Short Synthesis of Idraparinux by Applying a 2-O-Methyl-4,6-O-arylmethylene Thioidoside as a 1,2-trans-α-Selective Glycosyl Donor

Article abstract of DOI:10.1002/ejoc.201801349

The fully O-sulfated, O-methylated, heparin-related anticoagulant pentasaccharide idraparinux was prepared by a new synthetic pathway in 38 steps using d-glucose and methyl α-d-glucopyranoside as starting materials, with 23 steps for the longest linear route. The l-idose-containing GH fragment was obtained by a short and straightforward synthesis whereby a 4,6-cyclic-acetal-protected l-idosyl thioglycoside bearing a C2-nonparticipating group was used as the α-selective glycosyl donor. The novel l-idose donor was prepared with high chemo- and stereoselectivity by hydroboration–oxidation-based C5 epimerization starting from an orthogonally protected α-thioglucoside. The assembly of the pentasaccharide backbone was achieved by an F+GH and DE+FGH coupling sequence with full stereoselectivity in each glycosylation step.

Full text of DOI:10.1002/ejoc.201801349

A Journal of
Accepted Article
Title: Short synthesis of idraparinux by applying a 2-O-methyl-4,6-O-
arylmethylene thioidoside as a 1,2-trans alpha-selective glycosyl
donor
Authors: Fruzsina Demeter, Fanni Veres, Mihály Herczeg, and Anikó
Borbás
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801349
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801349
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10.1002/ejoc.201801349
European Journal of Organic Chemistry
FULL PAPER
Short synthesis of idraparinux by applying a 2-O-methyl-4,6-O-
arylmethylene thioidoside as a 1,2-trans α-selective glycosyl
donor
Fruzsina Demeter[a], Fanni Veres[a], Mihály Herczeg*[a,b] and Anikó Borbás*[a]
Dedication ((optional))
Abstract: The fully O-sulfated, O-methylated, heparin-related
anticoagulant pentasaccharide idraparinux was prepared by a new
synthetic pathway in 38 steps using D-glucose and methyl α-D-
glucopyranoside as starting materials, with 23 steps for the longest
linear route. The L-idose-containing GH fragment was obtained by a
short and straightforward synthesis whereby a 4,6-cyclic-acetal-
protected L-idosyl thioglycoside bearing a C2-nonparticipating group
was used as the α-selective glycosyl donor. The novel L-idose donor
was prepared with high chemo- and stereoselectivity by
hydroboration–oxidation-based C5 epimerization starting from an
orthogonally protected α-thioglucoside. The assembly of the
pentasaccharide backbone was achieved by an F+GH and DE+FGH
potency of idraparinux is associated with its long half-life which
allows a convenient once-a-week administration in humans.
However, in the lack of neutralizing agent, the long elimination
half-life proved to be a double-edged sword, and the development
of idraparinux was stopped due to major bleeding events during
treatment for more than six months.[6]
Recently, new antidotes have emerged in the anticoagulant
therapy.[7] Andexanet alfa, a recombinant protein designed as a
specific reversal agent against both direct and indirect factor Xa
inhibitors, was approved by FDA in 2018.[8] Aripazine
(ciraparantag), a synthetic small cationic compound is another,
clinically investigated reversal agent with promising activity
coupling sequence with full stereoselectivity in each glycosylation step. against heparinoid anticoagulants.[9] These new results might
attract renewed interest toward idraparinux.
Despite the simplified structure, the synthesis of idraparinux still
poses challenges like the efficient synthesis of the L-idosyl
building block as well as the introduction of methyl ethers onto the
Introduction
uronic acid residues which are prone to suffer β-elimination under
basic conditions of the etherification.
Heparin polysaccharide and its smaller fragments are invaluable
drugs in the prevention and treatment of thromboembolic
diseases owing to their anticoagulant properties.[1] Heparin binds
to and activates antithrombin which, in turn, inhibits blood
coagulation factors IIa and Xa.[2] Characterization of the shortest
heparin sequence able to activate antithrombin, the DEFGH
pentasaccharide 1, along with SAR studies led to the synthetic
antithrombotic drug fondaparinux (Arixtra, 2), possessing
selective factor Xa inhibitory activity by means of activation of
antithrombin[3] (Figure 1). The lengthy and demanding synthesis
of fondaparinux[4] spurred research to design simplified analogues
that are easier to prepare. The replacement of glucosamine by
glucose units and the introduction of methyl ethers to hydroxyls
on non-crucial positions resulted in the discovery of non-
glycosaminoglycan derivatives such as idraparinux (3)[3,5] which
Figure 1. Structure of the AT-binding pentasaccharide domain of heparin (1)
and the synthetic anticoagulant pentasaccharides fondaparinux (2) and
idraparinux (3).
