Constituents of holothuroidea, 16. Determination of absolute configuration of the branched methyl group in ante-iso type side chain moiety on long chain base of glucocerebroside from the sea cucumber Holothuria leucospilota

Article abstract of DOI:10.1248/cpb.53.1333

The absolute configuration of the branched methyl group in ante-iso type side chain moiety on the long chain base of glucocerebroside, HLC-2-A, which was isolated from the sea cucumber Holothuria leucospilota was determined. Oxidation of the glucocerebros

Full text of DOI:10.1248/cpb.53.1333

October 2005
Notes
Chem. Pharm. Bull. 53(10) 1333—1334 (2005)
1333
1)
Constituents of Holothuroidea, 16.
Determination of Absolute
Configuration of the Branched Methyl Group in Ante-iso Type Side Chain
Moiety on Long Chain Base of Glucocerebroside from the Sea Cucumber
Holothuria leucospilota
Koji YAMADA, Hiroyuki ONAKA, Masakazu TANAKA, Masanori INAGAKI, and Ryuichi HIGUCHI*
Faculty of Pharmaceutical Sciences, Kyushu University; 3–1–1 Maidashi, Higashi-ku, Fukuoka 812–8582, Japan.
Received April 21, 2005; accepted June 27, 2005
The absolute configuration of the branched methyl group in ante-iso type side chain moiety on the long
chain base of glucocerebroside, HLC-2-A, which was isolated from the sea cucumber Holothuria leucospilota was
determined. Oxidation of the glucocerebroside with ozone afforded C -fragment including the ante-iso moiety.
13
The optically active C -fragment was synthesized asymmetrically by using the Wittig reaction from chiral syn-
1
3
ton for comparison with the natural fragment.
Key words glycosphingolipid; glucocerebroside; absolute configuration; sea cucumber; Holothuria leucospilota
In our continuing research on biologically active glyco- regarding determination of the absolute configuration of
sphingolipids (GSLs) from echinoderms, a series of studies branched methyl group in the ante-iso type of side chain of
on the isolation and structural elucidation of the GSLs from sphingolipids and thus worthy of noting.
sea cucumber species have been performed in our laborato-
2
—12)
Experimental
ry.
In the preceding paper, we reported the isolation of a
Optical rotations were measured with a Jasco Dip-370 digital polarimeter
at 25 °C. ORD spectra were taken with a Jasco J-720W spectropolarimeter at
sphingosine-type glucocerebroside (HLC-2-A in Chart 1)
with ante-iso type side chain of the long-chain base (LCB)
moiety from the whole bodies of the sea cucumber
1)
Holothuria leucospilota (Nisekuronamako in Japanese).
However, the absolute configuration of the branched methyl
group (C -Me) in the ante-iso moiety has not yet been deter-
1
4
mined. In this paper, we report determination of the absolute
configuration of the branched methyl group of HLC-2-A.
Since study on the cerebroside itself was regarded as diffi-
cult, we focused on a fragment which included the ante-iso
moiety from the parent cerebroside. Trimethylsilylation fol-
lowed by ozone oxidation of HLC-2-A gave C -fragment (1)
1
3
which was released from the cerebroside by the fission of
C4–C5 bond. Compound 1 was converted to alcohol (natural
2
) by reduction with NaBH . The absolute configuration of
4
natural 2, 10-methyl dodecanol, was elucidated by compari-
son with synthetic optically active 2 as follows (Chart 1).
One of the primary alcohols of 1,4-butanediol (3) was pro-
tected by TBDMS ether to give 4. The remaining hydroxy
group of 4 was converted to bromide with CBr under stan-
4
dard conditions, producing 5. The triphenylphosphonium salt
(6) was synthesized from 5 with elimination of the TBDMS
group using the usual process. The Wittig reaction with 6
and (S)-6-methyl octanal (8), which was synthesized from
commercially-available (S)-6-methyl octanol (7) by PCC oxi-
dation, yielded (S)-10-methyl dodecenol (9). Finally, hydro-
genation of 9 with Pd–C gave (S)-10-methyl dodecanol (syn-
13)
thetic 2).
