Synthesis of glycosaminoglycan oligosaccharides. Part 5: Synthesis of a putative heparan sulfate tetrasaccharide antigen involved in prion diseases

Article abstract of DOI:10.1016/j.tet.2010.08.004

The synthesis of the putative prion-associated heparan sulfate tetrasaccharide containing two d-glucuronic acid units is reported. Key to the synthesis were the differentiation of the N-acetylated and N-unsubstituted glucosamine units, the high-yielding glucosylation at O-4 of an N-acetyl-d-glucosamine derivative and the α-selective glycosylation of the 4′-OH group of a β-d-GlcpA-(1→4)-d-GlcpNAc disaccharide building block with a disaccharide thioglycoside donor.

Full text of DOI:10.1016/j.tet.2010.08.004

Tetrahedron 66 (2010) 8036e8046
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of glycosaminoglycan oligosaccharides. Part 5: Synthesis of a putative
heparan sulfate tetrasaccharide antigen involved in prion diseasesq
*
Katalin Daragics, Péter Fügedi
Department of Carbohydrate Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Pusztaszeri út 59-67, H-1025 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 April 2010
Received in revised form 12 July 2010
Accepted 3 August 2010
Available online 7 August 2010
The synthesis of the putative prion-associated heparan sulfate tetrasaccharide containing two D-glu-
curonic acid units is reported. Key to the synthesis were the differentiation of the N-acetylated and
N-unsubstituted glucosamine units, the high-yielding glucosylation at O-4 of an N-acetyl- -glucosamine
derivative and the -GlcpA-(1/4)- -GlcpNAc
-selective glycosylation of the 40-OH group of a
disaccharide building block with a disaccharide thioglycoside donor.
D
a
b
-D
D
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Heparan sulfate
Prion diseases
Oligosaccharide synthesis
N-Acetyl-D-glucosamine
Glycosylation
Thioglycosides
1. Introduction
polysaccharide chains are responsible for the binding to individual
proteins.2a
Heparin (H) and heparan sulfate (HS), members of the glycos-
aminoglycan (GAG) family, are built up of linear chains of alter-
Evidence has been forthcoming for the possible involvement of
specific carbohydrate sequences of heparan sulfate in neurode-
generative pathologies, such as Alzheimer’s disease and trans-
missible spongiform encephalopathies (TSEs).3 TSEs are
characterized by the accumulation of scrapie prion protein
(PrPSc),4 a misfolded, abnormally protease-resistant isoform of the
normally existing cellular prion protein (PrPC).5 In particular,
heparan sulfate may play a role in the conversion of PrPC to
nating D
-glucosamine and hexuronic acid units.1 They are the most
heterogeneous polysaccharides since various epimerization and
sulfation patterns may occur along the linear carbohydrate back-
bone. The uronic acid may be either
-iduronic acid (IdoA), while O-sulfation may occur at the O-2
position of the uronic acids and at the O-3 and/or O-6-positions of
the aminosugar. Additionally, the amino group of the -glucos-
D-glucuronic acid (GlcA) or
L
D
PrPSc 3d,e
. This has arisen as a result of the finding that amyloid
amine unit can be N-sulfated, N-acetylated or remain unsub-
stituted. Heparan sulfate is more heterogeneous than heparin, and
plaques are rich in heparan sulfate proteoglycans.3a,c,6 Recently, it
has been shown that a heparan sulfate antigen recognized by the
monoclonal antibody 10E4 is uniquely codistributed with the ab-
normal prion protein (PrPSc) in scrapie infected mice.7 The anti-
gen-active fragment from heparan sulfate was isolated after partial
depolymerization with heparin lyase III, and its structure was
determined to be a non-sulfated tetrasaccharide with an inner
it contains more N-acetyl-
D-glucosamine and D-glucuronic acid
units, and less O- and N-sulfates.
Heparin and heparan sulfate interact and regulate the activity of
a large number of proteins, such as coagulation and growth factors,
cytokines, chemokines, viral proteins, and others.2 Though the
binding of heparin and heparan sulfate to some proteins are non-
specific, many of the biologically relevant interactions of H/HS
show a great deal of specificity. It is commonly assumed that spe-
cific oligosaccharide structures within the heterogeneous
N-unsubstituted
D-glucosamine and an N-acetyl-D-glucosamine
unit at the reducing end (UA-GlcN-UA-GlcNAc).7 The identity of
the uronic acid units was not firmly established, the four possible
isomeric structures are shown in Figure 1. There was some
evidence that the uronic acid at the non-reducing terminal is
D
-glucuronic acid and not L
-iduronic acid.7
In our ongoing program on the preparation of libraries of gly-
q
For Part 4, see Ref. 8d.
cosaminoglycan oligosaccharides,8 we thought that tetrasaccharide
* Corresponding author. Tel.: þ36 1 438 1100; fax: þ36 1 438 1145; e-mail
address: pfugedi@chemres.hu (P. Fügedi).
1 (Fig. 1) could be an interesting synthetic target molecule in
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.004

K. Daragics, P. Fügedi / Tetrahedron 66 (2010) 8036e8046
8037
orthoesters, acylated acceptors and other types of by-products.19
The reactivity problems associated with both the glycosyl donor
R3
R4
OH
O
O
HO
HO
O
R1
and the acceptor make the direct synthesis of the
b-D-GlcpA-
HO
OH
O
-GlcpNAc linkage very challenging.19c To the best of our
OH
O
H2N
(1/4)-
D
O
O
OH
HO
R2
knowledge there is only one example of successful direct creation
of this bond.20
HO
OH
NHAc
1
R
1 = CO2H, R2 = H, R3 = CO2H, R4 = H
1 = H, R2 = CO2H, R3 = CO2H, R4 = H
1 = CO2H, R2 = H, R3 = H, R4 = CO2H
Due to these problems, the syntheses of tetrasaccharides (1e3)
could only be accomplished by indirect ways. One of the indirect
routes used an O-1 to N-2 acetyl transfer for the regioselective
differentiation of the azide moiety at C-2 of the reducing end.10 By
this method, only the reducing sugars are accessible, in which the
anomeric configuration at the reducing end is not fixed. In the other
2
3
R
R
4 R1 = H, R2 = CO2H, R3 = H, R4 = CO2H
Figure 1.
approach, the
D-glucosamine units were differentiated by
employing an N,N-diacetyl moiety in the reducing-end unit.11 The
use of this group was also intended to alleviate the reactivity
problems associated with the N-acetyl group; nevertheless, the
yields in the glycosylations were moderate. In addition, the
N,N-diacetyl derivatives proved to be labile not only to basic, but
also to acidic conditions, thereby lowering the yields of the total
synthesis of the derivative of 3.
relation to prion-diseases and other neurodegenerative pathologies
as, e.g., Alzheimer’s disease. Parallel to our work9 the synthesis of
the free tetrasaccharides 1 and 2 has been reported.10 Additionally,
the synthesis of the (2-aminoethylsulfonyl)pentyl
a-glycoside of
the alternative structure 3 has also been described.11 Compounds 1
and 2 have been tested using a neoglycolipid technology, and the
antibody 10E4 was found to bind neither 1 nor 2.10 It should be
noted that compounds 1 and 2 were synthesized as free oligosac-
charides and tested as anomeric mixtures. Oligosaccharides with
free reducing ends are not well suited for biological testing due to
their aldehyde-like reactivity. In addition, reaction of the reducing
end with the free amino group of the oligosaccharide might occur.
This reaction has actually been observed in the synthesis of heparin
oligosaccharides and necessitated the resynthesis of the anti-
thrombin III-binding pentasaccharide in the form of its glycoside.12
A further challenge in the synthesis is the stereoselective for-
mation of the
been suggested that this requires the
a
-
D
-GlcpN-(1/4)-
D
-GlcpA linkage. It has previously
-glucuronic acid locked in
D
the unusual 1C4 conformation.21 As conformationally constrained
compounds, 1,2-O-acetals are proposed. The formation of this type
of derivative, however, is possible only for glycosyl acceptors, which
are at the reducing end; they cannot be prepared in oligosaccha-
rides in which the anomeric center of the
already involved in a glycosidic linkage.
D-glucuronic acid unit is
We now report on the synthesis of the methyl
a-glycoside of
We have developed a synthesis of compound 5 (Scheme 1), the
methyl -glycoside of tetrasaccharide 1, in which an N-acetyl-
glucosamine unit is used directly at the reducing end and stereo-
selective formation of the -GlcpN-(1/4)- -GlcpA linkage is
-glucuronic acid
compound 1, in which the reducing end is blocked and its config-
uration is fixed as the naturally occurring one.
a
D-
a
-D
D
2. Results and discussion
achieved by using a glycosyl acceptor having the D
unit in its natural 4C1 conformation.
2.1. Synthetic considerations
One of the chemical challenges in the synthesis of tetra-
saccharides 1e4 is the differentiation of the two amino groups of the
two D-glucosamine units. Although the chemical syntheses of some
HS oligosaccharides containing both N-acetylated and N-sulfated
units have already been described,13 the type of differentiation
needed for target molecule 1 still remains a challenge.14 Apparently,
CO2H
OH
O
O
HO
HO
O
CO2H
O
HO
OH
O
OH
H2N
O
O
HO
HO
HO
AcHN
OMe
5
the most obvious strategy would be to use N-acetylated
amine units for the reducing end. Derivatives of N-acetyl-
D
-glucos-
-glucos-
CO2tBu
OBn
O
D
BnO
O
O
CO2tBu
BnO
BnO
OBn
O
amine, however, are known to be poor nucleophiles in glycosylation
BzO
O
N3
reactions.15 The 4-OH group of N-acetyl-
D-glucosamine is generally
O
O
BnO
BnO
BzO
AcHN
considered to have particularly low reactivity: according to com-
petition experiments the 4-OH of a 2-deoxy-2-azido-glucose de-
rivative was ten times more reactive than that of the corresponding
N-acetyl acceptor.15b Furthermore, the oxygen of the acetamido
groupmayact as a competitivenucleophile, leading tothe formation
of unstable glycosyl imidate side-products.16 The difficulties caused
by the N-acetyl group do not seem to be restricted to the glycosyl-
OMe
6
CO2tBu
CO2tBu
OBn
O
OBn
O
O
O
BnO
BnO
HO
O
O
BnO
SPh
+
BnO
BnO
BzO
BzO
AcHN
N3
OMe
7
8
ation of the N-acetyl-
ted synthesis of the tetrasaccharide 1, a complete inhibitory effect of
remote N-acetyl group upon glycosylations with tri-
chloroacetimidate donors has been observed, even when not the
GlcNAc unit itself was glycosylated, but it was present at the re-
ducing end of a disaccharide.17
D-glucosamine unit itself. Thus, in an attemp-
OBn
O
CO2tBu
OCA
OBn
O
O
a
1NAPO
BnO
O
HO
BnO
BnO
SPh
+
O
BnO
BnO
BzO
11
BzO
9
N3
10
OC(NH)CCl3
AcHN
OMe
The reactivity problems associated with the N-acetyl-
amine unit are further aggravated by the fact that, compared to
other monosaccharides, -glucuronic acid derivatives are known to
be unreactive glycosyl donors.18 Glycosylations with different types
of -glucuronosyl donors often fail completely or give the desired
glycoside in low yields accompanied by side-products, such as
D-glucos-
OCA
OBn
O
O
1NAPO
BnO
HO
SEt
+
D
BnO
BzO
12
AcHN
13
OMe
CA = C(O)CH2Cl
D
Scheme 1. Retrosynthesis of tetrasaccharide 5.

8038
K. Daragics, P. Fügedi / Tetrahedron 66 (2010) 8036e8046
The synthesis of the tetrasaccharide 5 was envisioned by
OH
1Naph
O
O
HO
O
a
O
b
d
a convergent 2þ2 block synthesis approach to afford the fully
SEt
O
SEt
SEt
BnO
BnO
OH
18
protected tetrasaccharide precursor
6
from the disaccharide
OH
19
building blocks 7 and 8 using thioglycoside glycosyl donors in the
key glycosylation steps (Scheme 1). The two, differently
OH
O
1Naph
O
BnO
1NAPO
BnO
c
O
SEt
N-substituted,
N-acetyl group itself for the reducing-end unit, and masking the
free amino group of the interchain -glucosamine as an azide. To
D-glucosamine units were distinguished by using the
OBz
OBz
20
21
D
assure 1,2-trans selectivity in glycosylations, the benzoyl group,
which is known to give cleaner reactions and be less prone to
orthoester formation than the commonly used acetyl group,22 was
selected for the protection of O-2 of the D-glucuronic acid units,
whereas benzyl groups were used for permanent protection at
other positions. The non-reducing end disaccharide building block
OCA
O
1NAPO
BnO
1Naph = 1-naphthyl
SEt
OBz
12
Scheme 3. Reagents and conditions: (a) 1NaphCH(OMe)2, CSA, DMF, 84%; (b) BzCl,
pyridine, 94%; (c) BH3$THF, TMSOTf, CH2Cl2, 90%; (d) (ClCH2CO)2O, Et3N, CH2Cl2,
-30 ꢀC, 87%.
