Convenient synthesis of methyl L-Glycero-D-Manno-heptopyranoside

Article abstract of DOI:10.1081/CAR-100103956

Methyl L-glycero-D-manno-heptoside was prepared from a butane diacetal (BDA) derivative of methyl mannoside. Benzylation of the 3,4-BDA mannoside gave the 2-benzyl ether as a major product, which eliminated blocking and deblocking of the primary hydroxy g

Full text of DOI:10.1081/CAR-100103956

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CONVENIENT SYNTHESIS OF METHYL L-GLYCERO-D-
MANNO-HEPTOPYRANOSIDE
a
a
b
b
Ryohei Yamasaki , Akihiko Takajyo , Hiroyuki Kubo , Takeaki Matsui , Kazuyuki Ishii
a
a
&
Masashi Yoshida
a
Department of Biochemistry & Biotechnology , Tottori University , Tottori, 680-8553,
Japan
b
Central Research Laboratories , Maruho Co. Ltd. , Kyoto, 600-8815, Japan
Published online: 16 Aug 2006.
To cite this article: Ryohei Yamasaki , Akihiko Takajyo , Hiroyuki Kubo , Takeaki Matsui , Kazuyuki Ishii & Masashi Yoshida
(2001) CONVENIENT SYNTHESIS OF METHYL L-GLYCERO-D-MANNO-HEPTOPYRANOSIDE, Journal of Carbohydrate Chemistry,
20:2, 171-180, DOI: 10.1081/CAR-100103956
To link to this article: http://dx.doi.org/10.1081/CAR-100103956
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J. CARBOHYDRATE CHEMISTRY, 20(2), 171–180 (2001)
CONVENIENT SYNTHESIS OF METHYL
L-GLYCERO-D-MANNO-HEPTOPYRANOSIDE
1
,
2
Ryohei Yamasaki, * Akihiko Takajyo, Hiroyuki Kubo,
2
1
1
Takeaki Matsui, Kazuyuki Ishii, and Masashi Yoshida
1
Department of Biochemistry & Biotechnology, Tottori University,
Tottori 680-8553, Japan
2
Central Research Laboratories, Maruho Co. Ltd.,
Kyoto 600-8815, Japan
ABSTRACT
Methyl L-glycero-D-manno-heptoside was prepared from a butane diacetal
BDA) derivative of methyl mannoside. Benzylation of the 3,4-BDA manno-
(
side gave the 2-benzyl ether as a major product, which eliminated blocking and
deblocking of the primary hydroxy group for the preparation of a mannoside
bearing a free 6-OH. Swern oxidation of the 2-O-Bn-3,4-BDA mannoside
followed by a Grignard reaction and osmylation gave L-glycero-D-manno-3,
4-BDA heptoside in 79 % yield. We found that the 3,4-BDA mannoside, its 2-
O-Bn mannoside, and the 3,4-BDA heptoside could be prepared in a
semi-preparative scale (20ꢀ50 g). The 3,4-BDA mannoside is a convenient
precursor for preparation of L-glycero-D-manno-heptose.
INTRODUCTION
L-Glycero-D-manno-heptose is a common carbohydrate component of
1–3
lipooligo- and lipopolysaccharides produced by Gram-negative bacteria. The
heptose is expressed as a di- or trisaccharide in the inner cores of those glycolipids.
This carbohydrate has been generally synthesized by using methyl or benzyl man-
4–8
noside as a starting material. Swern oxidation of the 6-OH of suitably protected
mannosides and subsequent Grignard reaction provides the manno-heptosides.
*Corresponding author.
1
71
Copyright © 2001 by Marcel Dekker, Inc.
www.dekker.com

