Stereospecific synthesis of the α- and β-D-glucopyranosyl ureas

Article abstract of DOI:10.1021/jo0100751

A new, one-pot, two-stage procedure for the preparation of the α- and β-D-glucopyranosyl ureas has been developed. Oxidation of glucopyranosyl isocyanides provides glucopyranosyl isocyanates, which can be trapped in situ with amines to afford good yields of glucopyranosyl ureas. Application of this method establishes the successful synthesis of the hitherto unknown N,N′-di-α,α- and α,β-D-glucopyranosyl ureas.

Full text of DOI:10.1021/jo0100751

4200
J . Org. Chem. 2001, 66, 4200-4205
Ster eosp ecific Syn th esis of th e r- a n d â-D-Glu cop yr a n osyl Ur ea s
Yoshiyasu Ichikawa,* Taihei Nishiyama, and Minoru Isobe
Laboratory of Organic Chemistry, School of Bioagricultural Sciences, Nagoya University,
Chikusa, Nagoya 464-8601, J apan
ichikawa@agr.nagoya-u.ac.jp
Received J anuary 22, 2001
A new, one-pot, two-stage procedure for the preparation of the R- and â-D-glucopyranosyl ureas
has been developed. Oxidation of glucopyranosyl isocyanides provides glucopyranosyl isocyanates,
which can be trapped in situ with amines to afford good yields of glucopyranosyl ureas. Application
of this method establishes the successful synthesis of the hitherto unknown N,N′-di-R,R- and R,â-
D-glucopyranosyl ureas.
In tr od u ction
The first synthesis of glucopyranosyl ureas dates back
to the report from 1903 by Schoorl, who employed the
acid-catalyzed condensation of D-glucose with urea in
water.1 Further improvement of this method by Benn
established the synthesis of the N-â-D-glucopyranosyl
urea 1 and the N,N′-di-â,â-D-glucopyranosyl urea 2
(Figure 1).2 Fisher reported another method for the
preparation of 1 as shown in Scheme 1.3 In Fisher’s
method, reaction of the tetraacetylbromoglucose 3 with
silver cyanate in xylene provided the glucopyranosyl
isocyanate 4 which was treated with aqueous ammonia
to afford 1. Subsequent work by J ohnson and Bergman
demonstrated that Fisher’s preliminary experiments for
the synthesis of glucopyranosyl isocyanate 4 were not
stereospecific. Two types of glucopyranosyl isocyanates
were isolated, but their stereochemistry has never been
determined.4 More recently, the synthesis of sugar ureas
by employing the sugar phosphinimines have been
reported.5 Although many methods for the synthesis of
the â-D-glucopyranosyl ureas have been documented, they
are all limited in scope because no method for the
preparation of the R-D-glucopyranosyl urea is available.
F igu r e 1.
Sch em e 1
anates and ureas, where initial experimental reports
focused on the preparation of the glucopyranosyl isocy-
anates.7
Resu lts a n d Discu ssion
In the course of our research to explore a new type of
the glycopeptide mimic, we examined the synthesis of
glucopyranosyl isocyanates and their reactions with
amines for stereospecific synthesis of the R- and â-D-
glucopyranosyl ureas. Although synthesis of the R- and
â-D-glucopyranosyl isothiocyanates has been extensively
studied,6 no general method for the synthesis of the R-
and â-D-glucopyranosyl isocyanates has been reported.
Under this circumstance, we set out to develop a new
method for the synthesis of glucopyranosyl isocyanates
and ureas. In this report, we will discuss the details and
further efforts on the synthesis of glucopyranosyl isocy-
In itia l Ap p r oa ch to th e Syn th esis of Glu cop yr a -
n osyl Isocya n a tes. Our initial plan for the synthesis
of the glucopyranosyl isocyanates relied upon the reaction
of glucopyranosylamines with phosgen equivalent (COX2),
because a similar reaction of the glucopyranosylamines
with thiophosgene for the preparation of the glucopyra-
nosyl isothiocyanates has been well studied.8 In addition,
we planned to prepare both the R- and â-D-glucopyrano-
sylamines by reducing the R- and â-D-glucopyranosyl
azides. Scheme 2 shows our approach of this plan.
Catalytic hydrogenation of the â-azide 5 in the pres-
ence of triethylamine gave the â-amine 6 as crystals.9 A
solution of 6 in dichloromethane was treated with triph-
osgene and aqueous sodium hydrogencarbonate.10 After
(1) Schoorl, M. N. Rec. Trav. Chim. 1903, 22, 31.
(2) Benn, M. H.; J ones, A. S. J . Chem. Soc. 1960, 3837.
(3) Fisher, E. Ber. 1914, 47, 1377.
(4) J ohnson, T. B.; Bergmann, W. J . Am. Chem. Soc. 1932, 54, 3360.
(5) (a) Bannister, B. J . Antibio. 1972, 25, 377. (b) Pinter, I.; Kovacs;
J .; Toth, G. Carbohydr. Res. 1995, 273, 99.
(6) (a) M. J .; Fernandez-Resa, P.; Garcia-Lopez. M. T.; Heras, F. G.;
Mendez-Castrillon, P. P.; Felix, A. S. Synthesis 1984, 509. (b) Lindhorst,
T. K.; Kieburg, C. Synthesis 1995, 1228. (c) Benito, J . M.; Mellet, C.
O.; Sadalapure, K.; Lindhorst, T. K.; Defaye, J .; Garcua Fernandez, J .
M. Carbohydr. Res. 1999, 320, 37.
(7) For a preliminary account of this work, see: Ichikawa, Y.;
Nishiyama, T.; Isobe, M. Synlett 2000, 1253.
(8) Babiano Caballero, R.; Fuentes Mota, J .; Galbis Perez, J . A.
Carbohydr. Res. 1986, 154, 280.
(9) Ogawa reported that the use of less polar solvent and the
addition of triethylamine prevents anomerization during catalytic
hydrogenation of the glucopyranosyl azide. See: Ogawa, T.; Nakaba-
yashi, S.; Shibata, S. Agric. Biol. Chem. 1983, 47 (29), 281.