Comparison of the optical rotations of natural 2 (ꢀ50.3°)
and synthetic 2 (ꢀ53.3°) suggests the former is also (S)-10-
methyl dodecanol. Furthermore, their ORD spectra are iden-
tical. Therefore, the branched methyl group, C -Me, in the
1
4
ante-iso moiety of HLC-2-A must be S configuration as
shown in Chart 1.
The present study is, to the best of our knowledge, the first
Chart 1
∗
To whom correspondence should be addressed. e-mail: rhiguchi@ phar.kyushu-u.ac.jp
© 2005 Pharmaceutical Society of Japan

1
2
334
Vol. 53, No. 10
5 °C. IR spectra were obtained on a Jasco FT/IR-410 infrared spectropho-
(6H, m, 2ꢃCH3).
1
13
tometer. H- and C-NMR spectra were recorded on a Jeol GX-270 spec-
trometer (270, 67.8 MHz) or a Varian Unity-500 spectrometer (500,
(S)-10-Methyl Dodec-4-en-1-ol (9) A solution of n-BuLi (141 mg,
2.2 mmol) in n-hexane (1.4 ml) was added to a solution of compound 6
125 MHz). Positive-ion FAB-MS spectra were acquired with a Jeol JMS- (534 mg, 1.3 mmol) in anhydrous THF (15 ml) at ꢁ78 °C under an N2
SX102 mass spectrometer (xenon atom beam; matrix, m-nitrobenzyl alco- stream. After being stirred for 30 min at the same temperature, compound 8
hol). (S)-6-Methyl octanol (7) was purchased from Tokyo Kasei Kogyo Co., (79 mg, 0.4 mmol) in THF (1.0 ml) was added and the stirring was continued
Ltd.
for another 2.5 h at ꢁ78°C. The reaction mixture was partitioned between
Preparation of 10-Methyl Dodecanal (1) from HLC-2-A HLC-2-A AcOEt and saturated aqueous NH Cl solution, and the organic layer was
4
(
1.00 mg, 0.0013 mmol) was heated with TMS-imidazole (50 ml)–pyridine washed successively with saturated aqueous NaHCO and NaCl solutions,
3
(
50 ml) for 4 h at 70 °C, and the reaction mixture was concentrated in vacuo.
dried over MgSO , and concentrated. The crude reaction mixture was chro-
4
The residue (TMS ether) was dissolved to CHCl –MeOH (1 : 1) (1 ml) and
matographed on silica gel (solvent n-hexane–AcOEt, 9 : 1 to 8 : 2) to yield 9
3
1
the mixture was treated with ozone for 30 min at ꢁ40 °C. Superfluous ozone (7.0 mg, 0.035 mmol, 8.8%) as colorless oil. H-NMR (CDCl ) d: 5.30, 5.05
was driven out with an N stream, DMS (1 mg) was added, and the mixture
3
(each 1H, m, 4-H, 5-H), 4.03, 3.62 (each 1H, m, 1-H ), 2.27, 1.98, 1.93, 1.61
2
2
was stirred for 2 h at room temperature and concentrated. The residue was
(each 2H, m, 4ꢃCH ), 1.20 (8H, m), 0.81 (6H, m, 2ꢃCH ).
2
3
chromatographed on silica gel (solvent n-hexane–AcOEt, 8 : 2) to give 1
(S)-10-Methyl Dodecanol (Synthetic 2) 5% Pd–C (20 mg) was added
1
(
0.23 mg, 0.0012 mmol, 91%) as colorless oil. H-NMR (CDCl ) d: 0.81 to MeOH (10 ml) and the mixture was stirred for 30 min under an H atmo-
3
2
(3H, d, Jꢂ6.9, CH ), 0.77 (3H, t, Jꢂ7.1, CH ).
