Synthesis of cluster N-glycosides based on a β-cyclodextrin core

Article abstract of DOI:10.1002/(SICI)1521-3765(19990604)5:6<1775::AID-CHEM1775>3.0.CO;2-2

A convenient method for the synthesis of β-D-gluco-, β-D-galacto-, 2-acetamido-2-deoxy-β-D-gluco- and α-D-mannopyranosylamine clusters based on cyclomaltoheptaose (β-cyclodextrin) is presented. The synthesis involves: 1) the one-pot synthesis of the acetylated chloroacetyl N-glycoside derivatives of D-glucose, D-galactose, 2-acetamido-2-deoxy-D-glucose and D-mannose from the corresponding glycosyl azides, 2) conversion of the chloroacetyl N-glycosides into their isothiouronium derivatives, then 3) attachment of the N-glycosides onto heptakis(6-deoxy-6-iodo) and heptakis(6-chloroacetamido-6-deoxy) β-cyclodextrin by means of nuoleophilic displacement with caesium carbonate in dimethylformamide, and 4) de-O-acetylation of β-cyclodextrin derivatives. The chloroacetyl N-glycoside derivatives were easily prepared by mild reduction of the azide function by one of two methods : a) by the Staudinger reaction, with nBu₃P, and b) with 1,3-propanedithiol, as reducing reagents.

Full text of DOI:10.1002/(SICI)1521-3765(19990604)5:6<1775::AID-CHEM1775>3.0.CO;2-2

FULL PAPER
Synthesis of Cluster N-Glycosides Based on a b-Cyclodextrin Core
[b]
[a]
[b]
Juan J. García-L o pez, Francisco Santoyo-Gonz a lez,* Antonio Vargas-Berenguel,*
and Juan J. Gim e nez-Martínez[b]
Abstract: A convenient method for the
synthesis of b-d-gluco-, b-d-galacto-,
azides, 2) conversion of the chloroacetyl
N-glycosides into their isothiouronium
derivatives, then 3) attachment of the N-
glycosides onto heptakis(6-deoxy-6-io-
do) and heptakis(6-chloroacetamido-6-
deoxy) b-cyclodextrin by means of nu-
cleophilic displacement with caesium
carbonate in dimethylformamide, and
4) de-O-acetylation of b-cyclodextrin
derivatives. The chloroacetyl N-glyco-
side derivatives were easily prepared by
mild reduction of the azide function by
one of two methods: a) by the Stauding-
2-acetamido-2-deoxy-b-d-gluco- and a-
d-mannopyranosylamine clusters based
on cyclomaltoheptaose (b-cyclodextrin)
is presented. The synthesis involves:
1) the one-pot synthesis of the acety-
lated chloroacetyl N-glycoside deriva-
tives of d-glucose, d-galactose, 2-acet-
amido-2-deoxy-d-glucose and d-man-
nose from the corresponding glycosyl
er reaction, with nBu P, and b) with 1,3-
propanedithiol, as reducing reagents.
3
Keywords: carbohydrates ´ cluster
glycosides ´ cyclodextrins ´ glycosyl-
amines ´ Staudinger reaction
Introduction
inclusion complexes exhibit very poor target specificity owing
to the lack of biologically recognizable sites. Several research-
ers are addressing this problem using CDs conjugated with
target molecules with promising results, for example, increas-
es in both water solubility and recognition properties of the
carrier systems.[
The construction of systems that can selectively deliver
bioactive molecules to their sites of action within the organism
is currently a challenge in therapeutics. In this respect, much
effort has been focused on exploitation of the host-guest
properties of certain molecules such as cyclodextrins.[1±3] The
cyclodextrins (CDs) are cyclomaltooligosaccharides with six
5]
Oligosaccharides are known to play important roles in
many biological events, for example as cell-surface receptors
which enable adhesion of bacteria, parasites, and viruses in
the early stages of infection.[ Therefore, carbohydrates
involved in recognition processes are good candidates for
targetting molecules. However, unlike protein ± protein inter-
actions, carbohydrate ± protein interactions usually have low
(
a-CD), seven (b-CD) and eight (g-CD) a-(1 !4)-d-gluco-
6]
pyranosyl units, respectively, that are formed during the
[
1, 2]
enzymatic degradation of starch.
Most applications of CDs
are based on their ability to include spatially compatible
molecules (guest molecules) in their hydrophobic cavity to
[
3]
[7]
yield inclusion complexes without formation of any covalent
bonds. This supramolecular property can be used for the
solubilization, encapsulation and transport of bioactive mol-
dissociation constants. An effective means to increase
binding interactions between carbohydrates and proteins is
the use of clusters of carbohydrates.[ With the aim of
achieving much stronger affinity between receptors and
saccharides, several authors have reported the synthesis of
multivalent glycoconjugates on scaffolds of polymers and
8]
[
4]
ecules by CDs and their derivatives. Nevertheless, CD ± drug
[9±10]
[10±13]
[14]
[
[
a] Dr. F. Santoyo-Gonz a lez
Instituto de Biotecnología, Facultad de Ciencias
Universidad de Granada
oligomers,
dendrimers,
calix[4]arenes,
crown
[15]
[16]
[17]
ethers, surfactant aggregates, and metal complexes.
The well-defined torus-shaped structures of CDs provide a
versatile scaffold for the construction of branched structures
of bioactive molecules. In our research project we intend to
combine the scaffolding potential of the CDs for building
multivalent or dendrimerlike molecules with their host ± guest
properties, in order to develop drug carrier systems. Previ-
ously we have reported the synthesis of a variety of
persubstituted b-CD derivatives branched with O- and S-
glycosides and their recognition studies towards cell-wall
specific lectins.[
E-18071 Granada (Spain)
Fax : (‡ 34)958-243186
E-mail: fsantoyo@goliat.ugr.es
b] Dr. A. Vargas-Berenguel, J. J. García-L o pez,
Dr. J. J. Gim e nez-Martínez
Â
Area de Química Org a nica, Universidad de Almería
E-04120 Almería (Spain)
Fax : (‡ 34)950-215481
E-mail: avargas@ualm.es
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/chemistry/ or from the author.
18]
Chem. Eur. J. 1999, 5, No. 6
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F. Santoyo-Gonz a lez, A. Vargas-Berenguel et al.
FULL PAPER
Scheme 1. Synthesis of the glycopyranosylamine derivatives 5 ± 15 from the corresponding glycosyl azide derivatives 1 ± 4. Reagents and conditions: a) Bu
CH Cl , RT, then (ClCH CO) O/CH Cl P/CH Cl , 1 h, RT, then (ClCH CO) O/Et N/CH Cl
36%); c) (ClCH CO) O/CH Cl P, 3 h !RT: 7 (67%), 8a (80%); d) Et N/1,3-propanedithiol/MeOH, 3 ± 6 h, then (ClCH
, � 808C then Bu
(68%), 6 (76%), 7 (74%); e) Bu P/CH Cl , RT, then (ClCH CO) O/CH Cl N, 2 ± 10 h, 9 (88%), 10 (83%), 11 (37%);
, � 808C !RT, then AcSH/Et
CS/(CH CO, 72 h: 12 (82%), 13 (65%), 15 (80%); g) (NH CS/(CH CO/CH Cl , 168 h, 14 (78%).
3
P/
, � 808C !RT: 7
CO) O, 2 ± 10 h:
2
2
2
2
2
2
, � 808C !RT: 5 (68%), 6 (73%); b) Bu
3
2
2
2
2
3
2
2
(
2
2
2
2
3
3
2
2
5
3
2
2
2
2
2
2
3
f) (NH
2
)
2
3
)
2
2
)
2
3
)
2
2
2
In this paper we describe the synthesis of b-CD persub-
stituted with glycosyl amide derivatives. Most methods for the
synthesis of glycosyl amides involve either the reaction of a
nonprotected carbohydrate with aqueous ammonium bicar-
bonate or the reduction of the corresponding azide derived
from a protected glycosyl halide and then acylation of the
by treatment of phosphinimines derived from the correspond-
ing glycosyl azides with acetic formic anhydride,[ and
sugar ureas have been obtained from glycosyl triphenyl-
phosphinimines by treatment with amines and carbon
dioxide.[
21]
22]
Our interest in the synthesis of a set of glycosyl amide
building blocks suitable for their convenient attachment to b-
CD templates led us to explore a more efficient conversion of
glycosyl azides into N-glycosides, as reported in an earlier
[
19]
obtained glycosylamine. Both methods sometimes present
problems as a result of the formation of undesired by-
products. The conversion of glycosyl azides into N-glycoside
[
20]
[23]
derivatives by the Staudinger reaction provides an alter-
native mild route for the synthesis of N-glycosides. For
example, glycofuranosyl formamides have been prepared
communication.
Results and Discussion
Abstract in Spanish: Se describe un m e todo pr a ctico para la
síntesis de clusters de b-d-gluco-, b-d-galacto-, 2-acetamido-2-
desoxi-b-d-gluco- y a-d-manopiranosilaminas unidas a ciclo-
maltoheptaosa (b-ciclodextrina). La síntesis lleva consigo: 1) la
síntesis one-pot de los cloroacetil N-glic o sidos acetilados
derivados de d-glucosa, d-galactosa, 2-acetamido-2-desoxi-d-
glucosa y d-manosa a partir de las correspondientes glicosil
Our synthetic plan involves the preparation of thiolated
glycosyl amide building blocks in order to perform attach-
ment to b-CD by a nucleophilic substitution reaction. We first
studied the synthesis by the Staudinger reaction of the
[24]
chloroacetyl N-glycosides 5 ± 8a from glycosyl azides 1 ± 3
and 4.[ Thus, the glucopyranosyl 1 and galactopyranosyl
25]
azide 2 derivatives were treated sequentially with nBu P at
azidas; 2) la conversio
Ân de los N-glic o sidos en sus derivados
3
room temperature and chloroacetic anhydride at � 808C in
isotiouronio; a continuaci o n, 3) uni o n de los N-glic o sidos con
la heptakis(6-desoxi-6-yodo) y heptakis(6-cloroacetamido-6-
desoxi) b-ciclodextrina por medio de una reacci o n de despla-
zamiento nucleofílico utilizando carbonato de cesio en dime-
tilformamida; y 4) des-O-acetilaci o n de los derivados de b-
ciclodextrina. Los derivados cloroacetil N-glic o sidos se prepa-
dry CH Cl , and the glycosyl amides 5 and 6 in 68 and 73%
2
2
yields, respectively, were isolated in one pot after chromato-
graphic purification (Scheme 1). We had previously observed
that the reaction of 1 with Ph P occurred slowly, so we used
3
the more nucleophilic reagent nBu P. Reaction of the
3
N-acetylglucosamine derivative 3 with nBu P and chloro-
raron por reduccio
Ân suave de la funci o n azida siguiendo dos
3
acetic anhydride under the same conditions did not yield the
glycosyl amide 7, although TLC showed that the starting
material was not present in the reaction mixture after 1 h. We
m e todos: a) vía reacci o n de Staudinger, con nBu P, y
3
b) utilizando 1,3-propanoditiol, como agentes reductores.
1
776
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Chem. Eur. J. 1999, 5, No. 6

Cluster N-Glycosides
1775±1784
attributed this particular result to the poor reactivity of the
phosphinimine intermediate due to a lower nucleophilicity
of the phosphinimine nitrogen. This reactivity decrease
might be brought about by a hydrogen bond between that
nitrogen and the amide hydrogen. In fact, the addition of
triethylamine after chloroacetic anhydride allowed the iso-
lation of the desired N-glycoside 7, although in 36% yield
treatment with thiourea. Compounds 12 ± 15 were isolated in
82, 65, 78 and 80% yields, respectively, by precipitation
(Scheme 1).
Reaction of the isothiouronium derivatives 12 ± 15 with b-
CD derivatives was carried out at room temperature in dry
DMF under an argon atmosphere with two molar equivalents
of N-glycoside and 2 ± 3 equiv of Cs CO for every primary
2
3
(
Scheme 1).
halogen group of 16 and 17. After several days, the reaction
led to a mixture of products, as indicated by TLC; then acetic
anhydride, pyridine and 4-dimethylaminopyridine (4-DMAP)
were added. The peracetylation reaction was kept at 408C
for 48 h and then the branched b-CD derivatives 18 ± 25 were
isolated in excellent yields. Zempl e n deacetylation of
compounds 18 ± 25 furnished the b-CD derivatives branched
with N-glycosides through the spacer chain COCH2S
26 ± 29 in 94 ± 96% yields (Scheme 2) and through the spacer
chain COCH SCH CONH 30 ± 33 in 90 ± 94% yields
Application of the conditions mentioned above to man-
nopyranosyl azide derivative 4 gave an approximately 3.1:2
mixture of a anomer 8a and b anomer 8b that could not be
separated by column chromatography.