10.1021/jo0100751 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/16/2001

R- and â-D-Glucopyranosyl Ureas
J . Org. Chem., Vol. 66, No. 12, 2001 4201
Sch em e 2
Sch em e 4
Sch em e 3
to trap the unstable R-amine 9 in situ. Accordingly, the
reaction mixture was immediately treated with cyclo-
hexyl isocyanate after catalytic hydrogenation of 8;
however, the mixture we isolated consisted of ureas 10a
and 7a that were difficult to separate. Since R-amine 9
is so pronounced to isomerize into the â-amine 6, we have
concluded that a more stable precursor for the prepara-
tion of the R-D-glucopyranosyl isocyanate should be
selected.
Syn th esis of th e Glu cop yr a n osyl Ur ea s Sta r tin g
fr om th e Glu cop yr a n osyl Isocya n id es. Martin-Lomas
reported that the reaction of the tetraacetyl-R-D-gluopy-
ranosyl bromide with silver cyanide in boiling xylene
afforded a mixture of the R- and â-D-glucopyranosyl
isocyanides in 10 and 12% yield.14 Separation of this
mixture by silica gel chromatograghpy gave each isocya-
nide as stable crystals. Lead tetracetate oxidation of the
â-ribofuranosyl isocyanide into the corresponding â-iso-
cyanate has been reported by Zbiral.15 On the basis of
these two precedents, we planned to oxidize glucopyra-
nosyl isocyanides for the preparation of glucopyranosyl
isocyanates. In this plan, we have focused on the four
problems: (i) the synthesis of the â-D-glucopyranosyl
isocyanide has been well-known for some time,16 but
there appears to be no practical method for the prepara-
tion of the R-D-glucopyranosyl isocyanide; (ii) a toxic,
hazardous oxidizing reagent which, after use, must then
be disposed of, is not desirable; (iii) an anomerization
problem during oxidation of the R-D-glucopyranosyl iso-
cyanide; (iv) R-D-glucopyranosyl isocyanate has an un-
known stability. We initially focused on the synthesis of
the R-D-glucopyranosyl isocyanide as shown in Scheme
4.
30 min of vigorous stirring of the two-phase mixture, the
organic layer was separated, dried (Na2SO4), and then
treated with cyclohexylamine. After workup and purifica-
tion by chromatography, the â-D-glucopyranosyl urea 7a
was isolated in 77% yield. In this reaction sequence, it
should be noted that the reaction period of 6 with
triphosgene was crucial, since prolonged reaction periods,
for example, 120 min, yielded 7a in a decreased, 65%,
yield. In addition, we avoided isolating the â-isocyanate
4a , because we were concerned that the isolation proce-
dure would decrease the yield because of the high
reactivity associated with the isocyanate function. At-
tempts to isolate the reactive isocyanate 4a were carried
out by rapid concentration of the reaction mixture before
addition of cyclohexylamine. The resulting crude product
showed the isocyanate IR absorption at 2220 cm-1 and
the 13C NMR peak at 127.0 ppm which characterized the
structure of 4a . However, it proved to be extremely
difficult to purify 4a , because 4a easily solidified on
standing due to the pronounced oligomerization reaction
of the isocyanate.11,12
Encouraged by the successful synthesis of 7a , we also
investigated the catalytic hydrogenation of the R-azide
8 for the preparation of the R-amine 9 (Scheme 3). Many
attempts at catalytic hydrogenation, under a variety of
conditions, afforded a mixture of 9 and 6. Furthermore,
R-amine 9 rapidly isomerized into the thermodynamically
stable â-amine 6 during isolation.13 We also attempted
Catalytic hydrogenation of the R-azide 8 and successive
treatment of the reaction mixture with acetic formic
anhydride afforded a mixture of the formamides 11 and
12. Dehydration of the reaction mixture by employing
triphosgene and triethylamine and separation of the
reaction mixture by silica gel chromatography furnished
(10) Eckert, H.; Forster, B. Angew. Chem. 1987, 99, 922.
(11) Ulrich, H. Chemistry and Technology of Isocyanates, J ohn Wiley
& Sons: 1996.
(12) Studies are currently in progress to fully purify the glucopy-
ranosyl isocyanate and to determine the structure of the Fisher’s
isocyanates A and B. For Fisher’s isocyanates A and B, see ref 4.
(13) Takeda, T.; Sugiura, Y.; Ogihara, Y.; Shibata. S. Can. J . Chem.
1980, 58, 2600. See also ref 9.
(14) Martin-Lomas, M.; Chacon-Fuertes, E. Carbohydr. Res. 1977,
59, 604.
(15) Hiebl, J .; Zbiral, E. Liebigs Ann. Chem. 1988, 765.
(16) Witczak, Z. J . J . Carbohydr. Chem. 1984, 3(3), 359.

4202 J . Org. Chem., Vol. 66, No. 12, 2001
Ichikawa et al.
Sch em e 5
an 89% yield of the isocyanides 13 and 14, with the ratio
of 80:20. In this dehydration reaction, triphosgene ap-
pears to be a more convenient reagent than the one we
previously reported (PPh3, CBr4, Et3N),7 because the
latter reagent gave off a considerable amount of triph-
enylphosphine oxide. Using the same sequence of reac-
tions, the â-isocyanide 14 was also obtained starting from
the â-azide 5 in 90% overall yield.17
F igu r e 2.
Ta ble 1. Syn th esis of th e Glu cop yr a n osyl Ur ea s fr om
th e Glu cop yr a n osyl Isocya n id es
With the R- and â-isocyanides in hand, the develop-
ment of the oxidation of these isocyanides was under-
taken. Since we had hoped to employ a one-pot process
in order to convert the in-situ-generated isocyanates into
the corresponding ureas to avoid the isolation of the
reactive isocyanates, it was necessary to find a mild and
neutral oxidizing condition. After screening a number of
different oxidizing reagents and solvents, we finally
realized that pyridine N-oxide (3.0 equiv) and a catalytic
amount of iodine (0.07 equiv) in acetonitrile were the
most satisfactory oxidation conditions.18 A typical ex-
ample from the synthesis of the R-glucopyranosyl urea
10a has been shown in Scheme 5. An acetonitrile solution
of the R-isocyanide 13 and pyridine N-oxide in the
presence of powdered molecular sieves 3 Å was treated
with iodine. Oxidation reaction was performed at room
temperature for 30 min, and silica gel TLC analysis of
the reaction mixture showed the consumption of the
isocyanide 13. Subsequent treatment of the resulting
reaction mixture with cyclohexylamine converted the in-
situ-generated isocyanate 4b into the stable urea 10a .19
After workup, we were very pleased to find that exami-
entry
glucopyranosy isocyanide
product
yielda (%)
1
2
3
4
5
6
7
8
12
12
12
12
12
12
13
13
13
13
13
13
7a
7b
7c
7d
7e
7f
10a
10b
10c
10d
10e
10f
95b
95b
93b
92b
95c
87d
91b
89b
91b
91b
84c
86d
9
10
11
12
a
Yield of isolated product. b Glucopyranosyl isocyanide (1 equiv)
and amine (3 equiv) were employed. c Glucopyranosyl isocyanide
d
(1 equiv) and amine (1.4 equiv) were employed. Glucopyranosyl
isocyanide (2 equiv) and amine (1 equiv) were employed.
