(CH2)3MgBr, THF (73 ). (h) Ac2O, DMAP, C5H5N (96 ).
z
3
･
2H2O, THF (quant.). (c)
z
z
z
z
z
They could not get any copulatory activity with
from the excess Grignard reagent. To circumvent the
use of the sometimes-capricious copper-catalyzed
±
(
)-1 in individual bioassays. Its activity was seen
±
only when a group test was used with several stimula-
tory materials. According to Carlson, there may be a
``group eŠect'' causing nearby males to copulate with
decoys or objects that are near a ``real'' mating. This
may mean that some olfactory stimulant is released
from engaged male genitalia that causes nearby males
to become excited (Carlson, D. A., personal com-
munication dated November 22, 2002).
reaction, we synthesized ( )-15-methylpentacosan-
1-ol (11) in a diŠerent way as shown in Scheme 2.
±
(
)-Citronellol (14) was converted to 15 as report-
ed previously.2) Dihydroxylation of 15 with osmium
tetroxide and -methylmorpholine -oxide (NMO)
N
N
aŠorded a diastereomeric mixture of diol 16 as
crystals. Treatment of 16 with periodic acid dihy-
drate in tetrahydrofuran (THF) gave aldehyde 17.
This was treated with the Grignard reagent prepared
from 1.5 equivalents of 11-tetrahydropyranyloxyun-
Synthesis of a Stereoisomeric Mixture of 5-Aceto-
xy-19-methylnonacosane (
2
)
decyl bromide and magnesium to give 18 in a 90
z
As just described for the synthesis of 1, Schlosser's
copper-catalyzed carbon-carbon linking reaction5)
was employed for chain-elongation of 8 to give 11.
This reaction proved extremely useful in our synthe-
sis of aliphatic insect pheromones.2,4) However, it
sometimes failed to give the chain-elongated product
in an acceptable yield, although we were unable to
identify the reason for this failure. We observed a
low yield more often in the case of a Grignard
yield. Mesylation of 18 with methanesulfonyl (
＝
mesyl, Ms) chloride aŠorded 19, which was reduced
with lithium aluminum hydride. The resulting (
±
)-
15-methylpentacosyl tetrahydropyranyl ether was
±
treated with hot hydrochloric acid to furnish ( )-11
in a 67
z
yield after conventional chromatographic
±
)-11
puriˆcation and recrystallization. Thus,
(
could be readily and reproducibly prepared without
very careful and time-consuming chromatographic
puriˆcation, avoiding the use of a large excess of 11-
tetrahydropyranyloxydecylmagnesium bromide.
reagent with an
v-tetrahydropyranyloxy group than
in the case of a conventional alkylmagnesium
bromide. In addition, for the conversion of 9 to 10,
almost four equivalents of 11-tetrahydropyranylox-
yundecylmagnesium bromide had to be used to give
coupling product 10 in a good yield, and this caused
di‹culty in separating 11 from 1-undecanol derived
±
Oxidation of ( )-11 with PCC aŠorded aldehyde
±
(
±
)-20. Treatment of ( )-20 with butylmagnesium
bromide gave a racemic and diastereomeric mixture
of 19-methylnonacosan-5-ol (21) as crystals, mp
9
34–35 C. Acetylation of 21 with acetic anhydride

Synthesis of Pheromone Candidates of the Screwworm Fly
2227
and 4-(
N
,
N
-dimethylamino)pyridine (DMAP) in
pared from 11-THPO(CH2)11Br (11.0 g, 33 mmol)
and Mg (960 mg, 40 mmol) in dry THF (35 ml)
through a syringe. A solution of Li2CuCl4 in THF
(0.1 , 1 ml) was then added to the stirred and cooled
mixture. The reaction temperature was gradually
－
raised overnight from 789C to room temperature.
pyridine furnished ˆnal product 2. The overall yield
of 5-acetoxy-19-methylnonacosane (2) was 23
z
±
M
based on ( )-citronellol (14; 11 steps). A bioassay of
2 showed it to be totally inactive as the sex stimulant
3)
against male C. hominivorax
.
