Synthesis of (3S,7S)- and (3S,7S,15S)- stereoisomers of 3,7-dimethyl-2- heptacosanone and 3,7,15-trimethyl-2-heptacosanone, the ketones identified from the locust Schistocerca gregaria

Article abstract of DOI:10.1002/1099-0690(200004)2000:7<1307::AID-EJOC1307>3.0.CO;2-X

The (3S,7S) and (3S,7S,15S) stereoisomers of 3,7-dimethyl-2- heptacosanone (1) and 3,7,15-trimethyl-2-heptacosanone (2), the ketones identified from the locust Schistocerca gregaria, were synthesized by employing (2R,6S)-7-acetoxy-2,6-dimethyl-1-heptanol (4) as the starting material.

Full text of DOI:10.1002/1099-0690(200004)2000:7<1307::AID-EJOC1307>3.0.CO;2-X

FULL PAPER
Pheromone Synthesis, CCI[°]
Synthesis of (3S,7S)- and (3S,7S,15S)- Stereoisomers of 3,7-Dimethyl-2-
heptacosanone and 3,7,15-Trimethyl-2-heptacosanone, the Ketones Identified
from the Locust Schistocerca gregaria
Yoshihide Nakamura[b][°°] and Kenji Mori*[a]
Keywords: Ketones / Locust / Pheromones / Schistocerca gregaria
The (3S,7S) and (3S,7S,15S) stereoisomers of 3,7-dimethyl-2-
heptacosanone (1) and 3,7,15-trimethyl-2-heptacosanone (2),
the ketones identified from the locust Schistocerca gregaria,
were synthesized by employing (2R,6S)-7-acetoxy-2,6-di-
methyl-1-heptanol (4) as the starting material.
Introduction
similar aliphatic ketone had previously been isolated from
the female German cockroach (Blattella germanica) as the
sex pheromone; its structure was confirmed by synthetic
means as (3S,11S)-3,11-dimethyl-2-nonacosanone (3).[2] Al-
though the stereochemistry and biological function of 1 and
2 have not yet been clarified, we became interested in syn-
thesizing them to demonstrate the usefulness of the building
block (2R,6S)-4,[3] which was recently employed by us for
the synthesis of the pine sawfly pheromone.[4] Because
locusts and cockroaches are closely related taxonomically,
we decided to synthesize (3S,7S)-1 and (3S,7S,15S)-2,
which share the same S-configuration at their stereogenic
centers with that of the German cockroach pheromone
(3S,11S)-3. Our synthetic strategy was to utilize the nine-
carbon building block 4 for the construction of the (3S,7S)
chiral centers in 1 and 2.
Locust (Schistocerca gregaria) is a notorious migratory
grasshopper often stripping the areas passed of all vegeta-
tion. Very recently Francke and co-workers[1] identified
from locust two new ketones, 3,7-dimethyl-2-heptacosanone
(1, Scheme 1) and 3,7,15-trimethyl-2-heptacosanone (2). A
Scheme 2 summarizes the synthesis of (3S,7S)-1. Protec-
tion of the free hydroxy group of 4 as its tert-butyldiphenyl-
silyl (TBDPS) ether gave 5, the acetyl group of which was
removed to give the mono-TBDPS protected diol 6. This
was oxidized under Dess–Martin conditions[5] to afford the
aldehyde 7.[4] Treatment of 7 with methylmagnesium brom-
ide furnished 8. Protection of the newly generated second-
ary hydroxy group of 8 as its tetrahydropyranyl (THP) ether
provided 9. Removal of the TBDPS protective group of 9
yielded 10, which was tosylated to give 11. The (2R,6S,7S)
isomers of 8–11 were previously synthesized in the course
of our work on the pine sawfly pheromone.[4] In the present
case, we employed the diastereomeric mixture of 8–11 at C-
7, because in the final products 1 and 2 that position was
to be oxidized to give a carbonyl group. Chain-extension of
11 was performed by the method of Fouquet and
Schlosser,[6] yielding 12. After deprotection of the THP
group of 12, the resulting alcohol 13 was oxidized to give
(3S,7S)-1 as crystals. The overall yield of 1 was 38% based
on 4 (10 steps).
Scheme 1. Structures of the locust ketones (1 and 2) and related
compounds
[°]
Part CC: S. Kurosawa, K. Mori, Eur. J. Org. Chem.
2000, 955–962.
[a]
Department of Chemistry, Faculty of Science, Science
The synthesis of (3S,7S,15S)-2 is summarized in
Scheme 3. Initially, (S)-7-methylnonadecyl bromide (24)
had to be provided as the partner of the coupling reaction
with 11, and the commercially available methyl (S)-3-hy-
University of Tokyo,
Kagurazaka 1–3, Shinjuku-ku, Tokyo 162–8601, Japan
Fax: (internat.) ϩ 81-3/3235-2214
[°°] Research fellow on leave from Fuji Chemical Industries, Ltd.
(1998–2000).
Eur. J. Org. Chem. 2000, 1307Ϫ1312
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0407Ϫ1307 $ 17.50ϩ.50/0
1307

Y. Nakamura, K. Mori
FULL PAPER
droxy-2-methylpropanoate (14) was selected as the starting
material. Reduction of the corresponding THP ether 15
with lithium aluminum hydride yielded 16, which was tosyl-
ated to give (S)-17. The (R) isomer of 17 is a known com-
pound.[7] The Schlosser coupling[6] of 17 with 5-tert-butyld-
imethylsilyl (TBS) oxypentylmagnesium bromide took place
smoothly to give 18. Removal of the THP protective group
gave 19. The corresponding tosylate 20 was coupled with
undecylmagnesium bromide to give 21, the TBS group of
which was removed to afford (S)-7-methyl-1-nonadecanol
(22). This was converted into the bromide 24 via the tosyl-
ate 23. The Schlosser coupling[6] of the Grignard reagent
prepared from 24 with 11 furnished 25. Removal of the
THP protective group of 25 was followed by the Dess–Mar-
tin oxidation[5] of the alcohol 26 to give (3S,7S,15S)-2 as an
oil. The overall yield of 2 was 23% based on 14 (13 steps)
or 43% based on 4 (10 steps). Mass spectral comparison of
the ketones 1 and 2 with the locust ketones proved their
identity.