resulting R-isocyanate 4b was configurationally stable
enough to react with cyclohexylamine to provide the
R-urea 10a . Finally, purification of the crude reaction
mixture by chromatography yielded the R-urea 10a as
crystals in 91% yield. In this transformation, it should
be noted that higher and reproducible yields were
obtained by employing molecular sieves 3 Å to scavenge
water, and that the hygroscopic solid, pyridine N-oxide,
was purified by distillation before use. Similar results
were also observed in the transformation of the â-iso-
cynide 14 into the â-urea 7a in 95% yield. The structure
of the glucopyranosyl ureas prepared in this study are
shown in Figure 2, and the yields are summarized in
Table 1. Entries 4 and 10 clearly showed that even
sterically hindered diisopropylamine reacted to give the
corresponding ureas 7d and 10d in good yield. The ureas
7e and 10e (entries 5 and 11) represented the assembly
of monosaccharides through the urea glycosidic linkage.
Replacement of the glycosidic oxygen atom by other
1
nation of the crude reaction mixture by H NMR did not
show â-urea formation. This result confirmed that oxida-
tion of the R-isocyanide 13 proceeded with retention of
the configuration at the anomeric position, and that the
(17) Transformation of 12 into 14 by employing diphosgene as the
dehydrating reagent has been reported. See: Ziegler, T.; Kaisers, H.-
J .; Schlomer, R.; Koch, C. Tetrahedron 1999, 55, 8397. Diphosgene is
not commercially available in J apan.
(18) J ohnson, H. W.; Krutzsch, H. J . Org. Chem. 1967, 32, 1939.
While a few oxidizing reagents (lead tetraacetate,15 iodobenzene bis-
(trifluoroacetate), and 2,4,6-trimethylbenzonitrile oxide7) were found
to be effective in oxidizing the glucopyranosyl isocyanides, pyridine
N-oxide in the presence of iodine was chosen because it is safe,
commercially available, inexpensive, and a nonhazardous waste.
(19) Since the isocyanate 4b could not be observed by TLC analysis,
we employed 3 equiv of cyclohexylamine to optimize the yield.

R- and â-D-Glucopyranosyl Ureas
Ta ble 2. Dia gn ostic NMR Da ta
substance anomeric config δ H1 J H1,H2 (Hz) δ C1
J . Org. Chem., Vol. 66, No. 12, 2001 4203
Sch em e 7
7a
7b
7c
7d
7e
â
â
â
â
â
â
R
R
R
R
R
R
5.14a
9.5
80.2a
80.2a
80.0a
80.4a
80.1a
80.1a
77.5a
75.7a
76.9a
76.1a
76.6b
76.7b
5.20a
9.5
5.14a
9.5a
9.5
5.18-5.26a,c
5.16
9.5a
7f
5.06-5.14a,c
10a
10a
10b
10c
10d
10e
10f
5.39a
5
5
5
6
5
5.5
5.82
5.43a
5.84a
5.44-5.52a,c
5.68b
a
b
Measured in CDCl3. Measured in MeOH-d4. c Overlapped.
Sch em e 6
functional groups such as ureas appears to be an attrac-
tive approach to the development of potential glycosidase
inhibitors. The ureas 7f and 10f (entries 6 and 12)
present our approach to the synthesis of the glycopeptide
mimics in which O- and N-glycosyl linkages are replaced
by urea-glycosyl bonds.
We were interested in the synthesis of the N,N′-di-R,R-
D-glucopyranosyl urea, because such a urea glycoside
seems to mimic R,R-trehalose with the urea-glycosidic
bond. Moreover, such an R,R-isomer cannot be prepared
by the thermodynamically controlled acid-catalyzed con-
densation of D-glucose with urea. Following the same
sequence of reactions as before, the R-isocyanide 13 was
converted into the R,R-urea 16 in a 92% yield. The C2-
symmetric structure of 16 can be confirmed by the 2-fold
simplification of the 1H and 13C NMR spectra, and its
R-configuration was confirmed by a J H1,H2 coupling con-
stant of 6 Hz. In addition, the glucosidic carbon of 16 had
a shift of 75.5 ppm, which is consistent with the R-ureas
10a -f. Finally, oxidation of the R-isocyanide 13 and
successive treatment of the reaction mixture with the
â-amine 4 afforded the N,N′-di-R,â-D-glucopyranosyl
urea 17 in a 89% yield, establishing stereospecific
synthesis of the three isomers of N,N′-di-D-glucopyranosyl
ureas.
1H a n d 13C NMR An a lysis of th e Glu cop yr a n osyl
Ur ea s. Assignment of the anomeric stereochemistry of
the glucopyranosyl ureas can be confirmed by comparing
the J H1,H2 coupling constants as represented in Table 2.
The large coupling constants of 7a -f around 9 Hz
indicate that the axial-axial relationship between these
two protons determined the â-stereochemistry, and the
small J H1,H2 value around 5 Hz in the case of 10a -f was
consistent with the R-linkage. Moreover, the interesting
1
stereoregular patterns of the H and 13C NMR chemical
shift at anomeric positions can be observed. Thus, the
1H NMR of â-ureas 7a -f show anomeric protons at ca.
