Stereospecific α-D-mannosylation

Article abstract of DOI:10.1016/S0008-6215(99)00065-8

The stereospecific formation of α-D-mannosyl glycosidic linkages has been achieved in high yield using tetra-O-pivaloyl-α-D-mannopyranosyl fluoride and boron trifluoride diethyl etherate in dichloromethane. Examples of the α-D-mannosylation of primary, secondary, benzylic and phenolic hydroxyl groups are described. Copyright (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(99)00065-8

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Carbohydrate Research 317 (1999) 210–216
Note
Stereospecific a-
D
-mannosylation
Ian L. Scott a,*, Robert V. Market a, Russell J. DeOrazio b, Harold Meckler b,
Timothy P. Kogan a,1
a Texas Biotechnology Corporation, 7000 Fannin, Suite 1920, Houston, TX 77030, USA
b Albany Molecular Research, 21 Corporate Circle, Albany, NY 12203, USA
Received 13 April 1998; accepted 1 March 1999
Abstract
The stereospecific formation of a-
valoyl-a- -mannopyranosyl fluoride and boron trifluoride diethyl etherate in dichloromethane. Examples of the
a- -mannosylation of primary, secondary, benzylic and phenolic hydroxyl groups are described. © 1999 Elsevier
D-mannosyl glycosidic linkages has been achieved in high yield using tetra-O-pi-
D
D
Science Ltd. All rights reserved.
Keywords: Mannosylation; Stereospecific; Glycosyl fluorides
As part of our ongoing research into cell-
adhesion antagonists [1], we desired com-
as further purification was impractical at large
scale, we elected to look for a stereospecific
method of mannosylation.
pounds possessing two a-
such as 1,6-bis[3-(3-carboxymethylphenyl)-4-
(a- -mannopyranosyloxy)phenyl]hexane (1).
a- -Mannosylation is considered to be among
D-mannose units
D
D
the easiest of glycosylation reactions, and
when an acetyl group is incorporated at C-2,
the reaction is usually considered to be
stereospecific [2]. Unfortunately, mannosyl-
ation of 1,6-bis[3-(3-carboxymethylphenyl)-4-
hydroxyphenyl]hexane (4, Scheme 1) using
penta-O-acetyl-
D
-mannopyranose catalyzed
by BF3·OEt2 [3] gave the desired bis-a-
D-man-
noside 6a in 95% yield, but in only 95%
purity. This level of purity is insufficient for
purposes of pharmaceutical development, and
Analysis of the product mixture from glycos-
* Corresponding author. Present address: Albany Molecu-
lar Research, 21 Corporate Circle, Albany, NY 12203, USA.
Tel.: +1-518-464-0274.
E-mail address: ians@albmolecular.com (I.L. Scott)
1 Deceased 27th May 1998. This paper is dedicated to his
memory.
ylation of the appropriate bis-phenol 4 [1c]
with penta-O-acetyl- -mannopyranose by
D
NMR spectroscopy, after extensive HPLC to
remove as much of the major component as
0008-6215/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(99)00065-8

I.L. Scott et al. / Carbohydrate Research 317 (1999) 210–216
211
possible2, revealed the presence of three minor
impurities formed in approximately equal
amounts. These impurities comprised the
mono b anomer 23 and each of the two possi-
ble epimeric orthoesters 34 [4a]. As the similar-
ity of the structures of the four components
complicated purification of the desired com-
pound to an acceptable level, we elected to
develop a more selective glycosylation strat-
egy. We hypothesized that increasing the size
of the C-2 protecting/participating group
would lead to higher specificity for the a
anomer5. In order to investigate this hypothe-
sis, we first had to develop a more reactive
glycosylating agent. After a brief look at the
more commonly used activating groups and
Lewis acid catalysts, we selected a combina-
tion of the acyl-protected glycosyl fluoride 5a
and BF3·OEt2. Using this system, we observed
improvements in both the reaction rate and
yield. The percentage purity, as expected, re-
mained unchanged.
Scheme 1.