is an extremely potent heparinoid antithrombotic. Idraparinux
binds to antithrombin significantly stronger than fondaparinux
through the additional interaction of the extra sulfate group of the
H glucose unit as well as through hydrophobic interactions. The
In most syntheses, orthogonally protected 2-O-acyl L-idopyranose
or L-iduronic acid building block is prepared from D-glucose via
various lengthy procedures[10] and used as a C2-participating
glycosyl donor (Scheme 1, A). The 2-O-acyl group ensures the
required 1,2-trans stereoselectivity upon glycosylation, however,
its change into methyl ether further lengthens the synthesis at an
oligosaccharide level.[5,11-14] Recently, Lopatkiewicz and co-
workers established a nonglycosylating chemical strategy for the
synthesis of idraparinux in which the GH and EF disaccharide
units were prepared from the same cellobiose (Scheme 1, B).[15]
They introduced the needed methyl ethers at an early stage of the
synthesis and the functionalized cellobiose was transformed to
the GH unit via epimerization of C5’ by an elimination-addition
[a]
[b]
Department of Pharmaceutical Chemistry
University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
E-mail: borbas.aniko@pharm.unideb.hu
Homepage: http://pharmchem.unideb.hu/borbas_a.htm
Research Group for Oligosaccharide Chemistry
Hungarian Academy of Sciences
Egyetem tér 1, H-4032 Debrecen, Hungary
E-mail: herczeg.mihaly@science.unideb.hu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801349
European Journal of Organic Chemistry
FULL PAPER
sequence. The synthesis of fully protected idraparinux was
significantly shortened and improved by this imaginative
approach which still has weaknesses such as the low efficacy of
the C5’ epimerization step as well as the low stereoselectivity
during conversion of the 1,6-anhydro ring of unit H into methyl α-
glycoside.
Very recently, we published a straightforward new synthesis of L-
idosyl glycosyl donors starting from orthogonally protected α-
thioglucosides.[16] The key steps include C5 epimerization by
hydroboration/oxidation of the corresponding 5-enopyranosides
followed by a 4,6-O-acetal formation of the obtained L-idosides.
We demonstrated in model glycosylations of a GlcNAc acceptor
that the 4,6-arylmethylene acetal ensures full 1,2-trans α-
selectivity in the absence of a participating group at C2 position.
On the basis of these results we envisioned a significantly
shortened route to idraparinux by applying a 2,3-di-O-methylated
L-idosyl donor for the synthesis of the GH fragment.
product were introduced into positions 2 and 3 at this early stage
of synthesis to give 5 in 92% yield. Next, the regioselective ring
opening of the 4,6-O-(2-naphthyl)methylene acetal using the
LiAlH4-AlCl3 reagent combination in a 3:1 ratio[23] resulted in
compound 6 in an excellent 90% yield. Subsequent substitution
of the 6-OH group with iodine gave 7 in 84% yield. It is worth
mentioning that each compound of this reaction sequence was
obtained in crystalline form (Scheme 2).
Scheme 2. Synthesis of the 6-deoxy-6-iodo-α-thioglucoside derivative 7.
Conversion of 7 into the L-idoside derivative 8 was carried out by
the well-established C5-epimerization method including NaH-
mediated elimination, hydroboration using BH3·THF and oxidation
with H2O2 under basic conditions.[24,25]
While this reaction sequence had proceeded both in high yield
and high stereoselectivity starting from 2,3-di-O-benzyl α-
thioglucosides,[16] upon dehydrohalogenation of the 2,3-di-O-
methylated 7 with sodium hydride a number of byproducts were
observed by TLC and, after hydroboration/oxidation, the expected
L-idose derivative 8 was only formed in low 41% yield (Scheme 3,
Route A). Thus, we attempted to produce the 5,6-unsaturated 7a
derivative by another method using silver fluoride in dry pyridine
(Scheme 3., Route B). To our great satisfaction, the AgF-
mediated elimination provided cleanly the 6-deoxy-α-D-xylo-hex-
5-enopyranoside 7a which was subjected directly to
hydroboration-oxidation to produce the desired L-idose derivative
8 in a good yield of 66% over three steps (87% per step). As we
expected, the α-anomeric configuration of 7a ensured the
required high L-ido selectivity in the hydroboration step and the D-
gluco epimer by-product 6 was formed only in a negligible amount.
