Versatile routes to C-2- and C-6-functionalized glucose derivatives of iminodiacetic acid

Article abstract of DOI:10.1021/jo025978o

A series of novel D-glucose derivatives, functionalized at the C-2 or the C-6 position with an iminodiacetic acid moiety for transition-metal complexation, has been prepared. The sugar and the metal-chelating parts are separated by either propyl or octyl chains and were introduced by the reaction of bromoalkylamine. Either N-1-Boc-3-bromopropylamine (17) or N-(8-bromooctyl)-phthalimide (19) reacted with methyl 3,5,6-tri-O-benzyl-α-β-D-glucofuranoside (4) (C-2 position) and 1,2:3,5-(O-methylene)-α-D-glucose (11) (C-6 position), respectively, in the presence of sodium hydride in DMF at room temperature, affording the desired intermediates. For aminopropyl derivatives, yields varied between 57% and 65%, and for aminooctyl derivatives, yields varied between 40% and 71%. After deprotection of the amine functionality, the metal chelate was built up by dialkylation (6a-c and 13a,b) with methyl bromoacetate in the presence of triethylamine under reflux in THF. Yields varied between 56% and 69% for the glucose modified at the C-2 position and between 58% and 62% for the one modified at the C-6 position. All compounds were characterized by ¹H or ¹³C NMR or both, IR, and mass spectroscopy. Final products were isolated as a mixture of α and β anomers.

Full text of DOI:10.1021/jo025978o

Ver sa tile Rou tes to C-2- a n d C-6-F u n ction a lized Glu cose
Der iva tives of Im in od ia cetic Acid
Ce´cile Dumas,† Roger Schibli,*,† and P. August Schubiger†,‡
Center for Radiopharmaceutical Science of the ETH, PSI, USZ, Paul Scherrer Institute, CH-5232 Villigen
PSI, Switzerland, and Department of Applied Biosciences, ETH Zurich, CH-8057 Zurich, Switzerland
roger.schibli@psi.ch
Received May 28, 2002
A series of novel D-glucose derivatives, functionalized at the C-2 or the C-6 position with an
iminodiacetic acid moiety for transition-metal complexation, has been prepared. The sugar and
the metal-chelating parts are separated by either propyl or octyl chains and were introduced by
the reaction of bromoalkylamine. Either N-1-Boc-3-bromopropylamine (17) or N-(8-bromooctyl)-
phthalimide (19) reacted with methyl 3,5,6-tri-O-benzyl-R-â-D-glucofuranoside (4) (C-2 position)
and 1,2:3,5-(O-methylene)-R-D-glucose (11) (C-6 position), respectively, in the presence of sodium
hydride in DMF at room temperature, affording the desired intermediates. For aminopropyl
derivatives, yields varied between 57% and 65%, and for aminooctyl derivatives, yields varied
between 40% and 71%. After deprotection of the amine functionality, the metal chelate was built
up by dialkylation (6a -c and 13a ,b) with methyl bromoacetate in the presence of triethylamine
under reflux in THF. Yields varied between 56% and 69% for the glucose modified at the C-2 position
and between 58% and 62% for the one modified at the C-6 position. All compounds were
1
characterized by H or 13C NMR or both, IR, and mass spectroscopy. Final products were isolated
as a mixture of R and â anomers.
In tr od u ction
With a view to develop novel, metal-based, tumor-
targeting radiopharmaceuticals for diagnostic and thera-
peutic purposes, we previously reported the synthesis and
functionalization of â-glucose and 2-deoxy-R-glucose at
the C-1 position with an O-glycosidically linked imino-
diacetic acid (IDA) chelating moiety.8 Reaction of the
corresponding glucose and deoxyglucose derivatives with
the organometallic precursor [NEt4]2[ReBr3(CO)3] yielded
almost quantitatively highly stable and water-soluble
organometallic complexes.
Carbohydrates are interesting building blocks for
organic chemistry and drug development due to their
involvement in various biological systems, water solubil-
ity, and optical activity. The latter two characteristics
make them interesting, for example, in asymmetric
synthesis1 and in heterogeneous catalysis. Also, several
review papers recently appeared summarizing the im-
portance and growing application of carbohydrate-based
drugs.2 On the other hand, the chemistry and application
of carbohydrate-based transition-metal complexes in
other research areas is strikingly underdeveloped. Car-
bohydrate-based complexes could be extremely important
in research fields such as bioinorganic and bioorgano-
metallic chemistry, where they have attracted consider-
able attention, for example, in assay development and
nuclear medicine.3-7 The development of new sugar-
pendant ligand systems for site-specific transition-metal
coordination could significantly extend the scope of these
research topics.
However, to target either glucose transport systems
such as, e.g., Glut-1 (often overexpressed on malignant
tumors cells) or the active site of the enzyme hexokinase
or both, the functionalization of glucose at the C-69 or
C-2 position for transition-metal coordination would be
desirable.10 In the case of hexokinase, the C-2 position
appears to be the sole center where substitution is
tolerated without completely losing the biological activity
of glucose.11
We report here the first systematic synthesis of glucose
functionalized at the C-2 or C-6 position with a metal-
chelating moiety.
* To whom correspondence should be addressed. Phone: +41-56-
310-2837. Fax: +41-56-310-2849.
† Paul Scherrer Institute.
‡ ETH Zurich.
(1) Hollingsworth, R. I.; Wang, G. Chem. Rev. 2000, 100, 4267-4282.
(2) Chem. Rev. 2000, 100, 4265-4712.
(8) Petrig, J .; Schibli, R.; Dumas, C.; Alberto, R.; Schubiger, P. A.
Chem.sEur. J . 2001, 7, 1868-1873.
(3) J aouen, G.; Top, S.; Vessieres, A.; Pigeon, P.; Leclercq, G.; Laios,
I. Chem. Commun. 2001, 383-384.
(4) Morel, P.; Top, S.; Vessieres, A.; Stephan, E.; Laios, I.; Leclercq,
G.; J aouen, G. C. R. Acad. Sci., Ser. IIc: Chim. 2001, 4, 201-205.
(5) Metzler-Nolte, N. Angew. Chem., Int. Ed. 2001, 40, 1040-1043.
(6) Volkert, W. A.; Hoffman, T. J . Chem. Rev. 1999, 99, 2269-2292.
(7) J urisson, S. S.; Lydon, J . D. Chem. Rev. 1999, 99, 2205-2218.
(9) Halmos, T.; Santarromana, M.; Antonakis, K.; Scherman, D. Eur.
J . Pharmacol. 1996, 318, 477-484.
(10) Aleshin, A. E.; Zeng, C.; Bourenkov, G. P.; Bartunik, H. D.;
Fromm, H. J .; Honzatko, R. B. Structure 1998, 6, 39-50.
(11) Aleshin, A. E.; Zeng, C. B.; Bartunik, H. D.; Fromm, H. J .;
Honzatko, R. B. J . Mol. Biol. 1998, 282, 345-357.
10.1021/jo025978o CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/19/2002
512
J . Org. Chem. 2003, 68, 512-518

Glucose Derivatives of Iminodiacetic Acid
SCHEME 1
SCHEME 2 a
a
Reagents and conditions: (a) m-CPBA, MeOH, 64%; (b)
different conditions have been tested for this reaction; various
bases (KOH, NaOH, NaH), solvents (dioxane, DMF), and desic-
cants have been used as well as different temperature conditions.
