Synthesis of glycosaminoglycan oligosaccharides. Part 4: Synthesis of aza-l-iduronic acid-containing analogs of heparan sulfate oligosaccharides as heparanase inhibitors

Article abstract of DOI:10.1016/j.tet.2010.07.055

The synthesis of three azasugar-containing analogs of the disaccharide units of heparan sulfate, which are potential inhibitors of the enzyme heparanase, is reported. Synthetic routes were developed for the preparation of l-ido-nojirimycin type glycosyl a

Full text of DOI:10.1016/j.tet.2010.07.055

Tetrahedron 66 (2010) 7821e7837
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of glycosaminoglycan oligosaccharides. Part 4: Synthesis of
aza- -iduronic acid-containing analogs of heparan sulfate oligosaccharides
L
as heparanase inhibitorsq
*
Zsuzsánna Csíki, 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:
The synthesis of three azasugar-containing analogs of the disaccharide units of heparan sulfate, which
are potential inhibitors of the enzyme heparanase, is reported. Synthetic routes were developed for the
Received 31 March 2010
Received in revised form 1 July 2010
Accepted 20 July 2010
preparation of
with an O-6 functionalized 2-azido-2-deoxy-
L
-ido-nojirimycin type glycosyl acceptors with O-4 free. Glycosylation of these acceptors
-glucose thioglycoside donor afforded the -linked
D
a
Available online 24 July 2010
disaccharides in good yields. The advantages of using the 4-nitrobenzenesulfonyl group for the pro-
tection of the ring nitrogen of azasugars were demonstrated.
Keywords:
Azasugars
Ó 2010 Elsevier Ltd. All rights reserved.
Heparan sulfate
Heparanase inhibitors
Oligosaccharide synthesis
4-Nitrobenzenesulfonyl group
1. Introduction
glucuronidase, which specifically cleaves the HS chains at a limited
number of sites.6 It has been recognized that tumor metastasis
Heparan sulfate proteoglycans (HSPGs) are ubiquitous constitu-
ents of the extracellular matrix and of cell membranes.1 The struc-
ture of HSPG consists of a protein core to which linear chains of the
glycosaminoglycan, heparan sulfate (HS), are linked by O-glycosidic
occurs via complex multistage processes, which involves tumor
cell adhesion to various basement membrane components, and
degradation of the extracellular matrix and basement membranes.
As HS is an important constituent in these structures, cleavage of
HS by heparanase plays an important role in cell invasion of some
malignant tumors through basement membranes. Heparanase is
overexpressed in a number of human tumors.5b The expression
level of the enzyme is of diagnostic and prognostic value, and has
been correlated with the survival time of cancer patients.5b,7 The
inhibition of heparanase forms the basis of potential anti-
metastatic cancer therapy, and it has therefore been intensively
investigated.8
Azasugars are monosaccharide analogs having a nitrogen atom
instead of oxygen in the ring, and have received significant atten-
tion as carbohydrate mimetics.9 Compounds of this type, such as
1-deoxynojirimycin, are potent inhibitors of various glycosidases,
and are intensely investigated for their therapeutic potential as
antidiabetic, antiviral, and anticancer agents. Though mono-
saccharidic azasugars, in general, show some specificity to inhibit
certain types of glycosidases, this specificity is still fairly broad. One
way to increase specificity is to use larger size molecules, which are
closer mimics of the natural substrates of the enzymes. Thus,
oligosaccharides containing an azasugar component have been
synthesized for various biological purposes.10,11
bonds. The carbohydrate backbone of HS is built up of alternating
glucosamine and hexuronic acid ( -glucuronic acid and -iduronic
acid) units forming /4)- -IdopA-(1/4)- -GlcpN-(1/ and
/4)- -GlcpA-(1/4)- -GlcpN-(1/ disaccharides, which are
substituted at certain positions. Thus, O-3 and O-6 of the -glucos-
amine units, and O-2 of the uronic acid units can be O-sulfated,
furthermore, the amino group of -glucosamine canbe N-acetylated,
D-
D
L
a
-L
a-D
b
-D
a-D
D
D
N-sulfated, or remain unsubstituted.1,2 These variations result in an
enormous structural diversity.3 Heparan sulfate binds to a large
number of proteins, thereby influencing a variety of normal and
pathological processes including tumor growth and metastasis,
tissue repair, angiogenesis, and inflammation.4 Cleavage of HS
chains alters its interaction with proteins and thus influences the
above processes.
The most important cleavage enzyme in the catabolism of
heparan sulfate chains is heparanase.5 Heparanase is an endo-
b-
q
For Part 3, see Ref. 12.
* Corresponding author. Tel.: þ36 1 438 1100; fax: þ36 1 438 1145; e-mail
address: pfugedi@chemres.hu (P. Fügedi).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.055

7822
Z. Csíki, P. Fügedi / Tetrahedron 66 (2010) 7821e7837
In order to incorporate specificity in azasugars toward hep-
2. Results and discussion
aranase, we have designed azasugar-containing oligosaccharides
mimicking the structure of heparin and heparan sulfate
(Fig. 1).12 The synthesis of related aza-analogs of heparan sulfate
disaccharides,13 as well as an interglycosidically S-linked oligo-
saccharide14 has been reported recently for similar purpose.
2.1. Synthetic design
The target structures 3e5 should be available from the
2-azido-2-deoxy-
D
-glucopyranosyl donor (7) and the
L-idose
Figure 1. Designed azasugar-containing heparan sulfate disaccharides.
Compounds of type 1 and 2 contain a
-(1/4)-linked to an azasugar analog of -glucuronic acid and
-iduronic acid, respectively. Though heparanase is a -glucuronidase,
compounds of type 2 having an -ido-configured azasugar might also
D
-glucosamine unit
(8) and
(Scheme 1).
L
-iduronic acid (9) azasugar glycosyl acceptors
a
L
D
b
In the glycosyl donor 7, O-6 is masked by the temporary chloro-
acetyl group, which allows the selective release of O-6 in the syn-
thesis of the O-sulfated product (5). The carboxyl function in 9 is
protected as the tert-butyl ester. For the protection of the ring
nitrogen in the glycosyl acceptors, the benzyloxycarbonyl group,
most commonly used for this purpose in the azasugar field,10,13 was
selected originally. Due to inconveniences and an undesired side
reaction recognized during work with the N-benzyloxycarbonyl
protected derivatives, this group was replaced with the 4-nitro-
benzenesulfonyl (Ns) group at a later stage of this work. The syn-
thesis of glycosyl acceptors requires selective manipulations at O-4
and O-6, both 8 and 9 should be available from the (1-naphthyl)
methylene acetal 10 by different reductive acetal opening methods
giving the readily removable (1-naphthyl)methyl (1NAP) ethers18 at
L
be of interest as potential inhibitors. The rationale for this is that there
are several examples reported that azasugars of the ‘wrong’ config-
uration are good inhibitors of glycosidases having specificity for
a different configuration.15 Additionally, because of the known con-
formational mobility of
type 2 might fit into the active site of the enzyme. It was also of
interest, that an -iduronic acid-type 1-N-iminosugar has been
reported to have inhibitory activity of cancer metastasis.17
Previously only aza- -glucuronic acid-containing disaccharide
inhibitors of heparanase have been reported.13 As far as we are aware,
-ido-configured azasugar-containing oligosaccharides have not been
L-idose and L
-iduronic acid,2,16 compounds of
L
D
L
synthesized before, we have recently reported the first compound of
this type.12 We now describe the synthesis of three disaccharides
either O-4 or O-6. The synthesis of the derivatives having
configuration was envisioned by SN2 nucleophilic substitution of
N-nosyl protected
-gluco derivatives in the cyclization step.19
L-ido
(3e5) containing azasugar components having
L-ido configuration, as
well as the monosaccharide congener 6 (Fig. 2).
D
2.2. Oligosaccharide synthesis using N-benzyloxycarbonyl
protection
2.2.1. Synthesis of the glycosyl acceptors. Phenyl 1-thio-b-D-gluco-
pyranoside (11), readily obtained by Zemplén deacetylation of the
tetraacetate,20 was converted intothe (1-naphthyl)methylene acetal
12, which was benzylated to give 13 (Scheme 2).
The hemiacetal was released by reaction with NBS21 and 14 was
reduced to give the alditol 15. The primary hydroxyl was selectively
brominated using Ph3P and CBr422 to give 16 in excellent yield, then
Figure 2. Synthesized azasugar-containing heparan sulfate fragments.
Scheme 1. Retrosynthesis of heparanase inhibitory disaccharides.

Z. Csíki, P. Fügedi / Tetrahedron 66 (2010) 7821e7837
7823
Scheme 2. Reagents and conditions: (a) 1NaphCH(OMe)2, p-TSA, MeCN, 98%; (b) BnBr, NaH, DMF, 98%; (c) NBS, CH2Cl2, acetone, H2O, 93%; (d) NaBH4, THF, H2O, 97%; (e) Ph3P, CBr4,
pyridine, 98%; (f) Ac2O, pyridine, 98%; (g) NaN3, NH4Cl, DMF, H2O, 79%; (h) NaOMe, MeOH, 98%; (i) 1,3-propanedithiol, Et3N, pyridine, H2O, 96%; or Ph3P, pyridine, then 25% NH4OH,
77%; (j) NsCl, Et3N, CH2Cl2, 98%; (k) DEAD, Ph3P, CH2Cl2, 96%; (l) PhSH, K2CO3, DMF, 98%; (m) BnOCOCl, NaHCO3, MeOH, 97%.
the hydroxyl group was acetylated. Nucleophilic replacement of the
bromine in 17 with NaN3 in DMF and water afforded 18, which was
converted to 19 by Zemplén deacetylation. The azide was reduced
to the amine either by 1,3-propanedithiol or by Ph3P and hydrolysis
of the phosphimine, and the resulting 20 was selectively nosylated
to the 4-nitrobenzenesulfonamide 21 in excellent yield. Cyclization
of 21 using the Mitsunobu reaction took place with configurational
of the (1-naphthyl)methyleneacetal withNaBH3CNeHCl25 afforded 8
directly. For the synthesis of 9a, the 4-O-(1-naphthyl)methyl ether
was prepared by reduction with BH3$THFeTMSOTf,26 which gave 25
in 91% yield. One-step oxidation-esterification using pyridinium
inversion at C-5 and provided the -ido derivative 10b in 96%
L
yield.19 The 4-nitrobenzenesulfonyl group was exchanged to ben-
zyloxycarbonyl by treating 10b with PhSH and Et3N to give 22,
which, in turn, was reacted with benzyl chloroformate to give the
central intermediate 10a.
A shorter route from 14 to 20 involved DesseMartin oxidation23
of the hemiacetal to the lactone 23 (Scheme 3). The lactone ring
was opened with methanolic ammonia to give the amide 24, which
was reduced with LiAlH4 to give 20.24
The conversion of 10a to the glycosyl acceptors (8 and 9a) was
performed in the following ways (Scheme 4). Reductive ring opening
Scheme 3. Reagents and conditions: (a) DesseMartin periodinane, CH2Cl2, 90%;
(b) NH3eMeOH, 65%; (c) LiAlH4, THF, 70%.

7824
Z. Csíki, P. Fügedi / Tetrahedron 66 (2010) 7821e7837
Scheme 4. Reagents and conditions: (a) NaCNBH3, HCleEt2O, THF, 67%; (b) BH3$THF, TMSOTf, CH2Cl2, 91%; (c) PDC, Ac2O, t-BuOH, CH2Cl2, 68%; (d) CAN, MeCN, H2O, 65%.
dichromate (PDC) in the presence of acetic anhydride and tert-buta-
nol27 afforded the tert-butyl uronate 26. Removal of the (1-naphthyl)
methyl group by ceric ammonium nitrate (CAN)18 then gave 9a.
Treatment of 29 with CAN removed the (1-naphthyl)methyl
ether and afforded 31 in 71% yield. This product was dechloro-
acetylated using hydrazinedithiocarbonate (HDTC),31 and the
azido group of 32 was reduced with 1,3-propanedithiol to give
the amine 33. After N,O-acetylation, the O-acetyl groups of 34
were removed by Zemplén deacetylation. The resulting product
turned out to be a mixture, which in addition to the desired 35
also contained the 6-O,N-cyclic carbamate derivative 36. Forma-
tion of similar cyclic carbamates from N-benzyloxycarbonyl pro-
tected azasugars with loss of the benzyl group under basic
conditions has been reported earlier.10feh,32 The two compounds
could not be separated at this stage. For complete deprotection
the mixture was subjected to catalytic hydrogenolysis; 3 and 37
were obtained in pure state after careful column chromatographic
separation.
2.2.2. Synthesis of the glycosyl donor. Thiolysis of the 1,6-anhydro
derivative 2728 with PhSSiMe3eZnI2 gave the thioglycoside 2813 as
an about 2:1 a:b anomeric mixture (Scheme 5). Chloroacetylation
then afforded 7, which was used as an anomeric mixture in gly-
cosylation reactions.
For the synthesis of compound 4, first the chloroacetyl group
was removed from 30 as described before, then the azido group of
the obtained 38 was reduced with 1,3-propanedithiol to give the
amine 39 (Scheme 8). Peracetylation afforded 40, which was then
subjected to Zemplén deacetylation to yield 41. The tert-butyl ester
was hydrolyzed by treatment with trifluoroacetic acid (TFA) in
dichloromethane, and catalytic hydrogenation of the free acid
removed the benzyloxycarbonyl and benzyl groups to provide 4.
Preparation of the free monosaccharide 6 followed a similar
sequence (Scheme 9). Hydrolysis of the uronate 9a with 20% TFA in
CH2Cl2 followed by catalytic hydrogenation of 42 afforded 6.33
Scheme 5. Reagents and conditions: (a) PhSSiMe3, ZnI2, CH2Cl2, 80%; (b) (ClCH2CO)2O,
pyridine, CH2Cl2 74%.
2.2.3. Synthesis of disaccharides 3 and 4. The azasugar derivatives 8
and 9a proved to be good glycosyl acceptors. Reaction of 7 with 8
using DMTST29 as promoter in diethyl etheredichloromethane
afforded the
a-linked disaccharide in 59% yield (Scheme 6).
Reaction of 7 with 9a was promoted by Me2S2eTf2O30 and the
a
-linked disaccharide 30 was obtained in 80% yield.
The fully protected disaccharide 29 was transformed into the
free disaccharide 3 as shown in Scheme 7.
Scheme 6. Reagents and conditions: (a) DMTST, Et2O, CH2Cl2, 59%; (b) Me2S2eTf2O, Et2O, CH2Cl2, 80%.

Z. Csíki, P. Fügedi / Tetrahedron 66 (2010) 7821e7837
7825
Scheme 7. Reagents and conditions: (a) CAN, MeCN, H2O, 71%; (b) HDTC, DMF, 92%; (c) 1,3-propanedithiol, Et3N, pyridine, H2O, 81%; (d) Ac2O, pyridine, 83%; (e) NaOMe, MeOH,
87%; (f) H2, Pd/C, THF, H2O, (3) 43%, (37) 31%.
Scheme 8. Reagents and conditions: (a) HDTC, DMF, 72%; (b) 1,3-propanedithiol, Et3N, pyridine, H2O, 81%; (c) Ac2O, pyridine, 96%; (d) NaOMe, MeOH, 95%; (e) 1. TFA, CH2Cl2, 95%;
2. H2, Pd/C, THF, H2O, 88%.
commonly used group for this purpose. During the previous syn-
theses, however, we have experienced a series of drawbacks asso-
ciated with the use of this protecting group. A major inconvenience
was the doubling of signals in the NMR spectra of the N-benzy-
loxycarbonyl derivatives.10e,10g,12,32b This is due to the existence of
rotamers around the amide bond, and it necessitated running the
measurements at high temperature in DMSO-d6 to obtain simpler
and better-resolved spectra. Another problem with the N-benzyl-
oxycarbonyl group was the undesired formation of O,N-cyclic
carbamates (36 and 37, Section 2.2.3) during deacetylation. In
general, fairly strongly basic conditions are used for the preparation
Scheme 9. Reagents and conditions: (a) TFA, CH2Cl2, 97%; (b) H2, Pd/C, THF, H2O, 79%.
of this type of derivatives,10fe10h,32 their formation under the mildly
2.3. Oligosaccharide synthesis using N-nosyl protection
basic conditions of Zemplén deacetylation was somewhat
unexpected.
Our original choice for the protection of the ring nitrogen of
azasugars was the benzyloxycarbonyl group, which is the most
On the way to the synthesis of N-benzyloxycarbonyl derivatives,
it was recognized that the N-nosyl intermediates, such as 21 and

7826
Z. Csíki, P. Fügedi / Tetrahedron 66 (2010) 7821e7837
10b, gave simpler, better-resolved NMR spectra. As these com-
pounds were intermediates in the preparation of the N-benzylox-
ycarbonyl protected glycosyl acceptors, it was of interest to use the
N-nosyl protected derivatives in oligosaccharide synthesis to
shorten the synthetic route. In our previous communication12 we
have demonstrated that N-nosyl protection is fully compatible with
the transformations required for oligosaccharide synthesis, there-
fore N-benzyloxycarbonyl protection was abandoned, and com-
pound 5 was synthesized using nosyl protected derivatives.
For the synthesis of the glycosyl acceptor the (1-naphthyl)
methylene acetal ring of 10b was cleaved by BH3$THFeTMSOTf to
give the 4-O-(1-naphthyl)methyl ether 43 (Scheme 10). Reaction
with PDCeAc2Oet-BuOH afforded the tert-butyl uronate 44, from
which the 1-(naphthyl)methyl group was removed with CAN to
yield the nosyl-protected acceptor 9b.
Scheme 10. Reagents and conditions: (a) BH3$THF, TMSOTf, CH2Cl2, 93%; (b) PDC,
Ac2O, t-BuOH, CH2Cl2, 54%; (c) CAN, MeCN, H2O, 78%.
Glycosylation of 9b with 7 was promoted by Me2S2eTf2O using
Et2OeCH2Cl2 as solvent, and the reaction afforded the
disaccharide 45 in 90% yield (Scheme 11).
a-linked
Scheme 11. Reagents and conditions: (a) Me2S2eTf2O, Et2O, CH2Cl2, 90%.
The fully protected disaccharide 45 was converted to the sul-
fated disaccharide 5 by the sequence shown in Scheme 12.
This step was followed by catalytic hydrogenation which gave the
target compound 5.
Scheme 12. Reagents and conditions: (a) Me3P, THF, then Ac2O, 66%; (b) HDTC, DMF, 65%; (c) 1. TFA, CH2Cl2; 2. SO3$Pyr, DMF, 94%; (d) 1. PhSH, Et3N, DMF, 73%; 2. H2, Pd/C, THF, H2O,
60%.
Selective reduction of the azido group of 45 in the presence of
the nosyl group was accomplished with Me3P,12 then the amine was
acetylated to give 46. The primary hydroxyl group was released by
HDTC, the tert-butyl group of 47 was hydrolyzed, and the free 60-
hydroxyl group was sulfated with SO3$Pyr to give 48. Removal of
the nosyl group was accomplished with thiophenol and triethyl-
amine without affecting the acid and base sensitive sulfate group.12
3. Conclusion
In summary, we have synthesized three azasugar-containing
analogs of disaccharide units of heparan sulfate. We have developed
synthetic routes for azasugar glycosyl acceptors having
figuration. Glycosylation of these acceptors with a 2-azido-2-deoxy-
-glucopyranosyl thioglycoside afforded the -(1/4)-linked
L-ido con-
D
a