The mixture was poured into ice and sat. NH4Cl aq.,
and then extracted with hexane. The extract was
washed with brine, dried with MgSO4, and concen-
Conclusion
Synthesis of pheromone candidates (
R
)-1, (
S
)-1
trated in vacuo to give crude (
(ˆlm) cm－1: 1120 (m), 1080 (m), 1020 (s).
uenesulfonic acid monohydrate (0.1 g) was added to
a solution of crude ( )-10 (9.9 g) in MeOH (90 ml)
and THF (50 ml). The mixture was stirred at 60
S
)-10 (9.9 g), IR nmax
and 2 of the screwworm ‰y was achieved. As to the
synthesis of 2, a practical and reproducible chain-
extension process was devised by employing the Grig-
nard reaction and subsequent deoxygenation of the
p
-Tol-
S
9C
resulting secondary alcohol [17
ª
18
ª
19
ª
(
±
)-11].
for 1.5 h, neutralized with Na2CO3, and concentrated
in vacuo. The residue was diluted with water and
extracted with hexane-diethyl ether. The extract was
successively washed with water and brine, dried with
MgSO4, and concentrated in vacuo. The residue
(7.2 g) was chromatographed over SiO2 (50 g in
hexane). Elution with hexane-diethyl ether (20:1)
±
Since ( )-1 and 2 were biologically inactive, we
can now concentrate our eŠorts on the synthesis of
the stereoisomers of 3 and 6 so as to clarify the
stereochemistry-pheromone activity relationships in
C. hominivorax. Indeed, the stereochemistry of 3 is
important in its pheromone activity as was evident by
the recent observation that (6
S
, 19
R
)-3 was about
gave (
S)-11 (2.97 g, 75z) as a solid. This was
three times more active than a stereoisomeric mixture
recrystallized from hexane-acetone to give ˆne
25
＋
0.15 (c 4.84, hexane).
of 3 (Carlson, D. A., personal communication dated
needles, mp 42–43
9C, [
a
]
D
April 17, 2003). Although (
±
)-1 was pheromonally
IR nmax (nujol) cm－1: 3370 (m), 1060 (s), 725 (s).
＝
inactive, a bioassay of the enantiomers of 1 will be
conducted shortly with the hope that it might tell us
something about its stereochemistry-bioactivity
relationship.
NMR dH (CDCl3): 0.83 (3H, d,
J
6.3 Hz, 15-Me),
7.0 Hz, 25-H), 1.00–1.10 (2H, m),
1.10–1.40 (41H, br), 1.56 (2H, seemingly q, 7.2
6.9 Hz,
＝
J
0.88 (3H, t,
J
＝
＝
J
Hz, 2-H), 1.61 (1H, s, OH), 3.64 (2H, t,
1-H). NMR dC (CDCl3): 14.1, 19.7, 22.64, 22.68,
25.7, 27.1, 29.35, 29.43, 29.59, 29.61, 29.65, 29.67,
29.69, 29.70, 29.72, 30.0, 31.6, 31.9, 32.7, 32.8, 37.1,
Experimental
Melting point (mp) data are uncorrected. IR spec-
tra were measured with a Horiba FT-720 spectrome-
ter. 1H-NMR spectra were recorded at 300 MHz by a
63.1. Anal. Found: C, 81.88; H, 14.51
C26H54O: C, 81.60; H, 14.22
z
. Calcd. for
z.
＝
Varian Mercury-300 spectrometer (TMS at
d
0.00
(R)-15-Methyl-1-pentacosanol [(R)-11]. In the
same manner as that described for (S)-11, (R)-8
or CHCl3 at
d
7.26 as an internal standard). 13C-
＝
NMR spectra were recorded at 75 MHz also by the
(2.3 g) gave (
R
)-11 (1.8 g, 46
z
) as needles from
D
24
＝
－
0.11 (
Varian Mercury-300 spectrometer (CDCl3 at
d
77.0
hexane-acetone, mp 44–45
9
C, [a
]
c 5.20,
as an internal standard). Optical rotation values were
measured with a Jasco DIP-320 polarimeter, and
refractive index data were measured with an Atago
DMT-1 refractometer.
hexane). Its IR, 1H- and 13C-NMR spectra were iden-
tical with those reported for ( )-11. Anal. Found: C,
81.80; H, 14.47 . Calcd. for C26H54O: C, 81.60; H,
14.22
S
z
z
.