5.1-5.2 ppm, and anomeric carbons in the region of 80-
81 ppm. In the case of R-ureas 10a -f, the 1H NMR
chemical shift of anomeric protons appears in the region
of 5.4-5.8 ppm, and the 13C NMR chemical shift of the
ureido glycosidic carbon appears around 75-78 ppm.
Con clu sion
We have developed an efficient means of stereospecific
synthesis of the glucopyranosyl ureas. Pyridine N-oxide
oxidation of the glucopyranosyl isocyanides catalyzed by
iodine afford the glucopyranosyl isocyanates which can
be successively treated with a variety of amines in a one-
pot process to afford the glucopyranosyl ureas in good
yields. Our method seems to be useful for the preparation
of a combinatorial library of the glucopyranosyl urea
derivatives which may find widespread use in pharma-
ceutical industries.
Ster eosp ecific Syn th esis of th e Th r ee Isom er s of
N,N′-Di-D-glu cop yr a n osyl Ur ea s. During our initial
studies of oxidation of the â-isocyanide 14 in the absence
of molecular sieves 3 Å, we isolated octaacetyl N,N′-di-
â,â-D-glucopyranosyl urea 15 as a byproduct (Scheme 6).
This urea may be formed by the hydrolysis of the
moisture sensitive â-isocyanate 4a to give the amine 6
which successively reacted with 4a to afford 15. The
structure of 15 was confirmed by an independent syn-
thesis of 15 starting from D-glucose and the urea under
acidic condition and acetylation.2 Based on this observa-
tion, a method for the stereospecific synthesis of bis-
glucopyranosyl ureas has been designated and is shown
in Scheme 7. Thus, oxidation of the â-isocyanide 14 was
carried out according to the procedure described before.
After completion of oxidation, water was added to the
reaction mixture. After stirring at room temperature for
20 min, TLC analysis showed the formation of 15, which
was isolated in a 92% yield.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were recorded on a
Yanaco MP-S3 melting point apparatus and are not corrected.
Infrared spectra were recorded on
a J ASCO FT/IR-8300
spectrophotometer and are reported in wavenumber (cm-1).
Proton nuclear magnetic resonance (1H NMR) spectra and
carbon nuclear magnetic resonance (13C NMR) spectra were
recorded on Varian Gemini-2000 spectrometers. Optical rota-
tions were measured on a J ASCO DIP-370 digital polarimeter.

4204 J . Org. Chem., Vol. 66, No. 12, 2001
Ichikawa et al.
For thin-layer chromatography (TLC) analysis, Merck pre-
coated TLC plates (silica gel 60 F254, 0.25 mm) were used.
Column chromatography was performed on silica gel (Silica
gel 60) supplied by E. Merck. Preparative TLC separation was
made on plates prepared with a 2 mm layer of silica gel (Silica
gel PF254) obtained from E. Merck. Reactions were run under
atmosphere of nitrogen when the reactions were sensitive to
moisture or oxygen. Dichloromethane and acetonitrile were
stored over molecular sieves 3 Å. Pyridine N-oxide was purified
by distillation before use.20
P r ep a r a tion of 2,3,4,6-Tetr a -O-a cetyl-r-D-glycop yr a -
n osyl Isocya n id e (13). A solution of 8 (3.00 g, 8.04 mmol),
triethylamine (3.4 mL, 24.1 mmol) and palladium on activated
carbon (2%, 450 mg) in a mixture of ether and hexane (135
mL, 2:1) was stirred vigorously under hydrogen atmosphere
for 30 min. To the resulting solution was added acetic formic
anhydride (3.0 mL, 40.2 mmol) at room temperature, and
stirring continued for 20 min. The mixture was filtered on
Super Cell, and concentration of the filtrate gave a mixture of
formamides 11 and 12 (2.85 g) which was used for the next
reaction without further purification.
To a solution of formamides 11 and 12 (2.85 g, 7.60 mmol)
and triethylamine (3.19 mL, 22.8 mmol) dissolved in dichlo-
romethane (70 mL) cooled to 0 °C was added triphosgene (1.80
g, 6.08 mmol). After stirring at 0 °C for 55 min, additional
triethylamine (1.60 mL, 11.4 mmol) and triphosgene (0.90 g,
3.03 mmol) were added. The cooling bath was removed, and
the stirring was continued for 25 min. The reaction mixture
was poured into aqueous sodium bicarbonate solution, and the
aqueous layer was extracted with dichloromethane. The
combined organic extracts were washed with brine and dried
over anhydrous sodium sulfate. Concentration and purification
by silica gel chromatography (ethyl acetate:hexane, 1:5) gave
the R-glucopyranosyl isocyanide 13 (1.82 g), a mixture of 13
and 14 (298 mg, 2:3) and 14 (298 mg). The combined yield of
13 and 14 was 89% in the ratio of 80:20.
Gen er a l Meth od for th e P r ep a r a tion of th e Glu cop y-
r a n osyl Ur ea . To a solution of â-glucopyranosyl isocyanide
14 (100 mg, 0.28 mmol) and powdered molecular sieves 3 Å
(200 mg) in acetonitrile (2.0 mL) was added a solution of
pyridine N-oxide (80 mg, 0.84 mmol, dissolved in 0.5 mL of
acetonitrile) and iodine (5 mg, 0.02 mmol, dissolved in 0.5 mL
of acetonitrile) under nitrogen atmosphere. After stirring at
room temperature for 25 min, cyclohexylamine (96 µL, 0.84
mmol) was added. After stirring for 25 min, a saturated
aqueous solution of sodium hydrogensulfite was added. Aque-
ous layer was extracted with ethyl acetate, and combined
organic layers were washed with saturated aqueous sodium
chloride, dried over anhydrous sodium sulfate, and evaporated
to dryness. The resulting crude residue (131 mg) was purified
by silica gel chromatography (AcOEt:hexane, 1:3 and 1:2) to
afford â-glucopyranosyl urea 7a (126 mg, 95%).
) 10, 9.5), 5.20 (1H, t J ) 9.5), 5.29 (1H, d, J ) 9.5), 5.33 (1H,
t, J ) 9.5), 13C NMR (CDCl3, 75 MHz), δ 20.4, 20.6, 20.7, 25.3,
45.4, 61.6, 68.2, 70.7, 72.7, 72.9, 80.2, 154.6, 169.7, 169.9, 170.7,
171.5. Anal. Calcd for C19H28N2O10: C, 51.35; H, 6.35; N, 6.30.
Found: C, 51.33; H, 6.39; N, 6.24.
