Synthesis of (2S,2′R,3S,4R)-2-(2′-hydroxy-21′- methyldocosanoylamino)-1,3,4-pentadecanetriol, the ceramide sex pheromone of the female hair crab, Erimacrus isenbeckii

Article abstract of DOI:10.1271/bbb.66.1531

The ceramide sex pheromone [(2S,2′R,3S,4R)-2-(2′-hydroxy- 21′-methyldocosanoylamino)-1,3,4-pentadecanetriol (1)] of the female hair crab (Erimacrus isenbeckii) was synthesized by starting from (S)-serine and 12-bromo-1-dodecanol.

Full text of DOI:10.1271/bbb.66.1531

This article was downloaded by: [Rose Hulman Institute]
On: 01 December 2014, At: 11:56
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Bioscience, Biotechnology, and Biochemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/tbbb20
Synthesis of (2S,2′R,3S,4R)-2-(2′-Hydroxy-21′-
methyldocosanoylamino)- 1,3,4-pentadecanetriol,
the Ceramide Sex Pheromone of the Female Hair
Crab,…
Yui MASUDAa, Masao YOSHIDAa & Kenji MORIb
a Department of Chemistry, Graduate School of Science, Science University of Tokyo
Kagurazaka 1-3, Shinjuku-ku, Tokyo 162-8601, Japan
b 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: Yui MASUDA, Masao YOSHIDA & Kenji MORI (2002) Synthesis of (2S,2′R,3S,4R)-2-(2′-Hydroxy-21′-
methyldocosanoylamino)- 1,3,4-pentadecanetriol, the Ceramide Sex Pheromone of the Female Hair Crab,…, Bioscience,
Biotechnology, and Biochemistry, 66:7, 1531-1537, DOI: 10.1271/bbb.66.1531
To link to this article: http://dx.doi.org/10.1271/bbb.66.1531
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Biosci. Biotechnol. Biochem., 66 (7), 1531–1537, 2002
Synthesis of (2S,2?R,3S,4R)-2-(2?-Hydroxy-21?-methyldocosanoylamino)-
1,3,4-pentadecanetriol, the Ceramide Sex Pheromone of the Female
Hair Crab, Erimacrus isenbeckii†
2,††
Yui MASUDA,1 Masao YOSHIDA,1 and Kenji MORI
1Department of Chemistry, Graduate School of Science, Science University of Tokyo, Kagurazaka 1-3,
Shinjuku-ku, Tokyo 162-8601, Japan
2Insect Pheromone and Traps Division, Fuji Flavor Co. Ltd., Midorigaoka 3-5-8, Hamura-City,
Tokyo 205-8503, Japan
Received January 22, 2002; Accepted March 1, 2002
The ceramide sex pheromone [(2
-hydroxy-21 -methyldocosanoylamino)-1,3,4-pen-
tadecanetriol (1)] of the female hair crab (Erimacrus
S,2?R,3S,4R)-2-
(2?
?
isenbeckii) was synthesized by starting from (S)-serine
and 12-bromo-1-dodecanol.
Key words: ceramide; crab; Erimacrus isenbeckii
;
pheromone; sphingolipid, synthesis
Fig. 1. Structure of the Female Sex Pheromone of the Hair
Crab, Erimacrus isenbeckii
.
Sphingolipids possess diverse bioactivities such as
fruiting body formation,1,2) enzyme inhibition,3)
enzyme activation,4,5) and immunosuppression,6) in
addition to their important role in cell membrane sys-
tems. Fusetani and his co-workers reported in 2000
that the ceramide, (2
S,2?R,3S,4R)-2-(2?-hydroxy-
21 -methyldocosanoylamino)-1,3,4-pentadecanetriol
?
(1, Fig. 1), and its relatives functioned as the sex
pheromone of the hair crab (Erimacrus isenbeckii) in
the female urine, which elicited precopulatory
behavior in males.7) Since we are interested in both
pheromones and sphingolipids, we immediately start-
ed the synthesis of 1. This paper describes the method
we used to prepare 1. After our synthesis had been
completed, Fusetani and his co-workers reported the
synthesis of ceramide 1 by employing
D
-galactose as
the chiral building block.8)
A ceramide is usually synthesized by
N
-acylating
its sphingosine part with its carboxylic acid part. Ac-
cordingly, in the present case, we planned to ˆrst syn-
thesize the acid part and then the sphingosine part.
Scheme 1 summarizes our synthesis of the acid part,
Scheme 1. Synthesis of Acid Part (
Reagents: (a) (CH3)2CH(CH2)2MgBr, Li2CuCl4, THF (99
(b) TsCl, C5H5N (89 ). (c) THPO(CH2)6MgBr, Li2CuCl4, THF
). (d) TsOH, C2H5OH (97 ). (e) Jones' CrO3, (CH3)2CO
). (f) Br2, P, heat (84 ). (g) NaOH, H2O (90
). (i) TBSCl, imida-
R)-11.
z
).
z
(R)-11. Chain-elongation of commercially available
(79
(74
z
z
z
12-bromo-1-dodecanol (2) with 3-methylbutylmag-
nesium bromide was executed under Schlosser condi-
tions in the presence of dilithium tetrachlorocuprate9)
to give 3. Corresponding tosylate 4 was again
chain-elongated by a treatment with 6-(2-tetra-
＝
z). (h) CH2
z
CHOCOCH3, lipase PS, BHT, THF (23
zole, DMF (80 ).
z
z
†
Pheromone Synthesis, Part 217. For Part 216, see Furukawa, A., Shibata, C., and Mori, K. Biosci. Biotechnol. Biochem., 66,
1164–1169 (2002).
To whom correspondence should be addressed. Fax: +81-42-555-7920
††

1532
Y. MASUDA et al.
hydropyranyloxy)hexylmagnesium bromide under
Schlosser conditions9) to aŠord tetrahydropyranyl
(THP) ether 5. Removal of the THP protective group
of 5 gave alcohol 6. Oxidation of 6 with Jones
chromic acid furnished acid 7. To enable the in-
troduction of a hydroxy group at C-2, 7 was ˆrst
±
brominated to give bromo acid ( )-8. Alkaline
±
±
hydrolysis of ( )-8 yielded hydroxy acid ( )-9.