sphere. Compound 9 (7.0 mg, 0.035 mmol) in MeOH (5 ml) was added and
3
3
1
0-Methyl Dodecanol (Natural 2) Compound 1 (0.23 mg, 0.0012 the mixture was stirred a further 15 h under an H atmosphere. The reaction
2
mmol) was dissolved in MeOH (1 ml), and NaBH (2 mg) was added. After mixture was filtered, the filtrate was concentrated, and the residue was puri-
4
stirring the mixture at room temperature for 6 h, it was concentrated in
vacuo. The crude product was purified by silica gel column chromatography
fied by silica gel column chromatography (solvent n-hexane–AcOEt, 8 : 2) to
afford synthetic 2 (5.8 mg, 0.029 mmol, 83%) as colorless oil. [a]D ꢀ53.3°
(solvent n-hexane–AcOEt, 8 : 2) to yield natural 2 (0.20 mg, 0.001 mmol,
(cꢂ0.018, 1-PrOH), ꢀ21.0° (cꢂ0.11, CHCl ). ORD (cꢂ0.0025 M, 1-PrOH)
3
ꢁ3
8
3%) as colorless oil. [a] ꢀ50.3° (cꢂ0.018, 1-PrOH). ORD (cꢂ0.0025 M,
[f]ꢃ10 (nm): ꢀ4 (300), ꢀ4 (400), ꢀ3 (500), ꢀ4 (600). IR (CHCl )
3
ꢁ1 ꢀ 1
D
ꢁ3
1
-PrOH) [f]ꢃ10 (nm): ꢀ3 (300), ꢀ3 (400), ꢀ4 (500), ꢀ4 (600). IR
cm : 3627 (OH). Positive-ion FAB-MS m/z: 223 [MꢀNa] . H-NMR
ꢁ1
ꢀ 1
(CHCl ) cm : 3734 (OH). Positive-ion FAB-MS m/z: 223 [MꢀNa] . H- (CDCl ) d: 3.62 (2H, t, Jꢂ6.6, 1-H2), 1.55 (3H, m), 1.29 (14H, m, 7ꢃCH ),
3
3
2
NMR (CDCl ) d: 3.62 (2H, t, Jꢂ6.6, 1-H ), 0.84 (6H, m, 2ꢃCH ).
1.10 (2H, m, CH ), 0.84 (3H, d, Jꢂ7.1, 10-CH ), 0.82 (3H, t, Jꢂ3.2, CH ).
2 3 3
3
2
3
1
3
4
-(tert-Butyl-dimethyl-silanyloxy)-butan-1-ol (4) 1,4-Butanediol (3)
8.8 g, 98 mmol), TBDMS–Cl (16.3 g, 108 mmol), triethylamine (16.4 ml,
18 mmol), and DMAP (1.2 g, 9.8 mmol) were dissolved to anhydrous
CH Cl (150 ml) and the mixture was stirred for 15 h at room temperature
C-NMR (CDCl ) d: 63.1 (C-1), 34.4 (C-10), 36.6, 32.8, 30.1, 29.6, 29.5,
3
(
1
29.4, 27.1, 25.7 (9ꢃCH ), 19.2 (C -CH ), 11.4 (C-12).
2 10 3
Acknowledgments We thank Mr. Y. Tanaka and Ms. Y. Soeda of the
under an N atmosphere. The reaction mixture was washed successively with Faculty of Pharmaceutical Sciences, Kyushu University, for the NMR mea-
2
2
2
saturated aqueous NH Cl and NaHCO solutions, dried over MgSO , and the
surements. This work was supported in part by Grants-in-Aid for Scientific
organic layer was evaporated. The residue was purified by silica gel column Research No. 13024260 (Priority Area A) from the Ministry of Education,
chromatography (solvent n-hexane–AcOEt, 7 : 3) to afford (14.1 g, Culture, Sports, Science and Technology, Japan, and No. 16510163 from the
4
3
4
4
1
6
2
9 mmol, 70%) as colorless oil. H-NMR (CDCl ) d: 3.66 (4H, m, Japan Society for the Promotion of Science, which are gratefully acknowl-
ꢃOCH ), 1.64 (4H, m, 2ꢃCH ), 0.90 (9H, s, t-Bu), 0.07 (6H, s, 2ꢃCH ).