2,3,4,6-Tet r a -O-a cet yl-N-[(S)-(-)-â-m et h ylb en zyla m i-
n oca r bon yl]-â-D-glu cop yr a n osyla m in e (7c): mp 75 °C;
[R]27D ) -22.5 (c 1.17, CHCl3); IR (KBr) νmax 3368, 1753, 1652
1
cm-1; H NMR (CDCl3, 300 MHz), δ 1.44 (3H, d, J ) 7), 1.97
(3H, s), 2.01 (3H, s), 2.02 (3H, s), 2.06 (3H, s), 3.77 (1H, ddd,
J ) 10, 4.5, 2), 4.07 (1H, dd, J ) 12.5, 2), 4.31 (1H, dd, J )
12.5, 4.5), 4.80-4.90 (1H), 4.86 (1H, t, J ) 9.5), 5.04 (1H, t, J
) 9.5), 5.14 (1H, t, J ) 9.5), 5.20-5.28 (1H, br), 5.27 (1H, t, J
) 9.5), 5.47 (1H, d, J ) 9.5), 7.2-7.4 (5H); 13C NMR (CDCl3,
75 MHz), δ 20.4, 20.5, 20.6, 22.7, 49.8, 61.8, 68.3, 70.5, 72.9,
73.1, 80.0, 125.9, 127.3, 128.6, 143.9, 155.8, 169.8, 170.0, 170.8,
171.0. Anal. Calcd for C23H30N2O10: C, 55.86; H, 6.12; N, 5.67.
Found: C, 55.86; H, 6.19; N, 5.65.
2,3,4,6-Tetr a -O-a cetyl-N-(d iisop r op yla m in oca r bon yl)-
â-D-glu cop yr a n osyla m in e (7d ): mp 147 °C; [R]30 ) -12.6
D
(c 1.02, MeOH); IR (KBr) νmax 3429, 1754, 1660 cm-1; 1H NMR
(CDCl3, 300 MHz), δ 1.24 (12H, d, J ) 7), 2.02 (3H, s), 2.03
(3H, s), 2.04 (3H, s), 2.09 (3H, s), 3.72 (2H, sept, J ) 7), 3.81
(1H, ddd, J ) 10, 4, 2), 4.08 (1H, dd, J ) 13, 2), 4.36 (1H, dd,
J ) 13, 4.5), 4.96 (1H, t, J ) 9.5), 5.08 (1H, dd, J ) 10, 9.5),
5.18-5.26 (2H, H-1), 5.32 (1H, t, J ) 9.5); 13C NMR (CDCl3,
75 MHz), δ 20.5, 20.56, 20.62, 20.9, 21.0, 45.8, 61.6, 68.3, 70.6,
72.8, 73.0, 80.4, 155.1, 169.7, 170.0, 170.7, 171.3. Anal. Calcd
for C21H34N2O10: C, 53.16; H, 7.22; N, 5.90. Found: C, 53.13;
H, 6.95; N, 5.83.
6-Deoxy-1,2:3,4-d i-O-isop r op ylid en e-6-(2,3,4,6-tetr a -O-
a cet yl-â-D-glu cop yr a n osylu r eid o)-r-D-ga la ct op yr a n ose
(7e): mp 113 °C; [R]25 ) -19.2 (c 1.55, CHCl3); IR (KBr) νmax
D
3394, 1752, 1559 cm-1; 1H NMR (CDCl3, 300 MHz), δ 1.32 (3H,
s), 1.34 (3H, s), 1.44 (3H, s), 1.50 (3H, s), 2.01 (3H, s), 2.03
(3H, s), 2.05 (3H, s), 2.08 (3H, s), 3.19 (1H, ddd, J ) 13, 9, 3),
3.54-3.66 (1H, br), 3.78-3.90 (2H), 4.07 (1H, dd, J ) 12.5,
1.5), 4.20 (1H, dd, J ) 8, 1.5), 4.30 (1H, dd, J ) 12.5, 4), 4.31
(1H, dd, J ) 5, 2.5), 4.60 (1H, dd, J ) 8, 2.5), 4.91 (1H, t, J )
9.5), 5.06 (1H, t, J ) 9.5), 5.16 (1H, t, J ) 9.5), 5.30 (1H, t, J
) 9.5), 5.44 (1H, dd, J ) 8, 3), 5.52 (1H, d, J ) 5), 5.76 (1H, d,
J ) 9.5); 13C NMR (CDCl3, 75 MHz), δ 20.4, 20.5, 24.1, 24.8,
25.75, 25.84, 40.6, 61.8, 67.1, 68.3, 70.5, 70.6, 71.4, 72.9, 73.1,
80.1, 96.1, 108.7, 109.3, 156.8, 169.6, 169.9, 170.66, 170.74.
Anal. Calcd for C27H40N2O15
: C, 51.26; H, 6.37; N, 4.43.
Found: C, 51.17; H, 6.57; N, 4.46.
Meth yl N2-ben zyloxycar bon yl-N3-(2,3,4,6-tetr a-O-acetyl-
â-D-glu cop yr a n osyl-a m in oca r bon yl)-2(S),3-d ia m in op r o-
p a n oa te (7f): mp 99 °C; [R]27 ) +2.51 (c 0.40, CHCl3); IR
D
(KBr) νmax 3383, 1753, 1559 cm-1; 1H NMR (CDCl3, 300 MHz),
δ 2.01 (3H, s), 2.03 (3H, s), 2.04 (3H, s), 2.05 (3H, s), 3.5-3.7
(2H), 3.74 (3H, s), 3.79 (1H, ddd, J ) 10.5, 4.5, 2), 4.07 (1H,
dd, J ) 13, 2), 4.29 (1H, dd, J ) 13, 4.5), 4.34-4.42 (1H, br),
4.89 (1H, t, J ) 10), 5.05 (1H, t, J ) 10), 5.06-5.14 (3H), 5.28
(1H, t, J ) 10, H-3), 5.48 (1H, brt, J ) 6), 5.68 (1H, brt, J )
9.5), 6.09 (1H, brd, J ) 7), 7.3-7.4 (5H); 13C NMR (CDCl3, 75
MHz), δ 20.5, 20.6, 42.0, 52.7, 54.8, 61.8, 67.1, 68.2, 70.5, 72.9,
73.1, 80.1, 128.1, 128.3, 128.6, 136.2, 156.4, 157.1, 169.7, 170.0,
170.8, 171.1. Anal. Calcd for C27H35N3O14: C, 51.84; H, 5.64;
N, 6.72. Found: C, 51.84; H, 5.67; N, 6.48.
