Efficient Synthesis of Unsymmetrical Ureido-Linked Disaccharides

Article abstract of DOI:10.1002/ejoc.200300483

Five nonsymmetrical urea-linked disaccharides, in which two glycopyranoside units are bound at the 1→2, 1→4, and 1→6 positions, were efficiently synthesized. A mild and safe procedure, in which glycosyl isocyanates were coupled with a glycosylamine, was e

Full text of DOI:10.1002/ejoc.200300483

FULL PAPER
Efficient Synthesis of Unsymmetrical Ureido-Linked Disaccharides
Davide Prosperi,*[a] Silvia Ronchi,[b] Luigi Lay,[b] Anna Rencurosi,[a] and Giovanni Russo[b]
Keywords: Ureas / Intersaccharidic linkages / Carbohydrates / Glycosides / Oligosaccharides
Five nonsymmetrical urea-linked disaccharides, in which
two glycopyranoside units are bound at the 1Ǟ2, 1Ǟ4, and
1Ǟ6 positions, were efficiently synthesized. A mild and safe
procedure, in which glycosyl isocyanates were coupled with
a glycosylamine, was employed.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
Naturally occurring oligosaccharides, both as free en-
dogenous molecules and as components of glycoconjugates,
have crucial functions in numerous biological processes.[1Ϫ3]
They mediate cell adhesion and communication and are the
characteristic determinants of the human blood groups,[4,5]
of tumour-associated antigens[6] and of capsular polysacch-
arides (CPS) of highly infective bacteria.[7] In the light of
these important roles, the development of sugar-based
drugs could be of great pharmaceutical interest. However,
saccharide chains can be highly sensitive to chemical or en-
zymatic hydrolysis,[8] thereby causing the cleavage of the O-
glycosidic linkages and the degradation of the glycoconju-
gates. Therefore, it is highly desirable to have access to
modified structures endowed with an increased stability,
while maintaining the biological properties of the natural
compounds. Here, we report the synthesis of a series of di-
saccharides (compounds 1Ϫ5, see Figure 1) bound through
an ureido group, a stable and yet polar group, with which
the stability of the anomeric linkage is ensured. In the last
few years, an increasing interest in glycosylureido sugars
has emerged, with applications in the field of aminoglyco-
side antibiotics.[9,10] The glycosylϪurea bond is naturally
widespread in glycocinnamoylspermidine antibiotics.[11,12]
However, only a few methodologies for the formation of
glycosylureas are described in the literature. The first meth-
ods employed the acid-catalyzed condensation of -glucop-
yranose with urea in water,[13] which was also used in the
Figure 1. Intersaccharidic ureas 1Ϫ5
synthesis of symmetrical disaccharidic ureas,[14] the reaction
of silver cyanate with glycosyl halides,[15] and the carbodi-
imide approach.[16Ϫ18] More recently, Ichikawa et al. used
highly toxic phosgene or phosgene derivatives to generate
the isocyanate intermediate from the glycosylamine precur-
sor.[19] Obviously, the latter, hazardous techniques are not
suitable for large-scale preparations. For this reason, we re-
considered the procedure proposed by Ichikawa,[19,20] in
which the glycosyl isocyanate is obtained by a mild oxi-
dation of the corresponding isocyanide with pyridine N-ox-
ide. In the present work, we extend this approach to a gen-
eral procedure for the synthesis of intersaccharidic ureido
linkages. We focussed on the disaccharidic ureas 1Ϫ5 (Fig-
ure 1), in which ureido linkages between the 1Ǟ2, 1Ǟ4,
and 1Ǟ6 positions of two saccharide units are present. In
particular, 3 is involved in a β-mannosidic linkage with an
axial amino group in position 2 of the mannosamine ac-
ceptor. Examples of symmetrical ureas linking two anom-
eric positions of α- and β-glucopyranosidic subunits are
[a]
CNR Istituto di Scienze e Tecnologie Molecolari (ISTM),
via Golgi 19, 20133 Milan, Italy
Fax: (internat.) ϩ 39-0250-314061
E-mail: davide.prosperi@unimi.it
[b]
Dipartimento di Chimica Organica
e
Industriale, Centro
Applicazioni
Interdisciplinare Studi Bio-molecolari
e
`
Industriali (CISI), Universita degli Studi di Milano,
via Venezian 21, 20133 Milan, Italy
Fax: (internat.) ϩ 39-0250-314061
E-mail: luigi.lay@unimi.it
Eur. J. Org. Chem. 2004, 395Ϫ405
DOI: 10.1002/ejoc.200300483
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
395

D. Prosperi, S. Ronchi, L. Lay, A. Rencurosi, G. Russo
FULL PAPER
known,[14,19] as well as pseudodisaccharides involving posi- and afforded a mixture of α and β anomers (13a ϩ 13b),
tion 5 of a hexofuranosidic acceptor.[21] However, com- which was easily separated by silica-gel chromatography (α/
pounds 3 and 4 are the first glycosylureas in which the an- β ϭ 7:3). The α-anomeric configuration was attributed to
omeric position of a hexopyranose is connected to the non- the major product (13a) by the aid of an NOE difference
anomeric secondary position of a glycopyranosidic ac- experiment performed on both compounds. Compound 13b
ceptor.
showed an NOE contact between 1-H (δ ϭ 5.35 ppm) and
3-H (δ ϭ 5.60 ppm) that clearly demonstrated the β con-
figuration of compound 13b. This contact is absent in the
case of the α anomer 13a.
Results and Discussion
The synthesis of the 6-amino derivatives 20[30] and 21 is
illustrated in Scheme 2. Compounds 14[28] and 15,[29] ob-
tained from the corresponding commercially available α-
methyl glycosides, were submitted to acetolysis and pro-
vided the 6-O-acetyl derivatives 16 and 17 in almost quanti-
tative yields. Deacetylation, followed by Mitsunobu reac-
tion with tetrachlorophthalimide, provided the N-protected
derivatives 18 and 19 in excellent yields. The free amines 20
and 21 were generated by deprotection of the corresponding
TCP derivatives, 18 and 19, with ethanolic hydrazine and
were immediately used in the following coupling with the
appropriate isocyanates. To synthesize the ureas, the isocy-
anides 9 or 13a were dissolved in anhydrous acetonitrile and
treated with pyridine N-oxide in the presence of a catalytic
amount of iodine.[31] The resulting isocyanates 22 and 23
were not isolated but they directly afforded protected ureas
24 and 25, respectively, in high yields upon addition of the
amine acceptors (Scheme 3). In the 13C NMR spectra, the
ureido carbonyl groups of 24 and 25 exhibit signals at δ ϭ
156.6 and 157.7 ppm, respectively, while the ureido anom-
eric carbon atoms resonate at δ ϭ 78.5 and 77.5 ppm. Hy-
The retrosynthetic scheme relies on the coupling of two
key synthons for the formation of the glycosylureas: a gly-
cosyl isocyanate, obtained in situ by mild oxidation of the
corresponding glycosyl isocyanide and a properly protected
monosaccharide partner, containing a free amino group.
Glycosyl isocyanides 9,[22] 13a, and 13b were prepared ac-
cording to Scheme 1. Tetraacetyl-β-glucosyl azide 6,[23] was
converted into the corresponding formamidic derivative 8
after hydrogenation and an in situ reaction with freshly pre-
pared acetoformic anhydride.[24] The 1H NMR spectrum
shows that 8 was obtained as a pure β anomer but as a
mixture of (E) and (Z) diastereoisomers, due to the iminic
1
form of the formamido group. The H NMR analysis is
consistent with the literature data,[25] revealing a consider-
able prevalence of the (Z) isomer, which is evidenced by the
presence of a singlet at δ ϭ 8.25 ppm [in the (E) isomer, the
CHO signal at δ ϭ 8.21 ppm shows a doublet with
J
CHO,NH ϭ 10.5 Hz]. Dehydration of 8 furnished the desired
isocyanide 9 in 80% yield. An analogous procedure was
employed to convert the tetrabenzoyl-α-mannosyl azide
10[26] into the corresponding isocyanide 13a and 13b in ex-
1
cellent overall yields (98% for 13a ϩ 13b). The H NMR
´
drogenolysis, followed by Zemplen deacetylation, afforded
ureas 1[17]and 2 quantitatively.
spectrum shows that 12 is an inseparable mixture of α and
β anomers.[27] The mannosyl formamide 12 was dehydrated
Scheme 2. Reagents and conditions: a) ZnCl2 in acetic anhydride/
acetic acid (20:1) for 16, 1 h, 97%; Ac2O/TFA (4:1) for 17, 45 min,
99%; b) 1  NaOMe, dry MeOH; c) TCPNH, DIAD, PPh3, dry
THF, 30 min, 99%; d) NH2NH2, EtOH, 30 min, reflux
Compound 13b was employed in the synthesis of 29, a β-
mannosylurea, in which bridging occurs at the 2-axial posi-
tion of the mannosamine derivative 27 (see Scheme 4). This
synthesis was achieved from the corresponding allyl 2-azi-
domannoside 26[32] by a Staudinger reaction in 90% yield.
Scheme 1. Reagents and conditions: a) H2, Pd/C, TEA, diethyl
ether/hexane (2:1), 3 h; b) AcOCHO, 10 h; c) PPh3, CBr4, TEA,
dry DCM, Ϫ20 °C, 30 min
396
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Unsymmetrical Ureido-Linked Disaccharides
FULL PAPER
signals of C-2 (δ ϭ 50.9 ppm), C-1Ј (δ ϭ 79.0 ppm) and
CONH (δ ϭ 157.3 ppm) confirm the presence of a (1Ǟ2)-
ureido bond between the saccharide units. Compound 29
´
was first debenzylated and after Zemplen deacylation it af-
forded 3 in quantitative yields.
The (1Ǟ4)-ureido connection was also explored using 9
as a donor and the 4-aminoglucoside 33 as an acceptor
(see Scheme 5).
Scheme 5. Reagents and conditions: a) 90% TFA, DCM, 0 °C; b)
Bu2SnO, TBAI, BnBr, toluene, 60 °C, 77%; c) McCl, dry Py, 0 °C,
2 h; d) NaN3, dry DMF, 90 °C, 1 h, 91%; e) Pd/C, dry MeOH, H2,
3 h, 100%; f) 22, 30 min, 94%, g) H2, Pd/C, MeOH, 8 h; h) 1 
NaOMe, dry MeOH, 1 h, 100%
Removal of the benzylidene protecting group from com-
pound 30[33] under acidic conditions (90% TFA in dichloro-
methane) and subsequent selective monobenzylation gave
compound 31. It is worthy of note that the expected 3-O-
benzoyl-6-O-benzyl derivative was not observed. This can
be due to a double migration of the benzoyl group from the
3- to the 6-position, which is favoured by a syn arrangement
˚
Scheme 3. Reagents and conditions: a) PNO, I2 cat., MS (3 A), dry
CH3CN, 10 min; b) 20/21, 30 min, 89% (24), 82% (25); c) H2,
Pd/C, dry MeOH, 10 h; d) 1  NaOMe, dry MeOH, 2 h, 100%
1
of the 3,4,6-hydroxy groups. In the H NMR spectrum, 3-
H and 4-H resonate in the range δ ϭ 3.85Ϫ4.15 ppm, while
the signals of 6a-H and 6b-H are present as two doublets
of doublets at δ ϭ 4.47 and 4.63 ppm, respectively, typical
of a CH2OBz group. The 4-azido epimerization was
achieved by an SN2 reaction on the monochloromesyl[34]
(Mc) derivative of 31 and it afforded 32 in excellent yields.