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YAMASAKI ET AL.
This work describes synthesis of methyl L-glycero-D-manno-heptoside from
methyl ꢀ-D-mannoside. Conversion of the mannoside to its 3,4-butane diacetal
9
(
BDA) mannoside and subsequent benzylation provided a precursor bearing a free
-OH. Sequential oxidation and elongation of this compound provided a 3,4-BDA
mannoheptoside.
6
RESULTS AND DISCUSSION
Methyl 3,4-O-(2ꢁ,3ꢁ-dimethoxybutane-2ꢁ,3ꢁ-diyl)-ꢀ-D-mannopyranoside (2)
was prepared in 98% yield by treating methyl ꢀ-D-mannoside (1) with 2,3-butane-
dione (1.1 M equiv) and trimethyl orthoformate (3 M equiv) in methanol. Instead
9
of BF3/Et2O, (ꢂ)-camphor-10-sulfonic acid (0.1 M equiv) was used as a catalyst
for this acetalation. We also found that this reaction could be carried out on a semi-
preparative scale. Treatment of compound 1 (50 g, 257 mmol) with the same equiv-
alents of the reagents as described above gave compound 2 in 94% yield.
Treatment of compound 2 with t-butyldiphenylsilyl (TBDPS) chloride in
DMF for 20 h at room temperature followed by flash chromatography gave the 6-
O-TBDPS ether 3 in 69 % yield. Benzylation of compound 3 with benzyl bromide
and NaH in DMF gave the benzyl ether 4 in 94 % yield, and this compound was
treated with tetrabutylammonium fluoride in THF to give crystalline 5 in 93 % yield.
Alternatively, compound 5 was prepared directly from compound 2. Similar
1
0
to the use of a cyclohexane 1,2-diacetal (CDA) derivative of methyl mannoside,
benzylation of compound 2 (20 g) with BnBr (1M equiv) and NaH (2M equiv) in
DMF for 2 h at 0°C gave the 2-O-benzyl ether 5 in 68 % yield after purification by
flash chromatography. In addition to the 2,6-di-O-benzyl ether derivative (7 %),
the unreacted compound 2 (17 %) was recovered. Preferential benzylation of the
OH-2 was reproducible in a larger scale of the reaction. Treatment of 60 g of com-
pound 2 with BnBr and NaH in DMF for 16 h at room temperature and subsequent
purification by flash chromatography gave compound 5 in 62 % yield. Thus, iso-
lation of the 2-O-benzyl ether 5 as a major product led to elimination of two steps,
blocking and deblocking of the 6-OH of the mannoside, for the preparation of
methy manno-heptoside.
Although the pronounced reactivity of the 2-OH over the primary group has
been reported in benzylation of methyl 3,4-O-isopropylidene-ꢀ-D-galactopyra-
11
10
noside and the CDA derivative of methyl ꢀ-D-mannoside as described above ,
the reversed reactivity of the two hydroxyl groups has not yet been clarified. We
were not be able to isolate a 6-O-benzyl ether of the BDA compound 2 from the re-
action mixture, which indicated that the protecting group at O-3 and O-4 such as
BDA and CDA of methyl ꢀ-D-mannoside favors the formation of the 2-oxyanion
over the 6-oxyanion leading to preferential benzylation of the OH-2.
Swern oxidation of compound 5 (20 g) and subsequent treatment of the re-
sulting aldehyde with vinylmagnesium bromide gave methyl L-glycero-D-manno-
oct-7-eno-pyranoside 6 in 88 % yield after flash chromatography. We used similar
6
reaction conditions to those described by Dasser et al and found that the vinyla-