Resu lts a n d Discu ssion
In a recent review, Nicolaou12 presents a list of 20
different general methods to carry out an O-glycosylation,
which shows the diversity of carbohydrate chemistry.
However, syntheses of glucose derivatives at positions
other than C-1 with multiple functional groups, including
amines, are scarcely reported. Among the other positions,
the chemistry of C-6 is the most developed and described
due to the relatively easy access to a reactive precursor
such as, e.g., 1,2:3,5-(O-methylene)-R-D-glucose (11).13 On
the other hand, the C-2 position of glucose is exception-
ally problematic to C-substitute, presumably due to the
unreactivity of a C-2 leaving group toward displacement
with charged nucleophiles. This fact was attributed to
the electron-withdrawing effect of the anomeric carbon
atom and the unfavorable dipolar interaction in the
transition state of the substitution reaction.14,15 Last,
O-substitution of the hydroxyl group at the C-2 position
is rarely employed for purposes other than protection.
For our approach, we decided to follow the reaction
pathway using O-substitution, which was also recently
utilized to prepare different D-glucose-derivatized bisimi-
dazole compounds.16
Two options are reasonable for the retrosynthesis of
glucose derivatives at the C-2 and C-6 positions. The first
one is a convergent synthesis which includes the coupling
of a halogenoalkane already functionalized with the
chelating moiety (Scheme 1, method I) to the protected
glucose. The second alternative is a linear synthesis. In
the latter case, the first step is the O-alkylation of the
protected glucose by a halogenated primary alkylamine
to afford the spacer pendant carbohydrate. The chelating
moiety will subsequently be built up by dialkylation of
glucose derivative with methyl bromoacetate (Scheme 1,
method II). Although method I is straightforward, we
found that the basic conditions for the coupling of the
ligand system led to uncontrolled hydrolysis of the ester
functionalities rather than linkage of the ligand system
to glucose. Therefore, we followed method II.
Su bstitu tion a t th e C-2 P osition . Methyl 3,4,6-
tribenzyl-â-D-glucopyranoside (2) seemed to be an ideal
starting material for functionalization of glucose at the
C-2 position. The commercially available tribenzyl glucal
1 was treated with m-CPBA in methanol to afford the
desired methyl glucopyranose 2 (Scheme 2) as a mixture
of the R and â anomers (ratio 1:20) in 64% yield as
described by Danishefsky et al.17,18
However, attempts to alkylate the unprotected alcohol
at the C-2 position in the presence of different bases
(KOH, NaOH, or NaH) in DMF or dioxane with an alkyl
bromide or an alkyl tosylate yielded the desired product
only in trace amounts even at elevated temperatures. The
use of desiccant including Drierite, calcium carbonate,
and molecular sieves in the reaction solution did not
increase the yields either. Steric hindrance of the OH
group due to the bulky benzyl groups particularly in the
case of sugars in the pyranose form might be the reason
for these synthetic problems. We therefore chose to start
from a protected furanose precursor because, in this case,
the protecting groups are above and the OH group is
below the plane of the furanose ring system. The steric
hindrance should thus be reduced and the alkylation at
C-2 position facilitated.
The methyl 3,5,6-tri-O-benzyl-D-R-â-glucofuranoside (4)
prepared according to the synthesis reported by Lee et
al.19 has been successively coupled with 3-bromo-N-(1-
tert-butoxycarbonyl)propylamine,20 N-bromooctylphthal-
imide,21 and commercially available 1,2-bis(2-chlorethoxy)-
ethane in DMF at room temperature in the presence of
sodium hydride. The corresponding N-protected amino-
propyl and aminooctyl sugars 5a and 5b were obtained
after 14 h with respective yields of 65% and 71%.
Compound 5c was obtained from the alkylation reaction
and converted without purification into the azide 5d in
an 87% overall yield. The modified glucoses 5a -d were
all present as a mixture of the R and â anomers in a ratio
of 1:1, as evident from the 1H NMR spectra. The next
(12) Nicolaou, K. C.; Mitchell, H. J . Angew. Chem., Int. Ed. 2001,
40, 1576-1624.
(17) Danishefsky, S. J .; Behar, V.; Randolph, J . T.; Lloyd, K. O. J .
Am. Chem. Soc. 1995, 117, 5701-5711.
(13) Hough, L.; J ones, J . K. N.; Magson, M. S. J . Chem. Soc. 1952,
1525-1527.
(18) Danishefsky, S. J .; Bilodeau, M. T. Angew. Chem., Int. Ed. 1996,
35, 1380-1419.
(14) Miljkovic, M.; Gligorijevic, M.; Glisin, D. J . Org. Chem. 1974,
39, 3223-3226.
(19) Lee, D.-S.; Perlin, A. S. Carbohydr. Res. 1984, 125, 265-282.
(20) Mougenot, P.; Mertens, P.; Nguyen, M.; Touillaux, R.; March-
and-Brynaert, J . J . Org. Chem. 1996, 61, 408-412.
(21) Mary, A.; Renko, D. Z.; Guillou, C.; Thal, C. Bioorg. Med. Chem.
1998, 6, 1835-1850.
(15) Collins, P.; Ferrier, R. In Monosaccharides: Their Chemistry
and Their Roles in Natural Products, 2nd ed.; Wiley: Chichester, U.K.,
1995; pp 189-205.
(16) Zhou, C.; Hassner, A. Carbohydr. Res. 2001, 333, 313-326.
J . Org. Chem, Vol. 68, No. 2, 2003 513

Dumas et al.
SCHEME 3 a
SCHEME 4 a
a
Reagents and conditions: (a) NaH, 3-bromo-N-(1-tert-butoxy-
carbonyl)propylamine, N-bromooctylphthalimide, or 1,2-bis(2-chlo-
rethoxy)ethane, DMF, rt, 14 h, 65-71%; (b) NaN3, 2 h, DMF, 100
°C; (c) CF3CO2H, CH2Cl2, rt, 1 h, 86%; (d) NH2NH2, MeOH, rt, 2
h, 77%; (e) LiAlH4, THF, rt, 3 h, 71%. Pht ) phthalloyl.
step of the synthesis was the deprotection of the amine
functionality to build up the chelating moiety by dialky-
lation. Compound 6a was isolated after 1 h of reaction
without purification by deprotection of the Boc groups
in the presence of trifluoroacetic acid in dichloromethane
(Scheme 3). The phthalimide group of the glucose deriva-
tive 5b was removed in the presence of hydrazine in
methanol at room temperature to afford the aminoalkyl-
D-glucose 6b. The azide functionality of glucose derivative
5c was reduced overnight under reflux by the action of
LiAlH4 in THF to furnish the free amine derivative 6c.
The chelating moieties were obtained by double alky-
lation of the amines of furanoses 6a -c using methyl
bromoacetate in THF in the presence of triethylamine
to afford the diesters 7a -c with yields of 56-69%. The
following three steps led to final deprotections of the
sugar and the chelating moiety. The hydrogenolysis of
the benzyl groups occurred in methanol in the presence
of a catalytic amount of palladium hydroxide to give the
deprotected triols 8a -c in excellent yields (>85%). The
partial transformation of the furanose in pyranose and
the elimination of the methyl at the C-1 position22 were
achieved simultaneously in acetic anhydride in the
presence of trimethylsilyl triflate to afford hexaesters 9a ,
9b, and 9c (Scheme 4). Hexaesters 9a -c were obtained
as a mixture of the R and â anomers of the pyranose form.