Z. Csíki, P. Fügedi / Tetrahedron 66 (2010) 7821e7837
7827
disaccharides in good yields. The protected disaccharides were
transformed to the heparan sulfate analogs.
4.3. Phenyl 2,3-di-O-benzyl-4,6-O-1-(naphthyl)methylene-1-
thio- -glucopyranoside (13)
b-D
In addition, we have demonstrated that the 4-nitro-
benzenesulfonyl group can be used advantageously for the pro-
tection of the ring nitrogen of azasugars.
To a stirred solution of 12 (34.5 g, 84 mmol) in dry DMF
(300 mL), 60% NaH suspension (6.9 g, 168 mmol, 2 equiv) was
added at 0 ꢀC. After 30 min, benzyl bromide (14 mL, 117.7 mmol,
1.4 equiv) was added dropwise. Stirring was continued for 2 h and
then MeOH (20 mL) was added. After 30 min, the mixture was
diluted with CH2Cl2 (500 mL), washed with water (2ꢂ250 mL),
dried, and concentrated. The residue was crystallized from
EtOAcehexanes to afford 13 (59.8 g, 98%) as white crystals; mp
4. Experimental
4.1. General methods
Organic solutions were dried over MgSO4 and concentrated
under reduced pressure at temperatures not exceeding 40 ꢀC. Thin-
layer chromatography (TLC) was performed on Silica gel 60 F254
plates (E Merck, Darmstadt, Germany); the compounds were
detected under UV light and by spraying the plates with a 0.02 M
solution of resorcinol in 20% methanolic H2SO4 solution followed
by heating. For column chromatography, 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 room
temperature with a Jasco Optical Activity AA-10R polarimeter. The
IR spectra were recorded on a Thermo Nicolet Avatar 320 FT-IR
spectrometer. The NMR spectra were recorded on Varian Gemini
2000 (1H: 200 MHz; 13C: 50 MHz), Varian Gemini 3000 (1H:
300 MHz; 13C: 75 MHz) and Varian Unity-Inova 4000 (1H:
400 MHz; 13C: 100 MHz) spectrometers at ambient temperature,
unless indicated otherwise. The chemical shifts were referenced to
TMS (0.00 ppm for 1H) and to the central line of CDCl3 (77.16 ppm
for 13C) for solutions in CDCl3, to the central line of the solvent
(3.31 ppm for 1H, 49.00 ppm for 13C) for solutions in CD3OD, and to
the methyl signal of acetone (2.22 ppm for 1H, 30.89 ppm for 13C)
for solutions in D2O, as internal standards. Mass spectrometric
measurements were run on an Applied Biosystems 3200QTrap
hybrid mass spectrometer in electrospray ionization mode. Ele-
mental analyses were performed with an Elementar Vario EL III
instrument at the Analytical Department of the Chemical Research
Center, Hungarian Academy of Sciences.
155e156 ꢀC; [
a]
þ2.1 (c 0.2, CHCl3); IR nmax (film): 2869, 2348,
D
1077 cmꢁ1 1H NMR (200 MHz, CDCl3):
;
d 8.13 (m, 1H, aromatic),
7.83 (m, 2H, aromatic), 7.18e7.60 (m, 19H, aromatic), 6.13 (s, 1H,
1NaphCH), 4.77e4.90 (m, 3H, 3ꢂ½PhCH2), 4.82 (d, 1H, J1,2 9.9 Hz,
H-1), 4.67 (d, 1H, J 10.4 Hz, ½PhCH2), 4.49 (dd, 1H, J6a,6b 10.3 Hz,
J5,6b 5.0 Hz, H-6b), 3.80e4.00 (m, 4H, H-2, H-3, H-4, H-6a), 3.59 (m,
1H, H-5); 13C NMR (50 MHz, CDCl3):
d 138.24, 138.18, 133.9, 133.2,
132.5, 130.7, 129.9, 129.2, 128.8, 128.5, 128.4, 128.33, 128.31, 128.0,
127.8, 126.4, 125.8, 125.2, 124.2, 123.9 (aromatic), 100.2 (1NaphCH),
88.5 (C-1), 83.1, 82.1 and 80.7 (C-2, C-3, and C-4), 76.0 and 75.4 (2
PhCH2) 70.4 (C-5), 69.1 (C-6); MS-ESI: [MþH]þ 591.2, [MþNH4]þ
608.2, [MþNa]þ 613.2, [MþK]þ 629.2. Anal. Calcd for C37H34O5S: C:
75.23; H: 5.80; S: 5.43. Found: C: 75.25; H: 5.85; S: 5.40.
4.4. 2,3-Di-O-benzyl-4,6-O-(1-naphthyl)methylene-a,b-D-
glucopyranose (14)
To a solution of 13 (16.5 g, 28 mmol) in a mixture of CH2Cl2
(80 mL), acetone (30 mL), and water (12 mL), N-bromosuccinimide
(19.9 g, 112 mmol, 4 equiv) was added. The mixture was stirred at
0 ꢀC for 1 h, then 10% aq Na2S2O3 (20 mL) was added. The mixture
was diluted with CH2Cl2 (500 mL), and the organic layer was
washed with water (2ꢂ200 mL), dried, and concentrated. The
residue was purified by column chromatography (tolueneeacetone,
99:1/4:1) to give syrupy 14 (12.8 g, 93%); Rf (tolueneeacetone,
4:1) 0.73; [
1074 cmꢁ1; 1H NMR (200 MHz, CDCl3):
(m, 3H, aromatic), 7.20e7.54 (m, 13H, aromatic), 6.12 and 6.11 (2s,
1H, 1NaphCH), 5.22 (dd, ½H, J1,2 3.7 Hz, J1,OH 2.2 Hz, H-1
),
4.67e4.96 (m, 4H, PhCH2), 4.42 (2 dd, 1H, H-6b), 3.30e4.25 (m,
5½H, H-1
, H-2, H-3, H-4, H-5, H-6a), 3.16 (d, 1H, OH); 13C NMR
(50 MHz, CDCl3): 138.4, 133.9, 132.7, 132.5, 130.7, 129.9, 129.8,
a
]
þ18.5 (c 0.3, CHCl3); IR nmax (film): 2923, 1875,
D
d
8.14 (m,1H, aromatic), 7.84
a
4.2. Phenyl 4,6-O-(1-naphthyl)methylene-1-thio-b-D-
glucopyranoside (12)
b
d
To a solution of 11 (25 g, 91.9 mmol) in dry MeCN (250 mL),
1-naphtaldehyde dimethyl acetal (27 mL, 61.2 mmol, 1.5 equiv)
and p-toluenesulfonic acid monohydrate (0.9 g, 4.7 mmol,
0.05 equiv) were added. The mixture was stirred at room tem-
128.74, 128.70, 128.6, 128.4, 128.3, 128.2, 128.0, 127.7, 126.5, 126.4,
125.80,125.76,125.2, 124.3,124.2,124.0,123.9 (aromatic),100.4 and
100.2 (1NaphCH), 98.0 and 92.4 (C-1), 83.3, 82.6, 82.2, 81.0, 79.6 and
78.4 (C-2, C-3, and C-4), 75.5, 75.4, 75.2 and 74.0 (2 PhCH2) 69.5 and
69.1 (C-6), 66.5 and 62.7 (C-5); MS-ESI: [MþH]þ 499.2,
[MþNH4]þ516.2, [MþNa]þ 521.2, [MþK]þ 537.4. Anal. Calcd for
C31H30O6: C, 74.68; H, 6.07. Found: C, 74.03; H, 6.04.
perature for
4 h, neutralized with saturated aq NaHCO3
(300 mL), and concentrated. To the residue, hexanes (200 mL)
and water (200 mL) were added, and the mixture was stirred
intensively. The precipitated crystalline material was filtered off
and crystallized from EtOAce1,2-dichloroethaneehexanes to af-
4.5. 2,3-Di-O-benzyl-4,6-O-(1-naphthyl)methylene-D-
glucitol (15)
ford 12 (36.7 g, 98%) as white crystals; mp 217e219 ꢀC; [
a
]
D
ꢁ19.2 (c 0.7, CHCl3); IR nmax (film): 2956, 966 cmꢁ1
;
1H NMR
(200 MHz, CDCl3þDMSO-d6):
d
8.27 (m, 1H, aromatic), 7.28e7.90
To a solution of 14 (4.2 g, 8.6 mmol) in a mixture of THF and
water (4:1, 40 mL), NaBH4 (3.24 g, 85.8 mmol, 10 equiv) was added
in portions. The mixture was stirred for 2 h at room temperature,
and then it was treated with Amberlite IR 120 (Hþ) resin (pH ca. 7),
filtered, and concentrated. The residue was purified by column
chromatography (tolueneeacetone, 9:1/7:3) to give 15 (3.4 g,
(m, 11H, aromatic), 6.06 (s, 1H, 1NaphCH), 5.13 and 5.00 (2d,
2ꢂ1H, J 4.0 Hz and J 4.4 Hz, 2 OH), 4.76 (d, 1H, J1,2 9.9 Hz, H-1),
4.42 (dd, 1H, J6a,6b 10.6 Hz, J5,6b 4.4 Hz, H-6b), 3.89 (dd, 1H, J5,6a
10 Hz, H-6a), 3.76 (dd, 1H, J2,3zJ3,4 8.8 Hz, H-3), 3.58e3.70 (m,
2H, H-4, H-5), 3.48 (ddd, 1H, H-2); 13C NMR (50 MHz,
CDCl3þDMSO-d6):
d
133.0, 132.3, 132.0, 131.5, 129.8, 129.0, 128.2,
97%) as a colorless syrup; Rf (tolueneeacetone, 4:1) 0.60; [
(c 0.7, CHCl3); IR nmax (film): 3063, 3031, 2929, 2871, 2361, 1723,
1600, 1454, 1366, 1217, 1104, 1071, 1027 cmꢁ1 1H NMR (200 MHz,
a
]
D þ21.3
127.7, 126.9, 125.5, 125.0, 124.32, 124.26, 124.0 (aromatic), 100.7
(1NaphCH) 87.7 (C-1), 80.3 (C-4), 74.2 (C-3), 72.6 (C-2), 69.9 (C-
5), 68.3 (C-6); MS-ESI: [MþH]þ 410.8, [MþNH4]þ 427.9, [MþNa]þ
432.9, [MþK]þ 448.8. Anal. Calcd for C23H22O5S: C: 67.30; H:
5.40; S: 7.81. Found: C: 67.25; H: 5.43; S: 7.83.
;
CDCl3):
d 8.13 (m, 1H, aromatic), 7.79 (m, 3H, aromatic), 7.20e7.52
(m, 13H, aromatic), 5.96 (s, 1H, 1NaphCH), 4.74 (d, 1H, J 11.7 Hz,
½PhCH2), 4.65 (d, 1H, J 11.7 Hz, ½PhCH2), 4.62 (s, 2H, PhCH2), 4.32

7828
Z. Csíki, P. Fügedi / Tetrahedron 66 (2010) 7821e7837
(dd,1H, J6a,6b 10.6 Hz, J5,6b 4.7 Hz, H-6b), 3.78e4.06 (m, 6H, H-1b, H-
2, H-3, H-4, H-5, H-6a), 3.65 (dd, 1H, J1a,1bzJ1a,2 10 Hz, H-1a), 2.84
4.8. 5-O-Acetyl-1-azido-2,3-di-O-benzyl-1-deoxy-4,6-O-
(1-naphthyl)methylene- -glucitol (18)
D
and 2.37 (2s, 2ꢂ1H, 2 OH); 13C NMR (50 MHz, CDCl3):
d 138.1, 137.7,
133.8, 132.8, 130.6, 129.7, 128.7, 128.6, 128.5, 128.1, 126.3, 125.7,
125.1, 124.3, 124.2 (aromatic), 100.3 (1NaphCH), 81.7, 79.8 and 77.1
(C-2, C-3, and C-4), 74.4 and 73.3 (2 PhCH2), 71.2 (C-6), 62.3 (C-5),
61.8 (C-1); MS-ESI: [MþH]þ 501.2, [MþNH4]þ 518.2, [MþNa]þ 523.1,
[MþK]þ 539.2. Anal. Calcd for C31H32O6: C: 74.38; H: 6.44. Found: C:
74.40; H: 6.42.
To a solution of 17 (4 g, 6.6 mmol) in a mixture of DMF and water
(8:1, 40 mL) NaN3 (0.6 g, 9.9 mmol, 1.5 equiv) and NH4Cl (1 g,
19.8 mmol, 3 equiv) were added, and the reaction mixture was
heated to reflux for 2 days. The mixture was evaporated, the residue
was dissolved in CH2Cl2 (400 mL), and washed with water
(4ꢂ150 mL). The organic layer was dried, the solvent was evapo-
rated, and the residue was purified by column chromatography
(hexaneseEtOAc, 9:1/4:1) to give 18 (2.9 g, 79%) as a colorless
4.6. 2,3-Di-O-benzyl-1-bromo-1-deoxy-4,6-O-(1-naphthyl)
methylene-D-glucitol (16)
syrup; Rf (hexaneseEtOAc, 4:1) 0.66; [
(film): 2923, 2855, 2361, 2099, 1741, 1600, 1454, 1369, 1233, 1107,
1077, 1050, 1027 cmꢁ1 1H NMR (300 MHz, CDCl3):
8.14 (m, 1H,
a
]
D þ1.4 (c 0.7, CHCl3); IR nmax
;
d
To a solution of 15 (3.4 g, 6.8 mmol) in dry pyridine (30 mL),
Ph3P (3.58 g, 13.6 mmol, 2 equiv) and CBr4 (3.4 g, 10.2 mmol,
1.5 equiv) were added, and the mixture was stirred at 0 ꢀC for 3 h.
MeOH (10 mL) was added and the mixture was diluted with CH2Cl2
(250 mL) and washed with 2 M aq HCl (100 mL), saturated aq
NaHCO3 (100 mL), and water (100 mL). The organic layer was dried
and concentrated. The residue was purified by column chroma-
tography (tolueneeacetone, 98:2/9:1) to give 16 (3.8 g, 98%) as
a yellowish syrup; Rf (tolueneeacetone, 9:1) 0.54; IR nmax (film):
3061, 3031, 2925, 2856, 2361, 1739, 1601, 1454, 1368, 1234, 1107,
aromatic), 7.85 (m, 2H, aromatic), 7.75 (m, 1H, aromatic), 7.22e7.52
(m, 13H, aromatic), 6.02 (s, 1H, 1NaphCH), 5.21 (ddd, 1H, J4,5zJ5,6a
9.9 Hz, J5,6b 5.4 Hz, H-5), 4.72 (d,1H, J 11.5 Hz, ½PhCH2), 4.64 (d,1H, J
11.4 Hz, ½PhCH2), 4.58 (d, 1H, J 11.5 Hz, ½PhCH2), 4.57 (dd, 1H, J6a,6b
10.4 Hz, H-6b), 4.45 (d, 1H, J 11.4 Hz, ½PhCH2), 4.20 (dd, 1H, J3,4
9.9 Hz, J2,3 1.7 Hz, H-4), 3.91 (m, 1H, H-2), 3.65e3.75 (m, 2H, H-3, H-
6a), 3.45 (d, 2H, J1,2 4.4 Hz, H-1a, H-1b), 1.96 (s, 3H, OC(O)CH3); 13
NMR (75 MHz, CDCl3): 169.4 (OC(O)CH3), 137.9, 137.5, 133.7, 132.4,
C
d
130.4, 129.8, 129.0, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.8,
126.3, 125.7, 125.3, 125.0, 124.4, 124.3, 124.1 (aromatic), 100.5
(1NaphCH), 78.5 (C-2), 77.6 (C-4), 74.1 (C-3), 73.6 and 73.5 (2
PhCH2), 68.2 (C-6), 62.7 (C-5), 52.0 (C-1), 20.8 (OC(O)CH3); MS-ESI:
[MþH]þ 568.3, [MþNH4]þ 585.2, [MþNa]þ 590.2, [MþK]þ 606.3.
Anal. Calcd for C33H33N3O6: C, 69.83; H, 5.86. Found: C, 69.80; H,
5.89.
1078, 1027 cmꢁ1 1H NMR (200 MHz, CDCl3):
; d 8.12 (m, 1H, aro-
matic), 7.78 (m, 3H, aromatic), 7.10e7.52 (m, 13H, aromatic), 5.94
(s, 1H, 1NaphCH), 4.73 (d, 1H, J 11.4 Hz, ½PhCH2), 4.67 (d, 1H, J
11.7 Hz, ½PhCH2), 4.63 (d, 1H, J 11.4 Hz, ½PhCH2), 4.59 (d, 1H, J
11.7 Hz, ½PhCH2), 4.29 (dd, 1H, J6a,6b 10.3 Hz, J5,6b 4.7 Hz, H-6b),
3.86e4.08 (m, 5H, H-2, H-3, H-4, H-5, H-6a), 3.72 (dd, 1H, J1a,1b
11 Hz, J1b,2 3.6 Hz, H-1b), 3.57 (dd, 1H, J1a,2 7 Hz, H-1a), 2.41 (d, 1H,
4.9. 1-Azido-2,3-di-O-benzyl-1-deoxy-4,6-O-(1-naphthyl)
methylene-D-glucitol (19)
J5,OH 4 Hz, OH); 13C NMR (50 MHz, CDCl3):
d
137.9, 137.5, 133.8,
132.8, 130.6, 129.7, 129.1, 128.64, 128.61, 128.29, 128.25, 128.21,
126.3, 125.7, 125.4, 125.1, 124.2 (aromatic), 100.2 (1NaphCH), 81.3,
79.6 and 77.3 (C-2, C-3, and C-4), 74.4 and 74.0 (2 PhCH2), 71.1 (C-
6), 62.1 (C-5), 32.8 (C-1). Anal. Calcd for C31H31BrO5: C, 66.08; H,
5.55. Found: C, 66.05; H, 5.60.
To a solution of 18 (2.9 g, 5.2 mmol) in dry MeOH (30 mL),
a catalytic amount of NaOMe was added. The mixture was stirred
overnight at room temperature, neutralized with Amberlite IR 120
(Hþ) resin (pH ca. 7), filtered, and concentrated to give 19 (2.7 g,
98%) as a colorless syrup; Rf (tolueneeacetone, 9:1) 0.38; [
a
]
D þ24.7
(c 0.4, CHCl3); IR nmax (film): 2925, 2855, 2362, 2099, 1740, 1601,
4.7. 5-O-Acetyl-2,3-di-O-benzyl-1-bromo-1-deoxy-4,6-O-
1454, 1370, 1233, 1107, 1078, 1028 cmꢁ1; 1H NMR (200 MHz, CDCl3):
(1-naphthyl)methylene-
D
-glucitol (17)
d 8.10 (m, 1H, aromatic), 7.80 (m, 3H, aromatic), 7.12e7.52 (m, 13H,
aromatic), 5.95 (s, 1H, 1NaphCH), 4.70 (d, 1H, J 11.4 Hz, ½PhCH2),
4.67 (d, 1H, J 11.7 Hz, ½PhCH2), 4.65 (d, 1H, J 11.4 Hz, ½PhCH2), 4.56
(d, 1H, J 11.7 Hz, ½PhCH2), 4.30 (dd, 1H, J6a,6b 10.3 Hz, J5,6b 4.7 Hz, H-
6b), 3.80e3.94 (m, 4H, H-2, H-3, H-4, H-5), 3.63 (dd, 1H, J5,6azJ6a,6b
10.3 Hz, H-6a), 3.50 (d, 2H, J1,2 4.7 Hz, H-1a, H-1b), 2.36 (d, 1H, J5,OH
To a solution of 16 (3.8 g, 6.8 mmol) in dry pyridine (30 mL),
acetic anhydride (6.4 mL, 67.8 mmol, 10 equiv) was added at 0 ꢀC.
The mixture was stirred at room temperature overnight, then was
quenched with water (10 mL). The mixture was diluted with CH2Cl2
(400 mL), washed with 2 M aq HCl (200 mL), saturated aq NaHCO3
(200 mL), and water (200 mL). The organic layer was dried and
concentrated. The residue was purified by column chromatography
(tolueneeacetone, 9:1) to give 17 (4 g, 98%) as a yellowish syrup; Rf
4.0 Hz, OH); 13C NMR (50 MHz, CDCl3):
d 137.8, 137.4, 133.8, 132.7,
130.6, 129.7, 129.1, 128.7, 128.3, 126.3, 125.7, 125.4, 125.1, 124.2 (ar-
omatic), 100.1 (1NaphCH), 81.5, 79.0 and 76.0 (C-2, C-3, and C-4),
74.3 and 73.7 (2 PhCH2), 71.0 (C-6), 62.0 (C-5), 51.8 (C-1); MS-ESI:
[MþH]þ 526.0, [MþNH4]þ 543.1, [MþNa]þ 548.2, [MþK]þ 563.9.
Anal. Calcd for C31H31N3O5: C, 70.84; H, 5.94. Found: C, 70.88;
H, 5.90.
(tolueneeacetone, 9:1) 0.73; [
3030, 2924, 2856, 2361, 1739, 1600, 1454, 1368, 1234, 1107, 1077,
1028 cmꢁ1 1H NMR (200 MHz, CDCl3):
8.14 (m, 1H, aromatic),
a]
D þ2.6 (c 0.4, CHCl3); IR nmax (film):
;
d
7.76 (m, 3H, aromatic), 7.10e7.52 (m, 13H, aromatic), 5.99 (s, 1H,
1NaphCH), 5.22 (ddd, 1H, J4,5zJ5,6a 9.9 Hz, J5,6b 5.5 Hz, H-5), 4.73 (d,
1H, J 11.4 Hz, ½PhCH2), 4.66 (d, 1H, J 11.7 Hz, ½PhCH2), 4.57 (d, 1H, J
11.7 Hz, ½PhCH2), 4.54 (dd, 1H, J6a,6b 10.6 Hz, H-6b), 4.44 (d, 1H, J
11.4 Hz, ½PhCH2), 4.21 (dd, 1H, J3,4 2.0 Hz, H-4), 4.03 (ddd, 1H,
4.10. 1-Amino-2,3-di-O-benzyl-1-deoxy-4,6-O-(1-naphthyl)
methylene-D-glucitol (20)
To a solution of 19 (2.7 g, 5.1 mmol) in a mixture of pyridine and
water (9:1, 30 mL) 1,3-propanedithiol (10.3 mL, 102.2 mmol,
20 equiv) and 40 drops of Et3N (pH ca. 8) were added and the
mixture was stirred at room temperature for 3 days. It was then
evaporated and co-evaporated with toluene three times. The
product was purified by column chromatography (CH2Cl2eMeOH,
95:5/4:1) to give 20 (2.4 g, 96%), as white crystals; mp 128e130 ꢀC
J
1a,2zJ1b,2 6.6 Hz, J2,3 2.2 Hz, H-2), 3.62e3.74 (m, 3H, H-1b, H-3, H-
6a), 3.55 (dd, 1H, J1a,1b 11.4 Hz, H-1a), 1.92 (s, 3H, OC(O)CH3); 13C
NMR (50 MHz, CDCl3): 170.1 (OC(O)CH3), 138.7, 138.3, 134.5, 133.1,
d
131.1, 130.5, 129.7, 129.3, 129.2, 129.0, 128.9, 128.8, 128.6, 127.0,
126.4, 126.0, 125.7, 125.2, 124.9 (aromatic), 101.4 (1NaphCH), 79.8,
78.44 and 78.36 (C-2, C-3, and C-4), 74.55 and 74.48 (2 PhCH2), 68.9
(C-6), 63.5 (C-5), 34.6 (C-1), 21.5 (OC(O)CH3). Anal. Calcd for
C33H33BrO6: C, 65.46; H, 5.49. Found: C, 65.45; H, 5.50.
(from EtOAcehexanes); Rf (CH2Cl2eMeOH, 9:1) 0.33; [
a
;
]
D þ30.4 (c
0.5, CHCl3); IR nmax (film): 3604, 3307, 1642 cmꢁ1
1H NMR