2,3,4,6-Tetr a -O-a cetyl-N-(cycloh exyla m in oca r bon yl)-â-
D-glu cop yr a n osyla m in e (7a ): mp 83 °C; [R]27 ) -0.80 (c
D
1
0.98, MeOH); IR (KBr) νmax 3363, 1753, 1652 cm-1; H NMR
(CDCl3, 300 MHz), δ 1.0-1.9 (10H), 1.98 (3H, s), 1.99 (3H, s,
OAc), 2.02 (3H, s), 2.05 (3H, s), 3.38-3.54 (1H, br), 3.80 (1H,
ddd, J ) 10, 4.5, 2), 4.05 (1H, dd, J ) 12.5, 2), 4.31 (1H, dd, J
) 12.5, 4.5), 4.78 (1H, d, J ) 8), 4.88 (1H, t, J ) 9.5), 5.04
(1H, dd, J ) 10.0, 9.5), 5.14 (1H, t, J ) 9.5), 5.28 (1H, t, J )
9.5), 5.42 (1H, d, J ) 9.5); 13C NMR (CDCl3,75 MHz), δ 20.4,
20.6, 24.7, 25.3, 33.5, 49.1, 61.8, 68.3, 70.5, 72.9, 73.1, 80.2,
2,3,4,6-Tetr a -O-a cetyl-N-(cycloh exyla m in oca r bon yl)-r-
D-glu cop yr a n osyla m in e (10a ): mp 188 °C; IR (KBr) νmax
3370, 1756, 1652 cm-1; [R]26 ) +105.9 (c 1.12, CHCl3); 1H
D
155.6, 169.7, 170.0, 170.7, 171.1. Anal. Calcd for C21H32N2O10
:
NMR (CDCl3300 MHz), δ 1.0-2.0 (10H), 2.02 (3H, s), 2.04 (3H,
s, OAc), 2.08 (3H, s), 2.11 (3H, s), 3.58-3.72 (1H, br), 4.07-
4.20 (2H), 4.24 (1H, dd, J ) 12.5, 4.5), 5.01 (1H, brd, J ) 3.0),
5.06 (1H, t, J ) 9.5), 5.08 (1H, dd, J ) 10, 5), 5.20 (1H, brd J
) 8), 5.32 (1H, dd, J ) 10, 9.5), 5.39 (1H, dd, J ) 5, 3); 13C
NMR (CDCl3, 75 MHz), δ 20.4, 20.5, 20.6, 24.7, 25.4, 33.5, 48.8,
61.8, 67.0, 68.1, 68.9, 69.7, 77.5, 156.9, 169.3, 169.5, 170.0,
170.6. Anal. Calcd for C21H32N2O10: C, 53.38; H, 6.83; N, 5.93.
Found: C, 53.37; H, 6.86; N, 5.79.
C, 53.38; H, 6.83; N, 5.93. Found: C, 53.38; H, 6.82; N, 5.90.
2,3,4,6-Tetr a -O-a cetyl-N-(p yr r olid in oca r bon yl)-â-D-glu -
cop yr a n osyla m in e (7b): mp 182 °C; [R]27 ) -3.83 (c 0.97,
D
CHCl3); [R]20 ) -13.7 (c 0.66, CH3OH); IR (KBr) νmax 3396,
D
1753, 1660 cm-1; 1H NMR (CDCl3, 300 MHz), δ 1.86-1.96 (4H),
2.03 (3H, s), 2.04 (3H, s), 2.06 (3H, s), 2.08 (3H, s), 3.2-3.4
(4H), 3.84 (1H, ddd, J ) 10, 4, 2), 4.09 (1H, dd, J ) 12.5, 2),
4.34 (1H, dd, J ) 12.5, 4), 4.93 (1H, t J ) 9.5), 5.08 (1H, dd J
2,3,4,6-Tetr a -O-a cetyl-N-(pyr r olid in oca r bon yl)-r-D-glu -
cop yr a n osyla m in e (10b): mp 178 °C; IR (KBr) νmax 3416,
(20) Mosher, H. S.; Turner, L.; Carlsmith, A. Organic Syntheses;
Wiley: New York, 1963; Collect. Vol. IV, p 828.
1753, 1651 cm-1; [R]29 ) +77.9 (c 1.13, CHCl3); 1H NMR
D

R- and â-D-Glucopyranosyl Ureas
J . Org. Chem., Vol. 66, No. 12, 2001 4205
(CDCl3, 300 MHz), δ 1.94-1.99 (4H), 2.03 (3H, s, OAc), 2.04
(6H, s, OAc), 2.09 (3H, s), 3.36-3.48 (4H), 4.02 (1H, ddd, J )
10, 3.5, 2.5), 4.09 (1H, dd, J ) 12, 2.5), 4.35 (1H, dd, J ) 12,
3.5), 4.94 (1H, d, J ) 6.5), 5.03 (1H, dd, J ) 10, 9), 5.18-5.32
(2H), 5.82 (1H, dd, J ) 6.5, 5); 13C NMR (CDCl3, 75 MHz), δ
20.4, 20.5, 25.3, 45.6, 61.6, 67.0, 68.4, 68.5, 70.3, 75.7, 155.0,
168.9, 169.5, 170.3, 170.8. Anal. Calcd for C19H28N2O10: C,
51.35; H, 6.35; N, 6.30. Found: C, 51.34; H, 6.36; N, 6.26.