(7) was planned to be prepared by reaction of the
D-glucuronic acid
-glucosamine acceptor 1327 and the 2-azido-2-
trichloroacetimidate 9 with the 2-azido-2-deoxy-
D
-glucose thio-
The N-acetyl-
D
-glucose acceptor 1028 were prepared by literature
glycoside acceptor (10). As discussed above, the synthesis of the
reducing-end unit 8 was expected to present difficulties. Therefore,
the synthesis was planned so that the critical glycosylations could
deoxy-
D
methods.
be performed both on the
level. Thus, preparation of disaccharide 8 was designed by oxida-
tion from 11, which should be accessible from the -glucose thio-
glycoside donor 12 and the N-acetyl- -glucosamine acceptor 13.
The selection of a pair of orthogonal protecting groups, (1-naph-
thyl)methyl (1NAP) and chloroacetyl (CA) for O-4 and O-6,
respectively, in 12 assured that the coupling leading to the tetra-
D-glucose and on the D-glucuronic acid
2.3. Synthesis of disaccharide building blocks
D
The synthesis of the non-reducing end disaccharide building
block 7 was smoothly accomplished by TMSOTf-catalyzed reaction
D
of the 2-O-benzoyl-protected -glucuronic acid imidate 9 with the
D
azido acceptor 10, the reaction provided the desired disaccharide
donor 7 in 89% yield (Scheme 4).
saccharide, can be performed both on D-glucose and D-glucuronic
acid acceptors prepared from the same intermediates.
CO2tBu
OBn
O
O
BnO
BnO
HO
2.2. Synthesis of monosaccharide building blocks
+
SPh
BnO
BzO
N3
OC(NH)CCl3
For the synthesis of compound 9, the known thioglycoside 1423
was first benzoylated to give 15 (Scheme 2). Reductive ring-open-
ing of the benzylidene acetal using BH3$THFeTMSOTf24 afforded
the 4-O-benzyl ether 16 in 89% yield. Oxidation of 16 with pyr-
idinium dichromate (PDC) in the presence of acetic anhydride and
9
10
a
CO2tBu
OBn
O
O
O
BnO
BnO
SPh
tert-butanol25 gave the tert-butyl
-glucuronate (17), which was
D
BnO
BzO
7
N3
converted to the corresponding trichloroacetimidate donor (9) in
two steps in 64% yield.
Scheme 4. Reagents and conditions: (a) TMSOTf, toluene, ꢁ30 ꢀC, 89%.
O
BnO
O
Ph
Ph
a
c
O
O
O
O
b
SEt
SEt
BnO
For the synthesis of the disaccharide glycosyl acceptor 8
OH
BzO
15
(Scheme 5), the glycosylation of the N-acetyl-
D-glucosamine ac-
14
ceptor 13 with the -glucose donor 12 was studied using different
D
OH
CO2tBu
promoters (Table 1). Reactions promoted by dimethyl(methylthio)
sulfonium triflate (DMTST),22 and dimethyl disulfide-triflic anhy-
dride29 gave 11 in 64% and 50% yield, respectively. The best yield
was obtained by using methyl triflate,30 in this reaction 11 was
obtained in 81% yield.
O
d-e
BnO
BnO
O
BnO
BnO
SEt
SEt
BzO
16
BzO
17
CO2tBu
O
BnO
BnO
BzO
9
CCl3
O
OCA
O
OCA
O
OBn
O
OBn
O
1NAPO
BnO
1NAPO
BnO
a
HO
NH
SEt
O
+
BnO
BnO
BzO
BzO
12
AcHN
13
AcHN
OMe
OMe
Scheme 2. Reagents and conditions: (a) BzCl, CH2Cl2, pyridine, 91%; (b) BH3$THF,
TMSOTf, CH2Cl2, 89%; (c) PDC, Ac2O, t-BuOH, CH2Cl2, 74%; (d) NBS, CH3CNeH2O 9:1,
65%; (e) CCl3CN, DBU, CH2Cl2, 0 ꢀC, 98%.
11
OH
O
CO2tBu
OBn
OBn
O
1NAPO
BnO
1NAPO
BnO
O
b
O
c
O
O
BnO
BnO
BzO
BzO
23
AcHN
AcHN
OMe
For the synthesis of the -glucose donor 12, the known triol
D
OMe
22
1823b,26 was reacted with 1-naphthaldehyde dimethyl acetal in the
presence of camphorsulfonic acid (CSA) to afford 19 (Scheme 3).
After benzoylation of the free hydroxyl group, regioselective
reductive opening of the (1-naphthyl)methylene acetal of 20 with
BH3$THFeTMSOTf gave the corresponding 4-O-(1-naphthyl)
methyl derivative 21 in 90% yield. Chloroacetylation of 21 afforded
CO2tBu
OBn
O
d
O
HO
O
BnO
BnO
BzO
AcHN
OMe
8
Scheme 5. Reagents and conditions: (a) see Table 1; (b) HDTC, DMF, 77%; (c) PDC,
Ac2O, t-BuOH, CH2Cl2, 73%; (d) CAN, MeCN-H2O 9:1, 77%.
the -glucose thioglycoside donor 12 in 87% yield.
D

K. Daragics, P. Fügedi / Tetrahedron 66 (2010) 8036e8046
8039
Table 1
disaccharide 11 (Table 1), gave none of the desired tetrasaccharide 6.
On the other hand, glycosylation of the disaccharide acceptor 8 with
the thioglycoside 7 using DMTST as promoter resulted stereo-
Reaction of donor 12 and acceptor 13 using different promoters
Entry
Promoter
Equiv of
promoter
(equiv)
Reaction
temperature
Reaction
time (h)
Isolated
yield of
11 (%)
selectively in the
(Scheme 8). In contrast to the glycosylation of the acceptor 23 with
the same donor, no -linked tetrasaccharide could be isolated from
this reaction. The successful glycosylation of the N-acetyl- -glu-
a-linked tetrasaccharide 6, isolated in 56% yield
1
2
3
DMTST
Me2S2eTf2O
MeOTf
4
1.5
4
0
ꢀC/rt
0 ꢀ
ꢀC/rt
4
2
4
64
50
81
b
C
D
0
cosamine-containing acceptor also suggests that the previously
reported inhibitory effect of the remote N-acetyl group might be
overcome by the appropriate choice of the donor and the promoter.
Removal of the temporary chloroacetyl protecting group by
hydrazinedithiocarbonate (HDTC)31 afforded the alcohol 22. Oxida-
tive esterification of 22 using PDC in the presence of acetic anhydride
CO2tBu
CO2tBu
OBn
O
OBn
O
O
O
BnO
BnO
HO
O
O
and tert-butanol afforded the tert-butyl uronate 23. The
D
-glucuronic
+
SPh
BnO
BnO
BnO
BzO
BzO
acid glycosyl acceptor 8 was obtained by oxidative removal of the
(1-naphthyl)methyl group with ceric ammonium nitrate (CAN)8b in
77% yield.
Another disaccharide acceptor containing a free hydroxyl group at
O-4 on a
N3
AcHN
OMe
7
a
8
CO2tBu
OBn
O
O
BnO
BnO
O
D-glucose unit was synthesized by removing the temporary
CO2tBu
OBn
BnO
BzO
O
N3
O
(1-naphthyl)methyl group of 11 by CAN to give 24 (Scheme 6).
O
O
BnO
6
BnO
BzO
AcHN
OMe
OCA
OBn
O
a
O
HO
Scheme 8. Reagents and conditions: (a) DMTST, Et2O, CH2Cl2, 56%.
O
11
BnO
BnO
BzO
AcHN
OMe
24
2.5. Preparation of the unprotected heparan sulfate
tetrasaccharide
Scheme 6. Reagents and conditions: (a) CAN, MeCNeH2O 9:1, 71%.
2.4. Synthesis of the protected tetrasaccharide
For the conversion of the protected tetrasaccharide 6 to the
target compound 5, 6 was first debenzoylated using sodium
hydroxide in tetrahydrofuranemethanol (Scheme 9). Under the
DMTST-promoted glycosylation of the
disaccharide acceptor 24 with the disaccharide thioglycoside 7
afforded the -linked tetrasaccharide 25 as the major product,
isolated in 40% yield (Scheme 7). The -linked tetrasaccharide 25
was also obtained in 14% yield. The anomeric configuration of 25
D-glucose-containing
conditions employed possible
b-elimination in the D-glucuronic
a
a
acid units was avoided. The tert-butyl uronates of 27 were hydro-
lyzed next with 20% trifluoroacetic acid in dichloromethane, and
then catalytic hydrogenation of 28 with palladium on carbon re-
moved the benzyl groups and reduced the azido group, to afford the
b
b
a
is
3
1
supported by the J1c,2c and JC-1c,H-1c coupling constants being
4.0 Hz and 176.5 Hz, respectively, whereas the corresponding
methyl a-glycoside of the heparan sulfate tetrasaccharide 5.
values for 25
b
were 9.5 Hz and 165.0 Hz.32
CO2tBu
CO2tBu
OBn
O
OBn
O
O
a
BnO
BnO
BnO
BnO
O
O
O
+
7
24
CO2tBu
OCA
O
BnO
BnO
OBn
O
OBn
O
BzO
BzO
N3
O
N3
O
O
O
O
BnO
BnO
BnO
BnO
BzO
BzO
AcHN
AcHN
25a
OMe
OMe
6
CO2tBu
OBn
a-c
O
BnO
BnO
O
O
b
OH
O
c
CO2R1
O
BnO
OR2
OBn
O
BzO
N
R2O
R2O
O
3O
O
O
BnO
CO2R1
O
BnO
R2O
OR2
O
BzO
AcHN
HO
R3
OMe
O
26
O
R2O
R2O
HO
AcHN
OMe
CO2tBu
OBn
O
27 R1 = tBu, R2 = Bn, R3 = N3
O
BnO
BnO
O
28 R1 = H, R2 = Bn, R3 = N3
5
CO2tBu
BnO
OBn
O
BzO
O
N3
O
R1 = H, R2 = H, R3 = NH2
O
BnO
BnO
BzO
AcHN
OMe
Scheme 9. Reagents and conditions: (a) NaOH, THF, MeOH, 64%; (b) TFA, CH2Cl2, 91%;
(c) PdeC, MeOH, 70%.
6
Scheme 7. Reagents and conditions: (a) DMTST, Et2O, CH2Cl2, 40%; (b) HDTC, DMF,
55%; (c) PDC, Ac2O, t-BuOH, CH2Cl2, 53%.
3. Conclusion
Removal of the temporary chloroacetyl protecting group from
25a
by HDTC then afforded the alcohol 26, which was oxidized to
The synthesis of the methyl a-glycoside (5) of the putative prion-
the desired tetrasaccharide 6.
associated tetrasaccharide 1 was accomplished in a highly stereo-
selective manner without masking the N-acetyl group at the reducing
end. Glycosylations, which are considered problematic in the litera-
ture were successfully accomplished. Thus, high-yielding glycosyla-
The direct route to 6 involved the glycosylation of the D-glucur-
onic acid-containing disaccharide acceptor 8 with the disaccharide
thioglycoside donor 7. Interestingly, methyl triflate-promoted
glycosylation, which afforded the best results in the preparation of
tion of the unreactive 4-OH group of an N-acetyl-D-glucosamine

8040
K. Daragics, P. Fügedi / Tetrahedron 66 (2010) 8036e8046
acceptor and
GlcpA-(1/4)-
a
D
-selective glycosylation of the 40-OH group of a
-GlcpNAc disaccharide building block were achieved
b-D-
4.3. Ethyl 2-O-benzoyl-3,4-di-O-benzyl-1-thio-b-D-
glucopyranoside (16)
by using thioglycoside glycosyl donors.
To a solution of 15 (5.06 g,10 mmol) in dry CH2Cl2 (80 mL), a 1 M
solution of borane in THF (20 mL, 20 mmol, 2 equiv) was added
followed by TMSOTf (0.27 mL, 1.5 mmol, 0.15 equiv) and the mix-
ture was stirred under argon at rt. After 3 h, TLC (tolueneeacetone,
9:1) indicated the disappearance of the starting material. Et3N
(5 mL) was added, followed by careful addition of MeOH (10 mL)
until the evolution of H2 ceased. The mixture was concentrated, and
the residue was co-evaporated with MeOH (35 mL) three times.
Purification of the residue by silica gel column chromatography
(tolueneeacetone, 95:5/9:1) afforded 16 as white crystals (4.52 g,
89%); Rf (tolueneeacetone, 9:1) 0.46; mp 91e92 ꢀC (from
4. Experimental
4.1. General methods
Evaporations were performed under reduced pressure on
rotary evaporators with bath temperatures not exceeding 40 ꢀC.