[
23b]
When compounds 3
and 4 were treated dropwise with nBu P in the presence of
3
chloroacetic anhydride at � 808C in dry CH Cl , the N-
2
2
glycosides 7 and 8a were isolated in 67 and 80% yields,
respectively, after chromatographic purification (Scheme 1).
Under these reaction conditions compound 8a was the only
anomer observed by TLC. The configurations at the anomeric
positions in 8a and 8b could be established from the NMR
data obtained from the pure compound 8a and the mixture
2
2
(Scheme 3).
Branched b-CDs 18 ± 33 were characterized by NMR
spectroscopic techniques and FAB mass spectrometry. The
[
26]
1
8
a ‡ 8b. The isomers 8a and 8b exhibited J values larger
room-temperature H NMR spectra showed a considerable
1,2
4
than those normally observed in C conformations of d-
broadening of the signals; this indicates a restricted mobility
on the NMR time scale. When measurements of the NMR
data were performed at 80 ± 1008C, the resolution of the
spectra was improved considerably, allowing the assignment
of the spectroscopic signals. For the peracetylated compounds
18 ± 25, the NMR signals were assigned on the basis of COSY
and HMQC experiments. The success of the nucleophilic
perdisplacement became evident from the seven-fold sym-
metry of the products as deduced from NMR experiments.
Only two anomeric carbon signals were observed at d ˆ 96.1 ±
101.9 for C-1 and 75.2 ± 80.0 for C-1' as well as three
methylene carbon signals for compounds 18 ± 21 and 26 ± 29
1
mannopyranosides (J ˆ 4.8 and 1.4 Hz for the a anomer 8a
1,2
1
and the b anomer 8b, respectively). However, J
values of
C1,H1
1
65 and 156 Hz for 8a and 8b, respectively, were in accord
with an equatorial H-1 for 8a and axial H-1 for 8b. In
addition, a NOESY spectrum of the 8a/8b mixture showed a
correlation between NH, H-3 and H-5 for the major isomer
8
a and no such correlation for the minor isomer, as well as a
correlation between H-1, H-3 and H-5 for 8b and no such
correlation for the major isomer.
We also investigated an alternative method with 1,3-
[
27]
propanedithiol as reducing reagent. We found that reaction
of compounds 1 ± 3 with 1,3-propanedithiol and triethylamine
in anhydrous methanol followed by treatment with chloro-
acetic anhydride afforded the N-glycosides 5 ± 7 in 68, 76 and
at 33.1 ± 34.9 (C-6), 36.2 ± 37.6 (CH S) and 60.4 ± 61.9 (C-6'),
2
and four for compounds 22 ± 25 and 30 ± 33 at 39.1 ± 40.1 (C-6),
1
34.4 ± 34.9 (2CH S) and 60.4 ± 61.7 (C-6'). From the H NMR,
2
7
4% yields, respectively (Scheme 1).
To synthesize the thiolated N-glycosides 9 ± 11, compounds
± 3 were subjected to the reaction conditions described
the appearance of new signals such as those corresponding to
the anomeric H-1' of the N-glycosides (d ˆ 5.34 ± 5.60) clearly
established the assembly of the glycosyl amide building blocks
onto the b-CD derivatives.
1
above: first treatment with nBu P, then chloroacetic anhy-
3
dride, followed by a subsequent treatment with thioacetic acid
and triethylamine after completion of the chloroacetylation
reaction monitored by TLC. The S-acetylmercaptoacetyl N-
glycosides 9 ± 11 were then isolated in 88, 83 and 37% yields,
respectively (Scheme 1).
First attempts to introduce the N-glucopyranosyl moiety in
the b-CD involved the de-O,S-acetylation of 9 under standard
Zempl e n conditions as well as selective de-S-acetylation of 9
with hydrazinium acetate, and then reaction of the resulting
products with the b-CD derivative 16 in the presence of DBU
In summary, we report a very convenient method for the
attachment of N-glycoside derivatives onto b-CD. The
method involves the use of chloroacetyl N-glycoside building
blocks ready for their conversion into isothiouronium deriv-
atives and then incorporation onto the b-CD by a nucleophilic
displacement reaction. The building blocks were also easily
prepared by two convenient one-pot syntheses, by the
Staudinger reaction or with 1,3-propanedithiol as reducing
reagent, from the corresponding glycosyl azides. This method-
ology could be applied to the rapid preparation of N-
glycodendrimers from, for example, multivalent N-chloroa-
cetylated molecules. The two concepts, that is, the ability
to bind guest molecules and multivalency, converge in the
structure of the branched b-CDs and therefore constitute
potential drug delivery systems. The next stage in our
research project is the enhancement of the multivalency
by the synthesis of N-glycodendrimerlike structures based on
CD cores. This is currently under development in our
laboratories.
(
1,8-diazabicyclo[5.4.0]undec-7-ene) or Cs CO . Both at-
2 3
tempts failed, probably owing to the lack of stability of the
thiol derivative. In the course of an ongoing parallel
[
18]
research we found that glycosyl isothiouronium salts can
be employed as latent thiolate nucleophiles, thus avoiding side
reactions. These compounds react with alkyl halides, such as
1
6 and 17, in the presence of Cs CO to give sulfide
2 3
derivatives. Therefore N-chloroacetylated glycosides 5 ± 8
were transformed into their isothiouronium salts 12 ± 15 by
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F. Santoyo-Gonz a lez, A. Vargas-Berenguel et al.
FULL PAPER
2 3 2
Scheme 2. Synthesis of the branched b-cyclodextrin derivatives 18 ± 21 and 26 ± 29. Reagents and conditions: i) a) Cs CO /DMF, 7 d, RT; b) Ac O/Py, 48 h,
408C: 18 (92%), 19 (94%), 20 (95%), 21 (87%); ii) NaOMe/MeOH, 10 h, RT: 26 (96%), 27 (94%), 28 (95%), 29 (94%).
on a Perkin ± Elmer 141 polarimeter at room temperature (22 Æ 28C).
IR spectra were recorded on a Perkin ± Elmer 983G and ATI Mattson
FTIR. 1H and C NMR spectra were recorded at room temperature,
unless otherwise specified, on a Bruker AM300 and Bruker NMR
Experimental Section
13
TLC was performed on Merck silica gel 60F254 aluminium sheets with
detection by charring with 5% H SO in EtOH, and by UV light when
2
4
1
Avance DPX300 spectrometers. H chemical shifts are given in ppm and
applicable. Flash column chromatography was performed on silica gel
Scharlau (230 ± 400 mesh, ASTM). Melting points were measured on a
Büchi melting point B-540 apparatus and a Reichter hotplate microscope
and are uncorrected. Elemental analyses were carried out with Perkin ±
Elmer 240C and LECO932 instruments. Optical rotations were recorded
referenced to internal CHCl
.6) for (CD
SO solutions and HOD (d ˆ 4.79) for D
chemical shifts are given in ppm and referenced to CDCl
CD
SO (d ˆ 39.5) and external acetone (d ˆ 30.5) for D
3
(d ˆ 7.26) for CDCl
3
solutions, (CH
3
)
2
SO (d ˆ
13
2
3
)
2
2
O solutions.
C
3
(d ˆ 77.0),
(
3
)
2
2
O solutions. J
values are given in Hz. Assignments were based on COSY, HMQC,
1
778
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Cluster N-Glycosides
1775±1784
2 3 2
Scheme 3. Synthesis of the branched b-cyclodextrin derivatives 22 ± 25 and 30 ± 33. Reagents and conditions: i) a) Cs CO /DMF, 7 d, RT; b) Ac O/Py, 48 h,
408C: 22 (71%), 23 (81%), 24 (84%), 25 (80%); ii) NaOMe/MeOH, 10 h, RT: 30 (92%), 31 (90%), 32 (94%), 33 (93%).
NOESY, DEPT and APT. Mass spectra were recorded on a Micromass
Autospec-Q and LC-API-MS spectrometers. Anhydrous solvents were
prepared according to standard procedures,[ and were freshly distilled
prior to use.
cooled to � 808C, and a solution of chloroacetic anhydride (3.0 g,
17.6 mmol) in anhydrous CH Cl (10 mL) was added. The reaction mixture
was allowed to warm to room temperature and kept overnight. CH Cl
(150 mL) was added and the organic solution was washed with saturated
aqueous NaHCO
2
2
28]
2
2
3
(2 Â 150 mL) and H O (2 Â 100 mL). The organic layer
2
2
,3,4,6-Tetra-O-acetyl-N-chloroacetyl-b-d-glucopyranosylamine (5):
With nBu P (procedure A): nBu P (3.26 mL, 13.2 mmol) was added
dropwise to a solution of the glycosyl azide 1 (4.06 g, 11.0 mmol) in
anhydrous CH Cl (40 mL) at room temperature under Ar. Gas evolution
was observed to have ceased after 1 h; thereupon, the reaction mixture was
was dried (MgSO ), filtered, evaporated, and the crude product chromato-
4
graphed on silica gel (ether) to give 5 (3.14 g, 68%) as a solid.
3
3
[24]
With 1,3-propanedithiol: 1,3-Propanedithiol (0.301 mL, 3.0 mmol) and
2
2
Et
3
N (0.416 mL, 3 mmol) were added to a solution of compound 1
(1.5 mmol) in anhydrous MeOH (8 mL) under Ar. The solution was stirred
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F. Santoyo-Gonz a lez, A. Vargas-Berenguel et al.
FULL PAPER
at room temperature for 2 h and then, chloroacetic anhydride (1.49 g,
M.p. 1628C (decomp); [a]
D
ˆ � 6 (c ˆ 1 in chloroform); 1H NMR
3
8.7 mmol) was added. After 2 h at room temperature, the solvent was
(300 MHz, CDCl
3
): d ˆ 7.88 (d, 1H,
J
NH,1 ˆ 8.2 Hz, NH), 6.06 (d, 1H,
3
3
3
evaporated and the crude product chromatographed on silica gel (ether) to
give 5 (431 mg, 68%).
