Synthesis and glycosidic coupling reaction of substituted 2,6-dioxabicyco[3.1.1] heptanes: 1,3-anhydro-2-azido-4,6-di-O-benzyl-2-deoxy-β-D-mannopyranose

Article abstract of DOI:10.1016/S0008-6215(98)00219-5

The title 1,3-anhydro sugar was synthesized from methyl α-D-glucopyranoside. The key intermediate for the synthesis was 3-O-acetyl-2-azido-4,6-di-O-benzyl-2-deoxy-α-D-mannopyranosyl chloride (11) which was transformed into the target compound by ring closure with potassium tert-butoxide. Copyright (C) 1998 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(98)00219-5

Carbohydrate Research 312 (1998) 77±83
Note
Synthesis and glycosidic coupling reaction of
substituted 2,6-dioxabicyco[3.1.1] heptanes:
1,3-anhydro-2-azido-4,6-di-O-benzyl-2-deoxy-ꢀ-
d-mannopyranose
Guangbin Yang, Fanzuo Kong *
Research Center for Eco-Environmental Sciences, Academia Sinica, PO Box 2871, Beijing 100085,
People's Republic of China
Received 8 September 1997; accepted 6 June 1998
Abstract
The title 1,3-anhydro sugar was synthesized from methyl ꢁ-d-glucopyranoside. The key inter-
mediate for the synthesis was 3-O-acetyl-2-azido-4,6-di-O-benzyl-2-deoxy-ꢁ-d-mannopyranosyl
chloride (11) which was transformed into the target compound by ring closure with potassium
tert-butoxide. # 1998 Elsevier Science Ltd. All rights reserved
Keywords: 2,6-Dioxabicyclo[3.1.1]heptanes; Synthesis; Coupling reaction
2-Amino-2-deoxy-d-mannose occurs in important
natural materials. For example, the polysaccharide
linked to the peptidoglycan of the cell wall of
Micrococcus lysodeikticus contains residues of both
d-glucose and 2-amino-2-deoxy-mannuronic acid
[1], the O-antigenic polysaccharide from a strain of
Aeromonas caviae, isolated from the stools of a
patient with diarrhea, is composed of a penta-
saccharide unit containing N-acetyl-mannosamine
[2a], and the O-speci®c polysaccharide chain of
lipopolysaccharide of B. plantarii is composed of
N-acetyl-mannosamine and rhamnose [2b]. As a
part of our program on the synthesis of the 2,6-
dioxabicyclo[3.1.1]heptane ring system occurring in
thromboxane A2 (TXA2) [3,4], a compound of
substantial importance in biological chemistry, we
have investigated 1,3-anhydro-ꢀ-l-rhamno- [5], -ꢀ-
d-galacto- [6], -6-deoxy-ꢀ-d-gluco- [7], -6-azido-6-
deoxy-ꢀ-d-manno- [8], -ꢀ-d-fuco- [9], -ꢀ-d-talo-
[10], and -ꢁ-l-arabinopyranose [11] benzyl ethers.
The synthesis of 1,3-anhydro-ꢀ-d-gluco- [12,13]
and -ꢀ-d-mannopyranose derivatives [14,15] had
been reported earlier by Schuerch's group. We now
report the synthesis of 1,3-anhydro-2-azido-4,6-
di-O-benzyl-2-deoxy-ꢀ-d-mannopyranose whose
stereoregular polymerization and subsequent
deprotection could a€ord ꢁ-(1!3) linked 2-amino-
2-deoxy-d-mannopyranan and whose glycosidic
coupling reaction followed by deblocking can
a€ord oligosaccharides containing mannosamine
units.
* Corresponding author. Fax: +86-10-629-23563.
0008-6215/98/$Ðsee front matter # 1998 Elsevier Science Ltd. All rights reserved
PII S0008-6215(98)00219-5

78
G. Yang, F. Kong/Carbohydrate Research 312 (1998) 77±83
anhydride±acetic acid using sulfuric acid as the
1. Results and discussion
catalyst (Ac2O/AcOH/H2SO4=50/20/0.1) furn-
ished 1,3-di-O-acetyl-2-azido-4,6-di-O-benzyl-2-
deoxy-ꢁ-d-mannopyranose (10) and methyl 3,6-di-
O-acetyl-2-azido-4-O-benzyl-2-deoxy-ꢁ-d-manno-
pyranoside (15) in a ratio of 1:1 as determined by
1H NMR. TLC indicated that compounds 10 and
15 had the same Rf value, and could not be sepa-
rated by HPLC, but further reaction products were
easily separated. Since it was dicult to monitor
the acetolysis by TLC and, to separate the pro-
ducts by column chromatography, and since the
yields of acetolysis were variable, another method
was used for the preparation of the 1,3-diacetate.