All reactions sensitive to air or moisture were carried out under
argon atmosphere with anhydrous solvents. Air- and moisture-
sensitive liquids and solutions were transferred via a syringe.
ꢀ
Molecular sieves (4 A) were flame dried before use. Dichloro-
methane was distilled from CaH2, and stored over 4 A molecular
ꢀ
EtOAcehexanes); [
1722, 1266, 1093, 1028, 710 cmꢁ1
8.04e7.10 (m, 15H, aromatic), 5.28 (dd, 1H, J1,2 10.0 Hz, J2,3 9.0 Hz,
a
]
D
þ33.5 (c 0.26, CHCl3); IR nmax (film): 2961,
sieves. Solvents used for column chromatography were of tech-
nical grade and distilled before use. Thin layer chromatography
(TLC) was performed on silica gel 60 F254 plates (E. Merck,
Darmstadt), the compounds were detected under UV light and by
spraying the plates with a 0.02 M solution of resorcinol in 20%
methanolic H2SO4 followed by heating. For column chromato-
graphy silica gel 60 (0.040e0.063 mm) (E. Merck) was employed.
Melting points were determined in capillary tubes on a Griffin
melting point apparatus and are uncorrected. Optical rotations
were measured at rt with an Optical Activity P-2000 (Jasco)
polarimeter. The IR spectra were recorded on a Thermo Nicolet
Avatar 320 FT-IR spectrometer. The NMR spectra were recorded
on Varian Unity Inova 5000 (1H: 500 MHz, 13C: 125 MHz), Varian
Unity Inova 3000 (1H: 300 MHz; 13C: 75 MHz), and Varian Unity
Inova 2000 (1H: 200 MHz; 13C: 50 MHz) spectrometers at ambi-
ent temperature in CDCl3, and assigned using 2D-methods (COSY,
HSQC). The chemical shifts were referenced to TMS (0.00 ppm for
1H) and to the central line of CDCl3 (77.0 ppm for 13C), and to the
methyl signal of acetone (2.22 ppm for 1H, 30.89 ppm for 13C) for
solutions in D2O, as internal standards. Elemental analyses were
performed with an Elementar Vario EL III instrument at the An-
alytical Department of the Chemical Research Center, Hungarian
Academy of Sciences.
;
1H NMR (200 MHz, CDCl3):
d
H-2), 4.86 (d, 1H, J 10.7 Hz, ½PhCH2), 4.82e4.71 (m, 2H, PhCH2),
4.68 (d, 1H, J 11.0 Hz, ½PhCH2), 4.57 (d, 1H, J1,2 10 Hz, H-1),
3.94e3.66 (m, 4H, H-3,4,6a,6b), 3.58 (ddd, 1H, J4,5 9.4 Hz, J5,6a
4.8 Hz, J5,6b 2.8 Hz, H-5), 2.70 (q, 2H, SCH2CH3), 2.02 (s, 1H, OH), 1.22
(t, 3H, J 7.5 Hz, SCH2CH3); 13C NMR (50 MHz, CDCl3):
d 165.3 (C(O)
Ph), 137.8, 137.7, 133.2, 129.8, 128.5, 128.4, 128.3, 128.1, 128.0, 127.7
(aromatic), 84.1 (C-1), 83.8 (C-3), 79.8 and 77.7 (C-4, C-5), 75.3 and
75.2 (2 PhCH2), 72.5 (C-2), 62.1 (C-6), 24.1 (SCH2CH3), 14.9
(SCH2CH3). Anal. Calcd for C29H32O6S: C, 68.48; H, 6.34; S, 6.30.
Found: C, 68.30; H, 6.36; S, 6.32.
4.4. tert-Butyl (ethyl 3,4-di-O-benzyl-2-O-benzoyl-1-thio-b-D-
glucopyranoside)uronate (17)
To a solution of 16 (4.07 g, 8 mmol) in dry CH2Cl2 (60 mL), PDC
(6.02 g, 16 mmol, 2 equiv), Ac2O (7.6 mL, 80 mmol, 10 equiv), and
tert-butyl alcohol (15.3 mL, 160 mmol, 20 equiv) were added. The
mixture was stirred for 3 h at rt, and it was then applied on the top
of a silica gel column having a layer of EtOAc. The chromium
compounds were allowed to precipitate in the presence of EtOAc
and after 30 min the product was eluted with EtOAc. After evapo-
rating the solvent, the residue was purified by column chroma-
tography (tolueneeacetone, 98:2/95:5) to give 17 as white
crystals (3.42 g, 74%); Rf (tolueneeacetone, 95:5) 0.71; mp
4.2. Ethyl 2-O-benzoyl-3-O-benzyl-4,6-O-benzylidene-1-thio-
b-D
-glucopyranoside (15)
109e110 ꢀC (from EtOAcehexanes); [
nmax (film): 2977, 1732, 1453, 1368, 1265, 1154, 1070, 1026, 750,
710 cmꢁ1 1H NMR (200 MHz, CDCl3):
8.04e7.10 (m, 15H, aro-
a
]
þ6.3 (c 0.41, CHCl3); IR
D
Benzoyl chloride (2.8 mL, 24 mmol, 2 equiv) was added
dropwise to a solution of 1423 (4.83 g, 12 mmol) in a mixture of
dry CH2Cl2 (25 mL) and dry pyridine (20 mL) at 0 ꢀC. The reaction
mixture was stirred at rt overnight, after which the reaction was
quenched with water (5 mL). The mixture was diluted with
CH2Cl2 (500 mL), was washed with 2 M aq HCl (200 mL),
saturated aq NaHCO3 (200 mL) and water (200 mL), dried, and
concentrated. Purification by column chromatography (toluenee
acetone, 95:5/9:1) afforded 15 as white crystals (5.52 g, 91%); Rf
(tolueneeacetone, 9:1) 0.84; mp 124e125 ꢀC (from EtOAce
;
d
matic), 5.34 (dd, 1H, J1,2 9.9 Hz, J2,3 8.6 Hz, H-2), 4.83 (d, 1H,
J 10.7 Hz, ½PhCH2), 4.77e4.69 (m, 2H, PhCH2), 4.64 (d, 1H, J 11.0 Hz,
½PhCH2), 4.56 (d, 1H, J1,2 9.9 Hz, H-1), 4.03e3.85 (m, 2H, H-4,5),
3.83 (dd, 1H, J2,3 8.6 Hz, J3,4 9.0 Hz, H-3), 2.73 (m, 2H, SCH2CH3), 1.49
(s, 9H, C(CH3)3), 1.23 (t, 3H, J 7.5 Hz, SCH2CH3); 13C NMR (50 MHz,
CDCl3): d 167.1 (C-6), 165.2 (C(O)Ph), 137.9, 137.6, 133.2, 129.8, 128.4,
128.3, 128.2, 128.0, 127.8, 127.71, 127.67 (aromatic), 84.0 and 83.4
(C-1, C-3), 82.4 (C(CH3)3), 79.5 (2C, C-4, C-5), 75.2 and 75.1
(2 PhCH2), 72.0 (C-2), 27.9 (C(CH3)3), 23.9 (SCH2CH3), 14.9
(SCH2CH3). Anal. Calcd for C33H38O7S: C, 68.49; H, 6.62; S, 5.54.
Found: C, 68.31; H, 6.64; S, 5.55.
hexanes); lit.23b 127 ꢀC; [
(c 0.10, CHCl3); lit.33
CDCl3):
a
]
þ26 (c 0.63, CHCl3); lit.23b
[
a
]
ꢁ50
D
D
[
a
]
þ25.5 (c 1, CHCl3); 1H NMR (200 MHz,
D
d
8.00e7.08 (m, 15H, aromatic), 5.62 (s, 1H, PhCH), 5.34
(dd, 1H, J1,2 10.1 Hz, J2,3 8.8 Hz, H-2), 4.83 (d, 1H, J 11.9 Hz,
½PhCH2), 4.68 (d, 1H, J 11.9 Hz, ½PhCH2), 4.62 (d, 1H, J1,2 10.1 Hz,
H-1), 4.41 (dd, 1H, J5,6a 4.8 Hz, J6a,6b 10.4 Hz, H-6a), 3.95e3.78 (m,
3H, H-3,4,6b), 3.56 (ddd, 1H, J4,5 2.8 Hz, J5,6a 4.8 Hz, J5,6b 9.4 Hz, H-
5), 2.72 (q, 2H, SCH2CH3), 1.22 (t, 3H, J 7.4 Hz, SCH2CH3); 13C NMR
4.5. tert-Butyl (2-O-benzoyl-3,4-di-O-benzyl-1-O-
trichloroacetimidoyl-a-D-glucopyranose)uronate (9)
To a solution of 17 (2.72 g, 4.7 mmol) in 95% aq MeCN (30 mL),
N-bromosuccinimide (0.962 g, 5.4 mmol, 1.15 equiv) was added
at 0 ꢀC. After stirring for 30 min at rt, the reaction mixture was
quenched with saturated aq Na2S2O3 solution, diluted and extrac-
ted with CH2Cl2, washed with water, dried, and concentrated.
Purification by column chromatography (tolueneeacetone,
95:5/9:1) afforded the crude hemiacetal as white crystals (1.64 g,
(50 MHz, CDCl3):
d 165.3 (C(O)Ph), 137.9, 137.3, 133.3, 130.0, 129.9,
129.2, 128.5, 128.4, 128.3, 128.2, 127.7, 126.1 (aromatic), 101.4
(PhCH), 84.4 (C-1), 81.8 and 79.3 (C-3, C-4), 74.3 (PhCH2), 72.5
(C-2), 70.8 (C-5), 68.6 (C-6), 24.1 (SCH2CH3), 14.9 (SCH2CH3). Anal.
Calcd for C29H30O6S: C, 68.75; H, 5.97; S, 6.33. Found: C, 68.57; H,
5.98; S, 6.35.

K. Daragics, P. Fügedi / Tetrahedron 66 (2010) 8036e8046
8041
65%); mp 139e140 ꢀC (from EtOAcehexanes); [
a]
þ77 (c 0.52,
J 11.8 Hz, ½PhCH2), 4.51 (dd, 1H, J5,6a 4.9 Hz, J6a,6b 10.4 Hz, H-6a),
4.04e3.86 (m, 3H, H-3,4,6b), 3.69 (ddd, 1H, J4,5 9.5 Hz, J5,6a 4.9 Hz,
J5,6b 9.6 Hz, H-5), 2.76 (dq, 2H, J 7.5 Hz, SCH2CH3), 1.24 (t, 3H,
D
CHCl3). The hemiacetal was then dissolved in dry CH2Cl2 (20 mL) at
0 ꢀC under argon, followed by addition of CCl3CN (3.0 mL, 30 mmol,
10 equiv) and DBU (0.114 mL, 0.76 mmol, 0.25 equiv). After stirring
for 1 h at 0 ꢀC, TLC showed completion of reaction and the product
was purified by flash chromatography over a short silica gel column
(hexaneseEtOAc 4:1, þ1% Et3N) to yield 9 (2.04 g, 98%) as a color-
J 7.5 Hz, SCH2CH3); 13C NMR (50 MHz, CDCl3):
d 165.2 (C(O)Ph),
137.8, 133.9, 133.2, 132.4, 130.0, 129.9, 128.7, 128.4, 128.1, 127.6,
126.4, 125.8, 125.1, 124.2, 124.0 (aromatic), 100.5 (1NaphCH), 84.5
(C-1), 82.2 and 79.4 (C-3, C-4), 74.4 (PhCH2), 72.1 (C-2), 70.9 (C-5),
69.0 (C-6), 24.1 (SCH2CH3), 14.9 (SCH2CH3). Anal. Calcd for
C33H32O6S: C, 71.20; H, 5.79; S, 5.76. Found: C, 71.01; H, 5.81; S, 5.77.
less syrup (pure
a
-product); Rf (hexaneseEtOAc 4:1, þ0.5% Et3N)
0.41; [
a
]
D þ78 (c 1.02, CHCl3); 1H NMR (200 MHz, CDCl3):
d 8.53 (s,
1H, NH), 7.96e7.92 (dd, 2H, aromatic), 7.56e7.16 (m, 13H, aromatic),
6.66 (d, 1H, J1,2 3.6 Hz, H-1), 5.40 (dd, 1H, J1,2 3.6 Hz, J2,3 9.8 Hz, H-2),
4.88 (d, 1H, J 10.5 Hz, ½PhCH2), 4.79 (2d, 2H, J 11.0 Hz, PhCH2), 4.71
(d, 1H, J 10.5 Hz, ½PhCH2), 4.42e4.21 (m, 2H, H-4,5), 4.02 (dd, 1H,
J2,3 9.8 Hz, J3,4 9.4 Hz, H-3), 1.48 (s, 9H, C(CH3)3); 13C NMR (50 MHz,
4.8. Ethyl 2-O-benzoyl-3-O-benzyl-4-O-(1-naphthyl)methyl-
1-thio-b-D-glucopyranoside (21)
To a solution of 20 (2.50 g, 4.5 mmol) in dry CH2Cl2 (20 mL),
a 1 M solution of borane in THF (9 mL, 9 mmol, 2 equiv) was added
followed by TMSOTf (0.12 mL, 0.67 mmol, 0.15 equiv) and the
mixture was stirred under argon at rt. After 3 h, TLC (toluene-
eacetone, 9:1) indicated the disappearance of the starting material.