Traces of the corresponding anomers of the furanose form
have also been observed in the 1H NMR spectrum.
Transesterification of the four acetates of derivatives
9a -c in methanol with sodium methanolate and the
saponification of the methyl ester in an aqueous solution
of sodium hydroxide finally yielded the functionalized
glucose derivatives 10a -c. Overall yields of derivatives
10a -c were 16%, 23%, and 22% with respect to gluco-
furanose 4.
a
Reagents and conditions: (a) BrCH2CO2Me, NEt3, THF, reflux,
14 h, 56-69%; (b) H2, Pd(OH)2/C, MeOH, 85-99%; (c) TMSOTf,
AcOH, 0 °C, 40 min, 66-90%; (d) NaOMe, MeOH; (e) NaOH (0.091
N), Dowex 50W-X8, 85-89%.
SCHEME 5 a
a
Reagents and conditions: (a) NaH, 3-bromo-N-(1-tert-butoxy-
carbonyl)propylamine, DMF, rt, 14 h, 57%; (b) CF3CO2H, CH2Cl2,
rt, 1 h, 91%; (c) NaH, N-bromooctylphthalimide, DMF, rt, 14 h,
40%; (d) NH2NH2, MeOH, rt, 2 h, 81%.
moamine 3-bromo-N-(1-tert-butoxycarbonyl)propylamine
or N-bromooctylphthalimide to afford their corresponding
amino ethers 12a ,b (Scheme 5). The second step of the
synthesis is still the deprotection of the amine function-
ality to allow the preparation of the metal-chelating
moiety. Using the same method described for the C-2
position, the amines 12a and 12b were respectively
deprotected in the presence of trifluoroacetic acid in
dichloromethane or hydrazine monohydrate in methanol
to afford the corresponding primary amines 13a ,b.
The C-6-substituted glucose derivatives 13a ,b were
dialkylated in the same manner as compounds 7 to yield
the corresponding diester derivatives 14a and 14b
(Scheme 6). Finally, the two glucose derivatives 15a ,b
were obtained by saponification of the esters of carbohy-
drates 14a ,b in 1 M aqueous NaOH and the deprotection
of the acetals by addition of Dowex 50W-X8. Overall
yields of derivatives 15a ,b were 23% and 16% with
respect to bismethylene-D-glucofuranose 11.
Su bstitu tion a t th e C-6 P osition . The starting
material for the alkylation at the C-6 position, 1,2:3,5-
(O-methylene)-R-D-glucose (11), was prepared according
to the method described by Hough et al.13 in one step from
D-glucopyranose. As for the synthesis of sugar derivatives
10a -c, the substitution at the C-6 position started with
the insertion of the linker at the C-6 position. The
unprotected alcohol was alkylated in DMF in the pres-
ence of sodium hydride with either the protected bro-
(22) Angibeaud, P.; Utille, J .-P. J . Chem. Soc., Perkin Trans. I 1990,
1490-1493.
514 J . Org. Chem., Vol. 68, No. 2, 2003

Glucose Derivatives of Iminodiacetic Acid
SCHEME 6 a
5.01 (d, J ) 4.7 Hz, 0.5H), 4.86-4.67 (m, 2H), 4.66-4.50 (m,
5.5H), 4.38-4.28 (m, 1H), 4.17 (dd, J ) 5.6, J ) 3.5 Hz, 1H),
4.13-3.80 (m, 1.5H), 3.82-3.66 (m, 1.5H), 3.58-3.49 (m, 1H),
3.48-3.35 (m, 4H), 3.30-3.19 (m, 2H), 1.80-1.62 (m, 2H), 1.44
(s, 9H); HRMS m/z calcd for C36H47NO8 621.3302, found
621.3307.
Met h yl 3,5,6-Tr i-O-b en zyl-2-O-(8-p h t h a lim id ooct yl)-
r,â-D-glu cofu r a n osid e (5b). Compound 5b was prepared
from 4 and N-bromooctylphthalimide according to the prepa-
ration of 5a : yield 71%; Rf 0.45 (AcOEt); IR (neat) 1748, 1372,
1222 cm-1; 1H NMR δ 7.88-7.79 (m, 1H), 7.74-7.65 (m, 1H),
7.40-7.19 (m, 17H), 5.04 (d, J ) 4.8 Hz, 0.5H), 4.97 (d, J )
4.0 Hz, 0.5H), 4.81 (d, J ) 11.6 Hz, 1H), 4.75-4.48 (m, 6H),
4.39-4.18 (m, 2H), 4.18-3.99 (m, 2H), 3.97-3.84 (m, 1H),
3.83-3.62 (m, 2H), 3.60-3.30 (m, 2H), 3.47 (s, 1.5H), 3.42 (s,
1.5H), 1.78-1.40 (m, 4H), 1.40-1.18 (m, 8H); 13C NMR δ 179.9
(2C), 139.6, 139.3, 138.6, 132.8 (2C), 128.9 (4C), 128.8 (3C),
128.6 (2C), 128.3 (4C), 128.2 (3C), 128.0 (2C), 127.9, 109.3,
86.9, 81.1, 80.8, 77.5, 77.2, 74.0, 73.0, 72.8, 71.5, 70.6, 30.2,
29.9, 29.7, 27.4, 26.6. Anal. Calcd for C44H51NO8 (721.36): C,
73.21; H, 7.12; N, 1.94. Found: C, 73.44; H, 7.48; N, 2.31.
Meth yl 3,5,6-Tr i-O-ben zyl-2-O-[2-(2-azidoeth oxy)eth oxy]-
eth yl-r,â-D-glu cofu r a n osid e (5d ). To a solution of methyl
3,5,6-tri-O-benzyl-R-â-D-glucofuranoside (4) (1 g, 2.1 mmol, 1
equiv) and 1,2-bis(2-chlorethoxy)ethane (3.4 mL, 21.5 mmol,
10.2 equiv) in DMF (50 mL) at 0 °C was added portionwise
NaH (60% in oil) (430 mg, 10.8 mmol, 5.1 equiv). The obtained
suspension was stirred overnight with increasing temperature
from 0 °C to rt. The excess of NaH was then destroyed by
addition of methanol (0.5 mL) and water (1.5 mL) at 0 °C. The
solvents were removed by distillation to afford a yellow oil,
which was diluted in AcOEt (50 mL) and washed two times
with water (50 mL). The organic layer was dried over Na2-
SO4, filtered, and evaporated to dryness to provide an oil (1.2
g) composed of a mixture of 5c and 1,2-bis(2-chlorethoxy)-
ethane in a ratio of 2:3. To a solution of this oil in DMF (25
mL) was added at rt NaN3 (252 mg, 4.48 mmol, 2 equiv). The
resulting suspension was heated at 100 °C for 4 h. After
cooling, brine (188 mL) was added, and the mixture was
extracted with Et2O (3 × 110 mL). The combined organic layers
were dried over Na2SO4 and evaporated to dryness to afford a
brown oil, which was purified by chromatography on silica gel,
AcOEt/nHex (1:3): yield 87%; Rf 0.60 (AcOEt/nHex, 1:3); IR
(neat) 2106, 1110, 1062 cm-1; 1H NMR δ 7.57-7.19 (m, 15H),
5.09 (d, J ) 4.3 Hz, 0.2H), 4.97 (s, 0.8H), 4.93-4.84 (m, 1H),
4.77-4.58 (m, 5H), 4.41 (dd, J ) 9.0, 4.8 Hz, 1H), 4.23-4.08
(m, 2H), 4.01 (dd, J ) 10.5, 1.9 Hz, 1H), 3.98 (s large, 1H),
3.82 (dd, J ) 10.5, 5.2 Hz, 1H), 3.81-3.63 (m, 10H), 3.52 (s,
0.6H), 3.49 (s, 2.4H), 3.54-3.43 (m, 2H); 13C NMR δ 139.6,
139.3, 138.6, 129.9 (2C), 129.5, 129.2 (3C), 128.7 (2C), 128.4,
128.0 (2C), 127.7 (2C), 127.4 (2C), 110.3, 109.9, 108.2, 88.6,
87.3, 87.2, 81.3, 80.8, 80.2, 74.0, 72.8, 71.5, 71.4, 71.1, 70.0,
51.3; MS m/z 644.5 (MNa+). Anal. Calcd for C34H43N3O8
(621.73): C, 65.68; H, 6.97; N, 6.76. Found: C, 65.68; H, 6.98;
N, 6.68.