(S)-15-Methyl-1-pentacosanol [(S)-11].
uenesulfonyl chloride (2.3 g, 12 mmol) was added
portionwise to a stirred and ice-cooled solution of
p
-Tol-
(S)-15-Methylpentacosanal [(S)-12]. Powdered
sodium acetate (240 mg, 2.9 mmol) and powdered
MS 4A (100 mg) were added to a solution of (S)-11
(
S
)-8 (2.3 g, 10 mmol) in dry pyridine (10 ml) at 0–
C. Stirring was continued for 30 min at 0 C and
(1.9 g, 5.0 mmol) in dry CH2Cl2 (25 ml). The suspen-
sion was stirred vigorously at 0–5 C. To this was
added PCC (2.8 g, 13 mmol), and the dark mixture
was stirred for 30 min at 0–5 C and then for 3 h at
5
9
9
9
then for 1 h at room temperature. The mixture was
then poured into ice-water and extracted with
hexane-diethyl ether. The extract was successively
washed with ice-cooled dil. HCl, water, sat. NaHCO3
aq. and brine, dried with MgSO4, and concentrated
9
room temperature. The mixture was ˆltered through
SiO2 (20 g in diethyl ether), and the SiO2 column was
washed with diethyl ether. The combined ˆltrate and
washings were concentrated in vacuo. The residue
was chromatographed over SiO2 (30 g in hexane).
in vacuo. Resulting (
S)-9 [3.9 g, quant., IR nmax (ˆlm)
cm－1: 1175 (s), 660 (s), 553 (s)] was dissolved in dry
－
THF (40 ml) and stirred at 78
was added a solution of the Grignard reagent pre-
9C under Ar. To this
Elution with hexane-ethyl acetate (20:1) aŠorded
25
(
S
)-12 (1.5 g, 78
z
) as a waxy solid, [
a
]
＋
0.15.
D

2228
K. MORI
(
c
4.56, hexane). IR nmax (ˆlm) cm－1: 2715 (w), 1730
was added dropwise to a stirred and ice-cooled solu-
tion of (7RS, 21 )-13 (1.21 g, 2.59 mmol) in acetone
(100 ml) at 0–5 C. After the mixture had been stirred
for 30 min at 0–5 C, MeOH was added to destroy
excess CrO3. The mixture was concentrated in vacuo
and the residue was partioned between hexane and
water. The hexane extract was successively washed
with water and brine, dried with MgSO4, and concen-
＝
(s), 720 (m). NMR dH (CDCl3): 0.83 (3H, d,
J
S
9
＝
6.3 Hz, 15-Me), 0.87 (3H, t,
1.00–1.15 (2H, m), 1.20–1.40 (39H, br), 1.62 (2H, t,
7.2 Hz, 3-H), 2.41 (2H, dt, 1.4, 7.5 Hz, 2-H),
C (CDCl3): 14.1,
J
6.6 Hz, 25-H),
9
J
＝
J
＝
,
＝
9.76 (1H, t,
J
1.4 Hz 1-H). NMR
d
19.7, 22.1, 22.7, 27.1, 29.2, 29.35, 29.42, 29.58,
29.63, 29.65, 29.66, 29.68, 29.70, 29.73, 30.0, 31.9,
32.7, 37.1, 43.9, 202.9. Anal. Found: C, 82.10; H,
trated in vacuo to give crude (
S
)-1 as a solid.
13.94
z
. Calcd. for C26H52O: C, 82.03; H, 13.77
z
.
Recrystallization from acetone gave pure (
S
)-1
25
(0.84 g, 70
z) as ˆne needles, mp 42–439C, [a]
D
0.1 (c
5.3, hexane). IR nmax (ˆlm) cm－1: 2962 (m),
－
(R)-15-Methylpentacosanal [(R)-12]. In the same
manner as that described for ( )-12, ( )-11 (1.3 g)
gave ( )-12 (1.25 g, 97 ) as a waxy solid, [
0.04 (
5.10, hexane). Its IR, H- and 13C-NMR
spectra were identical with those reported for ( )-12.