Et3N (2 mL) was added, followed by careful addition of MeOH
(5 mL) until the evolution of H2 ceased. The mixture was concen-
trated and the residue was co-evaporated with MeOH (25 mL) three
times. Purification of the residue by silica gel column chromatog-
raphy (tolueneeacetone, 95:5/9:1) afforded 21 as white crystals
(2.26 g, 90%); Rf (tolueneeacetone, 9:1) 0.35; mp 122e123 ꢀC (from
CDCl3):
d 167.4 (C-6), 165.5 (C(O)Ph), 160.5 (CNH), 137.8, 133.4,
129.9, 129.3, 128.5 (2C), 128.4, 128.1, 128.0, 127.9 and 127.8 (aro-
matic), 93.9 (C-1), 82.8 (C(CH3)3), 79.4 and 78.7 (C-3, C-4), 75.60
and 75.55 (2 PhCH2), 74.1 (C-5), 72.4 (C-2), 28.0 (C(CH3)3); MS-ESI:
[MþNa]þ 700.3. Anal. Calcd for C33H34Cl3NO8: C, 58.38; H, 5.05; N,
2.06. Found: C, 58.19; H, 5.08; N, 2.07.
4.6. Ethyl 3-O-benzyl-4,6-O-(1-naphthyl)methylene-1-thio-
b-
D
-glucopyranoside (19)
To a solution of 1823b,26 (3.77 g, 12 mmol) in dry DMF (25 mL),
EtOAcehexanes); lit.24 mp 119e120 ꢀC; [
lit.24
D þ54 (c 0.47, CHCl3); IR nmax (film): 2959, 1726, 1267, 1070,
775, 710 cmꢁ1 1H NMR (200 MHz, CDCl3):
8.08e7.96 (m, 3H,
aromatic), 7.90e7.78 (m, 2H, aromatic), 7.60e7.38 (m, 7H, aro-
matic), 7.16e7.10 (m, 5H, aromatic), 5.41 (d, 1H, 11.7 Hz,
a]
þ56 (c 0.50, CHCl3);
D
1-naphthaldehyde dimethyl acetal (3.8 mL, 18 mmol, 1.5 equiv),
and CSA (0.28 g, 1.2 mmol) were added. The mixture was stirred at
50 ꢀC under reduced pressure (30 mbar) for 4 h, neutralized with
saturated aq NaHCO3 (10 mL), and concentrated. To the residue,
hexanes (100 mL) and water (100 mL) were added, and the mixture
was stirred overnight. The precipitated crystalline material was
filtered off and crystallized from EtOAcehexanes to afford 19 as
white crystals (4.57 g, 84%); Rf (tolueneeacetone, 9:1) 0.48; mp
[a]
;
d
J
½NaphCH2), 5.33 (dd, 1H, J2,3 8.8 Hz, H-2), 5.12 (d, 1H,
J 11.7 Hz, ½NaphCH2), 4.74 (2d, 2H, J 11.0 Hz, PhCH2), 4.58 (d, 1H, J1,2
10.2 Hz, H-1), 3.93 (dd, 1H, J3,4 9.2 Hz, H-3), 3.83 (dd, 1H, J4,5 9.5 Hz,
H-4), 3.77 (m, 1H, H-6a), 3.62 (dd, 1H, J 2.6 Hz, J 7.3 Hz, H-6b), 3.48
(m,1H, H-5), 2.72 (q, 2H, J 7.4 Hz, SCH2CH3),1.88 (t,1H, J 6.6 Hz, OH),
170e171 ꢀC; [
a
]
ꢁ12 (c 0.23, CHCl3); 1H NMR (200 MHz, CDCl3):
D
d
8.18e8.12 (dd, 1H, aromatic), 7.90e7.75 (m, 3H, aromatic),
1.25 (t, 3H, J 7.4 Hz, SCH2CH3); 13C NMR (50 MHz, CDCl3):
d 165.4 (C
7.54e7.24 (m, 8H, aromatic), 6.12 (s, 1H, 1NaphCH), 4.88 (d, 1H,
J 11.5 Hz, ½PhCH2), 4.72 (d, 1H, J 11.5 Hz, ½PhCH2), 4.52 (d, 1H, J1,2
9.7 Hz, H-1), 4.46 (dd, 1H, J5,6a 4.8 Hz, J6a,6b 10.4 Hz, H-6a),
3.96e3.83 (m, 2H, H-4,6b), 3.74e3.62 (m, 3H, H-2,3,5), 2.75 (q, 2H,
J 7.5 Hz, SCH2CH3), 2.56 (d, 1H, J2,OH 1.8 Hz, OH), 1.32 (t, 3H, J 7.5 Hz,
(O)Ph), 137.9 133.9, 133.8, 133.3, 131.6, 129.9, 129.0, 128.8, 128.6,
128.4, 128.0, 127.8, 126.8, 126.5, 126.0, 125.4, 123.8 (aromatic), 84.6
(C-1), 83.9 (C-3), 79.9 and 77.6 (C-4, C-5), 75.3 (PhCH2), 73.0
(PhCH2), 72.8 (C-2), 62.2 (C-6), 24.2 (SCH2CH3), 15.0 (SCH2CH3).
Anal. Calcd for C33H34O6S: C, 70.94; H, 6.13; S, 5.74. Found: C, 70.79;
H, 6.15; S, 5.76.
SCH2CH3); 13C NMR (50 MHz, CDCl3):
d 138.3, 133.9, 132.5, 130.6,
129.9, 128.7, 128.5, 128.2, 127.9, 126.4, 125.8, 125.1, 124.2, 124.0
(aromatic), 100.4 (1NaphCH), 86.8 (C-1), 81.8 and 81.6 (C-3, C-4),
74.8 (PhCH2), 73.2 (C-2), 70.9 (C-5), 69.0 (C-6), 24.6 (SCH2CH3), 15.3
(SCH2CH3). Anal. Calcd for C26H28O5S: C, 69.00; H, 6.24; S, 7.08.
Found: C, 68.82; H, 6.26; S, 7.10.
4.9. Ethyl 2-O-benzoyl-3-O-benzyl-6-O-chloroacetyl-4-O-
(1-naphthyl)methyl-1-thio-b-D-glucopyranoside (12)
To a stirred solution of 21 (1.90 g, 3.4 mmol) in dry CH2Cl2
(20 mL), Et3N (0.94 mL, 6.8 mmol, 2 equiv) was added, then a so-
lution of 90% chloroacetic anhydride (0.70 g, 3.7 mmol) in dry
CH2Cl2 (5 mL) was added dropwise at ꢁ30 ꢀC. The mixture was
stirred for 30 min at ꢁ30 ꢀC under argon, after which the reaction
was quenched with water (5 mL), diluted with CH2Cl2 (400 mL),
washed with 2 M aq HCl (150 mL), saturated aq NaHCO3 (150 mL)
and water (150 mL), dried, and concentrated. The residue was pu-
rified by column chromatography (tolueneeacetone, 95:5/9:1) to
give 12 as white crystals (1.88 g, 87%); Rf (tolueneeacetone, 9:1)
4.7. Ethyl 2-O-benzoyl-3-O-benzyl-4,6-O-(1-naphthyl)
methylene-1-thio-b-D-glucopyranoside (20)
Benzoyl chloride (0.87 mL, 7.5 mmol, 1.5 equiv) was added
dropwise to a solution of 19 (2.26 g, 5 mmol) in a mixture of dry
CH2Cl2 (10 mL) and dry pyridine (10 mL) at 0 ꢀC. The mixture was
stirred at rt overnight, after which the reaction was quenched with
water (5 mL). The mixture was diluted with CH2Cl2 (300 mL),
washed with 2 M aq HCl (150 mL), saturated aq NaHCO3 (150 mL)
and water (150 mL), dried, and concentrated. The residue was pu-
rified by column chromatography (tolueneeacetone, 95:5/9:1) to
give 20 as white crystals (2.62 g, 94%); Rf (tolueneeacetone, 9:1)
0.58; mp 89e90 ꢀC (from EtOAcehexanes); [
CHCl3); IR nmax (film): 2349, 1724, 1632, 1451, 1267, 1167, 1089, 1026,
773, 710 cmꢁ1 1H NMR (500 MHz, CDCl3):
8.06e8.02 (dd, 2H,
a
]
þ85 (c 0.28,
D
;
d
aromatic), 7.99e7.96 (dd, 1H, aromatic), 7.88e7.81 (m, 2H, aro-
matic), 7.59e7.38 (m, 7H, aromatic), 7.18e7.13 (m, 5H, aromatic),
5.40 (d,1H, J 11.8 Hz, ½NaphCH2), 5.34 (dd,1H, J1,2 9.9 Hz, J2,3 8.8 Hz,
H-2), 5.07 (d, 1H, J 11.8 Hz, ½NaphCH2), 4.76 (2d, 2H, J 11.9 Hz,
PhCH2), 4.54 (d, 1H, J1,2 9.9 Hz, H-1), 4.31 (dd, 1H, J5,6a 2.0 Hz, J6a,6b
11.8 Hz, H-6a), 3.99 (dd, 1H, J5,6b 4.4 Hz, H-6b), 3.94 (dd, 1H, J3,4
8.8 Hz, H-3), 3.87 (d, 1H, J 14.9 Hz, CH2Cl), 3.79 (dd, 1H, J3,4 8.8 Hz,
J4,5 9.9 Hz, H-4), 3.76 (d,1H, J 14.9 Hz, CH2Cl), 3.60 (m, 1H, H-5), 2.66
0.80; mp 145e147 ꢀC (from EtOAcehexanes), [
CHCl3); IR nmax (film): 2871, 1727, 1453, 1268, 1105, 1070, 1026, 755,
710 cmꢁ1 1H NMR (200 MHz, CDCl3):
8.20e8.14 (dd, 1H, aro-
a]
þ45 (c 0.95,
D
;
d
matic), 8.05e7.99 (dd, 1H, aromatic), 7.92e7.78 (m, 3H, aromatic),
7.62e7.42 (m, 7H, aromatic), 7.12e6.99 (m, 5H, aromatic), 6.14 (s,
1H, 1NaphCH), 5.39 (dd, 1H, J1,2 10.0 Hz, J2,3 8.4 Hz, H-2), 4.75 (d, 1H,
J 11.8 Hz, ½PhCH2), 4.66 (d, 1H, J1,2 10.0 Hz, H-1), 4.58 (d, 1H,

8042
K. Daragics, P. Fügedi / Tetrahedron 66 (2010) 8036e8046
(m, 2H, SCH2CH3), 1.19 (t, 3H, J 7.5 Hz, SCH2CH3); 13C NMR
(125 MHz, CDCl3): 166.5 (C(O)CH2Cl), 165.2 (C(O)Ph), 137.4, 133.6,
(1 g) in dry CH2Cl2 (10 mL) at 0 ꢀC under argon. The reaction mix-
ture was stirred at 0 ꢀC, after 2 h the reaction was quenched with
Et3N (1 mL). Processing the mixture as above afforded 11 (0.49 g,
50%) as white crystals.
d
133.2,133.1, 131.5, 129.8, 129.7,129.0,128.7,128.4, 128.3, 127.9,127.7,
127.1, 126.5, 125.9, 125.2, 123.5 (aromatic), 84.7 (C-3), 83.5 (C-1),
76.7 (C-5), 76.0 (C-4), 75.3 (CH2Ph), 72.5 (NaphCH2), 72.3 (C-2), 64.3
(C-6), 40.5 (CH2Cl), 24.0 (SCH2CH3), 14.9 (SCH2CH3). Anal. Calcd for
C35H35ClO7S: C, 66.18; H, 5.55; S, 5.05. Found: C, 66.01; H, 5.57; S,
5.06.
4.11.3. Using MeOTf as promoter (Table 1, entry 3). A mixture of 12
(0.62 g, 0.98 mmol, 1.3 equiv), 13 (0.31 g, 0.75 mmol), and activated
ꢀ
ꢀ
4 A molecular sieves (1 g) was stirred in dry CH2Cl2 (10 mL) at 0 C
under argon for 30 min, then MeOTf (0.43 mL, 3.9 mmol, 4 equiv)
was added and the reaction mixture was allowed to come to rt.
After 4 h, the reaction was quenched with Et3N (1 mL). Processing
the mixture as above gave 11 (0.60 g, 81%) as white crystals.