Moreover, the oxidation occurred with high chemoselectivity
indicated by the small extent of overoxidized by-product 9. (The
structure of 6 and 9 was identified on the basis of the MS data and
NMR spectra of their inseparable mixture.) The observed high
stereo- and chemoselectivity of the hydroboration/oxidation of the
α-thioglycoside is in line with our previous results.[16] A third by-
product, the 6-fluoro derivative (10) of the initial glucose
compound was also isolated from the reaction mixture in an 11%
yield. It must have been formed during the elimination reaction,
but could not be distinguished by TLC from the 5,6-unsaturated
derivative.
Scheme 1. Synthetic strategies toward the GH fragment of idraparinux.
Results and Discussion
We have developed an efficient synthetic strategy for
idraparinux[14] and related pentasaccharides[17,18] which was
based on the coupling of an FGH acceptor and a DE donor, both
containing a non-oxidized precursor of the hexuronic acid unit,
and formation of the uronic acids was performed in one step at
the pentasaccharide level. While keeping this post-glycosylation
oxidation strategy,[19] we devised a significantly shortened
synthesis for the GH building block by utilizing a new, non-
participating L-idosyl glycosyl donor which is readily available
from a suitably protected α-thioglucoside by our recent method.[16]
The synthesis of the starting α-thioglucoside 4[20] was
accomplished by stereoselective introduction of the ethylthio
aglycon
to
2-acetoxy-D-glucal
by
photoinduced
hydrothiolation[21,22] followed by deacetylation and 4,6-O-(2-
naphthyl)methylenation. The methyl ether functions of the final
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10.1002/ejoc.201801349
European Journal of Organic Chemistry
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Scheme 3. The elimination and epimerization reactions of compound 7.
Next, compound 8 was converted to the corresponding 4,6-O-(2-
napthyl)methylene derivative 11 by oxidative ring closure with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (Scheme 4). It
was followed by the key step of the synthesis, glycosylation of
monosaccharide acceptor 12[26] with the new, non-participating L-
idosyl donor 11. We demonstrated earlier that glycosylation
reaction between the 2,3-di-O-benzyl congener of 11 and a
GlcNAc acceptor of low reactivity proceeded with full 1,2-trans α-
selectivity.[16] However, it was questionable whether donor 11 was
able to ensure complete stereoselectivity when reacting with an
acceptor of higher reactivity. To our great delight, condensation of
acceptor 12 and donor 11 upon iodonium ion activation resulted
in the desired α-linked GH disaccharide with full stereoselectivity
in high yield and in crystalline form. The exclusive α-
stereoselectivity can be explained by the steric hinderence of the
C2-protecting group to prevent nucleophilic attack from the β-face
and by the controlling effect[27,28] of the 4,6-O-cyclic protecting
group which has been demonstrated to ensure α-selectivity in D-
glucosylation and D-galactosylation reactions.
Scheme 4. Preparation of GH disaccharide 13 and its transformations to
acceptors 14 and 16.
Glycosylation of disaccharide 16 with thioglycoside donor 17[31]
upon iodonium ion activation resulted in FGH trisaccharide 18
with the desired α-interglycosidic linkage in 88% yield (Scheme
5.).
Conversion of the fully protected disaccharide 13 to an acceptor
by regioselective ring opening reaction was first attempted with a
BF3·Et2O-Et3SiH[29] reagent combination. Unfortunately, the main
product of the reaction was diol 15 and the expected 6’-ether 14
was only formed in a low 20% yield. Hence, we turned to the
Me3N·BH3-AlCl3 reagent system which is known to cleave the 4,6-
O-acetals with a solvent dependent regioselectivity.[26,30] In THF,
the required 4’-OH/6’-O-ether 14 was isolated as the only product
in 80% yield. Diol 15 was also converted to a disaccharide
acceptor building block by regioselective silylation of the primary
hydroxyl group. Treatment of 15 with tert-butyldiphenylsilyl
chloride (TBDPSCl) in dry pyridine provided acceptor 16 in
excellent yield.
Scheme 5. Synthesis of the FGH disaccharide acceptors 19a and 21a.