Anal. Found: C, 82.28; H, 13.37 . Calcd. for
C26H52O: C, 82.03; H, 13.77
S
R
2918 (s), 2850 (s), 1703 (s), 1468 (s), 1412 (m), 1379
(m), 1128 (w), 987 (w), 721 (m). NMR dH (CDCl3):
25
R
c
z
a
]
D
1
－
0.83 (3H, d, J 6.6 Hz, 21-Me), 0.88 (6H, t, J
＝ ＝
S
6.9 Hz, 1-H, 31-H), 1.00–1.10 (2H, m), 1.18–1.40
(45H, br., centered at 1.25), 1.55 (4H, seemingly t,
z
＝
＝
7.5 Hz, 6-H,
z
.
J
7.5 Hz, 5-H, 9-H), 2.38 (4H, t,
J
8-H). NMR C (CDCl3): 14.0, 14.1, 19.7, 22.5, 22.7,
d
(7RS, 21S)-21-Methyl-7-hentriacontanol
[(7RS,
23.84, 23.89, 27.1, 28.9, 29.27, 29.35, 29.42, 29.48,
29.61, 29.65, 29.67, 29.69, 29.70, 29.72, 30.0, 31.6,
31.9, 32.7, 37.1, 42.8, 48.1, 65.3, 211.8. Anal.
21S)-13]. A Grignard reagent was prepared from
hexyl bromide (1.7 g, 10 mmol) and Mg (270 mg, 11
mmol) in dry THF (10 ml) under Ar. A solution of
Found: C, 82.90; H, 14.31
82.64; H, 13.88
z
. Calcd. for C32H64O: C,
(
S
)-12 (1.5 g, 3.9 mmol) in dry THF (10 ml) was
added dropwise to the stirred and ice-cooled Grig-
nard reagent under Ar at 0–5 C. The mixture was left
z.
9
(R)-21-Methyl-7-hentriacontanone [(R)-
same manner as that described for ( )-1, (7RS
21 )-13 (0.80 g) gave ( )-1 (0.75 g, 94 ) as a solid.
1]. In the
to stand overnight at room temperature, then poured
into ice and sat. NH4Cl aq., and extracted with
hexane. The extract was successively washed with
water and brine, dried with MgSO4, and concentrated
in vacuo. The residue was chromatographed over
SiO2 (30 g in hexane). Elution with hexane-ethyl
S
,
R
R
z
Recrystallization from acetone aŠorded ˆne needles,
21
D
1
mp 42–43
9
C. [
a
]
＋
0.1 (
c
4.4, hexane). Its IR, H-
and 13C-NMR spectra were identical with those
reported for (
S)-1. Anal. Found: C, 82.91; H,
acetate (20:1) gave (7RS, 21
S
)-13 (1.6 g, 89
z
) as a
13.98 . Calcd. for C32H64O: C, 82.64; H, 13.88 .
z
z
solid. Recrystallization from hexane-acetone
24
aŠorded ˆne needles, mp 41–44
9
C, [
a
]
－
0.8 (
c
(3RS, 6RS)-2,6-Dimethylhexadecane-2,3-diol (16).
Crude and oily 15 (30.3 g) was prepared from 14
(8.8 g, 57 mmol) according to ref. 2. A solution of
OsO4 (150 mg, 0.6 mmol) in tert-BuOH (15 ml) and
D
8.23, hexane). IR nmax (nujol) cm－1: 3350 (m), 1135
(m), 1080 (m), 720 (s). NMR dH (CDCl3): 0.83 (3H,
d, J 6.3 Hz, 21-Me), 0.88 (6H, t, J 7.2 Hz, 1-H,
＝ ＝
31-H), 1.00–1.10 (4H, m), 1.18–1.50 (51H, m), 1.59
(1H, s, OH), 3.58 (1H, m, 7-H). NMR dC (CDCl3):
14.08, 14.11, 19.7, 22.62, 22.69, 25.61, 25.65, 27.1,
29.36, 29.37, 29.62, 29.64, 29.66, 29.68, 29.69,
29.70, 29.72, 30.0, 31.8, 31.9, 32.7, 37.1, 37.5, 72.0.