Scheme 2. Synthesis of (3S,7S)-1; reagents: (a) TBDPSCl, imida-
zole, DMF (96%); (b) K2CO3, MeOH (99%); (c) Dess–Martin
periodinane, C5H5N, CH2Cl2 (95% for 7; 90% for 1); (d) MeMgBr,
THF (88%); (e) DHP, pTsOH, Et2O (98%); (f) Bu4NF, THF (99%);
(g) pTsCl, C5H5N (quant.); (h) Me(CH2)18MgBr, Li2CuCl4, THF
(62%); (i) pTsOH, 90% EtOH (89%)
In conclusion (3S,7S)-1 and (3S,7S,15S)-2 were synthe-
sized, and showed mass spectra identical with those of the
natural locust ketones. As for the absolute configuration of
the natural ketones, it remains undetermined due to the
lack of suitable analytical methods to clarify it. Even GC
analysis on a chiral stationary phase does not solve the
problem at present.[8]
Experimental Section
General: IR: Jasco A-102. – 1H NMR: Jeol JNM-EX 90A
(90 MHz), Jeol JNM-LA400 (400 MHz) and Jeol JNM-LA500
(500 MHz) (TMS at δ ϭ 0.00 or CHCl3 at δ ϭ 7.26 as an internal
standard). – 13C NMR: Jeol JNM–LA400 (100 MHz) and Jeol
JNM-LA500 (126 MHz) (CDCl3 at δ ϭ 77.0 as an internal stand-
ard). – Optical rotation: Jasco DIP-1000. – MS: Jeol JMS-
SX102A. – M.p.: Yanaco MP-S3. – Column chromatography:
Merck Kieselgel 60 Art 1.07734. – TLC: 0.25 mm Merck silica gel
plates (60F-254).
(2S/R,3S,7R)-8-tert-Butyldiphenylsilyloxy-3,7-dimethyl-2-octanol
(8): To a solution of 7[4] (2.74 g, 6.91 mmol) in dry THF (60 mL)
under argon was added dropwise MeMgBr (0.93  in THF, 15 mL,
14.0 mmol) at –78 °C. After stirring at this temperature for 1 h, the
mixture was warmed to 0 °C. It was then quenched with aqueous
1  HCl and extracted with diethyl ether. The organic phase was
washed with saturated aqueous NaHCO3 and brine, dried with
MgSO4, and concentrated in vacuo. The residue was chromato-
graphed on silica gel (50 g, hexane/ethyl acetate, 20:1) to give 2.50 g
(88%) of 8 as a colorless oil; n2D6 ϭ 1.5249. – [α]2D3 ϭ –7.7 (c ϭ 0.99,
CHCl3). – IR (film): ν˜ ϭ 3380 cm–1 (m, O–H), 1590 (w, aromatic),
1110 (s, Si–O), 705 (s). – 1H NMR (90 MHz, CDCl3): δ ϭ 0.85 (d,
J ϭ 6.4 Hz, 3 H, 7-CH3), 0.91 (d, J ϭ 6.4 Hz, 3 H, 3-CH3), 1.05
[s, 9 H, SiC(CH3)3], 1.12, 1.14 (each d, J ϭ 6.4 Hz, total 3 H, 1-
H3), 1.00–1.80 (m, 9 H, 3-, 7-H, 4–6-H2 and OH), 3.48 (d, J ϭ
6.8 Hz, 2 H, 8-H2), 3.65 (m, 1 H, 2-H), 7.38 (m, 6 H, Ar-H), 7.68
(m, 4 H, Ar-H). – C26H40O2Si (412.7): calcd. C 75.67, H 9.77;
found C 75.55 H 9.85. – HPLC [column: pegasil, 4.6 mm ϫ 25 cm;
solvent: hexane/THF, 9:1, flow rate: 0.4 mL/min; detection:
Scheme 3. Synthesis of (3S,7S,15S)-2; reagents: (a) DHP, pTsOH,
Et2O (99%); (b) LiAlH4, Et2O (94%); (c) pTsCl, C5H5N (quant.);
(d) TBSO(CH2)5MgBr, Li2CuCl4, THF (64%); (e) MgBr2, Et2O
(93%); (f) Me(CH2)10MgBr, Li2CuCl4, THF (90%); (g) Bu4NF,
THF (94%); (h) LiBr, Me2CO (88%); (i) 24, Mg, Li2CuCl4, THF
(63%); (j) pTsOH, 90%EtOH (94%); (k) Dess–Martin periodinane,
C5H5N, CH2Cl2 (94%)
1308
Eur. J. Org. Chem. 2000, 1307Ϫ1312

Pheromone Synthesis, CCI
254 nm], tR ϭ 21.0 min [(2S,3S)-8, 66.4%], 21.5 [(2R,3S)-8, 33.6%]. temperature for 1 h, the mixture was warmed slowly to 0 °C, and
FULL PAPER
The diastereomer ratio of (2S,3S)-8/(2R,3S)-8 was 2:1.