The new saccharidic configuration was confirmed by 1H
NMR spectrum, in which the 5-H signal is shifted upfield,
while those of 3-H and 4-H are split at δ ϭ 4.16 and
3.72 ppm, respectively, into two triplets, as expected for a
glucosidic ring. Subsequent hydrogenolysis in methanol
gave the corresponding highly stable amine 33, which was
1
completely characterized. In the H NMR spectrum, the 4-
H signal is shifted upfield (δ ϭ 3.01 ppm), while in the 13C
NMR spectrum C-4 resonates at δ ϭ 53.4 ppm. Urea 34
was obtained by reaction of amine 33 with isocyanide 9
under the usual conditions. The presence of both saccharide
Scheme 4. a) PPh3, H2O, THF, reflux, 4 h 90%; b) PNO, I2 cat.,
˚
MS (3 A), dry CH3CN, 10 min; c) H2, Pd/C, MeOH, 18 h; d) 1 
NaOMe, dry MeOH, 1 h, 100%
Interestingly, urea 29 was obtained in 87% yield in the β- portions was confirmed by the acetyl (δ ϭ 2.01Ϫ2.04 ppm)
1
anomeric configuration at C-1Ј only, thus showing that no and methoxy (δ ϭ 3.33 ppm) signals in the H NMR spec-
anomeric equilibration occurred during the formation of trum; the ureido carbonyl signal appears in the 13C NMR
the isocyanate (see Scheme 4). A NOESY experiment per- spectrum at δ ϭ 155.9 ppm and that of C-1 at δ ϭ
formed on compound 29 shows a weak contact between 1Ј- 97.2 ppm, while the C-1Ј signal is shifted to δ ϭ 80.1 ppm.
H (δ ϭ 5.87 ppm) and 3Ј-H (δ ϭ 5.73 ppm), consistent with This compound was deprotected under the same conditions
a β-ureido bond; moreover, in the 13C NMR spectrum, the used for 1Ϫ3 and afforded compound 4.
Eur. J. Org. Chem. 2004, 395Ϫ405
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D. Prosperi, S. Ronchi, L. Lay, A. Rencurosi, G. Russo
FULL PAPER
Scheme 6. Reagents and conditions: a) imidazole, TBDMSCl, dry THF, 3 h; b) BnBr, NaH, dry DMF, TBAI, 0 °C, 10 h, 73% overall
yield (o.y.); c) TBAF, THF, Ϫ78 °C, 1 h, then r.t., 2 h; d) McCl, Py, 45 min; e) NaN3, dry DMF, 1.5 h, 66% o.y.; f) HO(CH2)3NHFmoc,
TMSOTf, dry DCM, 1 h; g) Ac2O, Py, 1 h; h) H2, Pd/C, TEA, dry EtOAc, 10 h; i) BnBr, NaH, dry DMF, 15 h; l) TMSN3, SnCl4, dry
DCM, 3 h, 81% o.y.; m) H2, Pd/C, TEA, diethyl ether/hexane (2:1), 3 h; n) AcOCHO, 12 h; o) PPh3, CBr4, TEA, dry DCM, 20 min, 68%
˚
o.y. for α anomer; p) PNO, I2 cat., MS (3 A), dry CH3CN, 10 min; q) H2, Pd/C, dry MeOH, 10 min, 100%
The synthesis of compound 5 required a more complex compounds 24, 25, 29, and 34. Hydrogenolysis of com-
protecting-group pattern than that of the mannosidic urea pound 45 gave the 2,2Ј-di-O-acetylureidomannosidic disac-
2, both for the donor and the acceptor (see Scheme 6). charide 5 in quantitative yields. Finally, compounds 1Ϫ5
Moreover, the introduction of a properly N-protected pro- were all carefully purified by Sephadex chromatography
pylamino spacer at the anomeric position of the pseudodi- with a G10-120 column.
saccharide makes the molecule apt to conjugation for bio-
logical testing. A common building block was identified in
the orthoester 35. Selective silylation at the primary posi-
Conclusion
tion and subsequent benzylation provided compound 36,
which was readily converted into the corresponding 6-azido
derivative 37 after desilylation and nucleophilic displace-
In this paper we reported the synthesis of a series of in-
tersaccharidic urea derivatives, in which different monosac-
charidic units are used as donors and acceptors. The anom-
eric position was easily connected to primary and second-
ary positions, even in the case of axial amino groups. These
compounds are suitable to be employed as building blocks
for more complex elongations and in the synthesis of stabil-
ized oligosaccharide analogues. Work in this direction is un-
ment of the corresponding monochloromesylate. The ring
opening of the orthoester with Fmoc-aminopropanol[35] in
the presence of trimethylsilyl triflate yielded 38 along with
1
two by-products. The H NMR spectrum shows that the
major by-product, 39, was derived from the 2-O-deacety-
lation of 38. Compound 39 was easily recycled by conver-
sion into 38 (acetic anhydride, pyridine). The minor compo-
nent, identified as compound 40 (CH3O signal at δ ϭ
3.37 ppm), was produced by intramolecular rearrangement
of the orthoester moiety under Lewis acid catalysis. The
synthesis of the donor involved benzylation of 35, followed
by opening of the orthoester ring with trimethylsilylazide in
the presence of a catalytic amount of SnCl4. Conversion of
the azido group into the isocyanide 43 (α/β mixture in 85:15
ratio) was achieved as described previously. The azido
group in 38 was selectively hydrogenated in dry ethyl acetate
in the absence of concomitant benzyl removal and acetyl
transfer. The resulting amine 41 was coupled in the final
der way in our laboratory.
Experimental Section
List of Abbreviations: APT: attached proton test; DCM: dichloro-
methane; DIAD: diisopropyl azadicarboxylate; McCl: monochloro-
methanesulfonyl chloride; PNO: pyridine N-oxide; TBDMSCl:
tert-butyldimethylsilyl chloride; TBAB: tetrabutylammonium bro-
mide; TBAF: tetrabutylammonium fluoride; TBAI: tetrabutylam-
monium iodide; TCPNH: tetrachlorophthalimide; TEA: triethyl-
amine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TLC: thin
layer chromatography; TMSN3: trimethylsilyl azide; TMSOTf: tri-
step with isocyanate 44 under the same conditions as for methylsilyl trifluoromethansulfonate.
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Unsymmetrical Ureido-Linked Disaccharides
FULL PAPER
General Remarks: Reagents and dry solvents were added with oven-
H, 4 COCH3), 3.74 (ddd, J5,6a ϭ 2.2, J5,6b ϭ 4.6, J5,4 ϭ 9.5 Hz, 1
H, 5-H), 4.15 (dd, J6a,5 ϭ 2.2, J6a,6b ϭ 12.5 Hz, 1 H, 6a-H), 4.26
(dd, J6b,5 ϭ 4.6, J6b,6a ϭ 12.5 Hz, 1 H, 6b-H), 4.82 (br. d, 1 H, 1-
H), 5.09Ϫ5.20 (m, 3 H, 2-H, 3-H, 4-H). 13C NMR (50 MHz,
CDCl3, APT, ppm): δ ϭ 20.4, 20.7 (COCH3), 61.3 (C-6), 67.4 (C-
4), 70.8 (C-2), 72.2 (C-3), 74.7 (C-5), 79.6 (C-1), 164.7 (CN), 169.5,
170.2, 170.8 (CO). C15H19NO9 (357.3): calcd. C 50.42, H 5.36, N
3.92; found C 50.25, H 5.47, N 3.84. MALDI-TOF MS: m/z ϭ
379.4 [M ϩ Na]ϩ.
dried syringes through septa. Acetonitrile was dried with activated
˚
molecular sieves (4 A) and distilled from calcium hydride. THF
and DCM were freshly distilled from sodium/benzophenone and
calcium hydride, respectively. Flash chromatography was per-
formed on BDH silica gel (40Ϫ63 µm particle size). TLC was per-
formed on Merck silica gel 60 F254 plates, and visualized by char-
ring either with a mixture of 96% sulfuric acid (50 mL), methanol
(450 mL) and H2O (450 mL) or with a solution of (NH4)6Mo7O24
(21 g), of CeSO4 (1 g) and of 96% H2SO4 (31 mL) in 500 mL of
H2O, followed by heating. 1H and 13C NMR spectra were recorded
with a Bruker AC 200, AC 300 or AVANCE 400 instrument. The
aromatic signals are omitted. Specific optical rotations ([α]D) were
determined with a PerkinϪElmer 241 polarimeter at 20 °C. IR
spectra were recorded with a PerkinϪElmer 681 Infrared Spectro-
photometer. Melting points were determined with a Büchi appar-
atus and are uncorrected. Elemental analyses were performed using
the Carlo Erba elemental analyzer 1108. Mass spectral analyses
were performed with a Bruker OmniFLEXTM Bench-top MALDI-
TOF instrument.
2,3,4,6-Tetra-O-benzoyl-α-
2,3,4,6-Tetra-O-benzoyl-β-
D
-mannopyranosyl Isocyanide (13a) and
D-mannopyranosyl Isocyanide (13b):
Compound 10[26] (3.11 g, 5.00 mmol) was submitted to the same
procedure as for compound 9, affording formamide 12 (3.06 g,
98%). Compound 12 was converted into a mixture of 13a (α an-
omer) and 13b (β anomer) (2.96 g, 100%) as for 8. This mixture
was separated by flash chromatography (EtOAc/hexane, 6:4) and a
7:3 ratio was determined. Compound 13a resulted to be the major
product according to an NOE difference experiment (see discussion
in the text).
Compound 13a: White solid. M.p. 65Ϫ68 °C. [α]2D0 ϭ Ϫ37.6 (c ϭ
1.0, CHCl3). IR (KBr, cmϪ1): ν˜max ϭ 2131 (NC), 1738 (CO). 1H
2,3,4,6-Tetra-O-acetyl-β-D
-glucopyranosyl Isocyanide (9):[22] A solu-
tion of compound 6[23] (1.87 g, 5.01 mmol), a catalytic amount of
palladium on activated charcoal and TEA (2.1 mL, 15.0 mmol) and
a mixture of diethyl ether/hexane (2:1; 100 mL) was stirred under
hydrogen for 3 h. The reaction was monitored by TLC (pure
EtOAc) and the spot corresponding to the azido compound disap-
peared. Meanwhile, a solution of acetoformic anhydride was pre-
pared by heating a solution of acetic anhydride (10 mL, 100 mmol)
and formic acid (6 mL, 150 mmol) at 60 °C for 3 h. The resulting
solution was cooled to room temperature, then added to the amine
solution and left under vigorous stirring overnight. The mixture
was filtered through Celite and the crude solid obtained after con-
centration was purified by silica-gel filtration (AcOET) affording
formamide 8 (1.82 g, 97%). The formamide was dissolved in dry
DCM (60 mL) under nitrogen, together with carbon tetrabromide
(4.97 g, 14.99 mmol) and TEA (2.8 mL, 20.0 mmol); the resulting
solution was cooled to Ϫ20 °C. Triphenylphosphane (3.93 g,
14.95 mmol) in dry DCM (5 mL) was added. After stirring at Ϫ20
°C for 30 min, the mixture was diluted with DCM, washed with a
saturated solution of ammonium chloride and water, dried with
anhydrous sodium sulfate and concentrated. Purification by flash
chromatography (EtOAc/hexane, 8:2) afforded isocyanide 9[22]
(1.39 g, 80%).