a
Reagents and conditions: (a) BrCH2CO2Me, NEt3, THF, reflux,
14 h, 58-62%; (b) NaOH, rt, 2 h, Dowex 50W-X8, 77-78%.
Con clu sion
In summary the first practical and versatile method
for the substitution of glucose at the C-2 or C-6 position
with a functionalized side chain (10a -c and 15a ,b) has
been successfully developed. Although this method was
set up for D-glucose, it can presumably be extended to
the substitution/functionalization of other natural and
artificial monosaccharides. The synthetic intermediates
8a -c and 13a ,b may be particularly useful for the
preparation of functionalized carbohydrates for linkage
to peptides and lipids. They can also be powerful inter-
mediates for the formation of amine-containing ligand
systems tailor-made for various transition-metal centers.
In vitro evaluation of the bioaffinity of the corresponding
99mTc-labeled glucose derivatives 10a -c and 15a ,b for
hexokinase and Glut-1 are in progress.
Exp er im en ta l Section
Gen er a l P r oced u r es. Unless otherwise specified pur-
chased materials were used without further purification. Dry
THF was distilled from Na/benzophenone immediately before
use. Moisture-sensitive reactions were conducted in oven-dried
glassware under a nitrogen atmosphere. All reactions were
monitored by thin-layer chromatography performed on pre-
coated silica gel (60 F254) plates and visualized using UV light
and applying a solution of potassium permanganate (1% in
water). Similarly, amines were detected by ninhydrin (0.5%
in methanol). Column chromatography was accomplished on
silica gel 60 (0.062-200 mesh). High-resolution mass spec-
troscopy was done by the MS service of the Department of
Organic Chemistry at the Federal Institute of Technology
Zurich (ETHZ). The elemental analyses were performed by the
Laboratory of Microelementary Analysis from the Department
of Organic Chemistry at the ETHZ. The NMR spectra were
measured at 300 and 75 MHz for 1H and 13C, respectively.
Unless otherwise specified, spectra were recorded in CDCl3
as solvent, and chemical shifts are expressed in parts per
million relative to that of residual CHCl3 at 7.27 ppm for 1H
and that of CDCl3 at 77.7 ppm for 13C.
Meth yl 3,5,6-Tr i-O-ben zyl-2-O-(3-ter t-bu toxyca r bon yl-
a m in op r op yl)-r,â-D-glu cofu r a n osid e (5a ). To a solution of
methyl 3,5,6-tri-O-benzyl-R-â-D-glucofuranoside (4) (985 mg,
2.12 mmol, 1 equiv) and 3-bromo-N-(1-tert-butoxycarbonyl)-
propylamine (1.51 g, 6.36 mmol, 3 equiv) in DMF (30 mL) at
0 °C was added portionwise NaH (60% in oil) (340 mg, 8.5
mmol, 4 equiv). The obtained suspension was stirred overnight
with increasing temperature from 0 °C to rt. The excess of NaH
was then destroyed by addition of methanol (0.32 mL) and
water (0.63 mL) at 0 °C. The solvents were removed by
distillation to afford a brown oil, which was diluted in
dichloromethane and washed two times with water. The
organic layer was dried over Na2SO4, filtered, and evaporated
to dryness to provide a brown oil, which was purified by
chromatography on silica gel, CH2Cl2/acetone (95:5): yield
65%; Rf 0.27 (AcOEt/nHex, 1:3); 1H NMR δ 7.20-7.11 (m, 15H),
Met h yl 3,5,6-Tr i-O-b en zyl-2-O-(8-a m in ooct yl)-r,â-D-
glu cofu r a n osid e (6b). To a solution of 5b (279 mg, 0.39
mmol, 1 equiv) in methanol (6 mL) was added at rt hydrazine
(24% in water) (0.41 mL, 3.1 mmol, 8 equiv). After one night
of stirring the solvent was removed and the crude oil directly
used in the following step without any purification: yield 77%;
Rf 0.10 (AcOEt/nHex, 2:1); IR (neat) 1702, 1580, 1494 cm-1
;
1H NMR δ 7.35-7.19 (m, 15H), 4.84-4.71 (m, 2H), 4.65-4.45
(m, 5H), 4.28 (dd, J ) 9.0, 4.5 Hz, 1H), 4.12-4.03 (m, 1H),
3.98 (d, J ) 4.8 Hz, 1H), 3.89 (dd, J ) 10.5, 2.1 Hz, 1H), 3.77
(s large, 1H), 3.70 (dd, J ) 10.5, 5.4 Hz, 1H), 3.36 (s, 3H), 3.31
(t, J ) 6.6 Hz, 2H), 3.24-3.31 (m, 2H), 1.52-1.35 (m, 4H),
1.29-1.14 (m, 8H); HRMS m/z calcd for C36H49NO6 591.3560,
found 591.3555.
Meth yl 3,5,6-Tr i-O-ben zyl-2-O-[2-(2-a m in oeth oxy)eth -
oxy]eth yl-r,â-D-glu cofu r a n osid e (6c). To a solution of 5c
(1.83 g, 2.95 mmol, 1 equiv) in THF (25 mL) was added at rt
J . Org. Chem, Vol. 68, No. 2, 2003 515

Dumas et al.
a solution of LiAlH4 (2.3M) in THF (1.3 mL, 2.95 mmol, 1
equiv). After 3 h of reflux the resulting solution cooled, and
the excess LiAlH4 was destroyed by successive addition of
water (22 µL), NaOH (3.75 M, 221 µL), and water (620 µL).