stirred for a further 48 h. The mixture was quenched with saturated
aqueous NH4Cl, and extracted with diethyl ether. The organic
phase was washed with brine, dried with K2CO3, and concentrated
in vacuo. The residue was chromatographed on silica gel (12 g,
hexane/ethyl acetate, 300:1) to give 95 mg (62%) of 12 as a colorless
oil; n2D5 ϭ 1.4511. – [α]2D2 ϭ –1.1 (c ϭ 0.97, hexane). – IR (film):
(2R,6S,7R/S)-1-tert-Butyldiphenylsilyloxy-2,6-dimethyl-7-tetra-
hydropyranyloxyoctane (9): To a solution of 8 (0.44 g, 1.07 mmol)
in dry diethyl ether (7 mL) was added 3,4-dihydro-2H-pyran (DHP,
0.15 mL, 1.66 mmol) and p-toluenesulfonic acid monohydrate
(0.03 g) at room temperature. After stirring for 4 h, the mixture was
poured into saturated aqueous NaHCO3, and extracted with di-
ethyl ether. The organic phase was washed with brine, dried with
K2CO3, and concentrated in vacuo. The residue was chromato-
graphed on silica gel (10 g, hexane/ethyl acetate, 200:1) to give
520 mg (98%) of 9 as a colorless oil; n2D6 ϭ 1.5165. – [α]2D1 ϭ ϩ2.62
(c ϭ 1.02, CHCl3). – IR (film): ν˜ ϭ 1590 cm–1 (w, aromatic), 1250
(m, tBu), 1200 (m, C–O), 1115 (s, Si–O). – 1H NMR (90 MHz,
CDCl3): δ ϭ 0.84 (d, J ϭ 6.4 Hz, 3 H, 2-CH3), 0.92 (d, J ϭ 6.4 Hz,
3 H, 6-CH3), 1.05 [s, 9 H, SiC(CH3)3], 1.00–1.90 (m, 17 H, 2-, 6-
H, 3–5-H2, 3Ј–5Ј-H2 and 8-H3), 3.30–4.10 (m, 5 H, 7-H, 1-H2 and
6Ј-H2), 4.63 (br, 1 H, 2Ј-H), 7.38 (m, 6 H, Ar–H), 7.68 (m, 4 H,
Ar–H). This was employed in the next step without further puri-
fication.
1
ν˜ ϭ 1200 cm–1 (m, C–O), 1120 (m), 1080 (m), 1025 (s, C–O). – H
NMR (400 MHz, CDCl3): δ ϭ 0.83–0.92 (m, 9 H, 3-, 7-CH3 and
27-H3), 1.02, 1.05, 1.13, 1.17 (each d, J ϭ 6.3 Hz, total 3 H, 1-H3),
1.00–1.72 (m, 51 H, 4–6-, 8–26-, 3Ј–5Ј-H2 and 7-H), 1.82 (m, 1 H,
3-H), 3.48 (m, 1 H, 6Ј-Ha), 3.56–3.66 (m, 1 H, 2-H), 3.91 (m, 1 H,
6Ј-Hb), 4.60, 4.70 (each br, total 1 H, 2Ј-H). – C34H68O2 (508.9):
calcd. C 80.24, H 13.47; found C 80.67, H 13.11.
(2R/S,3S,7S)-3,7-Dimethyl-2-heptacosanol (13): To a solution of 12
(95 mg, 0.19 mmol) in 90%EtOH (5 mL) was added p-toluenesul-
fonic acid monohydrate (5.0 mg, 0.03 mmol) and the mixture was
stirred for 4 h under reflux. After neutralization with K2CO3, the
mixture was poured into brine and extracted with diethyl ether.
The organic phase was washed with brine, dried with MgSO4 and
concentrated in vacuo. The residue was chromatographed on silica
(2R,6S,7R/S)-2,6-Dimethyl-7-tetrahydropyranyloxy-1-octanol (10):
To a solution of 9 (520 mg, 1.05 mmol) in dry THF (5 mL) was gel (3 g, hexane/ethyl acetate, 100:1) to give 71 mg (89%) of 13.
added Bu4NF (1.0  solution in dry THF, 1.3 mL, 1.3 mmol) at
room temperature. After stirring at room temperature for 2 h, the
mixture was poured into water and extracted with diethyl ether.
The organic phase was washed with saturated aqueous NaHCO3
and brine, dried with K2CO3, and concentrated in vacuo. The res-
idue was chromatographed on silica gel (15 g, hexane/ethyl acetate,
20:1) to give 270 mg (99%) of 10 as a colorless oil; n2D6 ϭ 1.4596. –
[α]2D6 ϭ ϩ3.63 (c ϭ 1.05, hexane). – IR (film): ν˜ ϭ 3420 cm–1 (s,
This was recrystallized from pentane as white powder; m.p. 51.0–
52.5 °C – [α]2D3 ϭ –2.77 (c ϭ 1.01, hexane). – IR (KBr): ν˜ ϭ 3320
cm–1 (s, O–H), 2820 (vs), 1460 (s), 1375 (s). – 1H NMR (400 MHz,
CDCl3): δ ϭ 0.82 (d, J ϭ 6.6 Hz, 3 H, 7-CH3), 0.88 (t, J ϭ 6.7 Hz,
3 H, 27-H3), 0.89 (d, J ϭ 6.6 Hz, 3 H, 3-CH3), 1.12, 1.15 (each d,
J ϭ 6.3 Hz, total 3 H, 1-H3), 1.00–1.67 (m, 47 H, 3-, 7-H, 4–6-, 8–
26-H2 and OH), 3.63–3.74 (m, 1 H, 2-H). – 13C NMR (100 MHz,
CDCl3): δ ϭ 14.09, 14.14, 19.8, 20.3, 22.7, 24.7, 27.0, 29.3, 29.6,
O–H), 1200 (m, C–O), 1110 (m) 1040 (s, C–O). – 1H NMR 29.66, 29.69, 30.0, 31.9, 32.7, 33.0, 37.0, 37.3, 39.8, 71.3. – C29H60O
(90 MHz, CDCl3): δ ϭ 0.87 (d, J ϭ 6.4 Hz, 3 H, 2-CH3), 0.90 (d, (424.8): calcd. C 82.00, H 14.24; found C 81.82, H 14.60.
J ϭ 6.4 Hz, 3 H, 6-CH3), 1.00–1.90 (m, 18 H, 2-, 6-H, 3–5-H2, 3Ј–
5Ј-H2, 8-H3 and OH), 3.30–4.00 (m, 5 H, 7-H, 1-, 6Ј-H2), 4.63 (br,
1 H, 2Ј-H). – C15H30O3 (258.4): calcd. C 69.72, H 11.74; found C
69.81, H 11.71.