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10.1002/ejoc.201801349
European Journal of Organic Chemistry
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Conversion of 18 to acceptor 19a was achieved again by a
regioselective ring-opening reaction using the Me3N·BH3-AlCl3
reagent system in THF to produce the desired product in 65%
yield along with the regioisomeric by-product 19b isolated in 21%.
Following the above reaction path, the 6’-ONAP-containing 14
was converted to another trisaccharide acceptor, compound 21a,
with similar efficacy.
The assembly of the non-oxidized precursor of the final product
idraparinux was initially carried out by glycosylation of
trisaccharide acceptor 19a with the non-glucuronide type DE
disaccharide donor 22[32] (Scheme 6). Surprisingly, condensation
of disaccharide 22 and trisaccharide 19a upon NIS-AgOTf
activation provided the DEH trisaccharide 24 as the major product
in 46% yield, and the needed pentasaccharide 23 was formed in
a very low yield of 11%.
Scheme 7. Plausible mechanism of the formation of DEH trisaccharide 24.
In the hope of a more efficient synthesis of the protected
pentasaccharide skeleton, disaccharide 22 was reacted with the
NAP-group-containing disaccharide acceptor 21a upon NIS-TfOH
activation. This case the [2+3] coupling reaction proceeded with
high efficacy to provide the expected protected pentasaccharide
25 with complete β-stereoselectivity, in 70% yield (Scheme 8).
The significant difference in the DE+FGH coupling outcome upon
changing a remote protecting group in the acceptor FGH (19a
versus 21a) can be explained by the different steric and electronic
properties of the TBDMS and the NAP protecting group. Another
possible reason for the different efficacy of the two glycosylations
is that different promoter systems were applied in the two coupling
reactions. We hypothesize that under the NIS-AgOTf promotion
the orthoester formation may be more preferred compared to the
NIS-TfOH promotion. As the formation of the needed
pentasaccharide proceeded with high efficacy with acceptor 21a,
we did not study further the intriguing behaviour of acceptor 19a.
Scheme 6. Synthesis of the protected pentasaccharide 23 by applying the silyl-
containing acceptor 19a.
The formation of trisaccharide 24 can be explained either by direct
attack of the α-L-idosyl glycosidic oxygen onto the anomeric
carbon of the dioxolenium ion formed from 22 or by an
intramolecular glycosyl transfer reaction via the orthoester
intermediate 23a (Scheme 7). The intermolecular glycosyl
transfer to 22a could only occur if 19a adopts a conformation in
which the free hydroxyl group is extremely shielded thereby the
attack of the interglycosidic oxygen, nucleophilicity of which is
enhanced by the surrounding electron-donating ether
substituents, becomes dominant. Another, more probable
mechanism is the formation of orthoester 23a which then can
undergo either a conventional rearrangement to give the
expected pentasaccharide 23 or can be transformed to
trisaccharide 24 by intramolecular transfer of unit H onto the
glycosidic center of unit E.
Scheme 8. The [2+3] coupling reaction with the NAP-containing trisaccharide
acceptor 21a.
The synthesis was continued with the NAP-containing
pentasaccharide 25 of which we had a sufficient amount for the
remaining transformations (Scheme 9). First, compound 25 was
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10.1002/ejoc.201801349
European Journal of Organic Chemistry
FULL PAPER
subjected to Zemplén deacetylation to produce diol 26.
Introduction of the methyl ethers to the freed hydroxyls was
accomplished by standard alkylation using methyl iodide and
sodium hydride to afford the desired compound 27 in 80% yield.
Next, the primary hydroxyls that were to be oxidized in units E and
G were liberated in one step by oxidative cleavage of the NAP
groups with DDQ[33] to provide diol 28[14] in 70% yield. The final
transformations of 28 into idraparinux, involving TEMPO-BAIB-
mediated oxidation, removal of benzyl ethers by catalytic
hydrogenation and O-sulfation using SO3·Et3N, were performed
according to our previous method.[14]
group strategies for the synthesis of heparin and heparin sulfate
oligosaccharides. Another advantage of this new strategy to GH
unit is that most synthetic intermediates were obtained in
crystalline form. The idopyranosyl-containing GH unit was
successfully incorporated to a late-stage oxidation strategy
whereby the non-oxidized pentasaccharide backbone was
created by an F+GH and DE+FGH coupling sequence, with full
stereoselectivity in each glycosylation step, followed by
simultaneous formation of two carboxylic functions at the
pentasaccharide level.