Z. Csíki, P. Fügedi / Tetrahedron 66 (2010) 7821e7837
7829
(200 MHz, CDCl3):
d
8.16 (m, 1H, aromatic), 7.79 (m, 3H, aromatic),
NMR (100 MHz, CDCl3):
d
149.7,146.0,137.5,137.0,133.7,132.6,130.4,
7.18e7.52 (m, 13H, aromatic), 5.98 (s, 1H, 1NaphCH), 4.75 (d, 1H, J
11.7 Hz, ½PhCH2), 4.68 (d, 1H, J 11.7 Hz, ½PhCH2), 4.66 (d, 1H, J
11.4 Hz, ½PhCH2), 4.52 (d, 1H, J 11.4 Hz, ½PhCH2), 4.34 (dd, 1H, J5,6b
4.6 Hz, J6a,6b 10.6 Hz, H-6b), 3.86e4.08 and 3.62e3.84 (2 m, 3H and
2H, H-2, H-3, H-4, H-5, H-6a), 3.01 (dd, 1H, J1a,1b 13.4 Hz, J1b,2 3.6 Hz,
H-1b), 2.91 (dd, 1H, J1a,2 6.3 Hz, H-1a), 2.82 (br s, 3H, NH2 and OH);
129.9, 128.8, 128.60, 128.58, 128.3, 128.2, 127.9, 127.5, 126.3, 125.7,
125.1,124.0,123.3 (aromatic), 99.5 (1NaphCH), 78.5 (C-3), 74.9 (C-4),
74.0 (C-2), 72.0 (C-6), 71.9 and 70.8 (2 PhCH2), 47.8 (C-5), 44.1 (C-1);
MS-ESI: [MþNa]þ 689.7. Anal. Calcd for C37H34N2O8S: C, 66.65; H,
5.14; N, 4.20; S, 4.81. Found: C, 66.67; H, 5.17; N, 4.18; S, 4.85.
13C NMR (50 MHz, CDCl3):
d
138.3, 137.9, 133.9 133.0, 130.6, 129.7,
4.13. 2,3-Di-O-benzyl-1,5-dideoxy-4,6-O-(1-naphthyl)
128.8, 128.7, 128.6, 128.4, 128.2, 128.0, 126.2, 125.7, 125.1, 124.4
(aromatic), 100.4 (1NaphCH), 81.9, 80.6 and 77.2 (C-2, C-3, and C-4),
74.6 and 73.5 (2 PhCH2), 71.4 (C-6), 62.2 (C-5), 41.8 (C-1); MS-ESI:
[MþH]þ 500.0. Anal. Calcd for C31H33NO5: C, 74.53; H, 6.66. Found:
C, 74.55; H, 6.64.
methylene-1,5-imino-L-iditol (22)
To a stirred solution of 10b (3 g, 4.5 mmol) in dry DMF (30 mL),
PhSH (0.55 mL, 5.4 mmol, 1.2 equiv) and dry K2CO3 (1.9 g,
13.5 mmol, 3 equiv) were added and the mixture was stirred at
room temperature for 5 days. It was diluted with CH2Cl2 (400 mL)
and was washed with water (3ꢂ150 mL). The organic layer was
dried, the solvent was evaporated, and the residue was purified by
column chromatography (CH2Cl2eMeOH, 98:2/95:5) to give 22
(2.1 g, 98%) as a pale yellow syrup; Rf (CH2Cl2eMeOH, 95:5) 0.25;
4.11. 2,3-Di-O-benzyl-1-deoxy-4,6-O-(1-naphthyl)methylene-
1-(4-nitro)benzene-sulfonamido-D-glucitol (21)
Et3N (2.05 mL, 14.7 mmol, 3 equiv) and 4-nitrobenzenesulfonyl
chloride (1.35 g, 6.12 mmol, 1.25 equiv) were added to a solution of
20 (2.4 g, 4.9 mmol) in dry CH2Cl2 (25 mL) and the mixture was
stirred at 0 ꢀC under argon for 10 min. Then, water (40 mL) was
added and the mixture was diluted with CH2Cl2 (350 mL) and
washed with 2 M aq HCl (150 mL), saturated aq NaHCO3 (150 mL),
and water (150 mL). The organic layer was dried and concentrated.
The residue was purified by column chromatography (toluene-
eacetone, 95:5/4:1) to give syrupy 21 (3.3 g, 98%); Rf (toluene-
[a
]
ꢁ17.7 (c 0.2, CHCl3); IR nmax (film): 2924, 2363, 1879, 1123,
D
1075 cmꢁ1 1H NMR (200 MHz, CDCl3):
; d 8.18 (m, 1H, aromatic),
7.78 (m, 3H, aromatic), 7.20e7.48 (m, 13H, aromatic), 6.06 (s, 1H,
1NaphCH), 4.67 (d, 1H, J 11.7 Hz, ½PhCH2), 4.60 (d, 2H, J 13.5 Hz,
PhCH2), 4.48 (d, 1H, J 11.7 Hz, ½PhCH2), 4.23 (m, 2H), 4.15 (m, 1H),
3.92 (m, 1H), 3.41 (m, 1H), 3.21 (m, 2H) and 2.91 (m, 1H) skeleton
protons, 2.77 (br s, 1H, NH); 13C NMR (50 MHz, CDCl3):
d 138.4,
138.0, 134.1, 133.8, 133.5, 130.5, 129.8, 129.5, 128.6, 128.5, 128.3,
128.0, 127.70, 127.66, 127.5, 126.3, 125.6, 125.2, 124.9, 123.9 (aro-
matic), 100.4 (1NaphCH), 73.9, 73.6 and 72.6 (C-2, C-3, and C-4),
72.3 (C-6), 71.6 and 70.9 (2 PhCH2), 48.9 (C-5), 45.9 (C-1); MS-ESI:
[MþH]þ 481.9, [MþNa]þ 504.2. Anal. Calcd for C31H31NO4: C, 77.31;
H, 6.49; N, 2.91. Found: C, 77.31; H, 6.51; N, 2.93.
eacetone, 9:1) 0.25; [
2854, 2283, 1529, 1496, 1348, 1310, 1164, 1103, 1070, 1026,
1013 cmꢁ1 1H NMR (200 MHz, CDCl3):
8.14 (m, 1H, aromatic),
a
]D þ3.9 (c 0.31, CHCl3); IR nmax (film): 2924,
;
d
7.78e7.88 (m, 4H, aromatic), 7.64 (m, 1H, aromatic), 7.10e8.18 (m,
15H, aromatic), 5.88 (s,1H, 1NaphCH), 5.12 (dd,1H, JNH,H-1azJNH,H-1b
6.2 Hz, NH), 4.68 (d, 1H, J 11.4 Hz, ½PhCH2), 4.60 (d, 1H, J 11.4 Hz,
½PhCH2), 4.54 (d, 1H, J 11.6 Hz, ½PhCH2), 4.50 (d, 1H, J 11.6 Hz,
½PhCH2), 4.29 (dd, 1H, J5,6b 4.7 Hz, J6a,6b 11.0 Hz, H-6b), 3.80e4.00
and 3.59 (m and t, 5H, H-2, H-3, H-4, H-5, H-6a), 3.29 (ddd, 1H, J1a,1b
12.1 Hz, J1b,2 4.8 Hz, H-1b), 3.10 (ddd, 1H, J1a,2 5.8 Hz, H-1a), 2.07 (s,
4.14. 2,3-Di-O-benzyl-N-benzyloxycarbonyl-1,5-dideoxy-1,5-
imino-4,6-O-(1-naphthyl)methylene-L-iditol (10a)
To a solution of 22 (2.1 g, 4.4 mmol) in dry MeOH (20 mL), benzyl
chloroformate (0.74 mL, 5.3 mmol, 1.2 equiv) and NaHCO3 (0.44 g,
5.3 mmol, 1.2 equiv) were added. The mixture was stirred at room
temperature for 10 min. Saturated aq NaHCO3 (10 mL) was added,
and the mixture was diluted with CH2Cl2 (300 mL), washed with
2 M aq HCl (100 mL), saturated aq NaHCO3 (100 mL), and water
(100 mL), dried, and concentrated. The residue was purified by
column chromatography (hexaneseEtOAc, 95:5/4:1) to give 10a
1H, OH); 13C NMR (50 MHz, CDCl3):
d 149.6, 145.3, 137.6, 137.4,
133.8, 132.5, 130.4, 129.9, 129.1, 128.8, 128.7, 128.6, 128.44, 128.36,
128.3, 128.1, 127.8, 126.4, 125.9, 125.4, 125.1, 124.7, 124.3, 124.1 (ar-
omatic), 100.8 (1NaphCH), 80.6, 76.7 and 75.3 (C-2, C-3, and C-4),
73.9 and 73.2 (2 PhCH2), 71.3 (C-6), 61.5 (C-5), 43.6 (C-1); MS-ESI:
[MþH]þ 685.0, [MþNH4]þ 702.0, [MþNa]þ 707.2, [MþK]þ 723.0.
Anal. Calcd for C37H36N2O9S: C, 64.90; H, 5.30; N, 4.09; S, 4.68.
Found: C, 64.85; H, 5.32; N, 4.11; S, 4.70.
(2.6 g, 97%) as a colorless syrup; Rf (hexaneseEtOAc, 4:1) 0.36; [
þ46.6 (c 1.5, CHCl3); IR nmax (film): 2925, 1882, 1701, 1454, 1418,
1347, 1138, 1104,1074,1026 cmꢁ1; 1H NMR (200 MHz, CDCl3):
8.02
a]
D
4.12. 2,3-Di-O-benzyl-1,5-dideoxy-4,6-O-(1-naphthyl)
d
methylene-1,5-imino-N-(4-nitro)benzenesulfonyl-
iditol (10b)
L
-
(m, 1H, aromatic), 7.83 (m, 3H, aromatic), 7.20e7.58 (m, 18H, aro-
matic), 6.12 (s, 1H, 1NaphCH), 5.04e5.24 (m, 2H, C(O)OCH2Ph),
4.32e4.78 (m, 7H, 2 PhCH2 and 3 skeleton protons), 3.60e3.90 (m,
A mixture of 21 (3.3 g, 4.8 mmol), DEAD (1.51 mL, 9.6 mmol,
2 equiv), and Ph3P (3.77 g,14.4 mmol, 3 equiv) in dry CH2Cl2 (40 mL)
was stirred at room temperature under argon for 5 min. The mixture
was diluted with EtOAc (400 mL) and it was washed with saturated
aq NaHCO3 (2ꢂ150 mL), and water (200 mL). The organic layer was
dried and concentrated. The residue was purified by column chro-
matography (hexaneseEtOAc, 9:1/7:3) to give 10b (3.1 g, 96%) as
white crystals; mp 150e151 ꢀC (from EtOAcehexanes); Rf (hex-
5H, skeleton protons); 13C NMR (50 MHz, CDCl3):
d 155.7 (C(O)
OCH2Ph) 138.1, 137.8, 136.6, 134.2, 133.8, 133.1, 130.5, 129.7, 128.7,
128.63, 128.58, 128.5, 128.2,128.01, 128.00,127.8,126.4, 125.7, 125.3,
124.1, 123.5 (aromatic), 99.3 (1NaphCH), 80.1, 77.2 and 75.0 (C-2, C-
3, and C-4), 71.8 and 71.2 (2 PhCH2), 68.3 (C-6), 67.5 (PhCH2), 46.7
(C-5), 42.1 (C-1); MS-ESI: [MþH]þ 616.0, [MþNH4]þ 633.0,
[MþNa]þ 638.0, [MþK]þ 654.0. Anal. Calcd for C39H37NO6: C, 76.08;
H, 6.06; N, 2.27. Found: C, 76.06; H, 6.08; N, 2.28.
aneseEtOAc, 4:1) 0.35; [
2925, 2869, 2283, 1529, 1455, 1348, 1162, 1088 cmꢁ1
(400 MHz, CDCl3): 7.00e8.06 (m, 21H, aromatic), 6.14 (s, 1H,
1NaphCH), 4.79 (dd,1H, J5,6b 1.5 Hz, J6a,6b 12.5 Hz, H-6b), 4.52 (m,1H,
3,4zJ4,5 3.0 Hz, J2,4 0.8 Hz, H-4), 4.50 (d,1H, J 12.0 Hz, ½PhCH2), 4.46
a
]D þ6.2 (c 0.64, CHCl3); IR nmax (film): 2955,
;
1H NMR
4.15. 2,3-Di-O-benzyl-4,6-O-(1-naphthyl)methylene-D-
gluconic amide (24)
d
J
A mixture of 14 (0.7 g, 1.4 mmol) and freshly prepared
DesseMartin periodinane23 (0.65 g, 1.54 mmol, 1.1 equiv) in dry
CH2Cl2 (10 mL) was stirred at room temperature for 4 h. To the
mixture were added saturated aq NaHCO3 (5 mL) and 10% aq
Na2S2O3 (35 mL), and it was stirred for 30 min. The reaction
(d, 1H, J 12.0 Hz, ½PhCH2), 4.37 (d, 1H, J 11.7 Hz, ½PhCH2), 4.24 (dd,
1H, J5,6a 1.5 Hz, H-6a), 4.18 (d, 1H, J 11.7 Hz, ½PhCH2), 3.98 (dd, 1H,
J1a,1b 14.0 Hz, J1b,2 6.7 Hz, H-1b), 3.91 (dd,1H, J1a,2 10.4 Hz, H-1a), 3.79
(ddd, 1H, H-5), 3.74 (dd,1H, J2,3 2.0 Hz, H-3), 3.30 (ddd, 1H, H-2); 13
C