2,3,4,6-Tet r a -O-a cet yl-N-[(S)-(-)-r-m et h ylb en zyla m i-
n oca r bon yl]-r-D-glu cop yr a n osyla m in e (10c): mp 206 °C;
[R]26D ) +93.3 (c 1.14, CHCl3); IR (KBr) νmax 3359, 1755, 1656
acetonitrile) under nitrogen atmosphere. After stirring at room
temperature for 25 min, water (200 µL, 11.1 mmol) was added
and the stirring continued for 20 min. Saturated aqueous
solution of sodium hydrogensulfite was added to the resulting
reaction mixture, and the aqueous layer was extracted with
ethyl acetate. The combined organic layers were washed with
saturated aqueous sodium bicarbonate and brine, dried over
anhydrous sodium sulfate, and concentrated. The resulting
crude residue was purified by silica gel chromatography
(AcOEt:hexane, 3:2) to afford N,N′-di-â,â-D-glucopyranosyl
urea 15 (142 mg, 94%): mp 153 °C; [R]25 ) +0.46 (c 1.09,
D
cm-1; H NMR (CDCl3, 300 MHz), δ 1.50 (3H, d, J ) 7), 2.00
CHCl3); IR (KBr) νmax 3386, 1752, 1559 cm-1; 1H NMR (CDCl3,
300 MHz), δ 2.02 (6H, s), 2.04 (6H, s), 2.06 (6H, s), 2.08 (6H,
s), 3.84 (2H, ddd, J ) 10, 4.5, 2), 4.11 (2H, dd, J ) 12.5, 2),
4.31 (2H, dd, J ) 12.5, 4.5), 4.88 (2H, t, J ) 9.5), 5.04 (2H, t,
J ) 9.5), 5.31 (2H, t, J ) 9.5), 5.04-5.16 (2H), 5.89 (2H, d, J
) 9. 5); 1H NMR (CD3OD, 300 MHz), δ 1.97 (6H, s), 2.01 (12H,
s), 2.02 (6H, s), 3.91 (2H, ddd, J ) 10, 4.5, 2), 4.10 (2H, dd, J
) 12.5, 2), 4.26 (2H, dd, J ) 12.5, 4.5), 4.93 (2H, t, J ) 9.5),
5.01 (2H, dd, J ) 10, 9.5), 5.15 (2H, d, J ) 9.5), 5.32 (2H, t, J
) 9.5); 13C NMR (CDCl3, 75 MHz), δ. 20.5, 20.6, 61.7, 68.2,
70.5, 72.8, 73.2, 80.0, 155.5, 169.8, 170.0, 170.7, 171.2. Anal.
Calcd for C29H40N2O19: C, 48.33; H, 5.59; N, 3.89. Found: C,
48.33; H, 5.82; N, 3.89.
1
(3H, s), 2.02 (3H, s), 2.04 (3H, s), 2.08 (3H, s), 4.08-4.20 (2H),
4.25 (1H, J ) 5), 4.93-5.04 (1H, br), 5.05 (1H, t, J ) 10), 5.08
(1H, dd, J ) 10, 5), 5.14 (1H, d, J ) 3.5), 5.32 (1H, t, J ) 10),
5.43 (1H, dd, J ) 5, 3.5), 5.53-5.63 (1H, br), 7.2-7.4 (5H), 13
C
NMR (CDCl3, 75 MHz), δ 20.36, 20.42, 20.6, 22.7, 49.6, 61.8,
67.0, 68.2, 68.7, 69.9, 76.9, 125.9, 127.3, 128.7, 143.6, 156.9,
169.2, 169.5, 170.1, 170.7. Anal. Calcd for C23H30N2O10: C,
55.86; H, 6.12; N, 5.67. Found: C, 55.87; H, 6.25; N, 5.63.
2,3,4,6-Tetr a -O-a cetyl-N-(d iisop r op yla m in oca r bon yl)-
r-D-glu cop yr a n osyla m in e (10d ): mp 90 °C; [R]26 ) +60.0
D
(c 1.02, CHCl3); IR (KBr) νmax 3418, 1751, 1656 cm-1; 1H NMR
(CDCl3, 300 MHz), δ 1.29 (6H, d, J ) 7, Me), 1.30 (6H, d, J )
7), 2.02 (3H, s), 2.04 (3H, s), 2.05 (3H, s), 2.08 (3H, s), 3.98
(1H, ddd, J ) 10, 4.5, 2.5), 4.03 (2H, sept, J ) 7), 4.12 (1H,
dd, J ) 13, 2.5), 4.34 (1H, dd, J ) 13, 4.5), 4.98 (1H, d J ) 6),
5.04-5.14 (1H, m), 5.20-5.30 (2H), 5.84 (1H, brt, J ) 6); 13C
NMR (CDCl3, 75 MHz), δ 20.3, 20.48, 20.50, 20.6, 21.2, 44.9,
61.7, 67.5, 68.3, 68.7, 70.6, 76.1, 155.7, 168.7, 169.4, 170.4,
170.8. Anal. Calcd for C21H34N2O10: C, 53.16; H, 7.22; N, 5.90.
Found: C, 53.17; H, 7.18; N, 5.78.