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METHYL L-GLYCERO-D-MANNO-HEPTOPYRANOSIDE
173
tion of the oxidized product of the BDA compound is also highly stereoselective
and yields the L-product dominantly. Although we did not characterize minor prod-
ucts of the reaction, the formation of the D-isomer was minimal based upon the iso-
lated yield of 6 from the one-pot oxidation/elongation reaction. This reaction was
repeated several times, and we found that this L-streoselectivity was reproducible.
The vinyl function of compound 6 was confirmed by NMR spectroscopy (Table 1);
H-7, H-8a and H-8b were detected at 5.97, 5.18 and 5.35 ppm, respectively.
Compound 6 was quantitatively converted into the 6-acetate 7 by acetylation
with pyridine and acetic anhydride in the presence of catalytic amounts of dimethy-
laminopyridine. Oxidative cleavage of the acetate 7 with OsO4/NaIO4 and
subsequent reduction of the resulting aldehyde with NaBH4 gave the 3,4-diacetal hep-
tose derivative 8 (92 %) whose structure was confirmed by NMR analyses (Table 1).
The O-benzyl group of 8 was removed by hydrogenolysis to give 9 which was
treated with TFA/H O (9/1, v/v) to yield methyl L-glycero-D-manno-heptopyra-
2
noside (10). The L-stereochemistry at C-6 of this compound was determined by
1
2
HPAEC analysis. TFA hydrolysis of compound 10 gave L-glycero-D-manno-
heptose. Since L-glycero-D-manno-heptose is eluted much earlier than D-glycero-
D-manno-heptose under the condition used, we are able to determine the C-6 stere-
ochemistry of the D-manno-heptose. The identification of compound 10 confirmed
that compounds 6–9 have the L-stereochemistry at C-6. Although methyl L-glyc-
5
;13
ero-D-manno-heptoside has been cited in a couple of publications,
only partial
1
13
1
13
H NMR data are available. Therefore, we included complete H and C NMR
data as a reference in Table 1. Thus, methyl L-glycero-D-manno-heptoside 10 was
prepared in 8 steps as a total yield of 53 % from methyl mannoside 1.
As described earlier, methyl, benzyl, and allyl mannosides have been con-
4–8
8
verted to their corresponding heptoside. Recently, van Delft et al reported that
silicon-based hydroxymethylation of methyl 2,3,4-tri-O-benzyl-manno-hexodi-
aldo-1,5-pyranoside gave 2,3,4-tri-O-benzyl heptoside in 66 % yield. Although the
current procedure requires extra steps (Scheme 1), acetylation of the 6-OH of the
elongated compound before oxidative cleavage with OsO4/NaIO4 and subsequent
reduction, the yield (79 %) in converting a suitably protected mannopyranoside to
its heptoside derivative is better than that reported in the hydroxymethylation pro-
cedure described above.
The use of the 3,4-diacetal mannoside 2 for the preparation of a heptoside has
9
several advantages. First, the BDA derivative can be prepared quantitatively in a
semi-preparative scale. Second, protection of primary hydroxyl group and subse-
quent deprotection is unnecessary since benzylation of the 3,4-diacetal product
gives the 2-O-benzyl ether as a major product. As described earlier, over 50 g of 6
can be prepared in a single experiment. Third, Swern oxidation and subsequent
treatment with vinylmagnesium bromide of compound 5 gives an elongated prod-
uct of L-stereochemistry dominantly. Fourth, in addition to 2 and 5, compounds
6
–8 are also crystalline, which is convenient for preparation of the heptoside.
We converted the 3,4-BDA mannoside 5 into its mannoheptoside 8 in 79 %.
The BDA derivative of mannoside is a useful starting material to prepare L-glyc-
ero-D-manno-heptose.

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YAMASAKI ET AL.

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METHYL L-GLYCERO-D-MANNO-HEPTOPYRANOSIDE
175
Scheme 1.
EXPERIMENTAL
General Methods. Optical rotations were measured with a HORIBA SEPA-
200 polarimeter. Melting points were measured with a YANAGIMOTO micro melt-
ing point apparatus and are uncorrected. Elemental analyses were carried out by using
a Perkin-Elmer 2400 Series II CHNS/O Analyzer. NMR spectra [270 MHz (JEOL
GX) and 500 MHz (JEOL JNM-ECP 500)] were recorded in CDCl3 or D2O. TMS
1
was used as an internal standard for CDCl3, and 1 % CH3CN (ꢇ = 1.96 for H; ꢇ =
1
3
1
19.52, 1.30 for C) was used for D2O. 2D NMR spectra (500 MHz, JEOL JNM-
14;15
ECP 500) were obtained in a similar manner as described
; DQF-COSY (sweep
width for t1 and t2 ꢃ 2084 Hz, the 2K ꢆ 512 data points were processed to give the
final 1K ꢆ 256 points); HMQC (sweep width for t1 ꢃ 2084 Hz, sweep width for t2
ꢃ 16835 Hz, the 1K ꢆ 256 data points were processed to give the final 1K ꢆ 256
points). The data were processed by using an Alice2 program (JEOL) on an Impact
300 computer. IR spectra were recorded with a JASCO FT/IR-5300A spectrometer.
FABMS spectra were obtained with a JEOL JMS-600H mass spectrometer using
glycerol as a matrix (accelerating voltage of the primary ion, 3 kV; collision gas,
xenon; collision energy, 6 keV; collision gas pressure, 0.5 Pa; the data were processed
with a Hewlett Packard B132L computer). Merck Silica gel 60 (0.040–0.063 mm) and
Merck Silica gel 60 (0.063–0.20 mm) was used for flash and open-column chro-
matography, respectively. Silica gel 60 F254 (Merck) was used for thin-layer chro-
matography, and compounds were detected under UV light or by spraying 10 % conc
sulfuric acid in methanol and then by heating the plates at 120°C for 5 min. We ana-
lyzed L- and D-glycero-D-mannoheptoses by high-performance anion exchange chro-
12
matography as reported previously.