±
Asymmetric acetylation of ( )-9 with vinyl acetate
and lipase PS at 65 C (twice) in the presence of
9
butylated hydroxytoluene (BHT) as an antioxidant
was carried out according to the method of Sugai and
Ohta.10) Desired (
R
)-hydroxy acid 9 (98.1
estimated by an HPLC analysis) remained intact
after the enzymatic acetylation, while its ( )-isomer
was acetylated to give ( )-10. Acetoxy acid ( )-10
was more soluble in acetone than ( )-9, and there-
fore the latter could be separated from the former.
Protection of the hydroxy group of ( )-9 as a
z
e.e. as
S
S
S
R
R
t-
butyldimethylsilyl (TBS) ether completed the synthe-
z
sis of acid part (R)-11 in a 7.0 overall yield based
on 2 (9 steps).
Scheme 2. Synthesis of Ceramide Pheromone 1.
Reagents: (a) HC C(CH2)9CH3, CH3(CH2)3Li, THF (85
(b) Li, C2H5NH2. (c) TBSOTf, 2,6-lutidine, CH2Cl2 (2 steps,
72 ). (d) TsCl, C5H5N (90 ). (e) DMD, acetone (68 ). (f)
[(CH3)2CHCH2]2AlH, toluene (84 ). (g) Na, naphthalene,
CH3O(CH2)2OCH3. (h) TBSOTf, 2,6-lutidine, CH2Cl2 (2 steps,
81 ). (i) EDC, HOBt, CH2Cl2 (55 ). (j) TBAF, THF (71 ).
Scheme 2 illustrates the synthesis of sphingosine
ø
z
).
part 18 and its conversion to target pheromone 1.
z
z
z
Garner's
t-butoxycarbonyl(Boc)-protected aldehyde
z
1211,12) was prepared from (
S
)-serine, and alkynylated
with 1-dodecynyllithium to give 13 stereoselective-
ly.1–6) Reduction of 13 with lithium in ethylamine
proceeded with concomitant deprotection to give C15-
sphingosine, whose hydroxy groups were protected
as TBS ethers to aŠord 14. The amino group at C-2
z
z
z
In conclusion, we achieved an e‹cient synthesis of
the hair crab pheromone. Unfortunately, Professor
Fusetani has informed us that its bioassay is quite
di‹cult at present, and the biological evaluation of
our synthetic 1 will therefore remain as a task for the
future.
of 14 was then protected as p-toluenesulfonamide to
furnish 15. Epoxidation of the double bond of 15
with dimethyldioxirane (DMD) was followed by
chromatographic puriˆcation of the products to give
＝
b-epoxide 16 (Rf 0.66; silica gel plate;
later-eluted
solvent, hexane:EtOAc 5:1) in a 68
earlier-eluted -epoxide (Rf 0.76; silica gel plate;
solvent, hexane:EtOAc 5:1) in a 17 yield. Epoxi-
dation of the double bond of a sphingosine with
＝
z
yield and
Experimental
a
＝
＝
z
Melting point (mp) data were measured with a
Yanaco MP-S3 instrument and are uncorrected. IR
DMD is known to give a (4
R
,5
S
)-epoxide as the
spectra were measured with a Jasco FT IR-460 spec-
W
major isomer.13)
trometer. 1H-NMR spectra were recorded at 90 MHz
by a Jeol JNM-EX 90A spectrometer, at 400 MHz by
a Jeol JNM-LA400 spectrometer, and at 500 MHz by
a Jeol JNM-LA500 spectrometer. The peak for TMS,
Reduction of 16 with diisobutylaluminum hydride
cleaved the epoxy ring to give alcohol 17, whose
p
-
toluenesulfonyl protective group was then removed
by a treatment with sodium naphthalenide in 1,2-
dimethoxyethane to yield 18, after TBS protection of
the hydroxy group at C-4. Acylation of protected
or CHCl3 in CDCl3 (at
d 7.26), was used as the inter-
nal standard. 13C-NMR spectra were recorded at
100 MHz by a Jeol JNM-LA400 spectrometer and at
126 MHz by a Jeol JNM-LA500 spectrometer. The
sphingosine 18 with acid (R)-11 was achieved with 1-
ethyl-3-(3-dimethylaminopropyl)carbodiimide
peak for CDCl3 (at d 77.0) was used as the internal
hydrochloride (EDC) and 1-hydroxybenzotriazole
(HOBt),4) and the product was treated with
tetrabutylammonium ‰uoride (TBAF) to aŠord sex
pheromone 1 as a waxy solid. The 1H- and 13C-NMR
spectral properties of synthetic 1 were in good agree-
ment with those reported for the natural pheromone.
standard. Optical rotation values were measured with
a Jasco P-1010 polarimeter, and mass spectra were
measured with a Jeol JMS-SX102A spectrometer.
Column chromatography was carried out on Merck
Kieselgel 60 Art 1.07734, and TLC analyses were per-
formed on Merck 60F-254 silica gel plates.
The overall yield of 1 was 10.0
z based on 12 (10
steps) or 2.7 based on 2 (11 steps).
z
15-Methyl-1-hexadecanol (3). A dry THF solution

Synthesis of the Sex Pheromone of the Hair Crab
1533
(KBr) cm„1: 1120 (m, C-O-C), 1035 (s, C-O-C).
of 3-methylbutylmagnesium bromide was prepared
from 3-methylbutyl bromide (14.2 g, 94.2 mmol) and
magnesium (2.75 g, 113 mmol) in dry THF (90 ml).