J
NH,2 ˆ 8.2 Hz, NH), 5.14 (t, 1H, J ˆ 9.8 Hz, H-4), 5.07 (t, 1H, J ˆ 9.8 Hz,
3
3
2
H-3), 5.03 (dd, 1H, J1,2 ˆ 9.8 Hz, JNH,1 ˆ 8.2 Hz, H-1), 4.30 (dd, 1H, J6,6'
ˆ
3
3
3
1
12.5 Hz, J5,6 ˆ 4.2 Hz, H-6), 4.22 (dt, 1H, J ˆ 9.8 Hz, JNH,2 ˆ 8.2 Hz, H-2),
M.p. 167 ± 1688C; [a]
CDCl
5
D
ˆ ‡8 (c ˆ 1 in chloroform); H NMR (300 MHz,
2
3
2
3
3
4.09 (dd, 1H, J6,6' ˆ 12.5 Hz, J5,6' ˆ 2.3 Hz, H-6'), 4.04 (d, 1H, J ˆ 15.1 Hz,
3
): d ˆ 7.31 (d, 1H, JNH,1 ˆ 9.2 Hz, NH), 5.33 (t, 1H, J ˆ 9.5 Hz, H-3),
2
3
3
3
3
CHCl), 3.96 (d, 1H, J ˆ 15.1 Hz, CH'Cl), 3.78 (ddd, 1H,
J
4,5 ˆ 9.8 Hz,
.21 (dd, 1H, J1,2 ˆ 9.5 Hz, J ˆ 9.2 Hz, H-1), 5.09 (dd, 1H, J4,5 ˆ 10.1 Hz,
3
3
3
2
J
5,6 ˆ 4.2 Hz,
J
5,6' ˆ 2.3 Hz, H-5), 2.09 (s, 3H, CH
3
CO), 2.08 (s, 3H,
J
1
3,4 ˆ 9.5 Hz, H-4), 5.01 (t, 1H, J ˆ 9.5 Hz, H-2), 4.31 (dd, 1H,
J
6,6'
ˆ
13
2.5 Hz, 3
2
3
CH
(75.5 MHz, CDCl
(C-3, 4, 5), 61.6 (C-6), 53.0 (C-2), 42.2 (CH
3 CH
CO); IR (KBr): n ˆ 3456, 3313, 1738, 1693, 1660, 1529, 1376, 1230,
3
CO), 2.04 (s, 3H, CH
3
CO), 1.96 (s, 3H, CH
O), 80.6 (C-1), 73.6, 72.7, 67.5
Cl), 23.0 (CH CON), 20.7 ± 20.6
3
CON); C NMR
J
5,6 ˆ 4.4 Hz, H-6), 4.10 (dd, 1H,
J
6,6' ˆ 12.5 Hz,
J
5,6' ˆ 2.1 Hz,
3
): d ˆ 172.0 ± 167.4 (5 C
ˆ
2
2
2
H-6'), 4.07 (d, 1H, J ˆ 15.4 Hz, CHCl), 4.00 (d, 1H, J ˆ 15.4 Hz, CH'Cl),
3
3
3
3
3
.84 (ddd, 1H, J4,5 ˆ 10.1 Hz, J5,6 ˆ 4.4 Hz, J5,6' ˆ 2.1 Hz, H-5), 2.09 (s, 3H,
CO), 2.06 (s, 3H, CH CO), 2.04 (s, 3H, CH CO), 2.03 (s, 3H, CH CO);
C NMR (75.5 MHz, CDCl
): d ˆ 170.9 ± 166.9 (5CˆO), 78.6 (C-1), 73.9,
2.6, 70.3, 68.1 (C-2, 3, 4, 5), 61.6 (C-6), 42.3 (CH Cl), 20.8 ± 20.6
(
3
CH
3
3
3
3
�
1
1
3
1040 cm ; MS (FAB): m/z ˆ 423 for [M‡1]; C16
H23ClN
2
O
9
(422.8): calcd C
3
4
5.45, H 5.48, found C 45.84, H 5.59%.
7
2
(
1
C
4CH
3
CO); IR (KBr): n ˆ 3309 (NH), 1748 (CˆO), 1669, 1532 (CONH),
2,3,4,6-Tetra-O-acetyl-N-chloroacetyl-a-d-mannopyranosylamine (8a):
�
1
378, 1225, 1039 (C�O) cm
;
MS (FAB): m/z ˆ 424 for [M‡1];
This compound was prepared as described for 8 (Procedure B) with nBu P
3
16
H
22ClNO10 (423.8): calcd C 45.34, H 5.23, found C 45.00, H 5.28%.
(5.12 mL, 20.5 mmol), chloroacetic anhydride (3.161 g, 18.5 mmol), com-
[
25]
pound 4
2 2
(3.83 g, 10.3 mmol), and anhydrous CH Cl (60 mL). The
2
,3,4,6-Tetra-O-acetyl-N-chloroacetyl-b-d-galactopyranosylamine (6):
mixture was worked up as described and the purification was performed
with column chromatography (ether), and 8 was isolated (3.5 g, 80%) as a
With nBu P (Procedure A): This compound was prepared as described for 5
3
[
24]
(
2
(
Procedure A) with nBu
3
P (0.94 mL, 3.75 mmol), compound 2 (1.0 g,
.68 mmol), anhydrous CH Cl (20 mL), and chloroacetic anhydride
Cl (5 mL). For the work-up,
(100 mL) was added and the organic solution was washed with
saturated aqueous NaHCO O (100 mL). The organic
(2 Â 75 mL) and H
layer was dried (MgSO ), filtered and evaporated, and the crude product
1
solid: m.p. 1178C; [a]
D
ˆ ‡29 (c ˆ 0.5 in chloroform); H NMR (300 MHz,
2
2
3
3
CDCl
3
): d ˆ 7.30 (d, 1H, JNH,1 ˆ 8.4 Hz, NH), 5.63 (dd, 1H, JNH,1 ˆ 8.4 Hz,
646 mg, 3.75 mmol) in anhydrous CH
2
2
3
3
3
J
1,2 ˆ 4.8 Hz, H-1), 5.27 (dd, 1H, J3,4 ˆ 6.2 Hz, J2,3 ˆ 2.2 Hz, H-3), 5.26 (dd,
CH Cl
2
2
H, 3
3
3
1
J
1,2 ˆ 4.8 Hz,
J
2,3 ˆ 2.2 Hz, H-2), 5.14 (t, 1H, J ˆ 6.2 Hz, H-4), 4.43
3
2
2
3
2
(
dd, 1H,
J
6,6' ˆ 12.1 Hz, J5,6 ˆ 6.6 Hz, H-6), 4.23 (dd, 1H,
J
6,6' ˆ 12.1 Hz,
4
3
2
2
J
5,6' ˆ 4.0 Hz, H-6'), 4.10 (d, 1H, J ˆ 15.4 Hz, CHCl), 4.06 (d, 1H, J ˆ
chromatographed on silica gel (ether) to give 6 (853 mg, 73%) as a solid.
1
5.4 Hz, CH'Cl), 4.02 (ddd, 1H, J5,6 ˆ 6.6 Hz, J4,5 ˆ 6.2 Hz, J5,6' ˆ 4.0 Hz,
1
3
With 1,3-propanedithiol: Compound 6 was synthesized as described for 5
with the same amount of reagents and solvent. Similar work-up followed by
column chromatography (ether) gave 6 (486 mg, 76%).
1
3 3
H-5), 2.11 (s, 3H, CH CO), 2.09 (s, 9H, 3 CH CO); C NMR (75.5 MHz,
CDCl
(C-2, 3), 66.9 (C-4), 61.3 (C-6), 42.4 (CH
3
): d ˆ 170.6 ± 166.4 (5CˆO), 74.5 (C-1), 72.0 (C-5), 68.5, 67.8
2
Cl), 20.7 (4CH CO); IR (KBr):
3
�
1
n ˆ 3454, 1749, 1684, 1547, 1374, 1227, 1056 cm ; MS (FAB): m/z ˆ 424 for
M.p. 148 ± 1498C; [a]
D
ˆ ‡21 (c ˆ 1 in chloroform); H NMR (300 MHz,
3
3
[M‡1]; C16
H22ClNO10 (423.8): calcd C 45.34, H 5.23, found C 45.28, H
CDCl
3
): d ˆ 7.53 (d, 1H, JNH,1 ˆ 8.3 Hz, NH), 5.46 (dd, 1H, J4,5 ˆ 2.8 Hz,
3
5.36%.
J
3,4 ˆ 0.8 Hz, H-4), 5.17 (m, 3H, H-1,2,3), 4.13 (m, 2H, H-6,6'), 4.06 (m, 1H,
2
2
H-5), 4.09 (d, 1H, J ˆ 15.5 Hz, CHCl), 4.01 (d, 1H, J ˆ 15.5 Hz, CH'Cl),
2,3,4,6-Tetra-O-acetyl-N-(S-acetylmercaptoacetyl)-b-d-glucopyranosyla-
2
3
7
2
1
.16 (s, 3H, CH
H, CH
CO); 13C NMR (75.5 MHz, CDCl
8.6 (C-1), 72.4, 70.6, 67.9, 67.1 (C-2, 3, 4, 5), 61.1 (C-6), 42.2 (1CH
0.6 ± 20.5 (4CH
CO); IR (KBr): n ˆ 3314 (NH), 1749, 1724 (CˆO), 1698,
549 (CONH), 1370, 1227, 1086 cm (C�O); MS (FAB): m/z ˆ 424 for
22ClNO10 (423.8): calcd C 45.34, H 5.23, found C 45.25, H
3
CO), 2.07 (s, 3H, CH
3
CO), 2.04 (s, 3H, CH
): d ˆ 170.9 ± 166.7 (5 CˆO),
Cl),
3
CO), 2.01 (s,
mine (9): nBu P (0.94 mL, 3.75 mmol) was added dropwise to a solution of
3
3
3
2 2
the glycosyl azide 1 (1.0 g, 2.68 mmol) in anhydrous CH Cl (20 mL) at
room temperature under Ar. Gas evolution ceased after 1 h; thereupon, the
2
3
reaction mixture was cooled to � 808C, and a solution of chloroacetic
�
1
2 2
anhydride (0.646 mg, 3.75 mmol) in anhydrous CH Cl (15 mL) was added.
[
5
M‡1]; C16
H
The reaction mixture was allowed to warm to room temperature and kept
overnight. Then AcSH (0.9 mL, 11.26 mmol) and Et N (3 mL) were added.
After 2 h at room temperature CH Cl (150 mL) was added and the organic
solution was washed with saturated aqueous NaHCO
(2 Â 150 mL) and
O (2 Â 100 mL). The organic layer was dried (MgSO ), filtered and
evaporated, and the crude product chromatographed on silica gel (hexane/
.60%.
3
2
2
2
-Acetamido-3,4,6-tri-O-acetyl-N-chloroacetyl-2-deoxy-b-d-glucopyrano-
3
sylamine (7):
With nBu
dropwise to a solution of the glycosyl azide 3 (372 mg, 1.0 mmol) in
anhydrous CH Cl (15 mL) at room temperature under Ar. Gas evolution
H
2
4
3
3
P (Procedure A): nBu P (0.30 mL, 1.2 mmol) was added
[24]
EtOAc 3:2) to give 9 (1.1 g, 88%) as a solid: m.p. 134 ± 1358C; [a]
D
ˆ � 12
2
2
1
(
J
c ˆ 1 in chloroform); H NMR (300 MHz, CDCl
3
): d ˆ 6.95 (d, 1H,
ceased after 1 h; thereupon, the reaction mixture was cooled to � 808C, and
3
3
3
NH,1 ˆ 9.5 Hz, NH), 5.29 (t, 1H, J ˆ 9.5 Hz, H-3), 5.19 (t, 1H, J ˆ 9.5 Hz,
3 3
a solution of chloroacetic anhydride (264 mg, 1.5 mmol) in anhydrous
H-1), 5.06 (t, 1H, J ˆ 9.5 Hz, H-4), 4.92 (t, 1H, J ˆ 9.5 Hz, H-2), 4.29 (dd,
CH
allowed to warm to room temperature and kept overnight. CH
was added and the organic solution was washed with saturated aqueous
NaHCO O (50 mL). The organic layer was dried
(2 Â 50 mL) and H
MgSO ), filtered and evaporated, and the crude product chromatographed
on silica gel (EtOAc) to give 7 (150 mg, 36%) as a solid.
By Procedure B: nBu P (4.02 mL, 16.1 mmol) was added dropwise to a
solution of chloroacetic anhydride (2.482 g, 14.51 mmol) and glycosyl azide
(3.0 g, 8.1 mmol) in anhydrous CH Cl
(40 mL) at � 808C under Ar. The
reaction mixture was allowed to warm to room temperature and kept
overnight. CH Cl (150 mL) was added, and the organic solution was
washed with saturated aqueous NaHCO O (2 Â
(2 Â 150 mL) and H
00 mL). The organic layer was dried (MgSO ), filtered and evaporated,
and the crude product chromatographed on silica gel (EtOAc) to give 7
2.28 g, 67%).
2
Cl
2
(5 mL) and Et
3
N (0.5 mL) was added. The reaction mixture was
H, 2
3
2
3
1
2
J
6,6' ˆ 12.5 Hz,
J
5,6 ˆ 4.4, H-6), 4.08 (dd, 1H,
J
6,6' ˆ 12.5 Hz,
J
5,6'
ˆ
2
2
Cl (50 mL)
3
3
3
.1 Hz, H-6'), 3.81 (ddd, 1H,
J
4,5 ˆ 9.5 Hz,
J
5,6 ˆ 4.4 Hz,
J
5,6' ˆ 2.1 Hz,
2
2
H-5), 3.57 (d, 1H, J ˆ 15.5 Hz, CHS), 3.49 (d, 1H, J ˆ 15.5 Hz, CH'S), 2.44
3
2
(
s, 3H, CH
3
13
COS), 2.09 (s, 3H, CH
CO); C NMR (75.5 MHz, CDCl
3
CO), 2.03 (s, 3H, CH
3
CO), 2.01 (s, 3H,
(
4
CH
3
3
): d ˆ 195.1 (COS), 170.9 ± 168.4
(
4 CˆO), 78.3 (C-1), 73.7, 72.7, 70.3, 68.2 (C-2, 3, 4, 5), 61.7 (C-6), 32.8
(CH S), 30.2 (CH COS), 20.8 ± 20.6 (4CH
2
3
3
CO); IR (KBr): n ˆ 3339, 1742,
3
�
1
1695, 1668, 1520, 1375, 1231, 1068, 1041 cm ; MS (FAB): m/z ˆ 464 for
3
2
2
[M‡1]; C18
H25NO11S (463.5): calcd C 46.65, H 5.44, found C 46.33, H
5.58%.