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YAMASAKI ET AL.
Methyl ꢀ-D-mannoside was purchased from Sigma Chemical Co. (2ꢁS,3ꢁS)-
Methyl 3,4-O-(2ꢁ,3ꢁ-dimethoxybutane-2ꢁ,3ꢁ-diyl)-ꢀ-D-mannopyranoside (2) was
prepared in 98 % yield by treating methyl ꢀ-D-mannopyranoside (1) (1.2 g) with 1.1
9
M equiv of 2,3-butanedione according to the literature procedure except for that
23
D
(
ꢂ)-camphor-10-sulfonic acid was used as a catalyst. [ꢀ] ꢈ213° (c 1.0, CHCl3),
23
mp 140–141°C (ethyl acetate) {[ꢀ]D ꢈ252° (c 1.05, CHCl3), mp 140°C}. This ac-
etalation was also carried out in a semi-preparative scale as follows. A solution of
compound 1 (50 g, 257 mmol), the dione (24.4 g, 283 mmol), trimethyl orthofor-
mate (81.9 g, 772 mmol) and the sulfonic acid (6 g, 28 mmol) in methanol (500 mL)
was refluxed for 24 h. After cooling, the solution was treated with triethyamine (43
mL) and then concentrated to a dark syrup. Purification of the syrup by chromatog-
raphy (ethyl acetate/hexane 1/1 to 3/1 v/v) gave compound 2 (75g, 94%).
(2ꢁS,3ꢁS)-Methyl 6-O-Tert-butyldiphenylsilyl-3,4-O-(2ꢁ,3ꢁ-dimethoxybu-
tane-2ꢁ,3ꢁ-diyl)-ꢀ-D-mannopyranoside (3). Compound 2 (1.79 g, 5.8 mmol)
was treated with t-butyldiphenylsilyl chloride (1.91 g, 7.0 mmol) in dry DMF (12
mL) in the presence of imidazole (987 mg, 15 mmol) for 20 h at room temperature.
After terminating the reaction by adding water (10 mL), the product was extracted
with ethyl acetate (50 mL ꢆ 3). The organic extracts were concentrated to give a
residue which was purified by flash chromatography (hexane/ethyl acetate 3/1 v/v)
1
to give 3 as a syrup (2.19 g, 69 %). H NMR (270 MHz, CDCl3) ꢇ: 7.73–7.71 (m,
4
H, Ph), 7.41–7.35 (m, 6H, Ph), 4.74 (d, 1H, J1,2 ꢃ 1 Hz, H-1), 4.06–3.89 (5H, H-
2
, H-3, H-4, H-6a, H-6b), 3.82 (m, 1H, J4,5 ꢃ 10 Hz, H-5), 3.36, 3.27, 3.14 (s, 3H
each, OMe), 2.31 (d, 1H, J ꢃ 3.0, 2-OH), 1.31 ,1.25 (s, 3H each, Me), 1.05 (s, 9H,
24
t-Bu). [ꢀ]D ꢈ107° (c 0.5, CHCl3).
Anal. Calcd for C29H42O8Si: C, 63.71; H, 7.74. Found: C, 63.42; H, 7.99.
(
2ꢁS,3ꢁS)-Methyl 2-O-Benzyl-6-O-tert-butyldiphenylsilyl-3,4-O-(2ꢁ,3ꢁ-
dimethoxybutane-2ꢁ,3ꢁ-diyl)-ꢀ-D-mannopyranoside (4). Compound 3 (1.68
g, 3.1 mmol) was benzylated with benzyl bromide (0.44 mL, 3.7 mmol) and NaH
(60 % in paraffin liquid, 245 mg, 6.1 mmol) in dry DMF in the presence of molec-
ular sieves 4Å at 0°C for 2 h. After filtering through Celite, the filtrate was washed
with brine, dried over MgSO4, and concentrated to give a pale yellow syrup. Flash
chromatography (hexane/ethyl acetate 20/1 to 3/1 v/v) of the syrup gave compound
1
4
(1.84 g, 94 %). H NMR (270 MHz, CDCl3) ꢇ: 7.72–7.70 (m, 4H, Ph), 7.44–7.25
(
m, 11H, Ph), 4.95 (d, 1H, J ꢃ 12.2 Hz, PhCH), 4.69 (d, 1H, J1,2 ꢃ 1.1 Hz, H-1),
.65 (d, 1H, J ꢃ 12.2 Hz, PhCH), 4.17 (t, 1H, J4,5 ꢃ 10 Hz, H-4), 4.06 (dd, 1H,
J3,4 ꢃ 10 Hz, H-3), 3.91, 3.90 (s, 1H each, H-6a, H-6b), 3.78 (m, 1H, H-5, ), 3.68
dd, 1H, J2,3 ꢃ 3.0 Hz, H-2), 3.31, 3.27, 3.15 (s, 3H each, OMe), 1.32 ,1.26 (s, 3H
4
(
2
2
each, Me), 1.02 (s, 9H, t-Bu). [ꢀ]D ꢈ28° (c 0.5, CHCl3).
Anal. Calcd for C36H48O8Si: C, 67.89; H, 7.60. Found: C, 67.63; H, 7.85.
(
2ꢁS,3ꢁS)-Methyl 2-O-Benzyl-3,4-O-(2ꢁ,3ꢁ-dimethoxybutane-2ꢁ,3ꢁ-diyl)-
-D-mannopyranoside (5). Compound 4 (1.56 g, 2.5 mmol) was treated with
tetrabutyl ammonium fluoride (1M in THF, 4.9 mL, 4.9 mmol) in dry THF (5 mL)
ꢀ