NMR (400 MHz, CDCl3, ppm): δ ϭ 4.51 (dd, J6a,5 ϭ 3.8, J6a,6b
12.5 Hz, 1 H, 6a-H), 4.58 (ddd, J5,6b ϭ 1.9, J5,6a ϭ 3.8, J5,4
ϭ
ϭ
9.9 Hz, 1 H, 5-H), 4.77 (dd, J6b,5 ϭ 1.9, J6b,6a ϭ 12.5 Hz, 1 H, 6b-
H), 5.58 (d, J1,2 ϭ 1.7 Hz, 1 H, 1-H), 5.85 (dd, J2,1 ϭ 1.6, J2,3
ϭ
3.1 Hz, 1 H, 2-H), 5.96 (dd, J3,2 ϭ 3.1, J3,4 ϭ 9.9 Hz, 1 H, 3-H),
6.18 (t, J4,3 ϭ J4,5 ϭ 9.9 Hz, 1 H, 4-H). 13C NMR (100 MHz,
CDCl3, APT, ppm): δ ϭ 61.8 (C-6), 65.5, 68.9, 69.9 (C-2, C-3, C-
4), 72.1 (C-5), 79.1 (C-1), 164.9 (CN), 165.2, 165.9, 166.8, (CO).
C35H27NO9 (605.6): calcd. C 69.42, H 4.49, N 2.31; found C 69.38,
H 4.51, N 2.32. MALDI-TOF MS: m/z ϭ 628.1 [M ϩ Na]ϩ.
Compound 13b: White solid. M.p. 74Ϫ75 °C. [α]2D0 ϭ Ϫ101.8 (c ϭ
1.0, CHCl3). IR (KBr, cmϪ1): ν˜max ϭ 2149 (NC), 1734 (CO). 1H
NMR (300 MHz, CDCl3, ppm): δ ϭ 4.19 (ddd, J5,6b ϭ 2.5, J5,6a ϭ
4.8, J5,4 ϭ 9.8 Hz, 1 H, 5-H), 4.53 (dd, J6a,5 ϭ 4.8, J6a,6b ϭ 12.6 Hz,
1 H, 6a-H), 4.76 (dd, J6b,5 ϭ 2.5, J6b,6a ϭ 12.6 Hz, 1 H, 6b-H),
5.35 (d, J1,2 ϭ 1.2 Hz, 1 H, 1-H), 5.60 (dd, J3,2 ϭ 2.6, J3,4 ϭ 9.8 Hz,
1 H, 3-H), 6.02 (t, J4,3 ϭ J4,5 ϭ 9.8 Hz, 1 H, 4-H), 6.08 (d, J2,3
ϭ
2.6 Hz, 1 H, 2-H). 13C NMR (100 MHz, CDCl3, APT, ppm): δ ϭ
62.7 (C-6), 66.0, 69.4, 71.5, 75.5 (C-2, C-3, C-4, C-5), 79.2 (C-1),
165.0 (CN), 165.1, 165.5, 165.9, 166.4 (CO). C35H27NO9 (605.6):
calcd. C 69.42, H 4.49, N 2.31; found C 69.46, H 4.48, N 2.31.
MALDI-TOF MS: m/z ϭ 628.3 [M ϩ Na]ϩ.
2,3,4,6-Tetra-O-acetyl-N-formyl-β-D-glucopyranosylamine (8) [(Z)
Isomer]:[25] White solid. M.p. 146Ϫ148 °C. [α]2D0 ϭ ϩ20.7 (c ϭ 0.5,
Methyl 6-O-Acetyl-2,3,4-tri-O-benzyl-α-D-glucopyranoside (16):
CHCl3). IR (KBr, cmϪ1): ν˜max ϭ 3400 (NH), 1750 (CO acetyl),
Compound 14[28] (6.00 g, 10.8 mmol) was dissolved in a mixture of
acetic anhydride (20 mL) and acetic acid (10 mL). Melted ZnCl2
(12.0 g, 86.4 mmol), dissolved in the same mixture (10 mL), was
added rapidly to the first solution and left at room temperature for
1 h. Saturated NaHCO3 (40 mL) was added dropwise while cooling
with an ice bath, then the mixture was extracted with DCM (2 ϫ
50 mL) and the combined organic layers were washed with water,
dried with anhydrous sodium sulfate and concentrated. The re-
sulting brown oil was purified by flash chromatography (toluene/
1
1700 (CO formyl). H NMR (200 MHz, CDCl3, ppm): δ ϭ 2.03,
2.04, 2.07, 2.09 (s, 3 H, 4 COCH3), 3.83 (ddd, J5,6a ϭ 2.2, J5,6b
ϭ
4.5, J5,4 ϭ 9.5 Hz, 1 H, 5-H), 4.09 (dd, J6a,5 ϭ 2.2, J6a,6b ϭ 12.5 Hz,
1 H, 6a-H), 4.30 (dd, J6b,5 ϭ 4.5, J6b,6a ϭ 12.5 Hz, 1 H, 6b-H),
4.94 (t, J2,1 ϭ J2,3 ϭ 9.5 Hz, 1 H, 2-H), 5.07 (t, J4,5 ϭ J4,3 ϭ 9.5 Hz,
1 H, 4-H), 5.31 (t, J1,2 ϭ J1,NH ϭ 9.5 Hz, 1 H, 1-H), 5.32 (t, J3,2 ϭ
J3,4 ϭ 9.5 Hz, 1 H, 3-H), 6.32 (d, JNH,1 ϭ 9.5 Hz, 1 H, NH), 8.25
(s, 1 H, CHO). 13C NMR (50 MHz, CDCl3, APT, ppm): δ ϭ 20.4,
20.5, 20.6, 20.7 (COCH3), 61.3 (C-6), 67.9 (C-4), 70.3 (C-2), 72.7
(C-3), 73.7 (C-5), 76.6 (C-1), 161.0 (NHCO), 169.4, 169.5, 170.1,
170.7 (COCH3). C15H21NO10 (375.3): calcd. C 48.00, H 5.64, N
3.73; found C 48.16, H 5.58, N 3.76. MALDI-TOF MS: m/z ϭ
397.6 [M ϩ Na]ϩ.
diethyl ether, 9:1) to afford 5.32 g (97%) of a yellow oil. [α]2D0
ϭ
1
ϩ28.6 (c ϭ 1.0, CHCl3). H NMR (300 MHz, CDCl3, ppm): δ ϭ
2.02 (s, 3 H, COCH3), 3.38 (s, 3 H, OCH3), 3.47 (dd, J4,5 ϭ 10.0,
J4,3 ϭ 9.0 Hz, 1 H, 4-H), 3.53 (dd, J2,1 ϭ 3.6, J2,3 ϭ 9.6 Hz, 1 H,
2-H), 3.81 (ddd, J5,6a ϭ 3.8, J5,4 ϭ 10.1 Hz, 1 H, 5-H), 4.01 (dd,
J3,2 ϭ 9.6, J3,4 ϭ 9.0 Hz, 1 H, 3-H), 4.25Ϫ4.35 (m, 2 H, 6a-H, 6b-
Compound 9: White solid. M.p. 104Ϫ105 °C. [α]2D0 ϭ ϩ6.6 (c ϭ 1.0,
CHCl3). IR (KBr, cmϪ1): ν˜max ϭ 2160 (NC), 1751 (CO). 1H NMR H), 4.50Ϫ5.00 (m, 7 H, 1-H, 3 CH2Ph). The 1H NMR spectro-
(200 MHz, CDCl3, ppm): δ ϭ 2.12, 2.12, 2.03, 2.02 (each s, each 3 scopic data correspond to those reported in ref.[36] 13C NMR
Eur. J. Org. Chem. 2004, 395Ϫ405
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
399

D. Prosperi, S. Ronchi, L. Lay, A. Rencurosi, G. Russo
(50 MHz, CDCl3, APT, ppm): δ ϭ 20.8 (COCH3), 55.2 (OCH3), pyranoside (21): Compound 18 or 19 (1.49 g, 2.03 mmol) and 85%
FULL PAPER
63.0 (C-6), 68.5, 77.3, 79.8, 82.0 (C-2, C-3, C-4, C-5), 73.4, 75.0,
77.7 (3 C, CH2Ph), 99.0 (C-1), 170.7 (CO).
hydrazine (385 µL, 6.52 mmol) were dissolved in absolute ethanol
(30 mL) and refluxed for 30 min, until a white precipitate was
formed and the starting material had disappeared (TLC: EtOAc/
hexane, 1:1). After cooling, the residue was dissolved in a mixture
of DCM (50 mL) and 5% NaOH (80 mL). The aqueous phase was
extracted twice with DCM and the combined organic layers were
washed with water, dried with anhydrous sodium sulfate and con-
centrated. The crude products 20 and 21 were employed in the next
reaction without further purification.
Methyl 6-O-Acetyl-2,3,4-tri-O-benzyl-α-D-mannopyranoside (17):
Compound 15[29] (6.00 g, 10.82 mmol) was dissolved in a mixture
of acetic anhydride (20 mL) and TFA (5 mL). After 45 min at room
temperature, the mixture was cooled to 0 °C and saturated
NaHCO3 (20 mL) was added. The resulting mixture was extracted
with DCM (2 ϫ 50 mL) and the combined organic layers were
washed with water, dried with anhydrous sodium sulfate, and con-
centrated. Purification by flash chromatography (hexane/EtOAc,
8:2) gave a colourless oil (5.37 g, 98%). [α]2D0 ϭ ϩ26.9 (c ϭ 1.0,
CHCl3). 1H NMR (300 MHz, CDCl3, ppm): δ ϭ 2.01 (s, 3 H,
COCH3), 3.37 (s, 3 H, OCH3), 3.48 (t, J4,3 ϭ J4,5 ϭ 9.6 Hz, 1 H,
4-H), 3.52 (dd, J2,1 ϭ 3.7, J2,3 ϭ 9.6 Hz, 1 H, 2-H), 3.81 (ddd,
Allyl
2-Amino-3,4,6-tri-O-benzyl-2-deoxy-β-D-mannopyranoside
(27): Compound 26[32] (300 mg, 0.58 mmol) and triphenylphos-
phane (305 mg, 1.16 mmol) were dissolved in THF (5 mL). Water
(21 µL, 1.16 mmol) was added and the solution was refluxed for
4 h (TLC: EtOAc/hexane, 9:1). The mixture was concentrated in
vacuo and purified by flash chromatography (EtOAc/hexane, 8:2)
to yield 27 (257 mg, 90%) as a pale yellow syrup. [α]2D0 ϭ Ϫ45.7
(c ϭ 1.0, CHCl3). 1H NMR (200 MHz, CDCl3, ppm): δ ϭ 3.42
(ddd, J5,6a ϭ 3.9, J5,6a ϭ 4.4, J5,4 ϭ 9.3 Hz, 1 H, 5-H), 3.46 (br. d,
J2,3 ϭ 4.0 Hz, 1 H, 2-H), 3.58 (dd, J6a,6b ϭ 9.0, J6a,5 ϭ 3.9 Hz, 1
J
5,6a ϭ 3.4, J5,4 ϭ 10.1 Hz, 1 H, 5-H), 4.00 (t, J3,2 ϭ J3,4 ϭ 9.6 Hz,
1 H, 3-H), 4.25Ϫ4.35 (m, 2 H, 6a-H, 6b-H), 4.52Ϫ5.03 (m, 7 H, 1-
H, 3 CH2Ph). 13C NMR (50 MHz, CDCl3, APT, ppm): δ ϭ 20.8
(COCH3), 55.2 (OCH3), 63.0 (C-6), 68.5, 78.8, 79.8, 81.6 (C-2, C-
3, C-4, C-5), 73.4, 75.0, 75.7 (3 C, CH2Ph), 98.0 (C-1), 170.8 (CO).
C30H34O7 (506.6): calcd. C 71.13, H 6.76; found C 71.01, H 6.82.
MALDI-TOF MS: m/z ϭ 528.9 [M ϩ Na]ϩ.