2
2
2
,3,4,6-Tetra-O-acetyl-N-(S-acetylmercaptoacetyl)-b-d-galactopyranosyla-
mine (10): This compound was prepared as described for 9. nBu
3.24 mL, 12.90 mmol) was added to a solution of compound 2 (4.0 g,
3
2
3
P
1
4
(
1
1
0.72 mmol) in anhydrous CH
2.86 mmol) was added in anhydrous CH
N (6 mL) were added. After 2 h the mixture
was worked up and the product was purified by column chromatography
2
Cl
2
(40 mL). Chloroacetic anhydride (2.75 g,
(
2
Cl (15 mL). Then AcSH
2
With 1,3-Propanedithiol: 1,3-Propanedithiol (0.1 mL, 2 mmol) and Et
3
N
(3.05 mL, 42.88 mmol) and Et
3
(
0.14 mL, 2 mmol) were added to a solution of compound 3 (372 mg,
1
mmol) in anhydrous MeOH (10 mL) under Ar. The solution was stirred
(hexane/ether 1:5), and gave 10 (4.107 g, 83%) as a solid: m.p. 688C; [a]
D
ˆ
1
at room temperature for 6 h and then chloroacetic anhydride (1.026 g,
mmol) was added. After 18 h at room temperature the solvent was
� 7 (c ˆ 1 in chloroform); H NMR (300 MHz, CDCl
3
): d ˆ 6.96 (d, 1H,
3
3
3
6
J
NH,1 ˆ 9.0 Hz, NH), 5.38 (brd, 1H, J3,4 ˆ 2.2 Hz, H-4), 5.14 (t, 1H, J ˆ 9.0,
2
evaporated and the crude product chromatographed on silica gel (EtOAc)
to give 7 (315 mg, 74%).
H-1), 5.05 (m, 2H, H-2, 3), 4.13 ± 3.95 (m, 3H, H-5, 6, 6'), 3.55 (d, 1H, J ˆ
15.6 Hz, CHS), 3.45 (d, 1H, 2J ˆ 15.6 Hz, CH'S), 2.40 (s, 3H, CH
3
COS),
1
780
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0506-1780 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 6

Cluster N-Glycosides
1775±1784
2
3
.11 (s, 3H, CH
3
CO), 2.00 (s, 3H, CH
3
CO), 1.99 (s, 3H, CH
3
CO), 1.93 (s,
temperature for 7 d, and then CH
resulting precipitate gave 14 (1.46, 78%) as a solid: m.p. 1498C (decomp);
2
Cl
2
(15 mL) was added. Filtration of the
H, CH
3
CO); 13C NMR (75.5 MHz, CDCl
3
): d ˆ 195.0 (COS), 170.9 ± 168.2
1
(
3
5 CˆO), 78.4 (C-1), 72.3 (C-5), 70.6, 67.7 (C-2, 3), 67.0 (C-4), 61.1 (C-6),
[a]
D
ˆ ‡20 (c ˆ 0.25 in methanol); H NMR (300 MHz, (CD
3
)
2
SO): d ˆ
3
2.6 (CH
749, 1697, 1532, 1369, 1226, 1084, 1052 cm ; MS (FAB): m/z ˆ 464 for
25NO11S (463.5): calcd C 46.65, H 5.44, found C 46.44, H
2
S), 30.1 (CH
3
COS), 20.5 ± 20.4 (4 CH
3
CO); IR (KBr): n ˆ 3366,
9.45 (brs, 4H, 2 NH
2
), 9.24 (d, 1H,
J
NH,1 ˆ 9.1 Hz, NH), 8.11 (d, 1H,
�
1
3
3
3
1
J
NH,2 ˆ 8.8 Hz, NH), 5.29 (t, 1H, J ˆ 9.4 Hz, H-1), 5.24 (t, 1H, J ˆ 9.7 Hz,
3
2
3
[
M‡1]; C18
H
H-3), 4.92 (t, 1H, J ˆ 9.7 Hz, H-4), 4.27 (dd, 1H,
4.2 Hz, H-6), 4.13 (brs, 2H, CH
S), 4.09 (dd, 1H, 2
.2 Hz, H-6'), 3.95 (m, 2H, H-5, 2), 2.09 (s, 3H, CH
CH CO), 2.00 (s, 3H, CH CO), 1.84 (s, 3H, CH
CD
SO): d ˆ 170.0 ± 169.3 (5 CˆO), 167.5 (CˆN), 78.2 (C-1), 73.0 (C-3),
2.4 (C-5), 68.3 (C-4), 61.7 (C-6), 52.2 (C-2), 33.6 (CH S), 22.7 (CH CON),
0.6 ± 20.4 (3CH
J
6,6' ˆ 12.2 Hz,
J
5,6
ˆ
5
.27%.
2
J
6,6' ˆ 12.2 Hz, 3J5,6'
ˆ
2
3
CO), 2.05 (s, 3H,
2
-Acetamido-3,4,6-tri-O-acetyl-N-(S-acetylmercaptoacetyl)-2-deoxy-b-d-
CN); 13C NMR (75.5 MHz,
glucopyranosylamine (11): This compound was prepared following a
protocol similar to that described for the preparation of 9. nBu
1.6 mL, 6.45 mmol) was added to a solution of 3 (2.0 g, 5.38 mmol) in
anhydrous CH Cl (25 mL). A solution of chloroacetic anhydride (1.38 g,
.064 mmol) and Et N (0.5 mL) in anhydrous CH Cl (15 mL) was added.
After addition of AcSH (1.72 mL, 24.2 mmol) and Et N (3 mL) the
3
3
3
(
3 2
)
3
P
7
2
1
2
3
(
3
CO); IR(KBr): n ˆ 3228, 1751.2, 1662, 1535, 1369, 1218,
2
2
�
1
049 cm ; HRMS (FAB): calcd for C17
27 4 9
H N O S (without Cl) 463.1499,
8
3
2
2
‡
found 463.1498 for [M � Cl] .
3
reaction was left for 18 h. The mixture was worked up and the product was
purified by column chromatography (EtOAc) to give 11 (927 mg, 37%) as a
2,3,4,6-Tetra-O-acetyl-N-(isothiouronium acetyl)-a-d-mannopyranosyla-
mine hydrochloride (15): To a solution of 8 (2.57 g, 6.0 mmol) in dry
acetone (30 mL) was added thiourea (786 mg, 10.35 mmol). The reaction
mixture was stirred at room temperature for 72 h. The solution was
concentrated to approximately 10 mL under reduced pressure without
1
solid: m.p. 1728C (decomp); [a]
300 MHz, CDCl
D
ˆ � 7 (c ˆ 1 in chloroform); H NMR
3
(
3
): d ˆ 7.47 (d, 1H,
J
NH,1 ˆ 8.4 Hz, NH), 6.16 (brs, 1H,
2 3
NH), 5.1 (m, 3H, H-1, 3, 4), 4.29 (dd, 1H,
J
6,6' ˆ 12.5 Hz,
J
5,6 ˆ 4.1 Hz,
2
3
H-6), 4.15 (m, 1H, H-2), 4.09 (dd, 1H, J6,6' ˆ 12.5 Hz, J5,6' ˆ 2.0 Hz, H-6'),
heating. Filtration of the resulting precipitate gave 15 (2.057 g, 80%) as a
3
3
3
1
3
.80 (ddd, 1H, J4,5 ˆ 9.7 Hz, J5,6 ˆ 4.1 Hz, J5,6' ˆ 2.0 Hz, H-5), 3.60 (d, 1H,
solid: m.p. 1598C (decomp); [a]
(300 MHz, (CD
D
ˆ ‡54 (c ˆ 0.5 in methanol); H NMR
2
2
3
J ˆ 16.0 Hz, CHS), 3.52 (d, 1H, J ˆ 16.0 Hz, CH'S), 2.45 (s, 3H, CH
3
COS),
CO), 1.93 (s,
): d ˆ 171.8 ± 168.8 (5 CˆO),
0.3 (C-1), 73.7, 72.9, 67.9 (C-3, 4, 5), 61.8 (C-6), 52.9 (C-2), 32.8
3
)
2
SO): d ˆ 9.96 (d, 1H, JNH,1 ˆ 9.1 Hz, NH), 9.40 (brs, 4H,
3
3
2
3
8
.09 (s, 3H, CH
3
CO), 2.05 (s, 3H, CH
3
CO), 2.04 (s, 3H, CH
3
2NH
2
), 5.65 (dd, 1H,
J
3,4 ˆ 9.7 Hz,
J
2,3 ˆ 3.6 Hz, H-3), 5.56 (dd, 1H,
CON); 13C NMR (75.5 MHz, CDCl
3
J
NH,1 ˆ 9.1 Hz, J1,2 ˆ 1.7 Hz, H-1), 5.20 (t, 1H, J ˆ 9.7 Hz, H-4), 5.18 (dd,
3
3
H, CH
3
3
3
3
2
1H, J2,3 ˆ 3.6 Hz, J1,2 ˆ 1.7 Hz, H-2), 4.33 (d, 1H, J ˆ 16.4 Hz, CHS), 4.27
(d, 1H, 2J ˆ 16.4 Hz, CH'S), 4.25 (dd, 1H,
2
J
6,6' ˆ 12.0 Hz,
3
J
5,6 ˆ 4.5 Hz,
(
(
CH
2
S), 30.4 (CH
3
COS), 22.9 (CH
3
CN), 20.8 ± 20.6 (3 CH
3
CO); IR
KBr): n ˆ 3309, 1749, 1662, 1535, 1375, 1242, 1047 cm 1; MS (FAB):
�
H-6), 4.16 (m, 1H, H-5), 4.08 (dd, 1H, J6,6' ˆ 12.0 Hz, J5,6' ˆ 2.2 Hz, H-6'),
2
3
m/z ˆ 463 for [M‡1]; C18
H
26
N
2
O
10S (462.5): calcd C 46.75, H 5.67, found
2.21 (s, 3H, CH
3H, CH
CO); 13C NMR (75.5 MHz, (CD
67.0 (CˆN), 75.7 (C-1), 69.3 (C-5), 69.0 (C-3), 68.3 (C-2), 65.8 (C-4), 61.8
C-6), 33.7 (CH S), 20.7 ± 20.4 (4 CH
3
CO), 2.12 (s, 3H, CH
3
3
CO), 2.10 (s, 3H, CH CO), 2.04 (s,
C 46.69, H 5.58%.
3
3 2
)
SO): d ˆ 170.1 ± 169.4 (5CˆO),
1
2
,3,4,6-Tetra-O-acetyl-N-(isothiouronium
acetyl)-b-d-glucopyranosyla-
(
2
3
CO); IR (KBr): n ˆ 3370, 1755, 1744,
� 1
mine hydrochloride (12): To a solution of 5 (2.33 g, 5.50 mmol) in dry
acetone (30 mL) was added thiourea (627 mg, 8.25 mmol). The reaction
mixture was stirred at room temperature for 72 h. The solution was
concentrated to approximately 10 mL under reduced pressure without
heating. The precipitated product was filtered off and 12 was isolated as a
1
656, 1551, 1367, 1258, 1224, 1051 cm ; MS (ES): m/z ˆ 486 for [M �
‡
HCl‡Na] , 464 for [M � Cl]; C17
3
H26ClN O10S (499.9): calcd C 40.84, H
5
.24, found C 41.18, H 5.60%.