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METHYL L-GLYCERO-D-MANNO-HEPTOPYRANOSIDE
177
for 24 h. The reaction mixture was diluted with H2O (50 mL), and then extracted
with ethyl acetate (30 mL ꢆ 2). The combined extracts were washed with brine,
dried (MgSO4), and concentrated to a syrup. Purification of the syrup by flash
chromatography (hexane/ethyl acetate 3/1 to 1/1 v/v) gave compound 5 as a solid
1
(
904 mg, 93 %). H NMR (270 MHz, CDCl3) ꢇ: 7.44–7.29 (m, 5H, Ph), 4.95 (d,
1H, J ꢃ 11.9 Hz, PhCH), 4.67 (d, 1H, J1,2 ꢃ 1.1 Hz, H-1), 4.65 (d, 1H, J ꢃ 11.9
Hz, PhCH), 4.19 (dd, 1H, J4,5 ꢃ 9.5 Hz, H-4), 4.06 (dd, 1H, J3,4 ꢃ 9.5 Hz, H-3),
3
3
.83–3.73 (m, 3H, H-5, H-6a, H-6b), 3.69 (dd, 1H, J2,3 ꢃ 3.0 Hz, H-2), 3.31, 3.28,
.27 (s, 3H each, OMe), 1.33 ,1.30 (s, 3H each, Me). mp 132–133°C (recrystallized
2
2
from hexane-ethyl acetate), [ꢀ]D ꢈ227° (c 0.5, CHCl3).
Anal. Calcd for C20H30O8: C, 60.29; H, 7.59. Found: C, 60.12; H, 7.54.
Compound 5 was also prepared by directly benzylating 2 (12.0 g, 39 mmol)
with benzyl bromide (4.63 mL, 39 mmol) and NaH (3.12 g, 78 mmol) at 0°C for 2
h. The reaction was quenched with water (100 mL), and the mixture was extracted
with ethyl acetate (100 mL ꢆ 2). The extracts were washed with brine (100 mL ꢆ
2), dried (MgSO4), and concentrated to a syrup. Flash chromatography (ethyl ac-
etate/hexane 2/1 v/v) of the syrup gave compound 5 as a solid (11.2 g, 72 %). In
addition to 5, unreacted compound 2 (1.10 g, 17 %) and (2ꢁS,3ꢁS)-methyl 3,4-O-
(
2ꢁ,3ꢁ-dimethoxybutane-2ꢁ,3ꢁ-diyl)-2,6-di-O-benzyl-ꢀ-D-mannopyranoside [(1.31
23
22
9
g, 7 %), [ꢀ]D ꢈ141° (c 1.0, CHCl3) {[ꢀ]D ꢈ146° (c 1.0, CHCl3)} ] were ob-
tained. This benzylation was also carried out on a larger scale. Compound 2 (60.0
g, 194 mmol) was treated with NaH (7.3 g, 185 mmol) and BnBr (21.5 mL, 181
mmol) in DMF (540 mL) for 16 h at room temperature. Similar work-up as de-
scribed above and purification by flash chromatography (ethyl acetate/hexane 2/1
to 1/1 v/v) gave compound 5 (48.3 g, 63%).
(
2ꢁS,3ꢁS)-Methyl 2-O-Benzyl-7,8-dideoxy-3,4-O-(2ꢁ,3ꢁ-dimethoxybu-
tane-2ꢁ,3ꢁ-diyl)-ꢀ-D-manno-oct-7-enopyranoside (6). To a chilled solution (to
ꢉ70°C) of dry THF (150 mL), a mixture of oxalyl chloride (10.7 mL, 125 mmol)
and DMSO (17.8 mL, 251 mmol) in dry THF (20 mL) was added, and the mixture
was stirred for 15 min. Compound 5 (20.0 g, 50 mmol) in dry THF (100 mL) was
added dropwise (ꢀ15 min). The reaction mixture was stirred for 1 h at ꢉ60°C and
then for 1 h at ꢉ40°C. After adding triethylamine (69.7 mL, 502 mmol) and stir-
ring for 1 h at room temperature, the mixture was cooled down to ꢉ60°C. Vinyl
magnesium bromide (1M in THF, 251 mmol) was added dropwise (30 min), and
the mixture was stirred for 2 h at ꢉ60°C. The reaction was quenched with the ad-
dition of ethanol (20 mL), and after adding saturated aqueous NH4Cl (50 mL), the
whole reaction mixture was warmed to room temperature. The mixture was ex-
tracted with ethyl acetate (50 mL ꢆ 3), and the combined extracts were sequen-
tially washed with 5 % sodium hypochloride in water (100 mL ꢆ 4) and brine (100
mL ꢆ 2). After drying (MgSO4), the organic solution was concentrated to a syrup
which was purified by flash chromatography (hexane/ethyl acetate 3/2 v/v) to give
compound 6 as a solid (18.8 g, 88 %). mp 122–123°C (recrystallized from hexane-
24
ethyl acetate), [ꢀ]D ꢈ181° (c 0.5, CHCl3).
Anal. Calcd for C22H32O8: C, 62.25; H, 7.60. Found: C, 62.23; H, 7.63.