To a stirred and cooled solution of 2 (4.60 g,
17.3 mmol) in dry THF (50 ml) was added the result-
ing Grignard reagent and then a solution of Li2CuCl4
＝
NMR
21-Me, 22-H3), 1.05–1.35 (39 H, m, 3
21-H,), 1.38–1.88 (6H, m, 2-, 3 -, 5-H2), 3.20–4.01
(4H, m, 1-, 6 -H2), 4.56 (1H, br.s, 2 -H). Anal
Found: C, 79.17; H, 13.20 . Calcd. for C28H50O2:
C, 79.18; H, 13.29
d
H (90 MHz, CDCl3): 0.86 (6 H, d,
J
6.2 Hz,
¿
20-H2, 4?-H2,
?
?
?
.
z
z.
(0.12
M
in dry THF; 8.0 ml, 0.96 mmol) at „789C
under Ar. The resulting mixture was allowed to warm
to room temperature while stirring overnight. After
the reaction mixture had been quenched with saturat-
ed aq. NH4Cl, it was extracted with ethyl acetate. The
extract was successively washed with water, saturated
aq. NaHCO3 and brine, dried with MgSO4, and con-
centrated under reduced pressure. The residue was
21-Methyl-1-docosanol (
5 (4.97 g, 11.7 mmol) in ethanol (100 ml) was added
-toluenesulfonic acid monohydrate (ca. 0.1 g) at
6). To a stirred solution of
p
room temperature. After having been re‰uxed while
stirring for 3 h, the resulting solution was quenched
with saturated aq. NaHCO3 at room temperature and
extracted with diethyl ether. The extract was succes-
sively washed with water and brine, dried with
MgSO4, and concentrated under reduced pressure.
The residue was chromatographed on silica gel to
chromatographed on silica gel to give 3 (4.42 g, 99
z
)
as a colorless solid, mp 39–40 C. IR
9
n
max (KBr) cm„1
:
3350 (s, O-H). NMR dH (400 MHz, CDCl3): 0.86
＝
6.6 Hz, 15-Me, 16-H3), 1.10–1.40 (28 H,
(6 H, d,
m, 2 14-H2, 15-H, 1-OH), 3.64 (2H, t,
1-H). Anal. Found: C, 79.46; H, 14.15
C17H36O: C, 79.61; H, 14.15
J
give 6 (3.87 g, 97
IR nmax (KBr) cm„1: 3375 (w, O-H), 1055 (m, C-O).
NMR H (90 MHz, CDCl3): 0.86 (6 H, d, 6.1 Hz,
21-Me, 22-H3), 1.05–1.40 (40 H, m, 2 20-H2, 21-H,
1-OH), 3.64 (2H, t, 6.4 Hz, 1-H2). Anal. Found:
C, 80.87; H, 14.05 . Calcd. for C17H36O: C, 81.10;
H, 14.20
z 9
) as a colorless solid, mp 62–63 C.
＝
¿
J
6.4 Hz,
z
. Calcd. for
d
J
＝
z
.
¿
J
z
＝
15-Methylhexadecyl Tosylate (
3 (4.30 g, 16.8 mmol) in pyridine (40 ml) was added
-toluenesulfonyl chloride (4.79 g, 25.1 mmol) at
C. After having been stirred overnight at 4 C, the
4). To a solution of
z.
p
0
9
9
21-Methyldocosanoic Acid (
cooled suspension of 6 (2.21 g, 6.49 mmol) in acetone
(40 ml) was added Jones' CrO3 reagent (2.69
4.8 ml, 13.0 mmol) dropwise at 0 C, and the reaction
7). To a stirred and
reaction mixture was poured into dil. aq. HCl and ex-
tracted with diethyl ether. The extract was successive-
ly washed with saturated aq. CuSO4, water, saturated
aq. NaHCO3 and brine, dried with MgSO4, and con-
centrated under reduced pressure to give 4 (6.11 g,
M
;
9
mixture was stirred at room temperature for 1.5 h.
After the reaction mixture had been quenched with 2-
propanol, it was extracted with diethyl ether. The ex-
tract was successively washed with water and brine,
dried with MgSO4, and concentrated under reduced
pressure. The residue was chromatographed on silica
89
z) as a colorless solid. This was employed in the
next step without further puriˆcation. IR nmax (KBr)
cm„1: 1595 (w, Ar), 1465 (s, Ar), 1355 (m, SO2), 1175
(m, SO2). NMR dH (90 MHz, CDCl3): 0.86 (6 H, d,
＝
¿
＝
J
2
J
6.2 Hz, 15-Me, 16-H3), 1.10–1.40 (27 H, m,
14-H2, 15-H), 2.45 (3H, s, Ar-CH3), 4.02 (2H, t,
gel to give 7 (1.70 g, 74
71–72 C. IR
dH (90 MHz, CDCl3): 0.86 (6 H, d,
21-Me, 22-H3), 1.00–1.80 (38 H, m, 3 20-H2, 21-H,
1-OH), 2.36 (2H, t, 6.4 Hz, 2-H2). Anal. Found:
C, 77.65; H, 12.86 . Calcd. for C23H46O2: C, 77.90;
H, 13.07
z
) as a colorless solid, mp
max (KBr) cm„1: 1700 (m, C O). NMR
＝
9
n
6.4 Hz, 1-H2), 7.33 (2H, d, J 8.3 Hz, Ar), 7.79
＝
＝
J
6.2 Hz,
＝
8.3 Hz, Ar).
(2H, d,
J
¿
J
＝
21-Methyl-1-tetrahydropyranyloxydocosane (
5). A
z
dry THF solution of 6-(2-tetrahydropyranyloxy)hex-
ylmagnesium bromide was prepared from 6-(2-tetra-
hydropyranyloxy)hexyl bromide (13.4 g, 50.4 mmol)
and magnesium (1.47 g, 60.5 mmol) in dry THF
(90 ml). The resulting Grignard reagent and Li2CuCl4
z.
±
±
8
(
)-2-Bromo-21-methyldocosanoic Acid [( )- ].