General procedure for the synthesis of N-GlycoCDs 18 ± 25: A mixture of
[
29b]
solid (2.26 g, 82%): m.p. 1538C (decomp); [a]
anol); H NMR (300 MHz, (CD
D
ˆ ‡6 (c ˆ 0.25 in meth-
16
(0.84 mmol for reactions with 12, 13, and 15, 1.01 mmol for reaction
1
[18]
3
)
2
SO): d ˆ 9.44 (m, 4H, 2 NH
2
), 9.40 (d,
with 14) or 17 (0.84 mmol for reaction with 12, 1.26 mmol for reactions
3
3
3
1
9
4
H, JNH,1 ˆ 9.6 Hz, NH), 5.51 (t, 1H, J ˆ 9.6 Hz, H-1), 5.46 (t, 1H, J ˆ
with 13 ± 15), Cs
15 (2 equiv) in anhydrous DMF (8 ± 10 mL) was kept under Ar for 7 d at
room temperature. After this time, Ac O (12 mL), pyridine (8 mL) and
2 3
CO (2.5 ± 3.0 equiv) and the N-glycoside derivative 12 ±
3
3
.6 Hz, H-3), 5.00 (t, 1H, J ˆ 9.6 Hz, H-4), 4.93 (t, 1H, J ˆ 9.6 Hz, H-2),
2
3
.25 (dd, 1H, J6,6' ˆ 12.0 Hz, J5,6 ˆ 4.7 Hz, H-6), 4.22 (m, 1H, H-5), 4.21 (d,
2
2
2
1
H, J ˆ 15.6 Hz, CHS), 4.14 (d, 1H, J ˆ 15.6 Hz, CH'S), 4.06 (dd, 1H,
DMAP (catalytic amount) were added and the reaction mixture was stirred
for 48 h at 408C. Then the precipitated material was filtered and the filtrate
2
3
J
6,6' ˆ 12.0 Hz,
J
5,6' ˆ 3.3 Hz, H-6'), 2.10 (s, 3H, CH
3
CO), 2.08 (s, 3H,
CO); C NMR (75.5 MHz,
1
3
CH
(
7
3
CO), 2.05 (s, 3H, CH
CD
SO): d ˆ 170.0 ± 169.0 (5 CˆO), 167.3 (CˆN), 77.1 (C-1), 72.7 (C-3),
2.2 (C-5), 70.5 (C-2), 67.7 (C-4), 61.7 (C-6), 33.7 (CH S), 20.6 ± 20.3 (4
3
CO), 2.02 (s, 3H, CH
3
was poured over ice/H
aqueous layer extracted with Cl
phases were washed successively with aqueous HCl (5%, 100 mL),
saturated aqueous NaHCO O (2 Â 100 mL). The
(2 Â 150 mL) and H
organic solution was dried (Na SO ), filtered, evaporated, and gave a
2
O. Aqueous HCl (5%, 100 mL) was added and the
3
)
2
2
CH
2
(2 Â 100 mL). The combined organic
2
CH
1
4
3
CO); IR (KBr): n ˆ 3330, 3069, 1742, 1660, 1584, 1433, 1366, 1262,
3
2
�
1
047 cm ; HRMS (FAB): calcd for C17
H
26
N
3
O
10SCl 464.1339, found
2
4
‡
64.1337 for [M � Cl] .
residue that was subjected to column chromatography.
2,3,4,6-Tetra-O-acetyl-N-(isothiouronium acetyl)-b-d-galactopyranosyla-
Heptakis{2,3-di-O-acetyl-6-S-[N-(2,3,4,6-tetra-O-acetyl-b-d-glucopyrano-
syl)aminocarbonylmethyl]-6-thio}cyclomaltoheptaose (18): Column chro-
matography (EtOAc to EtOAc/MeOH 30:1) gave 18 (535 mg, 98%) as a
mine hydrochloride (13): To a solution of 6 (1.46 g, 3.46 mmol) in dry
acetone (10 mL) was added thiourea (262 mg, 3.456 mmol). The reaction
mixture was stirred at room temperature for 120 h and then the
solid. The isolated solid was dissolved in CH
2 2
Cl (2 mL) and ether (30 mL)
2
precipitated product was filtered off, dissolved in H O (10 mL) and
was added. The resulting precipitate was filtered and compound 18 was
concentrated to dryness by lyophilization. Dry acetone (5 mL) was added
to the resulting solid; this gave a precipitate that was filtered off, and 13 was
obtained (503 mg, 92%): m.p. 1558C; [a]
D
ˆ ‡54 (c ˆ 0.5 in chloroform);
1
3
H NMR (300 MHz, Cl
3
CD): d ˆ 7.81 (d, 7H, JNH,1 ˆ 9.3 Hz, NH), 5.36 (t,
3
3
3
isolated (1.295 g, 75%) as a solid: m.p. 1348C; [a]
D
ˆ ‡37 (c ˆ 0.5 in
7H, J ˆ 9.3 Hz, H-3'), 5.34 (t, 7H, J ˆ 9.3 Hz, H-1'), 5.27 (brdd, 7H, J2,3
ˆ
methanol); 1H NMR (300 MHz, (CD
.3 Hz, NH), 9.42 (brs, 4H, 2 NH
)
SO): d ˆ 9.44 (d, 1H,
3
J
ˆ
9.7 Hz,
J
3
J
3,4 ˆ 8.6 Hz, H-3), 5.12 (t, 7H, J ˆ 9.3 Hz, H-4'), 5.08 (d, 7H,
3 3
3
3
2
NH,1
3
3
9
2
), 5.46 (t, 1H, J ˆ 9.3 Hz, H-1), 5.40
1,2 ˆ 3.7 Hz, H-1), 5.06 (t, 7H, J ˆ 9.3 Hz, H-2'), 4.81 (dd, 7H,
J
2,3
ˆ
3
3
3
3
3
(
dd, 1H, J2,3 ˆ 9.3 Hz, J3,4 ˆ 3.5 Hz, H-3), 5.38 (brs, 1H, H-4), 5.13 (t, 1H,
9.7 Hz, J1,2 ˆ 3.7 Hz, H-2), 4.36 (dd, 7H, J6',6' ˆ 12.5, J5',6' ˆ 4.0 Hz, H-6'),
3
2
3
3
J ˆ 9.3 Hz, H-2), 4.44 (brt, 1H, H-5), 4.14 (dd, 1H, J6,6' ˆ 11.2 Hz, J5,6
ˆ
ˆ
4.15 (m, 7H, H-5), 4.09 (m, 7H, H-6'), 3.95 (m, 7H, H-5'), 3.71 (t, 7H, J ˆ
2
3
3
6
6
CH
1
6
.1 Hz, H-6), 4.12 (brs, 2H, CH
.7 Hz, H-6'), 2.20 (s, 3H, CH CO), 2.09 (s, 3H, CH
CO), 2.01 (s, 3H, CH
CO); 13C NMR (75.5 MHz, (CD
69.7 ± 169.1 (5 CˆO), 167.3 (CˆN), 77.4 (C-1), 71.5 (C-5), 70.6 (C-3 or 4),
8.1 (C-2), 67.5 (C-4 or 3), 61.3 (C-6), 33.5 (CH S), 20.3 ± 20.2 (4 CH CO);
2
S), 4.07 (dd, 1H,
J
6,6' ˆ 11.2 Hz,
J
5,6'
8.6 Hz, H-4), 3.41 (brs, 14H, CH
2
S), 3.20 (brd, 7H, J6,6 ˆ 13.5 Hz, H-6),
3
3
3
3
CO), 2.08 (s, 3H,
3.00 (dd, 7H, J6,6 ˆ 13.5 Hz, J5,6 ˆ 6.4 Hz, H-6), 2.08 (s, 63H, 21CH
2.05 (s, 21H, 7CH CO), 2.03 (s, 21H, 7CH CO), 2.02 (s, 21H, 7CH
C NMR (75.5 MHz, Cl
CD): d ˆ 170.7 ± 169.6 (7 peaks, CO), 96.8 (C-1),
79.7 (C-4), 78.3 (C-1'), 73.7 (C-5'), 73.1(C-3'), 71.8 (C-5), 70.7 (C-2', 3), 70.4
(C-2), 68.2 (C-4'), 61.9 (C-6'), 37.6 (CH S), 34.9 (C-6), 20.8 ± 20.6 (6 peaks,
CH
CO); IR (KBr): n ˆ 3460, 2940, 1752, 1684, 1532, 1522, 1372, 1230,
042 cm
3
CO),
3
3
3
)
2
SO): d ˆ
3
3
3
CO);
1
3
3
2
3
�
1
IR (KBr): n ˆ 3335, 1748, 1653, 1542, 1371, 1231, 1052 cm ; HRMS (FAB):
2
‡
calcd for C17
H
26
N
3
O
10SCl 464.1339, found 464.1330 for [M � Cl] .
3
�
1
‡
1
;
MS (FAB): m/z ˆ 4568 for [M‡Na � 2H] , calcd for
2
-Acetamido-3,4,6-tri-O-acetyl-N-(isothiouronium acetyl)-2-deoxy-b-d-
glucopyranosylamine hydrochloride (14): To a solution of 7 (1.58 g,
.74 mmol) in dry acetone (30 mL) and dry CH Cl (30 mL) was added
thiourea (426 mg, 5.61 mmol). The reaction mixture was stirred at room
182 245 7 112 7
C H N O S (4547).
3
2
2
Heptakis{2,3-di-O-acetyl-6-S-[N-(2,3,4,6-tetra-O-acetyl-b-d-galactopyra-
nosyl)aminocarbonylmethyl]-6-thio}cyclomaltoheptaose (19): Column
Chem. Eur. J. 1999, 5, No. 6
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0506-1781 $ 17.50+.50/0
1781

F. Santoyo-Gonz a lez, A. Vargas-Berenguel et al.
FULL PAPER
3
3
chromatography (EtOAc to EtOAc/MeOH 30:1) gave 19 (530 mg, 97%) as
H-3), 5.13 (d, 7H, J1,2 ˆ 3.0 Hz, H-1), 4.92 (t, 7H, J ˆ 9.5 Hz, H-4'), 4.89 (t,
3
3
3
a solid. The isolated solid was dissolved in CH
2
Cl
2
(2 mL) and ether
7H, J ˆ 9.5 Hz, H-2'), 4.81 (dd, 7H, J2,3 ˆ 9.4 Hz, J1,2 ˆ 3.0 Hz, H-2), 4.16
2 3
(
30 mL) was added. The resulting precipitate was filtered and afforded 19
(dd, 7H, J6',6' ˆ 13.1 Hz, J5',6' ˆ 5.2 Hz, H-6'), 4.03 (m, 21H, H-5, 5', 6'), 3.77
2
(
514 mg, 94%): m.p. 1638C (decomp); [a]
D
ˆ ‡63 (c ˆ 0.5 in chloroform);
(m, 14H, H-4, 6), 3.49 (m, 7H, H-6), 3.37 (d, 7H, J ˆ 14.3 Hz, CHS), 3.28
1
3
2
2
H NMR (300 MHz, Cl
3
CD): d ˆ 7.54 (d, 7H, JNH,1 ˆ 9.3 Hz, NH), 5.52 (d,
(d, 7H, J ˆ 14.3 Hz, CHS), 3.28 (d, 7H, J ˆ 12.6 Hz, CHS), 3.23 (d, 7H,
3
3
2
7
5
9
7
7
1
1
CH
(
7
H, J3,4 ˆ 3.3 Hz, H-4'), 5.41 (t, 7H, J ˆ 9.3 Hz, H-1'), 5.35 (brt, 7H, H-3),
J ˆ 12.6 Hz, CHS), 2.11 (s, 21H, 7CH
3
CO), 2.10 (s, 21H, 7CH
3
CO), 2.08
3
3
3
.30 (dd, 7H,
J
2',3' ˆ 9.8 Hz,
J
3',4' ˆ 3.3 Hz, H-3'), 5.22 (dd, 7H,
J
2',3'
ˆ
(s, 21H, 7CH
3
CO), 2.06 (s, 21H, 7CH CO), 2.03 (s, 21H, 7CH CO), 2.01 (s,
3
3
3
3
CO); 13C NMR (75.5 MHz, (CD
.8 Hz,
J
1',2' ˆ 9.3 Hz, H-2'), 5.13 (d, 7H,
J
1,2 ˆ 3.6 Hz, H-1), 4.85 (dd,
21H, 7CH
3
3
)
2
SO, 353 K): d ˆ 169.4 ± 168.7
3
3
H, J2,3 ˆ 9.9 Hz, J1,2 ˆ 3.6 Hz, H-2), 4.21 (m, 28H, H-5, 5', 6', 6'), 3.82 (t,
(7 peaks, CO), 96.1 (C-1), 77.1 (C-1'), 76.7 (C-4), 72.7 (C-3'), 72.2 (C-5'),
70.4 (C-2'), 70.1, 69.8, 69.5 (C-2, 3, 5), 68.0 (C-4'), 61.5 (C-6'), 39.1 (C-6),
3
3
3
H, J3,4 ˆ 8.8 Hz, H-4), 3.48 (d, 7H, J ˆ 16.1 Hz, CHS), 3.41 (d, 7H, J ˆ
3
3
6.1 Hz, CHS), 3.28 (brd, 7H,
4.2 Hz, 3
5,6 ˆ 6.0 Hz, H-6), 2.22 (s, 21H, 7 CH
CO), 2.10 (s, 42H, 14 CH CO), 2.03 (s, 21H, 7 CH
75.5 MHz, Cl
CD): d ˆ 170.8 ± 169.8 (7 peaks, CO), 96.6 (C-1), 79.0 (C-4),
8.7 (C-1'), 72.6 (C-5'), 71.5 (C-5), 71.1 (C-3'), 70.8 (C-3), 70.7 (C-2), 68.7
S), 34.8 (C-6), 20.9 ± 20.6 (6 peaks,
J
6,6 ˆ 14.2 Hz, H-6), 3.10 (dd, 7H,
CO), 2.12 (s, 42H, 14
CO); 13C NMR
J
6,6
ˆ
34.8 (CH
2
S), 34.6 (CH
2
S), 20.1 ± 19.7 (6 peaks, CH
3
CO); IR (KBr): n ˆ
� 1
J
3
3470, 2941, 1752, 1663, 1545, 1370, 1229, 1043 cm ; MS (FAB): m/z ˆ 4968
‡
3
3
3
for [M‡Na � 1] , calcd for C196
266 14 119 7
H N O S (4946).