H, 6a-H), 3.65Ϫ3.87 (m, 2 H, 3-H, 6b-H), 3.84 (t, J4,5 ϭ J4,3
ϭ
9.3 Hz, 1 H, 4-H), 4.09 (br. dd, JA,B ϭ 12.8, JA,X ϭ 6.3 Hz, 1 H,
CHAHBCHϭCH2), 4.41 (br. dd, JB,A ϭ 12.8, JB,X ϭ 4.8 Hz, 1 H,
CHAHBCHϭCH2), 4.40Ϫ4.66 (m, 7 H, CH2Ph, 2 CHHPh, 1-H,
NH2), 4.74 (d, J ϭ 11.8 Hz, 1 H, CHHPh), 4.89 (d, J ϭ 11.0 Hz,
1 H, CHHPh), 5.13Ϫ5.24 (m, 1 H, CHϭCHH), 5.21Ϫ5.35 (m, 1 H,
CHϭCHH), 5.82Ϫ6.06 (m, 1 H, CHϭCH2). 13C NMR (50 MHz,
CDCl3, APT, ppm): δ ϭ 52.0 (C-2), 69.3, 69.8 (C-6, OCH2CHϭ
CH2), 71.1, 73.4, 75.0 (3 C, CH2Ph), 74.1, 75.4, 82.2 (C-3, C-4, C-
5), 99.7 (C-1), 117.4 (OCH2CHϭCH2), 134.1 (OCH2CHϭCH2).
C30H35NO5 (489.6): calcd. C 73.59, H 7.21, N 2.86; found C 73.72,
H 7.10, N 2.80. MALDI-TOF MS: m/z ϭ 490.8 [M ϩ H]ϩ.
Methyl
imid-2-yl)-α-
2,3,4-Tri-O-benzyl-6-deoxy-6-(4,5,6,7-tetrachlorophthal-
-glucopyranoside (18): Compound 16 (1.09 g,
D
´
2.15 mmol) was deacetylated according to Zemplen. A mixture of
the resulting 6-OH derivative, TCPNH (0.62 g, 2.15 mmol) and
PPh3 (0.68 g, 2.48 mmol) was dissolved in dry THF (30 mL) under
nitrogen. A solution of DIAD (500 µL, 2.48 mmol) in dry THF
(5 mL) was added dropwise. The reaction was complete in 30 min
(TLC EtOAc/hexane, 3:7). The solvent was removed under reduced
pressure and the residue dissolved in DCM (30 mL) and washed
twice with water. The organic layers were dried, concentrated, and
purified by flash chromatography (EtOAc/hexane, 1:9) to furnish
18 (1.56 g, 99%) as an amorphous white solid. [α]2D0 ϭ ϩ28.1 (c ϭ
Methyl 2,6-Di-O-benzoyl-3-O-benzyl-α-D-galactopyranoside (31): A
solution of 30[33] (3.50 g, 7.13 mmol) in DCM (100 mL) was cooled
to 0 °C. 90% TFA (20 mL) was added and the mixture was left for
30 min. The reaction was quenched with saturated NaHCO3
(40 mL) in an ice bath. The mixture was diluted with DCM
(100 mL) and NaHCO3 (100 mL) and extracted twice; the com-
bined organic layers were washed with brine, dried with anhydrous
sodium sulfate, and concentrated. The resulting diol was dissolved
in dry toluene (300 mL) and dibutyltin oxide (2.60 g, 10.65 mmol)
was added in one portion. The mixture was refluxed for 3 h, then
concentrated to 1/3 of its volume and cooled to 50Ϫ60 °C. TBAI
(3.95 g, 10.65 mmol) and BnBr (2.5 mL, 21.3 mmol) were added;
the temperature was raised to 95 °C and vigorous stirring was
maintained overnight. The reaction was quenched with methanol
(20 mL) and the solvent evaporated in vacuo. Flash chromatogra-
phy afforded 31 (2.69 g, 77%) as a syrup. [α]2D0 ϭ ϩ96.3 (c ϭ 1.0,
CHCl3). IR (KBr, cmϪ1): ν˜max ϭ 3440 (OH), 1720 (CO). 1H NMR
(200 MHz, CDCl3, ppm): δ ϭ 3.38 (s, 3 H, OCH3), 3.85Ϫ4.20 (m,
3 H, 3-H, 4-H, 5-H), 4.47 (dd, J6a,6b ϭ 11.2, J6a,5 ϭ 6.5 Hz, 1 H,
6a-H), 4.63 (dd, J6b,6a ϭ 11.2, J6b,5 ϭ 5.2 Hz, 1 H, 6b-H), 4.52 (d,
J ϭ 12.0 Hz, 1 H, CHHPh), 4.64 (d, J ϭ 12.0 Hz, 1 H, CHHPh),
5.19 (d, J1,2 ϭ 3.6 Hz, 1 H, 1-H), 5.35 (dd, J2,1 ϭ 3.6, J2,3 ϭ 9.6 Hz,
1 H, 2-H). 13C NMR (50 MHz, CDCl3, APT, ppm): δ ϭ 55.4
(CH3O), 63.7 (C-6), 68.3 (C-2), 68.9 (C-4), 69.8 (C-3), 70.8 (C-5),
74.2 (CH2Ph), 97.7 (C-1), 165.2, 166.1, 166.5 (CO). C28H28O8
(492.5): calcd. C 68.28, H 5.73; found C 68.15, H 5.79. MALDI-
TOF MS: m/z ϭ 514.8 [M ϩ Na]ϩ.
1
1.2, CHCl3). H NMR (200 MHz, CDCl3, ppm): δ ϭ 3.34 (s, 3 H,
OCH3), 3.45Ϫ3.57 (m, 1 H, 5-H), 3.69Ϫ4.01 (m, 5 H, 2-H, 3-H, 4-
H, 6a-H, 6b-H), 4.55Ϫ4.90 (m, 7 H, 1-H, 3 CH2Ph). 13C NMR
(50 MHz, CDCl3, APT, ppm): δ ϭ 39.2 (C-6), 55.4 (OCH3), 65.5
(C-5), 70.6, 75.3, 75.9 (CH2Ph), 74.0, 79.6, 80.7 (C-2, C-3, C-4),
97.7 (C-1), 163.3 (CO phthal). C35H27NO9 (731.4): calcd. C 59.11,
H 4.27, N 1.91; found C 59.18, H 4.23, N 1.85. MALDI-TOF MS:
m/z ϭ 754.0 [M ϩ Na]ϩ.
Methyl 2,3,4-Tri-O-benzyl-6-deoxy-6-(4,5,6,7-tetrachlorophtalimid-
2-yl)-α-D-mannopyranoside (19): Compound 17 (0.90 g, 1.78 mmol)
was submitted to the same procedure as for compound 16 to afford
19 (1.28 g, 99%) as a colourless foam. [α]2D0 ϭ ϩ43.0 (c ϭ 1.4,
CHCl3). 1H NMR (300 MHz, CDCl3, ppm): δ ϭ 3.26 (s, 3 H,
OCH3), 3.39 (t, J4,3 ϭ J4,5 ϭ 9.6 Hz, 1 H, 4-H), 3.50 (dd, J2,1
3.4, J2,3 ϭ 9.6 Hz, 1 H, 2-H), 3.72 (dd, J6a,5 ϭ 7.1, J6a,6b ϭ 13.7 Hz,
1 H, 6a-H), 3.92Ϫ4.10 (m, 1 H, 3-H, 5-H, 6b-H), 4.52 (d, J1,2
ϭ
ϭ
3.4 Hz, 1 H, 1-H), 4.57 (d, J ϭ 12.0 Hz, 1 H, CHHPh), 4.61 (d,
J ϭ 12.0 Hz, 1 H, CHHPh), 4.73 (d, J ϭ 11.0 Hz, 1 H, CHHPh),
4.75 (d, J ϭ 12.0 Hz, 1 H, CHHPh), 4.97 (d, J ϭ 12.0 Hz, 1 H,
CHHPh), 4.99 (d, J ϭ 11.0 Hz, 1 H, CHHPh). 13C NMR (50 MHz,
CDCl3, APT, ppm): δ ϭ 38.9 (C-6), 55.2 (OCH3), 65.1 (C-5), 71.6,
72.2, 75.3, (CH2Ph), 74.7, 78.6, 80.4 (C-2, C-3, C-4), 97.3 (C-1),
163.2 (CO phthal). C35H27NO9 (731.4): calcd. C 59.11, H 4.27, N
1.91; found C 59.00, H 4.35, N 1.94. MALDI-TOF MS: m/z ϭ
754.1 [M ϩ Na]ϩ.
Methyl 4-Azido-2,6-di-O-benzoyl-3-O-benzyl-4-deoxy-α-D-glucopyr-
Methyl
6-Amino-2,3,4-tri-O-benzyl-6-deoxy-α-
D
-glucopyranoside
anoside (32): McCl (155 µL, 1.74 mmol) was added to a stirred
solution of 31 (570 mg, 1.16 mmol) in pyridine (8 mL) at 0 °C un-
(20)[30] and Methyl 6-Amino-2,3,4-tri-O-benzyl-6-deoxy-α-
D-manno-
400
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 395Ϫ405

Unsymmetrical Ureido-Linked Disaccharides
FULL PAPER
der nitrogen (TLC: diethyl ether/toluene, 3:7). After 2 h, the solu-
tion was diluted with cold water (30 mL) and diethyl ether (50 mL).
The extracted organic layer was washed with 1  HCl, saturated
NaHCO3, and brine. After concentration, the crude monochloro-
mesyl derivative was dissolved directly in dry DMF (3 mL). Sodium
azide (225 mg, 3.45 mmol) was added under nitrogen and the re-
sulting mixture heated to 90 °C. The reaction proceeded in 1 h.
After cooling, the mixture was diluted with water (20 mL) and di-
ethyl ether (30 mL) and extracted. The organic layer was dried with
H), 3.27 (s, 3 H, OCH3), 3.71 (dd, J3,2 ϭ 4.0, J3,4 ϭ 9.3 Hz, 1 H,
3-H), 3.80 (dd, J6a,5 ϭ 1.0, J6a,6b ϭ 11.0 Hz, 1 H, 6a-H), 3.93 (dd,
J6b,5 ϭ 3.3, J6b,6a ϭ 11.0 Hz, 1 H, 6b-H), 3.99 (t, J4,3 ϭ J4,5
ϭ
9.3 Hz, 1 H, 4-H), 4.34 (dd, J2,1 ϭ 2.1, J2,3 ϭ 4.0 Hz, 1 H, 2-H),
4.74 (d, J ϭ 10.8 Hz, 1 H, CHHPh), 4.78 (d, J ϭ 12.2 Hz, 1 H,
CHHPh), 4.81 (d, J ϭ 12.2 Hz, 1 H, CHHPh), 4.93 (d, J ϭ
10.8 Hz, 1 H, CHHPh), 5.30 (d, J1,2 ϭ 2.1 Hz, 1 H, 1-H). The
NMR spectroscopic data are consistent with those reported in
ref.[38] C29H42O7 (530.7): calcd. C 65.63, H 7.98; found C 65.64, H
anhydrous sodium sulfate and concentrated in vacuo, affording a 7.98. MALDI-TOF MS: m/z ϭ 553.2 [M ϩ Na]ϩ.
dark syrup which was purified by flash chromatography (toluene/
6-Azido-3,4-di-O-benzyl-6-deoxy-1,2-O-(1-methoxyethylidene)-β-D-
diethyl ether, 8:2). Compound 32 (546 mg, 91%, two steps) was
obtained as a colourless oil. [α]2D0 ϭ Ϫ35.5 (c ϭ 1.0, CHCl3). IR
mannopyranose (37): Compound 36 (1.35 g, 2.55 mmol) was dis-
solved in dry THF (15 mL) under nitrogen and cooled to Ϫ78 °C.