Applying this new approach the target pentasaccharide 3 could
be achieved in a 38-step synthesis starting from D-glucose and
methyl α-D-glucopyranoside with 23 steps for the longest linear
route. To the best of our knowledge, this is the shortest route to
idraparinux yet reported.
Experimental Section
General Information. Optical rotations were measured at room
temperature on a Perkin–Elmer 241 automatic polarimeter. TLC analysis
was performed on Kieselgel 60 F254 (Merck) silica–gel plates with
visualization by immersing in a sulfuric-acid solution (5% in EtOH) followed
by heating. Column chromatography was performed on silica gel 60
(Merck 0.063–0.200 mm) and Sephadex LH-20 (Sigma–Aldrich, bead
size: 25–100 mm). Organic solutions were dried over MgSO4 and
concentrated under vacuum. 1H and 13C NMR spectroscopy (1H: 400 and
500 MHz; 13C: 100.28 and 125.76 MHz) were performed on Bruker DRX-
400 and Bruker Avance II 500 spectrometers at 25 °C. Chemical shifts are
referenced to SiMe4 or sodium 3-(trimethylsilyl)-1-propanesulfonate (DSS,
δ = 0.00 ppm for 1H nuclei) and to solvent signals (CDCl3: δ = 77.00 ppm,
CD3OD: δ = 49.15 ppm for 13C nuclei). MALDI-TOF MS analyses of the
compounds were carried out in the positive reflektron mode using a
BIFLEX III mass spectrometer (Bruker, Germany) equipped with delayed-
ion extraction. 2,5-Dihydroxybenzoic acid (DHB) was used as matrix and
F3CCOONa as cationising agent in DMF. HRMS measurements were
carried out on a maXis II UHR ESI-QTOF MS instrument (Bruker) in
positive ionization mode. The following parameters were applied for the
electrospray ion source: capillary voltage: 3.6 kV; end plate offset: 500 V;
nebulizer pressure: 0.5 bar; dry gas temperature: 200 °C and dry gas flow
rate: 4.0 L/min. Constant background correction was applied for each
spectrum, the background was recorded before each sample by injecting
the blank sample matrix (solvent). Na-formate calibrant was injected after
each sample which enabled internal calibration during data evaluation.
Mass spectra were recorded by otofControl version 4.1 (build: 3.5, Bruker)
and processed by Compass DataAnalysis version 4.4 (build: 200.55.2969).
Scheme 9. The transformation of the 6-O-NAP containing protected
pentasaccharide.
Conclusions
We have developed a new approach to the synthesis of
idraparinux in which the novel and efficient preparation of a 4,6-
O-acetal-containing L-idose donor and its utilization for the
synthesis of the GH disaccharide fragment were the key steps.
The synthesis of the new idosyl donor was achieved from a
properly protected α-thioglucoside in four steps including AgF-
mediated elimination, stereoselective hydroboration using
BH3·THF, chemoselective oxidation with H2O2 and DDQ-
mediated oxidative acetal ring-closure. By applying this donor,
due to the controlling effect of the 4,6-acetal group, the GH
building block was prepared with full 1,2-trans-α-stereoselectivity
in the absence of a participating group at C2 position. Typically,
L-idose or L-iduronic acid donors with a C2 participating group
have been applied for the construction of the α-L-idosyl glycosidic
linkage.[10,34] The demonstrated α-stereodirecting effect of the 4,6-
cyclic acetal in the presence of an ether protecting group at C2
position pave the way to designing new, more diverse protecting
Ethyl
2,3-di-O-methyl-4,6-O-(2-naphthyl)methylene-1-thio-α-D-
glucopyranoside (5). Compound 4[20] (540 mg, 1.766 mmol) was
dissolved in dry DMF (8.0 mL) and NaH (60%, 170 mg, 4.238 mmol, 1.2
equiv./OH) was slowly added to the solution at 0 °C. After stirring for 30
min at 0 °C, MeI (275 µL, 4.415 mmol, and 1.25 equiv./OH) was added.