(3S,7S)-3,7-Dimethyl-2-heptacosanone (1): To a solution of Dess–
Martin periodinane (55 mg, 0.13 mmol) in dry CH2Cl2 (3 mL) un-
der argon was added pyridine (0.10 mL) at room temperature, and
the mixture was stirred for 30 min. A solution of 13 (37 mg,
(2R,6S,7R/S)-2,6-Dimethyl-7-tetrahydropyranyloxyoctyl
Tosylate
0.087 mmol) in dry CH2Cl2 (2 mL) was then added dropwise at
room temperature. After stirring for 2 h, the mixture was diluted
with Et2O and quenched by adding solutions of saturated aqueous
NaHCO3 (3 mL) and saturated aqueous sodium thiosulfate (3 mL).
The resulting mixture was stirred for 10 min, and extracted with
Et2O. The organic phase was washed with saturated aqueous
NaHCO3 and brine, dried with MgSO4, and concentrated in vacuo.
The residue was chromatographed on silica gel (3 g, hexane/ethyl
acetate, 500:1) to give 33 mg (90%) of 1. This was recrystallized
from EtOH to give crystalline 1 as colorless needles; m.p. 39.0–40.0
°C – [α]2D4 ϭ ϩ4.4 (c ϭ 0.75, hexane). – IR (KBr): ν˜ ϭ 2930 cm–1
(s), 2860 (s), 1710 (s, CϭO), 1465 (s), 1360 (s), 1180 (w), 1160 (w),
(11): To a solution of 10 (233 mg, 0.90 mmol) in dry pyridine
(4 mL) was added p-toluenesulfonyl chloride (259 mg, 1.36 mmol)
at 0 °C. After stirring at this temperature for 10 h, the mixture was
diluted with water and extracted with diethyl ether. The organic
phase was washed with saturated aqueous CuSO4, water, saturated
aqueous NaHCO3 and brine, dried with K2CO3, and concentrated
in vacuo to give 373 mg (quant.) of crude 11. This was employed
in the next step without further purification; IR (film): ν˜ ϭ 1600
cm–1 (m, aromatic), 1360 (m, SO2), 1200 (m, C–O), 1190 (s, SO2),
1
1180 (s, SO2), 1025 (m, C–O). – H NMR (90 MHz, CDCl3): δ ϭ
0.88 (d, J ϭ 6.6 Hz, 6 H, 2-, 6-CH3), 0.90–2.00 (m, 17 H, 2-, 6-H,
3–5-H2, 3Ј–5Ј-H2 and 8-CH3), 2.45 (s, 3 H, Ar-CH3), 3.20–4.10 (m,
3 H, 7-H and 6Ј-H2), 3.84 (dd, J ϭ 2.0, 5.9 Hz, 2 H, 1-H2), 4.63
(br, 1 H, 2Ј-H), 7.34 (d, J ϭ 8.2 Hz, 2 H, Ar-H), 7.79 (d, J ϭ
8.2 Hz, 2 H, Ar-H).
1
960 (w), 725 (m). – H NMR (500 MHz, CDCl3): δ ϭ 0.83 (d, J ϭ
6.7 Hz, 3 H, 7-CH3), 0.88 (t, J ϭ 7.0 Hz, 3 H, 27-H3), 1.08 (d, J ϭ
7.0 Hz, 3 H, 3-CH3), 1.04–1.37 (m, 44 H, 4–6-, 8–26-H2), 1.63 (m,
1 H, 7-H), 2.13 (s, 3 H, 1-H3), 2.50 (sextet like, J ϭ 6.8 Hz, 1 H,
(2R/S,3S,7S)-3,7-Dimethyl-2-tetrahydropyranyloxyheptacosane (12): 3-H). – 13C NMR (126 MHz, CDCl3): δ ϭ 14.1, 16.2, 19.6, 22.7,
Preparation of the Grignard reagent. Magnesium (66 mg,
24.7, 27.1, 28.0, 29.4, 29.65, 29.70, 30.0, 31.9, 32.6, 33.6, 37.0, 37.1,
2.7 mmol) was added to an argon-purged flask. To the metal was 47.3, 213.0. – EI MS (as measured by Prof. Dr. W. Francke); m/z
added dropwise a solution of Me(CH2)18Br (556 mg, 1.60 mmol)
in dry THF (8 mL), and the mixture was stirred for 2 h under re-
flux. The resulting solution was used immediately. Under argon, to
a solution of 11 (125 mg, 0.303 mmol) in dry THF (3 mL) was
(%): 422 (19) [Mϩ], 404 (1) [(M – H2O)ϩ], 375 (1), 348 (2), 141 (6),
123 (5), 111 (4), 97 (2), 85 (8), 72 (100), 57 (11), 43 (12). – HRMS
(C29H58O): calcd. 422.4488; found 422.4503. – C29H58O (422.8):
calcd. C 82.39, H 13.83; found C 82.17, H 14.12. – GC [column:
added the Grignard reagent solution and a solution (0.1 , 0.1 mL, TC-wax 0.53 mm ϫ 15 m, 170 to 200 °C, ϩ10.0 °C/min; carrier
0.01 mmol) of Li2CuCl4 in THF at –78 °C. After stirring at this
Eur. J. Org. Chem. 2000, 1307Ϫ1312
gas: He, pressure 110 kPa]: tR ϭ 12.9 min [1, 97.9%].
1309

Y. Nakamura, K. Mori
FULL PAPER
Methyl (S)-2-Methyl-3-tetrahydropyranyloxypropanoate (15): Ac-
cording to the reported procedure for (R)-15,[7] compound 14
(21.0 g, 178 mmol) was converted into 35.8 g (99%) of (S)-15 which
20:1) to give 3.55 g (93%) of 19 as a colorless oil; n2D6 ϭ 1.4462. –
[α]2D2 ϭ ϩ6.83 (c ϭ 1.00, CHCl3). – IR (film): ν˜ ϭ 3350 cm–1 (m,
O–H), 1255 (m, tBu), 1100 (s, Si–O). – 1H NMR (90 MHz, CDCl3):
δ ϭ 0.05 (s, 6 H, Si–CH3), 0.89 (s, 9 H, tBu), 0.91 (d, J ϭ 6.4 Hz,
3 H, 2-CH3), 1.00–1.80 (m, 12 H, 2-H, 3–7-H2 and OH), 3.39 (dd,
J ϭ 6.1, 10.3 Hz, 1 H, 1-Ha), 3.53 (dd, J ϭ 5.7, 10.3 Hz, 1 H, 1-
was isolated as a colorless oil, b.p. 102–105 °C/7 Torr. n2D5
ϭ
1.4379. – [α]2D1 ϭ ϩ16.5 (c ϭ 1.10, Et2O) {ref[7] [α]2D1 ϭ –16.3 (c ϭ
1.39, Et2O) for the (R)-enantiomer}. – IR (film): ν˜ ϭ 1710 cm–1 (S,
1
CϭO), 1200 (m, C–O), 1125 (s, C–O), 1040 (s, C–O). – H NMR Hb), 3.60 (t, J ϭ 6.2 Hz, 2 H, 8-H2). – C15H34O2Si (274.5): calcd.