The resulting suspension was filtered over a Celite pad and
the filtrate evaporated to dryness to afford a colorless oil: yield
filtered over a Celite pad, and the solution was evaporated to
dryness to afford a colorless oil used without purification in
the following step: yield 85%; Rf 0.52 (AcOEt); IR (neat) 1748
1
cm-1; (7a r) H NMR (D2O) δ 5.94 (d, J ) 3.9 Hz, 1H), 5.04-
4.87 (m, 5H), 4.71-4.64 (m, 1H), 4.47 (d, J ) 3.9 Hz, 1H),
4.43-3.35 (m, 1H), 4.24-4.01 (m, 2H), 4.00-3.70 (m, 6H),
3.68-3.40 (m, 5H), 3.29 (t, J ) 6.9 Hz, 2H), 1.80-1.69 (m, 2H);
50%; Rf 0.26 (AcOEt/nHex, 5:1); IR (neat) 1108, 1062 cm-1
;
1H NMR δ 7.60-7.21 (m, 15H), 5.09 (d, J ) 4.0 Hz, 0.4H),
4.97 (s, 0.6H), 4.88 (dd, J ) 11.4, 6.0 Hz, 1H), 4.82-4.59 (m,
5.4H), 5.13-4.37 (m, 1H), 4.35-4.28 (m, 0.6H), 4.23-4.08 (m,
2H), 4.05-3.95 (m, 2H), 3.89-3.64 (m, 10H), 3.62-3.55 (m,
1
(7a â) H NMR (CD3OD) δ 5.32 (d, J ) 3.3 Hz, 1H), 4.54 (d, J
) 7.8 Hz, 1H), 4.48-4.24 (m, 4H), 4.17-4.04 (m, 1H), 4.03-
3.48 (m, 6H), 3.87 (s, 9H), 3.43-3.20 (m, 2H), 2.13-1.99 (m,
2H); HRMS m/z calcd for C16H29NO10 395.1791, found 395.1788.
2H), 3.52 (s, 1.2H), 3.49 (s, 1.8H); HRMS m/z calcd for C34H45
-
Meth yl 2-O-[Bis-N-[(1-m eth oxyca r bon yl)m eth yl]a m i-
n ooctyl]-r,â-D-glu cofu r a n ose (8b). Compound 8b was pre-
pared from 7b according to the preparation of 8a : yield 99%;
Rf 0.30 (AcOEt/nHex, 5:3); IR (neat) 1750, 1656 cm-1; 1H NMR
(CD3OD) δ 4.97 (d, J ) 4.7 Hz, 1H), 4.72 (s large, 1H), 4.15 (d,
J ) 3.9 Hz, 1H), 3.99-3.64 (m, 6H), 3.79 (s, 6H), 3.62-3.43
(m, 4H), 3.36-3.21 (m, 2H), 3.28 (s, 3H), 1.74-1.42 (m, 4H),
1.38-1.22 (m, 8H); 13C NMR (CD3OD) δ 168.8 (2C), 110.1, 90.9,
83.5, 75.8, 72.6, 71.9, 65.9, 58.9, 56.6, 56.1 (2C), 54.6 (2C), 31.6,
31.0, 30.9, 28.2, 27.9, 26.0; HRMS m/z calcd for C21H40NO10
465.2652, found 465.2652 (MH+).
NO8 595.3145, found 595.3137.
Meth yl 3,5,6-Tr i-O-ben zyl-2-O-[bis-N-[(1-m eth oxyca r -
bon yl)m eth yl]a m in op r op yl]-r,â-D-glu cofu r a n osid e (7a ).
To a solution of 5a (857 mg, 1.38 mmol, 1 equiv) in CH2Cl2 (5
mL) was added at rt TFA (0.85 mL, 16.8 mmol, 8 equiv). The
resulting solution was stirred for 1 h and then washed with
water (10 mL) and a saturated solution of NaHCO3 (10 mL).
The organic layer was dried over Na2SO4 and evaporated to
afford 6a as a crude oil directly used in the following step: Rf
0.26 (CH2Cl2). Triethylamine (0.35 mL, 2.5 mmol, 2.1 equiv)
and methyl bromoacetate (0.23 mL, 2.5 mmol, 2.1 equiv) were
added to a solution of 6a (617 mg, 1.19 mmol, 1 equiv) in THF
(8 mL), and the solution was refluxed overnight. After cooling,
the mixture was filtered; the filtrate was diluted with CH2Cl2
(15 mL) and washed with water (15 mL). The organic layer
was dried over Na2SO4, and the solvent was removed under
reduced pressure. The crude product was purified by column
chromatography on silica gel, AcOEt/nHex (1:2): yield 59%
from 5a ; Rf 0.34 (AcOEt/nHex, 1:3); IR (neat) 1710, 1452, 1364,
Meth yl 2-O-[2-[Bis-N-[(1-m eth oxycar bon yl)m eth yl]am i-
n oeth oxy]eth oxy]eth yl-r,â-D-glu cofu r a n osid e (8c). Com-
pound 8c was prepared from 7c according to the preparation
1
of 8a : yield quantitative; Rf 0.31 (AcOEt); H NMR δ 4.83-
4.76 (m, 1H), 4.71 (d, J ) 11.8 Hz, 0.5H), 4.51 (d, J ) 11.8 Hz,
0.5H), 4.34-4.28 (m, 0.5H), 4.17-4.05 (m, 1.5H), 3.99-3.64
(m, 3H), 3.71-3.47 (m, 10H), 3.65 (s, 6H), 3.63 (s, 4H), 3.33
(s, 1.5H), 3.32 (s, 1.5H), 2.98-2.86 (m, 2H); 13C NMR δ 172.2,
172.1, 108.5, 107.8, 88.8, 87.8, 82.7, 81.7, 79.8, 75.0, 72.7 (2C),
71.6, 71.3, 71.2, 71.0, 70.9 (2C), 70.8, 70.7, 70.6 (2C), 70.6, 70.3
(2C), 70.1 (2C), 69.9, 64.7, 64.6, 56.2, 56.0, 55.9, 55.8, 54.1,
1
1206 cm-1; H NMR δ 7.36-7.23 (m, 15H), 4.82 (s, 1H), 4.77
(d, J ) 11.4 Hz, 1H), 4.61-4.54 (m, 4H), 4.52 (d, J ) 11.1 Hz,
1H), 4.32-4.20 (m, 1H), 4.12-4.04 (m, 1H), 4.01-3.98 (m, 1H),
3.96-3.84 (m, 1H), 3.84-3.62 (m, 2H), 3.68 (s, 6H), 3.53 (s,
4H), 3.43 (t, J ) 6.3 Hz, 2H), 3.38 (s, 3H), 2.75 (t, J ) 7.2 Hz,
2H), 1.74-1.64 (m, 2H); MS m/z 688.5 (MNa+). Anal. Calcd
for C37H47NO10 (665.32): C, 66.75; H, 7.12; N, 2.10. Found:
C, 66.70; H, 7.09; N, 1.74.
54.0, 52.2, 52.0; MS m/z 492.2 (MNa+). Anal. Calcd for C19H35
-
NO12 (469.22): C, 48.61; H, 7.51; N, 2.98. Found: C, 48.95; H,
7.11; N, 2.99.
1,3,5,6-Tetr a-O-acetyl-2-O-[bis-N-[(1-m eth oxycar bon yl)-
m eth yl]]a m in op r op yl-r,â-D-glu cop yr a n ose (9a ). To a sus-
pension of 8a (130 mg, 0.28 mmol, 1 equiv) in anhydride acetic
(3 mL) was added at 0 °C and under nitrogen flux TMSOTf
(49 µL, 0.28 mmol, 1 equiv). After 40 min of stirring at 0 °C,
the solution was diluted in dichloromethane and poured into
a NaHCO3/ice mixture. The biphasic solution was stirred, and
NaHCO3 was added until a constant basic pH was reached.