Red phosphorus (311 mg, 10.0 mmol) was added to 7
(2.74 g, 7.73 mmol), and the mixture was heated at
(0.12
sively added to a solution of 4 (6.11 g, 14.9 mmol) in
dry THF (200 ml) at „78 C under Ar. This mixture
M
in dry THF; 4.2 ml, 0.50 mmol) were succes-
959C. Bromine (4.9 g, 1.6 ml, 30.9 mmol) was added
dropwise to the heated mixture, and heating and stir-
ring were continued at 95 C for 6 h. Water was then
9
9
was allowed to warm to room temperature while stir-
ring overnight. After the reaction mixture had been
quenched with saturated aq. NH4Cl, it was extracted
with ethyl acetate. The extract was successively
washed with water and brine, dried with MgSO4, and
concentrated under reduced pressure. The residue
was chromatographed on silica gel to give 5 (5.01 g,
added, and the mixture was stirred for 20 min. The
separated acid was extracted with diethyl ether, and
the extract was successively washed with water and
brine, dried with MgSO4, and concentrated under
reduced pressure. The residue was recrystallized from
hexane to give (
solid, mp 75–76
O-H), 1700 (m, C O), 660 (w, C-Br). NMR dH
±
9
)-8 (2.83 g, 84
z
) as a colorless
C. IR nmax (KBr) cm„1: 3000 (br,
79
z) as a colorless solid, mp 33.5–34.59C. IR nmax
＝

1534
Y. MASUDA et al.
＝
(90 MHz, CDCl3): 0.86 (6 H, d,
J
6.2 Hz, 21-Me,
20-H2, 21-H, 1-OH),
7.3 Hz,
. Calcd. for
＝
of the (
R
)-9 methyl ester: tR 13.89 min (99.05
z
＝
)-9
);
22-H3), 1.00–1.60 (36 H, m, 4
¿
(
R
)-MTPA ester of the (
S
)-9 methyl ester: tR
1.90–2.10 (2H, m, 3-H2), 4.25 (1H, t,
2-H). Anal. Found: C, 63.77; H, 10.40
C23H45BrO2: C, 63.72; H, 10.46
J
＝
17.53 min (0.95
was therefore 98.1
z
). The enantiomeric purity of (
R
z
z
e.e.
z
.
(R)-2-tert-Butyldimethylsilyloxy-21-methyl-
±
(
)-2-Hydroxy-21-methyldocosanoic
Acid
docosanoic Acid [(R)-11]. To a stirred solution of
[(
(25 ml) was added to ( )-8 (2.79 g, 6.44 mmol), and
the mixture was stirred and heated at 80 C for 24 h.
±
)-9]. Sodium hydroxide (2.1 g, 51 mmol) in water
(R)-9 (50 mg, 0.13 mmol) and imidazole (35 mg,
±
0.52 mmol) in DMF (5 ml) was added TBSCl (58 mg,
0.39 mmol) at 0 C. The reaction mixture was stirred
9
9
After cooling, the mixture was acidiˆed with dil. aq.
HCl and extracted with diethyl ether. The extract was
successively washed with water and brine, dried with
MgSO4, and concentrated under reduced pressure.
The residue was recrystallized from acetone to give
)-9 (2.15 g, 90
IR nmax (KBr) cm„1: 3510 (m, O-H) 3000 (br, COO-
H), 1740 (m, C O). NMR dH (90 MHz, CDCl3):
for 4 h at room temperature and then quenched with
water. It was extracted with diethyl ether, before the
extract was succesively washed with water and brine,
dried with MgSO4, and concentrated under reduced
pressure. The residue was diluted with THF (5 ml)
(
±
z 9
) as a colorless solid, mp 93–96 C.
and then acidiˆed with 0.1
M
HCl (1 ml). The reac-
tion mixture was stirred for 4 h at room temperature.
It was then poured into water and extracted with
diethyl ether. The extract was successively washed
with water and brine, dried with MgSO4, and concen-
trated under reduced pressure. The residue was chro-
＝
＝
0.86 (6 H, d,
(39 H, m, 3
(1H, t,
12.71
J
¿
6.2 Hz, 21-Me, 22-H3), 1.00–1.65
20-H2, 21-H, 2-OH, COO-H), 4.27
J
＝
6.6 Hz, 2-H). Anal. Found: C, 74.70; H,
z
. Calcd. for C23H46O3: C, 74.57; H, 12.51
z.
matographed on silica gel to give (
R)-11 (50.4 mg,
80
z
) as a colorless oil, n2D2 1.4421. [
a
]2D5+1.63 (
c
1.05,
CHCl3). IR nmax (ˆlm) cm„1: 1725 (C O), 1250 (Si-
(R)-2-Hydroxy-21-methyldocosanoic Acid [(R)-
9
].
＝
Lipase PS (Amano Pharmaceutical Co.; 1.06 g) was
O). NMR
0.88 (6H, d,
-Bu), 1.16–1.38 (38H, m, 3
4.29 (1H, t, 5.4 Hz, 2-H). Anal. Found: C, 71.79;
H, 12.25 . Calcd. for C29H60O3Si: C, 71.84; H,
12.47
dH (500 MHz, CDCl3): 0.13 (6H, s, Si-Me),
suspended in a solution of (
±
)-9 (1.13 g, 3.05 mmol),
＝
J
6.1 Hz, 21-Me, 22-H3), 0.94 (9H, s,
20-H2, 21-H, O-H),
and BHT (butylated hydroxytoluene, 40 mg) in vinyl
acetate (11 ml) and THF (11 ml), and the mixture
t
¿
J
＝
9
stirred at 65 C for 30 h. After cooling, the mixture
z
was ˆltered through Celite, and the Celite layer was
washed with diethyl ether. The combined ˆltrate and
washings were concentrated under reduced pressure,
and the residue was dissolved in vinyl acetate (11 ml)
and THF (11 ml) containing BHT (40 mg). Lipase PS
(1.06 g) was added to the solution, and the mixture
z
.
tert-Butyl (4S,1
2,2-dimethyl-3-oxazolidinecarboxylate
stirred solution of 1-dodecyne (8.55 g, 51.4 mmol) in
dry THF (90 ml) was added -butyllithium (1.56 in
hexane; 28 ml, 43.8 mmol) dropwise at „40 C under
Ar. After the reaction mixture had been stirred at
„23 C for 30 min, a solution of Garner's aldehyde
(12, 8.63 g, 37.6 mmol) in dry THF (90 ml) was
added dropwise at „30 C. After having been stirred
at „23 C for 1.5 h, the resulting solution was quen-
?