(90 MHz, CDCl3): δ ϭ 1.19 (d, J ϭ 7.0 Hz, 3 H, 2-CH3), 1.30–1.90
(m, 6 H, 3Ј–5Ј-H2), 2.77 (sext-like, J ϭ 6.8 Hz, 1 H, 2-H), 3.35–
4.01 (m, 4 H, 3-H2 and 6Ј-H2), 3.69 (s, 3 H, CO2CH3), 4.61 (br, 1
H, 2Ј-H).
C 65.63, H 12.48; found C 65.19, H 12.56.
(R)-8-tert-Butyldimethylsilyloxy-2-methyloctyl Tosylate (20): To a
solution of 19 (3.00 g, 10.9 mmol) in dry pyridine (20 mL) was ad-
ded p-toluenesulfonyl chloride (3.03 g, 15.9 mmol) at 0 °C. After
stirring at 0 °C for 12 h, the mixture was poured into ice and water,
and extracted with CH2Cl2. The organic phase was washed with
saturated aqueous CuSO4, water, saturated aqueous NaHCO3 and
brine, dried with MgSO4, and concentrated in vacuo to give 4.75 g
(quant.) of crude 20. This was employed in the next step without
further purification; IR (film): ν˜ ϭ 1600 cm–1 (s, aromatic), 1360
(R)-2-Methyl-3-tetrahydropyranyloxy-1-propanol (16): According to
the reported procedure for (S)-16,[7] compound 15 (34.6 g,
171 mmol) was converted into 27.9 g (94%) of (R)-16 which was
isolated as a colorless oil, b.p. 111–113 °C/6 Torr. – n2D6 ϭ 1.4547. –
[α]2D7 ϭ ϩ1.27 (c ϭ 1.07, Et2O) {ref[7] [α]2D1 ϭ –1.2 (c ϭ 1.47, Et2O)
for the (S)-enantiomer}. – IR (film): ν˜ ϭ 3420 cm–1 (s, O–H), 1200
(m, C–O), 1120 (s, C–O), 1030 (s, C–O). – 1H NMR (90 MHz, (s, SO2), 1250 (m, tBu), 1190 (s, SO2), 1180 (s, SO2), 1100 (s, Si–
CDCl3): δ ϭ 0.88 (d, J ϭ 6.8 Hz, 3 H, 2-CH3), 1.20–1.90 (m, 6 H, O), 665 (s, C–S). – H NMR (90 MHz, CDCl3): δ ϭ 0.05 (s, 6 H,
1
3Ј–5Ј-H2), 1.98 (m, 1 H, 2-H), 2.39 (br, 1 H, OH), 3.24–3.98 (m, 6 Si–CH3), 0.87 (d, J ϭ 6.4 Hz, 3 H, 2-CH3), 0.89 (s, 9 H, tBu), 1.00–
H, 1-, 3-, 6Ј-H2), 4.56 (br, 1 H, 2Ј-H).
1.90 (m, 11 H, 2-H and 3–7-H2), 2.45 (s, 3 H, Ar-CH3), 3.58 (t,
J ϭ 6.2 Hz, 2 H, 8-H2), 3.77 (dd, J ϭ 6.2 Hz, J ϭ 9.3 Hz, 1 H, 1-
Ha), 3.90 (dd, J ϭ 5.9 Hz, J ϭ 9.3 Hz, 1 H, 1-Hb), 7.34 (d, J ϭ
8.2 Hz, 2 H, Ar-H), 7.79 (d, J ϭ 8.2 Hz, 2 H, Ar-H).
(S)-2-Methyl-3-tetrahydropyranyloxypropyl Tosylate (17): Accord-
ing to the reported procedure for (R)-17,[7] compound 16 (5.00 g,
28.7 mmol) gave 10.5 g (quant.) of crude (S)-17. This was employed
in the next step without further purification; IR (film): ν˜ ϭ 1600
cm–1 (s, aromatic), 1360 (s, SO2), 1190 (s, SO2), 1180 (s, SO2), 1120
(s, C–O), 1030 (s, C–O), 665 (s, C–S). – 1H NMR (90 MHz,
(S)-1-tert-Butyldimethylsilyloxy-7-methylnonadecane (21): Prepara-
tion of the Grignard reagent. Magnesium (1.59 g, 65.4 mmol) was
added to an argon-purged flask. To the metal was added dropwise
CDCl3): δ ϭ 0.94 (d, J ϭ 6.8 Hz 3 H, 2-CH3), 1.20–1.90 (m, 6 H, a solution of undecyl bromide (10.3 g, 43.8 mmol) in dry THF
3Ј–5Ј-H2), 2.08 (m, 1 H, 2-H), 2.44 (s, 3 H, Ar-CH3), 3.09–4.18 (m, (80 mL), and the mixture was stirred at 45 °C for 1 h. The resulting
6 H, 1-, 3-, 6Ј-H2), 4.34 (br, 1 H, 2Ј-H), 7.33 (d, J ϭ 8.2 Hz, 2 H, solution was used immediately. To a solution of 20 (4.75 g,
Ar-H), 7.80 (d, J ϭ 8.2 Hz, 2 H, Ar-H).