TBAF (1 ) in THF (900 µL, 3.06 mmol) was added dropwise.
After 1 h, the solution was warmed to room temperature, until the
reaction was complete (additional 2 h; TLC: EtOAc/hexane, 1:1).
The mixture was diluted with ethyl acetate (30 mL), washed with
brine, dried, and concentrated. The crude product was dissolved in
pyridine (10 mL) and McCl (227 µL, 2.55 mmol) was added at 0
°C. The reaction mixture was stirred for 45 min (TLC: toluene/
diethyl ether, 7:3). The mixture was diluted with cold water and
extracted with DCM. The organic layers were washed with 1 
HCl, saturated NaHCO3, and water. After drying, the solvent was
evaporated and the resulting brown syrup employed as such in the
next step. A mixture of the crude product and sodium azide
(350 mg, 5.28 mmol) was dissolved in dry DMF (6 mL) under ni-
trogen and left whilst stirring at 80 °C overnight. After cooling,
water (20 mL) and diethyl ether (30 mL) were added. The ethereal
phase was washed twice with water, dried with anhydrous sodium
sulfate, and concentrated, affording a brown foam which was puri-
fied by flash chromatography. Compound 37 (744 mg, 66% over 3
steps) was isolated as a colourless foam. [α]2D0 ϭ ϩ14.5 (c ϭ 1.0,
1
(CH2Cl2 solution, cmϪ1): ν˜max ϭ 2112 (N3), 1718 (CO). H NMR
(200 MHz, CDCl3, ppm): δ ϭ 3.40 (s, 3 H, OCH3), 3.67 (t, J4,5
J4,3 ϭ 9.0 Hz, 1 H, 4-H), 3.88 (ddd, J5,6b ϭ 2.0, J5,6a ϭ 4.3, J5,4
ϭ
ϭ
9.0 Hz, 1 H, 5-H), 4.16 (t, J3,4 ϭ J3,2 ϭ 9.0 Hz, 1 H, 3-H), 4.54
(dd, J6a,5 ϭ 4.3, J6a,6b ϭ 12.1 Hz, 1 H, 6a-H), 4.66 (dd, J6b,5 ϭ 2.0,
J6b,6a ϭ 12.1 Hz, 1 H, 6b-H), 4.83 (s, 2 H, CH2Ph), 5.06 (d, J1,2
ϭ
3.6 Hz, 1 H, 1-H), 5.15 (dd, J2,1 ϭ 3.6, J2,3 ϭ 9.0 Hz, 1 H, 2-H).
13C NMR (50 MHz, CDCl3, APT, ppm): δ ϭ 55.5 (CH3O), 62.2
(C-4), 63.4 (C-6), 68.0 (C-2), 73.8, 78.4 (C-3, C-5), 75.7 (CH2Ph),
97.3 (C-1), 165.9, 166.2 (CO). C28H27N3O7 (517.5): calcd. C 64.98,
H 5.26, N 8.12; found C 64.87, H 5.38, N 8.16. MALDI-TOF MS:
m/z ϭ 539.9 [M ϩ Na]ϩ.
Methyl 4-Amino-2,6-di-O-benzoyl-3-O-benzyl-4-deoxy-α-D-glucopy-
ranoside (33): Palladium on activated charcoal (2 mg) was added to
a solution of 32 (235 mg, 0.45 mmol) in dry methanol (5 mL).
Selective hydrogenolysis of the azido group was achieved quantitat-
ively in 3 h whilst stirring under hydrogen. [α]2D0 ϭ ϩ18.9 (c ϭ 0.3,
CHCl3). 1H NMR (300 MHz, CDCl3, ppm): δ ϭ 3.01 (t, J4,5
J4,3 ϭ 9.7 Hz, 1 H, 4-H), 3.40 (s, 3 H, OCH3), 3.87 (ddd, J5,6b
4.9, J5,6a ϭ 1.8, J5,4 ϭ 9.7 Hz, 1 H, 5-H), 3.93 (t, J3,4 ϭ J3,2
ϭ
ϭ
ϭ
1
CHCl3). IR (KBr, cmϪ1): ν˜max ϭ 2119 (N3). H NMR (300 MHz,
9.7 Hz, 1 H, 3-H), 4.56 (dd, J6a,5 ϭ 1.8, J6a,6b ϭ 12.0 Hz, 1 H, 6a-
CDCl3, ppm): δ ϭ 1.75 (s, 3 H, CH3 orthoester), 3.29 (s, 3 H,
H), 4.69 (dd, J6b,5 ϭ 4.9, J6b,6a ϭ 12.0 Hz, 1 H, 6b-H), 4.68 (d, J ϭ OCH3), 3.36Ϫ3.43 (m, 2 H, 5-H, 6a-H), 3.51Ϫ3.59 (m, 1 H, 6b-
11.1 Hz, 1 H, CHHPh), 4.89 (d, J ϭ 11.1 Hz, 1 H, CHHPh), 5.10
(d, J1,2 ϭ 3.6 Hz, 1 H, 1-H), 5.16 (dd, J2,1 ϭ 3.6, J2,3 ϭ 9.7 Hz, 1
H), 3.73 (dd, J3,2 ϭ 3.8, J3,4 ϭ 8.8 Hz, 1 H, 3-H), 3.88 (t, J4,3
J4,5 ϭ 8.8 Hz, 1 H, 4-H), 4.42 (dd, J2,1 ϭ 1.4, J2,3 ϭ 3.8 Hz, 1 H,
ϭ
H, 2-H). 13C NMR (75 MHz, CDCl3, APT, ppm): δ ϭ 53.4 (C-4), 2-H), 4.65 (d, J ϭ 10.8 Hz, 1 H, CHHPh), 4.78 (s, 2 H, CH2Ph),
55.2 (CH3O), 63.9 (C-6), 75.5 (CH2Ph), 71.0, 74.8, 74.8, (C-3, C-4, 4.97 (d, J ϭ 10.8 Hz, 1 H, CHHPh), 5.34 (d, J1,2 ϭ 1.4 Hz, 1 H,
C-5), 80.1 (C-2), 97.5 (C-1), 165.9, 166.5 (CO). C28H29NO7 (491.7): 1-H). 13C NMR (50 MHz, CDCl3, APT, ppm): δ ϭ 24.0 (CH3 or-
calcd. C 68.42, H 5.95, N 2.85; found C 68.38, H 5.97, N 2.86.
thoester), 39.9 (C-6), 50.0 (OCH3), 74.0, 74.7, 76.8, 78.7 (C-2, C-
3, C-4, C-5), 72.4, 75.2 (CH2Ph), 97.6 (C-1). C23H27N3O6 (441.5):
calcd. C 62.57, H 6.16, N 9.52; found C 62.69, H 6.04, N 9.58.
MALDI-TOF MS: m/z ϭ 463.8 [M ϩ Na]ϩ.
MALDI-TOF MS: m/z ϭ 492.6 [M ϩ H]ϩ.
3,4-Di-O-benzyl-6-O-tert-butyldimethylsilyl-1,2-O-(1-methoxy-
ethylidene)-β-D-mannopyranose
(36):[37]
TBDMSCl
(1.40 g,
9.33 mmol) was added to a stirred solution of the known orthoester
35[38] (2.00 g, 8.49 mmol) and imidazole (1.30 g, 18.67 mmol) in
THF (40 mL). After 3 h, the mixture was filtered through Celite
and the filter cake washed copiously with diethyl ether. The com-
bined filtrates were concentrated. The crude silyl derivative and
N-Fmoc-3Ј-aminopropyl 2-O-Acetyl-6-azido-3,4-di-O-benzyl-6-de-
oxy-α-D-mannopyranoside (38): A solution of 37 (500 mg,
1.11 mmol) and N-Fmoc-3-aminopropanol[35] (660 mg, 2.22 mmol)
in dry DCM (12 mL) was cooled to 0 °C. After 15 min, TMSOTf
(60 µL, 0.33 mmol) was added dropwise. After 1 h, complete disap-
TBAI (0.12 g, 0.32 mmol) were dissolved in DMF (40 mL), then pearance of the starting material was observed, revealing the for-
benzyl bromide (3.30 mL, 27.79 mmol) and NaH (1.10 g,
27.79 mmol) were added portionwise during 30 min at 0 °C. The
solution was warmed to room temperature and stirring continued
overnight (TLC: EtOAc/hexane, 1:1). The solution was treated with
mation of three spots in TLC (hexane/EtOAc, 6:4). The solution
was diluted with DCM (30 mL) and washed with saturated sodium
hydrogen carbonate, then water. The organic layers were dried and
concentrated in vacuo affording a brown oil. Flash chromatogra-
iced water (50 mL) and the mixture extracted with DCM (2 ϫ phy (hexane/EtOAc, 8:2) gave three products in a quantitative total
50 mL). The combined organic layers were washed with water and
brine, dried with anhydrous sodium sulfate, and concentrated to
give a brown syrup, which was purified by flash chromatography
(EtOAc/hexane, 3:7). The pure benzylated silyl orthoester 36
(3.29 g, 73%) was obtained as a clear yellow oil. 1H NMR
yield: compound 38 (460 mg, 60%) corresponds to the intermediate
spot, the most polar product was attributed to 39 (166 mg, 23%),
while the less polar was identified as 40 (83 mg, 17%). Compound
38 was isolated as a yellow syrup. [α]2D0 ϭ ϩ36.9 (c ϭ 0.9, CHCl3).
IR (KBr, cmϪ1): ν˜max ϭ 2120 (N3), 1749, 1690 (CO). 1H NMR
(300 MHz, CDCl3, ppm): δ ϭ 0.06 [s, 6 H, (CH3)2Si], 0.89 [s, 9 H, (300 MHz, CDCl3, ppm):
δ
ϭ
1.72Ϫ1.87 (m,
2
H,
(CH3)3CSi], 1.73 (s, 3 H, CH3 orthoester), 3.18Ϫ3.24 (m, 1 H, 5- OCH2CH2CH2N), 2.16 (s, 3 H, COCH3), 3.18Ϫ3.31 (m, 2 H,
Eur. J. Org. Chem. 2004, 395Ϫ405
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
401

D. Prosperi, S. Ronchi, L. Lay, A. Rencurosi, G. Russo
FULL PAPER
OCH2CH2CH2N), 3.32Ϫ3.46 (m, 2 H, 6a,b-H), 3.69Ϫ3.81 (m, 3
added and the resulting solution stirred for 3 h (TLC: hexane/
H, 3-H, 4-H, 5-H), 3.90Ϫ3.94 (m, 1 H, OCHHCH2CH2N), EtOAc, 8:2). When the reaction was terminated, saturated
4.17Ϫ4.25 (m, 1 H, OCHHCH2CH2N), 3.87Ϫ4.01 (m, 1 H, CO- NaHCO3 (2 mL) was added and stirring continued for additional
OCHHCH), 4.16Ϫ4.28 (m, 1 H, COOCHHCH), 4.34Ϫ4.42 (m, 1 30 min, until a white suspension was formed. The mixture was di-
H, COOCH2CH), 4.52 (d, J ϭ 11.0 Hz, 1 H, CHHPh), 4.56 (d, luted with water (20 mL) and DCM (20 mL), extracted twice, dried
J ϭ 11.1 Hz, 1 H, CHHPh), 4.69 (d, J ϭ 11.0 Hz, 1 H, CHHPh), with anhydrous sodium sulfate and concentrated. Flash chromatog-
4.79 (s, 1 H, 1-H), 4.91 (d, J ϭ 11.1 Hz, 1 H, CHHPh), 4.87Ϫ4.99 raphy (hexane/EtOAc, 9:1) afforded 42 (889 mg, 81%) as a yellow
(br. t, 1 H, NH), 5.34 (br. s, 1 H, 2-H). 13C NMR (50 MHz, CDCl3, oil. [α]2D0 ϭ ϩ41.3 (c ϭ 1.4, CHCl3). IR (CH2Cl2 solution, cmϪ1):
1
APT, ppm): δ ϭ 21.1 (COCH3), 32.3 (NCCCO), 38.0 (CO-
ν˜max ϭ 2117 (N3), 1748 (CO). H NMR (300 MHz, CDCl3, ppm):
OCH2CH), 38.8 (C-6), 47.2 (NCCCO), 62.5 (NCCCO), 66.5 (CO- δ ϭ 2.16 (s, 3 H, COCH3), 3.72 (d, J6a,6b ϭ 10.9 Hz, 1 H, 6a-H),
OCH2CH), 68.9, 71.3, 74.4, 78.2 (4 C, C-2, C-3, C-4, C-5), 72.1, 3.83 (d, J6b,6a ϭ 10.9 Hz, 1 H, 6b-H), 3.85Ϫ3.95 (m, 3 H, 3-H, 4-
75.2 (CH2Ph), 97.7 (C-1), 157.3 (CO Fmoc), 170.5 (COCH3). H, 5-H), 4.48 (d, J ϭ 11.1 Hz, 1 H, CHHPh), 4.51 (d, J ϭ 10.8 Hz,
C40H42N4O7 (690.8): calcd. C 69.55, H 6.13, N 8.11; found C 69.95, 1 H, CHHPh), 4.52 (d, J ϭ 12.1 Hz, 1 H, CHHPh), 4.66 (d, J ϭ
H 6.18, N 7.78. MALDI-TOF MS: m/z ϭ 713.9 [M ϩ Na]ϩ.