Rf (tolueneeacetone, 3:1) 0.39; mp 166e167 ꢀC (from
4.10. Phenyl [tert-butyl (2-O-benzoyl-3,4-di-O-benzyl-
glucopyranosyl)uronate]-(1/4)-(2-azido-3,6-di-O-benzyl-2-
deoxy-1-thio- -glucopyranoside) (7)
b-D-
b-D
A
mixture of
9
(2.04 g, 3 mmol, 1.36 equiv), 10 (1.05 g,
EtOAcehexanes); [
2349, 1731, 1655, 1509, 1452, 1364, 1266, 1071, 1026, 753, 711 cmꢁ1
1H NMR (300 MHz, CDCl3):
8.02e7.92 (m, 4H, aromatic),
a
]
þ93 (c 0.29, CHCl3); IR nmax (film): 2896,
D
ꢀ
2.2 mmol), and freshly activated 4 A molecular sieves (2 g) in dry
toluene (30 mL) was stirred at ꢁ30 ꢀC under argon for 30 min. Then
TMSOTf (0.136 mL, 0.75 mmol, 0.25 equiv) was added dropwise.
After stirring at ꢁ30 ꢀC for 1 h, the reaction was quenched by the
addition of Et3N (2 mL). The mixture was filtered through a pad of
Celite, the filtrate was diluted with CH2Cl2 (400 mL) and washed
with 2 M aq HCl (150 mL), saturated aq NaHCO3 (150 mL), and
water (150 mL); it was dried and concentrated. The residue was
purified by silica gel column chromatography (hexaneseEtOAc,
9:1/4:1) to provide disaccharide 6 (1.94 g, 89%) as a colorless
;
d
7.64e7.08 (m, 23H, aromatic), 5.35 (d, 1H, J 11.9 Hz, ½NaphCH2),
5.29 (dd, 1H, J2b,1b 9.2 Hz, J2b,3b 8.3 Hz, H-2b), 5.16 (d, 1H, JNH,2a
8.8 Hz, NH), 5.02 (d, 1H, J 11.9 Hz, ½NaphCH2), 4.86 (d, 1H, J 12.4 Hz,
½PhCH2), 4.77 (d, 1H, J 12.2 Hz, ½PhCH2), 4.74 (d, 1H, J 10.9 Hz,
½PhCH2), 4.68e4.61 (m, 2H, H-1b, ½PhCH2), 4.59 (d, 1H, J1a,2a
3.5 Hz, H-1a), 4.51 (d, 1H, J 12.4 Hz, ½PhCH2), 4.35 (d, 1H, J 12.2 Hz,
½PhCH2), 4.14 (ddd, 1H, J2a,1a 3.5 Hz, J2a,3a 10.2 Hz, JNH,2a 8.8 Hz,
H-2a), 4.12e3.93 (m, 2H, H-6b,6b0), 3.98 (dd, 1H, J4a,3a 9.0 Hz, J4a,5a
9.6 Hz, H-4a), 3.76e3.66 (m, 3H, H-3b,4b,5b), 3.58 (2d, 2H, J 14.9 Hz,
CH2Cl), 3.54e3.36 (m, 4H, H-3a,5a,6a,6a0), 3.18 (s, 3H, OCH3), 1.71 (s,
syrup; Rf (hexaneseEtOAc, 4:1) 0.46; [
NMR (500 MHz, CDCl3):
a
]
D ꢁ18.5 (c 0.38, CHCl3); 1H
d
7.90e7.87 (dd, 2H, aromatic), 7.55e7.05
(m, 28H, aromatic), 5.31 (dd, 1H, J2d,3d 9.1 Hz, J2d,1d 8.3 Hz, H-2d),
5.11 (d, 1H, J 11.1 Hz, ½PhCH2), 4.82 (d, 1H, J1d,2d 8.3 Hz, H-1d), 4.80
(d, 1H, J 10.3 Hz, ½PhCH2), 4.74e4.62 (m, 4H, 2 PhCH2), 4.58 (d, 1H, J
11.2 Hz, ½PhCH2), 4.37 (d, 1H, J 12.1 Hz, ½PhCH2), 4.22 (d, 1H, J1c,2c
10.2 Hz, H-1c), 4.01 (dd, 1H, J4d,3d 9.0 Hz, J4d,5d 9.1 Hz, H-4d), 3.97
(dd, 1H, J4c,3c 9.0 Hz, J4c,5c 9.4 Hz, H-4c), 3.82 (d, 1H, J4d,5d 9.1 Hz,
H-5d), 3.69 (dd, 1H, J3d,2d 9.1 Hz, J3d,4d 9.0 Hz, H-3d), 3.66 (dd, 1H,
3H, CH3C(O)NH); 13C NMR (75 MHz, CDCl3):
d 169.6 (NHC(O)CH3),
166.5 (C(O)CH2Cl), 164.8 (C(O)Ph), 139.3, 138.2, 137.5, 133.7, 133.4,
133.2, 131.5, 129.7, 129.6, 128.9, 128.7, 128.63, 128.56, 128.3, 128.1,
128.06, 127.99, 127.9, 127.8, 127.6, 127.4, 126.9, 126.5, 125.9, 125.2,
123.6 (aromatic), 100.2 (C-1b), 98.3 (C-1a), 83.3 (C-3b), 77.3 and
77.1 (C-3a, C-4b), 76.7 (C-5b), 75.2 (PhCH2), 74.1 (C-4a), 73.9 and
73.6 (2 PhCH2), 72.40 (NaphCH2), 72.37 (C-2b), 70.2 (C-5a), 67.6
(C-6a), 64.1 (C-6b), 55.0 (OCH3), 52.2 (C-2a), 40.4 (CH2Cl), 23.2
(CH3C(O)NH). Anal. Calcd for C56H58ClNO13: C, 68.04; H, 5.91; N,
1.42. Found: C, 67.90; H, 5.93; N, 1.41.
J5c,6c 3.3 Hz, J6c,6c 11.2 Hz, H-6c), 3.49 (dd, 1H, J5c,6c 1.4 Hz, H-6c0),
3.39 (dd, 1H, J3c,2c 9.5 Hz, J3c,4c 9.0 Hz, H-3c), 3.27 (dd, 1H, J2c,3c
9.5 Hz, J2c,1c 10.2 Hz, H-2c), 3.09 (m, 1H, H-5c), 1.40 (s, 9H, C(CH3)3);
0
0
13C NMR (125 MHz, CDCl3):
d 167.0 (C-6d), 164.6 (C(O)Ph), 138.1,
137.9, 137.8, 137.4, 133.3, 133.2, 131.1, 129.5, 129.3, 128.9, 128.8,
128.48, 128.45, 128.40, 128.2, 128.12, 128.10, 128.08, 127.81, 127.77,
127.6, 127.5, 127.4, 125.2 (aromatic), 100.3 (C-1d), 86.0 (C-1c), 82.4
(C(CH3)3), 82.3 (C-3c), 81.6 (C-3d), 79.6 (C-4d), 78.6 (C-5c), 76.0
(C-4c), 75.6 (C-5d), 75.3, 74.8, and 74.7 (3CH2Ph), 73.6 (C-2d), 73.4
(CH2Ph), 67.5 (C-6c), 64.6 (C-2c), 27.8 (C(CH3)3). Anal. Calcd for
C57H59N3O11S: C, 68.86; H, 5.98; N, 4.23; S, 3.23. Found: C, 68.70; H,
6.00; N, 4.22; S, 3.24.
4.12. Methyl [2-O-benzoyl-3-O-benzyl-4-O-(1-naphthyl)
methyl-b-
D-glucopyranosyl]-(1/4)-(2-acetamido-3,6-di-O-
benzyl-2-deoxy-a-D-glucopyranoside) (22)
To a solution of 11 (0.69 g, 0.7 mmol) in dry DMF (10 mL),
a 0.417 M solution of HDTC31 (5.0 mL, 2.1 mmol, 3 equiv) in etha-
nolewateredioxane (4:2:1) was added. The mixture was stirred at
rt for 30 min, diluted with CH2Cl2 (300 mL), washed with 2 M aq
HCl (100 mL), saturated aq NaHCO3 (100 mL), and water (100 mL);
it was dried, and concentrated. The residue was purified by column
chromatography (tolueneeacetone, 4:1) to give 22 as white crystals
(0.49 g, 77%); Rf (tolueneeacetone, 2:1) 0.27; mp 158 ꢀC (from
4.11. Methyl [2-O-benzoyl-3-O-benzyl-6-O-chloroacetyl-4-O-
(1-naphthyl)methyl-
acetamido-3,6-di-O-benzyl-2-deoxy-
b
-
D
-glucopyranosyl]-(1/4)-(2-
-glucopyranoside) (11)
a-D
EtOAcehexanes); [
1729, 1654, 1541, 1453, 1364, 1267, 1071, 1047, 772, 700 cmꢁ1
NMR (500 MHz, CDCl3): 7.98e7.77 (m, 4H, aromatic), 7.61e7.02
a
]
þ69 (c 0.35, CHCl3); IR nmax (film): 2349,
D
4.11.1. Using DMTST as promoter (Table 1, entry 1). A mixture of 12
;
1H
(0.83 g,1.3 mmol,1.3 equiv),1327 (0.42 g,1 mmol), and activated 4 A
d
ꢀ
molecular sieves (1 g) was stirredin dry CH2Cl2 (10 mL) at 0 ꢀC under
argon for 30 min, then DMTST (1.34 g, 5.2 mmol, 4 equiv) was added
and the reaction temperature was allowed to reach rt. After 4 h, the
reaction was quenched with Et3N (1 mL). The mixture was filtered
through a pad of Celite, the filtrate was diluted with CH2Cl2 (300 mL)
and washed with 2 M aq HCl (125 mL), saturated aq NaHCO3
(125 mL) and water (125 mL), dried, and concentrated. The residue
was purified by column chromatography (tolueneeacetone,
9:1/3:1) to give 11 as white crystals (0.63 g, 64%).
(m, 23H, aromatic), 5.29 (d, 1H, J 11.6 Hz, ½NaphCH2), 5.27e5.22
(m, 2H, NH, ½NaphCH2), 5.19 (dd, 1H, J2b,3b 9.2 Hz, J2b,1b 8.4 Hz, H-
2b), 5.02 (d, 1H, J 11.7 Hz, ½PhCH2), 4.84 (d, 1H, J 12.0 Hz, ½PhCH2),
4.69 (d, 1H, J1b,2b 8.4 Hz, H-1b), 4.64 (d, 1H, J 12.2 Hz, ½PhCH2), 4.57
(d, 1H, J1a,2a 3.6 Hz, H-1a), 4.54e4.44 (m, 2H, PhCH2), 4.28 (d, 1H,
J 12.2 Hz, ½PhCH2), 4.10 (ddd, 1H, J2a,1a 3.6 Hz, J2a,3a 10.4 Hz, JNH,2a
8.7 Hz, H-2a), 3.92 (dd, 1H, J4a,3a 9.2 Hz, J4a,5a 9.2 Hz, H-4a),
3.63e3.50 (m, 4H, H-3b,5b,6a,6b), 3.45 (dd, 1H, J3a,4a 9.2 Hz, J3a,2a
10.4 Hz, H-3a), 3.38e3.29 (m, 2H, H-4b,5a), 3.26e3.17 (m, 2H, H-
6a0,6b0), 3.15 (s, 3H, OCH3), 1.76 (s, 3H, CH3C(O)NH), 1.71 (br s, 1H,
4.11.2. Using Me2S2eTf2O as promoter (Table 1, entry 2). A 1 M so-
lution of Me2S2eTf2O (1.9 mL, 1.9 mmol, 1.5 equiv) in dry CH2Cl2
OH); 13C NMR (125 MHz, CDCl3):
d 169.7 (NHC(O)CH3), 165.0 (C(O)
Ph), 138.7, 137.9, 137.6, 133.6, 133.5, 133.2, 131.3, 129.7, 129.5, 128.8,
128.7, 128.6, 128.57, 128.46, 128.4, 128.2, 128.1, 128.0, 127.7, 127.63,
127.58, 126.4, 126.3, 125.8, 125.6, 125.2, 123.6 (aromatic), 100.2
was added to
a mixture containing 12 (0.80 g, 1.26 mmol,
ꢀ
1.26 equiv), 13 (0.42 g, 1 mmol), and activated 4 A molecular sieves

K. Daragics, P. Fügedi / Tetrahedron 66 (2010) 8036e8046
8043
(C-1b), 98.5 (C-1a), 82.9 (C-3b), 78.0 and 77.6 (C-3a, C-4b), 76.8 and
75.4 (C-4a, C-5b), 75.0, 74.5, and 74.3 (3 PhCH2), 73.6 (C-2b), 72.7
(NaphCH2), 70.3 (C-5a), 67.5 (C-6a), 61.8 (C-6b), 55.1 (OCH3), 52.2
(C-2a), 23.3 (CH3C(O)NH). Anal. Calcd for C54H57NO12: C, 71.11; H,
6.30; N, 1.54. Found: C, 70.96; H, 6.32; N, 1.55.