3
Heptakis{2,3-di-O-acetyl-6-amino-N-[S-(N-(2,3,4,6-tetra-O-acetyl-b-d-gal-
actopyranosyl)aminocarbonylmethyl)mercaptoacetyl]-6-deoxy}cyclomal-
toheptaose (23): Column chromatography (EtOAc to EtOAc/MeOH 40:1)
gave 23 (838 mg, 90%) as a solid. The isolated solid was dissolved in
CH Cl (2 mL) and ether (30 mL) was added. The resulting precipitate was
2 2
filtered and afforded 23 (757 mg, 81%): m.p. 1518C (decomp); [a]
(
C-2'), 67.3 (C-4'), 60.9 (C-6'), 37.3 (CH
2
CH
3
CO); IR (KBr): n ˆ 3611, 3356, 2935, 1750, 1694.9, 1539, 1423, 1371,
�
1
‡
1224, 1044 cm
;
MS (FAB): m/z ˆ 4570 for [M‡Na] , calcd for
182 245 7 112 7
C H N O S (4547).
D
ˆ ‡35
1
Heptakis{2,3-di-O-acetyl-6-S-[N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-
b-d-glucopyranosyl)aminocarbonylmethyl]-6-thio}cyclomaltoheptaose (20):
Column chromatography (EtOAc to EtOAc/MeOH 20:1) gave 20 (644 mg,
(c ˆ 0.5 in chloroform); H NMR (300 MHz, (CD
3
)
2
SO, 353 K): d ˆ 8.69 (d,
3
3
7H, JNH,1' ˆ 9.3 Hz, NH-C-1'), 7.79 (brs, 7H, NH ± C-6), 5.42 (t, 7H, J ˆ
3
3
9.3 Hz, H-1'), 5.41 (d, 7H, J3,4 ˆ 3.4 Hz, H-4'), 5.35 (dd, 7H, J2',3' ˆ 9.6 Hz,
3
3
3
9
8%) as a solid. The isolated solid was dissolved in CH
ether (30 mL) was added. The resulting precipitate was filtered and
afforded 20 (624 mg, 95%): m.p. 1818C (decomp); [a]
2
Cl
2
(2 mL) and
J
3',4' ˆ 3.4 Hz, H-3'), 5.30 (t, 7H, J ˆ 9.6 Hz, H-3), 5.24 (d, 7H,
J
1,2
ˆ
3
3
3.4 Hz, H-1), 5.15 (t, 7H, J ˆ 9.6 Hz, H-2'), 4.91 (dd, 7H,
J
2,3 ˆ 9.6 Hz,
3
3
2
D
ˆ ‡62 (c ˆ 0.5 in
J
1,2 ˆ 3.4 Hz, H-2), 4.36 (brt, 7H, J ˆ 6.3 Hz, H-5'), 4.15 (dd, 7H, J6',6'
ˆ
ˆ
chloroform); 1H NMR (300 MHz, (CD
SO, 373 K): d ˆ 8.5 (brs, 7H,
11.2 Hz,
11.2 Hz, 3
3
J
5',6' ˆ 6.3 Hz, H-6'), 4.13 (m, 7H, H-5), 4.10 (dd, 7H,
2
J
6',6'
3
)
2
3
NH ± C-1'), 7.74 (brs, 7H, NH ± C-2'), 5.36 (t, 7H, J ˆ 9.9 Hz, H-1'), 5.31 (t,
J
5',6' ˆ 6.3 Hz, H-6'), 3.88 (m, 14H, H-4, 6), 3.59 (m, 7H, H-6),
3
3
3
2
2
7
H, J ˆ 9.8 Hz, H-3), 5.29 (t, 7H, J ˆ 9.7 Hz, H-3'), 5.17 (d, 7H,
J
1,2
ˆ
3.47 (d, 7H, J ˆ 14.3 Hz, CHS), 3.38 (d, 7H, J ˆ 14.3 Hz, CHS), 3.38 (d,
3
3
7H, 2J ˆ 14.1 Hz, CHS), 3.32 (d, 7H, J ˆ 14.1 Hz, CHS), 2.20 (s, 21H,
2
3
.4 Hz, H-1), 4.98 (t, 7H, J ˆ 9.7 Hz, H-4'), 4.86 (dd, 7H,
J
2,3 ˆ 9.8 Hz,
3
3
3
J
1,2 ˆ 3.4 Hz, H-2), 4.29 (dd, 7H, J6',6' ˆ 12.5 Hz, J5',6' ˆ 4.6 Hz, H-6'), 4.24
7CH
7CH
3
3
CO), 2.12 (s, 21H, 7CH
3
CO), 2.09 (s, 21H, 7CH
CO), 2.01 (s, 21H, 7CH
3
CO), 2.08 (s, 21H,
3
13
(
m, 7H, H-5), 4.00 (m, 14H, H-2', 6'), 3.98 (t, 7H, J ˆ 9.8 Hz, H-4), 3.95 (m,
CO), 2.07 (s, 21H, 7CH
3
3
CO); C NMR
2
2
7
3
2
H, H-5'), 3.52 (d, 7H, J ˆ 15.2 Hz, CHS), 3.43 (d, 7H, J ˆ 15.2 Hz, CHS),
.20 (m, 14H, H-6, 6), 2.12 (s, 21H, 7CH CO), 2.10 (s, 42H, 14CH CO),
.07 (s, 21H, 7CH CO), 2.04 (s, 21H, 7CH CO), 1.93 (s, 14H, 7CH CON);
C NMR (75.5 MHz, (CD
SO, 353 K): d ˆ 169.6 ± 168.7 (5 peaks, CO),
6.2 (C-1), 78.3 (C-1', 4), 73.0 (C-3'), 72.3 (C-5'), 71.2 (C-5), 70.0, 69.8 (C-2,
), 68.6 (C-4'), 61.7 (C-6'), 52.1 (C-2'), 36.5 (CH S), 33.7 (C-6), 22.1
(75.5 MHz, (CD
77.3 (C-1'), 76.6 (C-4), 71.3 (C-5'), 70.6 (C-3'), 70.1 (C-3), 69.8 (C-5), 69.5 (C-
2), 68.1 (C-2'), 67.4 (C-4'), 60.9 (C-6'), 39.1 (C-6), 34.8 (CH S), 34.5 (CH S),
20.0 ± 19.7 (6 peaks, CH
CO); IR (KBr): n ˆ 3470, 3067, 2938, 1749, 1664,
3
)
2
SO, 353 K): d ˆ 169.4 ± 168.7 (6 peaks, CO), 96.1 (C-1),
3
3
3
3
3
2
2
1
3
3
)
2
3
�
1
‡
9
3
1542, 1372, 1230, 1050 cm , MS (FAB): m/z ˆ 4969 for [M‡Na] , calcd for
(4946).
2
196 266 14 119 7
C H N O S
(
1
CH
3
CN), 20.0 ± 19.8 (4 peaks, CH
3
CO); IR (KBr): n ˆ 3474, 3067, 2928,
Heptakis{2,3-di-O-acetyl-6-amino-N-[S-(N-(2-acetamido-3,4,6-tri-O-ace-
tyl-2-deoxy-b-d-glucopyranosyl)aminocarbonylmethyl)mercaptoacetyl]-6-
deoxy}cyclomaltoheptaose (24): Column chromatography (EtOAc/MeOH
20:1 to 5:1) gave 24 (847 mg, 91%) as a solid. The isolated solid was
dissolved in CH Cl (2 mL) and ether (30 mL) was added. The resulting
2 2
precipitate was filtered and afforded 24 (782 mg, 84%): m.p. 1798C
�
1
‡
743, 1663, 1540, 1370, 1039 cm ; MS (FAB): m/z ˆ 4563 for [M‡Na] ,
calcd for C182
252 14 105 7
H N O S (4540).