The layers were separated, and the aqueous one was extracted
two times with dichloromethane. The combined organic layers
were then dried over Na2SO4, filtered, and evaporated to
dryness to afford a yellow oil, which was purified by chroma-
tography on silica gel, AcOEt/nHex (2:1). The desired product
was obtained as a colorless oil with a yield of 90%: Rf 0.36
(AcOEt/nHex, 2:1); IR (neat) 1750, 1436, 1370 cm-1; 1H NMR
δ 6.34 (d, J ) 3.9 Hz, 0.2H), 5.55 (d, J ) 8.0 Hz, 0.3H), 5.34-
5.25 (m, 0.5H), 5.18-4.92 (m, 1H), 4.30-4.20 (m, 1H), 4.12-
3.99 (m, 1H), 3.82-3.35 (m, 5H), 3.67 (s, 6H), 3.49 (s, 4H),
2.74-2.64 (m, 2H), 2.06 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 1.99
(s, 3H), 1.68-1.55 (m, 2H); HRMS m/z calcd for C23H36NO14
550.2136, found 550.2136 (MH+).
Meth yl 3,5,6-Tr i-O-ben zyl-2-O-[bis-N-[(1-m eth oxyca r -
b on yl)m et h yl]a m in ooct yl]-r,â-D-glu cofu r a n osid e (7b ).
Compound 7b was prepared from 6b according to the prepara-
1
tion of 7a : yield 56%; Rf 0.52 (AcOEt/nHex, 5:3); H NMR δ
7.38-7.21 (m, 15H), 4.83-4.74 (m, 2H), 4.63-4.48 (m, 5H),
4.28 (dd, J ) 9.1, 4.6 Hz, 1H), 4.08 (ddd, J ) 9.0, 5.4, 1.8 Hz,
1H), 3.99 (d, J ) 4.5 Hz, 1H), 3.90 (dd, J ) 10.5, 1.8 Hz, 1H),
3.77 (s, 1H), 3.73 (d, J ) 5.4 Hz, 1H), 3.70 (s, 6H), 3.55 (s,
4H), 3.38 (s, 3H), 3.32 (t, J ) 6.6 Hz, 2H), 2.68 (m, Hz, 2H),
1.54-1.39 (m, 4H), 1.32-1.20 (m, 8H); 13C NMR δ 172.4 (2C),
139.9, 139.5, 138.8, 129.0 (3C), 128.9 (2C), 128.8 (2C), 128.6
(2C), 128.3, 128.2 (3C), 128.0, 127.9, 109.3, 86.9, 81.2, 80.8,
77.5, 74.0, 73.1, 72.8, 71.6, 70.7, 56.6, 55.6 (2C), 55.2 (2C), 52.2,
30.3, 30.1, 30.0, 28.5, 27.8, 26.6; MS m/z 736.3 (MH+). Anal.
Calcd for C42H57NO10 (735.40): C, 68.55; H, 7.81; N, 1.90.
Found: C, 68.29; H, 7.94; N, 1.64.
Meth yl 3,5,6-Tr i-O-ben zyl-2-O-[2-[bis-N-[(1-m eth oxy-
ca r bon yl)m eth yl]a m in oeth oxy]eth oxy]eth yl-r,â-D-glu co-
fu r a n osid e (7c). Compound 7c was prepared from 6c accord-
ing to the preparation of 7a : yield 62%; Rf 0.24 (AcOEt/nHex,
1:1); 1H NMR δ 7.55-7.25 (m, 15H), 4.96 (s, 1H), 4.88 (d, J )
11.4 Hz, 1H), 4.84-4.58 (m, 4H), 4.62 (d, J ) 11.4 Hz, 1H),
4.40 (dd, J ) 9.0, 4.8 Hz, 1H), 4.18 (ddd, J ) 9.0, 5.7, 2.1 Hz,
1H), 4.14 (d, J ) 4.5 Hz, 1H), 4.08-3.46 (m, 12H), 4.01 (dd, J
) 10.5, 2.1 Hz, 1H), 3.8 (s, 6H), 3.73 (4H), 3.49 (s, 3H), 3.06 (t,
J ) 5.7 Hz, 2H). Anal. Calcd for C40H53NO12 (739.36): C, 65.03;
H, 7.09; N, 1.90. Found: C, 65.01; H, 6.94; N, 1.51.
Meth yl 2-O-[Bis-N-[(1-m eth oxyca r bon yl)m eth yl]a m i-
n op r op yl]-r,â-D-glu cofu r a n osid e (8a ). To a solution of 7a
(450 mg, 0.67 mmol, 1 equiv) in methanol (15 mL) was added
at rt Pd(OH)2/C (10% by weight) (45 mg). The resulting
suspension was stirred under 1 atm of hydrogen till the TLC
showed no more starting material. The suspension was then
1,3,5,6-Tetr a-O-acetyl-2-O-[bis-N-[(1-m eth oxycar bon yl)-
m eth yl]a m in ooctyl]-r,â-D-glu cop yr a n ose (9b). Compound
9b was prepared from 8b according to the preparation of 9a :
1
yield 66%; Rf 0.38 (AcOEt/nHex, 2:1); H NMR δ 6.35 (d, J )
4.8 Hz, 0.03H), 6.17 (s, 0.18H), 5.86 (d, J ) 5.1 Hz, 0.34H),
5.81 (d, J ) 4.5 Hz, 0.45H), 5.54-5.33 (m, 1.7H), 5.28-5.19
(m, 0.3H), 4.74-4.50 (m, 0.5H), 4.42-4.32 (m, 0.5H), 4.21-
4.12 (m, 1H), 3.93-3.44 (m, 4H), 3.77 (s, 6H), 3.61 (s, 4H),
2.78-2.69 (m, 2H), 2.19-2.06 (m, 12H), 1.66-1.48 (m, 4H),
1.39-1.28 (m, 8H); 13C NMR δ 172.2 (2C), 171.2, 170.6, 170.3,
169.6, 94.2, 89.9, 79.3, 74.8, 73.1, 72.3, 71.4, 70.3, 69.9, 68.7,
62.3 (2C), 55.4 (2C), 52.2, 51.8, 51.6, 29.3, 29.0, 21.6, 21.4, 21.3;
MS m/z 620.2 (MH+). Anal. Calcd for C28H45NO14 (619.28): C,
54.27; H, 7.32; N, 2.26. Found: C, 54.13; H, 7.37; N, 2.38.
516 J . Org. Chem., Vol. 68, No. 2, 2003

Glucose Derivatives of Iminodiacetic Acid
1,3,5,6-Tetr a -O-a cetyl-2-O-[2-[bis-N-[(1-m eth oxyca r bo-
n yl)m eth yl]a m in oeth oxy]eth oxy]eth yl-r,â-D-glu cop yr a -
n ose (9c). Compound 9c was prepared from 8c according to
the preparation of 9a : yield 41%; Rf 0.44 (AcOEt); 1H NMR δ
6.24 (dd, J ) 8.5, 4.3 Hz, 0.06H), 6.04 (d, J ) 11.4 Hz, 0.27H),
5.86 (d, J ) 5.5 Hz, 0.17H), 5.74 (d, J ) 5.2 Hz, 0.27H), 5.74
(d, J ) 8.2 Hz, 0.23H), 5.41-5.17 (m, 2H), 5.13-5.06 (m, 0.5H),
4.81-4.36 (m, 1.5H), 4.33-4.19 (m, 0.8H), 4.17-3.96 (m, 2.2H),
3.89-3.41 (m, 10.99H), 3.63 (s, 6H), 3.39 (s, 0.81H), 3.36 (s,
0.69H), 3.28 (s, 0.51H); 2.93-2.83 (m, 2H), 2.09-1.94 (m, 12H);
MS m/z 646.2 (MNa+). Anal. Calcd for C26H41NO16 (623.61):
C, 50.08; H, 6.63; N, 2.25. Found: C, 50.17; H, 6.37, N, 2.29.