J4b,5b 9.4 Hz, H-5b), 3.50 (dd, 1H, J3a,4a 8.9 Hz, J3a,2a 9.2 Hz, H-3a),
3.48 (dd, 1H, J3b,4b 9.2 Hz, J3b,2b 8.1 Hz, H-3b), 3.42 (m, 1H, H-5a),
3.36 (dd, 1H, J5a,6a 1.8 Hz, J6a,6a 10.9 Hz, H-6a0), 3.17 (s, 3H, OCH3),
1.72 (s, 3H, CH3C(O)NH), 1.43 (s, 9H, C(CH3)3); 13C NMR (75 MHz,
0
0
CDCl3):
d 169.8 (NHC(O)CH3), 168.2 (C-6b), 164.8 (C(O)Ph), 139.3,
138.0, 137.9, 133.2, 129.7, 129.5, 129.0, 128.6, 128.5, 128.41, 128.36,
128.3, 128.24, 128.16, 128.1, 128.02, 128.01, 127.9, 127.8, 127.74,
127.68, 127.6, 127.5, 127.4, 125.2 (aromatic), 100.4 (C-1b), 98.2 (C-
1a), 83.3 (C(CH3)3), 81.0 (C-3b), 77.4 (C-3a), 77.2 (C-4a), 74.5 (C-5b),
74.3, 74.0, and 73.5 (3CH2Ph), 73.1 (C-2b), 72.6 (C-4b), 70.0 (C-5a),
67.5 (C-6a), 55.0 (OCH3), 52.2 (C-2a), 27.8 (C(CH3)3), 23.2 (CH3C(O)
NH). Anal. Calcd for C47H55NO13: C, 67.05; H, 6.58; N, 1.66. Found: C,
66.91; H, 6.60; N, 1.66.
4.13. Methyl {tert-butyl [2-O-benzoyl-3-O-benzyl-4-O-
(1-naphthyl)methyl-b-D-glucopyranosyl]uronate}-(1/4)-
(2-acetamido-3,6-di-O-benzyl-2-deoxy-a-D-glucopyranoside)
(23)
To a solution of 22 (0.46 g, 0.5 mmol) in dry CH2Cl2 (10 mL), PDC
(0.38 g, 1 mmol, 2 equiv), Ac2O (0.47 mL, 5 mmol, 10 equiv), and tert-
butyl alcohol (0.96 mL, 10 mmol, 20 equiv) were added. The mixture
wasstirred atrtfor6 h, anditwasthenappliedonthetopofasilicagel
column in EtOAc with a 10 cm layer of EtOAc on top of the gel. The
chromium compounds were allowed to precipitate in the presence of
EtOAc and, after 30 min, the product was eluted with EtOAc. After
evaporating the solvent, the residue was purified by column chro-
matography (tolueneeacetone, 4:1/3:1) to give 23 as white crystals
(0.36 g, 73%); Rf (tolueneeacetone, 2:1) 0.32; mp 84e85 ꢀC (from
4.15. Methyl (2-O-benzoyl-3-O-benzyl-6-O-chloroacetyl-
glucopyranosyl)-(1/4)-(2-acetamido-3,6-di-O-benzyl-2-
deoxy- -glucopyranoside) (24)
b-D-
a-D
To a solution of 11 (0.49 g, 0.5 mmol) in MeCNewater (10 mL,
9:1), CAN (0.82 g, 1.5 mmol, 3 equiv) was added. The mixture was
stirred at rt for 1 h, then it was diluted with CH2Cl2 (200 mL),
washed with saturated aq NaHCO3 (75 mL), brine (75 mL), and
water (75 mL); it was dried and concentrated. The residue was
purified by column chromatography (tolueneeacetone, 4:1) to give
24 as white crystals (0.30 g, 71%); Rf (tolueneeacetone, 2:1) 0.28;
EtOAcehexanes); [
1737, 1666, 1539, 1453, 1368, 1266, 1153, 1094, 1070, 1049, 793, 749,
711 cmꢁ1; 1H NMR (500 MHz, CDCl3):
7.98e7.76 (m, 5H, aromatic),
a]D þ42 (c 0.52, CHCl3); IR nmax (film): 2926, 2361,
d
7.60e6.98 (m, 22H, aromatic), 5.35 (dd, 1H, J2b,3b 8.8 Hz, J2b,1b 8.2 Hz,
H-2b), 5.21(s, 2H, NaphCH2),5.04(d,1H, JNH,2a 8.7 Hz,NH),4.98(d,1H,
J 12.6 Hz, ½PhCH2), 4.72 (d, 1H, J 12.3 Hz, ½PhCH2), 4.70 (d, 1H, J1b,2b
8.2 Hz, H-1b), 4.66 (d, 1H, J1a,2a 3.5 Hz, H-1a), 4.61 (d, 1H, J
11.2 Hz,½PhCH2),4.58(d,1H, J12.6 Hz, ½PhCH2),4.53(d,1H, J11.2 Hz,
½PhCH2), 4.34 (d, 1H, J 12.3 Hz, ½PhCH2), 4.14 (dd, 1H, J4b,3b
9.3 Hz, J4b,5b 9.0 Hz, H-4b), 4.10 (ddd, 1H, J2a,1a 3.5 Hz, J2a,3a 8.8 Hz,
JNH,2a 8.7 Hz, H-2a), 4.06 (dd,1H, J4a,3a 8.9 Hz, J4a,5a 9.5 Hz, H-4a), 3.86
(d, 1H, J4b,5b 9.0 Hz, H-5b), 3.70e3.62 (m, 2H, H-3b,6a), 3.52 (dd, 1H,
mp 168e169 ꢀC (from EtOAcehexanes); [
nmax (film): 2904, 1713, 1656, 1548, 1496, 1453, 1370, 1316, 1270,
1088, 1071, 1049, 1028, 751, 711, 700 cmꢁ1 1H NMR (200 MHz,
CDCl3): 7.95e7.06 (m, 20H, aromatic), 5.40 (d, 1H, JNH,2a 8.7 Hz,
a
]
D þ38 (c 0.47, CHCl3); IR
;
d
NH), 5.21 (dd, 1H, J2b,3b 9.2 Hz, J2b,1b 8.4 Hz, H-2b), 4.90 (d, 1H,
J 12.4 Hz, ½PhCH2), 4.75 (d, 1H, J 11.3 Hz, ½PhCH2), 4.72e4.67 (m,
3H, H-1b, PhCH2), 4.65 (d, 1H, J1a,2a 3.6 Hz, H-1a), 4.52 (d, 1H,
0
J 12.4 Hz, ½PhCH2), 4.40 (dd, 1H, J5b,6b 4.2 Hz, J6b,6b 11.7 Hz, H-6b),
4.35e4.25 (m, 2H, H-6b0, ½PhCH2), 4.11 (ddd, 1H, J2a,1a 3.6 Hz, J2a,3a
8.8 Hz, JNH,2a 8.7 Hz, H-2a), 4.01 (dd,1H, J4a,3a 9.9 Hz, J4a,5a 9.2 Hz, H-
4a), 3.94e3.82 (m, 4H, H-4b,5b, CH2Cl), 3.64 (dd, 1H, J3b,2b 9.2 Hz,
0
J3a,4a 8.9 Hz, J3a,2a 8.8 Hz, H-3a), 3.41 (m,1H, H-5a), 3.38 (dd,1H, J5a,6a
1.5 Hz, J6a,6a 10.2 Hz, H-6a0), 3.16 (s, 3H, OCH3), 1.71 (s, 3H, CH3C(O)
0
NH),1.40 (s, 9H, C(CH3)3); 13C NMR(125 MHz,CDCl3):
d169.8 (NHC(O)
0
CH3), 167.2 (C-6b), 164.8 (C(O)Ph), 139.2, 138.0, 137.5, 133.6, 133.5,
133.2, 131.1, 129.6, 129.4, 128.9, 128.5, 128.4, 128.32, 128.30, 128.27,
128.22, 128.18, 128.16, 128.12, 128.08, 128.06, 128.02, 127.99, 127.91,
127.79, 127.67, 127.61, 127.56, 127.4, 127.3, 126.0, 125.8, 125.6, 125.2,
123.6 (aromatic),100.5 (C-1b), 98.2 (C-1a), 82.4 (C(CH3)3), 81.7 (C-3b),
79.7 (C-4b), 77.4 (2C, C-3a, C-4a), 75.6 (C-5b), 74.7, 74.2, and 73.7
(3 PhCH2), 73.5 (C-2b), 72.6 (NaphCH2), 70.0 (C-5a), 67.4 (C-6a), 54.9
(OCH3), 52.2 (C-2a), 27.7 (C(CH3)3), 23.1 (CH3C(O)NH). Anal. Calcd for
C58H63NO13: C, 70.93; H, 6.47; N,1.43. Found: C, 70.76; H, 6.49; N,1.44.
J3b,4b 9.3 Hz, H-3b), 3.62 (dd, 1H, J5a,6a 3.3 Hz, J6a,6a 11.6 Hz, H-6a),
3.49 (dd, 1H, J3a,4a 9.9 Hz, J3a,2a 8.8 Hz, H-3a), 3.44e3.30 (m, 2H, H-
5a,6a0), 3.18 (s, 3H, OCH3), 1.71 (s, 3H, CH3C(O)NH); 13C NMR
(50 MHz, CDCl3):
d 170.0 (NHC(O)CH3), 167.6 (C(O)CH2Cl). 164.9 (C
(O)Ph), 139.2, 138.0, 137.9, 133.3, 129.6, 129.5, 128.5, 128.4, 128.32,
128.30, 128.2, 128.1, 128.0, 127.95, 127.91, 127.88, 127.79, 127.6, 127.3
(aromatic), 100.4 (C-1b), 98.3 (C-1a), 82.1 (C-3b), 77.3 (C-3a), 77.0
(C-5b), 74.6 and 73.8 (2 PhCH2), 73.7 (C-4a), 73.5 (CH2Ph), 73.3 (C-
2b), 70.5 and 70.1 (C-4b, C-5a), 67.5 (C-6a), 64.5 (C-6b), 55.0 (OCH3),
52.2 (C-2a), 40.6 (CH2Cl), 23.2 (CH3C(O)NH). Anal. Calcd for
C45H50ClNO13: C, 63.71; H, 5.94; N, 1.65. Found: C, 63.55; H, 5.96; N,
1.66.
4.14. Methyl [tert-butyl (2-O-benzoyl-3-O-benzyl-
glucopyranosyl)uronate]-(1/4)-(2-acetamido-3,6-di-O-
benzyl-2-deoxy- -glucopyranoside) (8)
b-D-
a-D
4.16. Methyl [tert-butyl(2-O-benzoyl-3,4-di-O-benzyl-
glucopyranosyl)uronate]-(1/4)-(2-azido-3,6-di-O-benzyl-2-
deoxy- -glucopyranosyl)-(1/4)-(2-O-benzoyl-3-O-benzyl-
6-O-chloroacetyl- -glucopyranosyl)-(1/4)-(2-acetamido-
3,6-di-O-benzyl-2-deoxy- -glucopyranoside) (25
b-D-
To a solution of 23 (0.35 g, 0.36 mmol) in MeCNewater (10 mL,
9:1), CAN (0.59 g, 1 mmol, 3 equiv) was added. The mixture was
stirred at rt for 3 h, then it was diluted with CH2Cl2 (200 mL),
washed with saturated aq NaHCO3 (75 mL), brine (75 mL), and
water (75 mL); it was dried and concentrated. The residue was
purified by column chromatography (tolueneeacetone, 9:1/3:1)
to give 8 (0.23 g, 77%) as a syrup; Rf (tolueneeacetone, 3:2) 0.40;
a-D
b-D
a
-D
a)
A mixture of 7 (0.50 g, 0.5 mmol, 1.25 equiv), 24 (0.34 g,
0.4 mmol), 2,6-di-tert-butyl-4-methylpyridine (0.08 g, 0.4 mmol,
[
a]
þ56 (c 0.37, CHCl3); 1H NMR (300 MHz, CDCl3):
d
7.92e7.87
1 equiv), and activated 4 A molecular sieves (1 g) was stirred in
ꢀ
D
(dd, 2H, aromatic), 7.60e7.12 (m, 18H, aromatic), 5.35 (dd, 1H, J2b,3b
8.1 Hz, J2b,1b 8.2 Hz, H-2b), 5.11 (d, 1H, JNH,2a 8.6 Hz, NH), 4.96 (d, 1H,
J 12.8 Hz, ½PhCH2), 4.75 (d, 1H, J 12.2 Hz, ½PhCH2), 4.70e4.64 (m,
3H, H-1b, PhCH2), 4.62 (d, 1H, J1a,2a 3.6 Hz, H-1a), 4.57 (d, 1H,
J 12.8 Hz, ½PhCH2), 4.32 (d, 1H, J 12.2 Hz, ½PhCH2), 4.10 (ddd, 1H,
J2a,1a 3.6 Hz, J2a,3a 9.2 Hz, JNH,2a 8.6 Hz, H-2a), 4.03 (dd, 1H, J4a,3a
8.9 Hz, J4a,5a 9.6 Hz, H-4a), 3.95 (dd, 1H, J4b,3b 9.2 Hz, J4b,5b 9.4 Hz,
a mixture of dry CH2Cl2 (4 mL) and dry Et2O (12 mL) at 0 ꢀC under
argon for 30 min, then DMTST (0.52 g, 2 mmol, 4 equiv) was added.