Removal of the protecting groups proved
initially troublesome due to the high stability
of the pivalate group under basic conditions.
The preferred conditions that were found in-
volved use of a freshly prepared solution of
sodium methoxide in a mixture of methanol
and tetrahydrofuran6. Under these conditions,
the amount of deglycosylation was minimized,
and no loss of anomeric purity was observed.
Next, we investigated the effect of changing
the size of the acyl protecting groups of the
sugar moiety on the stereochemical outcome
of the glycosylation (Table 1). Increasing the
size of the protecting groups to pivalate on the
glycosyl fluoride essentially eliminated the for-
mation of both the b anomer and orthoesters
in the formation of 6d. The major impurity
visible by reversed-phase HPLC (after depro-
tection) was the monoglycoside (0.2%) that
was formed by deglycosylation during the
cleavage of the pivaloyl groups.
To determine the overall utility of this ap-
proach, we extended our studies to the glyco-
sylation of other alcohols using tetra-O-
Scheme 2.
Table 1
Mannosylation of 4 a
pivaloyl-a- -mannopyranosyl fluoride (Table
D
2). In each case, the glycosylation yields are
given after chromatography: only the a gly-
coside was observed by either NMR spec-
troscopy or by HPLC (Scheme 2).
Acyl protecting
group
Chemical yield
(1+2+3) (%)
Ratio
1:(2+3) b (%)
Acetate 5a
95
75
73
91
95:5
98:2
97.5:2.5
99.3:0.7
Benzoate 5b
Isobutyrate 5c
Pivalate 5d
2 As the yield suggests, other side products were formed.
These were removed by flash chromatography and were not
characterized. Other known side reactions include: acyl trans-
fer, disaccharide formation, and C-glycosylation [2c,d,4].
3 13C NMR: (100 MHz, CDCl3) l 96.3 ppm.
a Mannosylation and deprotection reactions were run fol-
lowing the general procedures.
b Determined by reversed-phase HPLC after hydrolytic
cleavage of all protecting groups.
4 13C NMR: (100 MHz, CDCl3) l 114.2 and 114.4 ppm.
5 Similar results have been reported in the formation of
6 The THF was required to increase the solubility of the
fully protected glycoside.
a-D-glucopyranosides [5].

212
I.L. Scott et al. / Carbohydrate Research 317 (1999) 210–216
Table 2
h. The mixture was poured into aq NaHCO3
and extracted with EtOAc. The organic solu-
tion was washed with water and satd NaCl,
dried over MgSO4 and concentrated under
reduced pressure. Purification by flash chro-
matography (SiO2, 2:1–3:2–1:1 hexanes–
EtOAc) yielded 1,6-bis[3-(3-ethoxycarbonyl-
a-Mannosylation using 2,3,4,6-tetra-O-pivaloyl-a-
pyranosyl fluoride (5d)
D-manno-
Alcohol Mannosylation yield
(%)
Deprotection yield (%)
4
91
100
100
100
95 c
92 a
85 b
100
92
7a
7b
7c
7d
methylphenyl)-4-(2,3,4,6-tetra-O-acetyl-a- -
D
mannopyranosyloxyphenyl)]hexane (6a, 88.0
1
77
g, 95%). H NMR (400 MHz, CDCl3): l 7.41
(m, 6 H), 7.27 (m, 2 H), 7.17 (d, 2 H, J 1.5
Hz), 7.07 (m, 4 H), 5.39 (s, 2 H, H-1), 5.27 (m,
6 H), 4.16 (dd, 2 H, J6,6% 12.0 Hz, J5,6 4.7 Hz,
H-6), 4.15 (4 H, q, J 7 Hz, CH2CH3), 3.94 (dd,
2 H, J5,6% 2.2 Hz, H-6%), 3.79 (ddd, 2 H, J4,5 9.5
Hz, H-5), 3.70 (s, 4 H, CH2CO2), 2.58 (t, 4 H,
J 7.7 Hz, ArCH2CH2), 2.13, 2.02, 2.00, and
1.97 (4 s, all 3 H, COCH3), 1.60 (m, 4 H,
ArCH2CH2), 1.36 (m, 4 H, Ar CH2CH2CH2),
a After hydrolysis to 1.
b Methyl ester.
c Glycosyl fluoride used as limiting reagent due to coelution
of fluoride and product.