Thus conversion of 8 to 9 by aqueous hydrolysis
was carried out; hydrolysis in 70% acetic acid in
the presence of p-toluenesuꢀlfonic acid or cam-
phorsulfonic acid [20] at 100 C for 16 h gave 3-O-
acetyl-2-azido-4,6-di-O-benzyl-2-deoxy-d-manno-
pyranose (9) in an acceptable yield (65%), while
hydrolysis in 70±80% acetic acid in the presence of
hydrochloric acid produced a complex, unsepar-
able mixture. Acetylation of 9 by standard
methods a€orded 10 as a mixture of ꢁ and ꢀ
anomers in a ratio of 5/1. Chlorination of 10 with
hydrogen chloride in diethyl ether furnished the
key intermediate, 3-O-acetyl-2-azido-4,6-di-O-ben-
zyl-2-deoxy-ꢁ-d-mannopyranosyl chloride (11) in
satisfactory yield (84%). Ring closure of 11 pro-
ceeded smoothly with potassium tert-butoxide in
oxolane, a€ording 1,3-anhydro-2-azido-4,6-di-O-
benzyl-2-deoxy-ꢀ-d-mannopyranose (12) in good
yield (82.5%). The 1,3-anhydro sugar was identi-
Methyl 4,6-di-O-benzyl-ꢁ-d-glucopyranoside (1)
[16], prepared from methyl 2,3-di-O-allyl-4,6-di-O-
benzyl-ꢁ-d-glucopyranoside [17] via deallylation,
was selectively 2-O-allylated by either the phase
transfer method or via a dibutylstannylene com-
plex to give methyl 2-O-allyl-4,6-di-O-benzyl-ꢁ-d-
glucopyranoside 2. The dibutylstannylene method
gave better selectivity and yield (72%), while the
phase transfer method is more suitable for large
scale preparations. Benzoylation of 2 with benzoyl
chloride in pyridine gave ester 3, which was deal-
lylated with palladium chloride (1/20 w/w) [18] in
methanol at room temperature to give methyl 3-O-
benzoyl-4,6-di-O-benzyl-a-d-glucopyranoside (4)
crystals in good yield (75%). Isomerization of the
allyl group of 3 with tris(triphenylphosphine)-
rhodium(I) chloride followed by acid treatment
was also used successfully for deallylation (80%
yield). Tri¯ation of compound 4 with tri¯ic anhꢀ y-
dride in dichloromethane and pyridine at 10 C,
then at room temperature for 4 h furnished methyl
3-O-benzoyl-4,6-di-O-benzyl-2-O-tri¯uoromethane-
sulfonyl-ꢁ-d-glucopyranoside (5). Treatment of 5
ꢀ
with sodium azide in DMF at 80 C for 2±3 h
gave methyl 2-azido-3-O-benzoyl-4,6-di-O-benzyl-
2-deoxy-ꢁ-d-mannopyranoside (6).
In the conversion of 5 to 6, some decomposition
occurred when the reaction time was too long, and
the addition of ammonium chloride reduced the
decomposition [19]. Debenzoylation of 6 with a
catalytic amount of sodium methoxide in methanol
to give 7, followed by acetylation with acetic
anhydride in pyridine, gave methyl 3-O-acetyl-2-
azido-4,6-di-O-benzyl-2-deoxy-ꢁ-d-mannopyrano-
side (8) quantitatively. Acetolysis of 8 with acetic
1
®ed by elemental analysis and from its H NMR
spectrum, which showed a characteristic doublet at
4
5.39 for H-1 with J1,3=3.6 Hz, a triplet at ꢂ 4.49
for H-3 with J1,3=J3,4=3.6 Hz and a singlet [5]

G. Yang, F. Kong/Carbohydrate Research 312 (1998) 77±83
79
[15] at ꢂ 4.21 for H-2. The anhydrosugar 12 was
quite reactive; ring-opening with methanol in the
presence of ZnCl2 a€orded the ꢁ-linked methyl
mannopyranoside 7 as the sole product, while its
coupling reaction with 1,2:3,4-di-O-isopropylidene-
ꢁ-d-galactopyranose in dry oxolane with ZnCl2 as
the promoter gave ꢁ-linked disaccharide 13 in good
yield (76%). Acetylation of 13 with acetic anhydride
in pyridine gave 14 quantitatively, and its 1H NMR
spectrum showed a doublet of doublets at ꢂ 5.35
Method B. Compound 1 (1 g, 2.7 mmol) and
dibutyltin oxide (720 mg, 3.0 mmol) were sus-
pended in methanol (10 mL), the mixture was
re¯uxed for 2±3 h until the suspension became clear,
and re¯uxing was continued for 1 h. The solution
was cooled and evaporated to give a white, foamy
residue. To the residue was added dry toluene
(10 mL), tetrabutylammonium iodide (1 g, 2.7 mmol)
and allyl bromide (0.3 mL, 3.5 mmol), and the
mixture was boiled for 16 h, at the end of which
time TLC (2/1 petroleum ether±ethyl acetate)
showed the disappearance of the starting material.
Sodium hydrogen carbonate (0.4 g) was added and,
the reaction mixture was steam distilled to remove
excess allyl bromide. The resulting syrup was sub-
jected to chromatography (2/1 petroleum ether±
ethyl acetate) over silica gel to give 2 as a syrup
(0.8 g , 72%); [ꢁ]d +107ꢀ (c 0.4, CHCl3); 1H NMR
(CDCl3): ꢂ 7.38±7.20 (m, 10 H, Ph-H), 5.94 (m, 1
H, Jtrans 17.3 Hz, Jcis 10.0 Hz, J 6.0 Hz, CH2 ˆ CH-
0
0
0
0
(J2 ,3 =3.9 Hz, J3 ,4 =9.6 Hz) arising from H-3 of
the mannose moiety and a singlet at ꢂ 2.03
(CH3CO), further con®rming the structure of 12.