R)-4-(1
?
-hydroxy-2
?
(
-tridecynyl)-
13). To
a
n
M
was stirred at 65
centration, the residue was recrystallized from ace-
tone to give ( )-9 (270 mg 23 ) as a powder, mp
„2.2 ( 0.5, CHCl3:MeOH 1:1). Its
IR and H-NMR spectra were identical with those of
)-9. Anal. Found: C, 74.64; H, 12.72 . Calcd.
for C23H46O3: C, 74.54; H, 12.51
9
C for 3 h. After ˆltration and con-
9
R
z
9
22
＝
91–93
9
C. [
a
]
c
D
1
9
(
±
z
9
z.
ched with water and extracted with ethyl acetate. The
extract was successively washed with water and brine,
dried with MgSO4, and concentrated under reduced
pressure. The residue was chromatographed on silica
Determination of the Enantiomeric Purity of
(R)- )- -Methoxy- -tri‰uoromethylphenylacetyl
chloride (MTPA Cl; 50 mg, 0.2 mmol) was added to
a solution of the methyl ester derived from ( )-9
(50 mg, 0.13 mmol; prepared by treating ( )-9 with
diazomethane) in dry pyridine (2 ml), and the mix-
ture was stirred at 0 C for 12 h. The reaction was
9
.
(
S
a
a
gel to give 13 (12.7 g, 85
z
) as a colorless oil, nD23
25
R
1.4661. [
cm„1: 3450 (br.w, OH), 2230 (w, C
O). NMR dH (500 MHz, CDCl3): 0.88 (3H, t,
7.1 Hz, 13 -H), 1.20–1.41 (15H, m,
2-Me), 1.43–1.66 (17H, m, 5 12 -H2, 1
-H2), 3.90 (1H, br.s, 1
4.05–4.12 (2H, m, 3-H), 4.66 (1H, br.s, 4-H). Anal
Found: C, 69.60; H, 10.27; N, 3.26 . Calcd. for
C23H41NO4: C, 69.83; H, 10.45; N,3.54
a
]
„46.6 (
c
1.00, CHCl3). IR nmax (ˆlm)
D
R
ø
C), 1700 (s, C
＝
＝
J
9
?
t
-Bu, 2-Me,
-OH), 2.19
-H),
quenched by adding water, and the mixture was
diluted with diethyl ether. The ethereal solution was
successively washed with sat. CuSO4 aq., sat.
NaHCO3 aq., water and brine, dried with Na2SO4,
and concentrated under reduced pressure. The
residue was analyzed by HPLC (Pegasil-Senshu
?¿
?
?
＝
(2H, t,
J
5.8 Hz, 4
?
?
.
z
z.
×
column, 25 cm 4.6 mm; eluent,
acetate 60:1; ‰ow rate, 1 ml min). (
n
-hexane-ethyl
(2S,3R,4E)-2-Amino-1,3-bis-tert-butyldimethyl-
silyloxy-4-pentadecene (14). A solution of 13 (11.8 g,
＝
R)-MTPA ester
W

Synthesis of the Sex Pheromone of the Hair Crab
1535
＝
29.8 mmol) in dry THF (100 ml) was added dropwise
to a blue solution of lithium (3.01 g, 447 mmol) in
ethylamine (88 g) while stirring at „70 C for 1 h.
HaHb), 3.81 (1H, dd,
J
10.2, 4.1 Hz, 1-HaHb), 4.24
＝ ＝
6.4, 5.9 Hz, 3-H), 4.63 (1H, d, J
(1H, dd-like,
J
＝
9
6.8 Hz, N–H), 5.21 (1H, dd,
J
15.8, 6.4 Hz, 4-H),
5.60 (1H, dt-like, J 15.8, 6.1 Hz, 5-H), 7.27 (2H, d,
8.2 Hz, -Ar), 7.74 (2H, d, 8.2 Hz, -Ar).
Anal. Found: C, 64.07; H, 10.49; N, 1.93 . Calcd.
for C34H65NO4SSi2: C, 63.79; H, 10.23; N, 2.19
＝
The mixture was then stirred overnight while being
allowed to warm to room temperature, before being
quenched with NH4Cl (ca. 48 g, 894 mmol). After
removing the ethylamine by evaporation, the mixture
was diluted with water and extracted with diethyl
ether. The extract was successively washed with water
and brine, dried with Na2SO4, and concentrated un-
der reduced pressure to give the reduction product
(8.14 g, quant.) as a brown waxy solid. This reduc-
tion product was used for the next reaction without
puriˆcation.
J
＝
m
J
＝
o
z
z.
(2S,3S,4R,5S)-1,3-bis-tert-Butyldimethylsilyloxy-
4,5-epoxy-2-p-toluenesulfonylaminopentadecane
(
16). A solution of dimethyldioxirane in acetone
(prepared from 250 g of Oxone}, 120 g of NaHCO3,
200 ml of H2O and 160 ml of acetone) was added to
15 (200 mg, 0.31 mmol) at 0
ture was stirred at 0 C for 4 d, before being concen-
trated under reduced pressure. The residue was chro-
matographed on silica gel to give later-eluted
epoxide 16 (139 mg, 68
) as a colorless oil, nD24
9C, and the reaction mix-
To a stirred mixture of the reduction product
(8.14 g, 31.6 mmol) in dry CH2Cl2 (100 ml) were
added 2.6-lutidine (2,6-dimethylpyridine; 18.4 ml,
9
b
-
160 mmol) and TBSOTf (29 ml, 128 mmol) at 0
9
C.
z
25
After having been stirred at room temperature for
1 h, the resulting solution was quenched with
methanol. It was then poured into water and extract-
ed with diethyl ether. The extract was successively
washed with water, saturated aq. NaHCO3 and brine,
dried with MgSO4, and concentrated under reduced
1.4827. [
a
]
„20.2 (c 1.05, CHCl3). IR nmax (ˆlm)
D
cm„1: 3290 (w, N–H), 1600 (w, Ar), 1335 (m, SO2),
1255 (m, Si-Me), 1165 (s, SO2), 1095 (m, Si–O).