MS m/z 484.3(MNa+). Anal. Calcd for C24H31NO8 (461.206):
C, 62.46; H, 6.77; N, 3.04. Found: C, 62.47; H, 6.82; N, 3.20.
1,2:3,5-(O-Met h ylen e)-6-O-(3-a m in op r op yl)-r-D-glu co-
fu r a n ose (13a ). Compound 13a was prepared from 12a
according to the preparation of 6a : yield 91%; Rf 0.15 (CH2-
20
1
Cl2/acetone, 95:5); [R]D ) +13.4, c 0.047, MeOH; H NMR δ
5.99 (d, J ) 3.6 Hz, 1H), 5.04 (d, J ) 4.8 Hz, 1H), 5.01 (d, J )
4.8 Hz, 1H), 4.88 (s, 2H), 4.53 (d, J ) 3.3 Hz, 1H), 4.24-4.22
(m, 1H), 4.05-4.01 (m, 2H), 3.83-3.74 (m, 3H), 3.65-3.57 (m,
1H), 3.30-3.19 (m, 2H), 2.04-1.99 (m, 2H); 13C NMR δ 105.1
(t), 104.9 (t), 97.0 (d, 2C), 88.5 (t, 2C), 84.2 (t), 84.0 (t), 71.6
(d), 66.4 (d). Anal. Calcd for C11H19NO6 (261.12): C, 50.57; H,
7.33; N, 5.36. Found: C, 50.25; H, 7.00; N, 5.63.
2-O-[Bis(car boxym eth yl)am in opr opyl]-r,â-D-glu co pyr -
a n ose (10a ). NaOMe (13.4 mg, 0.25 mmol, 1 equiv) was added
to a solution of 9a (137.2 mg, 0.25 mmol, 1 equiv) in dry
methanol (1 mL) at rt under nitrogen flux. After 3 h of reaction
the solvent was removed, and the product was dissolved in
NaOH (0.091 N, 1 mL) and stirred overnight. The solution was
neutralized by addition of Dowex 50W-X8 till pH 7 was
attained. The solution was then filtered and evaporated to
1,2:3,5-(O-Meth ylen e)-6-O-(8-am in ooctyl)-r-D-glu cofu r a-
n ose (13b). Compound 13b was prepared from 12b according
to the preparation of 6b: yield 81%; Rf 0.33 (CH2Cl2/acetone,
20
95:5); [R]D ) -12, c 0.00084, MeOH; IR (neat) 1708, 1634
cm-1; 1H NMR δ 6.13 (d, J ) 3.9 Hz, 1H), 5.23 (d, J ) 6.0 Hz,
1H), 5.20-5.10 (m, 2H), 4.88 (d, J ) 6.0 Hz, 1H), 4.56 (d, J )
4.8 Hz, 1H), 4.46 (d, J ) 2.4 Hz, 1H), 4.29-4.20 (m, 1H), 4.17-
4.09 (m, 1H), 3.92-3.81 (m, 1H), 3.81-3.70 (m, 1H), 3.56-
3.45 (m, 2H), 2.96-2.84 (m, 2H), 2.90-1.05 (m, 12H); 13C NMR
δ 105.2, 104.8, 97.2, 84.5, 76.9, 76.6, 72.8, 72.5, 72.3, 72.0, 32.3,
30.2, 29.9, 27.4, 26.8, 23.3; MS m/z 332.3 (MH+). Anal. Calcd
for C16H29NO6 (331.20): C, 57.99; H, 8.82; N, 4.23. Found: C,
58.37; H, 8.56; N, 4.34.
1
afford an oil: yield 85%; IR (neat) 1632, 1402 cm-1; H NMR
(CD3OD) δ 5.44 (m, 0.5H), 4.72 (d, J ) 8.1 Hz, 0.5H), 4.26-
3.59 (m, 8H), 3.56-3.45 (m, 2H), 3.39-3.10 (m, 1H), 3.21-
3.18 (m, 0.5H), 3.06-2.92 (m, 0.5H), 2.28-2.01 (m, 2H), 1.56-
1.40 (m, 2H); MS m/z 357.0 (MH4+). Anal. Calcd for C13H23NO10
(353.13): C, 44.19; H, 6.56; N, 3.96. Found: C, 43.83; H, 6.57;
N, 3.62.
6-O-[Bis-N-[(1-m eth oxycar bon yl)m eth yl]am in opr opyl]-
1,2:3,5-(O-m eth ylen e)-r-D-glu cofu r a n ose (14a ). Compound
14a was prepared from 13a according to the preparation of
7a , AcOEt/nHex (1:2): yield 58%; Rf 0.87 (CH2Cl2/acetone, 95:
5); [R]D20 ) -37.9, c 0.0380, MeOH; 1H NMR δ 5.88 (d, J ) 3.7
Hz, 1H), 5.04-4.89 (m, 3H), 4.79-4.67 (m, 1H), 4.39 (dd, J )
8.7, 3.7 Hz, 1H), 4.23 (dd, J ) 12.7, 1.7 Hz, 1H), 4.08-4.01
(m, 1H), 3.95-3.90 (m, 1H), 3.72-3.54 (m, 2H), 3.62 (s, 6H),
3.56-3.34 (m, 2H), 3.47 (s, 4H), 2.77-2.68 (m, 2H), 1.75-1.61
(m, 2H); 13C NMR δ 146.4, 140.0, 105.1, 104.9, 97.3, 97.2, 88.9,
88.5, 84.3, 76.6, 76.4 (2C), 72.2, 72.1, 68.6 (2C), 68.5; MS m/z
428.3 (MNa+). Anal. Calcd for C17H27NO10 (405.16): C, 50.37;
H, 6.71; N, 3.46. Found: C, 50.56; H, 6.37; N, 3.48.
2-O-[Bis(ca r boxym eth yl)a m in ooctyl]-r,â-D-glu cop yr a -
n ose (10b). Compound 10b was prepared from 9b according
to the preparation of 10a : yield 89%; IR (neat) 1596, 1354
1
cm-1; H NMR (CD3OD) δ 5.37 (d, J ) 3.3 Hz, 0.5H), 4.64-
4.59 (m, 0.5H), 4.12-3.56 (m, 9H), 3.52-3.45 (m, 1H), 3.39-
3.34 (m, 1H), 3.34-3.22 (m, 2.5H), 3.01 (dd, J ) 8.7, 8.1 Hz,
0.5H), 1.89-1.78 (m, 2H), 1.76-1.65 (m, 2H), 1.57-1.40 (m,
8H); MS m/z 423.2 (M). Anal. Calcd for C18H33NO10 (423.21):
C, 51.05; H, 7.85; N, 3.31. Found: C, 51.00; H, 7.88; N, 3.46.
2-O-[2-[Bis(ca r boxym eth yl)a m in oeth oxy]eth oxy]eth yl-
r,â-D-glu cop yr a n ose (10c). Compound 10c was prepared
from 9c according to the preparation of 10a : yield 81%; 1H
NMR (CD3OD) δ 5.48-5.35 (m, 0.45H), 5.26-5.10 (m, 0.55H),
4.60-4.49 (m, 0.5H), 4.08-3.81 (m, 2H), 3.76-3.48 (m, 1.5H),
3.36-3.10 (m, 3H), 3.10-2.75 (m, 13H), 2.39-2.25 (m, 2H);
MS m/z 427.3 (M). Anal. Calcd for C16H29NO12 (427.17): C,
44.96; H, 6.84; N, 3.28. Found: C, 44.89; H, 6.82; N, 3.15.