NMO (50z aq., 26.0 g, 111 mmol) were added to a
stirred solution of crude 15 (30.3 g) in a mixture of
acetone (240 ml), tert-BuOH (100 ml) and H2O
(60 ml). Stirring was continued for 3 days at room
temperature. The color of the mixture changed from
･
Anal. Found: C, 82.66; H, 14.83
C32H66O: C, 82.32; H, 14.25
z. Calcd. for
dark brown to almost colorless. Solid Na2SO3 7H2O
z
.
(15 g) was added to the stirred mixture. After 30 min,
the solvents were removed in vacuo. The residue was
diluted with water, and extracted with ethyl acetate.
The extract was successively washed with water and
(7RS, 21R)-21-Methyl-7-hentriacontanol
21R)-13]. In the same manner as that described for
(7RS, 21 )-13, ( )-12 (0.92 g) gave (7RS, 21 )-13
(0.80 g, 71
ane-acetone yielded ˆne needles, mp 40–43
＋
spectra were identical with those reported for (7RS
21 )-13. Anal. Found: C, 82.39; H, 14.49 . Calcd.
for C32H66 O: C, 82.32; H, 14.25
[(7RS,
S
R
R
brine, dried with MgSO4, and concentrated in vacuo.
z
) as a solid. Recrystallization from hex-
The residue was chromatographed over SiO2 (180 g in
hexane). After washing out the hydrocarbons with
20
9
C, [
a
]
D
1
0.7 (
c
5.20, hexane). Its IR, H- and 13C-NMR
hexane, 16 (12.1 g, 75z based on 14, 3 steps) was
,
eluted with hexane-ethyl acetate (10:1„5:1). Partial-
S
z
ly solidiˆed 16 was recrystallized from acetone to give
z.
crystalline 16 (5.3 g, 33z) as prisms, mp 55–569C.
IR nmax (nujol) cm－1: 3400 (m), 1050 (s). NMR dH
＝
6.9 Hz, 6-Me), 0.88 (3H, t,
(S)-21-Methyl-7-hentriacontanone [(S)-
chromic acid (2.67 , 1.0 ml, 2.67 mmol
1
＝
]. Jones
(CDCl3): 0.87 (3H, d,
J
M
3 equiv.)
J 6.6 Hz, 16-H), 1.16 (3H, s, 1-H or 2-Me), 1.22
＝

Synthesis of Pheromone Candidates of the Screwworm Fly
2229
(3H, s, 1-H or 2-Me), 1.10–1.50 (24H, br., centered
at 1.26), 1.96 (1H, s, OH), 2.11 (1H, s, OH), 3.34
(1H, m, 3-H). NMR dC (CDCl3): 14.1, 19.5, 22.7,
23.2, 26.5, 27.1, 29.1, 29.3, 29.64, 29.68, 29.7, 30.0,
31.9, 32.8, 34.0, 37.2, 73.2, 78.9. Anal. Found: C,
19.64, 19.7, 22.7, 25.5, 25.61, 25.65, 26.2, 27.00,
27.04, 29.3, 29.45, 29.55, 29.59, 29.63, 29.69, 29.71,
30.0, 30.3, 30.7, 31.9, 32.6, 32.77, 32.82, 32.86, 32.9,
34.87, 34.92, 36.88, 36.95, 37.1, 37.4, 37.5, 62.3,
63.4, 67.7, 72.3, 72.4, 98.8. Oily 18 was used for the
next step without further puriˆcation.
75.71; H, 13.50
13.37
z. Calcd. for C18H38O2: C, 75.46; H,
z.
(12RS, 15RS)-12-Methanesulfonyloxy-15-methyl-
(RS)-4-Methyltetradecanal (17). A solution of 16
pentacosan-1-ol Tetrahydropyranyl Ether
(19).