2. Experimental
General meꢀthods.ÐOptical rotations were deter-
mined at 20 C with a Perkin±Elmer Model 241-
MC automatic polarimeter. Melting points were
determined with a Mel-Temp apparatus and are
uncorrected. 1H and 13C NMR spectra were recor-
ded on Varian XL-400 and XL-200 spectrometers
in CDCl3 solutions. Chemical shifts are given in
ppm down®eld from Me4Si. Analytical LC was
carried out in stainless-steel columns packed with
Silica Gel (10Â150 mm or 4.6Â250 mm) or Lichro-
sorb-NH2 (4.6Â250 mm) , with peak detection by a
di€erential refractometer (Perkin±Elmer LC-25 RI
Detector). A mixture of ethyl acetate and petro-
leum ether (bp 60±90 ꢀC) was used as the eluent, at
2
4
CH2 ), 5.30 (m, 1 H, Jtrans 17.3 Hz, J 1.4 Hz, J
1.2 Hz, CHH ˆ CH-CH2), 5.22 (m, 1 H, Jcis
2
4
10.0 Hz, J 1.4 Hz, J 1.2 Hz, CHH ˆ CH-CH2),
4.86 (d, 1 H, J1,2 3.7 Hz, H-1), 4.85, 4.53 (qAB, 2 H,
2
2J 11.1 Hz, H, PhCH2), 4.65, 4.50 (qAB, 2 H, J
12.1 Hz, PhCH2), 4.16 (m, 2 H, J 6.0 Hz, 4J 1.2 Hz,
CH2 ˆ CH-CH2), 4.04 (t, 1 H, J2,3 9.3 Hz, J3,4
9.3 Hz, H-3), 3.78±3.64 (m, 3 H, H-5,6), 3.59 (t, 1
H, J3,4 9.3 Hz, J4,5 9.3 Hz, H-4), 3.39 (dd, 1 H, J1,2
3.7 Hz, J2,3 9.3 Hz, H-2), 3.40 (s, 3 H, OCH3).
Anal. Calcd for C24H30O6: C, 69.57; H, 7.25.
Found: C, 69.55; H, 7.45.
1
a ¯ow rate of 1±4 mL min . TLC was performed
on Silica Gel G and HF, with detection either by
charring with 30% (v/v) H2SO4 in MeOH or by
UV light. Preparative chromatography was per-
formed on columns (16Â240, 18Â300, and
35Â400 mm) of Silica Gel (100±200 mesh).
Methyl 2-O-allyl-3-O-benzoyl-4,6-di-O-benzyl-a-
d-glucopyranoside (3).ÐTo a cold solution (0 C)
ꢀ
of 2 (2.96 g, 7.1 mmol) in dichloromethane (40 mL)
and pyridine (4 mL) was added benzoyl chloride
(1.6 mL), and the mixture was allowed to gradually
warm to ambient temperature for 4 h, at the end of
which time TLC (3/1 petroleum ether±ethyl acet-
ate) indicated that the reaction was complete. The
mixture was poured into ice water (100 mL) and,
extracted with dichloromethane, and the organic
phase was washed with 1 M HCl solution twice
(50 mL) and, then with satd NaHCO3 and water,
dried over Na2SO4 and concentrated. Column
chromatography (3/1 petroleum ether±ethyl ace-
tate) of the residue gave 3 as a syrup in quantitative
Methyl 2-O-allyl-4,6-di-O-benzyl-a-d-glucopyr-
anoside (2).ÐMethod A. To a solution of com-
pound
1
(10.5 g, 28 mmol) [16], tetrabutyl-
ammonium hydrogen sulfate (1 g, 3 mmol), and
allyl bromide (4 mL, 46 mmol) in dichloromethane
(200 mL) was added aqueous sodium hydroxide
(100 mL, 5%), and the mixture was stirred at
room temperature for 48 h. TLC (2/1 petroleum
ether±ethyl acetate) indicated that the reaction was
complete. The mixture was extracted with dichloro-
methane and, washed with water, and the organic
layer was concentrated to a syrup and puri®ed by
column chromatography using 2/1 petroleum
ether-ethyl acetate as the eluent to give syrupy 2
(7 g, 60%).
yield (3.7 g, 100%); [ꢁ]d +41ꢀ (c 0.5, CHCl3); H
1
NMR (CDCl3): ꢂ 8.04 (d, 2 H, J 7 Hz. Bz-H), 7.60±
6.98 (m, 13 H, Ph-H and Bz-H), 5.83±5.63 (m, 2 H,
Jtrans 17.9 Hz, Jcis 10.0 Hz, J 5.7 Hz, J2,3 9.3 Hz, J3,4
9.3 Hz, CH2 ˆ CH-CH2, H-3), 5.15 (m, 1 H, Jtrans

80
G. Yang, F. Kong/Carbohydrate Research 312 (1998) 77±83
17.9 Hz, 2J 1.4 Hz, 4J 1.2 Hz, CHH=CH-CH2),
over 2 h, and then at room temperature for 6 h, at
the end of which time TLC (3/1 petroleum ether±
ethyl acetate) showed that the reaction was com-
plete. The mixture was poured into ice water
(100 mL) and, extracted with dichloromethane, and
the organic phase was washed with 1 M HCl twice,
with satd. NaHCO3 and water, dried over Na2SO4,
and concentrated. Column chromatography (3/1
petroleum ether±ethyl acetate) of the residue gave 5
as a syrup (3 g, 90%); [ꢁ]d +56ꢀ (c 4.6, CHCl3); 1H
NMR (CDCl3): ꢂ 8.02 (d, 2 H, J 6.9 Hz. Bz-H),
7.65±6.95 (m, 13 H, Ph-H and Bz-H), 5.92 (t, 1 H,
J2,3 10.4 Hz, J3,4 10.4 Hz, H-3), 5.05 (d, 1 H, J1,2
3.4 Hz, H-1), 4.87 (dd, 1 H, J1,2 3.4 Hz, J2,3
2
4
5.07 (m, 1H, Jcis 10.0 Hz, J 1.4 Hz, J 1.2 Hz,
CHH=CH-CH2), 4.89 (d, 1 H, J1,2 3.3 Hz, H-1),
4.68, 4.52 (qAB, 2 H, 2J 12.0 Hz, PhCH2), 4.49, 4.38
2
(qAB, 2 H, J 10.7 Hz, PhCH2), 4.03 (m, 2 H, J
5.7 Hz, 4J 1.2 Hz, CH2=CH-CH2), 3.87±3.69 (m, 3
H, H-5,6), 3.70 (t, 1 H, J3,4 9.3 Hz, J4,5 9.3 Hz, H-
4), 3.63 (dd, 1 H, J1,2 3.3 Hz, J2,3 9.3 Hz, H-2), 3.43
(s, 3 H, OCH3). Anal. Calcd for C31H34O7: C,
71.81; H, 6.56. Found: C, 71.62; H, 6.89.