Heptakis{2,3-di-O-acetyl-6-S-[N-(2,3,4,6-tetra-O-acetyl-a-d-mannopyra-
nosyl)aminocarbonylmethyl]-6-thio}cyclomaltoheptaose (21): Column
chromatography (EtOAc to EtOAc/MeOH 30:1) gave 21 (533 mg, 97%)
1
as a solid. The isolated solid was dissolved in CH
2
Cl
2
(2 mL) and ether
(decomp); [a]
(CD
D
ˆ ‡55 (c ˆ 0.5 in chloroform); H NMR (300 MHz,
3
(
30 mL) was added. The resulting precipitate was filtered and afforded 21
3
)
2
SO, 353 K): d ˆ 8.45 (dd, 7H,
J
NH,1 ˆ 8.8 Hz, NH ± C-1'), 7.80 (m,
3
(
475 mg, 87%): m.p. 1468C (decomp); [a]
D
ˆ ‡106 (c ˆ 0.5 in chloroform);
14H, 2 NH ± C-2', 6), 5.29 (m, 28H, H-1', 1, 3', 3), 4.95 (t, 7H, J ˆ 9.4 Hz,
1
3
3
3
3
H NMR (300 MHz, (CD
3
)
2
SO, 373 K): d ˆ 8.93 (d, 7H,
J
NH,1' ˆ 8.5 Hz,
H-4'), 4.90 (dd, 7H, J2,3 ˆ 8.5 Hz, J1,2 ˆ 3.6 Hz, H-2), 4.27 (dd, 7H, J6',6'
12.2 Hz,
5',6' ˆ 4.4 Hz, H-6'), 4.13 (m, 7H, H-5), 4.11 (dd, 7H,
12.2 Hz, 3
ˆ
ˆ
3
3
3
NH ± C-1'), 5.61 (m, 14H, H-1', 3'), 5.33 (t, 7H, J ˆ 9.6 Hz, H-3), 5.23 (brd,
J
J
6',6'
3
3
3
7
H, J2',3' ˆ 3.4 Hz, H-2'), 5.20 (t, 7H, J ˆ 9.0 Hz, H-4'), 5.20 (d, 7H, J1,2
ˆ
J
5',6' ˆ 3.3 Hz, H-6'), 4.05 (brdd, 7H, H-2'), 3.92 (m, 7H, H-5'),
3
3
3
2
3
.6 Hz, H-1), 4.83 (dd, 7H, J2,3 ˆ 9.6 Hz, J1,2 ˆ 3.6 Hz, H-2), 4.27 (dd, 7H,
3.90 (m, 14H, H-4, 6), 3.60 (brd, 7H, J5,6' ˆ 12.4 Hz, H-6), 3.45 (d, 7H, J ˆ
2
3
2
2
J
6',6' ˆ 12.1 Hz,
J
5',6' ˆ 4.9 Hz, H-6'), 4.27 (m, 7H, H-5), 4.17 (dd, 7H,
14.0 Hz, CHS), 3.42 (d, 7H, J ˆ 14.5 Hz, CHS), 3.37 (d, 7H, J ˆ 14.0 Hz,
2J6',6' ˆ 12.1 Hz, J5',6' ˆ 3.0 Hz, H-6'), 4.12 (m, 7H, H-5'), 4.06 (t, 7H, J ˆ
3
3
CHS), 3.35 (d, 7H, J ˆ 14.5 Hz, CHS), 2.11 (s, 42H, 14CH
2
CO), 2.10 (s,
CO), 1.88 (s,
3
2
2
9
.6 Hz, H-4), 3.55 (d, 7H, J ˆ 14.1 Hz, CHS), 3.47 (d, 7H, J ˆ 14.1 Hz,
21H, 7CH
21H, 7CH
3
CO), 2.07 (s, 21H, 7CH
CN); C NMR (75.5 MHz, (CD
3
CO), 2.02 (s, 21H, 7CH
3
2
3
2
13
CHS), 3.32 (dd, 7H, J6,6 ˆ 14.7 Hz, J5,6 ˆ 3.0 Hz, H-6), 3.21 (dd, 7H, J6,6
ˆ
3
3
)
2
SO, 353 K): d ˆ 169.4 ± 168.7
3
1
7
7
3
7
2
4.7 Hz,
CH
CH
J
5,6 ˆ 5.3 Hz, H-6), 2.19 (s, 21H, 7CH
3
CO), 2.13 (s, 21H,
(4 peaks, CO), 96.1 (C-1), 78.2 (C-1'), 76.6 (C-4), 73.0 (C-3'), 72.3 (C-5'),
70.1 (C-3), 69.8 (C-5), 69.5 (C-2), 68.6 (C-4'), 61.7 (C-6'), 52.1 (C-2'), 39.1
3
CO), 2.12 (s, 21H, 7CH
CO), 2.05 (s, 21H, 7CH
3
CO), 2.11 (s, 21H, 7CH
3
CO), 2.10 (s, 21H,
SO,
CO); 13C NMR (75.5 MHz, (CD
)
(C-6), 34.7 (2 Â CH
3
3
3
2
2 3 3
S), 22.1 (CH CN), 20.1 ± 19.8 (3 peaks, CH CO); IR
�
1
53 K): d ˆ 169.4 ± 168.7 (7 peaks, CO), 96.3 (C-1), 78.0 (C-4), 75.4 (C-1'),
(KBr): n ˆ 3412, 3070, 2938, 1750, 1663, 1545, 1371, 1243, 1046 cm ; MS
‡
1.2 (C-5), 70.0, 69.9 (C-2, 3), 69.0 (C-5', C-2', or 4'), 68.1 (C-3'), 66.2 (C-4' or
(FAB): m/z 4961 for [M‡Na � 1] , calcd for C196
273 21 112 7
H N O S (4939).
2 3
'), 61.7 (C-6'), 36.2 (CH S), 33.6 (C-6), 20.0 ± 19.7 (6 peaks, CH CO); IR
Heptakis{2,3-di-O-acetyl-6-amino-N-[S-(N-(2,3,4,6-tetra-O-acetyl-a-d-
mannopyranosyl)aminocarbonylmethyl)mercaptoacetyl]-6-deoxy}cyclomal-
toheptaose (25): Column chromatography (EtOAc to EtOAc/MeOH 20:1)
gave 25 (829 mg, 89%) as a solid. The isolated solid was dissolved in
�
1
(
(
KBr): n ˆ 3457, 2940, 1750, 1654, 1540, 1431, 1371, 1229, 1050 cm ; MS
‡
FAB): m/z ˆ 4570 for [M‡Na] , calcd for C182
245 7 112 7
H N O S (4547).
Heptakis{2,3-di-O-acetyl-6-amino-N-[S-(N-(2,3,4,6-tetra-O-acetyl-b-d-
glucopyranosyl)aminocarbonylmethyl)-mercaptoacetyl]-6-deoxy}cyclomal-
toheptaose (22): Column chromatography (EtOAc to EtOAc/MeOH 20:1)
gave 22 (496 mg, 80%) as a solid. The isolated solid was dissolved in
2 2
CH Cl (2 mL) and ether (30 mL) was added. The resulting precipitate was
filtered and afforded 25 (745 mg, 80%): m.p. 1548C (decomp); [a]
D
ˆ ‡72
1
(c ˆ 0.5 in chloroform); H NMR (300 MHz, (CD
3
)
2
SO, 353 K): d ˆ 9.15 (d,
3
CH
2
Cl
2
(2 mL), and ether (30 mL) was added. The resulting precipitate was
7H,
J
NH,1' ˆ 9.0 Hz, NH ± C-1'), 7.80 (brs, 7H, NH ± C-6), 5.61 (dd, 7H,
3 3 3
3
filtered and afforded 22 (439 mg, 71%): m.p. 1498C; [a]
D
ˆ ‡22 (c ˆ 0.5 in
J
3',4' ˆ 9.4 Hz,
J
2',3' ˆ 3.3 Hz, H-3'), 5.58 (dd, 7H,
J
NH,1' ˆ 9.0 Hz,
J
1',2'
ˆ
1
3
3
chloroform); H NMR (300 MHz, (CD
3
)
2
SO, 353 K): d ˆ 8.66 (d, 7H,
2.0 Hz, H-1'), 5.30 (t, 7H, J ˆ 9.7 Hz, H-3), 5.22 (brd, 7H, J2',3' ˆ 3.3 Hz,
3
3
3
3
3
J
NH,1' ˆ 9.5 Hz, NH ± C-1'), 7.80 (brs, 7H, NH ± C-6), 5.34 (t, 7H, J ˆ
J
1',2' ˆ 2.0, H-2'), 5.19 (d, 7H, J1,2 ˆ 3.3 Hz, H-1), 5.18 (t, 7H, J ˆ 9.4 Hz,
3
3
3
3
9
.5 Hz, H-1'), 5.30 (t, 7H, J ˆ 9.5 Hz, H-3'), 5.20 (t, 7H, J ˆ 9.4 Hz,
H-4'), 4.90 (dd, 7H, 1,2 ˆ 3.3 Hz, H-2), 4.25 (dd, 7H,
J
2,3 ˆ 9.7 Hz,
J
1
782
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0947-6539/99/0506-1782 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 6

Cluster N-Glycosides
1775±1784
2J6',6' ˆ 12.0 Hz, 3J5',6' ˆ 5.0 Hz, H-6'), 4.16 (dd, 7H, 2J6',6' ˆ 12.0 Hz, 3J5',6''
ˆ
(
6
1
C
C-1'), 77.5, 76.4, 71.7, 69.1 (C-2', 3', 4', 5'), 72.7, 71.9, 70.1 (C-2, 3, 5), 60.4 (C-
3
3
.0 Hz, H-6'), 4.13 (m, 7H, H-5), 4.10 (m, 7H, H-5'), 3.88 (m, 14H, H-4, 6),
'), 40.0 (C-6), 34.7 (2  CH S); IR (KBr): n ˆ 3398, 2919, 1655, 1548, 1418,
2
2
2
.62 (brd, 7H, J6,6 ˆ 12.0 Hz, H-6), 3.52 (d, 7H, J ˆ 14.4 Hz, CHS), 3.45
� 1
‡
081, 1043 cm
;
MS (FAB): m/z ˆ 3204 for [M‡Na] , calcd for
2
(
brs, 14H, CH
2
S), 3.42 (d, 7H, J ˆ 14.4 Hz, CHS), 2.20 (s, 21H, 7CH
3
CO),
CO),
112
H
182
N
14
O
77
S
7
(3181).
2
2
1
6
.12 (s, 21H, 7CH
.05 (s, 21H, 7CH
3
CO), 2.11 (s, 42H, 14CH
3
CO), 2.10 (s, 21H, 7CH
CO); 13C NMR (75.5 MHz, (CD
3
Heptakis{6-amino-N-[S-(N-b-d-galactopyranosylaminocarbonylmethyl)-
mercaptoacetyl]-6-deoxy}cyclomaltoheptaose (31): Yield 213 mg (90%):
m.p. 1778C (decomp); [a]
D
3
3
)
2
SO, 353 K): d ˆ
69.4 ± 168.7 (7 peaks, CO), 96.1 (C-1), 76.7 (C-4), 75.2 (C-1'), 70.1 (C-3),
9.8 (C-5), 69.6 (C-2), 69.0 (C-2', 5'), 68.1 (C-3'), 66.3 (C-4'), 61.7 (C-6'), 39.1
1
D
ˆ ‡63 (c ˆ 0.5 in water); H NMR (300 MHz,
3
3
2
O): d ˆ 5.05 (d, 7H, J1,2 ˆ 3.0 Hz, H-1), 4.90 (d, 7H, J1',2' ˆ 8.5 Hz, H-1'),
(
2 2 3
C-6), 34.9 (CH S), 34.7 (CH S), 20.0 ± 19.8 (6 peaks, CH CO); IR (KBr):
4
(
1
.10 ± 3.30 (m, 112H, H-2, 2', 3, 3', 4, 4', 5, 5', 6', 6', 6, 6, 2CH
75.5 MHz, D
O): d ˆ 172.7, 171.7 (2  CO), 101.8 (C-1), 82.7 (C-4), 80.0 (C-
'), 76.6, 73.3, 69.3, 68.5 (C-2', 3', 4', 5'), 72.7, 72.1, 70.0 (C-2, 3, 5), 60.8 (C-6'),
S); 13C NMR
2
�
1
n ˆ 3455, 2937, 1748, 1537, 1369, 1227, 1046 cm ; MS (FAB): m/z ˆ 4970 for
2
‡
[
M‡Na‡H] , calcd for C196
266 14 119 7
H N O S (4946).
General procedure for the Zempl e n de-O-acetylation of N-glycoCDs 18 ±
40.1 (C-6), 34.7 (2  CH S); IR (KBr): n ˆ 3430, 2918, 1654, 1542, 1417,
2
�
1
‡
2
0
0
5:
A
solution of compound 18 (387 mg, 0.60 mmol), 19 (377 mg,
1082, 1046 cm ; MS (FAB): m/z ˆ 3203 for [M‡Na � H] , calcd for
.58 mmol), 20 (371 mg, 0.57 mmol), 21 (334 mg, 0.51 mmol), 22 (375 mg,
.51 mmol), 23 (361 mg, 0.49 mmol), 24 (364 mg, 0.49 mmol), or 25
C112H182N O S (3181).
14
77 7
Heptakis{6-amino-N-[S-(N-(2-acetamido-2-deoxy-b-d-glucopyranosyl)-
aminocarbonylmethyl)mercaptoacetyl]-6-deoxy}cyclomaltoheptaose (32):
(
360 mg, 0.48 mmol) in dry MeOH (5 ± 6 mL) was made alkaline to pH 9
(
indicator paper) with a methanolic solution of NaOMe (1m). The reaction
Yield 244 mg (94%): m.p. 1978C (decomp); [a]
D
ˆ ‡71 (c ˆ 0.5 in water);
mixture was stirred overnight at room temperature and the precipitated
material was filtered, washed with MeOH and dissolved in H O (6 mL).
1
H NMR (300 MHz, D
2
O): d ˆ 5.05 (d, 14H, H-1, 1'), 4.10 ± 3.30 (m, 112H,
2
H-2, 2', 3, 3', 4, 4', 5, 5', 6', 6', 6, 6, 2 CH
2
S), 1.98 (s, 21H, 7 CH
CN); C NMR
13
3
The solution was concentrated by lyophilization and gave a solid.