(11.4 g, 39.9 mmol) in THF (50 ml) was added drop-
Methanesulfonyl chloride (1.5 ml, 2.2 g, 19.4 mmol)
was added dropwise to a stirred and ice-cooled
solution of 18 (3.0 g, 6.0 mmol) in CH2Cl2 (15 ml)
and dry pyridine (10 ml). The mixture was kept in a
refrigerator for 3 days, poured into ice-water, and
extracted with hexane. The extract was successively
washed with water, CuSO4 aq., water and brine,
dried with MgSO4, and concentrated in vacuo to give
19 (3.5 g, quant.) as an oil. IR nmax (ˆlm) cm－1: 1350
･
wise to a stirred and ice-cooled solution of HIO4
2H2O (9.5 g, 41.7 mmol) in THF (150 ml). Stirring
was continued for 1 h at 0–5 C to precipitate HIO3.
9
The mixture was diluted with water and extracted
with hexane. The extract was successively washed
with water, NaHCO3 aq., water and brine, dried with
MgSO4, and concentrated in vacuo. The residue was
chromatographed over SiO2 (100 g in hexane).
Elution with hexane-ethyl acetate (50:1) gave 17
(m), 1175 (s), 900 (s), 530 (s). NMR
(3H, d, 6.3 Hz, 15-Me), 0.89 (3H, t,
25-H), 1.10–1.45 (43H, m), 1.48–1.62 (4H, m, 2-H,
-H), 1.62–1.86 (2H, m, 3 -H), 3.00 (3H, s,
d
H (CDCl3): 0.87
(8.9 g, 99
z
) as an oil which solidiˆed in a refrigera-
J
＝
J
＝
6.9 Hz,
tor. IR nmax (ˆlm) cm－1: 2710 (w), 1728 (s), 721 (w).
＝
NMR dH (CDCl3): 0.87 (3H, d,
0.88 (3H, t,
J
6.3 Hz, 6-Me),
5
?
?
＝
＝
6.6, 9.0 Hz, 1-H),
J
6.0 Hz, 16-H), 1.14 (2H, m),
SO2Me), 3.34–3.42 (1H, dt,
＝
3.46–3.55 (2H, m, 2-H, 4?-H), 3.68–3.78 (1H, dt, J
J
1.22–1.38 (16H, m), 1.40–1.50 (2H, m, 4-H),
1.60–1.72 (2H, m, 3-H), 2.32–2.52 (2H, m, 2-H),
6.6, 9.0 Hz, 1-H), 3.82–3.92 (2H, m, 6
?-H), 4.58
＝
＝
4.5 Hz, 2
9.77 (1H, t,
J
1.0 Hz 1-H). NMR
d
C (CDCl3): 14.1,
(1H, t,
quint.,
J
J
?
-H), 4.64–4.74 (1H, seemingly
＝
6.0 Hz, 12-H). This compound was em-
19.3, 22.7, 26.9, 28.9, 29.3, 29.6, 29.9, 31.9, 32.4,
36.7, 41.7, 203.0. Anal. Found: C, 79.72; H,
ployed immediately for the next step.
13.62
z. Calcd. for C15 H30O: C, 79.57; H, 13.36z.
(RS)-15-Methylpentacosan-1-ol [(
±
)-11]. A solu-
(12RS, 15RS)-15-Methylpentacosane-1,12-diol 1-
Tetrahydropyranyl Ether (18). A Grignard reagent
was prepared under Ar by adding a solution of 11-
THPO(CH2)11Br (10.7 g, 30 mmol) in dry THF
tion of 19 (3.5 g, 6.0 mmol) in dry THF (20 ml) was
added dropwise to a stirred and ice-cooled suspen-
sion of LiAlH4 (1.0 g, 26 mmol) in THF (50 ml) at
0–59C. The mixture was stirred and heated under
(40 ml) to Mg (800 mg, 33 mmol) at 60
9
C in the
re‰ux for 1.5 h. It was then ice-cooled, and water
(5 ml) was added dropwise to destroy the excess
LiAlH4. The mixture was acidiˆed with dil. HCl
presence of a few mg of iodine. A solution of 17
(4.7 g, 21 mmol) in dry THF (10 ml) was added drop-
wise to the stirred and ice-cooled solution of the
(conc. HCl:H2O
＝
1:1, 30 ml), stirred and heated
Grignard reagent at 0–5
9C under Ar, and the mixture
under re‰ux for 30 min, cooled, and extracted with
hexane. The extract was successively washed with
water, sat. NaHCO3 aq. and brine, dried with
MgSO4, and concentrated in vacuo to give 2.5 g of a
crude oil. This oil was chromatographed over SiO2
(70 g in hexane). Elution with hexane-ethyl acetate
was left to stand for 2 days. It was then poured into
ice and sat. NH4Cl aq., and extracted with hexane.