After stirring for 6 h at rt, the reaction was quenched with Et3N
(1 mL). The mixture was filtered through a pad of Celite, the filtrate
was diluted with CH2Cl2 (250 mL), and washed with 2 M aq HCl
(100 mL), saturated aq NaHCO3 (100 mL), and water (100 mL); it
was dried and concentrated. The residue was purified by column
chromatography (tolueneeacetone, 9:1/4:1) to give first the
0
H-4b), 3.64 (dd, 1H, J5a,6a 3.0 Hz, J6a,6a 10.9 Hz, H-6a), 3.61 (d, 1H,

8044
K. Daragics, P. Fügedi / Tetrahedron 66 (2010) 8036e8046
b
-anomer (25
b
) as a syrup (0.10 g, 14%); Rf (tolueneeacetone, 4:1)
4.17. Methyl [tert-butyl(2-O-benzoyl-3,4-di-O-benzyl-
glucopyranosyl)uronate]-(1/4)-(2-azido-3,6-di-O-benzyl-2-
deoxy- -glucopyranosyl)-(1/4)-[tert-butyl (2-O-benzoyl-3-
O-benzyl- -glucopyranosyl)uronate]-(1/4)-(2-acetamido-
3,6-di-O-benzyl-2-deoxy- -glucopyranoside) (26)
b-D-
0.34; [
d
a
]
D
þ29 (c 0.56, CHCl3); 1H NMR (500 MHz, CDCl3):
8.14e8.10 (d, 1H, aromatic), 7.95e7.90 (d, 2H, aromatic), 7.58e7.02
a-D
(m, 42H, aromatic), 5.36 (dd, 1H, J2d,3d 8.2 Hz, J2d,1d 8.8 Hz, H-2d),
5.28 (dd, 1H, J2b,1b 8.6 Hz, J2b,3b 9.0 Hz, H-2b), 5.06 (d, 1H, JNH,2a
7.8 Hz, NH), 4.97e4.92 (m, 2H, PhCH2), 4.86 (d, 1H, J 11.0 Hz,
½PhCH2), 4.83 (d, 1H, J 10.9 Hz, ½PhCH2), 4.80 (d, 1H, J 12.4 Hz,
½PhCH2), 4.77 (d, 1H, J 12.7 Hz, ½PhCH2), 4.75e4. 58 (m, 8H, 3
PhCH2, H-1c, H-1d), 4.57 (d, 1H, J1b,2b 8.6 Hz, H-1b), 4.55e4.45 (m,
b-D
a-D
To a solution of 25a (0.42 g, 0.24 mmol) in dry DMF (8 mL),
a 0.417 M solution of HDTC31 (1.73 mL, 0.72 mmol, 3 equiv) in
ethanolewateredioxane (4:2:1) was added. The mixture was stir-
red at rt for 2 h, diluted with CH2Cl2 (200 mL), washed with 2 M aq
HCl (75 mL), saturated aq NaHCO3 (75 mL), and water (75 mL); then
it was dried and concentrated. The residue was purified by column
chromatography (tolueneeacetone, 4:1) to give 26 as a syrup
0
3H, PhCH2, H-1a), 4.36 (d, 1H, J6b,6b 12.1 Hz, H-6b), 4.13 (s, 2H,
CH2Cl), 4.05 (ddd, 1H, J2a,1a 3.4 Hz, J2a,3a 10.3 Hz, JNH,2a 7.8 Hz, H-2a),
4.02e3.95 (m, 3H, H-4a,4c,4d), 3.94e3.87 (m, 2H, H-5d,6b0), 3.82
(dd, 1H, J3b,4b 8.9 Hz, J4b,5b 9.2 Hz, H-4b), 3.78e3.67 (m, 4H, H-
0
3a,3b,3d,5b), 3.67 (dd,1H, J5c,6c 3.0 Hz, J6c,6c 11.1 Hz, H-6c), 3.62 (dd,
(0.22 g, 55%); Rf (tolueneeacetone, 3:1) 0.30; [
a
]
þ37 (c 0.22,
D
1H, J5,6a 2.0 Hz, J6a,6a 11.6 Hz, H-6a), 3.46 (dd, 1H, J2c,1c 9.5 Hz, J2c,3c
CHCl3); 1H NMR (500 MHz, CDCl3):
d
7.94e7.90 (dd, 2H, aromatic),
0
9.8 Hz, H-2c), 3.43e3.34 (m, 4H, H-3c,5a,6a0,6c0), 3.19 (m, 1H, H-5c),
7.86e7.83 (d, 2H, aromatic), 7.60e7.04 (m, 41H, aromatic), 5.48 (d,
1H, J1c,2c 4.0 Hz, H-1c), 5.28 (dd, 1H, J2d,3d 8.1 Hz, J2d,1d 8.4 Hz, H-2d),
5.23 (dd, 1H, J2b,3b 9.3 Hz, J2b,1b 8.2 Hz, H-2b), 5.20e5.16 (m, 2H, NH,
½PhCH2), 4.84 (d, 1H, J 12.3 Hz, ½PhCH2), 4.81 (d, 1H, J 10.9 Hz,
3.16 (s, 3H, OCH3), 1.70 (s, 3H, CH3C(O)NH), 1.44 (s, 9H, C(CH3)3); 13
C
NMR (125 MHz, CDCl3):
d 169.7 (NHC(O)CH3), 167.2 (C(O)CH2Cl),
166.4 (C-6d), 165.2 and 164.7 (2C(O)Ph), 139.0, 138.1, 137.8, 137.7,
137.6, 137.4, 137.3, 137.1, 133.3, 133.2, 129.6, 129.4, 129.3, 129.0,
128.99,128.8,128.7,128.5,128.44,128.40,128.3,128.2,128.1,128.05,
128.03, 127.98, 127.9, 127.8, 127.74, 127.70, 127.65, 127.58, 127.51,
127.43,127.40,127.3,127.18,127.16,126.9,125.1 (aromatic),100.2 (C-
1d, JC-1d,H-1d 165.4 Hz), 98.6 (C-1b, JC-1b,H-1b 163.6 Hz), 98.3 (C-1c, JC-
½PhCH2), 4.80 (d, 1H,
J 12.2 Hz, ½PhCH2), 4.74 (d, 1H,
J 12.3 Hz, ½PhCH2), 4.71 (d, 1H, J 11.1 Hz, ½PhCH2), 4.69e4.64 (m,
4H, PhCH2, H-1b, H-1d), 4.62 (d, 1H, J1a,2a 3.6 Hz, H-1a), 4.59 (d, 1H,
J 11.8 Hz, ½PhCH2), 4.56e4.47 (m, 3H, 1½PhCH2), 4.36 (2d, 2H,
J 10.4 Hz, PhCH2), 4.15 (ddd, 1H, J2a,1a 3.6 Hz, J2a,3a 9.6 Hz, JNH,2a
8.7 Hz, H-2a), 4.02 (dd, 1H, J4d,3d 9.3 Hz, J4d,5d 9.0 Hz, H-4d),
4.00e3.94 (m, 3H, H-4a,4b,4c), 3.81e3.73 (m, 2H, H-5b,5d),
3.69e3.58 (m, 5H, H-3a,3d,6a,6b,6c), 3.46 (dd,1H, J3b,4b 8.2 Hz, J3b,2b
165.0 Hz), 98.0 (C-1a, JC-1a,H-1a 172.5 Hz), 83.3 (C-3b), 82.4
1c,H-1c
(2C, C-3c, C(CH3)3), 81.4 (C-3d), 79.1 (C-4d), 77.5 (C-4b), 76.4 and
75.5 (C-5c, C-5d), 75.4 and 75.2 (C-3a, C-4a), 74.81 (PhCH2), 74.76
(2C, C-4c, C-5b), 74.6, 74.3, 74.1, 73.8, 73.6, and 72.9 (6 PhCH2), 72.6
and 72.3 (C-2b, C-2d), 70.1 (C-5a), 67.9 (C-6c), 67.2 (C-6a), 65.35 and
65.32 (C-2c, C-6b), 55.0 (OCH3), 52.1 (C-2a), 41.1 (CH2Cl), 27.8 (C
(CH3)3), 23.1 (CH3C(O)NH). Anal. Calcd for C96H103ClN4O24: C, 66.56;
H, 5.99; N, 3.23. Found: C, 66.41; H, 6.01; N, 3.24.
9.0 Hz, H-3b), 3.42e3.33 (m, 4H, H-3c,5a,6a0,6c0), 3.31 (dd, 1H, J5b,6b
0
1.6 Hz, J6b,6b 10.1 Hz, H-6b0), 3.19 (s, 3H, OCH3), 3.14 (m, 1H, H-5c),
0
3.04 (dd, 1H, J2c,1c 4.1 Hz, J3c,2c 11.0 Hz, H-2c), 1.82 (s, 3H, CH3C(O)
NH), 1.44 (s, 9H, C(CH3)3); 13C NMR (125 MHz, CDCl3):
d 169.7 (NHC
(O)CH3), 167.0 (C-6d), 164.9 and 164.7 (2C(O)Ph), 138.9, 138.3, 138.0,
137.9, 137.62, 137.58, 137.2, 133.40, 133.36, 129.6, 129.5, 129.3, 129.2,
128.99,128.8,128.6,128.5,128.44,128.40,128.3,128.2,128.1,128.05,
128.03, 127.98, 127.9, 127.7, 127.63, 127.59, 127.5, 127.4, 127.3, 127.1
(aromatic), 100.3 (C-1d, JC-1d,H-1d 162.6 Hz), 99.7 (C-1b, JC-1b,H-1b
156.7 Hz), 98.4 (C-1a, JC-1a,H-1a 167.5 Hz), 97.6 (C-1c, JC-1c,H-1c
176.4 Hz), 83.4 (C-3b), 82.3 (2C, C-3c, C(CH3)3), 81.6 (C-3d), 79.6 (C-
4d), 77.6 (C-4b), 76.3 (C-5c), 75.6 (C-5d), 75.2 and 74.9 (C-3a, C-4a),
74.85 (PhCH2), 74.81 (C-4c), 74.6, 74.3, 74.0, 73.9 73.7, 73.5 (6
PhCH2), 73.6 and 72.7 (C-2b, C-2d), 70.7 and 70.1 (C-5a, C-5b), 67.2
(C-6c), 67.0 (C-6a), 62.3 (C-2c), 61.1 (C-6b), 55.0 (OCH3), 52.1 (C-2a),
27.8 (C(CH3)3), 23.3 (CH3C(O)NH). Anal. Calcd for C94H102N4O23: C,
68.18; H, 6.21; N, 3.38. Found: C, 68.01; H, 6.23; N, 3.39.