N ,N ′-Di-r,r-2,3,4,6-oct a -O-a ce t yl-D-glu cop yr a n osy-
lu ea (16): mp 114 °C; [R]25 ) +107.6 (c 0.86, CHCl3); IR
D
(KBr) νmax 3393, 1753, 1553 cm-1; 1H NMR (CDCl3, 300 MHz),
δ 2.04 (12H, s), 2.07 (6H, s), 2.11 (6H, s), 4.06 (2H, ddd, J )
9.5, 4.5, 2.5), 4.16 (2H, dd, J ) 12.5, 2.5), 4.32 (2H, dd, J )
12.5, 4.5), 5.08 (2H, t, J ) 9.5), 5.12 (2H, dd, J ) 9.5, 5), 5.32
(2H, t, J ) 9.5), 5.65 (2H, t, J ) 5), 5.98 (2H, brd, J ) 5); 13C
NMR (CDCl3, 75 MHz), δ 20.4, 20.5, 61.7, 68.0, 68.6, 69.6, 76.1,
6-Deoxy-1,2:3,4-d i-O-isop r op ylid en e-6-(2,3,4,6-tetr a -O-
a cet yl-r-D-glu cop yr a n osylu r eid o)-r-D-ga la ct op yr a n ose
(10e): mp 124 °C; [R]24D ) +48.7 (c 0.56, CHCl3); IR (KBr) νmax
3394, 1753, 1560 cm-1; 1H NMR (CDCl3, 300 MHz), δ 1.30 (3H,
s), 1.34 (3H, s), 1.45 (3H, s), 1.49 (3H, s), 2.02 (6H, s), 2.67
(3H, s), 2.10 (3H, s), 3.10-3.26 (1H, br), 3.56-3.70 (1H, br),
3.94 (1H, brd, J ) 9), 4.08-4.18 (3H), 4.22 (1H, dd, J ) 8, 1),
4.30 (1H, dd, J ) 4.5, 2,), 4.39 (1H, dd, J ) 13, 3), 4.60 (1H,
dd, J ) 8, 2), 5.11 (1H, dd, J ) 10, 5), 5.30 (1H, t, J ) 9.5),
5.14 (1H, t, J ) 10), 5.34 (1H, t, J ) 10), 5.44-5.52 (1H), 5.51
(1H, d, J ) 4.5), 5.7-5.8 (1H, br); 13C NMR (CD3OD, 75 MHz),
δ 20.6, 20.7, 24.5, 25.2, 26.3, 41.5, 63.2, 68.0, 68.4, 69.9, 70.5,
71.7, 71.8, 72.0, 72.7, 76.6, 97.7, 110.1, 110.7, 159.9, 171.6,
171.8, 172.2, 173.0. Anal. Calcd for C27H40N2O15: C, 51.26; H,
6.37; N, 4.43. Found: C, 51.26; H, 6.38; N, 4.25.
156.5, 169.2, 169.4, 170.1, 170.7. Anal. Calcd for C29H40N2O19
:
C, 48.33; H, 5.59; N, 3.89. Found: C, 48.24; H, 5.80; N, 3.89.
N ,N ′-Di-r,â-2,3,4,6-oct a -O-a ce t yl-D-glu cop yr a n osy-
lu ea (17): mp 192 °C; [R]25D ) +60.2 (c 1.24, CHCl3); IR (KBr)
ν
max 3393, 1751, 1559 cm-1; 1H NMR (CDCl3, 300 MHz), δ 2.02
(3H, s), 2.03 (3H, s), 2.035 (3H, s), 2.04 (3H, s), 2.045 (3H, s),
2.05 (3H, s), 2.10 (3H, s), 2.11 (3H, s), 3.82 (1H, ddd, J ) 10,
4, 2), 4.00 (1H, dt, J ) 9.5, 2.5), 4.10 (1H, dd, J ) 12.5, 2),
4.21 (1H, dd, J ) 12.5, 2.5), 4.30 (1H, dd, J ) 12.5, 4), 4.41
(1H, dd, J ) 12.5, 2.5), 4.92 (1H, t, J ) 9.5), 5.06 (1H, t, J )
9.5), 5.14 (1H, t, J ) 9.5), 5.14 (1H, dd, J ) 10, 5.5), 5.23 (1H,
t, J ) 9.5), 5.30 (1H, dd, J ) 10, 9. 5), 5.32 (1H, t, J ) 10),
5.56 (1H, t, J ) 5.5), 5.78 (1H, br), 5.98 (1H, d, J ) 9.5); 13C
NMR (CD3OD, 75 MHz), δ 20.5, 20.6, 20.7, 63.1, 69.0, 69.6,
69.8, 70.5, 71.7, 71.9, 74.2, 74.6, 76.4, 80.5, 158.6, 171.6, 171.8,
171.9, 172.1, 172.3, 172.97, 173.03. Anal. Calcd for
Meth yl N2-ben zyloxycar bon yl-N3-(2,3,4,6-tetr a-O-acetyl-
r-D-glu cop yr a n osyl-a m in oca r bon yl)-2(S),3-d ia m in op r o-
C
29H40N2O19: C, 48.33; H, 5.59; N, 3.89. Found: C, 48.33; H,
p a n oa te (10f): mp 74 °C; [R]27 ) +86.9 (c 0.47, CHCl3); IR
D
5.55; N, 3.54.
(KBr) νmax 3380, 1752, 1559 cm-1; 1H NMR (CD3OD, 300 MHz),
δ 1.99 (3H, s), 2.00 (6H, s), 2.02 (3H, s), 3.43 (1H, dd, J ) 14,
7), 3.62 (1H, dd, J ) 14, 5), 3.72 (3H, s), 3.90 (1H, ddd, J ) 10,
4, 2), 4.04 (1H, dd, J ) 12, 2), 4.27 (1H, dd, J ) 12, 4), 4.32
(1H, dd, J ) 7, 5), 5.00 (1H, dd, J ) 10, 5.5), 5.05 (1H, dd, J
) 10, 9.5), 5.09 (2H, s), 5.43 (1H, dd, J ) 10, 9.5), 5.68 (1H, d,
J ) 5.5), 7.3-7.4 (5H); 13C NMR (CD3OD, 75 MHz), δ 20.4,
20.57, 20.63, 41.9, 53.0, 55.9, 63.2, 67.9, 68.8, 70.0, 70.6, 71.7,
76.7, 129.0, 129.2, 129.6, 138.1, 158.6, 159.7, 171.4, 171.5,
171.9, 172.7, 172.8. Anal. Calcd for C27H35N3O14: C, 51.84; H,
5.64; N, 6.72. Found: C, 51.85; H, 5.68; N, 6.61.
Ack n ow led gm en t. This research was financially
supported by a Grant-In-Aid for Scientific Research
from the J apanese Ministry of Education, Science,
Sports and Culture and by J SPS-RFTF. Elemental
analysis were performed by Mr. S. Kitamura in Analyti-
cal Laboratory at School of Agricultural Sciences,
Nagoya University, to whom the authors gratefully
acknowledge.
N ,N ′-Di-â,â-2,3,4,6-oct a -O-a ce t yl-D-glu cop yr a n osy-
lu ea (15). To a solution of â-glucopyranosyl isocyanide 14 (150
mg, 0.42 mmol) and powdered molecular sieves 3 Å (200 mg)
in acetonitrile (2.0 mL) was added a solution of pyridine
N-oxide (120 mg, 1.26 mmol, dissolved in 1.0 mL of acetoni-
trile) and iodine (10 mg, 0.04 mmol, dissolved in 0.5 mL of
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for Scheme 2; 1H and 13C NMR data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0100751