Methyl 3-O-benzoyl-4,6-di-O-benzyl-a-d-gluco-
pyranoside (4).ÐMethod A. To a solution of com-
pound 3 (0.7 g, 1.4 mmol) in ethanol (90%, 5 mL)
was added tris(triphenylphosphine)rhodium chlor-
ide (35 mg), and the reaction mixture was heated
under re¯ux for 12 h, at the end of which time TLC
(2/1 petroleum ether±ethyl acetate) indicated the
disappearance of the starting material. Hydro-
chloric acid (1 M, 0.5 mL) was added and the
mixture was boiled for a further 2 h. The solution
was concentrated, the residue was dissolved in
dichloromethane, and the solution was washed
with satd NaHCO3, dried over Na2SO4, and con-
centrated. Column chromatography (2/1 petroleum
ether±ethyl acetate) of the residue gave 4 as crystals
(0.52 g, 80%).
2
10.4 Hz, H-2), 4.66, 4.53 (qAB, 2 H, J 12.0 Hz,
2
PhCH2), 4.47, 4.41(qAB, 2 H, J 11.4 Hz, PhCH2),
3.94 (t, 1 H, J3,4 10.4 Hz, J4,5 10.4 Hz, H-4), 3.94±
0
3.88 (m, 1 H, H-5), 3.80 (dd, 1 H, J5,6 2.7 Hz, J6,6
0
0
10.5 Hz, H-6), 3.69 (dd, 1 H, J5,6 1.2 Hz, J6,6
10.5 Hz, H-60), 3.50 (s, 3 H, OCH3). Anal. Calcd
for C29H29O9F3S: C, 57.05; H, 4.75. Found: C,
57.00; H, 4.70.
Methyl 2-azido-3-O-benzoyl-4,6-di-O-benzyl-2-
deoxy-a-d-mannopyranoside (6).ÐTo a solution of
compound 5 (2.90 g, 4.8 mmol) in dry DMF
(30 mL) was added NaN3 (1.9 g, 29 mmol) and
NH4Cl (70 mg), and the reaction mixture was
Method B. To a solution of compound 3 (4.33 g,
8.4 mmol) in methanol (60 mL) was added palla-
dium chloride (220 mg), and the mixture was stir-
red at room temperature for 12 h, at the end of
which time TLC (2/1 petroleum ether±ethyl acet-
ate) showed the disappearance of the starting
material. The solution was concentrated, and the
insoluble palladium chloride was removed by cen-
trifugation. Puri®cation by column chromato-
graphy using petroleum ether±ethyl acetate (2/1) as
the eluent gave compound 4 aꢀs white crystals (3 g,
ꢀ
heated out at 80 C for 2 h, at the end of which
time TLC (3/1 petroleum ether±ethyl acetate) indi-
cated that the reaction was complete. The reaction
solution was concentrated, the residue was dis-
solved in dichloromethane, washed with water,
dried over Na2SO4, and concentrated. Column
chromatography (4/1 petroleum ether±ethyl acet-
ate) of the residue gave 6 as a syrup (1.90 g, 80%);
ꢀ
1
[ꢁ]d +72 (c 2.9, CHCl3); H NMR (CDCl3): ꢂ
8.12 (d, 2 H, J 7.4 Hz. Bz-H), 7.63±7.01 (m, 13 H,
Ph-H and Bz-H), 5.66 (d, 1 H, J2,3 4.2 Hz, J3,4
9.2 Hz, H-3), 4.79 (d, 1 H, J1,2 1.6 Hz, H-1), 4.72,
ꢀ
1
75%); mp 85±86 C; [ꢁ]d +88 (c 1.5, CHCl3); H
NMR (CDCl3): ꢂ 8.04 (d, 2 H, J 6.4 Hz. Bz-H),
7.60±6.95 (m, 13 H, Ph-H and Bz-H), 5.55 (t, 1 H,
J2,3 9.1 Hz, J3,4 9.1 Hz, H-3), 4.86 (d, 1H, J1,2
2
4.54 (qAB, 2 H, J 12.2 Hz, PhCH2), 4.62, 4.48
2
(qAB, 2 H, J 10.6 Hz, PhCH2), 4.14 (dd, 1 H, J1,2
1.6 Hz, J2,3 4.2 Hz, H-2), 4.04 (t, 1 H, J3,4 9.2 Hz,
J4,5 9.2 Hz, H-4), 3.88±3.80 (m, 1 H, H-5), 3.79 (dd,
2
3.8 Hz, H-1), 4.68, 4.54 (qAB, 2 H, J 12.4 Hz,
2
PhCH2), 4.56, 4.43 (qAB, 2 H, J 10.5 Hz, PhCH2),
0
3.92±3.65 (m, 5 H, H-2,4,5,6), 3.45 (s, 3 H, OCH3).