6-O-[Bis-N-[(1-m eth oxyca r bon yl)m eth yl]a m in ooctyl]-
1,2:3,5-(O-m eth ylen e)-r-D-glu cofu r a n ose (14b). Compound
14b was prepared from 13b according to the preparation of
7a : yield 62%; [R]D20 ) +122, c 0.0043, MeOH; IR (neat) 1746,
1
1660 cm-1; H NMR δ 6.15 (d, J ) 3.9 Hz, 1H), 5.25 (d, J )
6.0 Hz, 1H), 5.21-5.19 (m, 1H), 5.19-5.16 (m, 1H), 4.90 (d, J
) 5.7 Hz, 1H), 4.58 (d, J ) 3.9 Hz, 1H), 4.48 (d, J ) 1.8 Hz,
1H), 4.24-4.20 (m, 1H), 4.18-4.15 (m, 1H), 3.86-3.82 (m, 1H)
3.81 (s, 6H), 3.80-3.76 (m, 1H), 3.66 (s, 4H), 3.59-3.50 (m,
2H), 2.79 (dd, J ) 7.5, 5.4 Hz, 2H), 1.73-1.29 (m, 12H); MS
m/z 498.6 (MNa+); HRMS m/z calcd for C22H37NO10 475.2417,
found 475.2426.
6-O-(3-ter t-Bu toxycar bon ylam in opr opyl)-1,2:3,5-(O-m e-
th ylen e)-r-D-glu cofu r a n ose (12a ). Compound 12a was pre-
pared from 1,2:3,5-(O-methylene)-R-D-glucofuranose (11) and
3-bromo-N-(1-tert-butoxycarbonyl)propylamine according to
the preparation of 5a : yield 57%; Rf 0.38 (CH2Cl2/acetone, 95:
20
5); [R]D ) +0.7, c 0.008, MeOH; IR (neat), 2922, 1710 cm-1
;
1H NMR δ 6.01 (d, J ) 3.9 Hz, 1H), 5.12-4.97 (m, 4H), 4.82
(dd, J ) 9.4, 5.9 Hz, 1H), 4.46 (dd, J ) 9.4, 3.9 Hz, 1H), 4.32
(dd, J ) 6.5, 2.4 Hz, 1H), 4.15-4.08 (m, 1H), 4.03-3.99 (m,
1H), 3.76 (dd, J ) 10.5, 3.9 Hz, 1H), 3.66 (dd, J ) 10.5, 4.8
Hz, 1H), 3.59-3.41 (m, 2H), 3.28-3.11 (m, 2H), 1.82-1.70 (m,
6-O-[Bis(ca r boxym eth yl)a m in op r op yl]-r,â-D-glu cop y-
r a n ose (15a ). Compound 14a (117 mg, 0.29 mmol, 1 equiv)
was dissolved in a 1 M solution of NaOH (1 mL). After 2 h of
stirring at rt, the solution was neutralized by addition of
Dowex 50W-X8 till pH 5-6 was attained. The solution was
then filtered and evaporated to afford an oil: yield 78%; IR
2H), 1.42 (s, 9H); MS m/z 384.3 (MNa+). Anal. Calcd for C16H27
-
1
(neat) 1716, 1654, 1560 cm-1; H NMR (CD3OD) δ 5.94 (d, J
NO8 (361.17): C, 53.18; H, 7.53; N, 3.88. Found: C, 53.17; H,
7.26; N, 4.01.
) 3.9 Hz, 0.5H), 5.09 (d, J ) 6.3 Hz, 0.5H), 5.07-5.02 (m, 1H),
5.01-4.96 (m, 1H), 4.70 (d, J ) 6.6 Hz, 0.5H), 4.54-4.39 (m,
0.5H), 4.39-4.28 (m, 0.5H), 4.17-3.92 (m,1.5H), 3.86-3.65 (m,
1H), 3.76 (s, 2H), 3.74 (s, 2H), 3.56-3.47 (m, 2H), 3.43-2.30
(m, 2H), 1.89-1.76 (m, 2H); MS m/z 356.1 (MH3+). Anal. Calcd
for C13H23NO10 (353.13): C, 44.19; H, 6.56; N, 3.96. Found:
C, 44.05; H, 6.61; N, 4.08.
1,2:3,5-(O-Meth ylen e)-6-O-(8-ph th alim idooctyl)-r-D-glu -
cofu r a n ose (12b). Compound 12b was prepared from 11 and
N-bromooctylphthalimide according to the preparation of 5a :
20
yield 40%; Rf 0.33 (CH2Cl2/acetone, 95:5), [R]D ) +18.0, c
1
0.0183, MeOH; IR (neat) 1772, 1712, 1400 cm-1; H NMR δ
8.08-7.89 (m, 2H), 7.57-7.34 (m, 2H), 5.97 (d, J ) 3.6 Hz,
1H), 5.12-4.94 (m, 3H), 4.75 (dd, J ) 6.0, 5.7 Hz, 1H), 4.42
(dd, J ) 8.4, 3.9 Hz, 1H), 4.30 (dd, J ) 12.0, 2.4 Hz, 1H), 4.13-
4.02 (m, 1H), 4.00-3.95 (m, 1H), 3.73 (dd, J ) 10.5, 3.6 Hz,
1H), 3.62 (dd, J ) 10.5, 4.8 Hz, 1H), 3.45-3.26 (m, 4H), 1.69-
1.43 (m, 4H), 1.42-1.16 (m, 8H); 13C NMR δ 166.1 (2C), 134.7,
134.2, 132.7 (2C), 124.0, 123.3, 105.0, 104.5, 97.1, 78.1, 76.8,
76.4, 72.7, 72.3, 72.2, 71.8, 30.0, 29.7, 29.6, 29.1, 27.3, 26.6;
6-O-[Bis(ca r boxym eth yl)a m in ooctyl]-r,â-D-glu cop yr a -
n ose (15b). Compound 15b was prepared from 14b according
to the preparation of 9a : yield 77%; IR (neat) 1602, 1402 cm-1
;
1H NMR (CD3OD) δ 6.14 (d, J ) 6.5 Hz, 0.6H), 5.18-5.09 (m,
2.4H), 4.70-4.64 (m, 1H), 4.59 (s large, 1H), 4.39-4.32 (m,
1H), 4.13-3.98 (s large, 1H), 4.08-3.96 (m, 1H), 3.85 (s large,
1H), 3.81-3.59 (m, 4H), 3.34-3.02 (m, 2H), 1.84-1.32 (m,
J . Org. Chem, Vol. 68, No. 2, 2003 517

Dumas et al.
12H); MS m/z 423.1 (M). Anal. Calcd for C18H33NO10 (423.21):
C, 51.05; H, 7.85; N, 3.31. Found: C, 50.98; H, 7.88; N, 3.39.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
all the products and 13C NMR spectra of 5b, 5d , 7b, 7c, 8c,
9c, 12b, and 14a . This material is available free of charge via
the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We thank Professor A. Vasella
for his helpful discussions and Mallinckrodt Inc. for
financial support of this work.
J O025978O
518 J . Org. Chem., Vol. 68, No. 2, 2003