In conclusion, we have developed a rapid,
clean, high yielding, and stereospecific method
for the introduction of a- -mannosidic link-
ages [6].
13
1.24 (t, 6 H, CH2CH3); C NMR (100 MHz,
D
CDCl3): l 13.6, 20.1, 20.3, 28.7, 31.1, 34.7,
40.8, 60.5, 61.7, 65.5, 68.5, 69.0, 69.2, 96.9,
116.5, 128.3, 128.4, 128.7 , 130.7, 131.2, 132.2,
134.5, 138.3, 151.0, 170.2, 170.3, 170.5, 171.1,
172.3; IR (cm−1): (neat) 1743.
1. Experimental
General procedure for the preparation of
Preparation of 2,3,4,6-tetra-O-acetyl-h-
mannopyranosyl fluoride (5a).—To a stirred
slurry of -mannose pentaacetate (100 g,
D
-
2,3,4,6-tetra-O-acyl-h- -mannopyranosyl
D
fluorides
D
2,3,4,6-Tetra-O-pi6aloyl-h-
yl fluoride (5d). To a solution of 2,3,4,6-tetra-
O-acetyl-a- -mannopyranosyl fluoride (5a,
D
-mannopyranos-
0.256 mol) in CH2Cl2 (10 mL) in a PFE flask
was added cold HF–pyridine (100 g). The
resulting solution was stirred overnight,
sealed, at 40 °C. The solution was poured into
a PFE separating funnel containing water (500
mL) and CHCl3 (200 mL) and shaken. The
CHCl3 layer was washed with water and satd
NaHCO3. The organic layer was dried over
MgSO4 and concentrated under reduced pres-
sure. Purification by chromatography (SiO2,
3:1–2:1 hexanes–EtOAc) gave 2,3,4,6-tetra-
D
74.06 g, 211.4 mmol) in MeOH (1 L) was
added K2CO3 (0.50 g, 3.6 mmol). The result-
ing mixture was stirred at room temperature
(rt) until the reaction was indicated to be
complete by TLC. The solvent was evaporated
under reduced pressure, and residual MeOH
was removed by co-evaporation of 1,2-
dimethoxyethane (3×). The residue was dis-
solved in pyridine (500 mL) and cooled to
0 °C. Pivaloyl chloride (200 mL, 1.62 mol) was
added dropwise, followed by 4-dimethyl-
aminopyridine (DMAP, 3.0 g, 27 mmol). The
resulting mixture was stirred at 0 °C for 30
min, at rt for 30 min, and then at 70 °C
overnight. After cooling to 50 °C, MeOH (50
mL) was added, and the mixture was stirred at
50 °C for 1 h. After cooling to rt, the mixture
was diluted with EtOAc, filtered, and washed
with additional EtOAc. The combined organic
O-acetyl-a- -mannopyranosyl fluoride (5a)
D
(74.06 g, 83%) as a clear oil. The compound’s
NMR spectrum matched that reported [7].
1,6 - Bis[3 - (3 - ethoxycarbonylmethylphenyl)-
4-(2,3,4,6-tetra-O-acetyl-h- -mannopyranosyl-
D
oxyphenyl)]hexane (6a).—To an ice-cold solu-
tion of 4 (45.4 g, 76 mmol) and 2,3,4,-
6-tetra-O-acetyl-a- -mannopyranosyl fluoride
D
(5a, 77 g, 220 mmol) in CH2Cl2 (400 mL) was
added BF3·OEt2 (81.2 mL, 660 mmol) drop-
wise, and the mixture was stirred at 0 °C for 3

I.L. Scott et al. / Carbohydrate Research 317 (1999) 210–216
213
extracted with EtOAc. The organic solution
was washed with water and satd NaCl, dried
over MgSO4, and concentrated under reduced
pressure. Purification by flash chromatogra-
phy (SiO2, 14:1–9:1 hexanes–EtOAc) yielded
layers were washed with water, 2 M HCl
(2×), water, 2 M NaOH, water and brine.