7830
Z. Csíki, P. Fügedi / Tetrahedron 66 (2010) 7821e7837
mixture was diluted with CH2Cl2 (250 mL) and washed with water
(2ꢂ100 mL). The organic layer was dried and evaporated to give
crude 23 (0.63 g, 90%) as a syrup. The crude 23 (0.63 g, 1.3 mmol)
was stirred in saturated methanolic ammonia (10 mL) at room
temperature for 10 min. The mixture was evaporated and it was
purified by column chromatography (CH2Cl2eMeOH, 98:2/95:5)
to give 24 (0.42 g, 65%) as white crystals; mp 143e144 ꢀC (from
4.18. 2,3-Di-O-benzyl-N-benzyloxycarbonyl-1,5-dideoxy-1,5-
imino-4-O-(1-naphthyl)methyl- -iditol (25)
L
1 M BH3$THF (8.6 mL, 8.6 mmol, 3 equiv) and TMSOTf (0.062 mL,
0.343 mmol, 0.12 equiv) were added to a solution of 10a (1.76 g,
2.86 mmol) in dry CH2Cl2 (20 mL) and the mixture was stirred at
room temperature under argon for 7 h. The mixture was cooled and
it was treated with Et3N (5 mL) and MeOH (5 mL), then it was
evaporated and co-evaporated with MeOH (20 mL) three times. The
residue was purified by column chromatography (tolueneeacetone,
98:2/9:1) to yield 25 (1.6 g, 91%) as a colorless syrup; Rf (tolue-
EtOAcehexanes); Rf (CH2Cl2eMeOH, 95:5) 0.30; [
CHCl3); IR nmax (film): 3448, 1636 cmꢁ1 1H NMR (200 MHz,
CDCl3): 8.20 (m, 1H, aromatic), 7.72e7.88 (m, 3H, aromatic),
a]
þ12.4 (c 0.7,
D
;
d
7.24e7.52 (m, 13H, aromatic), 6.68 (d, 1H J 3.3 Hz, ½NH2), 6.04 (m,
2H, ½NH2 and 1NaphCH), 4.68 (s, 2H, PhCH2), 4.67 (d, 1H, J 11.0 Hz,
½PhCH2), 4.57 (d, 1H, J 11.0 Hz, ½PhCH2), 4.10e4.40 (m, 4H, H-2,
H-3, H-4, H-5), 4.06 (dd, 1H, J6a,6b 10.3 Hz, J5,6a 4.8 Hz, H-6b), 3.68
(t, 1H, J5,6a 9.8 Hz, H-6a), 2.67 (s, 1H, OH); 13C NMR (50 MHz,
neeacetone, 9:1) 0.25; [
a
]
þ1.2 (c 0.83, CHCl3); IR nmax (film):
D
3419, 1636 cmꢁ1 1H NMR (200 MHz, CDCl3):
;
d 8.04e7.10 (m, 22H,
aromatic), 5.10 (m, 5H, C(O)OCH2Ph, 3ꢂ½PhCH2), 4.10e4.92 (m, 5H,
H-5, H-1b, ½PhCH2, 1NaphCH2), 3.60e4.06 (m, 4H, H-3, H-4, H-6a,
H-6b), 3.46 (br s,1H, H-2), 2.92 (m,1H, H-1a), 2.41 (br s,1H, OH); 13C
CDCl3):
d 174.1 (C-1), 137.6, 136.9, 133.9, 132.9, 130.7, 129.8, 128.8,
128.6, 128.4, 128.3, 126.3, 125.7, 125.1, 124.4, 124.3 (aromatic), 100.5
(1NaphCH), 80.7, 79.6 and 79.2 (C-2, C-3, and C-4), 75.2 and 74.1 (2
PhCH2), 71.3 (C-6), 63.1 (C-5); MS-ESI: [MþH]þ 514, [MþNa]þ 536.
Anal. Calcd for C31H31NO6: C, 72.50; H, 6.08; N, 2.73. Found: C,
72.45; H, 6.12; N, 2.70.
NMR (50 MHz, CDCl3): d 156.1 and 155.8 (C(O)OCH2Ph) 138.8, 138.0,
136.4,133.7,133.3,131.6,128.9,128.6,128.4,128.3,128.1,127.8,127.7,
127.5, 126.7, 126.4, 125.9, 125.2, 123.8 (aromatic), 82.1, 79.2 and 78.1
(C-2, C-3, and C-4), 75.4 (1NaphCH2), 72.9, 71.8 and 71.6 (2 PhCH2),
67.7 (C(O)OCH2Ph), 59.1 (C-6), 54.3 and 54.7 (C-5), 41.9 and 41.6 (C-
1); MS-ESI: [MþH]þ 618.1, [MþNa]þ 640.1, [MþK]þ 656.1. Anal.
Calcd for C39H39NO6: C, 75.83; H, 6.36; N, 2.27. Found: C, 75.81; H,
6.37; N, 2.32.
4.16. 1-Amino-2,3-di-O-benzyl-1-deoxy-4,6-O-(1-naphthyl)
methylene-D-glucitol (20)
To a solution of 24 (0.42 g, 0.8 mmol) in THF (5 mL), LiAlH4
(0.16 g, 4.1 mmol, 5 equiv) was added. The mixture was heated to
reflux and stirred for 7 h. To the reaction mixture was added EtOAc
(20 mL) and it was stirred for 10 min, then it was treated with cold
water (20 mL) and saturated aq NaHCO3 (50 mL). The mixture was
filtered, the filtrate was diluted with CH2Cl2 (200 mL) and the
organic layer was washed with brine (50 mL) and water (50 mL), it
was dried and concentrated. The residue was purified by column
chromatography (CH2Cl2eMeOH, 98:2/4:1) to give 20 (0.3 g,
70%) as white crystals; mp 128e130 ꢀC (from EtOAcehexanes).
The 1H and 13C NMR spectra were identical with those described
in Section 4.10.
4.19. tert-Butyl [2,3-di-O-benzyl-N-benzyloxycarbonyl-
1,5-dideoxy-1,5-imino-4-O-(1-naphthyl)methyl-L-iditol]
uronate (26)
Pyridinium dichromate (1.95 g, 5.18 mmol, 2 equiv), acetic an-
hydride (2.47 mL, 26 mmol, 10 equiv), and tert-butyl alcohol
(4.87 mL, 51.8 mmol, 20 equiv) were added to a stirred solution of
25 (1.6 g, 2.6 mmol) in dry CH2Cl2 (20 mL). The mixture was stirred
for 8 h at room temperature and was then applied on the top of
a silica gel column in EtOAc, with a 5 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. The crude product was purified by column chromatography
(hexaneseEtOAc, 95:5/4:1) to give 26 (1.21 g, 68%) as a colorless
4.17. 2,3-Di-O-benzyl-N-benzyloxycarbonyl-1,5-dideoxy-1,5-
imino-6-O-(1-naphthyl)methyl-
L
-iditol (8)
syrup; Rf (hexaneseEtOAc, 4:1) 0.66; [
a]
D ꢁ10.3 (c 0.58, CHCl3); IR
nmax (film): 1753, 1720, 1636 cmꢁ1 1H NMR (200 MHz, CDCl3):
;
To a mixture of 10a (1.0 g, 1.6 mmol), NaBH3CN (1.02 g, 16 mmol,
10 equiv) and 3 Å molecular sieves (1 g) in dry THF (10 mL), an
ethereal solution of HCl was added until the pH reached ca. 3. The
mixture was stirred at 0 ꢀC under argon for 30 min, then it was
filtered, diluted with CH2Cl2 (200 mL), and was washed with sat-
urated aq NaHCO3 (2ꢂ75 mL) and water (100 mL). The organic layer
was dried and was concentrated. The residue was purified by col-
umn chromatography (tolueneeacetone, 98:2/9:1) to give syrupy
d 8.10e7.10 (m, 22H, aromatic), 5.00e5.40 (m, 4H, 2 PhCH2),
4.55e4.95 (m, 4H, H-5, ½PhCH2, 1NaphCH2), 4.40 (dd, 1H, J1a,1b
13.0 Hz, J1b,2 4.5 Hz, H-1b), 3.90e4.25 (m, 2H, H-3, H-4), 3.25e3.55
(m, 2H, H-2, H-1a), 1.32 (s, 9H, C(CH3)3); 13C NMR (50 MHz, CDCl3):
d
168.9 and 168.5 (C-6), 155.6 and 155.3 (C(O)OCH2Ph), 138.8, 138.4,
136.4, 133.7, 133.5, 131.6, 128.7, 128.62, 128.56, 128.5, 128.3, 128.2,
128.1,128.0,127.8,127.5,126.3, 125.8,125.2,124.1 (aromatic), 82.1 (C
(CH3)3), 81.1, 80.7, 78.2 and 77.5 (C-2, C-3, and C-4), 75.0, 72.7, 71.7,
71.3 and 67.8 (3 PhCH2 and 1NaphCH2), 57.1 and 56.4 (C-5), 43.3 (C-
1), 28.1 (C(CH3)3); MS-ESI: [MþH]þ 688.4, [MþNH4]þ 705.6,
[MþNa]þ 710.4, [MþK]þ 726.4. Anal. Calcd for C43H45NO7: C, 75.09;
H, 6.59; N, 2.04. Found: C, 75.12; H, 6.60; N, 2.08.
8 (0.67 g, 67%); Rf (tolueneeacetone, 9:1) 0.40; [
CHCl3); IR nmax (film): 3455, 1636 cmꢁ1; 1H NMR (400 MHz, CDCl3):
8.10e7.20 (m, 22H, aromatic), 5.08 (s, 2H, C(O)OCH2Ph), 4.98 (d,
a
]
D
ꢁ6.6 (c 0.3,
d
1H, J 12.0 Hz, ½PhCH2), 4.90 (d, 1H, J 12.0 Hz, ½PhCH2), 4.87 (d, 1H, J
12.1 Hz, ½1NaphCH2), 4.66 (ddd, 1H, J5,6a 4.4 Hz, J5,6b 6.5 Hz, J4,5
6.0 Hz, H-5), 4.61 (d, 1H, J 11.4 Hz, ½PhCH2), 4.58 (d, 1H, J 12.1 Hz,
½1NaphCH2), 4.57 (d, 1H, J 11.4 Hz, ½PhCH2), 4.28 (dd, 1H, J1a,1b
13.2 Hz, J1b,2 5.7 Hz, H-1b), 3.86 (dd, 1H, J6a,6b 10.2 Hz, H-6b), 3.82
(dd, 1H, H-6a), 3.69 (dd, 1H, J3,4 9.3 Hz, J4,OH 2.7 Hz, H-4), 3.65 (dd,
1H, J2,3 7.5 Hz, H-3), 3.44 (m, 1H, H-2), 2.98 (dd, 1H, J1a,2 10.6 Hz, H-
4.20. tert-Butyl (2,3-di-O-benzyl-N-benzyloxycarbonyl-1,5-
dideoxy-1,5-imino-L-iditol)uronate (9a)
Compound 26 (1.21 g, 1.76 mmol) was dissolved in a mixture of
MeCN and water (9:1, 15 mL), CAN (1.93 g, 3.52 mmol, 2 equiv) was
added and the mixture was stirred for 3 h at room temperature. It
was diluted with chloroform (300 mL) and was washed with sat-
urated aq NaHCO3 (150 mL) and water (100 mL). The aqueous layer
was back-extracted with chloroform (200 mL). The combined or-
ganic layers were dried and concentrated. Column chromatography
of the residue (tolueneeacetone, 98:2/9:1) gave syrupy 9a
1a), 2.40 (s, 1H, OH); 13C NMR (100 MHz, CDCl3):
d 155.7 (C(O)
OCH2Ph) 138.6, 138.0, 136.5, 133.8, 133.5, 131.6, 128.5, 127.9, 126.3,
125.8, 125.2, 123.9 (aromatic), 82.5 (C-3), 78.5 (C-2), 75.1
(1NaphCH2), 72.4 and 71.7 (2 PhCH2), 70.6 (C-4), 67.6 (C(O)OCH2Ph),
66.4 (C-6), 53.9 (C-5), 42.6 (C-1); MS-ESI: [MþH]þ 618.1, [MþNa]þ
640.1, [MþK]þ 656.1. Anal. Calcd for C39H39NO6: C, 75.83; H, 6.36; N,
2.27. Found: C, 75.80; H, 6.35; N, 2.29.
(0.962 g, 65%); Rf (tolueneeacetone, 9:1) 0.43; [
a]
þ12 (c 0.33,
D

Z. Csíki, P. Fügedi / Tetrahedron 66 (2010) 7821e7837
7831
CHCl3); IR nmax (film): 3125, 3051, 2995, 1754, 1720 cmꢁ1
;
1H NMR
½PhCH2), 4.94 (d, 1H, J 12.0 Hz, ½PhCH2), 4.80 (d, 1H, J 11.0 Hz,
½PhCH2), 4.79 (s, 2H, 1NaphCH2), 4.76 (d, 1H, J 12.4 Hz, ½PhCH2), 4.70
(d, 1H, J 11.6 Hz, ½PhCH2), 4.61 (d, 1H, J 11.6 Hz, ½PhCH2), 4.59 (ddd,
1H, J4,5 11.2 Hz, J5,6a 3.6 Hz, J5,6b 7.6 Hz, H-5), 4.58 (d, 1H, J 11.0 Hz,
½PhCH2), 4.55 (d, 1H, J 12.0 Hz, ½PhCH2), 4.13e4.29 (m, 5H, H-4, H-
6a0, H-6b0, C(O)CH2Cl), 4.19 (dd, 1H, J1a,1b 13.2 Hz, J1b,2 5.2 Hz, H-1b),
3.95 (dd, 1H, J6a,6b 10.8 Hz, H-6b), 3.85 (dd, 1H, H-6a), 3.84 (ddd, 1H,
(200 MHz, CDCl3): 7.22e7.48 (m, 15H, aromatic), 4.94e5.26 (m,
d
3H, PhCH2 and H-5), 4.87 and 4.67 (2 s, 4H, 2 PhCH2), 4.40 (dd, 1H,
J1a,1b 12.8 Hz, J1b,2 5.1 Hz, H-1b), 4.12e4.22 and 3.34e3.80 (2 m, 4H,
H-1a, H-2, H-3, H-4), 2.19 (s, 1H, OH), 1.39 (s, 9H, C(CH3)3); 13C NMR
(50 MHz, CDCl3):
d 170.0 (C-6), 155.4 (C(O)OCH2Ph), 138.7, 138.1,
136.3, 128.6, 128.55, 128.50, 128.3, 128.2, 128.0, 127.9, 127.8 (aro-
matic), 83.5 (C(CH3)3), 82.6, 77.6 and 73.0 (C-2, C-3, and C-4), 75.3,
71.5 and 67.9 (3 PhCH2), 57.6 (C-5), 43.9 (C-1), 28.1 (C(CH3)3); MS-
ESI: [MþH]þ 548.1, [MþNH4]þ 565.1, [MþNa]þ 570.1, [MþK]þ 586.1.
Anal. Calcd for C32H37NO7: C, 70.18; H, 6.81; N, 2.56. Found: C,
70.22; H, 6.79; N, 2.54.
J4 ,5 8.8 Hz, J5 ,6a 2.0 Hz, J5 ,6b 3.6 Hz, H-50), 3.80 (dd, 1H, J2 ,3 11.0 Hz,
0
0
0
0
0
0
0
0
0
J3 ,4 10.0 Hz, H-3 ), 3.79 (t, 1H, J2,3zJ3,4 3.2 Hz, H-3), 3.57 (dd,1H, H-40),
0
0
3.51 (dd, 1H, H-20), 3.46 (ddd, 1H, J1a,2 11.0 Hz, J1b,2 5.2 Hz, H-2), 2.86
(dd, 1H, H-1a); 13C NMR (100 MHz, DMSO-d6, 100 ꢀC):
d 167.5 (OC(O)
CH2Cl), 155.2 (C(O)OCH2Ph), 138.7, 137.9, 137.6, 137.2, 136.5, 133.8,
133.3, 131.6, 128.7, 128.6, 128.4, 128.33, 128.27, 128.1, 127.9, 127.5, 126.5,
126.4, 126.3, 128.2, 125.9, 125.8, 125.24, 125.19, 124.1, 124.0 (aromatic),
98.9 (C-10), 82.6 (C-3), 80.2 (C-30), 78.9 (C-2), 77.9 (C-4), 77.2 (C-40),
75.5 (1NaphCH2), 75.3, 75.2, 75.0 and 72.7 (4 PhCH2), 70.0 (C-50), 67.6
(C(O)OCH2Ph), 66.1 (C-6), 64.5 (C-60), 63.2 (C-20), 53.8 (C-5), 42.1 (C-1),
40.9 (C(O)CH2Cl); MS-ESI: [MþH]þ 1061.5, [MþNH4]þ 1078.5,
[MþNa]þ 1083.5, [MþK]þ 1099.3. Anal. Calcd for C61H61ClN4O11: C,
69.01; H, 5.79; N, 5.28. Found: C, 69.05; H, 5.82; N, 5.25.
4.21. Phenyl 2-azido-3,4-di-O-benzyl-6-O-chloroacetyl-2-
deoxy-1-tio-a,b-D-glucopyranoside (7)
To a solution of 2728 (19.7 g, 53.7 mmol) in dry CH2Cl2 (150 mL),
PhSSiMe3 (30.4 mL, 161 mmol, 3 equiv) and ZnI2 (34.3 g, 107 mmol,
2 equiv) were added. The mixture was stirred at room temperature
overnight, then it was filtered through a pad of Celite. The filtrate
was diluted with CH2Cl2 (500 mL), after which first a solution of HCl
in dioxane (20 mL), then water (10 mL) were added. The mixture
was stirred at room temperature for 10 min; the organic layer was
washed with 2 M aq HCl (200 mL), saturated aq NaHCO3 (200 mL),
and water (200 mL), dried, and concentrated. Column chromatog-
raphy of the residue (tolueneeacetone, 98:2/9:1) gave syrupy
4.23. (2-Azido-3,4-di-O-benzyl-6-O-chloroacetyl-2-deoxy-
a-D-
glucopyranosyl)-(1/4)-[tert-butyl (2,3-di-O-benzyl-N-
benzyloxycarbonyl-1,5-dideoxy-1,5-imino-
L-iditol)
uronate] (30)
2813 (20.5 g, 80%) as an about 2:1 mixture of the
a
and
b
anomers. A
A mixture of 9a (0.165 g, 0.298 mmol), 7 (0.207 g, 0.373 mmol,
1.25 equiv), and 2,6-di-tert-butyl-4-methylpyridine (0.041 g,
0.2 mmol) in a mixture of dry diethyl ether and CH2Cl2 (4:1, 6 mL)
was stirred with 4 Å molecular sieves (1 g) at ꢁ30 ꢀC under argon
for 30 min, then a 1 M solution of Me2S2eTf2O (0.56 mL, 1.5 equiv/
donor) in CH2Cl2 was added. The mixture was stirred for 5 min,
then, it was neutralized with Et3N, was diluted with CH2Cl2
(250 mL), and filtered through a pad of Celite. The filtrate was
washed with 2 M aq HCl (100 mL), saturated aq NaHCO3 (100 mL)
and water (100 mL). The organic layer was dried and concentrated.
The residue was purified by column chromatography (hex-
aneseEtOAc, 9:1/4:1) to give 30 (0.234 g, 80%) as a colorless
solution of 90% chloroacetic anhydride (3.6 g, 20.9 mmol, 2 equiv)
in CH2Cl2 (10 mL) was added dropwise to a stirred solution of 28
(5 g, 10.5 mmol) in a mixture of dry CH2Cl2 (15 mL) and dry pyridine
(25 mL) at ꢁ20 ꢀC. After 10 min, the reaction was quenched with
water (15 mL) and stirred for 1 h. The mixture was diluted with
CH2Cl2 (500 mL), washed with 2 M aq HCl (200 mL), saturated aq
NaHCO3 (200 mL), and water (200 mL), dried, and concentrated.
Column chromatography of the residue (hexaneseEtOAc, 9:1/4:1)
gave syrupy 7 (4.1 g, 74%); Rf (hexaneseEtOAc, 4:1) 0.54; IR nmax
(film): 2952, 2109, 1764 cmꢁ1
d
;
1H NMR (300 MHz, CDCl3):
7.12e7.70 (m, 15H, aromatic), 5.57 (d, 0.7H, J1,2 5.0 Hz, H-1 ), 4.40
), 3.20e5.00 (m, 12H, skeleton protons, C
166.7 (C(O)
a
(d, 0.3H, J1,2 10.1 Hz, H-1
b
syrup; Rf (hexaneseEtOAc, 4:1) 0.60; [
nmax (film): 2109, 1737, 1699, 1217, 1144 cmꢁ1
CDCl3, 65 ꢀC):
7.22e7.37 (m, 25H, aromatic), 5.22 (d, 1H, J1 ,2
a
]
D þ49.7 (c 0.81, CHCl3); IR
(O)CH2Cl and 2 PhCH2); 13C NMR (75 MHz, CDCl3):
d
;
1H NMR (400 MHz,
0
0
CH2Cl), 137.3, 137.2, 133.9, 133.4, 132.9, 132.7, 132.0, 130.6, 129.1,
128.9, 128.8, 128.54, 128.46, 128.1, 128.0, 127.8, 127.7 (aromatic),
86.9 (C-1 a), 86.1 (C-1 b), 85.2, 81.9, 81.3, 76.94, 76.90, 76.1, 76.0,
75.2, 75.1, 70.0, 65.2, 64.41 and 64.38 (C-6), 64.2, 40.7 and 40.6
(C(O)CH2Cl); MS-ESI: [MþNH4]þ 571.2. Anal. Calcd for
C28H28ClN3O5S: C, 60.70; H, 5.09; N, 7.58; S, 5.79. Found: C, 61.54; H,
5.23; N, 6.30; S, 5.73.
d
4.0 Hz, H-10), 5.14 (d, 1H, J 12.4 Hz, ½PhCH2), 5.09 (d, 1H, J 12.4 Hz,
½PhCH2), 4.96 (d, 1H, J 10.8 Hz, ½PhCH2), 4.90 (d, 1H, J 10.8 Hz,
½PhCH2), 4.86 (d, 1H, J 11.2 Hz, ½PhCH2), 4.85 (d, 1H, J 10.8 Hz,
½PhCH2), 4.81 (d, 1H, J 10.8 Hz, ½PhCH2), 4.62 (s, 2H, C(O)CH2Cl),
4.61 (d, 1H, J4,5 7.0 Hz, H-5), 4.59 (d, 1H, J 11.2 Hz, ½PhCH2),
4.06e4.26 (m, 5H, H-1b, H-3, H-50, H-6a0, H-6b0), 3.95 (dd, 1H, J2 ,3
0
0
10.4 Hz, J3 ,4 8.8 Hz, H-30), 3.78 (dd, 1H, J3,4 9.2 Hz, H-4), 3.39e3.49
(m, 2H, H-2, H-40), 3.35 (dd, 1H, J1a,1b 12.4 Hz, J1a,2 11.2 Hz, H-1a),
3.25 (dd, 1H, H-20), 1.47 (s, 9H, C(CH3)3); 13C NMR (100 MHz, CDCl3,
0
0
4.22. (2-Azido-3,4-di-O-benzyl-6-O-chloroacetyl-2-deoxy-
glucopyranosyl)-(1/4)-[2,3-di-O-benzyl-N-
a-D-
benzyloxycarbonyl-1,5-dideoxy-1,5-imino-6-O-(1-naphthyl)
methyl- -iditol] (29)
65 ꢀC):
d 168.1 (C-6), 166.4 (OC(O)CH2Cl), 155.1 (C(O)OCH2Ph),
L
138.9, 138.1, 137.9, 137.6, 136.2, 128.7, 128.6, 128.53, 128.50, 128.4,
128.2, 128.1, 127.8, 127.7, 127.5 (aromatic), 99.7 (C-10), 82.7 (C
(CH3)3), 81.3 (C-3), 80.2 (C-30), 78.4 (C-2), 78.3 (C-4), 75.9 (C-40),
75.4, 75.1, 75.0 and 72.7 (4 PhCH2), 69.9 (C-50), 68.0 (PhCH2), 64.4
(C-60), 63.6 (C-20), 58.1 (C-5), 43.1 (C-1), 40.6 (OC(O)CH2Cl), 28.2 (C
(CH3)3); MS-ESI: [MþNH4]þ 1008.6, [MþNa]þ 1013.5, [MþK]þ
1029.5. Anal. Calcd for C54H59ClN4O12: C, 65.41; H, 6.00; N, 5.65.
Found: C, 65.43; H, 6.02; N, 5.60.
A mixture of 8 (0.43 g, 0.78 mmol), 7 (0.67 g, 0.97 mmol,
1.25 equiv), and 4 Å molecular sieves (2 g) was stirred in a mixture of
dry diethyl ether and CH2Cl2 (4:1, 12 mL) at 0 ꢀC under argon for
30 min, then DMTST (1 g, 3.9 mmol, 5 equiv) was added. After 1 day,
the reaction was quenched with Et3N (2 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 (150 mL), saturated aq NaHCO3 (150 mL),
and water (150 mL), dried, and concentrated. The residue was purified
by column chromatography (hexaneseEtOAc, 9:1/7:3) to give 29 as
4.24. (2-Azido-3,4-di-O-benzyl-6-O-chloroacetyl-2-deoxy-
a-D-
glucopyranosyl)-(1/4)-(2,3-di-O-benzyl-N-
a colorless syrup (0.486 g, 59%); Rf (hexaneseEtOAc, 4:1) 0.58; [
a
]
benzyloxycarbonyl-1,5-dideoxy-1,5-imino-L-iditol) (31)
D
þ38.6 (c 1.04, CHCl3); IR nmax (film): 2926, 2108, 1764 cmꢁ1; 1H NMR
(400 MHz, DMSO-d6, 100 ꢀC):
d
7.19e8.21 (m, 32H, aromatic), 5.26 (d,
Compound 29 (0.48 g, 0.46 mmol) was dissolved in a mixture
of MeCN and water (9:1, 10 mL), CAN (0.51 g, 0.92 mmol, 2 equiv)
1H, J1 ,2 3.6 Hz, H-10), 5.07 (s, 2H, C(O)OCH2Ph), 5.00 (d, 1H, J 12.4 Hz,
0
0