3
edged.
2
2
3
(4-Bromo-butoxy)-tert-butyl-dimethyl-silane (5) To 150 ml of anhy-
drous CH Cl , compound 4 (7.0 g, 34 mmol), triphenylphosphine (10.7 g,
References and Notes
2
2
4
1 mmol), and CBr4 (17.0 g, 51 mmol) were added, and the mixture was
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mixture was washed successively with saturated aqueous NaHCO and NaCl
solutions, dried over MgSO , and the organic layer was concentrated. The
2
3
4
crude reaction mixture was chromatographed on silica gel (solvent n-
3) Higuchi R., Inagaki M., Togawa K., Miyamoto T., Komori T., Liebigs
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hexane–CHCl , 9 : 1 to 6 : 4) to yield 5 (2.1 g, 8.0 mmol, 23%) as colorless
3
1
oil. H-NMR (CDCl ) d: 3.64 (2H, t, Jꢂ6.2, OCH ), 3.45 (2H, t, Jꢂ6.8,
3
2
CH Br), 1.94 (2H, m, CH ), 1.66 (2H, m, CH ), 0.89 (9H, s, t-Bu), 0.05 (6H,
2
2
2
s, 2ꢃCH3).
5) Yamada K., Harada Y., Nagaregawa Y., Miyamoto T., Isobe R.,
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Triphenylphosphonium Salt (6) Bromide (5) (320 mg, 1.2 mmol) and
triphenylphosphine (310 mg, 1.2 mmol) were added to toluene (5 ml), and
the mixture was refluxed for 19.5 h at 150 °C under an N stream. The reac-
2
tion mixture was filtered and the collected crude product was washed with n-
hexane at 70 °C to give 6 (314 mg, 0.76 mmol, 63%) as white powder. IR
7) Yamada K., Harada Y., Miyamoto T., Isobe R., Higuchi R., Chem.
Pharm. Bull., 48, 157—159 (2000).
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ꢁ1
1
(
(
CHCl ) cm : 3365 (OH). H-NMR (CDCl ) d: 7.74 (15H, m, 3ꢃPh), 3.45
3
3
2H, m, OCH ), 1.91 (4H, m, 2ꢃCH ), 1.73 (2H, m, CH ).
2
2
2
(
S)-6-Methyl Octanal (8) A solution of (S)-6-methyl octanol (7)
9) Yamada K., Sasaki K., Harada Y., Isobe R., Higuchi R., Chem. Pharm.
Bull., 50, 1467—1470 (2002).
(
100 mg, 0.69 mmol) in anhydrous CH Cl (1 ml) was added to a suspension
2
2
of anhydrous AcONa (56.5 mg, 0.69 mmol), Celite (300 mg), and PCC
297 mg, 1.38 mmol) in anhydrous CH Cl2 (20 ml) and the mixture was
10) Kaneko M., Kisa F., Yamada K., Miyamoto T., Higuchi R., Eur. J. Org.
Chem., 2003, 1004—1008 (2003).
(
2
stirred for 1.5 h at room temperature under an N atmosphere. The reaction 11) Yamada K., Hamada A., Kisa F., Miyamoto T., Higuchi R., Chem.
2
mixture was filtered with Celite, the filtrate was concentrated, and the
Pharm. Bull., 51, 46—52 (2003).
residue was purified by silica gel column chromatography (solvent n- 12) Kisa F., Yamada K., Kaneko M., Inagaki M., Higuchi R., Chem.
hexane–AcOEt, 9 : 1) to afford 8 (98 mg, 0.69 mmol, 100%) as colorless oil.
Pharm. Bull., 53, 382—386 (2005).
13) R isomer could not be synthesized since (R)-7 was not available.
1
H-NMR (CDCl ) d: 9.77 (1H, t, Jꢂ2.0, CHO), 2.43 (2H, dt, Jꢂ1.9, 10.4,
3
2
-H ), 1.63 (1H, m, 6-H), 1.59 (2H, m, CH ), 1.31 (6H, m, 3ꢃCH ), 0.87
2
2
2