11.1 Hz, 1 H, CHHPh), 4.69 (d, J ϭ 12.1 Hz, 1 H, CHHPh), 4.85
(d, J ϭ 10.8 Hz, 1 H, CHHPh), 5.22 (s, 1 H, 1-H), 5.41 (s, 1 H, 2-
H). 13C NMR (50 MHz, CDCl3, APT, ppm): δ ϭ 21.0 (COCH3),
68.5 (C-2), 68.6 (C-6), 72.0, 73.5, 75.2 (CH2Ph), 73.6 (C-5), 73.8
(C-4), 77.2 (C-3), 88.0 (C-1), 170.3 (COCH3). C29H31N3O6 (517.6):
calcd. C 67.30, H 6.04, N 8.12; found C 67.26, H 6.05, N 8.11.
MALDI-TOF MS: m/z ϭ 540.1 [M ϩ Na]ϩ.
N-Fmoc-3Ј-aminopropyl 6-Azido-3,4-di-O-benzyl-6-deoxy-α-
D
-
mannopyranoside (39): 1H NMR (300 MHz, CDCl3, ppm): δ ϭ
1.72Ϫ1.87 (m, 2 H, OCH2CH2CH2N), 3.15Ϫ3.52 (m, 4 H,
OCH2CH2CH2N, 6a-H, 6b-H), 3.63Ϫ3.89 (m, 4 H, 3-H, 4-H, 5-H,
OCHHCH2CH2N), 3.97Ϫ4.04 (br. s, 1 H, 2-H), 4.17Ϫ4.25 (m, 2
H, OCHHCH2CH2N, COOCHHCH), 4.36Ϫ4.44 (m, 2 H, CO-
OCH2CH, COOCHHCH), 4.57 (d, J ϭ 11.0 Hz, 1 H, CHHPh),
4.67 (s, 2 H, CH2Ph), 4.86 (s, 1 H, 1-H), 4.88 (d, J ϭ 11.0 Hz, 1
H, CHHPh), 4.92Ϫ5.01 (br. t, 1 H, NH). C38H40N4O6 (648.7):
calcd. C 70.35, H 6.21, N 8.64; found C 70.59, H 6.09, N 8.46.
MALDI-TOF MS: m/z ϭ 671.5 [M ϩ Na]ϩ.
2-O-Acetyl-3,4,6-tri-O-benzyl-α-D-mannopyranosyl Isocyanide (43):
The azido compound 42 (233 mg, 0.45 mmol) was transformed into
the corresponding isocyanide according to the procedure used for
compounds 9 and 13. Compound 43 (α anomer) (153 mg, 68%)
was obtained as a syrup. [α]2D0 ϭ ϩ29.3 (c ϭ 1.1, CHCl3). IR (KBr,
cmϪ1): ν˜max ϭ 2135 (NC), 1750 (CO). 1H NMR (300 MHz, CDCl3,
ppm): δ ϭ 2.16 (s, 3 H, COCH3), 3.70 (d, J6a,6b ϭ 11.2 Hz, 1 H,
6a-H), 3.83 (d, J6b,6a ϭ 11.2 Hz, 1 H, 6b-H), 3.87Ϫ3.98 (m, 2 H,
3-H, 4-H), 4.02Ϫ4.09 (m, 1 H, 5-H), 4.49 (2d, J ϭ 11.0 Hz, 2 H, 2
CHHPh), 4.59 (d, J ϭ 10.8 Hz, 1 H, CHHPh), 4.66 (d, J ϭ
11.0 Hz, 1 H, CHHPh), 4.69 (d, J ϭ 10.8 Hz, 1 H, CHHPh), 4.84
(d, J ϭ 10.8 Hz, 1 H, CHHPh), 5.29 (s, 1 H, 1-H), 5.38 (m, 1 H,
2-H). 13C NMR (50 MHz, CDCl3, APT, ppm): δ ϭ 21.2 (COCH3),
68.7 (C-6), 71.8 (C-2), 71.9, 72.5, 75.2 (CH2Ph), 73.1 (C-5), 74.3 (C-
4), 77.0 (C-3), 79.7 (C-1), 164.8 (CN), 170.3 (COCH3). C30H31NO6
(501.6): calcd. C 71.84, H 6.23, N 2.79; found C 71.67, H 6.35, N
2.70. MALDI-TOF MS: m/z ϭ 524.4 [M ϩ Na]ϩ.
Methyl
2-O-Acetyl-6-azido-3,4-di-O-benzyl-6-deoxy-α-D-manno-
pyranoside (40): [α]2D0 ϭ ϩ58.1 (c ϭ 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3, ppm): δ ϭ 2.16 (s, 3 H, COCH3), 3.37 (s, 3 H,
OCH3), 3.38 (dd, J6a,5 ϭ 5.1, J6a,6b ϭ 13.0 Hz, 1 H, 6a-H), 3.52 (d,
J6b,6a ϭ 13.0 Hz, 1 H, 6b-H), 3.73 (t, J4,5 ϭ J4,3 ϭ 8.6 Hz, 1 H, 4-
H), 3.73Ϫ3.84 (m, 1 H, 5-H), 3.96 (dd, J3,2 ϭ 3.1, J3,4 ϭ 8.6 Hz, 1
H, 3-H), 4.51 (d, J ϭ 11.2 Hz, 1 H, CHHPh), 4.56 (d, J ϭ 11.2 Hz,
1 H, CHHPh), 4.69 (d, J ϭ 11.2 Hz, 1 H, CHHPh), 4.70 (s, 1 H,
1-H), 4.93 (d, J ϭ 11.2 Hz, 1 H, CHHPh), 5.35 (br. s, 1 H, 2-H).
13C NMR (75 MHz, CDCl3, APT, ppm): δ ϭ 21.0 (COCH3), 51.3
(C-6), 55.1 (OCH3), 68.5, 71.1, 74.9, 77.9 (C-2, C-3, C-4, C-5), 71.7,
75.3 (CH2Ph), 98.7 (C-1), 170.4 (COCH3). C23H27N3O6 (441.5):
calcd. C 62.57, H 6.16, N 9.52; found C 62.63, H 6.11, N 9.59.
MALDI-TOF MS: m/z ϭ 464.2 [M ϩ Na]ϩ.
Methyl 2,3,4-Tri-O-benzyl-6-deoxy-6-[NЈ-(2Ј,3Ј,4Ј,6Ј-tetra-O-ace-
tyl-β-D-glucopyranosyl)ureido]-α-D-glucopyranoside (24): PNO
(115 mg, 1.2 mmol), dissolved in acetonitrile (0.5 mL), and iodine
(8 mg, 0.03 mmol) were added to a mixture of glycosyl isocyanide
˚
N-Fmoc-3Ј-aminopropyl 6-Amino-2-O-acetyl-3,4-di-O-benzyl-6-de-
oxy-α-D-mannopyranoside (41): Compound 38 (100 mg, 0.15 mmol)
9 (143 mg, 0.40 mmol) and powdered molecular sieves (3 A,
300 mg) in dry acetonitrile (5 mL) under nitrogen. After 10 min,
amine 20 (185 mg, 0.40 mmol) dissolved in dry acetonitrile (1 mL)
was added and stirring continued for 30 min. The reaction was
monitored by TLC (EtOAc/hexane, 4:6). The oxidizing mixture was
then quenched with a saturated solution of sodium hydrogen sul-
fate (5 mL), extracted with DCM (20 mL), and washed with brine
(20 mL). After drying with anhydrous sodium sulfate and evapor-
ation of the solvent, the crude product was purified by flash chro-
matography (EtOAc/hexane, 3:7), affording glycosylurea 24
was dissolved in dry ethyl acetate (5 mL) and palladium on acti-
vated charcoal (2 mg) was added. Hydrogenolysis was performed
under hydrogen (10 h). The mixture was filtered through Celite and
the filtrate concentrated in vacuo. The resulting amine 41 was used
for the reaction with 43 without further purification.