When complete conversion of the starting material into a main spot had
been observed by TLC analysis (24 h at room temperature), CH3OH (2.5
mL) was added. The reaction mixture was stirred for 5 min and the solvents
were evaporated. The residue was dissolved in CH2Cl2 (100 mL), and
washed with H2O (2 x 35 mL), the organic layer was dried, filtered and
evaporated. The crude product was purified by column chromatography
25
(7:3 n-hexane/acetone) to give 5 (634 mg, 92%) as white crystals. [α]D
+203.6 (c 0.14, CHCl3); M.p.: 145-147 °C (EtOAc/n-hexane); Rf 0.43 (7:3
n-hexane/acetone); 1H NMR (CDCl3, 500 MHz) δ 7.97-7.47 (m, 7H, arom),
5.70 (s, 1H, Hac), 5.54 (d, J = 4.9 Hz, 1H, H-1), 4.34-4.28 (m, 2H, H-5, H-
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10.1002/ejoc.201801349
European Journal of Organic Chemistry
FULL PAPER
6a), 3.83-3.79 (m, 1H, H-6b), 3.64 (s, 3H, OCH3), 3.61-3.56 (m, 3H, H-2,
H-3, H-4), 3.52 (s, 3H, OCH3), 2.65-2.54 (m, 2H, SCH2CH3), 1.31 (t, J =
7.4 Hz, 3H, SCH2CH3) ppm; 13C NMR (CDCl3, 125 MHz) δ 134.8, 133.8,
133.0 (3C, 3 x Cq arom), 128.5-123.9 (7C, arom), 101.8 (1C, Cac), 83.8
(1C, C-1), 82.4, 81.4, 80.3 (3C, C-2, C-3, C-4), 69.1 (1C, C-6), 62.9 (1C,
C-5), 61.3, 58.6 (2C, 2 x OCH3), 24.0 (1C, SCH2CH3), 14.9 (SCH2CH3)
ppm; MS (ESI-TOF): m/z calcd for C21H26NaO5S: 413.1393 [M+Na]+;
found: 413.1403.
Ethyl
2,3-di-O-methyl-4-O-(2-naphthyl)methyl-1-thio-β-L-
idopyranoside (8), ethyl 2,3-di-O-methyl-4-O-(2-naphthyl)methyl-1-
thio-β-L-idopyranoside sulfoxide (9) and ethyl 6-deoxy-6-fluoro-2,3-
di-O-methyl-4-O-(2-naphthyl)methyl-1-thio-α-D-glucopyranoside (10).
Method I.: A vigorously stirred solution of iodide 7 (1.38 g, 2.746 mmol) in
dry DMF (23 mL) was cooled to 0 °C, NaH (132 mg, 5.494 mmol, 2.0
equiv.) was added and the reaction mixture was stirred at room
temperature for 24 h. After the complete disappearance of the starting
material, MeOH (2.0 mL) was added and the mixture was concentrated.
The residue was dissolved in CH2Cl2 (250 mL) and washed with H2O (2 x
50 mL). The organic layer was separated, dried over MgSO4 and
concentrated under reduced pressure. To a stirred solution of the crude
product (954 mg, 2.548 mmol) in anhydrous THF (6.5 mL) a solution of
BH3·THF complex in THF (1M, 25.5 mL, 25.487 mmol, 10.0 equiv.) was
added at 0 °C. The reaction mixture was kept at this temperature for 1.5 h.
Then H2O2 (30%, 6.5 mL) and an aqueous solution of NaOH (2M, 13.5 mL)
were added at 0 °C and the reaction mixture was stirred at room
temperature for 50 min. Subsequently, the reaction mixture was diluted
with EtOAc (150 mL) and washed with saturated aqueous solution of
NH4Cl (2 x 25 mL), H2O (25 mL) and brine (25 mL). The organic layer was
separated, dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by column chromatography (7:3 n-
hexane/acetone) to give 8 (411 mg, 41% for three steps) as a colourless
syrup and 6 and 9 (100 mg, ~10% inseparable mixture, ratio of 6 : 9 ≈ 3 :
1) as a colourless syrup.