Anal. Calcd for C28H30O7: C, 70.29; H, 6.28.
Found: C, 70.40; H, 6.17.
1 H, J5,6 3.9 Hz, J6,6 10.7 Hz, H-6), 3.69 (dd, 1 H,
J5,6 1.7 Hz, J6,6 10.7 Hz, H-60), 3.42 (s, 3 H,
OCH3). Anal. Calcd for C28H29N3O6: C, 66.80; H,
5.77; N, 8.35. Found: C, 66.70; H, 5.80; N, 8.40.
0
0
Methyl 3-O-benzoyl-4,6-di-O-benzyl-2-O-tri¯yl-
a-d-glucopyranoside (5).ÐTo a solution of com-
pound 4 (2.61 g, 5.5 mmol) in dichloromethane
(60 mL) and pyridine (1.4 mL) at 10 ꢀC was added
tri¯uoromethanesulfonic anhydride (2.5 mL). The
Methyl
2-azido-4,6-di-O-benzyl-2-deoxy-a-d-
mannopyranoside (7).ÐTo a solution of compound
6 (1.80 g, 3.6 mmol) in methanol (20 mL) was
added solid sodium methoxide (0.17 g, 3.2 mmol) at
room temperature and the reaction was carried out
ꢀ
mixture was allowed to warm gradually to 0 C

G. Yang, F. Kong/Carbohydrate Research 312 (1998) 77±83
81
overnight. The solution was concentrated, and the
resulting residue was puri®ed by column chroma-
tography (2/1 petroleum ether±ethyl acetate) to
give compound 7 as a syrup (1.43 g, 100%); [ꢁ]d
TLC (2/1 petroleum ether±ethyl acetate) indicated
that the starting material disappeared. The solution
was extracted with dichloromethane, and the
organic phase was washed with satd. NaHCO3 and
water, dried over Na2SO4, and concentrated. Col-
umn chromatography (2/1 petroleum ether±ethyl
acetate) of the residue gave crude 9 as a syrup
(850 mg, 65%). Acetylation of 9 with acetic anhy-
dride (3 mL) in pyridine (4 mL) at room tempera-
ture for 4 h gave 10 in quantitative yield as a
syrupy mixture (920 mg, 99%) of ꢁ and ꢀ anomers
ꢀ
1
+94.6 (c 0.3, CHCl3); H NMR (CDCl3): 7.37±
7.20 (m, 10 H, Ph-H), 4.75 (d, 1 H, J1,2 1.8 Hz, H-
2
1), 4.71, 4.54 (qAB, 2 H, J 12.5 Hz, PhCH2), 4.67,
2
4.57 (qAB, 2 H, J 11.3 Hz, PhCH2), 4.09 (d, 1 H,
J2,3 4.0 Hz, J3,4 9.5 Hz, H-3), 3.89 (dd, 1 H, J1,2
1.8 Hz, J2,3 4.0 Hz, H-2), 3.77 (dd, 1 H, J5,6 3.8 Hz,
0
J6,6 11.3 Hz, H-6), 3.75 (t, 1 H, J3,4 9.5 Hz, J4,5
9.5 Hz, H-4), 3.72±3.65 (m, 2 H, H-5,60), 3.37 (s, 3
H, OCH3). Anal. Calcd for C21H25N3O5: C, 63.16;
H, 6.27; N 10.53. Found: C, 63.20; H, 6.34; N,
10.50.