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YAMASAKI ET AL.
(
2ꢁS,3ꢁS)-Methyl
6-O-Acetyl-2-O-benzyl-7,8-dideoxy-3,4-O-(2ꢁ,3ꢁ-
dimethoxybutane-2ꢁ,3ꢁ-diyl)-ꢀ-D-manno-oct-7-enopyranoside (7). Com-
pound 6 (8.55 g, 20 mmol) was acetylated with pyridine/acetic anhydride in the
presence of catalytic amounts of dimethylaminopyridine. Usual work up and flash
chromatography (hexane/ethyl acetate 2/1 v/v) gave compound 7 (9.07 g, 97 %).
1
H NMR (270 MHz, CDCl3) ꢇ: 7.45–7.26 (m, 5H, Ph), 5.94 (ddd, 1H, J7,8a
ꢃ 17.3 Hz, J7,8b ꢃ 10.8 Hz, H-7), 5.59 (m, 1H, J6,7 ꢃ 6.8 Hz, J6,8a ꢃ 1.6 Hz,
J6,8b ꢃ 1.6 Hz, H-6), 5.35 (ddd, 1H, J8a,8b ꢃ 1.6 Hz, H-8a), 5.25 (ddd, 1H, H-
8
1
b), 4.91 (d, 1H, J ꢃ 12.2 Hz, PhCH), 4.76 (d, 1H, J1,2 ꢃ 1.1 Hz, H-1), 4.69 (d,
H, J ꢃ 12.2 Hz, PhCH) , 4.22 (dd, 1H, J4,5 ꢃ 10.0 Hz, H-4), 4.05 (dd, 1H, J3,4
ꢃ 10.0 Hz, H-3), 3.77 (dd, 1H, J5,6 ꢃ 1.9 Hz, H-5), 3.68 (dd, 1H, J2,3 ꢃ 3.0 Hz,
H-2), 3.27, 3.26, 3.18 (s, 3H each, OMe), 2.10 (s, 3H, CH3CO), 1.33 ,1.29 (s, 3H
2
4
each, Me). mp 125°C (recrystallized from EtOH), [ꢀ]D ꢈ157° (c 0.5, CHCl3).
Anal. Calcd for C24H34O9: C, 61.79; H, 7.35. Found: C, 61.83; H, 7.37.
(
2ꢁS,3ꢁS)-Methyl 2-O-Benzyl-3,4-O-(2ꢁ,3ꢁ-dimethoxybutane-2ꢁ,3ꢁ-diyl)-
L-glycero-ꢀ-D-manno-heptopyranoside (8). Compound 7 (9.07 g, 19 mmol) in
ethyl ether/water (240 mL, 1/1 v/v) was cooled in an ice bath and treated with
sodium metaperiodate (20.8 g, 97 mmol) and 1 % aqueous OsO4 (24 mL). After stir-
ring the mixture for 24 h at room temperature, it was extracted with ethyl ether (100
mL ꢆ 2) and the combined extracts were washed with water (100 mL ꢆ 2). The
combined extracts were concentrated to a syrup which was then treated with NaBH4
(2.94 g, 78 mmol) in methanol/water (360 mL, 2/1 v/v) for 15 h at room tempera-
ture. The mixture was extracted with CH2Cl2 (100 mL ꢆ 2), and the combined ex-
tracts were washed with H2O (50 mL ꢆ 4). After drying (MgSO4), the combined