7832
Z. Csíki, P. Fügedi / Tetrahedron 66 (2010) 7821e7837
was added and the mixture was stirred for 2 h at room temper-
ature. It was diluted with chloroform (100 mL) and was washed
with saturated aq NaHCO3 (50 mL) and water (50 mL). The
aqueous layer was back-extracted with chloroform (50 mL). The
combined organic layers were dried and concentrated. Column
chromatography of the residue (tolueneeacetone, 95:5/9:1) gave
1H, ½PhCH2), 4.53 (d, 1H, J 11.0 Hz, ½PhCH2), 4.48 (d, 1H, J 11.0 Hz,
½PhCH2), 4.17 (dd, 1H, J1a,1b 13.2 Hz, J1b,2 5.1 Hz, H-1b), 3.34e4.08
(m, 11H, H-2, H-3, H-4, H-5, H-6a, H-6b, H-30, H-40, H-50, H-6a0, H-
6b0), 2.96 (dd, 1H, J1a,2 11.3 Hz, H-1a), 2.71 (br m, 1H, H-20), 2.49 (s,
4H, NH2 and 2 OH); 13C NMR (50 MHz, CDCl3):
d 156.1 (C(O)
OCH2Ph), 138.5, 138.4, 137.9, 137.8, 136.3, 128.61, 128.58, 128.5,
128.4, 128.2, 128.1, 127.9, 127.8, 127.6, 127.5 (aromatic), 101.7 (C-10),
83.4, 81.2, 78.9, 78.8 and 78.5 (C-2, C-3, C-4, C-30, and C-40), 75.6,
75.0, 74.9 and 72.7 (4 PhCH2), 73.8 (C-50), 67.8 (PhCH2), 61.6 (C-60),
58.2 (C-6), 56.3 (C-5), 53.4 (C-20), 41.7 (C-1); MS-ESI: [MþH]þ 819.4,
[MþNa]þ 841.6, [MþK]þ 857.6. Anal. Calcd for C48H54N2O10: C,
70.40; H, 6.65; N, 3.42. Found: C, 70.45; H, 6.60; N, 3.45.
syrupy 31 (0.35 g, 71%); Rf (tolueneeacetone, 9:1) 0.26; [
(c 0.36, CHCl3); IR nmax (film): 3446, 2106, 1636 cmꢁ1
(200 MHz, CDCl3):
a
;
]
D þ55.2
1H NMR
0 0
d
7.10e7.42 (m, 25H, aromatic), 5.33 (d, 1H, J1 ,2
3.3 Hz, H-10), 5.10 (s, 2H, PhCH2), 4.80e5.00 (m, 4H, H-5,
3ꢂ½PhCH2), 4.52e4.66 (m, 4H, 2 PhCH2), 4.42 (d, 1H, J 11.0 Hz,
½PhCH2), 4.12 (dd, 1H, J1a,1b 13.0 Hz, J1b,2 6.0 Hz, H-1b), 3.40e4.20
(m, 12H, H-2, H-3, H-4, H-6a, H-6b, H-30, H-40, H-50, H-6a0, H-6b0, C
(O)CH2Cl), 3.24 (dd, 1H, J2 ,3 10.3 Hz, H-20), 2.94 (dd, 1H, J1a,2
4.27. (2-Acetamido-6-O-acetyl-3,4-di-O-benzyl-2-deoxy-
a-D-
0
0
11.4 Hz, H-1a), 2.00 (br s, 1H, OH); 13C NMR (50 MHz, CDCl3):
glucopyranosyl)-(1/4)-(6-O-acetyl-2,3-di-O-benzyl-N-
d
166.7 (OC(O)CH2Cl), 156.1 (C(O)OCH2Ph), 138.6, 137.8, 137.6, 137.3,
benzyloxycarbonyl-1,5-dideoxy-1,5-imino-L-iditol) (34)
136.3, 129.2, 129.1, 128.8, 128.7, 128.6, 128.5, 128.3, 128.2, 128.1,
128.0, 127.7, 127.6 (aromatic), 99.1 (C-10), 82.5 (C-3), 80.2 (C-30),
79.3 (C-2), 78.9 (C-40), 78.0 (C-4), 75.7, 75.4, 75.34, 75.31 and 72.9
(5 PhCH2), 68.0 (C-50), 64.5 (C-6), 63.3 (C-20), 59.0 (C-60), 56.1 (C-
5), 41.8 (C-1), 40.9 (C(O)CH2Cl); MS-ESI: [MþH]þ 921.4, [MþNa]þ
946.6, [MþK]þ 959.6. Anal. Calcd for C50H53ClN4O11: C, 65.17; H,
5.80; N, 6.08. Found: C, 65.12; H, 5.83; N, 6.10.
To a solution of 33 (0.19 g, 0.24 mmol) in dry pyridine (2 mL),
acetic anhydride (0.23 mL, 2.4 mmol, 10 equiv) was added at 0 ꢀC.
The mixture was stirred at room temperature overnight, and then
the reaction was quenched with water (1 mL). The mixture was
diluted with CH2Cl2 (200 mL), washed with 2 M aq HCl (2ꢂ75 mL),
saturated aq NaHCO3 (75 mL), and water (75 mL). The organic layer
was dried and concentrated. The residue was purified by column
chromatography (tolueneeacetone, 9:1/4:1) to give syrupy 34
4.25. (2-Azido-3,4-di-O-benzyl-2-deoxy-
(1/4)-(2,3-di-O-benzyl-N-benzyloxycarbonyl-1,5-dideoxy-
1,5-imino- -iditol) (32)
a-D-glucopyranosyl)-
(0.188 g, 83%); Rf (tolueneeacetone, 4:1) 0.36; [
a
]
D
þ34.8 (c 0.52,
L
CHCl3); IR nmax (film): 3336, 3030, 2926, 1742, 1706, 1236 cmꢁ1; 1H
NMR (200 MHz, CDCl3): d 7.10e7.48 (m, 25H, aromatic), 5.93 (d, 1H,
0
0
0
To a solution of 31 (0.3 g, 0.325 mmol) in dry DMF (4 mL)
J2 ,NH 9.1 Hz, NH), 5.23 (d, 1H, J 12.1 Hz, ½PhCH2), 5.10 (d, 1H, J1 ,2
a
freshly prepared solution of HDTC31 (2.24 mL, 0.42 M,
3.7 Hz, H-10), 5.03 (d, 1H, J 10.6 Hz, ½PhCH2), 4.94 (d, 1H, J 11.4 Hz,
½PhCH2), 4.91 (d, 1H, J 11.0 Hz, ½PhCH2), 4.83 (d, 1H, J 11.0 Hz,
½PhCH2), 4.77 (d, 1H, J 11.4 Hz, ½PhCH2), 4.60 (s, 2H, PhCH2), 4.55
(d, 1H, J 10.6 Hz, ½PhCH2), 4.49 (d, 1H, J 12.1 Hz, ½PhCH2),
3.40e4.70 (m, 13H, H-1b, H-2, H-3, H-4, H-5, H-6a, H-6b, H-20, H-30,
H-40, H-50, H-6a0, H-6b0), 2.91 (dd, 1H, J1a,1b 12.0 Hz, J1a,2 11.0 Hz, H-
0.935 mmol, 3 equiv) was added and the mixture was stirred at
room temperature for 30 min. The mixture was diluted with CH2Cl2
(200 mL), and was washed with 2 M aq HCl (75 mL), saturated aq
NaHCO3 (75 mL) and water (75 mL), it was dried and evaporated.
Column chromatography (tolueneeacetone, 95:5/4:1) gave 32
(0.252 g, 92%) as a colorless syrup; Rf (tolueneeacetone, 9:1) 0.42;
1a), 2.00 and 1.85 (2s, 6H, 2C(O)CH3), 1.38 (s, 3H, NHC(O)CH3); 13
NMR (50 MHz, CDCl3): 170.8 (NHC(O)CH3), 170.6 and 170.1 (2 OC
C
[
a
]
D þ36.4 (c 0.41, CHCl3); IR nmax (film): 3441, 2107, 1637 cmꢁ1; 1H
d
NMR (200 MHz, CDCl3):
d
7.12e7.50 (m, 25H, aromatic), 5.31 (d, 1H,
(O)CH3), 155.4 (C(O)OCH2Ph), 138.2, 137.9, 137.7, 137.6, 137.5, 136.2,
129.1, 128.72, 128.68, 128.6, 128.5, 128.4, 128.3, 128.23, 128.16, 128.1,
127.9 (aromatic), 100.5 (C-10), 81.1, 80.8, 78.6, 78.2 and 77.5 (C-2, C-
3, C-4, C-30, and C-40), 75.5, 75.2 and 75.1 (3 PhCH2), 72.7 (C-50), 71.1
and 67.8 (2 PhCH2), 62.8 and 62.7 (C-6 and C-60), 59.2 (C-5), 53.0
and 52.8 (C-20), 41.7 and 41.3 (C-1), 22.7 (NHC(O)CH3), 21.5 and 20.7
(2C(O)CH3); MS-ESI: [MþH]þ 945.6, [MþNa]þ 967.6, [MþK]þ 983.6.
Anal. Calcd for C54H60N2O13: C, 68.63; H, 6.40; N, 2.96. Found: C,
68.60; H, 6.42; N, 2.92.
J1 ,2 3.7 Hz, H-10), 5.09 (s, 2H, PhCH2), 4.80e4.95 (m, 4H, 2 PhCH2),
4.58e4.68 (m, 4H, 2 PhCH2), 3.34e4.30 (m, 12H, H-1b, H-2, H-3, H-
4, H-5, H-6a, H-6b, H-30, H-40, H-50, H-6a0, H-6b0), 3.25 (br m, 1H, H-
0
0
20), 2.93 (br m, 1H, H-1a); 13C NMR (50 MHz, CDCl3):
d 156.1 (C(O)
OCH2Ph), 138.6, 137.9, 137.8, 137.7, 136.3, 129.1, 128.71, 128.67, 128.6,
128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.7 (aromatic), 99.5 (C-10),
82.2, 80.0, 78.8, 78.2 and 77.2 (C-2, C-3, C-4, C-30, and C-40), 75.5,
75.4, 75.3, 73.0 (4 PhCH2), 72.8 (C-50), 68.0 (PhCH2), 63.5 (C-20), 61.5
(C-60), 58.5 (C-6), 56.4 (C-5), 41.7 (C-1); MS-ESI: [MþH]þ 845.6,
[MþNa]þ 867.6, [MþK]þ 883.6. Anal. Calcd for C48H52N4O10: C,
68.23; H, 6.20; N, 6.63. Found: C, 68.25; H, 6.22; N, 6.59.
4.28. 2-Acetamido-2-deoxy-
dideoxy-1,5-imino- -iditol (3)
a-D-glucopyranosyl-(1/4)-1,5-
L
4.26. (2-Amino-3,4-di-O-benzyl-2-deoxy-
glucopyranosyl)-(1/4)-(2,3-di-O-benzyl-N-
benzyloxycarbonyl-1,5-dideoxy-1,5-imino- -iditol) (33)
a
-
D
-
To a solution of 34 (0.18 g, 0.2 mmol) in dry MeOH (2 mL), a cata-
lytic amount of NaOMe was added. The mixture was stirred overnight
at room temperature, neutralized with Amberlite IR 120 (Hþ) resin
(pH ca. 7), filtered, and concentrated to give a syrup (0.148 g, 87%),
which contained 35 and 36. The syrup was dissolved in a mixture of
THF and water (1:1, 4 mL) and was hydrogenated in the presence of
10% Pd/C catalyst (0.100 g) for 5 days at atmospheric pressure at room
temperature. The mixture was filtered through a pad of Celite and the
filtrate was concentrated. The residue was separated by column
L
To a solution of 32 (0.25 g, 0.29 mmol) in a mixture of pyridine
and water (9:1, 5 mL), 1,3-propanedithiol (0.6 mL, 5.96 mmol,
20 equiv) and six drops of Et3N (pH ca. 8) were added and the
mixture was stirred at room temperature for 2 days. It was then
evaporated and co-evaporated with toluene three times. The resi-
due was purified by column chromatography (CH2Cl2eMeOH,
98:2/95:5) to give syrupy 33 (0.197 g, 81%); Rf (CH2Cl2eMeOH,
chromatography (2-propanoleacetoneewater, 4:2:3) to give
3
(0.042 g, 43%) as a syrup and syrupy 37 (0.022 g, 31%). They were
further purified on a column of Sephadex G-25 using water as eluent
and then freeze dried to give the products as white foams.
95:5) 0.33; [
a
]
þ40.4 (c 0.45, CHCl3); IR nmax (film): 2920,
D
1695 cmꢁ1 1H NMR (200 MHz, CDCl3):
;
d 7.10e7.46 (m, 25H, aro-
matic), 5.08 (m, 3H, H-10, PhCH2), 4.91 (d, 1H, J 10.0 Hz, ½PhCH2),
4.87 (d, 1H, J 10.0 Hz, ½PhCH2), 4.79 (d, 1H, J 11.0 Hz, ½PhCH2), 4.69
(d, 1H, J 11.4 Hz, ½PhCH2), 4.61 (d, 1H, J 11.4 Hz, ½PhCH2), 4.56 (s,
Compound 3: Rf (2-propanoleacetoneewater, 4:1:1) 0.30; [a]
D
0
þ56.4 (c 0.48, H2O); 1H NMR (400 MHz, D2O):
d
5.04 (d, 1H, J1 ,2
0
3.7 Hz, H-10), 3.90 (d, 1H, J2,3zJ3,4 4.5 Hz, H-3), 3.89 (dd, 1H, J2 ,3
0
0