10.9 mmol) in dry THF (50 mL) under argon was added the Grig-
nard reagent solution and a solution (0.5 , 0.6 mL, 0.30 mmol) of
Li2CuCl4 in dry THF at –78 °C. After stirring at –78 °C for 1 h,
the mixture was warmed slowly to 0 °C, and stirred for 24 h. The
mixture was quenched with saturated aqueous NH4Cl, and ex-
tracted with diethyl ether. The organic phase was washed with
brine, dried with MgSO4, and concentrated in vacuo. The residue
was chromatographed on silica gel (100 g, hexane) to give 4.34 g
(96%) of 21 as a colorless oil; n2D5 ϭ 1.4474. – [α]2D6 ϭ –0.53 (c ϭ
1.47, hexane). – IR (film): ν˜ ϭ 1255 cm–1, (m, tBu), 1105
(R)-8-tert-Butyldimethylsilyloxy-2-methyl-1-tetrahydropyranyloxy-
octane (18): Preparation of the Grignard reagent. Magnesium
(2.59 g, 107 mmol) was added to an argon-purged flask. To the
metal was added dropwise a solution of 5-tert-butyldimethylsily-
loxypentyl bromide (20.0 g, 71.1 mmol) in dry THF (70 mL), and
the mixture was stirred at 45 °C for 1 h. The resulting solution was
used immediately. To a solution of 17 (10.5 g, ca. 28.7 mmol) in
dry THF (60 mL) under argon was added the Grignard reagent
solution and a solution (0.5 , 1.2 mL, 0.60 mmol) of Li2CuCl4 in
dry THF at –78 °C. After stirring at –78 °C for 1 h, the mixture
was warmed slowly to 0 °C, and stirred at this temperature for 20 h.
The mixture was quenched with saturated aqueous NH4Cl, and
extracted with diethyl ether. The organic phase was washed with
brine, dried with K2CO3, and concentrated in vacuo. The residue
was chromatographed on silica gel (150 g, hexane/ethyl acetate
(200:1) to give 6.55 g (64%) of 18 as a colorless oil; n2D5 ϭ 1.4494. –
[α]2D2 ϭ –0.88 (c ϭ 1.02, CHCl3). – IR (film): ν˜ ϭ 1255 cm–1 (m,
1
(s, Si–O), 835 (s), 775 (s). – H NMR (90 MHz, CDCl3): δ ϭ 0.05
(s, 6 H, Si–CH3), 0.84 (d, J ϭ 6.3 Hz, 3 H, 7-CH3), 0.87 (t, J ϭ
6.6 Hz, 3 H, 19-H3), 0.90 (s, 9 H, tBu), 1.00–1.70 (m, 33 H, 2–6-,
8–18-H2 and 7-H), 3.60 (t, J ϭ 6.3 Hz, 2 H, 1-H2). – C26H56OSi
(412.8): calcd. C 75.65, H 13.67; found C 75.51, H 13.45.
(S)-7-Methyl-1-nonadecanol (22): To a solution of 21 (4.13 g,
10.0 mmol) in dry THF (40 mL) was added Bu4NF (1.0  solution
in dry THF, 15.0 mL, 1.50 mmol) at room temperature. After stir-
tBu), 1200 (m, C–O), 1100 (s, Si–O), 1025 (s, C–O). – 1H NMR ring at room temperature for 4 h, the mixture was poured into
(90 MHz, CDCl3): δ ϭ 0.05 (s, 6 H, Si–CH3), 0.89 (s, 9 H, tBu), water and extracted with diethyl ether. The organic phase was
0.90, 0.92 (each d, J ϭ 6.4 Hz, total 3 H, 2-CH3), 1.00–1.90 (m, 17
washed with saturated aqueous NaHCO3 and brine, dried with
H, 3–7-, 3Ј–5Ј-H2 and 2-H), 3.04–3.93 (m, 6 H, 2-H, 1-, 6-, 6Ј-H2), MgSO4, and concentrated in vacuo. The residue was chromato-
4.55 (br, 1 H, 2Ј–H). – C20H42O3Si (358.6): calcd. C 66.98, H 11.80;
found C 67.07, H 11.63.
graphed on silica gel (70 g, hexane/ethyl acetate, 25:1) to give 2.81 g
(94%) of 22; n2D5 ϭ 1.4535. – [α]2D3 ϭ –0.67 (c ϭ 0.99, CHCl3). – IR
(film): ν˜ ϭ 3340 cm–1 (s, O–H), 1465 (s), 1380 (m), 1060 (s), 725
(R)-8-tert-Butyldimethylsilyloxy-2-methyl-1-octanol (19): To a solu-
tion of 18 (4.98 g, 13.9 mmol) in dry Et2O (150 mL) was added
anhydrous MgBr2 (7.67 g, 41.7 mmol) at room temperature. After
stirring for 4 h, the mixture was poured into water and extracted
with diethyl ether. The organic phase was washed with water and
brine, dried with MgSO4, and concentrated in vacuo. The residue
was chromatographed on silica gel (150 g, hexane/ethyl acetate,
1
(m). – H NMR (90 MHz, CDCl3): δ ϭ 0.84 (d, J ϭ 6.3 Hz, 3 H,
7-CH3), 0.88 (t, J ϭ 6.6 Hz, 3 H, 19-H3), 1.00–1.70 (m, 34 H, 2–6-,
8–18-H2, 2-H and OH), 3.64 (t, J ϭ 6.4 Hz, 2 H, 1-H2). – C20H42O
(298.6): calcd. C 80.46, H 14.18; found C 80.32, H 14.43.