extracts were concentrated to a residue which was purified by flash chromatogra-
1
phy (ethyl acetate/hexane 2/1 v/v) to give compound 8 (7.66 g, 92 %). H NMR (270
MHz, CDCl3) ꢇ: 7.44–7.26 (m, 5H, Ph), 4.97 (d, 1H, J ꢃ 11.9 Hz, PhCH), 4.68 (d,
1
1
6
1
H, J1,2 ꢃ 1.1 Hz, H-1), 4.64 (d, 1H, J ꢃ 11.9 Hz, PhCH) , 4.34 (dd, 1H, J4,5 ꢃ
0.3 Hz, H-4), 4.05 (dd, 1H, J2,3 ꢃ 2.7 Hz, J3,4 ꢃ 10.3 Hz, H-3), 3.96 (m, 1H, H-
), 3.81–3.69 (m, 4H, H-2, H-5, H-7), 3.33, 3.29, 3.27 (s, 3H each, OMe), 2.53 (br,
H, OH), 2.28 (br, 1H, OH), 1.34 ,1.30 (s, 3H each, Me). mp 142–143°C (recrys-
2
3
tallized from hexane-ethyl acetate), [ꢀ]D ꢈ172° (c 0.5, CHCl3).
Anal. Calcd for C21H32O9: C, 58.87; H, 7.53. Found: C, 58.60; H, 7.46.
(
2ꢁS,3ꢁS)-Methyl 3,4-O-(2ꢁ,3ꢁ-Dimethoxybutane-2ꢁ,3ꢁ-diyl)-L-glycero-ꢀ-
D-manno-heptopyranoside (9). Compound 8 (7.66 g, 18 mmol) was hydro-
genated with Pd-C (ꢀ5 g) in EtOH (120 mL) for 20 h. After filtration, the reaction
mixture was concentrated to a syrup which was purified by chromatography
2
4
(
1
CH2Cl2/methanol 10/1 v/v) to give compound 9 (5.95 g, 98 %). [ꢀ] ꢈ209° (c
D
ꢈ
.0, CHCl3), FABMS: m/z [Found (MNa ) 361.1474. C8H17O7 requires MNa,
3
61.1429].
Methyl L-glycero-ꢀ-D-manno-heptopyranoside (10). A solution of com-
pound 9 (200 mg, 0.59 mmol) in TFA/H2O (5 mL, 9/1 v/v) was heated for 1 h.

ORDER
REPRINTS
METHYL L-GLYCERO-D-MANNO-HEPTOPYRANOSIDE
179
After cooling, the mixture was concentrated to a residue. Purification by flash
chromatography (ethyl acetate/methanol 9/1 to 1/9 v/v) to give a hygroscopic solid
2
4
ꢈ
(
2
130 mg, 98 %). [ꢀ]D ꢈ70° (c 1.0, methanol), FABMS: m/z [Found (MH )
25.0975. C8H17O7 requires MH, 225.0723].
ACKNOWLEDGMENTS
This work was supported by Grant-in-Aid (10306022) for Scientific Re-
search of the Ministry of Education of Japan. We thank Masayuki Hosoe for
FABMS analyses.
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Received September 7, 2000
Accepted November 25, 2000

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