2-O-Acetyl-3,4,6-tri-O-benzyl-α-
D-mannopyranosyl Azide (42):
Compound 35 (500 mg, 2.12 mmol) was dissolved in dry DMF
(7 mL) under nitrogen. Benzyl bromide (1 mL, 9.54 mmol) was ad- (298 mg, 89%) as a white solid. M.p. 81Ϫ82 °C. [α]2D0 ϭ ϩ12.8 (c ϭ
ded dropwise and sodium hydride (60% suspension in silicon oil;
560 mg, 14.32 mmol) was added portionwise under vigorous stir-
1.0, CHCl3). IR (CH2Cl2 solution, cmϪ1): ν˜max ϭ 1758 (CO acet-
ate), 1659 (CO urea). 1H NMR (200 MHz, CDCl3, ppm): δ ϭ 2.00
ring, carefully keeping self-heating controlled. After NaH addition, (s, 6 H, COCH3), 2.02 (s, 3 H, COCH3), 2.08 (s, 3 H, COCH3),
the mixture was allowed to react overnight (TLC: hexane/EtOAc, 3.26 (t, J4,5 ϭ J4,3 ϭ 9.3 Hz, 1 H, 4-H), 3.35 (s, 3 H, OCH3),
7:3). The solution was quenched with methanol and concentrated
in vacuo. The resulting brown syrup was diluted with DCM
(30 mL) and washed with water (2 ϫ 30 mL); the organic layers
were dried, concentrated, and filtered through sylica gel. The trib-
enzyl derivative was dissolved in dry DCM (10 mL) at room tem-
3.35Ϫ3.42 (m, 1 H, 6a-H), 3.46 (dd, J6b,5 ϭ 3.4, J6b,6a ϭ 9.6 Hz, 1
H, 6b-H), 3.59Ϫ3.70 (m, 1 H, 5-H), 3.77 (ddd, J5Ј,6bЈ ϭ 4.2, J5Ј,6aЈ
2.0, J5Ј,4Ј ϭ 9.3 Hz, 1 H, 5Ј-H), 3.98 (t, J3,4 ϭ J3,2 ϭ 9.3 Hz, 1 H,
3-H), 4.06 (dd, J6aЈ,5Ј ϭ 2.0, J6aЈ,6bЈ ϭ 12.5 Hz, 1 H, 6aЈ-H), 4.30
(dd, J6bЈ,5Ј ϭ 4.2, J6bЈ,6aЈ ϭ 12.5 Hz, 1 H, 6bЈ-H), 4.52 (br. t, 1 H,
ϭ
perature. TMSN3 (362 µL, 2.76 mmol), and SnCl4 (100 µL) were NH), 4.55Ϫ5.35 (m, 12 H, 1-H, 1Ј-H, 2Ј-H, 3Ј-H, 4Ј, 3-H CH2Ph,
402  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 395Ϫ405

Unsymmetrical Ureido-Linked Disaccharides
FULL PAPER
NH). 13C NMR (75 MHz, CDCl3, APT, ppm): δ ϭ 20.6, 20.7 (4 3.70Ϫ3.82 (m, 2 H, 5-H, 5Ј-H), 4.03Ϫ4.13 (m, 2 H, 3-H, 6aЈ-H),
COCH3), 41.2 (C-6), 55.3 (CH3O), 61.9 (C-6Ј), 68.3, 69.7, 70.6, 4.15 (t, J4,5 ϭ J4,3 ϭ 9.8 Hz, 1 H, 4-H), 4.28 (dd, J6bЈ,5Ј ϭ 4.2,
73.1, 73.1, 80.1, 80.1, 81.8 (8 C, sugar ring), 73.3, 75.0, 76.7 (3 C, J6bЈ,6aЈ ϭ 12.3 Hz, 1 H, 6bЈ-H), 4.39 (dd, J6a,5 ϭ 5.5, J6a,6b
ϭ
CH2Ph), 78.5 (C-1Ј), 97.9 (C-1), 156.6 (CO urea), 169.7, 169.8, 12.2 Hz, 1 H, 6a-H), 4.51Ϫ4.63 (m, 3 H, 1-H, 6b-H, CHHPh), 4.71
170.6, 170.8 (COCH3). C43H52N2O15 (836.9): calcd. C 61.71, H (d, J ϭ 11.3 Hz, 1 H, CHHPh), 4.81 (br. t, 1 H, NH), 4.96Ϫ5.15
6.26, N 3.35; found C 61.68, H 6.27, N 3.35. MALDI-TOF MS:
(m, 4 H, 1Ј-H, 2-H, 2Ј-H, 4Ј-H), 5.18Ϫ5.24 (br. s, 1 H, NH), 5.26
(t, J3Ј,4Ј ϭ J3Ј,2Ј ϭ 9.1 Hz, 1 H, 3Ј-H). 13C NMR (75 MHz, CDCl3,
APT, ppm): δ ϭ 20.6 (COCH3), 52.9 (C-4), 55.3 (CH3O), 61.9 (C-
6Ј), 63.9 (C-6), 68.4, 69.0, 70.6, 72.9, 73.1, 74.3 (6 C, sugar ring),
74.5 (CH2Ph), 75.9 (C-1Ј), 80.1 (C-2), 97.2 (C-1), 155.9 (CO urea),
165.7, 166.4 (CO Bz), 169.6, 169.8, 170.6, 171.2 (COCH3).
C43H48N2O17 (864.8): calcd. C 59.72, H 5.59, N 3.24; found C
59.77, H 5.60, N 3.24. MALDI-TOF MS: m/z ϭ 887.2 [M ϩ Na]ϩ.
m/z ϭ 859.6 [M ϩ Na]ϩ.
Methyl 2,3,4-Tri-O-benzyl-6-deoxy-6-[NЈ-(2Ј,3Ј,4Ј,6Ј-tetra-O-ben-
zoyl-α-D-mannopyranosyl)ureido]-α-D-mannopyranoside (25): Isocy-
anide 13a (242 mg, 0.40 mmol) was submitted to the same pro-
cedure as compound 24. The coupling with compound 21 (185 mg,
0.40 mmol) afforded glycosylurea 25 as a white solid (356 mg,
82%). M.p. 89Ϫ90 °C. [α]2D0 ϭ ϩ9.0 (c ϭ 1.0, CHCl3). IR (CH2Cl2
1
solution, cmϪ1): ν˜max ϭ 1734 (CO benzoate), 1662 (CO urea). H
N-Fmoc-3ЈЈ-aminopropyl
2-O-Acetyl-3,4-di-O-benzyl-6-deoxy-6-
-mannopyranosyl)ureido]-
-mannopyranose (45): Isocyanide 43 (200 mg, 0.40 mmol) was
NMR (300 MHz, CDCl3, ppm): δ ϭ 3.24 (t, J4,5 ϭ J4,3 ϭ 9.1 Hz, [NЈ-(2Ј-O-acetyl-3Ј,4Ј,6Ј-tri-O-benzyl-α-
1 H, 4-H), 3.36 (s, 3 H, OCH3), 3.35Ϫ3.47 (m, 3 H, 2-H, 6a-H), α-
D
D
3.59Ϫ3.70 (m, 2 H, 5-H, 6b-H), 3.70Ϫ3.79 (m, 1 H, 5Ј-H), 3.99 (t, submitted to the same procedure as compound 24. Coupling with
J3,4 ϭ J3,2 ϭ 9.1 Hz, 1 H, 3-H), 4.38Ϫ4.55 (m, 2 H, 6aЈ-H, H6bЈ), compound 41 (265 mg, 0.40 mmol) afforded glycosylurea 45 as a
4.62Ϫ5.35 (m, 8 H, 1-H, 1Ј-H, 3 CH2Ph), 5.49 (br. s, 1 H, NH),
5.68Ϫ5.87 (m, 2 H, 2Ј-H, 3Ј-H), 6.14 (t, J4,3 ϭ J4,5 ϭ 9.2 Hz, 1 H, CHCl3). IR (CH2Cl2 solution, cmϪ1): ν˜max ϭ 1750 (CO acetate),
4-H). 13C NMR (75 MHz, CDCl3, APT, ppm): δ ϭ 40.8 (C-6), 55.3 1716 (CO Fmoc), 1653 (CO urea). 1H NMR (300 MHz, CDCl3,
white solid (416 mg, 88%). M.p. 61Ϫ62. [α]2D0 ϭ ϩ93.8 (c ϭ 1.0,
(CH3O), 62.5 (C-6Ј) 66.8, 69.1, 69.8, 70.1, 80.3, 82.0 (8 C, sugar ppm): δ ϭ 1.67Ϫ1.78 (m, 2 H, OCH2CH2CH2N), 2.10 (s, 6 H, 2
ring), 73.2, 74.9, 75.8 (3 C, CH2Ph), 77.5 (C-1Ј), 97.9 (C-1), 157.7 COCH3), 2.94Ϫ3.25 (m, 2 H, OCH2CH2CH2N), 3.28Ϫ3.46 (m, 2
(CO urea), 165.3, 165.7, 166.1 (COCH3). C63H60N2O15 (1085.2): H, 6a-H, 6b-H), 3.50Ϫ3.86 (m, 6 H, 3-H, 4-H, 5-H, 6aЈ-H, 6bЈ-H,
calcd. C 69.73, H 5.57, N 2.58; found C 69.63, H 5.55, N 2.57.
NH), 3.87Ϫ3.94 (m, 4 H, OCHHCH2CH2N, 3Ј-H, 4Ј-H, 5Ј-H),
4.11Ϫ4.22 (m, 2 H, OCHHCH2CH2N, COOCHHCH), 4.31Ϫ4.42
(m, 2 H, COOCHHCH, COOCH2CH), 4.48Ϫ4.87 (m, 12 H, 5
CH2Ph, 1-H, NH), 5.01 (br. s, 1 H, NH), 5.16 (s, 1 H, 2-H), 5.27
(s, 1 H, 1Ј-H), 5.48 (s, 1 H, 2Ј-H). 13C NMR (75 MHz, CDCl3,
APT, ppm): δ ϭ 20.9 (COCH3) 33.7 (NCCCO), 38.0 (CH), 38.2
(C-6), 47.3 (NCCCO), 63.3 (NCCCO), 66.6 (CH2O), 68.8 (C-6),
68.4, 68.7, 70.6, 71.6, 72.7, 74.1, 74.2, 78.0 (8 C, sugar ring), 78.0
(C-1Ј), 71.8, 72.1, 73.4, 74.9, 75.2 (5 C, CH2Ph), 97.7 (C-1), 156.5
(CO urea), 158.9 (CO Fmoc), 170.1, 170.4 (COCH3). C70H75N3O14
(1182.4): calcd. C 71.11, H 6.39, N 3.55; found C 71.01, H 6.45, N
3.50. MALDI-TOF MS: m/z ϭ 1204.5 [M ϩ Na]ϩ.
MALDI-TOF MS: m/z ϭ 1107.5 [M ϩ Na]ϩ.
Allyl 3,4,6-Tri-O-benzyl-2-deoxy-2-[NЈ-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzoyl-
β-D-mannopyranosyl)ureido]-β-D-mannopyranoside (29): Isocyanide
13b (242 mg, 0.40 mmol) was submitted to the same procedure as
compound 24. Coupling with compound 27 (196 mg, 0.40 mmol)
afforded glycosylurea 29 as a white solid (387 mg, 87%). M.p.
113Ϫ114. [α]2D0 ϭ Ϫ92.3 (c ϭ 1.0, CHCl3). IR (CH2Cl2 solution,
cmϪ1): ν˜max ϭ 1733 (CO benzoate), 1658 (CO urea), 1638 (CHϭ
CH2). 1H NMR (400 MHz, CDCl3, COSY, NOESY, ppm): δ ϭ
3.32Ϫ3.46 (m, 1 H, 5-H), 3.46Ϫ3.52 (br. s, 1 H, NH), 3.58Ϫ3.65
(m, 2 H, 6a-H, H6b), 4.06 (dd, J ϭ 6.7 Hz, 13.2 Hz, 2 H, CH2CHϭ
CH2), 4.25Ϫ4.34 (m, 3 H, 3-H, 4-H, 5Ј-H), 4.46 (s, 1 H, 1-H), Methyl 6-Deoxy-6-[NЈ-(β-D-glucopyranosyl)ureido]-α-D-glucopyr-
4.46Ϫ4.52 (m, 4 H, 2 CHHPh, CH2Ph), 4.56 (dd, J6aЈ,5Ј ϭ 3.8,
J6aЈ,6bЈ ϭ 12.2 Hz, 1 H, 6aЈ-H), 4.70 (s, 1 H, 2-H), 4.71 (dd, J6bЈ,5Ј
anoside (1): Compound 24 (210 mg, 0.25 mmol) was dissolved in
methanol (2 mL), containing a suspension of palladium on acti-
ϭ
2.3, J6bЈ,6aЈ ϭ 12.2 Hz, 1 H, 6bЈ-H), 4.78 (d, J ϭ 11.0 Hz, 1 H, vated charcoal (2 mg). Stirring was continued under hydrogen until
CHHPh), 4.93 (d, J ϭ 11.0 Hz, 1 H, CHHPh), 5.17 (d, JA,X
10.5, 1 H, CHXϭCHAHB), 5.25 (br. s, 1 H, NH), 5.27 (d, JB,X
ϭ
the starting material disappeared (TLC: EtOAc/hexane, 2:1). The
mixture was filtered through Celite, that was washed abundantly
ϭ
17.2, 1 H, CHXϭCHAHB), 5.73 (dd, J3Ј,2Ј ϭ 3.1, J3Ј,4Ј ϭ 10.1 Hz, with methanol. Collected methanolic solutions were reduced to
1 H, 3Ј-H), 5.85Ϫ5.89 (m, 1 H, CHXϭCHAHB), 5.87 (d, J1Ј,NH
ϭ
2 mL and freshly prepared 1  NaOMe was added (25 µL) (TLC:
9.5 Hz, 1 H, 1Ј-H), 5.95 (d, J2Ј,3Ј ϭ 3.1 Hz, 1 H, 2Ј-H), 6.15 (t,
EtOAc/MeOH/H2O, 8:2:1). The basicity was neutralized with Am-
J4Ј,5Ј ϭ J4Ј,3Ј ϭ 9.8 Hz, 1 H, 4Ј-H). 13C NMR (100 MHz, CDCl3, berlite IR-120 (Hϩ form). The resin was filtered and the solvent
APT, ppm): δ ϭ 50.9 (C-2), 63.4 (C-6Ј) 66.8 (C-2Ј), 69.2 (C-6), 70.2 evaporated in vacuo, quantitatively affording 1 (100 mg, 100%) as
(allylic CH2), 71.3, 73.6, 75.1 (3 C, CH2Ph), 71.9, 73.4, 74.0, 74.5,
75.4, 80.8 (6 C, sugar ring), 79.0 (C-1Ј), 99.2 (C-1), 117.9 (CHϭ
CH2), 157.3 (CO urea), 165.8, 165.8, 165.9, 166.5 (COCH3).