NMR
d
H (500 MHz, CDCl3): „0.05, 0.02, 0.04, 0.05
-Bu), 0.85
6.9 Hz, 15-H3),
14-H2), 1.52–1.61 (2H, m,
(total 12H, each s, Si-Me), 0.82 (9H, s,
t
＝
t-Bu), 0.88 (3H, t, J
(9H, s,
1.26–1.43 (16H, br.s, 7
6-H2), 2.41 (3H, s, Ar-Me), 2.66 (1H, dd,
Hz, 4-H), 2.78 (1H, m, 5-H), 3.27 (1H, ddt,
5.2, 4.9 Hz, 2-H), 3.55 (1H, dd, 10.4, 4.9 Hz, 1-
10.4, 4.9 Hz, 1-HaHb), 3.77
5.2 Hz, 3-H), 4.76 (1H, d, 6.7 Hz,
pressure. The residue was chromatographed on silica
¿
24
＝
5.2, 2.2
gel to give 14 (10.4 g, 85
z
) as a pale yellow oil, nD
J
24
＝
6.7,
1.4542. [
a
]
„1.48 (
c
1.01, CHCl3). IR nmax (ˆlm)
H (500 MHz, CDCl3):
J
D
cm„1: 1255 (m, Si-Me). NMR
d
J
＝
＝
J
0.01, 0.04 (6H, each s, Si-Me), 0.06 (6H, s, Si-Me),
HaHb), 3.71 (1H, dd,
(1H, t,
N–H), 7.27 (2H, d,
8.1 Hz, -Ar). Anal. Found: C, 62.06; H, 9.79; N,
1.87 . Calcd. for C34H65NO5SSi2: C, 62.24; H, 9.99;
N, 2.13
The earlier-eluted
tained as an oil (36 mg, 17
0.86–0.90 (21H, m,
t
-Bu, 15-H3), 1.22–1.32 (16H, m,
J
＝
J
＝
＝ ＝
8.1 Hz, m-Ar), 7.75 (2H, J
7
¿
14-H2), 1.34–1.41 (2H, m, N-H2), 2.04 (2H, dd,
J
＝
＝
6.7, 4.9 Hz,
J
13.6, 6.7 Hz, 6-H2), 2.78 (1H, dt,
J
o
2-H), 3.55 (1H, dd,
J
＝
9.8, 6.7 Hz, 1-HaHb), 3.70
z
＝
＝
(1H, dd,
ϑ
9.8, 4.9 Hz, 1-HaHb), 4.04 (1H, t,
15.4, 6.7 Hz,
15.4, 6.7 Hz, 5-H). Anal
Found: C, 66.47; H, 12.28; N, 2.79 . Calcd. for
C27H59NO2Si2: C, 66.74; H, 12.24; N, 2.88
J
z.
6.7 Hz, 3-H), 5.38 (1H, dd-like,
J
＝
a
-epoxy isomer was also ob-
).
＝
4-H), 5.70 (1H, dt,
J
.
z
z
z
.
(2S,3S,4R)-1,3-bis-tert-Butyldimethylsilyloxy-2-p-
toluenesulfonylamino-4-pentadecanol
(17). To a
(2S,3R,4E)-1,3-bis-tert-Butyldimethylsilyloxy-2-p-
toluenesulfonylamino-4-pentadecene (15). To an ice-
cooled solution of 14 (9.78 g, 20.1 mmol) in dry pyri-
dine (90 ml), TsCl (5.76 g, 30.2 mmol) was added,
and the mixture was stirred for 24 h at room tempera-
ture. The reaction mixture was then poured into dil.
aq. HCl and extracted with diethyl ether. The extract
was successively washed with saturated aq. CuSO4,
water, saturated aq. NaHCO3 and brine, dried with
MgSO4, and concentrated under reduced pressure.
The residue was chromatographed on silica gel to
stirred and cooled solution of 16 (1.63 g, 2.48 mmol)
in dry toluene (20 ml), a solution of diisobutylalumi-
num hydride (1.01
was added dropwise at „78
ture was warmed gradually to 0
M
in toluene; 8.8 ml, 8.9 mmol)
C under Ar. This mix-
C while stirring for
9
9
3 h, quenched with saturated aq. Rochelle's salt and
then diethyl ether was added. The resulting slurry
was stirred at room temperature until two clear layers
had formed. These layers were separated, and the a-
queous layer was extracted with diethyl ether. The ex-
tract was successively washed with water and brine,
dried with Na2SO4, and concentrated under reduced
pressure. The residue was chromatographed on silica
give 15 (11.6 g, 90
z
) as a colorless oil, n2D4 1.4834.
[
a
]2D6 „2.43 (
c
1.04, CHCl3). IR n
max (ˆlm) cm„1: 3290
(m, N–H), 1600 (w, Ar), 1335 (m, SO2), 1255 (m, Si-
Me), 1165 (s, SO2). NMR dH (90 MHz, CDCl3):
„0.05 (6H, s, Si-Me), „0.01, 0.00 (6H, each s, Si-
gel to give 17 (1.37 g, 84
z
) as a colorless oil, nD25
25
1.4841. [
a
]
„1.51 (c 1.03, CHCl3). IR nmax (ˆlm)
D
cm„1: 3540 (m, O-H), 3320 (m, N–H), 1600 (m, Ar),
1335 (s, SO2), 1255 (s, Si-Me), 1160 (s, SO2). NMR
dH (500 MHz, CDCl3): „0.05, „0.02, 0.09, 0.11
Me), 0.76–0.98 (21H, m,
14-H2), 1.96 (2H, m, 6-H2), 2.41 (3H, s, Ar-Me),
3.15 (1H, m, 2-H), 3.45 (1H, dd, 10.2, 6.1 Hz, 1-
t-Bu, 15-H3), 1.26 (16H, m,
7
¿
J
＝
(total 12H, each s, Si-Me), 0.82 (9H, s, t-Bu), 0.88