The extract was successively washed with water and
brine, dried with MgSO4 and concentrated in vacuo
.
The residual oil (15 g) was chromatographed over
SiO2 (100 g in hexane). Elution with hexane-ethyl
(15:1) gave 1.95 g (88
z
) of ( )-11 as a solid.
±
±
acetate (10:1) gave 9.3 g (90
z
) of 18 as an oil which
Recrystallization from acetone gave ( )-11 (1.52 g,
C. IR nmax (ˆlm) cm－
:
1
solidiˆed upon storage in a refrigerator. This solid
was triturated with pentane, and ˆltered to give 3.9 g
67
z
) as prisms, mp 35–36
9
3400 (m), 1060 (s), 720 (s), 600 (s). NMR
d
H (CDCl3):
＝
＝
(38
tane gave needles, mp 43–45
3400 (m), 1122 (m), 1074 (m), 1025 (s). NMR dH
z
) of crystalline 18. Recrystallization from pen-
0.83 (3H, d,
6.3 Hz, 25-H), 1.00–1.20 (2H, m), 1.20–1.50 (42H,
J
6.3 Hz, 15-Me), 0.88 (3H, t,
J
1
9
C. IR nmax (ˆlm) cm－
:
＝
J
br. s), 1.50–1.70 (2H, m, 2-H), 3.64 (2H, t,
＝
(CDCl3): 0.86 (3H, d,
J
6.9 Hz, 15-Me), 0.88 (3H,
6.6 Hz, 1-H). NMR dC (CDCl3): 14.1, 19.7, 22.65,
22.69, 25.7, 27.1, 29.36, 29.60, 29.62, 29.67, 29.69,
29.70, 29.71, 29.74, 31.6, 31.9, 32.7, 32.8, 37.1, 63.1.
t, 7.0 Hz, 25-H), 1.05–1.40 (43H, m), 1.50–1.60
J
＝
(4H, m, 2-H, 5
?
-H), 1.62–1.86 (2H, m, 3
?-H),
＝
3.35–3.40 (1H, dt,
J
6.6, 9.6 Hz, 1-H), 3,42–3.65
Anal. Found: C, 81.68; H, 14.49
C26H54O: C, 81.60; H, 14.22
z. Calcd. for
＝
(3H, m, 12-H, 3
9.6 Hz, 1-H) 3.82–3.92 (2H, m, 6
3.6 Hz, 2 -H). NMR dC (CDCl3): 14.1, 19.58,
?
-H), 3.68–3.80 (1H, dt,
J
6.6,
z
.
?-H), 4.58 (1H, t,
J
＝
?

2230
K. MORI
±
(RS)-15-Methylpentacosanal [( )-20]. Powdered
for 1.5 h at room temp, poured into ice-water, and
extracted with hexane. The extract was washed suc-
cessively with dil. HCl, sat. NaHCO3 aq. and brine,
dried with MgSO4, and concentrated in vacuo. The
residue was chromatographed over SiO2 (8 g in
hexane). Elution with hexane-ethyl acetate (70:1)
sodium acetate (240 mg, 2.9 mmol) and powdered
±
MS 4A (100 mg) were added to a solution of ( )-11
(1.1 g, 2.9 mmol) in dry CH2Cl2 (25 ml). The ice-
9
cooled suspension was stirred vigorously at 0–5 C.