in a ratio of 5/1; [ꢁ]d +8.8 (c 0.1, CHCl3); H
NMR (CDCl3): ꢂ 7.38±7.10 (m, 10 H, Ph-H), 6.12
(d, 5/6 H, J1,2 1.5 Hz, Hꢁ-1), 5.80 (d, 1/6 H, J1,2
0.8 Hz, Hꢀ-1), 5.35 (dd, 5/6 H, J2,3 4.1 Hz, J3,4
9.7 Hz, Hꢁ-3), 5.02 (dd, 1/6 H, J2,3 4.9 Hz, J3,4
9.7 Hz, Hꢀ-3), 4.74±4.45 (m, 4/6 H, PhCH2ꢀ), 4.70,
ꢀ
1
Methyl
3-O-acetyl-2-azido-4,6-di-O-benzyl-2-
deoxy-a-d-mannopyranoside (8).ÐAcetylation of
compound 7 (1.36 g, 3.4 mmol) with acetic anhy-
dride (2 mL) in pyridine (4 mL) at room tempera-
ture for 4 h gave 8 (1.5 g) in quantitative yield as a
syrup; [ꢁ]d +72ꢀ (c 0.5, CHCl3); 1H NMR
(CDCl3): ꢂ 7.39±7.14 (m, 10 H, Ph-H), 5.34 (dd, 1
H, J2,3 3.8 Hz, J3,4 9.5 Hz, H-3), 4.72 (d, 1 H, J1,2
2
4.50 (qAB, 10/6 H, J 12.3 Hz, PhCH2ꢁ), 4.63, 4.53
(qAB, 10/6 H, 2J 11.3 Hz, PhCH2ꢁ), 4.16 (dd, 1/6 H,
J1,2 0.8 Hz, J2,3 4.1 Hz, Hꢀ-2), 4.10 (t, 5/6 H, J3,4
9.7 Hz, J4,5 9.7 Hz, Hꢁ-4), 4.04 (dd, 5/6 H, J1,2
1.5 Hz, J2,3 4.1 Hz, Hꢁ-2), 4.00 (t, 1/6 H, J3,4
9.7 Hz, J4,5 9.7 Hz, Hꢀ-4), 3.87±3.85 (m, 5/6 H, Hꢁ-
2
0
0
1.5 Hz, H-1), 4.71, 4.52 (qAB, 2 H, J 12.3 Hz,
2
5), 3.76 (dd, 5/6 H, J5,6 4.6 Hz, J6,6 12.3 Hz, Hꢁ-
PhCH2), 4.62, 4.49 (qAB, 2 H, J 11.3 Hz, PhCH2),
4.02 (dd, 1 H, J1,2 1.5 Hz, J2,3 3.8 Hz, H-2), 3.97 (t,
1 H, J3,4 9.5 Hz, J4,5 9.5 Hz, H-4), 3.78±3.73 (m, 2
60), 3.72±3.68 (m, 1/6 H, Hꢀ-5), 3.65 (dd, 5/6 H,
J5,6 1.0 Hz, J6,6 12.3 Hz, Hꢁ-60), 3.56 (dd, 1/6 H,
0
0
J5,6 2.0 Hz, J6,6 10.8 Hz, Hꢀ-60), 3.40 (d, 1/6 H,
0
0
H, H-5,6), 3.65 (dd, 1 H, J5,6 1.5 Hz, J6,6 9.2 Hz,
H-60), 3.38 (s, 3 H, OCH3), 2.06 (s, 3 H, CH3CO).
Anal. Calcd for C23H27N3O6: C, 62.59; H, 6.12; N,
9.52. Found: C, 62.80; H, 6.62; N, 9.47.
J6,6 10.8 Hz, Hꢀ-60), 2.20, 2.10 (2 s, 6/6 H, CH3CO
0
0
0
for ꢀ form), 2.13, 2.09 (2 s, 30/6 H, CH3CO for ꢁ
form). Anal. Calcd for C24H27N3O7: C, 61.41; H,
5.76; N, 8.96. Found: C, 61.47; H, 5.85; N, 9.00.
3-O-Acetyl-2-azido-4,6-di-O-benzyl-2-deoxy-a-d-
mannopyranosyl chloride (11).ÐAnhydrous HCl
gas was bubbled into a solution of 10 (500 mg,
1.1 mmol) in dry diethylꢀ ether (20 mL) under a
nitrogen atmosphere at 0 C until the solution was
saturated. The solution was kept at room tem-
perature in a sealed bottle for 2 h, at the end of
which time TLC (3/1 petroleum ether±ethyl ace-
tate) indicated that the reaction was complete. The
solution was concentrated, then diluted with
dichloromethane and concentrated again. This
procedure was repeated several times to remove the
hydrogen chloride. Puri®cation of the product by
column chromatography (3/1 petroleum ether±
ethyl acetate) gave 11 as a syrup (400 mg, 84%);
1,3-di-O-Acetyl-2-azido-4,6-di-O-benzyl-2-deoxy-
d-mannopyranose (10).ÐMethod A. Acetolysis of
compound 8 (100 mg, 0.23 mmol) with Ac2O/
AcOH/H2SO4 (50/20/0.1, 0.8 mL) at room tem-
perature for 25 min furnished a mixture (95 mg) of
10 and methyl 3,6-di-O-acetyl-2-azido-4-O-benzyl-
2-deoxy-ꢁ-d-mannopyranoside (15) in a ratio of
1:1 as determined by 1H NMR. 1H NMR (CDCl3):
ꢂ 6.12 (d, 0.5 H, J1,2 1.5 Hz, H-1 for 10), 5.39±5.30
(m, 1 H, H-3 for 10 and 15), 3.39 (s, 1.5 H, OCH3
for 15), 2.13, 2.09 (for 10), 2.08, 2.07 (for 15) (4 s, 6
H, CH3CO). TLC (3/1 or 2/1 petroleum ether±
ethyl acetate) indicated that compounds 10 and 15
had the same Rf value and could not be separated.
Further chlorination of the mixture with hydrogen
chloride in diethyl ether transformed 10 to the
corresponding chloride 11 but did not a€ect 15.