1536
Y. MASUDA et al.
＝
(9H, s,
t
-Bu), 0.88 (3H, t,
J
6.9 Hz, 15-H3),
18 (40.2 mg, 0.065 mmol) in dry CH2Cl2 (5 ml) was
added EDC [1-ethyl-3-(3-dimethylaminopropyl)-car-
bodiimide hydrochloride; 18.7 mg, 0.098 mmol] and
HOBt (1-hydroxybenzotriazole; 25.6 mg, 0.20 mmol)
at room temperature. The reaction mixture was
stirred for 12 h at room temperature and then quen-
ched with water. It was extracted with ethyl acetate,
and the extract was successively washed with water
and brine, dried with MgSO4, and concentrated un-
der reduced pressure. The residue was chro-
matographed on silica gel to give the product (38 mg,
0.035 mmol) as a yellow oil. This product was used
for the next reaction without further puriˆcation. To
a stirred mixture of the product (38 mg, 0.035 mmol)
1.18–1.38 (18H, m, 6
¿
14-H2), 1.40–1.51 (2H, m,
5-H2), 2.42 (3H, s, Ar-Me), 2.57 (1H, br, 4-OH),
3.41 (1H, m, 4-H), 3.52–3.60 (2H, m, 1-HaHb, 2-H),
3.69 (1H, dd, J 10.2, 6.5 Hz, 1-HaHb), 3.81 (1H,
＝
＝
＝
dd,
J
4.7, 3.2 Hz, 3-H), 4.81 (1H, d,
J
6.7 Hz,
-Ar), 7.73 (2H, d,
-Ar). Anal. Found: C, 61.88; H, 10.28;
. Calcd. for C34H67NO5SSi2: C, 62.05; H,
10.26; N, 2.13
＝
N–H), 7.29 (2H, d,
J
8.3 Hz, m
＝
N, 2.13
J
8.3 Hz,
o
z
z
.
(2S,3S,4R)-2-Amino-1,3,4-tris-tert-butyldimethyl-
silyloxypentadecane (18). Preparation of sodium
naphthalenide: To a stirred solution of naphthalene
(2.47 g, 19.3 mmol) in dry DME (20 ml), Na (400 mg,
17.4 mmol) was added under Ar. The mixture was
stirred for 2 h at room temperature.
To a solution of 17 (1.26 g, 1.93 mmol) in dry
DME (20 ml), the prepared sodium naphthalenide
C under Ar. The mix-
ture was then warmed gradually to „10
ring for 4 h and diluted with water. The mixture was
extracted with diethyl ether. The extract was succes-
sively washed with water and brine, dried with
K2CO3, and concentrated under reduced pressure.
The residue was chromatographed on silica gel to
) and the detosylation
product (490 mg, 87 based on consumed 17) as a
yellow oil. This detosylation product was used for the
next reaction without further puriˆcation.
To a stirred mixture of the detosylation product
(490 mg, 0.972 mmol) in dry CH2Cl2 (5 ml) were
added 2,6-lutidine (2,6-dimethylpyridine; 340
2.92 mmol) and TBSOTf (450 l, 1.94 mmol) at 0
in dry THF (1 ml) was added TBAF in THF (1.0
M
,
0.21 ml, 0.21 mmol) at 0 C under Ar, and stirring
9
was continued for 4 h at room temperature. The reac-
tion mixture was poured into brine and extracted
with CHCl3. The extract was successively washed
with water and brine, dried with MgSO4, and concen-
trated under reduced pressure. The residue was chro-
matographed on silica gel to give 1 (15 mg, 2 steps,
was added dropwise at „78
9
9
C while stir-
40
z
129–133
based on consumed 18) as a colorless solid, mp
22
＝
C. [a] +14 (c 0.70, CHCl3:MeOH 1:1).
9
D
IR nmax (ˆlm) cm„1: 3340 (br.m, O-H, and N–H),
＝
2915 (s), 2850 (s), 1645 (m, C O), 1560 (w), 1470
give recovered 17 (526 mg, 42
z
(m), 1080 (w), 720 (w). NMR dH (400 MHz,
CDCl3:CD3OD
＝
1:1): 0.82–0.85 (9H, m, 15-, 22
?
-H3,
z
21-Me), 1.10–1.35 (57H, m, 6
21 -H, 1-OH, 3-OH, 4-OH, 2
m, 5-, 3 -H2), 3.49–3.57 (2H, m, 2?
¿14-H2, 4?¿20?
-H2,
?
?
-OH), 1.35–1.50 (4H,
?
-, 4-H), 3.71 (1H,
＝
＝
11.2,
dd,
4.9 Hz, 1-HaHb), 4.01 (1H, dd,
4.09 (1H, m, 2-H), 4.43 (1H, s, N–H). NMR dC
(100 MHz, CDCl3:CD3OD 1:1): 13.7, 14.3, 22.8,
J
11.1, 4.7 Hz, 1-HaHb), 3.76 (1H, dd,
J
m
l,
J
＝
8.0, 3.9 Hz, 3-H),
m
9
C.
After having been stirred at room temperature for
1 h, the resulting solution was quenched with
methanol. It was then poured into water and extract-
ed with diethyl ether. The extract was successively
washed with water, saturated aq. NaHCO3 and brine,
dried with K2CO3, and concentrated under reduced
pressure. The residue was chromatographed on silica
＝
23.0, 25.6, 26.2, 27.7, 28.3, 29.70, 29.86, 29.94,
29.99, 30.01, 30.04, 30.09, 30.26, 32.27, 32.99, 34.8,
39.4, 51.89, 51.98, 61.3, 72.30, 72.65, 75.6, 176.3.