(S)-7-Methylnonadecyl Tosylate (23): To a solution of 22 (2.00 g,
7.00 mmol) in dry pyridine (20 mL) and dry CH2Cl2 (40 mL) was
1310
Eur. J. Org. Chem. 2000, 1307Ϫ1312

Pheromone Synthesis, CCI
FULL PAPER
added p-toluenesulfonyl chloride (2.17 g, 11.4 mmol) at 0 °C. After
stirring at 0 °C for 10 h, the mixture was poured into ice and 1 
hydrochloric acid and extracted with CH2Cl2. The organic phase
was washed with saturated aqueous CuSO4, water, saturated aque-
ous NaHCO3 and brine, dried with MgSO4, and concentrated in
vacuo to give 3.18 g (quant.) of crude 23. This was employed in the
next step without further purification; IR (film): ν˜ ϭ 1600 cm–1 (s,
(c ϭ 1.00, hexane). – IR (film): ν˜ ϭ 3360 cm–1 (s, O–H), 2820 (vs),
1460 (s), 1375 (s). – 1H NMR (500 MHz, CDCl3): δ ϭ 0.83 (d, J ϭ
6.4 Hz, 3 H, 15-CH3), 0.84 (d, J ϭ 6.2 Hz, 3 H, 7-CH3), 0.88 (t,
J ϭ 7.2 Hz, 3 H, 27-H3), 0.89 (d, J ϭ 7.0 Hz, 3 H, 3-CH3), 1.12,
1.15 (each d, J ϭ 6.4 Hz, total 3 H, 1-H3), 1.00–1.50 (m, 46 H, 3-,
7-, 15-H, 4–6-, 8–14-, 16–26-H2 and OH), 3.64–3.74 (m, 1 H, 2-
H). – 13C NMR (126 MHz, CDCl3): δ ϭ 14.1, 14.2, 19.3, 19.7,
19.8, 20.3, 22.7, 24.7 24.8, 27.1, 29.4, 29.65, 29.73, 29.8, 30.0, 31.9,
aromatic), 1365 (s, SO2), 1190 (s, SO2), 1180 (s, SO2), 665 (s, C–
1
S). – H NMR (90 MHz, CDCl3): δ ϭ 0.78–0.91 (m, 6 H, 7-CH3 32.7, 32.9, 33.0, 37.0, 37.1, 37.4, 39.8, 40.1, 71.4. – C30H62O (438.8):
and 19-H3), 1.00–1.80 (m, 33 H, 2–6-, 8–18-H2 and 2-H), 2.45 (s,
3 H, Ar-CH3), 4.02 (t, J ϭ 6.4 Hz, 2 H, 1-H2), 7.33 (d, J ϭ 8.2 Hz,
2 H, Ar-H), 7.83 (d, J ϭ 8.2 Hz, 2 H, Ar-H).
calcd. C 82.11, H 14.24; found C 82.16, H 13.96.
(3S,7S,15S)-3,7,15-Trimethyl-2-heptacosanone (2): Under argon, to
a solution of Dess–Martin periodinane (108 mg, 0.256 mmol) in
dry CH2Cl2 (5 mL) was added pyridine (0.10 mL) at room temper-
ature, and the mixture was stirred for 30 min. A solution of 26
(75 mg, 0.171 mmol) in dry CH2Cl2 (3 mL) was then added drop-
wise at room temperature. After stirring for 1 h, the mixture was
diluted with Et2O and quenched by adding solutions of saturated
aqueous NaHCO3 (10 mL) and saturated aqueous sodium thiosulf-
ate (10 mL). The resulting mixture was stirred for 10 min and then
extracted with Et2O. The organic phase was washed with saturated
aqueous NaHCO3 and brine, dried with MgSO4, and concentrated
in vacuo. The residue was chromatographed on silica gel (3 g, hex-
ane/ethyl acetate, 500:1) to give 70 mg (94%) of 2 as a colorless oil;
n2D6 ϭ 1.4542. – [α]2D5 ϭ ϩ5.91 (c ϭ 1.01, hexane). – IR (film): ν˜ ϭ
2930 cm–1 (s), 2860 (s), 1715 (s, CϭO), 1460 (s), 1375 (m), 1355
(S)-7-Methylnonadecyl Bromide (24): To a solution of 23 (3.18 g,
7.0 mmol) in dry acetone (50 mL) was added lithium bromide
(0.99 g, 11.4 mmol) at room temperature. After stirring for 6 h un-
der reflux, the mixture was concentrated in vacuo. The residue was
diluted with water and extracted with diethyl ether. The organic
phase was washed with water and brine, dried with MgSO4, and
concentrated in vacuo. The residue was chromatographed on silica
gel (40 g, hexane/ethyl acetate, 100:1) to give 2.23 g (88%) of 24 as
a colorless oil; n2D6 ϭ 1.4630. – [α]2D6 ϭ –0.62 (c ϭ 1.02, CHCl3). –
IR (film): ν˜ ϭ 2920 cm–1 (s, C–H), 2850 (s, C–H), 1465 (m, C–H),
1375 (m, C–H), 1255 (m), 725 (m). – 1H NMR (500 MHz, CDCl3):
δ ϭ 0.84 (d, J ϭ 6.4 Hz, 3 H, 7-CH3), 0.88 (t, J ϭ 6.9 Hz, 3 H,
19-H3), 1.05–1.46 (m, 31 H, 7-H, 3–6-, 8–18-H2), 1.85 (quint-like,
J ϭ 7.2 Hz, 2 H, 2-H2), 3.41 (t, J ϭ 6.9 Hz, 2 H, 1-H2); – 13C
NMR (126 MHz, CDCl3): δ ϭ 14.1, 19.7, 22.7, 26.9, 27.1, 28.2,
29.1 29.4, 29.65, 29.70, 29.73, 30.0, 31.9, 32.7, 32.9, 34.0, 36.9,
37.1. – C20H41Br (361.44): calcd. C 66.46, H 11.43; found C 66.59,
H 11.68.
1
(m), 1165 (w), 1140 (w), 950 (w), 720 (m). – H NMR (500 MHz,
CDCl3): δ ϭ 0.83 (d, J ϭ 6.4 Hz, 3 H, 15-CH3), 0.84 (d, J ϭ 6.4 Hz,
3 H, 7-CH3), 0.88 (t, J ϭ 7.0 Hz, 3 H, 27-H3), 1.08 (d, J ϭ 7.0 Hz,
3 H, 3-CH3), 1.04–1.35 (m, 43 H, 4–6-, 8–14-, 16–26-H2 and 15-
H), 1.63 (m, 1 H, 7-H), 2.13 (s, 3 H, 1-H3), 2.50 (sext-like, J ϭ
6.8 Hz, 1 H, 3-H). – 13C NMR (126 MHz, CDCl3): δ ϭ 14.1, 16.2,
19.63, 19.71, 22.7, 24.7, 27.06, 27.08, 28.0, 29.3 29.6, 29.70, 29.72,
29.8, 30.01, 30.03, 31.9, 32.62, 32.74, 33.3, 37.0, 37.06, 37.10, 47.2,
213.0. – EI MS (as measured by Prof. Dr. W. Francke); m/z (%):
436 (30) [Mϩ], 418 (4) [(M – H2O)ϩ], 389 (2), 362 (5), 151 (1), 141
(8), 123 (7), 111 (7), 97 (3), 85 (8), 72 (100), 57 (13), 43 (12). –
HRMS [C30H60O]: calcd. 436.4644; found 436.4655. – C30H60O
(436.8): calcd. C 82.49, H 13.85; found C 82.27, H 13.76. – GC
[column: TC-wax 0.53 mm ϫ 15 m, 170 to 200 °C, ϩ10.0 °C/min;
carrier gas: He, pressure 110 kPa]: tR ϭ 12.9 min [2, 97.6%].