Method B. To a solution of compound 8 (1.35 g,
3.1 mmol) in 70% AcOH (30 mL) was added cam-
phorsulfonic acid (5 mg) and the mixture was
ꢀ
1
[ꢁ]d +53.5 (c 0.6, CHCl3); H NMR (CDCl3): ꢂ
7.35±7.12 (m, 10 H, Ph-H), 6.05 (d, 1 H, J1,2
1.3 Hz, H-1), 5.57 (dd, 1 H, J2,3 3.9 Hz, J3,4 9.1 Hz,
2
H-3), 4.67, 4.45 (qAB, 2 H, J 11.9 Hz, PhCH2),
4.63, 4.55 (qAB, 2 H, 2J 11.0 Hz, PhCH2), 4.30 (t, 1
H, J3,4 9.1 Hz, J4,5 9.1 Hz, H-4), 4.25 (dd, 1 H, J1,2
ꢀ
heated at 100 C for 16 h, at the end of which time

82
G. Yang, F. Kong/Carbohydrate Research 312 (1998) 77±83
1.3 Hz, J2,3 3.9 Hz, H-2), 4.08±4.04 (m, 1 H, H-5),
0
1,3-anhydro sugar ether had disappeared. The
solution was concentrated to a syrup, which was
subjected to separation by analytical LC using 2/1
petroleum ether±ethyl acetate as the eluent. Com-
pound 13 was obtained as a syrup (26 mg, 76%);
3.79 (dd, 1 H, J5,6 2.8 Hz, J6,6 11.9 Hz, H-6), 3.64
(dd, 1 H, J5,6 1.3 Hz, J6,6 11.9 Hz, H-60), 2.06 (s, 3
H, CH3CO). Anal. Calcd for C22H24ClN3O5: C,
59.26; H, 5.39; N, 9.43. Found: C, 59.50; H, 5.42;
N, 9.45.
0
0
[ꢁ]d +2ꢀ (c 1.2, CHCl3); H NMR (CDCl3): ꢂ
1
1,3-Anhydro-2-azido-4,6-di-O-benzyl-2-deoxy-b-
d-mannopyranose (12).ÐTo a solution of 11
(100 mg, 0.22 mmol) in dry oxolane (10 mL) was
added potassium tert-butoxide (50 mg, 0.45 mmol)
and the mixture was stirred at room temperature
for 6 h, at the end of which time TLC (3/1 petro-
leum ether±ethyl acetate) indicated that the reac-
tion was complete. The solution was concentrated
to dryness, and the residue was repeatedly extrac-
ted with 3/1 petroleum ether±ethyl acetate. Con-
centration of the combined extracts followed by
separation by analytical LC (3/1 petroleum ether±
ethyl acetꢀate) yielded 12 as a syrup (68 mg, 82.5%);
7.38±7.20 (m, 10 H, Ph-H), 5.52 (d, 1 H, J1,2
6.2 Hz, H-1), 4.93 (d, 1 H, J1 ,2 1.1 Hz, H-10), 4.74,
0
0
2
4.53 (qAB, 2 H, J 12.7 Hz, PhCH2), 4.68, 4.57
2
(qAB, 2 H, J 12.0 Hz, PhCH2), 4.62 (dd, 1 H, J2,3
2.9 Hz, J3,4 8.4 Hz, H-3), 4.33 (dd, 1 H, J1,2 6.2 Hz,
J2,3 2.9 Hz, H-2), 4.21 (dd, 1 H, J3,4 8.4 Hz, J4,5
0
0
0
0
1.8 Hz, H-4), 4.14 (dd, 1 H, J2 ,3 4.4 Hz, J3 ,4
9.8 Hz, H-30), 3.77±3.72 (m, 2 H, H-20,5), 3.84±3.66
(m, 6 H, H-40,50, 6, 60), 1.55, 1.47, 1.35, 1.34 (4 s, 12
H, CH3). Anal. Calcd for C32H41N3O10: C, 61.24;
H, 6.54; N, 6.70. Found: C, 61.11; H, 6.31; N, 6.93.
O-(3-O-Acetyl-2-azido-4,6-di-O-benzyl-2-deoxy-
a-d-mannopyranosyl)-(1!6)-1,2:3,4-di-O-isoprop-
ylidene-a-d-galactopyranose (14).ÐCompound 13
(20 mg, 0.033 mmol) was acetylated with acetic
anhydride (0.6 mL) in pyridine (0.8 mL) by stan-
dard methods to a€ord 14 (21 mg, 98%) as a syrup;
1
[ꢁ]d +25 (c 1.2, CHCl3); H NMR (CDCl3): ꢂ
7.36±7.17 (m, 10 H, Ph-H), 5.39 (d, 1 H, J1,3
2
3.6 Hz, H-1), 4.60, 4.56 (qAB, 2 H, J 12.7 Hz,
PhCH2), 4.53 (s, 2 H, PhCH2), 4.49 (t, 1 H, J1,3
3.6 Hz, J3,4 3.6 Hz H-3), 4.29±4.25 (m, 1 H, H-5),
4.21 (s, 1 H, H-2), 4.07 (dd, 1 H, J3,4 3.6 Hz, J4,5
7.2 Hz, H-4), 3.62 (d, 2 H, J5,6 4.3 Hz, H-6). Anal.
Calcd for C20H21N3O4: C, 65.40; H, 5.72; N, 11.44.
Found: C, 65.32; H, 5.80; N, 11.40.
Ring-opening of the 1,3-anhydrosugar 12 with
methanol.ÐTo a solution of compound 12 (10 mg,
0.027 mmol) in dry methanol (0.5 mL) was added
freshly prepared zinc chloride (5 mg, 0.04 mmol).
The mixture was stirred at room temperature for
4 h, at the end of which time TLC (2/1 petroleum
ether±ethyl acetate) indicated that the starting
material had disappeared. The solution was con-
centrated and the residue was dissolved in dichlor-
omethane, washed with water, dried over Na2SO4,
and concentrated. Column chromatography (2/1
petroleum ether±ethyl acetate) of the residue gave a
syrupy product (10 mg, 92%) that gave a 1H NMR
spectrum identical to that of 7.