The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The
residue was purified by flash chromatography
(SiO2, gradient 30:1–4:1 hexanes–ethyl ac-
4-bromophenyl 2,3,4,6-tetra-O-pivaloyl-a- -
D
etate) to give 2,3,4,6-tetra-O-pivaloyl-a- -
D
mannopyranoside (8b, 0.21 g, 100%) as a
1
mannopyranosyl fluoride (5d, 87.48 g, 80%):
white solid: mp 60 °C; H NMR (400 MHz,
1
mp 144 °C; H NMR (400 MHz, CDCl3): l
C6D6): l 7.09 and 6.44 (2 d, both 2 H, J 9 Hz,
Ar), 5.87 (dd, 1 H, J2,3 3.3 Hz, J3,4 10.2 Hz,
H-3), 5.76 (t, 1 H, J4,5 10.2 Hz, H-4), 5.66 (dd,
1 H, J1,2 1.9 Hz, H-2), 5.11 (d, 1 H, H-1), 4.16
(dd, 1 H, J5,6 4.6 Hz, J6,6% 12.5 Hz, H-6), 4.06
(dd, 1 H, J5,6 % 1.7 Hz, H-6%), 3.96 (ddd, 1 H,
H-5), 1.28, 1.19, 1.18, and 1.13 (4 s, each 9 H,
t-Bu); 13C NMR (100 MHz, CDCl3): l 26.5,
38.4, 38.5, 61.6, 64.7, 68.9, 69.6, 96.1, 115.6,
118.5, 132.8, 155.3, 177.4, 177.7, 177.9, 178.7;
IR (cm−1, KBr): 2973, 1737, 1486, 1281, 1150,
1124, 1030, 826; CIMS (CH4) m/z 673 [M+
1]+, 499. Anal. Calcd for C32H47BrO10: C,
57.23; H, 7.05. Found: C, 57.19; H, 6.83.
Ethyl 6-(2,3,4,6-tetra-O-pi6aloyl-h-manno-
pyranosyloxy)hexanoate (8a). Compound 8a
was prepared by the general method except
that the reaction was set up at 0 °C and then
stored at 4 °C overnight. Yield (0.2 g, 100%):
5.51 (dd, 1 H, J1,F 49.8 Hz, J1,2 1.5 Hz, H-1),
5.55 (t, 1 H, J3,4 =J4,5 10 Hz, H-4), 5.39 (m,
2 H), 4.20 (m, 3 H), 1.26, 1.23, 1.15, and 1.11
(4 s, all 9 H, t-Bu); 13C NMR (100 MHz,
CDCl3): l 26.5, 38.3, 38.4, 38.5, 60.9, 63.8,
67.3 (d, J 40 Hz), 68.3, 70.9, 105.1 (d, J 224
Hz), 177.1, 177.4, 177.7, 178.6; IR (cm−1):
(neat) 1743; CIMS (CH4) m/z 519 [M+1]+,
499 [M−F]+. Anal. Calcd for C26H43FO9: C,
60.21; H, 8.36. Found: C, 60.01; H, 8.46.
Preparation of 2,3,4,6-tetra-O-benzoyl-h- -
D
mannopyranosyl fluoride (5b). Compound 5b
was prepared by the above method: yield (6.91
g, 81%). The compound’s NMR spectrum
matched that reported [7].