Z. Csíki, P. Fügedi / Tetrahedron 66 (2010) 7821e7837
7833
10.0 Hz, H-20), 3.83 (m, 1H, H-4), 3.78 (dd, 1H, J6a ,6b 12.0 Hz, J6b ,5
(film): 3430, 1637 cmꢁ1 1H NMR (200 MHz, CDCl3):
; d 7.10e7.48
0
0
0
0
0
0
4.8 Hz, H-6b0), 3.77 (d, 1H, H-2), 3.75 (s, 2H, H-6), 3.70 (dd, 1H, J6a ,5
(m, 25H, aromatic), 5.10 (br s, 1H, H-10), 4.50e5.00 (m, 10H, 5
PhCH2), 3.10e4.50 (m, 11H, H-1a, H-1b, H-2, H-3, H-4, H-5, H-30,
H-40, H-50, H-6a0, H-6b0), 2.73 (m, 1H, H-20), 1.64 (br s, 3H, OH,
0
2.5 Hz, H-6a0), 3.62 (dd, 1H, J3 ,4 9.6 Hz, H-30), 3.56 (ddd, 1H, J4 ,5
0
0
0
9.4 Hz, H-50), 3.42 (dd, 1H, H-40), 3.37 (m, 1H, H-5), 3.14 (dd, 1H,
J1a,1b 13.2 Hz, J1a,2 4.5 Hz, H-1a), 2.98 (dd, 1H, J1b,2 3.0 Hz, H-1b), 1.93
NH2), 1.42 (s, 9H, C(CH3)3); 13C NMR (50 MHz, CDCl3):
d 168.2 (C-
(s, 3H, NHC(O)CH3); 13C NMR (100 MHz, D2O):
d
174.6 (NHC(O)CH3),
6), 155.1 (C(O)OCH2Ph), 138.8, 138.7, 138.6, 138.1, 136.2, 128.6,
128.53, 128.49, 128.4, 128.3, 128.0, 127.9, 127.8, 127.7, 127.6 (aro-
matic), 102.0 (C-10), 82.5 (C(CH3)3), 83.8, 80.7, 78.4, 78.3 and 75.9
(C-2, C-3, C-4, C-30, and C-40), 75.6, 75.1, 74.6 and 72.7 (4 PhCH2),
72.5 (C-50), 67.9 (PhCH2), 61.5 (C-60), 58.0 (C-5), 56.3 (C-20), 42.9
(C-1), 28.1 (C(CH3)3); MS-ESI: [MþH]þ 889.6, [MþNa]þ 911.6.
Anal. Calcd for C52H60N2O11: C, 70.25; H, 6.80; N, 3.15. Found: C,
70.20; H, 6.83; N, 3.17.
96.5 (C-10), 73.5 (C-4), 73.3 (C-50), 71.6 (C-30), 69.9 (C-40), 68.0 (C-2),
66.9 (C-3), 60.7 (C-60), 59.0 (C-6), 56.6 (C-5), 53.7 (C-20), 45.4 (C-1),
22.2 (NHC(O)CH3); MS-ESI: [MþH]þ 367.2, [MþNa]þ 389.2. Anal.
Calcd for C14H26N2O9: C, 45.90; H, 7.15; N, 7.65. Found: C, 45.93; H,
7.13; N, 7.67.
Compound 37: Rf (2-propanoleacetoneewater, 4:1:1) 0.73; [a]
D
0
þ35.8 (c 0.98, H2O); 1H NMR (400 MHz, D2O):
d
5.05 (d, 1H, J1 ,2
0
3.6 Hz, H-10), 4.45 (dd, 1H, J6a,6b 9.0 Hz, J6b,5 8.8 Hz, H-6b), 4.33 (dd,
1H, J6a,5 4.0 Hz, H-6a), 4.27 (ddd, 1H, J4,5 2.5 Hz, H-5), 4.005 (dd, 1H,
4.31. (2-Acetamido-6-O-acetyl-3,4-di-O-benzyl-2-deoxy-
a-D-
0
0
J2,3 3.6 Hz, J3,4 3.3 Hz, H-3), 3.88 (dd,1H, J2 ,3 10.5 Hz, H-2 ), 3.86 (dd,
glucopyranosyl)-(1/4)-[tert-butyl (2,3-di-O-benzyl-N-
0
0
0
0
1H, J1a,2 2.8 Hz, J1b,2 1.5 Hz, H-2), 3.81 (dd, 1H, J6a ,6b 12.0 Hz, J6b ,5
benzyloxycarbonyl-1,5-dideoxy-1,5-imino-
uronate] (40)
L-iditol)-
5.4 Hz, H-6b0), 3.78 (dd, 1H, H-4), 3.71 (dd, 1H, J6a ,5 2.6 Hz, H-6a0),
0
0
3.63 (ddd, 1H, J4 ,5 9.7 Hz, H-50), 3.62 (d, 1H, J1a,1b 14.5 Hz, H-1b),
0
0
3.57 (dd, 1H, J3 ,4 9.2 Hz, H-30), 3.44 (dd, 1H, H-1a), 3.41 (dd, 1H, H-
To a solution of 39 (0.11 g, 0.12 mmol) in dry pyridine (2 mL),
acetic anhydride (0.12 mL, 1.25 mmol, 10 equiv) was added at 0 ꢀC.
The mixture was stirred at room temperature overnight, and then
the reaction was quenched with water. The mixture was diluted
with CH2Cl2 (150 mL), washed with 2 M aq HCl (2ꢂ50 mL), satu-
rated aq NaHCO3 (50 mL), and water (50 mL). The organic layer was
dried and concentrated. The residue was purified by column
chromatography (tolueneeacetone, 9:1/4:1) to give 40 (0.117 g,
0
0
40), 1.93 (s, 3H, NHC(O)CH3); 13C NMR (100 MHz, D2O):
d
174.7 (NHC
(O)CH3), 160.2 (NC(O)O), 96.6 (C-10), 74.0 (C-4), 73.6 (C-50), 71.6 (C-
30), 69.9 (C-40), 67.4 (C-2), 65.5 (C-3), 64.9 (C-6), 60.8 (C-60), 53.7 (Cþ-
20), 53.4 (C-5), 43.6 (C-1), 22.2 (NHC(O)CH3); MS-ESI: [MþH]
393.4, [MþNa]þ 415.4. Anal. Calcd for C15H24N2O10: C, 45.92; H,
6.17; N, 7.14. Found: C, 45.90; H, 6.15; N, 7.17.
4.29. (2-Azido-3,4-di-O-benzyl-2-deoxy-
(1/4)-[tert-butyl (2,3-di-O-benzyl-N-benzyloxycarbonyl-1,5-
dideoxy-1,5-imino- -iditol)uronate] (38)
a
-
D
-glucopyranosyl)-
96%) as a colorless syrup; Rf (tolueneeacetone, 4:1) 0.33; [
(c 0.64, CHCl3); IR nmax (film): 3446, 2360, 1638 cmꢁ1
(200 MHz, CDCl3):
a
;
]
D þ48.5
1H NMR
0
L
d
7.06e7.34 (m, 25H, aromatic), 5.69 (d, 1H, J2 ,NH
8.5 Hz, NH), 5.09 (d, 1H, J1 ,2 3.6 Hz, H-10), 4.45e5.05 (m, 10H, 5
PhCH2), 3.30e4.40 (m, 11H, H-1b, H-2, H-3, H-4, H-5, H-20, H-30, H-
40, H-50, H-6a0, H-6b0), 2.99 (m, 1H, H-1a), 1.89 (br s, 3H, OC(O)CH3),
1.31 (br s, 12H, C(CH3)3 and NHC(O)CH3); 13C NMR (50 MHz, CDCl3):
0
0
To a solution of 30 (0.212 g, 0.25 mmol) in dry DMF (4 mL)
a freshly prepared solution of HDTC (1.54 mL, 0.42 M, 0.643 mmol,
3 equiv) was added and the mixture was stirred at room temper-
ature for 10 min. The mixture was diluted with CH2Cl2 (200 mL),
and was washed with 2 M aq HCl (75 mL), saturated aq NaHCO3
(75 mL), and water (75 mL), it was dried and evaporated. Column
chromatography (tolueneeacetone, 98:2/9:1) gave 38 (0.141 g,
d
170.6 and 169.9 (2 OC(O)CH3), 167.8 (C-6), 154.8 (C(O)OCH2Ph),
138.2,138.1,137.9,137.6,136.1,128.6,128.5,128.4,128.3,128.2,127.9,
127.8, 127.7, 127.1 (aromatic), 100.1 (C-10), 82.7 (C(CH3)3), 80.7, 79.6,
78.0, 77.6 and 76.3 (C-2, C-3, C-4, C-30, and C-40), 75.0, 74.8, 74.4 and
72.4 (4 PhCH2), 70.3 (C-50), 67.9 (PhCH2), 62.5 (C-60), 57.6 (C-5), 52.4
(C-20), 42.7 (C-1), 28.0 (C(CH3)3), 22.7 (NHC(O)CH3), 20.7 (OC(O)
CH3); MS-ESI: [MþH]þ 973.6, [MþNa]þ 995.4, [MþK]þ 1011.4. Anal.
Calcd for C56H64N2O13: C, 69.12; H, 6.63; N, 2.88. Found: C, 69.15; H,
6.62; N, 2.90.
72%) as a yellowish syrup; Rf (tolueneeacetone, 9:1) 0.31; [a]
D
þ34.8 (c 0.43, CHCl3); IR nmax (film): 3446, 2925, 1732 cmꢁ1
;
1H
NMR (200 MHz, CDCl3):
d 7.10e7.50 (m, 25H, aromatic), 5.23 (br s,
1H, H-10), 4.56e5.18 (m, 10H, 5 PhCH2), 3.32e4.50 (m, 11H, H-1a, H-
1b, H-2, H-3, H-4, H-5, H-30, H-40, H-50, H-6a0, H-6b0), 3.25 (dd, 1H,
J1 ,2 3.6 Hz, J2 ,3 10.2 Hz, H-20), 1.80 (br s, 1H, OH), 1.45 (s, 9H, C
0
0
0
0
(CH3)3); 13C NMR (50 MHz, CDCl3):
d
168.2 (C-6), 155.1 (C(O)
4.32. (2-Acetamido-3,4-di-O-benzyl-2-deoxy-
a-D-
OCH2Ph), 138.9, 138.3, 138.2, 137.8, 136.2, 129.1, 128.6, 128.54,
128.50, 128.44, 128.41, 128.3, 128.2, 128.0, 127.8, 127.6 (aromatic),
100.0 (C-10), 82.7 (C(CH3)3), 81.0, 79.9, 78.3, 78.0 and 76.0 (C-2, C-3,
C-4, C-30, and C-40), 75.4, 75.3, 74.9 and 72.8 (4 PhCH2), 72.1 (C-50),
68.0 (PhCH2), 63.5 (C-60), 61.2 (C-20), 58.0 (C-5), 42.9 (C-1), 28.2 (C
(CH3)3); MS-ESI: [MþNa]þ 937.6. Anal. Calcd for C52H58N4O11: C,
68.25; H, 6.39; N, 6.12. Found: C, 68.23; H, 6.40; N, 6.13.
glucopyranosyl)-(1/4)-[tert-butyl (2,3-di-O-benzyl-N-
benzyloxycarbonyl-1,5-dideoxy-1,5-imino-
L-iditol)-
uronate] (41)
To a solution of 40 (0.11 g, 0.12 mmol) in dry MeOH (2 mL),
a catalytic amount of NaOMe was added. The mixture was stirred
overnight at room temperature, neutralized with Amberlite IR 120
(Hþ) resin (pH ca. 7), filtered, and concentrated. The residue was
purified by column chromatography (CH2Cl2eMeOH, 95:5/4:1) to
4.30. (2-Amino-3,4-di-O-benzyl-2-deoxy-
a-D-
glucopyranosyl)-(1/4)-[tert-butyl (2,3-di-O-benzyl-N-
give syrupy 41 (0.106 g, 95%); Rf (CH2Cl2eMeOH, 4:1) 0.55; [a]
D
benzyloxycarbonyl-1,5-dideoxy-1,5-imino-
uronate] (39)
L
-iditol)
þ84.4 (c 0.26, CHCl3); IR nmax (film): 3446, 2962, 2360, 1638,
1216 cmꢁ1
;
1H NMR (200 MHz, CDCl3):
d 7.14e7.32 (m, 25H, aro-
matic), 5.68 (d, 1H, J2 ,NH 9.9 Hz, NH), 4.90 (d, 1H, J1 ,2 3.3 Hz, H-10),
4.45e5.05 (m, 10H, 5 PhCH2), 3.20e4.40 (m, 11H, H-1b, H-2, H-3, H-
4, H-5, H-20, H-30, H-40, H-50, H-6a0, H-6b0), 2.97 (dd, 1H, J1 12.0 Hz,
H-1a), 2.40 (br s, 1H, OH), 1.31 (br s, 12H, C(CH3)3 and NHC(O)CH3);
0
0
0
To a solution of 38 (0.14 g, 0.15 mmol) in a mixture of pyri-
dine and water (9:1, mL) 1,3-propanedithiol (0.31 mL,
5
3.08 mmol, 20 equiv) and six drops of Et3N (pH ca. 8) were
added and the mixture was stirred at room temperature for 6
days. It was then evaporated and co-evaporated with toluene
three times. The product was purified by column chromatogra-
phy (CH2Cl2eMeOH, 98:2/9:1) to give syrupy 39 (0.111 g, 81%);
13C NMR (50 MHz, CDCl3):
d 170.0 (NHC(O)CH3), 167.8 (C-6), 154.9
(C(O)OCH2Ph), 138.4, 138.3, 138.1, 137.7, 136.1, 128.6, 128.5, 128.44,
128.38, 128.3, 128.0, 127.93, 127.89, 127.7, 127.3 (aromatic), 100.2 (C-
10), 82.8 (C(CH3)3), 80.4, 79.7, 78.1, 77.9 and 76.5 (C-2, C-3, C-4, C-30,
and C-40), 74.87, 74.86 and 74.6 (3 PhCH2), 72.6 (C-50), 72.5 and 68.0
Rf (CH2Cl2eMeOH, 95:5) 0.33; [
a]
þ41.4 (c 0.41, CHCl3); IR nmax
D