(
75.5 MHz, D
2
O): d ˆ 174.4, 172.2, 171.4 (3  CO), 101.9 (C-1), 82.6 (C-4),
Heptakis[6-S-(N-b-d-glucopyranosylaminocarbonylmethyl)-6-thio]cyclo-
78.6 (C-1'), 77.6, 74.0, 69.4 (C-3', 4', 5'), 72.7, 72.0, 69.8 (C-2, 3, 5), 60.4 (C-6'),
maltoheptaose (26): Yield 227 mg (96%): m.p. 1868C (decomp); [a]
D
ˆ
54.2 (C-2'), 39.9 (C-6), 34.4 (2 Â CH
2
S), 22.1 (CH
3
CN); IR (KBr): n ˆ 3411,
1
� 1
‡
39 (c ˆ 0.5 in water); H NMR (300 MHz, D
2
O, 333 K): d ˆ 5.46 (d, 7H,
2916, 1652, 1547, 1373, 1079, 1046 cm ; MS (FAB): m/z ˆ 3489 for
3
3
‡
J
1,2 ˆ 3.5 Hz, H-1), 5.34 (d, 7H,
J
1',2' ˆ 9.9 Hz, H-1'), 4.39 (m, 7H, H-5),
[M‡Na] , calcd for C126
203 21 77 7
H N O S (3466).
3
2
3
4
.27 (t, 7H, J ˆ 9.7 Hz, H-3), 4.26 (dd, 7H, J6',6' ˆ 12.2 Hz, J5',6' ˆ 2.0 Hz,
Heptakis{6-amino-N-[S-(N-a-d-mannopyranosylaminocarbonylmethyl)-
mercaptoacetyl]-6-deoxy}cyclomaltoheptaose (33): Yield 220 mg (93%):
2
3
H-6'), 4.12 (dd, 7H,
J
6',6' ˆ 12.2 Hz,
J
5',6' ˆ 4.8 Hz, H-6'), 4.02 (dd, 7H,
3
3
3
1
J
2,3 ˆ 9.7 Hz,
J
1,2 ˆ 3.5 Hz, H-2), 3.96 (t, 7H, J ˆ 9.7 Hz, H-4), 3.93 (m,
m.p. 1938C (decomp); [a] ˆ ‡102 (c ˆ 0.5 in water); H NMR (300 MHz,
D
1
7
4H, CH
2
S), 3.88 (m, 7H, H-5'), 3.86 ± 3.76 (m, 21H, H-2', 3', 4'), 3.62 (brd,
D O): d ˆ 5.44 (brs, 7H, H-1'), 5.05 (d, 7H, H-1), 4.10 ± 3.20 (m, 112H, H-2,
2
2
2
3
13
H, J6,6 ˆ 14.2 Hz, H-6), 3.39 (dd, 7H, J6,6 ˆ 14.2 Hz, J5,6 ˆ 7.3 Hz, H-6);
2', 3, 3', 4, 4', 5, 5', 6', 6', 6, 6, 2 CH S); C NMR (75.5 MHz, D O): d ˆ 172.1,
2
2
1
3
C NMR (75.5 MHz, D
2
O): d ˆ 173.5 (CO), 101.6 (C-1), 83.9 (C-4), 79.6
171.6 (2 Â CO), 101.8 (C-1), 82.8 (C-4), 78.8 (C-1'), 74.0, 72.7, 72.0, 70.4,
(
C-1'), 77.5, 76.5, 71.8, 69.1 (C-2', 3', 4', 5'), 72.7 (C-3), 71.9 (C-2), 71.7 (C-5),
69.5, 66.5 (C-2, 2', 3, 3', 4', 5, 5'), 60.7 (C-6'), 40.1 (C-6), 34.7 (2 Â CH S); IR
2
6
1
0.5 (C-6'), 36.2 (CH
361, 1070, 1040.4 cm ; MS (FAB): m/z ˆ 2803 for [M‡Na � H] , calcd for
(2781).
2
�
S), 33.7 (C-6); IR (KBr): n ˆ 3407, 2920, 1651, 1556,
(KBr): n ˆ 3424, 2922, 1653, 1540, 1417, 1155, 1046 cm� 1
.
1
‡
Supporting information for this article (copies of 13C NMR spectra of
98 161 7 70 7
C H N O S
compounds 12 ± 15 and 18 ± 33) is available on the WWW under http://
Heptakis[6-S-(N-b-d-galactopyranosylaminocarbonylmethyl)-6-thio]cy-
www.wiley-vch.de/home/chemistry/ or from the author.
clomaltoheptaose (27): Yield 216 mg (94%): m.p. 1838C (decomp); [a]
D
ˆ
ˆ
1
3
‡
50 (c ˆ 0.5 in water); H NMR (300 MHz, D
2
O): d ˆ 5.09 (d, 7H, J1,2
3
3
7
.4 Hz, H-1), 4.92 (d, 7H, J1',2' ˆ 8.5 Hz, H-1'), 4.00 (m, 7H, H-5), 3.97 (d,
3
3
H, J3',4' ˆ 2.9 Hz, H-4'), 3.89 (t, 7H, J ˆ 9.3 Hz, H-3), 3.82 ± 3.44 (m, 63H,
Acknowledgements
2
H-2, 2', 3', 4, 5', 6', 6', CH
2
S), 3.23 (brd, 7H, J6,6 ˆ 14.1 Hz, H-6), 3.00 (dd,
3
13
7
1
6
H, 2
J
6,6 ˆ 14.1 Hz,
J
5,6 ˆ 7.5 Hz, H-6); C NMR (75.5 MHz, D
2
O): d ˆ
The authors acknowledge the support of the Direcci o n General de
Ense nÄ anza Superior (PB95-1207 and PB96-1505) and the Junta de
Andalucía for a scholarship (J.J.G.L.).
73.6 (CO), 101.5 (C-1), 83.9 (C-4), 80.0 (C-1'), 76.5, 73.9, 73.3, 72.6, 71.8,
2
9.3, 68.5 (C-2, 2', 3, 3', 4', 5, 5'), 60.8 (C-6'), 36.2 (CH S), 33.6 (C-6); IR
(
KBr): n ˆ 3399, 2918, 1661, 1540, 1374, 1153, 1043 cm� 1.
Heptakis{6-S-[N-(2-acetamido-2-deoxy-b-d-glucopyranosyl)aminocarbo-
nylmethyl]-6-thio}cyclomaltoheptaose (28): Yield 237 mg (95%): m.p.
1
[1] Cyclodextrins and Their Industrial Uses, Editions de Sant e (Ed. D.
Duch eà ne), Paris, 1987.
2
D
018C (decomp); [a]
D
ˆ ‡57 (c ˆ 0.5 in water); H NMR (300 MHz,
2
O): d ˆ 5.04 (d, 14H, H-1, 1'), 3.99 (m, 7H, H-5), 3.94 ± 3.35 (m, 77H,
2
[2] a) M. L. Bender, M. Komiyama, Cyclodextrins Chemistry; Springer,
New York, 1978; b) J. L. Atwood, J. E. D. Davies, D. MacNicol,
Inclusion Compounds, Academic Press, London, 1984; c) J. Szejtli,
Cyclodextrins and Their Inclusion Complexes, Academiae Kiado,
Budapest, 1982; d) J. Szejtli, Cyclodextrins Technology, Kluwer
Academic, Boston, 1988.
H-2, 2', 3, 3', 4, 4', 5', 6', 6', CH
2
S), 3.16 (brd, 7H, J6,6 ˆ 14.2 Hz, H-6), 2.91
dd, 7H, 2
3
(
J
6,6 ˆ 14.2 Hz,
J
5,6 ˆ 7.0 Hz, H-6), 2.01 (s, 21H, 7 CH
3
CN);
1
3
C NMR (75.5 MHz, D
), 78.9 (C-1'), 77.5, 74.0, 69.5 (C-3', 4', 5'), 72.7, 72.0, 71.7, (C-2, 3, 5), 60.5 (C-
'), 54.2 (C-2'), 36.3 (CH S), 33.8 (C-6), 22.1 (CH
2
O): d ˆ 174.4, 173.0 (2  CO), 101.7 (C-1), 83.8 (C-
4
6
2
2
3
CN); IR (KBr): n ˆ 3405,
�
1
919, 1651, 1539, 1373, 1068, 1041 cm ; MS (FAB) m/z ˆ 3090 for
‡
[3] J. Szejtli, Cyclodextrins, Pergamon, New York, 1996.
[
M‡Na � 2H] , calcd for C112
182 14 70 7
H N O S (3069).
[
4] a) D. Duch eà ne, New Trends in Cyclodextrin and Derivatives, Editions
de Sant e , Paris, 1991; b) J. Szejtli, Med. Res. Rev. 1994, 14, 353 ± 386.
5] a) S. Cottaz, H. Driguez, Synthesis 1989, 755 ± 758; b) C. Lancelon-
Pin, H. Driguez, Tetrahedron Lett. 1992, 33, 3125 ± 3128; c) F.
Djedaïni-Pilard, J. D e salos, B. Perly, Tetrahedron Lett. 1993, 34,
Heptakis[6-S-(N-a-d-mannopyranosylaminocarbonylmethyl)-6-thio]cyclo-
maltoheptaose (29): Yield 192 mg (94%): m.p. 1908C (decomp); [a]
D
ˆ
[
1
3
‡
82 (c ˆ 0.5 in water); H NMR (300 MHz, D
2
O): d ˆ 5.47 (d, 7H, J1',2'
ˆ
3
1
.3 Hz, H-1'), 5.07 (d, 7H, J1,2 ˆ 2.4 Hz, H-1), 4.10 ± 3.40 (m, 84H, H-2, 2', 3,
2
3
J
(
', 4, 4', 5, 5', 6', 6', CH
6,6 ˆ 13.6 Hz,
2
S), 3.30 (brd, 7H, J6,6 ˆ 13.6 Hz, H-6), 2.90 (dd, 7H,
2
457 ± 2460; d) L. de Robertis, C. Lancelon-Pin, H. Driguez, F.
Attioui, R. Bonaly, A. Marsura, Bioorg. Med. Chem. Lett. 1994, 4,
127 ± 1130; e) V. Lain e , A. Coste-Sarguet, A. Gadelle, J. Defaye, B.
Perly, F. Djedaïni-Pilard, J. Chem. Soc. Perkin Trans. 2 1995, 1479 ±
487; f) E. Leray, H. Parrot-Lopez, C. Aug e , A. W. Coleman, C.
2
3
13
J
5,6 ˆ 8.0 Hz, H-6); C NMR (75.5 MHz, D
2
O): d ˆ 172.6
CO), 101.4 (C-1), 84.2 (C-4), 78.8 (C-1'), 74.0, 70.4, 69.6, 66.5 (C-2', 3', 4',
'), 72.7, 72.3, 71.9 (C-2, 3, 5), 60.8 (C-6'), 35.7 (CH S), 33.1 (C-6); IR (KBr):
n ˆ 3420, 2920, 1667, 1652, 1538, 1406, 1151, 1066, 1043.9 cm
1
5
2
�
1
.
1
Heptakis{6-amino-N-[S-(N-b-d-glucopyranosylaminocarbonylmethyl)-
Finance, R. Bonaly, J. Chem. Soc. Chem. Commun. 1995, 1019 ± 1020;
g) J. M. García Fern a ndez, C. Ortiz Mellet, S. Maciejewski, J. Defaye,
Chem. Commun. 1996, 2741 ± 2742; h) H. Imata, K. Kubota, K.
Hattori, M. Aoyagi, C. Jindoh, Bioorg. Med. Chem. Lett. 1997, 7, 109 ±
112; i) R. Kassab, C. F e lix, H. Parrot-Lopez, R. Bonaly, Tetrahedron
Lett. 1997, 38, 7555 ± 7558.
mercaptoacetyl]-6-deoxy}cyclomaltoheptaose (30): Yield 228 mg (92%):
1
m.p. 1888C (decomp); [a]
D
ˆ ‡50 (c ˆ 0.5 in water); H NMR (300 MHz,
3
3
D
2
O): d ˆ 5.06 (d, 7H, J1,2 ˆ 3.4 Hz, H-1), 4.95 (d, 7H, J1',2' ˆ 9.0 Hz, H-1'),
4
.10 ± 3.20 (m, 112H, H-2, 2', 3, 3', 4, 4', 5, 5', 6', 6', 6, 6, 2 CH
S); 13C NMR
2
(
75.5 MHz, D
2
O): d ˆ 172.6, 171.6 (2  CO), 101.6 (C-1), 82.5 (C-4), 79.5
Chem. Eur. J. 1999, 5, No. 6
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0506-1783 $ 17.50+.50/0
1783

F. Santoyo-Gonz a lez, A. Vargas-Berenguel et al.
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Received: October 19, 1998 [F1400]
1
784
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