2,3,4,6-Tetra-O-isobutyryl-h- -mannopyran-
D
osyl fluoride (5c). Compound 5c was pre-
pared by the above method. Yield (2.14 g,
81%): mp 33 °C; 1H NMR (400 MHz, CDCl3):
l 5.55 (dd, 1 H, J1,2 1.84 Hz, J1,F 48.7 Hz,
H-1), 5.46 (t, 1 H, J3,4=J 4,5 10 Hz, H-4), 5.36
(m, 2 H), 4.25, (dd, 1 H, J6,6% 12.4 Hz, J5,6 4.4
Hz, H-6), 4.19 (dd, 1 H, J5,6% 2 Hz, H-6%), 4.16
(ddd,1 H, H-5), 2.64, 2.60, 2.51, and 2.43 (4
septets, all 1 H, J 7 Hz, CH(CH3)2), 1.24,
1.21, 1.20, 1.19, 113, 1.11, 1.09, and 1.07 (8 d,
all 3 H, J 7 Hz, CH(CH3)2)); 13C NMR (100
MHz, CDCl3): l 17.9, 18.0, 18.1, 18.2, 18.2,
18.2, 18.2, 18.4, 33.3, 33.4, 60.9, 64.0, 67.1 (d,
J 39 Hz), 68.1, 70.9 (d, J 2 Hz), 105.0 (d, J
224 Hz), 176.0, 176.1, 176.1, 176.1; IR (cm−1):
(neat) 1743.
1
mp 76 °C; H NMR (400 MHz, CDCl3): l
5.46 (t, 1 H, J3,4 =J4,5 10.1 Hz, H-4), 5.36 (dd,
1 H, J2,3 3.3 Hz, H-3), 5.22 (dd, 1 H, J1,2 1.8
Hz, H-2), 4.74 (d, 1 H, H-1), 4.19 (dd, 1 H,
J5,6 4.4 Hz, J6,6% 12.4 Hz, H-6), 4.12 (q, 2 H, J
7.4 Hz, CH2CH3), 4.11 (dd, 1 H, J5,6%1.8 Hz,
H-6%), 4.01 (ddd, 1 H, H-5), 3.70 (dt, 1 H, J
6.6, 9.9 Hz), 3.48 (m, 2 H), 3.43 (dt, 1 H, J
6.6, 9.5 Hz), 2.31 (t, 2 H, J 7.5 Hz), 1.63 (m,
4 H), 1.25 (m, 11 H), 1.23, 1.16, and 1.11 (4 s,
each 9 H, t-Bu); 13C NMR (100 MHz,
CDCl3): l 13.6, 24.1, 25.1, 26.5, 26.6, 28.5,
33.7, 38.4, 38.5, 60.0, 61.8, 65.0, 67.9, 69.3,
69.4, 97.8, 174.2, 177.4, 177.8, 178.8; IR
(cm−1, KBr): 2971, 1737, 1482, 1285, 1155,
1134, 1077, 1046, 973; CIMS (CH4) m/z 499
(100%, M−O(CH2)5CO2Et)]+). Anal. Calcd
for C34H58O12: C, 61.99; H 8.87. Found: C,
61.82; H, 8.91.
General procedure for the preparation of
tetra-O-acyl-h-
D
-mannopyranosides
4-Bromophenyl tetra-O-pi6aloyl-h-
D-man-
nopyranoside (8b). To an ice-cold solution of
4-bromophenol (7b, 55.4 mg, 0.32 mmol) and
2,3,4,6-tetra-O-pivaloyl-a- -mannopyranosyl
D
4-Nitrobenzyl 2,3,4,6-tetra-O-pi6aloyl-h- -
D
fluoride (5d, 0.25 g, 0.48 mmol) in CH2Cl2 (1.5
mL) was added BF3·OEt2 (180 mL, 1.5 mmol),
and the mixture was stirred at 0 °C for 2 h.