These spectral data are in good agreement with the
reported values.7,8) HRFABMS m z (M+H)+: calcd.
W
for C38H78NO5, 628.5880; found, 628.5879.
gel to give 18 (556 mg, 2 steps, 81
z based on con-
sumed 17) as a pale yellow oil, nD24 1.4551. [
a
]
25
D
Acknowledgments
„6.30 (c
1.00, CHCl3). IR nmax (ˆlm) cm„1: 1255 (s,
Si-Me). NMR dH (500 MHz, CDCl3): 0.05, 0.06,
We thank Prof. N. Fusetani (the University of
Tokyo) for his kind advice.
0.063, 0.07, 0.09 (total 18H, each s, Si-Me),
0.85–0.93 (30H, m, t-Bu, 15-H3), 1.18–1.34 (18H, m,
6
¿14-H2), 1.35–1.44 (2H, m, 5-H2), 1.45–1.59 (2H,
References
＝
m, NH2), 2.92 (1H, m, 2-H), 3.47 (1H, dd,
J
9.5,
6.4 Hz, 1-Ha), 3.81
8.1, 4.9, 1.5 Hz, 4-H), 3.84 (1H, dd,
9.8, 3.7 Hz, 1-Hb). Anal. Found: C, 64.18; H,
12.23; N, 2.48 . Calcd. for C33H75NO3Si3: C, 64.11;
H, 12.23; N, 2.27
1) Abe, T. and Mori, K., Synthesis of sphingosine rela-
＝
J
8.1 Hz, 3-H), 3.56 (1H, br.d,
tives, XV. Synthesis of (2 ,2
S ?S,3R,4E,8E )-N-2?-
＝
J
(1H, ddd,
hydroxyoctadecanoyl-1- -(b- -glucopyranosyl)-9-
O
D
＝
J
methyl-4,8-sphingadienine (Pen III), a cerebroside
isolated from Penicillium funiculosum as the fruiting-
inducer against Schizophyllum commune. Biosci.
Biotechnol. Biochem., 58, 1671–1674 (1994).
z
z.
(2S,2
docosanoylamino)-1,3,4-pentadecanetriol (
stirred solution of ( )-11 (31.5 mg, 0.065 mmol) and
?
R,3S,4R)-2-(2
?
-Hydroxy-21
?
-methyl-
2) Mori, K. and Uenishi, K., Synthesis of sphingosine
1
). To a
relatives, XVII. Synthesis of (2
S ?R,3R,3?E,
,2
4
Z
,8 )-1- -( -glucopyranosyl)- -(2
E
O
b
-
D
N
?
-hydroxy-3?-
R

Synthesis of the Sex Pheromone of the Hair Crab
1537
octadecanoyl)-9-methyl-4,8-sphingadienine (Pen II),
the major cerebroside isolated from Penicillium
funiculosum as the fruiting-inducer against
Schizophyllum commune. Liebigs Ann., 1–6 (1996).
3) Yajima, A., Takikawa, H., and Mori, K., Synthesis
of sphingosine relatives, XVIII. Synthesis of
penazetidine A, an alkaloid inhibitor of protein
kinase C isolated from marine sponge Penares sollasi.
Liebigs Ann., 1083–1089 (1996).
4) Mori, K. and Uenishi, K., Synthesis of sphingosine
relatives, XIV. A new synthesis of symbioramide, a
CaZ-ATPase activator from Symbiodinium sp. Lie-
bigs Ann. Chem., 41–48 (1994).
5) Takikawa, H., Maeda, T., Seki, M., Koshino, K.,
and Mori, K., Synthesis of sphingosine relatives,
XIX. Synthesis of penaresidin A and B, azetidine
alkaloids with actomyosin ATPase activating proper-
ties. J. Chem. Soc., Perkin Trans. 1, 97–111 (1997).
6) Seki, M. and Mori. K., Synthesis of a prenylated and
immunosuppressive marine galactosphingolipid with
beckii, Part 1: Isolation and structure of novel cer-
amides. Tetrahedron, 56, 9895–9899 (2000).
8) Asai, N., Fusetani, N., and Matsunaga, S., Sex
pheromone of the hair crab Erimacrus isenbeckii. II.
Synthesis of ceramides. J. Nat. Prod., 64, 1210–1215
(2001).
9) Fouquet, C. and Schlosser, M., Improved carbon-
carbon linking by controlled copper catalysis. Angew.
Chem. Int. Ed. Engl., 13, 82–83 (1974).
10) Sugai, T. and Ohta, H., Lipase-catalyzed kinetic
resolution of 2-hydroxyhexadecanoic acid and its
esters. Agric. Biol. Chem., 54, 3337–3338 (1990).
11) Garner, P. and Park, J. M., The synthesis and
conˆgurational stability of diŠerentially protected
b
-hydroxy-a-amino aldehydes. J. Org. Chem., 52,
2361–2364 (1987).
12) Garner, P., Park, J. M., and Malecki, E., A stereo-
divergent synthesis of
D
-
erythro-sphingosine and
D
-
threo-sphingosine from
L
-serine. J. Org. Chem., 53,
4395–4398 (1988).
cyclopropane-containing alkyl chains: (2
12 ,2!? ,5!? ,11!? ,12!? )-plakoside A, and its
(2 ,3 ,11 ,12 ,2!? ,5!? ,11!? ,12!? ) isomer. Eur.
J. Org. Chem., 3797–3809 (2001).
S
,3
R
,11
S
,
13) Takikawa, H., Muto, S., and Mori, K., Synthesis of
sphingosine relatives, XX. Diastereoselective epoxi-
dation of the double bond at C-4 of sphingosines to
R
S
R
Z
S
R
R
Z
R
R
S
R
S
provide phytosphingosine relatives such as
a-galac-
7) Asai, N., Fusetani, N., Matsunaga, S., and Sasaki,
tosylceramide KRN 7000. Tetrahedron, 54, 3141–
J., Sex pheromone of the hair crab Erimacrus isen-
3150 (1998).