O-(2-Azido-4,6-di-O-benzyl-2-deoxy-a-d-manno-
pyranosyl)-(1!6)-1,2:3,4-di-O-isopropylidene-a-d-
galactopyranose (13).ÐTo a solution of 12 (20 mg,
0.054 mmol) in dry oxolane (1 mL) was added a
mixture of 1,2:3,4-di-O-isopropylidene-ꢁ-d-galac-
topyranose (17 mg, 0.065 mmol) [21] and freshly
prepared zinc chloride (10 mg, 0.075 mmol) in dry
oxolane (1.5 mL). The mixture was stirred at room
temperature for 6 h, after which time TLC (2/1
petroleum ether±ethyl acetate) indicated that the
[ꢁ]d +5ꢀ (c 1.0, CHCl3); H NMR (CDCl3): ꢂ
1
7.38±7.12 (m, 10 H, Ph-H), 5.49 (d, 1 H, J1,2
0
0
0
0
5.7 Hz, H-1), 5.35 (dd, 1 H, J2 ,3 3.9 Hz, J3 ,4
0
9.6 Hz, H-30), 4.90 (d, 1 H, J1 ,2 1.0 Hz, H-10), 4.72,
0
2
4.48 (qAB, 2 H, J 12.4 Hz, PhCH2), 4.60, 4.48
2
(qAB, 2 H, J 12.4 Hz, PhCH2), 4.61 (dd, 1 H, J2,3
2.5 Hz, J3,4 7.8 Hz, H-3), 4.30 (dd, 1 H, J1,2 5.7 Hz,
J2,3 2.5 Hz, H-2), 4.23 (dd, 1 H, J3,4 7.8 Hz, J4,5
0
0
0
0
1.4 Hz, H-4), 4.07 (dd, 1 H, J1 ,2 1.0 Hz, J2 ,3
3.9 Hz, H-20), 4.01 (t, 1 H, J3 ,4 9.6 Hz, J4 ,5 9.6 Hz,
H-40), 3.97±3.91 (m, 1 H, H-5), 3.85±3.63 (m, 5 H,
H-50, 6, 60), 2.03 (s, 3 H, CH3CO), 1.55, 1.47, 1.35,
1.34 (4 s, 12 H, CH3). Anal. Calcd for C34H43
N3O11: C, 60.99; H, 6.43; N, 6.28. Found: C, 61.12;
H, 6.53; N, 6.51.
0
0
0
0
Acknowledgements
Project 29672049 was supported by The
National Natural Science Foundation of China.
References
[1] Nasir-un-Din and R.W. Jeanloz, Carbohydr. Res.,
28 (1973) 243±251.
[2] (a) M. Linnerborg, G. Widmalm, M.M. Rahman,
P.-E. Jansson, T. Holme, F. Qadri, and
M.J. Albert, Carbohydr. Res., 291 (1996) 165±174.
(b) U. Zahringer, H. Rettenmaier, H. Mall,

G. Yang, F. Kong/Carbohydrate Research 312 (1998) 77±83
83
S.N. Senchenkova, and Y.A. Knirel, Carbohydr.
Res., 300 (1997) 143±151.
[12] H. Ito, R. Eby, S. Kramer, and C. Schuerch, Car-
bohydr. Res., 86 (1980) 193±202.
[3] M. Hamberg, J. Svensson, and B. Samuelsson,
Proc. Natl. Acad. Sci. U.S.A., 72 (1975) 2994±2998.
[4] S.S. Bhagwat, P.R. Hamann, and W.C. Still, J.
Am. Chem. Soc., 107 (1985) 6372±6376.
[5] E. Wu, F. Kong, and B. Su, Carbohydr. Res., 161
(1987) 235±246.
[13] F. Good and C. Schuerch, Carbohydr. Res., 125
(1984) 165±171.
[14] A.J. Varma and C. Schuerch, J. Org. Chem., 46
(1981) 799±803.
[15] F. Kong and C. Schuerch, Carbohydr. Res., 112
(1983) 141±147.
[6] F. Kong, D. Lu, and S. Zhou, Carbohydr. Res., 198
(1990) 141±148.
[16] P.J. Garegg and B. Samuelsson, Synthesis, (1979)
813±814.
[7] X. Wu, F. Kong, D. Lu, and P. Zhang, Carbohydr.
Res., 229 (1992) 75±87.
[17] J.M. Kuester and I. Dyong, Justus Liebigs Ann.
Chem., (1975) 2179±2189.
[8] X. Wu, F. Kong, and D. Lu, J. Carbohydr. Chem.,
10 (1991) 363±375.
[18] W. Liao and D. Lu, Carbohydr. Res., 300 (1997)
347±349.
[9] C. Yang, L. Cao, and F. Kong, J. Carbohydr.
Chem., 11 (1992) 379±395.
[19] J. Banoub, P. Boullanger, and D. Lafont. Chem.
Rev., 92 (1992) 1167±1195.
[10] Z. Gan and F. Kong, Carbohydr. Lett., 1 (1994)
27±30.
[20] S. Takahashi, H. Inoue, and H. Kuzuhara. J. Car-
bohydr. Chem., 14 (1995) 273±285.
[11] Y. Du and F. Kong, Carbohydr. Res., 275 (1995)
259±273.
[21] R.L. Whistler, M.L. Wolfrom, and J.N. BeMiller.
Methods Carbohydr. Chem., 2 (1963) 318±325.