a white solid, which was purified by Sephadex chromatography
with a G10-120 column (eluent water) and lyophilised. [α]2D0
ϩ71.2 (c ϭ 1.5, D2O). NMR spectroscopic data are in agreement
ϭ
C65H62N2O15 (1111.2): calcd. C 70.26, H 5.62, N 2.52; found C with those previously reported.[17] C14H26N2O11 (398.4): calcd. C
70.24, H 5.66, N 2.54. MALDI-TOF MS: m/z ϭ 1133.6 [M ϩ
42.21, H 6.58, N 7.03; found C 42.23, H 6.57, N 7.04. MALDI-
Na]ϩ.
TOF MS: m/z ϭ 420.7 [M ϩ Na]ϩ.
Methyl
2,6-Di-O-benzoyl-3-O-benzyl-4-deoxy-4-[NЈ-(2Ј,3Ј,4Ј,6Ј-
Methyl 6-Deoxy-6-[NЈ-(α-D-mannopyranosyl)ureido]-α-D-mannopyr-
tetra-O-acetyl-β-
D
-glucopyranosyl)ureido]-α- -glucopyranoside (34): anoside (2): Compound 25 (210 mg, 0.25 mmol) was submitted to
D
Isocyanide 9 (143 mg, 0.40 mmol) was submitted to the same pro-
cedure as compound 24. Coupling with compound 33 (197 mg,
0.40 mmol) afforded glycosylureas 34 as a white solid (325 mg
the same procedure as for compound 1 affording 2 (100 mg, 100%)
as a white solid. M.p. 85Ϫ87 °C. [α]2D0 ϭ ϩ58.7 (c ϭ 1.0, MeOH).
1H NMR (300 MHz, D2O, ppm): δ ϭ 3.27Ϫ3.41 (m, 2 H, 6a-H,
94%). M.p. 214Ϫ215 °C. [α]2D0 ϭ ϩ56.4 (c ϭ 1.0, CHCl3). IR 6b-H), 3.42 (s, 3 H, OCH3), 3.43Ϫ3.44 (m, 1 H, 5Ј-H), 3.52Ϫ3.96
(CH2Cl2 solution, cmϪ1): ν˜max ϭ 1750 (CO acetate), 1734 (CO ben-
(m, 9 H, 2-H, 2Ј-H, 3-H, 3Ј-H, 4-H, 4Ј-H, 5-H, 6aЈ-H, 6bЈ-H), 4.81
zoate), 1662 (CO urea). 1H NMR (300 MHz, CDCl3, ppm): δ ϭ (s, 1 H, 1Ј-H), 5.12 (s, 1 H, 1-H). 13C NMR (75 MHz, D2O, APT,
2.01 (s, 3 H, COCH3), 2.04 (s, 9 H, COCH3), 3.33 (s, 3 H, OCH3), ppm): δ ϭ 41.2 (C-6), 55.8 (CH3O), 61.8 (C-6Ј) 67.3, 71.1, 71.4,
Eur. J. Org. Chem. 2004, 395Ϫ405
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
403

D. Prosperi, S. Ronchi, L. Lay, A. Rencurosi, G. Russo
FULL PAPER
71.7, 72.0, 73.7, 74.3, 78.0 (8 C, sugar ring), 79.7 (C-1Ј), 99.9 (C-
1), 160.1 (CO urea). C14H26N2O11 (398.4): calcd. C 42.21, H 6.58,
N 7.03; found C 42.21, H 6.57, N 7.03. MALDI-TOF MS: m/z ϭ
420.4 [M ϩ Na]ϩ.
Acknowledgments
This work was supported by Regione Lombardia, Assessorato alla
`
Sanita and CNR Istituto di Scienze e Tecnologie Molecolari.
Propyl 2-Deoxy-2-[NЈ-(β-D-mannopyranosyl)ureido]-β-D-mannopyr-
[1]
H. Lis, N. Sharon, Eur. J. Biochem. 1993, 218, 1Ϫ27.
anoside (3): Compound 29 (278 mg, 0.25 mmol) was submitted to
the same procedure as for compound 1 affording 3 (107 mg, 100%)
as a white solid. M.p. 92Ϫ93 °C. [α]2D0 ϭ Ϫ36.3 (c ϭ 1.0, MeOH).
1H NMR (400 MHz, D2O, ppm): δ ϭ 0.80 (t, J ϭ 7.2 Hz, 3 H,
OCH2CH2CH3), 1.50 (q, J ϭ 7.2 Hz, 3 H, OCH2CH2CH3),
3.27Ϫ3.41 (m, 3 H, 4Ј-H, 5-H, 5Ј-H), 3.46Ϫ3.56 (m, 2 H, 3Ј-H, 4-
H), 3.60Ϫ3.74 (m, 6 H, 3-H, 6a-H, 6aЈ-H, OCH2CH2CH3),
3.80Ϫ3.88 (m, 3 H, 2Ј-H, 6b-H, 6bЈ-H), 4.23 (br. d, J2,NH ϭ 3.6 Hz,
2-H), 4.70 (s, 1 H, 1Ј-H), 5.01 (s, 1 H, 1-H). 13C NMR (100 MHz,
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δ
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10.0 (OCH2CH2CH3), 22.5
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Methyl 4-Deoxy-4-[NЈ-(β-D-glucopyranosyl)ureido]-α-D-glucopyr-
anoside (4): Compound 34 (216 mg, 0.25 mmol) was submitted to
the same procedure as for compound 1 affording 4 (100 mg, 100%)
as a white solid. M.p. 87Ϫ88 °C. [α]2D0 ϭ ϩ76.1 (c ϭ 1.0, MeOH).
1H NMR (400 MHz, D2O, ppm): δ ϭ 3.30 (t, J4,5 ϭ J4,3 ϭ 9.1 Hz,
1 H, 4Ј-H), 3.32Ϫ3.35 (m, 1 H, 2-H), 3.35 (s, 3 H, OCH3),
3.41Ϫ3.47 (m, 1 H, 5Ј-H), 3.47 (t, J3,4 ϭ J3,2 ϭ 9.1 Hz, 1 H, 3Ј-H),
3.51Ϫ3.57 (m, 1 H, 5-H), 3.56 (dd, J6b,5 ϭ 3.7, J6b,6a ϭ 9.5 Hz, 1
H, 6b-H), 3.59Ϫ3.71 (m, 5 H, -H 2Ј-H, 3-H, 4-H, 6a-H, 6aЈ-H),
3.81 (dd, J6bЈ,5Ј ϭ 2.0, J6bЈ,6aЈ ϭ 12.3 Hz, 1 H, 6bЈ-H), 4.76 (d,
J1,2 ϭ 6.5 Hz, 1Ј-H), 4.78 (br. s, 1 H, 1-H). 13C NMR (100 MHz,
D2O, APT, ppm): δ ϭ 52.6 (C-4), 55.4 (OCH3), 61.0, 61.3 (C-6, C-
6Ј), 69.8, 71.4, 71.5, 72.0, 72.3, 76.9, 77.5 (7 C, sugar ring), 81.5
(C-1Ј), 99.6 (C-1), 159.7 (CO urea). C14H26N2O11 (398.4): calcd. C
42.21, H 6.58, N 7.03; found C 42.23, H 6.58, N 7.04. MALDI-
TOF MS: m/z ϭ 399.2 [M ϩ Na]ϩ.
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´
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J. M. Garcıa Fernandez, C. Ortiz Mellet, V. M. Dıaz Perez, J.
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Fuentes, J. Kovacs, I. Pinter, Tetrahedron Lett. 1997, 38,
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[18]
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´
´
V. M . D ıaz Perez, C. O. Mellet, J. Fuentes, J. M. Garcıa Fer-
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M. I. Garcıa-Moreno, J. M. Benito, C. Ortiz Mellet, J. M. Gar-
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(355 mg, 0.30 mmol) was dissolved in methanol (5 mL), containing
a suspension of palladium on activated charcoal (5 mg). Stirring
was continued under hydrogen until the starting material had dis-
appeared (TLC: EtOAc/hexane, 4:1). The mixture was filtered
through Celite, which was washed abundantly with methanol.
Evaporation of the solvent afforded 5 (117 mg, 98%) as a white
foam which was purified by Sephadex chromatography with a G10-
120 column (eluent water) and lyophilised. [α]2D0 ϭ ϩ14.3 (c ϭ 1.0,
CHCl3). 1H NMR (200 MHz, D2O, ppm): δ ϭ 1.69Ϫ1.75 (m, 2 H,
OCH2CH2CH2N), 2.10 (s, 6 H, 2 COCH3), 2.95Ϫ3.26 (m, 2 H,
OCH2CH2CH2N), 3.27Ϫ3.42 (m, 2 H, 6a-H, 6b-H), 3.45Ϫ3.89 (m,
8 H, 3-H, 3Ј-H, 4-H, 4Ј-H, 5-H, 5Ј-H, 6aЈ-H, 6bЈ-H), 3.91Ϫ3.94 (m,
1 H, OCHHCH2CH2N,), 4.11Ϫ4.22 (m, 2 H, OCHHCH2CH2N,
COOCHHCH), 4.30Ϫ4.39 (m, 2 H, COOCHHCH, COOCH2CH),
4.87 (s, 1 H, 1-H), 5.18 (s, 1 H, 2-H), 5.23 (s, 1 H, 1Ј-H), 5.39 (s, 1
H, 2Ј-H). 13C NMR (50 MHz, D2O, APT, ppm): δ ϭ 20.9
(COCH3), 33.8 (NCCCO), 38.2 (CH), 38.3 (C-6), 47.3 (NCCCO),
63.2 (NCCCO), 66.5 (CH2O), 68.1 (C-6Ј), 69.2, 69.4 (2 C, C-2, C-
2Ј), 71.2, 71.3, 72.5, 73.2, 75.3, 77.9 (6 C, sugar ring), 78.8 (C-1Ј),
99.7 (C-1), 158.9 (CO Fmoc), 160.5 (CO urea). C35H45N3O14
(731.7): calcd. C 57.45, H 6.20, N 5.74; found C 57.49, H 6.18, N
5.73. MALDI-TOF MS: m/z ϭ 753.9 [M ϩ Na]ϩ.
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Eur. J. Org. Chem. 2004, 395Ϫ405

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405