The mixture was poured into aq NaHCO3 and
mannopyranoside (8c). Compound 8c was pre-
pared by the above method except that the
reaction was set up at 0 °C and then stored at

214
I.L. Scott et al. / Carbohydrate Research 317 (1999) 210–216
2 H, J 8 Hz), 7.08 (dd, 2 H, J 8.4 and 2.2 Hz),
5.38 (2 H, t, J3,4=J4,5 10.2 Hz, H-4), 5.36 (d,
2 H, J1,2 1.8 Hz, H-1), 5.32 (dd, 2 H, J2,3 3.2
Hz, H-2), 5.30 (dd, 2 H, H-3), 4.14 (q, 4 H, J
7.0 Hz, OCH2CH3), 3.90 (dd, 2 H, (dd, 2 H,
J5,6 4.4 Hz, J6,6% 12.4 Hz, H-6), 3.81 (dd, 2 H,
J5,6% 1.8 Hz, H-6%), 3.72 and 23.69 (2 d, both 2
H, J 15.0 Hz, ArCH2CO2Et), 3.55 (ddd, 2 H,
H-5), 2.58 (t, 4 H, J 7.7 Hz, ArCH2CH2–),
1.60 and 1.37 (2 m, both 4 H), 1.24 (t, 6 H, J
7.3 Hz, CO2CH2CH3), 1.23, 1.14, 1.10, and
1.10 (4 s, each 9 H, t-Bu); 13C NMR (100
MHz, CDCl3): l 13.6, 26.5, 26.6, 28.7, 31.1,
34.8, 38.3, 38.3, 38.4, 40.8, 60.5, 61.4, 64.5,
68.8, 69.1, 69.4, 97.6, 117.3, 128.3, 128.5,
128.8, 128.9, 130.8, 131.1, 132.8, 134.6, 138.5,
138.7, 151.0, 172.3, 177.2, 177.4, 177.7, 178.6;
IR (cm−1): (neat) 1736; FABMS m/z 1490
[M−(t-BuCO2H)]+, 499. Anal. Calcd for
C90H126O24: C, 67.90; H 7.98. Found: C, 67.61;
H, 7.90.
4 °C overnight. Yield (0.20 g, 100%): mp
146 °C; H NMR (400 MHz, CDCl3): l 8.23
1
and 7.51 (2 d, both 2 H, J 9 Hz, Ar), 5.51 (t,
1 H, J3,4 =J4,5 10.1 Hz, H-4), 5.41 (dd, 1 H,
J2,3 3.3 Hz, H-3), 5.33 (dd, 1 H, J1,2 1.6 Hz,
H-2), 4.87 (d, 1 H, H-1), 4.84 and 4.65 (2 d,
both 1 H, J 13.2 Hz, PhCHH), 4.19 (dd, 1 H,
J5,6 4.4 Hz, J6,6% 12.5 Hz, H-6), 4.14 (dd, 1 H,
J5,6%1.8 Hz, H-6%), 4.05 (ddd, 1 H, H-5), 1.26,
13
1.24, 1.15, and 1.12 (4 s, each 9 H, t-Bu); C
NMR (100 MHz, CDCl3): l 26.6, 38.4, 38.5,
61.6, 68.0, 69.1, 69.1, 69.3, 97.5, 124.1, 124.1,
144.2, 148.0, 176.6, 177.8, 178.0, 178.7; IR
(cm−1, KBr): 2981, 1742, 1524, 1477, 1279,
1129, 1077, 978; CIMS (CH4) m/z 652 M+,
499 (100%). Anal. Calcd for C33H49NO12: C,
60.82; H 7.58; N, 2.15. Found: C, 60.47; H,
7.42; N, 2.11.
Methyl 3-(2,3,4,6-tetra-O-pi6aloyl-h- -man-
D
nopyranosyloxy)lithocholate (8d). Compound
8d was prepared by the general method except
that the reaction was run for 3 h at 0 °C.