(2R/S,3S,7S,15S)-3,7,15-Trimethyl-2-tetrahydropyranyloxyheptaco-
sane (25): Preparation of the Grignard reagent. Magnesium
(131 mg, 5.39 mmol) was added to an argon-purged flask. To the
metal was added dropwise a solution of bromide 24 (1.30 g,
3.60 mmol) in dry THF (10 mL), and the mixture was stirred for
2 h under reflux. The resulting solution was used immediately. To
a solution of 11 (300 mg, 0.73 mmol) in dry THF (5 mL) under
argon was added the Grignard reagent solution and a solution (0.1
, 0.2 mL, 0.02 mmol) of Li2CuCl4 in THF at –78 °C. After stirring
at –78 °C for 1 h, the mixture was warmed slowly to 0 °C, and
stirred for 24 h. The mixture was quenched with saturated aqueous
NH4Cl, and extracted with diethyl ether. The organic phase was
washed with brine, dried with K2CO3, and concentrated in vacuo.
The residue was chromatographed on silica gel (30 g, hexane/ethyl
Acknowledgments
acetate, 300:1) to give 239 mg (63%) of 25 as a colorless oil; n2D6
ϭ
We thank Prof. Dr. W. Francke (Universität Hamburg) for the
mass-spectrometric comparison of 1 and 2 with the locust ketones.
Our thanks are also due to Dr. Y. Hirose (Amano Pharmaceutical
Co.) for his kind gift of lipases PS to prepare 4, and also to Dr.
K. Sakashita (Mitsubishi Rayon Co.) for providing 14. Financial
support of this work by Fuji Chemical Industries, Ltd. is acknow-
ledged with thanks.
1.4613. – [α]2D3 ϭ –3.53 (c ϭ 1.00, hexane). – IR (film): ν˜ ϭ 1205
cm–1 (m, C–O), 1120 (m), 1080 (m), 1020 (s, C–O). – 1H NMR
(500 MHz, CDCl3): δ ϭ 0.83–0.92 (m, 12 H, 3-, 7-, 15-CH3 and
27-H3), 1.02, 1.05, 1.13, 1.17 (each d, J ϭ 6.4 Hz, total 3 H, 1-H3),
1.00–1.75 (m, 50 H, 7-, 15-H and 4–6-, 8–14-, 16–26-, 3Ј–5Ј-H2 ),
1.82 (m, 1 H, 3-H), 3.48 (m, 1 H, 6Ј-Ha), 3.56–3.67 (m, 1 H, 2-H),
3.91 (m, 1 H, 6Ј-Hb), 4.60, 4.70 (each br, total 1 H, 2Ј-H). –
C35H70O2 (522.9): calcd. C 80.39, H 13.49; found C 80.33, H 13.66.
[1]
W. Francke, U. Brunnemann, G. Schmidt, unpublished results
(2R/S,3S,7S,15S)-3,7,15-Trimethyl-2-heptacosanol (26): To a solu-
tion of 25 (150 mg, 0.29 mmol) in 90% EtOH (15 mL) was added
p-toluenesulfonic acid monohydrate (10.0 mg, 0.06 mmol) and the
mixture was stirred for 3 h under reflux. After neutralization with
K2CO3, the mixture was poured into brine and extracted with di-
ethyl ether. The organic phase was washed with brine, dried with
MgSO4 and concentrated in vacuo. The residue was chromato-
graphed on silica gel (4 g, hexane/ethyl acetate, 100:1) to give
119 mg (94%) of 26 as a colorless oil; n2D6 ϭ 1.4599. – [α]2D3 ϭ –6.74
as cited by W. Francke, in Comprehensive Natural Products
Chemistry, vol. 8 (Ed.: K. Mori), Elsevier Science, Oxford,
1999, p.247; see also: W. Francke, G. H. Schmidt, Proceedings
of the CEC-Workshop on New Strategies for Locust Control
(Eds.: H. Rembold, J. A. Benson, H. Franzen, B. Weickel, F.
A. Schulz), ATSAF e. V., Bonn, Germany, 1994, p. 48–52.
[2]
K. Mori, S. Masuda, T. Suguro, Tetrahedron 1981, 37, 1329–
1340.
[3]
ˆ
R. Chenevert, M. Desjardins, J. Org. Chem. 1996, 61, 1219–
1222.
Eur. J. Org. Chem. 2000, 1307Ϫ1312
1311

Y. Nakamura, K. Mori
FULL PAPER
[4]
Y. Nakamura, K. Mori, Eur. J. Org. Chem. 1999, 2175–2182.
solute Configuration, in Methods in Chemical Ecology, vol.1
(‘‘Chemical Methods’’) (Eds.: J. C. Millar, K. F. Haynes),
Kluwer, Norwell, 1998, p. 295–338.
[5]
D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156.
[6]
C. Fouquet, M. Schlosser, Angew. Chem. 1974, 86, 50–51; An-
gew. Chem. Int. Ed. Engl. 1974, 13, 82–83.
Received November 2, 1999
[7]
K. Mori, Tetrahedron 1983, 39, 3107–3109.
[O99610]
[8]
K. Mori, Separation of Enantiomers and Determination of Ab-
1312
Eur. J. Org. Chem. 2000, 1307Ϫ1312