7834
Z. Csíki, P. Fügedi / Tetrahedron 66 (2010) 7821e7837
(2 PhCH2), 61.5 (C-60), 57.7 (C-5), 52.6 (C-20), 42.7 (C-1), 28.1 (C
(CH3)3), 22.8 (NHC(O)CH3); MS-ESI: [MþH]þ 931.4, [MþNa]þ 953.4,
[MþK]þ 969.4. Anal. Calcd for C54H62N2O12: C, 69.66; H, 6.71; N,
3.01. Found: C, 69.70; H, 6.69; N, 3.03.
4.35. (1,5-Dideoxy-1,5-imino-L-iditol)uronic acid (6)
A solution of 42 (0.065 g, 0.13 mmol) in a mixture of THF and
water (1:1, 3 mL) was hydrogenated in the presence of 10% Pd/C
(0.050 g) for 2 days at atmospheric pressure at room temperature.
The mixture was filtered through a pad of Celite and the filtrate was
concentrated. The residue was purified by column chromatography
(2-propanoleacetoneewater, 4:1:1) to give a syrup, which was
desalted on a column of Sephadex G-25 using water as eluent to
4.33. (2-Acetamido-2-deoxy-a-D-glucopyranosyl)-(1/4)-
[(1,5-dideoxy-1,5-imino- -iditol)uronic acid] sodium salt (4)
L
Compound 41 (0.1 g, 0.11 mmol) was dissolved in a solution of
TFA in CH2Cl2 (20 v/v%, 3 mL) and the solution was stirred for 2 h.
The reaction mixture was concentrated and the residue was co-
evaporated with toluene twice. The resulting syrup was purified by
column chromatography (CH2Cl2eMeOH, 98:2/9:1). The material
obtained was converted into the sodium salt by stirring with
Dowex 50WX8 [Naþ] resin in MeOH, the mixture was filtered and
the filtrate was concentrated to give (2-acetamido-3,4-di-O-ben-
afford
6
(0.019 g, 79%) as
a
a
white foam; Rf (2-prop-
anoleacetoneewater, 4:1:1) 0.36; [
]
D þ30.7 (c 0.75, H2O), lit33
[a]
D
þ34 (c 0.35, H2O); 1H NMR (400 MHz, D2O):
d 4.09 (dd, 1H, J3,4
4.8 Hz, J4,5 2.6 Hz, H-4), 3.87 (dd,1H, J2,3 3.8 Hz, H-3), 3.83 (m,1H, H-
2), 3.79 (d, 1H, H-5), 3.23 (dd, 1H, J1a,1b 13.5 Hz, J1b,2 2.5 Hz, H-1b),
3.13 (dd,1H, J1a,2 3.5 Hz, H-1a); 13C NMR (100 MHz, D2O):
d 173.4 (C-
6), 69.2 (C-4), 69.0 (C-3), 66.8 (C-2), 58.3 (C-5), 45.2 (C-1); MS-ESI:
[MþH]þ 178.1, [MþNa]þ 200.1. Anal. Calcd for C6H11NO5: C, 40.68;
H, 6.26; N, 7.91. Found: C, 40.70; H, 6.25; N, 7.90.
The 1H and 13C NMR data are in agreement with those
reported.33
zyl-2-deoxy-a-D-glucopyranosyl)-(1/4)-[(2,3-di-O-benzyl-N-ben-
zyloxycarbonylamino-1,5-dideoxy-1,5-imino-L-iditol)uronic acid]
(0.1 g, 95%) as a syrup; [
a
]
þ50 (c 0.8, CHCl3); MS-ESI: [MþH]þ
875.6, [MþNa]þ 897.6, [MþDK]þ 913.6.
To a solution of this syrup (0.091 g, 0.104 mmol) in a mixture
of THF and water (1:1, 5 mL) two drops of acetic acid was
added, and the mixture was hydrogenated in the presence of
10% Pd/C catalyst (0.050 g) for 3 days at atmospheric pressure at
room temperature. The mixture was neutralized with saturated
aq NaHCO3, was filtered through a pad of Celite, and the filtrate
was concentrated. The residue was purified by column chro-
matography (2-propanoleacetoneewater, 4:1:1) to give a syrup,
which was desalted on a column of Sephadex G-25 using water
as eluent to afford 4 (0.035 g, 88%) as a white foam; Rf (2-
4.36. 2,3-Di-O-benzyl-1,5-dideoxy-1,5-imino-4-O-
(1-naphthyl)methyl-N-(4-nitro)benzenesulfonyl-L-iditol (43)
1 M BH3$THF (9.0 mL, 9.0 mmol, 3 equiv) and TMSOTf (0.07 mL,
0.39 mmol, 0.13 equiv) were added to a solution of 10b (2.0 g,
3.0 mmol) in dry CH2Cl2 (50 mL) and the mixture was stirred at
room temperature under argon for 7 h. The mixture was cooled,
Et3N (5 mL) and MeOH were added, then the mixture was evapo-
rated, and the residue was co-evaporated with MeOH three times.
The residue was purified by column chromatography (hex-
aneseEtOAc, 4:1/7:3) to yield 43 (1.6 g, 93%) as a syrup; Rf (hex-
propanoleacetoneewater, 4:2:3) 0.36; [
a
]
þ13.3 (c 0.3, H2O);
D
0
1H NMR (400 MHz, D2O):
d
5.04 (d, 1H, J1 ,2 3.6 Hz, H-10), 4.09
0
(dd, 1H, J2,3 2.8 Hz, J3,4 4.2 Hz, H-3), 4.00 (dd, 1H, J4,5 2.6 Hz, H-
aneseEtOAc, 7:3) 0.30; [
a
]
D
þ10.5 (c 0.95, CHCl3); IR nmax (film):
4), 3.86 (dd, 1H, J2 ,3 10.5 Hz, H-20), 3.74 (d, 2H, H-6a0, H-6b0),
3446, 2925, 1643, 1529, 1348, 1160, 1087 cmꢁ1; 1H NMR (200 MHz,
0
0
0
0
3.72 (ddd, 1H, J1a,2 2.8 Hz, J1b,2 2.5 Hz, H-2), 3.69 (ddd, 1H, J4 ,5
CDCl3): d 7.10e8.00 (m, 21H, aromatic), 5.09 (d, 1H, J 11.8 Hz,
10.3 Hz, J5 ,6 6.0 Hz, H-50), 3.68 (d, 1H, H-5), 3.63 (dd, 1H, J3 ,4
½PhCH2), 4.91 (d, 1H, J 11.8 Hz, ½PhCH2), 4.68 (s, 2H, 1NaphCH2),
4.57 (d, 1H, J 11.6 Hz, ½PhCH2), 4.47 (d, 1H, J 11.6 Hz, ½PhCH2), 3.99
(m, 1H, J1a,1b 13.5 Hz, J1b,2 7.0 Hz, H-1b), 3.34e3.84 (m, 5H, H-2, H-3,
H-4, H-5, H-6b), 3.15 (ddd, 1H, J6a,6b 11.0 Hz, J6a,OH 8.4 Hz, J5,6a
0
0
0
0
9.0 Hz, H-30), 3.42 (dd, 1H, H-40), 3.08 (dd, 1H, J1a,1b 14.0 Hz, H-
1b), 3.00 (dd, 1H, H-1a), 1.94 (s, 3H, NHC(O)CH3); 13C NMR
(100 MHz, D2O):
d
175.2 (C-6), 174.6 (NHC(O)CH3), 95.0 (C-10),
72.9 (C-4), 72.3 (C-50), 71.6 (C-30), 69.8 (C-40), 66.9 (C-2), 65.3 (C-
3), 60.4 (C-60), 58.6 (C-5), 53.8 (C-20), 45.5 (C-1), 22.2 (NHC(O)
CH3); MS-ESI: [MþH]þ 381.2, [MþNa]þ 403.2, [MþK]þ 419.2.
Anal. Calcd for C14H23N2NaO10: C, 41.79; H, 5.76; N, 6.96. Found:
C, 41.82; H, 5.74; N, 6.94.
5.5 Hz, H-6a), 2.86 (dd, 1H, J1a,2 11.3 Hz, H-1a), 1.98 (t, 1H, OH); 13
C
NMR (50 MHz, CDCl3): d 149.8,146.0,138.5,137.8,133.8,133.0,131.6,
129.2, 128.7, 128.6, 128.4, 128.1, 128.0, 127.8, 127.7, 127.1, 126.6, 126.1,
125.3, 124.3, 123.8 (aromatic), 82.1 (C-3), 78.2 (C-2), 77.3 (C-4), 75.7,
73.2 and 71.9 (2 PhCH2, 1NaphCH2), 58.6 (C-6), 57.0 (C-5), 43.1 (C-1);
MS-ESI: [MþNa]þ 691.3. Anal. Calcd for C37H36N2O8S: C, 66.45; H,
5.43; N, 4.19; S, 4.79. Found: C, 66.46; H, 5.40; N, 4.21; S, 4.75.
4.34. (2,3-Di-O-benzyl-N-benzyloxycarbonyl-1,5-dideoxy-1,5-
imino-L-iditol)uronic acid (42)
4.37. tert-Butyl [2,3-di-O-benzyl-1,5-dideoxy-1,5-imino-4-O-
Compound 9a (0.078 g, 0.142 mmol) was dissolved in a solution
of TFA in CH2Cl2 (20 v/v%, 2 mL) and was stirred for 1 h. The reaction
mixture was evaporated and co-evaporated with toluene twice. The
residue was purified by column chromatography (CH2Cl2eMeOH,
95:5/9:1). The material obtained was converted into the sodium
salt by stirring with Dowex 50WX8 [Naþ] resin in MeOH, the
mixture was filtered, and the filtrate was concentrated to give 42
(0.067 g, 97%) as a colorless syrup; Rf (2-propanoleacetoneewater,
(1-naphthyl)methyl-N-(4-nitro)benzenesulfonyl-L-iditol]
uronate (44)
Pyridinium dichromate (1.7 g, 4.52 mmol, 2 equiv), acetic an-
hydride (2.15 mL, 22.6 mmol, 10 equiv), and tert-butyl alcohol
(4.24 mL, 45.2 mmol, 20 equiv) were added to a stirred solution of
43 (1.5 g, 2.26 mmol) in dry CH2Cl2 (20 mL). The mixture was stirred
for 19 h at room temperature and was then applied on the top of
a silica gel column in EtOAc, with a 5 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. The crude product was purified by column chromatography
(hexaneseEtOAc, 95:5/4:1) to give 44 (0.875 g, 54%) as white
crystals; mp 110e111 ꢀC (from EtOAcehexanes); Rf (hex-
4:1:1) 0.26; [
2360, 1706, 1257 cmꢁ1; 1H NMR (200 MHz, CDCl3):
15H, aromatic), 2.80e5.50 (m, 12H, 3 PhCH2, H-1a, H-1b, H-2, H-3,
H-4, H-5), 1.26 (s, 1H, OH); 13C NMR (50 MHz, CDCl3):
176.6 (C-6),
a]
ꢁ7.5 (c 0.3, CHCl3); IR nmax (film): 3446, 2926,
D
d
6.40e7.60 (m,
d
157.1 (C(O)OCH2Ph), 139.2, 138.3, 136.3, 128.5, 128.3, 128.0, 127.8,
127.6, 127.3 (aromatic), 83.0 and 77.6 (C-2 and C-3), 74.9 and 72.6 (2
PhCH2), 71.0 (C-4), 68.1 (PhCH2), 58.6 (C-5), 44.0 (C-1); MS-ESI:
[MþH]þ 492.2, [MþNH4]þ 509.2, [MþNa]þ 514.2, [MþK]þ 530.2.
Anal. Calcd for C28H29NO7: C, 68.42; H, 5.95; N, 2.85. Found: C,
68.45; H, 5.93; N, 2.84.
aneseEtOAc, 4:1) 0.40; [
2923,1730,1532,1350,1165, 1088 cmꢁ1; 1H NMR (300 MHz, CDCl3):
7.10e8.30 (m, 21H, aromatic), 5.21 (d, 1H, J 11.7 Hz, ½PhCH2), 5.11
(d, 1H, J 11.7 Hz, ½PhCH2), 4.80 (d, 1H, J4,5 6.4 Hz, H-5), 4.74 (s, 2H,
a
]
D
ꢁ24.2 (c 0.41, CHCl3); IR nmax (film):
d

Z. Csíki, P. Fügedi / Tetrahedron 66 (2010) 7821e7837
7835
1NaphCH2), 4.71 (d, 1H, J 11.7 Hz, ½PhCH2), 4.62 (d, 1H, J 11.7 Hz,
½PhCH2), 3.84e3.98 (m, 2H, H-1b, H-3), 3.78 (dd, 1H, J2,3 6.7 Hz,
J1a,2 9.1 Hz, H-2), 3.42e3.54 (m, 2H, H-4, H-1a),1.20 (s, 9H, C(CH3)3);
1H, J1a,1b 12.1 Hz, H-1a), 3.28 (dd, 1H, H-20), 1.28 (s, 9H, C(CH3)3); 13C
NMR (100 MHz, CDCl3): 167.4 (OC(O)CH2Cl), 166.8 (C-6), 150.2,
d
145.0, 138.6, 137.8, 137.43, 137.36, 128.6, 128.5, 128.44, 128.40, 128.3,
128.11,128.07,128.0, 127.9,127.6,127.5,124.5 (aromatic), 99.8 (C-10),
83.7 (C(CH3)3), 81.0 (C-3), 80.1 (C-30), 78.3 (C-2), 78.1 (C-40), 75.9 (C-
4), 75.5, 75.4, 75.1 and 73.2 (4 PhCH2), 69.9 (C-50), 64.7 (C-60), 63.3
(C-20), 58.4 (C-5), 43.9 (C-1), 40.9 (C(O)CH2Cl), 28.0 (C(CH3)3); MS-
ESI: [MþNa]þ 1064.2. Anal. Calcd for C52H56ClN5O14S: C, 59.91; H,
5.41; N, 6.72; S, 3.08. Found: C, 59.88; H, 5.39; N, 6.75; S, 3.10.
13C NMR (75 MHz, CDCl3):
d 167.3 (C-6), 150.0, 144.8, 138.4, 138.0,
133.6, 132.9, 131.4, 128.8, 128.5, 128.4, 128.3, 128.2, 127.9, 127.8,
127.7, 127.5, 126.5, 126.4, 125.9, 125.1, 124.3, 123.9 (aromatic), 82.9
(C(CH3)3), 80.8 (C-3), 78.3 (C-2), 77.3 (C-4), 75.4, 73.2 and 71.4 (2
PhCH2, 1NaphCH2), 57.0 (C-5), 44.2 (C-1), 27.8 (C(CH3)3); MS-ESI:
[MþNa]þ 761.3. Anal. Calcd for C41H42N2O9S: C, 66.65; H, 5.73; N,
3.79; S, 4.34. Found: C, 66.60; H, 5.75; N, 3.77; S, 4.39.
4.40. (2-Acetamido-3,4-di-O-benzyl-6-O-chloroacetyl-2-
4.38. tert-Butyl [2,3-di-O-benzyl-1,5-dideoxy-1,5-imino-N-
deoxy-a-D-glucopyranosyl)-(1/4)-[tert-butyl (2,3-di-O-
(4-nitro)benzenesulfonyl-
L-iditol]uronate (9b)
benzyl-1,5-dideoxy-1,5-imino-N-(4-nitro)benzenesulfonyl-L-
iditol)uronate] (46)
Compound 44 (0.850 g, 1.15 mmol) was dissolved in a mixture of
MeCN and water (9:1, 10 mL), CAN (1.26 g, 2.3 mmol, 2 equiv) was
added and the mixture was stirred for 3 h at room temperature. It
was diluted with chloroform (500 mL) and was washed with sat-
urated aq NaHCO3 (200 mL) and water (150 mL). The aqueous layer
was back-extracted with chloroform (300 mL). The combined or-
ganic layers were dried and concentrated. Column chromatography
of the residue (hexaneseEtOAc, 9:1/4:1) gave syrupy 9b (0.535 g,
A solution of Me3P in toluene (0.235 mL,1 M, 0.235 mmol,1 equiv)
was added to a solution of compound 45 (0.235 g, 0.22 mmol) in dry
THF (5 mL) at room temperature under argon. After cessation of the
nitrogen evolution (w20 min), acetic anhydride (0.021 mL,
0.22 mmol, 1 equiv) was added and the mixture stirred at room
temperature for 24 h. It was evaporated and co-evaporated with
toluene three times. The product was purified by column chroma-
tography (hexaneseEtOAc, 4:1/3:2) to give 46 (0.156 g, 66%) as
78%); Rf (hexaneseEtOAc, 4:1) 0.35; [
nmax (film): 3448, 2924, 2360, 1728, 1531, 1350, 1144, 1088 cmꢁ1; 1H
NMR (300 MHz, CDCl3): 8.28 (m, 2H, aromatic), 7.88 (m, 2H, ar-
a
]
þ6.4 (c 0.47, CHCl3); IR
D
a colorless syrup; Rf (hexaneseEtOAc, 3:2) 0.40; [
a
]
þ42.3 (c 0.69,
D
d
CHCl3); IR nmax (film): 3441, 2924, 1644, 1529, 1456, 1370, 1180,
omatic), 7.20e7.42 (m, 10H, aromatic), 4.90 (d, 1H, J 11.4 Hz,
½PhCH2), 4.76 (d, 1H, J 11.4 Hz, ½PhCH2), 4.62e4.76 (m, 3H, H-5,
PhCH2), 3.91 (ddd, 1H, J1a,1b 12.5 Hz, J1b,2 5.5 Hz, H-1b), 3.60e3.80
(m, 2H, H-3, H-4), 3.50 (ddd, 1H, J2,3 8.1 Hz, J1a,2 10.6 Hz, H-2), 3.20
(dd, 1H, H-1a), 2.84 (d, 1H, J4,OH 4.8 Hz, OH), 1.28 (s, 9H, C(CH3)3);
1027 cmꢁ1; 1H NMR (200 MHz, CDCl3):
d
8.30 (d, 2H, aromatic), 7.90
0
(d, 2H, aromatic), 7.10e7.42 (m, 20H, aromatic), 5.53 (d, 1H, J2 ,NH
9.5 Hz, NH), 4.99 (d, 1H, J1 ,2 4.0 Hz, H-10), 4.95 (d, 1H, J 12.0 Hz,
½PhCH2), 4.87 (d, 1H, J 10.6 Hz, ½PhCH2), 4.77 (d, 1H, J 12.0 Hz,
½PhCH2), 4.63 (d, 1H, J 11.0 Hz, ½PhCH2), 4.61 (s, 2H, PhCH2), 4.60 (d,
1H, J 11.0 Hz, ½PhCH2), 4.57 (d, 1H, J 10.6 Hz, ½PhCH2), 4.46 (d, 1H,
0
0
13C NMR (75 MHz, CDCl3):
d 168.1 (C-6), 150.3, 145.4, 138.4, 137.9,
0
0
0
0
0
0
128.7, 128.5, 128.3, 128.2, 128.1, 128.0, 124.5 (aromatic), 83.9 (C
(CH3)3), 81.5 (C-3), 77.7 (C-2), 75.4 and 73.3 (2 PhCH2), 71.3 (C-4),
58.4 (C-5), 44.7 (C-1), 28.0 (C(CH3)3); MS-ESI: [MþNa]þ 621.2. Anal.
Calcd for C30H34N2O9S: C, 60.19; H, 5.72; N, 4.68; S, 5.36. Found: C,
60.10; H, 5.75; N, 4.65; S, 5.38.
J6a ,6b 11.0 Hz, H-6b ), 4.30 (dd, 1H, J5 ,6a 4.7 Hz, H-6a ), 3.37e4.22 (m,
11H, H-1b, H-2, H-3, H-4, H-5, H-20, H-30, H-40, H-50 and C(O)CH2Cl),
3.15 (dd,1H, J1a,1b 12.3 Hz, J1a,2 10.6 Hz, H-1a),1.38 (s, 3H, NHC(O)CH3),
1.32 (s, 9H, C(CH3)3); 13C NMR (50 MHz, CDCl3):
d 169.9 (NHC(O)CH3),
167.4 (OC(O)CH2Cl), 166.7 (C-6), 145.3, 138.1, 137.9, 137.8, 137.6, 128.7,
128.6, 128.5, 128.3, 128.2, 128.1, 128.0, 127.1, 124.6 (aromatic),100.8 (C-
10), 83.7 (C(CH3)3), 80.6, 80.1, 78.3, 77.6 and 77.3 (C-2, C-3, C-4, C-30,
and C-40), 75.2, 75.1, 75.0 and 73.1 (4 PhCH2), 70.5 (C-50), 64.6 (C-60),
58.5 (C-5), 52.3 (C-20), 43.9 (C-1), 40.9 (C(O)CH2Cl), 28.1 (C(CH3)3),
22.9 (NHC(O)CH3); MS-ESI: [MþH]þ 1066.1, [MþNa]þ 1088.2,
[MþK]þ 1104.1. Anal. Calcd for C54H60ClN3O15S: C, 61.27; H, 5.71; N,
3.97; S, 3.03. Found: C, 61.30; H, 5.68; N, 3.95; S, 3.05.
4.39. (2-Azido-3,4-di-O-benzyl-6-O-chloroacetyl-2-deoxy-
a-D-
glucopyranosyl)-(1/4)-[tert-butyl (2,3-di-O-benzyl-1,5-
dideoxy-1,5-imino-N-(4-nitro)benzenesulfonyl-L-iditol)
uronate] (45)
A mixture of 9b (0.17 g, 0.284 mmol), 7 (0.197 g, 0.355 mmol,
1.25 equiv), and 2,6-di-tert-butyl-4-methylpyridine (0.06 g,
0.3 mmol) in a mixture of dry diethyl ether and CH2Cl2 (4:1, 6 mL)
was stirred with 4 Å molecular sieves (1 g) at ꢁ30 ꢀC under argon
for 30 min, then a 1 M solution of Me2S2eTf2O (0.53 mL, 1.5 equiv/
donor) in CH2Cl2 was added. The mixture was stirred for 5 min,
then, it was neutralized with Et3N, was diluted with CH2Cl2
(300 mL), and filtered through a pad of Celite. The filtrate was
washed with 2 M aq HCl (100 mL), saturated aq NaHCO3 (100 mL),
and water (100 mL). The organic layer was dried and concentrated.
The residue was purified by column chromatography (hex-
aneseEtOAc, 9:1/4:1) to give syrupy 45 (0.266 g, 90%); Rf (hex-
4.41. (2-Acetamido-3,4-di-O-benzyl-2-deoxy-
a-D-
glucopyranosyl)-(1/4)-[tert-butyl (2,3-di-O-benzyl-1,5-
dideoxy-1,5-imino-N-(4-nitro)benzenesulfonyl-L-iditol)
uronate] (47)
To a solution of 46 (0.15 g, 0.15 mmol) in dry DMF (3 mL)
a freshly prepared solution of HDTC (1.06 mL, 0.42 M, 0.442 mmol,
3 equiv) was added and the mixture was stirred at room tem-
perature for 20 min. The mixture was diluted with CH2Cl2
(300 mL), and was washed with 2 M aq HCl (100 mL), saturated aq
NaHCO3 (100 mL), and water (100 mL), it was dried and evapo-
rated. Column chromatography (tolueneeacetone, 9:1/7:3) gave
47 (0.094 g, 65%) as a colorless syrup; Rf (tolueneeacetone, 9:1)
aneseEtOAc, 4:1) 0.38; [
a
]
þ24.7 (c 0.36, CHCl3); IR nmax (film):
D
2109, 1754, 1722, 1533, 1351, 1328, 1172, 1121 cmꢁ1
;
1H NMR
0 0
(400 MHz, CDCl3):
d 7.02e8.40 (m, 24H, aromatic), 5.23 (d, 1H, J1 ,2
3.8 Hz, H-10), 4.96 (d, 1H, J 10.7 Hz, ½PhCH2), 4.89 (2d, 2H,
Jz11.0 Hz, PhCH2), 4.83 (dd, 2H, J 10.6 Hz, PhCH2), 4.69 (d, 1H, J
11.7 Hz, ½PhCH2), 4.66 (d, 1H, J4,5 6.9 Hz, H-5), 4.63 (d, 1H, J 11.7 Hz,
0.24; [
1529, 1370, 1180, 1027 cmꢁ1; 1H NMR (200 MHz, CDCl3):
2H, aromatic), 7.93 (d, 2H, aromatic), 7.10e7.50 (m, 20H, aromatic),
a
]
þ37.4 (c 0.27, CHCl3); IR nmax (film): 3425, 2924, 1637,
D
d
8.28 (d,
5.55 (d, 1H, J2 ,NH 9.5 Hz, NH), 5.01 (d, 1H, J1 ,2 3.6 Hz, H-10), 4.93 (d,
1H, J 11.3 Hz, ½PhCH2), 4.85 (d, 1H, J 11.0 Hz, ½PhCH2), 4.80 (d, 1H,
J 11.3 Hz, ½PhCH2), 4.78 (d, 1H, J 11.0 Hz, ½PhCH2), 4.64 (d, 1H, J
12.1 Hz, ½PhCH2), 4.60 (s, 2H, PhCH2), 4.59 (d, 1H, J 12.1 Hz,
0
0
0
0
0
½PhCH2), 4.61 (d, 1H, J 10.7 Hz, ½PhCH2), 4.46 (dd, 1H, J5 ,6b 1.7 Hz,
0
0
0
0
0
0
J6a ,6b 11.5 Hz, H-6b ), 4.22 (dd, 1H, J5 ,6a 5.8 Hz, H-6a ), 4.18 (d, 1H, J
0
0
0
14.9 Hz, ½C(O)CH2Cl), 4.15 (ddd, 1H, J4 ,5 9.7 Hz, H-5 ), 4.09 (d, 1H, J
14.9 Hz, ½C(O)CH2Cl), 4.04 (dd,01H, J2,3zJ3,4 9.4 Hz, H-3), 3.86 (m,
0
0
0
0
0
0
0
0
0
0
2H, J2 ,3 10.5 Hz, J3 ,4 8.6 Hz, H-3 and H-1b), 3.83 (dd, 1H, H-4), 3.54
½PhCH2), 4.32 (ddd, 1H, J4 ,5 10.0 Hz, J5 ,6a 3.3 Hz, J5 ,6b 3.7 Hz,
(ddd, 1H, J1a,2 10.8 Hz, J1b,2 5.6 Hz, H-2), 3.43 (dd, 1H, H-40), 3.39 (dd,
H-50), 3.47e4.20 (m, 10H, H-1a, H-2, H-3, H-4, H-5, H-20, H-30, H-40,