Yield (0.73 g, 95%): mp 175 °C; 1H NMR (400
MHz, CDCl3) l 5.44 (t, 1 H, J3,4=J4,5 10.2
Hz, H-4), 5.40 (dd, 1 H, J2,3 2.9 Hz, H-3), 5.18
(dd, 1 H, J1,2 1.8 Hz, H-2), 4.91 (d, 1 H, H-1),
4.12 (m, 3 H, H-5, 6, and 6%), 3.66 (s, 3 H,
CO2Me), 3.56 (m, 1 H), 2.33 (ddd, 1 H, J 15,
9.9, and 4.7 Hz), 2.22 (ddd, 1 H, J 15, 9.9, and
7.0 Hz), 1.94 (m, 1 H), 1.77 (m, 6 H), 1.5–1.0
(m, 19 H), 1.25 (m, 2 H), 1.25, 1.22, 1.15, and
1.11(4 s, each 9 H, t-Bu), 0.91, 0.90, and
General deacylation procedure
Preparation of 4-bromophenyl h-
nopyranoside (9b). To an ice-cold solution of
4-bromophenyl 2,3,4,6-tetra-O-pivaloyl-a-
D
-man-
D-
mannopyranoside (8b, 0.26 g, 0.39 mmol) in
THF (1.2 mL) was added a freshly prepared
solution of sodium methoxide (1.1 mL, 0.5
M), prepared from sodium and methanol. The
ice-bath was removed, and the solution was
stirred at rt overnight. After diluting with
methanol (2 mL), sufficient Dowex-50W (H+)
resin was added to give an acidic solution.
After removal of the resin by filtration, the
solution was neutralized by filtration through
a pad of barium carbonate. The solution was
concentrated, and the residue was purified by
flash chromatography (SiO2, 4:1 CHCl3–
13
0.89(s, 3 H); C NMR (100 MHz, CDCl3): l
12.3, 18.5, 21.1, 23.6, 24.4, 26.5, 27.3, 27.4,
28.4, 28.6, 31.2, 32.7, 34.9, 35.6, 36.0, 38.9,
39.0, 39.1, 40.6, 42.3, 42.9, 51.6, 56.2, 56.6,
62.6, 65.7, 69.2, 69.7, 70.5, 78.8, 96.5, 174.9,
177.4, 178.0; IR (cm−1, KBr): 2945, 1743,
1280, 1131, 1072; CIMS (CH4) m/z 787 [M−
(t-BuCO2H)]+, 499 (100%). Anal. Calcd for
C51H84O12: C, 68.89; H 9.52. Found: C, 68.76;
H, 9.47.
MeOH) to give 4-bromophenyl a- -mannopy-
D
ranoside (9b, 0.13 g, 100%) as a white solid:
1
mp 209 °C, lit. mp 207–209 °C [8]; H NMR
(400 MHz, Me2SO-d6): l 7.45 (d, 2 H, Jm,p
9
1,6 - Bis[3 - (3 - ethoxycarbonylmethylphenyl)-
Hz, Ar.), 7.05 (d, 2 H, Ar), 5.36 (d, 1 H, J1,2
1.8 Hz, H-1), 4.95 (d, 1 H, J2,OH 4.4 Hz,
2-OH), 4.75 (d, 1 H, J4,OH 5.9 Hz, 4-OH), 4.66
(d, 1 H, J3,OH 6.2 Hz, 3-OH), 4.36 (dd, 1 H,
J6%,OH 5.9 Hz, J6,OH 6.2 Hz, 6-OH), 3.82 (ddd,
1 H, J2,3 3.1 Hz, 2-H), 3.66 (ddd, 1 H, J3,4 9.2
Hz, 3-H), 3.60 (ddd, 1 H, J5,6 2.2 Hz, J6,6% 11.7
Hz, 6-H), 3.50 (ddd, 1 H, J4,5 9.5 Hz, H-4),
4-(2,3,4,6-tetra-O-pi6aloyl-h- -mannopyranos-
D
yloxy)phenyl]hexane (6d). Compound 6d was
prepared by the general method except that
the reaction was run for 1.5 h at 0 °C. Yield
1
(11.24 g, 91%): mp 133 °C; H NMR (400
MHz, CDCl3): l 7.44 (m, 6 H), 7.27 (dt, 2 H,
J 6.6, 1.8 Hz), 7.17 (d, 2 H, J 1.8 Hz), 7.10 (t,

I.L. Scott et al. / Carbohydrate Research 317 (1999) 210–216
215
24.4, 26.6, 27.4, 28.2, 28.6, 30.9, 31.2, 32.8,
34.9, 35.3, 35.7, 35.9, 40.5, 41.9, 42.9, 51.7,
56.5, 62.0, 67.8, 71.4, 71.6, 74.5, 75.9, 98.6,
174.2; IR (cm−1, KBr): 3434, 2941, 2868,
1737, 1449, 1114, 1061, 1025, 972, 684;
HRMS (FAB, MNBA matrix): Calcd for
3.45 (ddd, 1 H, J5,6% 5.9 Hz, 6%-H), 3.36 (ddd, 1
H, H-5); 13C NMR (100 MHz, Me2SO-d6): l
61.8, 67.5, 70.7, 71.4, 75.8, 99.8, 114.2, 118.7,
119.8, 132.9, 156.4; IR (cm−1, KBr): 3402,
3277, 2941, 1486, 1239, 1077, 1014, 983, 826;
HRMS (MALDI, DHB matrix): Calcd for
C12H15BrO6·Na; 356.9933, found 356.9932.