Eluted second was the
Rf (tolueneeacetone, 4:1) 0.31; [
(film): 2924, 2110, 1732, 1636, 1453, 1368, 1265, 1070, 699 cmꢁ1; 1H
NMR (500 MHz, CDCl3): 7.94e7.90 (dd, 2H, aromatic), 7.86e7.83
a
-anomer (25
a) (0.28 g, 40%) as a syrup;
a
]
D
þ34 (c 0.62, CHCl3); IR nmax
d
(d, 2H, aromatic), 7.60e7.04 (m, 41H, aromatic), 5.48 (d, 1H, J1c,2c
4.0 Hz, H-1c), 5.27 (dd, 1H, J2d,3d 8.1 Hz, J2d,1d 8.4 Hz, H-2d), 5.23
(dd, 1H, J2b,3b 9.3 Hz, J2b,1b 8.2 Hz, H-2b), 5.20e5.16 (m, 2H, NH,
½PhCH2), 4.83 (d, 1H, J 12.2 Hz, ½PhCH2), 4.80 (d, 1H, J 10.9 Hz,
½PhCH2), 4.74 (d, 1H, J 12.2 Hz, ½PhCH2), 4.72e4.63 (m, 6H, 2
PhCH2, H-1b,1d), 4.61 (d, 1H, J1a,2a 3.6 Hz, H-1a), 4.59 (d, 1H,
J
11.8 Hz, ½PhCH2), 4.57e4. 53 (m, 3H, 1½PhCH2), 4.50e4.47 (m,
2H, PhCH2), 4.36 (m, 1H, H-6b), 4.18 (s, 2H, CH2Cl), 4.06 (ddd, 1H,
J2a,1a 3.6 Hz, J2a,3a 9.6 Hz, JNH,2a 8.7 Hz, H-2a), 4.02 (dd, 1H, J4d,3d
9.3 Hz, J4d,5d 9.0 Hz, H-4d), 4.00e3.94 (m, 3H, H-4a,4b,4c),
3.81e3.72 (m, 3H, H-5b,5d,6b0), 3.68e3.59 (m, 4H, H-3a,3d,6a,6c),
3.45 (dd, 1H, J3b,4b 8.2 Hz, J3b,2b 9.0 Hz, H-3b), 3.42e3.32 (m, 4H, H-
3c,5a,6a0,6c0), 3.24 (dd, 1H, J2c,1c 4.0 Hz, J3c,2c 11.0 Hz, H-2c), 3.19 (s,
3H, OCH3), 3.14 (m, 1H, H-5c), 1.72 (s, 3H, CH3C(O)NH), 1.41 (s, 9H, C
4.18. Methyl [tert-butyl(2-O-benzoyl-3,4-di-O-benzyl-
glucopyranosyl)uronate]-(1/4)-(2-azido-3,6-di-O-benzyl-2-
deoxy- -glucopyranosyl)-(1/4)-[tert-butyl (2-O-benzoyl-3-
O-benzyl- -glucopyranosyl)uronate]-(1/4)-(2-acetamido-
3,6-di-O-benzyl-2-deoxy- -glucopyranoside) (6)
b-D-
a-D
b-D
a-D
(CH3)3); 13C NMR (125 MHz, CDCl3):
d 169.7 (NHC(O)CH3), 167.0 (C
(O)CH2Cl), 166.4 (C-6d), 164.9, 164.7 (2C(O)Ph), 139.1, 138.1, 137.9,
137.8, 137.6, 137.5, 137.3, 137.2, 133.2, 133.0, 129.5, 129.4, 129.3,
129.1, 129.0, 128.9, 128.8, 128.6, 128.51, 128.46, 128.4, 128.3, 128.2,
128.1, 128.05, 128.03, 127.98, 127.9, 127.8, 127.74, 127.70, 127.65,
127.58, 127.51, 127.43, 127.40, 127.3, 127.18, 127.16, 126.9, 125.1
(aromatic), 100.3 (C-1d, JC-1d,H-1d 165.0 Hz), 99.7 (C-1b, JC-1b,H-1b
163.7 Hz), 98.4 (C-1a, JC-1a,H-1a 172.8 Hz), 98.2 (C-1c, JC-1c,H-1c
176.5 Hz), 83.0 (C-3b), 82.3 (2C, C(CH3)3, C-3c), 81.8 (C-3d), 79.7 (C-
4d), 77.3 (C-4b), 76.9 and 75.7 (C-5c, C-5d), 75.6 and 75.3 (C-3a, C-
4a), 74.9 (PhCH2), 74.8 and 74.7 (C-4c, C-5b), 74.6, 74.3, 74.0, 73.7,
73.5, and 73.2 (6 PhCH2), 72.3 and 71.7 (C-2b, C-2d), 70.1 (C-5a),
67.4 (C-6c), 66.9 (C-6a), 63.9 (C-6b), 62.5 (C-2c), 55.0 (OCH3), 52.2
(C-2a), 40.6 (CH2Cl), 27.8 (C(CH3)3), 23.2 (CH3C(O)NH). Anal. Calcd
for C96H103ClN4O24: C, 66.56; H, 5.99; N, 3.23. Found: C, 66.40; H,
6.01; N, 3.24.
4.18.1. By oxidation of 26 (Scheme 7). To a solution of 26 (0.12 g,
0.072 mmol) in dry CH2Cl2 (6 mL), PDC (0.054 g, 0.14 mmol,
2 equiv), Ac2O (0.07 mL, 0.72 mmol, 10 equiv), and tert-butyl alco-
hol (0.14 mL, 1.45 mmol, 20 equiv) were added. The mixture was
stirred overnight at rt, and it was then applied on the top of a silica
gel column in EtOAc with a 10 cm layer of EtOAc on top of the gel.
The chromium compounds were allowed to precipitate in the
presence of EtOAc and, after 30 min, the product was eluted with
EtOAc. After evaporating the solvent, the residue was purified by
column chromatography (tolueneeacetone, 4:1/3:1) to give 6 as
a syrup (0.066 g, 53%).
4.18.2. By glycosylation of 8 (Scheme 8). A mixture of 8 (0.22 g,
ꢀ
0.26 mmol), 7 (0.32 g, 0.32 mmol, 1.24 equiv), and 4 A molecular
sieves (1 g) was stirred in a mixture of dry CH2Cl2 (3 mL) and dry

K. Daragics, P. Fügedi / Tetrahedron 66 (2010) 8036e8046
8045
Et2O (9 mL) at 0 ꢀC under argon for 30 min, then DMTST (0.41 g,
1.6 mmol, 5 equiv) was added. After 2 days, the reaction was
quenched with Et3N (1 mL). The mixture was filtered through a pad
of Celite, the filtrate was diluted with CH2Cl2 (200 mL), and washed
with 2 M aq HCl (75 mL), saturated aq NaHCO3 (75 mL), and water
(75 mL); then it was dried and concentrated. The residue was pu-
rified by column chromatography (tolueneeacetone, 4:1/3:1) to
3.5 Hz, H-1a), 4.42 (d, 1H, J1b,2b 7.9 Hz, H-1b), 4.38 (d, 1H, J1d,2d
8.0 Hz, H-1d), 3.87e3.81 (m, 2H, H-3a,3c), 3.80e3.70 (m, 8H,
H-2a,5a,5b,5c,6a,6a0,6c,6c0), 3.70e3.60 (m, 3H, H-3b,4b,5d),
3.60e3.51 (m, 2H, H-4a,4c), 3.43e3.35 (m, 3H, H-3d,4d,5a), 3.28 (m,
1H, H-2b), 3.25 (s, 3H, OCH3), 3.22 (m, 1H, H-2d), 3.18 (dd, 1H, J2c,3c
10.3 Hz, J2c,1c 3.6 Hz, H-2c), 1.89 (s, 3H, CH3C(O)NH); 13C NMR
(75 MHz, D2O):
d 175.0 and 174.8 (2C) (NHC(O)CH3, C-6b, C-6d),
give 6 (0.25 g, 56%) as a syrup; Rf (tolueneeacetone, 3:1) 0.34; [
a
]
102.6 (C-1d), 102.5 (C-1b), 98.1 (C-1a), 95.6 (C-1c), 79.5 (C-4a), 78.0
(C-4c), 76.4 (2C), 76.3 and 76.2 (C-3b, C-4b, C-5b, C-5d), 75.4, 73.4
(2C) and 72.2 (C-3d, C-4d, C-2b, C-2d), 70.7 (C-5c), 70.0 (C-3c), 69.9
(C-5a), 68.7 (C-3a), 60.3 (2C, C-6a, C-6c), 55.6 (OCH3), 54.4 (C-2c),
53.7 (C-2a), 22.3 (CH3C(O)NH); MS-ESI: [MþH]þ 749.1; HRMS (ESþ)
calcd for C27H44N2NaOþ22 [MþHþNa]þ 771.2283; Found: 771.2271.
D
þ37 (c 0.57, CHCl3); 1H NMR (500 MHz, CDCl3):
d 7.93e7.90 (dd, 2H,
aromatic), 7.82e7.79 (d, 2H, aromatic), 7.60e7.02 (m, 41H, aro-
matic), 5.48 (d, 1H, J1c,2c 4.0 Hz, H-1c), 5.28 (dd, 1H, J2d,3d 9.4 Hz,
J2d,1d 8.4 Hz, H-2d), 5.24 (dd, 1H, J2b,3b 9.4 Hz, J2b,1b 8.2 Hz, H-2b),
5.12 (d, 1H, J 11.1 Hz, ½PhCH2), 4.90 (d, 1H, JNH,2 8.6 Hz, NH), 4.83 (d,
1H, J 12.2 Hz, ½PhCH2), 4.80 (d, 1H, J 10.9 Hz, ½PhCH2), 4.78 (d, 1H,
J 12.2 Hz, ½PhCH2), 4.74 (d, 1H, J 12.3 Hz, ½PhCH2), 4.71 (d, 1H,
J 11.1 Hz, ½PhCH2), 4.69e4.64 (m, 4H, PhCH2, H-1b,1d), 4.62 (d, 1H,
J1a,2a 3.6 Hz, H-1a), 4.59 (d, 1H, J 11.8 Hz, ½PhCH2), 4.56e4.47 (m,
3H, 1½PhCH2), 4.37 (2d, 2H, J 12.2 Hz, PhCH2), 4.15 (ddd, 1H, J2a,1a
3.6 Hz, J2a,3a 9.6 Hz, JNH,2a 8.7 Hz, H-2a), 4.02 (dd, 1H, J4d,3d 9.3 Hz,
J4d,5d 9.0 Hz, H-4d), 4.00e3.94 (m, 3H, H-4a,4b,4c), 3.81e3.73 (m,
2H, H-5b,5d), 3.68e3.59 (m, 5H, H-3a,3b,3d,6a,6c), 3.42e3.33 (m,
5H, H-3c,5a,5c,6a0,6c0), 3.24 (dd,1H, J2c,1c 4.0 Hz, J3c,2c 11.0 Hz, H-2c),
3.18 (s, 3H, OCH3), 1.74 (s, 3H, CH3C(O)NH), 1.42 (2s, 18H, C(CH3)3);
Acknowledgements
We are grateful to Dr. Tibor Bakó (Egis Pharmaceuticals Ltd.) for
the assistance in recording the NMR spectra and for helpful dis-
cussions. We also thank Dr. Pál Szabó (Chemical Research Center,
Hungarian Academy of Sciences) and Zsuzsánna Csíki (Chemical
Research Center, Hungarian Academy of Sciences) for the assistance
in recording the MS and IR spectra, respectively.
13C NMR (125 MHz, CDCl3):
d 169.7 (NHC(O)CH3), 167.0 (C-6d),
Supplementary data
166.3 (C-6b), 164.7 and 164.6 (2C(O)Ph), 139.2, 138.2, 138.1, 137.9,
137.8, 137.5, 137.4, 137.2, 133.4, 133.3, 129.73, 129.67, 129.5, 129.3,
128.79, 128.77, 128.71, 128.6, 128.5, 128.4, 128.33, 128.27, 128.25,
128.22,128.20, 127.9, 127.8, 127.70, 127.64,127.59,127.5,127.4,127.3,
127.1 (aromatic), 100.5 (C-1d), 99.9 (C-1b), 98.2 (C-1a), 97.3 (C-1c),
82.5 (C-3b), 82.3 (3C, C-3c, 2C(CH3)3), 82.1 (C-3d), 79.7 (C-4d), 77.3
(C-4b), 76.0 (C-5c), 75.6 (C-5d), 75.1 (2C, C-3a, C-4a), 75.0 (PhCH2),
74.8 (C-4c), 74.6, 74.3, 74.1, 73.8, 73.7, and 73.54 (6 PhCH2), 73.51
and 73.4 (C-2b, C-2d), 70.7 and 69.9 (C-5a, C-5b), 67.2 (C-6c), 66.9
(C-6a), 62.8 (C-2c), 55.1 (OCH3), 52.2 (C-2a), 27.9 (C(CH3)3), 27.6 (C
(CH3)3), 23.2 (CH3C(O)NH). Anal. Calcd for C98H108N4O24: C, 68.20;
H, 6.31; N, 3.25. Found: C, 68.03; H, 6.33; N, 3.26; MS-ESI: [MþH]þ
1725.4; HRMS (ESþ) calcd for C49H56N2O1þ2 [Mþ2H]2þ 864.3799.
Found: 864.3833.
Supplementary data (copies of NMR spectra) associated with
this article can be found, in the online version, at doi:10.1016/
j.tet.2010.08.004.
References and notes
1. (a) Lane, D. A.; Lindahl, U. Heparin. Chemical and Biological Properties, Clinical
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b
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b-D-
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THFeMeOH (5 mL, 2:1), 1 M aq NaOH solution (40
m
The reaction mixture was stirred for 3 days at rt, neutralized with
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was purified by column chromatography (tolueneemethanol, 9:1)
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a
]
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(EtOAceMeOHeH2O, 2:2:1) 0.24; [
(300 MHz, D2O):
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5
(0.019 g, 70%) as
a
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]
þ26 (c 0.30, H2O); 1H NMR
D
d
5.52 (d, 1H, J1c,2c 3.6 Hz, H-1c), 4.74 (d, 1H, J1a,2a

8046
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