To this was added PCC (3.0 g, 14 mmol), and the
dark-colored mixture was stirred for 20 min at 0–5
and then for 2 h at room temperature. The mixture
was then diluted with diethyl ether (200 ml) and
ˆltered through SiO2 (20 g in diethyl ether). The SiO2
column was washed with diethyl ether (100 ml). The
combined ˆltrate and washings were concentrated in
vacuo to give a residual oil (1.1 g). This oil was chro-
matographed over SiO2 (30 g in hexane). Elution with
9
gave 2 (263 mg, 96
z
) as an oil, n2D1 1.4527. IR nmax
(ˆlm) cm－1: 1737 (s), 1238 (s), 1020 (m), 721 (w).
＝
NMR dH (CDCl3): 0.83 (3H, d,
0.89 (3H, t, 6.3 Hz, CH2C
6.3 Hz, CH2C 3), 1.00–1.15 (2H, m), 1.18–1.40
(45H, m), 1.44–1.58 (4H, m, 4-H, 6-H), 2.03 (3H, s,
J
6.6 Hz, 19-Me),
J
＝
H
H
3), 0.90 (3H, t,
J
＝
＝
6.3 Hz,
COC
H
3), 4.86 (1H, seemingly quint.,
J
5-H). NMR
d
C (CDCl3): 14.0, 14.1, 19.7, 21.3, 22.6,
hexane-ethyl acetate (15:1) gave (
±
)-20 (0.8 g,
22.7, 25.3, 27.1, 27.5, 29.4, 29.5, 29.6, 29.66, 29.67,
29.68, 29.70, 29.71, 29.74, 30.0, 32.7, 33.8, 34.1,
73.5 ) which solidiˆed in a refrigerator. IR nmax
z
(ˆlm) cm－1: 2710 (w), 1730 (s), 720 (m). NMR dH
37.1, 74.4, 170.9. MS (EI) m z (relative intensity): 57
W
＝
(CDCl3): 0.83 (3H, d,
J
6.3 Hz, 15-Me), 0.88 (3H,
(100), 73 (90), 89 (95), 97 (50), 111 (30), 129 (45), 131
＝
t,
J
6.6 Hz, 25-H), 1.00–1.07 (2H, m), 1.20–1.40
(42), 154 (4), 167 (20), 182 (6), 420 (3, M＋-AcOH).
(39H, br. s), 1.63 (2H, seemingly quint.,
J
＝
7.5 Hz,
1.8, 7.5 Hz, 2-H), 9.76 (1H, t,
1.8 Hz, 1-H). NMR C (CDCl3): 14.1, 19.7, 22.1,
z
Anal. Found: C, 80.15; H, 13.65 . Calcd. for
＝
3-H), 2.42 (2H, dt,
＝
J
z
C32H64O2: C, 79.93; H, 13.42 .
J
d
22.7, 27.1, 29.2, 29.36, 29.43, 29.58, 29.64, 29.66,
29.67, 29.69, 29.71, 29.73, 30.0, 31.9, 32.7, 37.1,
43.9, 203.0. Anal. Found: C, 81.80; H, 13.40
Calcd. for C26H52O: C, 82.03; H, 13.21
Acknowledgments
z
.
I thank Dr. David A. Carlson (the United States
Department of Agriculture) for bioassays and discus-
sions. I also thank Professor H. Ohrui and Dr. K.
Imaizumi (Tohoku University) for the HPLC analy-
sis of 11 and 13. My thanks are also due to Mr. M.
Hagihara, the president of Fuji Flavor Co., Ltd., Dr.
H. Shigematsu, Dr. M. Chiba and other members of
Insect Pheromone and Traps Division of Fuji Flavor
Co., Ltd. for their support.
z
.
(5RS, 19RS)-19-Methylnonacosan-5-ol
[(5RS,
19RS)-21]. A Grignard reagent was prepared from
butyl bromide (1.5 g, 11 mmol) and magnesium
(300 mg, 12 mmol) in dry THF (20 ml) under Ar. A
±
solution of ( )-20 (0.8 g, 2.1 mmol) in dry THF
(10 ml) was added dropwise to the stirred and
ice-cooled Grignard reagent under Ar at 0–5
9
C. The
mixture was stirred for 30 min at 0–5
9
C and for an
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2
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