C31H52O8
553.3737.
[M−H]+
553.3742;
found
Methyl 6-(h- -mannopyranosyoxyl)hexan-
D
Preparation of 1,6-bis[3-(3-carboxymethyl-
phenyl) - 4 - (h - - mannopyranosyloxy)phenyl]-
oate (9a). Compound 9a was prepared by the
general method. Yield (117 mg, 85%): mp
55 °C; 1H NMR (400 MHz, Me2SO-d6, 50 °C):
l 4.59 (d, 1 H, J 1.5 Hz, 1-H), 4.55 (d, 1 H,
J4,OH 5.1 Hz, 4-OH), 4.51 (d, 1 H, J 4.4 Hz,
OH), 4.35 (d, 1 H, J 5.9 Hz, OH), 4.25 (dd, 1
D
hexane (1).—Compound 1 was prepared by
the general method except that the deacylation
reaction was run for 5 h at 0 °C. The precipi-
tate was collected by filtration, washed with a
small volume of 2:1 THF–MeOH and ace-
tone, and then dissolved in water. The pH was
adjusted to 14 by the addition of NaOH (2
M), and the mixture was stirred at rt until the
hydrolysis was complete by TLC. The
aqueous solution was acidified using dilute
HCl, and the precipitate was collected and
dried under high vacuum over P2O5. Yield
(14.1 g, 91%): mp 106–108 °C, lit. 106–108 °C
[1c].
H, J
5.8 Hz, J
6.2 Hz, 6-OH), 3.65
(ddd, 61%,OHH, J5,6 2.4 Hz6,,OJH6,6% 11.5 Hz, 6-H), 3.60
(s, 3 H, OMe), 3.60 (m, 3 H, H-2 and
OCH2CH2), 3.46 (dt, 1 H, J
3.46 (m, 1 H, H-3), 3.39 (td, 1 H, J
5.9 Hz, 6%-H),
5,6%
9.5 Hz,
4,5
H-4), 3.35 (ddd, 1 H, H-5), 2.30 (t, 2 H, J 7.3
Hz, CH2CO2Me), 1.56 and 1.52 (2 quint.,
both 2 H, J 7.3 Hz, –CH2 –), 1.33 (m, 2 H,
–CH2–); 13C NMR (100 MHz, CDCl3): l
24.8, 25.8, 29.2, 34.0, 51.7, 61.1, 66.4, 67.7,
71.2, 71.8, 72.4, 100.2, 174.3; IR (cm−1, KBr):
3392, 2941, 1737, 1439, 1239, 1135, 1098,
1061, 962, 684. Anal. Calcd for C13H24O8: C,
50.64; H, 7.85. Found: C, 50.40; H, 7.68.
Acknowledgements
The authors thank Dr George Krudy for
performing the NMR analyses.
Preparation of 4-nitrobenzyl h- -mannopy-
D
ranoside (9c). Compound 9c was prepared by
the general method. Yield (0.9 g, 92%): mp
155 °C. The compound’s NMR spectrum
matched that reported in Ref. [9].
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