7836
Z. Csíki, P. Fügedi / Tetrahedron 66 (2010) 7821e7837
H-6a0, H-6b0), 3.15 (dd, 1H, J1a,1b 12.5 Hz, J1a,2 11.4 Hz, H-1a), 2.20 (s,
4.15 (m, 1H, H-3), 4.09 (dd, 1H, J5 ,6a 2.9 Hz, H-6a0), 3.97 (m, 2H, H-2,
0
0
1H, OH), 1.37 (s, 3H, NHC(O)CH3), 1.28 (s, 9H, C(CH3)3); 13C NMR
H-5), 3.89 (dd, 1H, J2 ,3 10.1 Hz, H-2 ), 3.81 (ddd, 1H, J4 ,5 9.2 Hz, H-5 ),
0
0
0
0
0
0
(50 MHz, CDCl3):
d 169.9 (NHC(O)CH3), 166.6, (C-6), 150.2, 145.5,
3.57 (dd, 1H, J3 ,4 9.5 Hz, H-30), 3.49 (dd, 1H, H-40), 3.30 (m, 2H, H-1a,
0
0
138.3, 138.1, 137.9, 137.6, 129.1, 128.7, 128.6, 128.5, 128.3, 128.2,
128.03, 127.96, 127.9, 127.8, 127.2, 125.4, 124.4 (aromatic), 100.9 (C-
10), 83.5 (C(CH3)3), 80.5, 80.0, 78.5, 78.2 and 77.6 (C-2, C-3, C-4, C-
30, and C-40), 75.1, 75.0, 74.8 and 73.1 (4 PhCH2), 73.0 (C-50), 62.0
(C-60), 58.3 (C-5), 52.5 (C-20), 43.8 (C-1), 27.9 (C(CH3)3), 22.8 (NHC
(O)CH3); MS-ESI: [MþNa]þ 1004.6, [MþK]þ 1020.5. Anal. Calcd for
C52H59N3O14S: C, 63.59; H, 6.06; N, 4.28; S, 3.26. Found: C, 63.60;
H, 6.09; N, 4.30; S, 3.22.
H-1b),1.89 (s, 3H, NHC(O)CH3); 13C NMR (75 MHz, D2O):
d
173.3 (C-6),
169.9 (NHC(O)CH3), 93.1 (C-10), 70.4 (C-30), 70.0 (C-4), 69.4 (C-50), 67.9
(C-40), 65.3 (C-60), 64.2 (C-2), 61.8 (C-3), 56.7 (C-5), 52.1 (C-20), 44.2
(C-1), 21.0 (NHC(O)CH3); MS-ESI: [MꢁH]ꢁ 459.3. Anal. Calcd for
C14H22N2Na2O13S: C, 33.34; H, 4.40; N, 5.55; S, 6.36. Found: C, 33.30;
H, 4.43; N, 5.57; S, 6.40.
Acknowledgements
4.42. (2-Acetamido-3,4-di-O-benzyl-2-deoxy-6-O-sulfo-
glucopyranosyl)-(1/4)-[(2,3-di-O-benzyl-1,5-dideoxy-1,5-
imino-N-(4-nitro)benzenesulfonyl- -iditol)uronic acid] (48)
a-D-
We are grateful for Dr. Timea Imre and for Mária Kajtár-Peredy
for their assistance in recording the MS and NMR spectra,
respectively.
L
Compound 47 (0.09 g, 0.09 mmol) was dissolved in a solution of
TFA in CH2Cl2 (20 v/v %, 3 mL) and was stirred at room temperature
for 2 h. The reaction mixture was evaporated and co-evaporated
with toluene twice. The crude syrup was dissolved in dry DMF
(2 mL) and sulfur trioxide pyridine complex (0.03 g, 0.019 mmol,
2 equiv) was added. The mixture was stirred at room temperature
for 10 min, the excess of reagent was decomposed with saturated
aq NaHCO3, and the mixture was concentrated. The residue was
purified by column chromatography (CH2Cl2eMeOH, 9:1/4:1).
The material obtained was converted into the sodium salt by stir-
ring with Dowex 50WX8 [Naþ] resin in MeOH, the mixture was
filtered and the filtrate was concentrated to give 48 (0.091 g, 94%) as
Supplementary data
The supplementary data associated with this article can be
found in the on-line version at doi:10.1016/j.tet.2010.07.055. These
data include MOL files and InChIKeys of the most important com-
pounds described in this article.
References and notes
1. (a) Lane, D. A.; Lindahl, U. Heparin. Chemical and Biological Properties, Clinical
Applications; CRC: Boca Raton, FL, USA, 1989; (b) Kjellén, L.; Lindahl, U. Annu.
Rev. Biochem. 1991, 60, 443e475; (c) Garg, H. G.; Linhardt, R. J.; Hales, C. A.
Chemistry and Biology of Heparin and Heparan Sulfate; Elsevier: Amsterdam, The
Netherlands, 2005.
2. Casu, B.; Lindahl, U. Adv. Carbohydr. Chem. Biochem. 2001, 57, 159e206.
3. (a) Conrad, E. H. Heparin-binding Proteins; Academic: San Diego, CA, USA, 1998;
(b) Fügedi, P. Mini-Rev. Med. Chem. 2003, 3, 659e667.
4. Velleman, S. G.; Liu, C. In Chemistry and Biology of Heparin and Heparan Sulfate;
Garg, H. G., Linhardt, R. J., Hales, C. A., Eds.; Elsevier: Amsterdam, The Neth-
erlands, 2005; pp 29e54.
5. (a) Bame, K. J. Glycobiology 2001, 11, 91Re98R; (b) Bame, K. J. In Chemistry and
Biology of Heparin and Heparan Sulfate; Garg, H. G., Linhardt, R. J., Hales, C. A.,
Eds.; Elsevier: Amsterdam, The Netherlands, 2005; pp 259e283.
a colorless syrup; Rf (CH2Cl2eMeOH, 9:1) 0.50; [
CH3OH); IR nmax (film): 3446, 1636 cmꢁ1 1H NMR (200 MHz,
CD3OD):
a
]
þ27.2 (c 0.41,
D
;
d
8.14 (d, 2H, aromatic), 7.92 (d, 2H, aromatic), 7.00e7.40
(m, 20H, aromatic), 4.97 (br s, 1H, H-10), 4.81 (s, 4H, 2 PhCH2),
3.66e4.76 and 3.04e3.48 (2 m, 12þ4H, H-1a, H-1b, H-2, H-3, H-4,
H-5, H-20, H-30, H-40, H-50, H-6a0, H-6b0, and 2 PhCH2), 1.56 (s, 3H,
NHC(O)CH3); 13C NMR (50 MHz, CD3OD):
d 174.9 (C-6), 172.9 (NHC
(O)CH3), 151.4, 146.7, 140.0, 139.7, 139.6, 139.2, 129.7, 129.5, 129.3,
129.24, 129.18, 129.1, 128.9, 128.6, 128.5, 128.2, 125.4 (aromatic),
99.6 (C-10), 81.9, 80.8, 79.6, 78.0 and 75.6 (C-2, C-3, C-4, C-30, and C-
40), 76.3, 75.9, 75.0 and 73.0 (4 PhCH2), 71.9 (C-50), 67.9 (C-60), 61.6
(C-5), 54.2 (C-20), 44.6 (C-1), 22.8 (NHC(O)CH3); MS-ESI:
[MþH2NaA]þ 1028.34 [MþHNa2A]þ 1050.4, [MþHNa3A]þ 1072.4.
Anal. Calcd for C48H50N3O17S2: C, 57.36; H, 5.01; N, 4.18; S, 6.38.
Found: C, 57.33; H, 5.05; N, 4.15; S, 6.40.
6. (a) Vlodavsky, I.; Friedmann, Y. J. Clin. Invest. 2001, 108, 341e347; (b) Gong, F.;
Jemth, P.; Galvis, M. L. E.; Vlodavsky, I.; Horner, A.; Lindahl, U.; Li, J. J. Biol. Chem.
2003, 278, 35152e35158.
7. (a) Ilan, N.; Elkin, M.; Vlodavsky, I. Int. J. Biochem. Cell Biol. 2006, 38, 2018e2039;
(b) Rohloff, J.; Zinke, J.; Schoppmeyer, K.; Tannapfel, A.; Witzigmann, H.;
Mossner, J.; Wittekind, C.; Caca, K. Br. J. Cancer 2002, 86, 1270e1275.
8. (a) Ferro, V.; Hammond, E.; Fairweather, J. K. Mini-Rev. Med. Chem. 2004, 4,
693e702; (b) Simizu, S.; Ishida, K.; Osada, H. Cancer Sci. 2004, 95, 553e558; (c)
Hammond, E.; Bytheway, I.; Ferro, V. In New Developments in Therapeutic Gly-
comics; Delehedde, M., Lortat-Jacob, H., Eds.; Research Signpost: India, 2006;
pp 251e282.
9. (a) Iminosugars as Glycosidase InhibitorsdNojirimycin and Beyond; Stütz, A., Ed.;
Wiley-VCH: Weinheim, Germany, 1999; (b) IminosugarsdFrom Synthesis to
Therapeutic Applications; Compain, P., Martin, O., Eds.; John Wiley & Sons:
Chichester, England, 2007.
4.43. (2-Acetamido-2-deoxy-6-O-sulfo-
a
-D
-glucopyranosyl)-
(1/4)-[(1,5-dideoxy-1,5-imino-L-iditol)uronic acid] disodium
salt (5)
10. (a) Liu, P. S. J. Org. Chem. 1987, 52, 4717e4721; (b) Anzeveno, P. B.; Creemer, L. J.;
Daniel, J. K.; King, C.-H. R.; Liu, P. S. J. Org. Chem. 1989, 54, 2539e2542; (c) Furui,
H.; Kiso, M.; Hasegawa, A. Carbohydr. Res. 1992, 229, C1eC4; (d) Kiso, M.;
Katagiri, H.; Furui, H.; Hasegawa, A. J. Carbohydr. Chem. 1992, 11, 627e644; (e)
Moss, S. F.; Vallance, S. L. J. Chem. Soc., Perkin Trans. 1 1992, 1959e1967; (f)
Spohr, U.; Bach, M.; Spiro, R. G. Can. J. Chem. 1993, 71, 1928e1942; (g) Spohr, U.;
Bach, M. Can. J. Chem. 1993, 71, 1943e1954; (h) Ogawa, H.; Harada, Y.; Kyotani,
Y.; Ueda, T.; Kitazawa, S.; Kandori, K.; Seto, T.; Ishiyama, K.; Kojima, M.; Ohgi, T.;
Ezure, Y.; Kise, M. J. Carbohydr. Chem. 1998, 17, 729e738; (i) Blattner, R.; Fur-
neaux, R. H.; Pakulski, Z. Carbohydr. Res. 2006, 341, 2115e2125.
11. (a) Liotta, L. J.; Bernotas, R. C.; Wilson, D. B.; Ganem, B. J. Am. Chem. Soc. 1989,
111, 783e785; (b) Yoshikuni, Y.; Ezure, Y.; Seto, T.; Mori, K.; Watanabe, M.;
Enomoto, H. Chem. Pharm. Bull. 1989, 37, 106e109; (c) Suzuki, K.; Hashimoto, H.
Tetrahedron Lett. 1994, 35, 4119e4122; (d) Izumi, M.; Suhara, Y.; Ichikawa, Y.
J. Org. Chem. 1998, 63, 4811e4816; (e) Banwell, M. G.; Ma, X.; Asano, N.; Ikeda, K.;
Lambert, J. L. Org. Biomol. Chem. 2003, 1, 2035e2037; (f) Spreitz, J.; Stütz, A. E.
Carbohydr. Res. 2004, 339, 1823e1827; (g) Boucheron, C.; Toumieux, S.; Compain,
P.; Martin, O. R.; Ikeda, K.; Asano, N. Carbohydr. Res. 2007, 342, 1960e1965.
12. Csíki, Z.; Fügedi, P. Tetrahedron Lett. 2010, 51, 391e395.
PhSH (0.011 mL, 0.11 mmol, 1.2 equiv) and dry Et3N (10 drops, pH
ca. 8) were added to a stirred solution of 48 (0.09 g, 0.09 mmol) in dry
DMF (2 mL), and the mixture was stirred for 24 h at room temper-
ature. It was neutralized with saturated aq NaHCO3, concentrated,
and the residue was purified by column chromatography
(CH2Cl2eMeOH, 9:1/7:3) to give the denosylated compound
(0.057 g, 73%). To a solution of this syrup (0.057 g, 0.07 mmol) in
a mixture of THF and water (1:1, 5 mL) two drops of acetic acid was
added, and the mixture was hydrogenated in the presence of 10% Pd/
C (0.050 g) for 4 days at atmospheric pressure at room temperature.
The mixture was neutralized with saturated aq NaHCO3, was filtered
through a pad of Celite, and the filtrate was concentrated. The residue
was purified by column chromatography (2-propanoleacetonee
water, 4:1:1) to give a syrup, which was desalted on a column of
Sephadex G-25 using water as eluent to afford 5 (0.014 g, 60%) as
13. (a) Takahashi, S.; Kuzuhara, H. Chem. Lett. 1994, 2119e2122; (b) Takahashi, S.;
Kuzuhara, H.; Nakajima, M. Tetrahedron 2001, 57, 6915e6926.
14. Cao, H.; Yu, B. Tetrahedron Lett. 2005, 46, 4337e4340.
15. For examples of inhibition by the “wrong” configuration, see: (a) Bols, M. Acc.
Chem. Res. 1998, 31, 1e8; (b) Dhavale, D. D.; Matin, M. M.; Sharma, T.;
a white foam; Rf (2-propanoleacetoneewater, 4:1:1) 0.22; [
a
]
D þ37.5
(c 0.2, water); 1H NMR (300 MHz, D2O):
d
5.02 (d, 1H, J1 ,2 3.6 Hz, H-
0
0
10), 4.27 (br s,1H, H-4), 4.23 (dd,1H, J6a ,6b 11.1 Hz, J5 ,6b 3.1 Hz, H-6b ),
0
0
0
0
0

Z. Csíki, P. Fügedi / Tetrahedron 66 (2010) 7821e7837
7837
Sabharwal, S. G. Bioorg. Med. Chem. 2003, 11, 3295e3305; (c) Patil, N. T.; John, S.;
Sabharwal, S. G.; Dhavale, D. D. Bioorg. Med. Chem. 2002, 10, 2155e2160; (d)
Shilvock, J. P.; Nash, R. J.; Watson, A. A.; Winters, A. L.; Butters, T. D.; Dwek, R. A.;
Winkler, D. A.; Fleet, G. W. J. J. Chem. Soc., Perkin Trans. 11999, 2747e2754; (e) Le
Merrer, Y.; Poitout, L.; Depezay, J.-C.; Dosbaa, I.; Geoffroy, S.; Foglietti, M.-J.
Bioorg. Med. Chem. 1997, 5, 519e533.
22. (a) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801e811; (b) Lee, J. B.; Nolan,
T. J. Can. J. Chem. 1966, 44, 1331e1334.
23. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155e4156.
24. For a similar synthetic route to 1-amino-1-deoxy-alditols, see: Ref. 19.
25. Garegg, P. J.; Hultberg, H. Carbohydr. Res. 1981, 93, C10eC11.
26. Daragics, K.; Fügedi, P. Tetrahedron Lett. 2009, 50, 2914e2916.
27. Corey, E. J.; Samuelsson, B. J. Org. Chem. 1984, 49, 4735.
28. Dasgupta, F.; Garegg, P. J. Synthesis 1988, 626e628.
29. (a) Fügedi, P.; Garegg, P. J. Carbohydr. Res. 1986, 149, C9eC12; (b) Andersson, F.;
Fügedi, P.; Garegg, P. J.; Nashed, M. Tetrahedron Lett. 1986, 27, 3919e3922; (c)
Fügedi, P. In E-EROS, Electronic Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley-Interscience: 2002; http://www.mrw.interscience.
wiley.com/eros/eros_articles_fs.html.
16. (a) Ferro, D. R.; Provasoli, A.; Ragazzi, M.; Torri, G.; Casu, B.; Gatti, G.; Jacquinet,
J.-C.; Sinaÿ, P.; Petitou, M. J. Am. Chem. Soc. 1986, 108, 6773e6778; (b) Casu, B.;
Petitou, M.; Provasoli, M.; Sinaÿ, P. Trends Biochem. Sci. 1988, 13, 221e225; (c)
Ferro, D. R.; Provasoli, A.; Ragazzi, M.; Casu, B.; Torri, G.; Bossenec, V.; Perly, B.;
Sinaÿ, P.; Petitou, M.; Choay, J. Carbohydr. Res. 1990, 195, 157e167.
17. Nishimura, Y.; Satoh, T.; Adachi, H.; Kondo, S.; Takeuchi, T.; Azetaka, M.;
Fukuyasu, H.; Iizuka, Y. J. Am. Chem. Soc. 1996, 118, 3051e3052.
18. (a) Fügedi, P.; Antal, Z. 20th International Carbohydrate Symposium, Hamburg,
Germany, August 27eSeptember 1, 2000; abstract B-046; (b) Tatai, J.; Fügedi, P.
Tetrahedron 2008, 64, 9865e9873.
19. Sawada, D.; Takahashi, H.; Ikegami, S. Tetrahedron Lett. 2003, 44, 3085e3088.
20. (a) Ferrier, R. J.; Furneaux, R. H. Carbohydr. Res. 1976, 52, 63e68; (b) Ferrier, R. J.;
Furneaux, R. H. Methods Carbohydr. Chem. 1980, 8, 251e253.
30. Tatai, J.; Fügedi, P. Org. Lett. 2007, 9, 4647e4650.
31. van Boeckel, C. A. A.; Beetz, T. Tetrahedron Lett. 1983, 24, 3775e3778.
32. (a) Heiker, F.-R.; Schueller, A. M. Carbohydr. Res. 1990, 203, 314e318;
(b) Paulsen, H.; Matzke, M.; Orthen, B.; Nuck, R.; Reutter, W. Liebigs Ann.
Chem. 1990, 953e963; (c) Fuchss, T.; Schmidt, R. R. J. Carbohydr. Chem. 2000,
19, 677e691.
21. Motawia, M. S.; Marcussen, J.; Moller, B. L. J. Carbohydr. Chem. 1995, 14,
33. Bashyal, B. P.; Chow, H.-F.; Fellows, L. E.; Fleet, G. W. J. Tetrahedron 1987, 43,
415e422.
1279e1294.