Ethyl
2,3-di-O-methyl-4-O-(2-naphthyl)methyl-1-thio-α-D-
glucopyranoside (6). To a stirred solution of the 4,6-O-acetal derivative 5
(1.53 g, 3.918 mmol) in a mixture of dry CH2Cl2 (44 mL) and dry Et2O (18
mL) were added successively LiAlH4 (669 mg, 17.631 mmol, 4.5 equiv.)
and a solution of AlCl3 (784 mg, 5.877 mmol, 1.5 equiv.) in dry Et2O (11
mL) under argon at 0 °C. When the TLC (6:4 n-hexane/EtOAc) indicated
complete disappearance of the starting material (1 h), the reaction mixture
was cooled in an ice-bath, and the excess of reagent was decomposed by
careful addition of EtOAc (79 mL) followed by H2O (19 mL), and the stirring
was continued for additional 5 min. The mixture obtained, consisting of a
grey, non-filterable suspension and a clear organic phase, was poured into
a separating funnel and diluted with EtOAc (200 mL). The layers were
separated and the organic phase was washed with H2O (3 x 50 mL), dried
over MgSO4 and concentrated. The residue was purified by column
chromatography (6:4 n-hexane/EtOAc) to give 6 (1.38 g, 90%) as white
25
crystals. [α]D +230.0 (c 0.10, CHCl3); M.p.: 103-105 °C (EtOAc/n-
hexane); Rf 0.43 (7:3 n-hexane/acetone); 1H NMR (CDCl3, 400 MHz) δ
7.84-7.44 (m, 7H, arom), 5.48 (d, J = 5.1 Hz, 1H, H-1), 5.03 (d, J = 11.4
Hz, 1H, NAP-CH2a), 4.83 (d, J = 11.4 Hz, 1H, NAP-CH2b), 4.09 (dt, J = 3.3
Hz, J = 8.9 Hz, 1H, H-5), 3.83-3.73 (m, 3H), 3.66, 3.50 (2 x s, 6H, 2 x
OCH3), 3.57-3.47 (m, 2H), 2.61-2.50 (m, 2H, SCH2CH3), 1.74 (t, 1H, H-6-
OH), 1.28 (t, J = 7.4 Hz, 3H, SCH2CH3) ppm; 13C NMR (CDCl3, 100 MHz)
δ 135.8, 133.4, 133.1 (3C, 3 x Cq arom), 128.3-126.1 (7C, arom), 84.3 (1C,
C-1), 82.8, 82.0, 77.5, 71.1 (4C, skeleton carbons), 75.0 (1C, NAP-CH2),
62.1 (1C, C-6), 61.3, 58.3 (2C, 2 x OCH3), 24.0 (1C, SCH2CH3), 14.8 (1C,
SCH2CH3) ppm; MS (ESI-TOF): m/z calcd for C21H28NaO5S: 415.1550
[M+Na]+; found: 415.1574; C21H28KO5S: 431.1289 [M+Na]+; found:
431.1286.
Method II.: A vigorously stirred solution of iodide 7 (440 mg, 0.876 mmol)
in dry pyridine (8.8 mL) AgF (556 mg, 4.379 mmol, 5.0 equiv.) was added
and the reaction mixture was stirred in the dark at room temperature for 24
h. After the complete disappearance of the starting material the mixture
was diluted with EtOAc (15 mL), filtered through a pad of Celite® and
concentrated under reduced pressure. To a stirred solution of the crude
product (300 mg, 0.801 mmol) in anhydrous THF (2.0 mL) a solution of
BH3·THF complex in THF (1M, 8.0 mL, 8.011 mmol, 10.0 equiv.) was
added at 0 °C. The reaction mixture was kept at this temperature for 1.5 h.
Then H2O2 (30%, 2.0 mL) and an aqueous solution of NaOH (2M, 4.25 mL)
were added at 0 °C and the reaction mixture was stirred at room
temperature for 50 min. Subsequently, the reaction mixture was diluted
with EtOAc (100 mL) and washed with saturated aqueous solution of
NH4Cl (2 x 15 mL), H2O (15 mL) and brine (15 mL). The organic layer was
separated, dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by column chromatography (6:4 n-
hexane/acetone) to give 8 (204 mg, 66% for three steps) as a colourless
syrup and 6 and 9 (34 mg, ~11% inseparable mixture, ratio of 6 : 9 ≈ 2 : 1)
as a colourless syrup and 10 (34 mg, 11%).
Ethyl 6-deoxy-6-iodo-2,3-di-O-methyl-4-O-(2-naphthyl)methyl-1-thio-
α-D-glucopyranoside (7). To the solution of thioglucoside 6 (419 mg,
1.068 mmol) in dry toluene (6.3 mL), triphenylphosphine (420 mmol, 1.602
mmol, 1.5 equiv.), imidazole (218 mg, 3.204 mmol, 3.0 equiv.) and iodine
(387 mg, 1.495 mmol, 1.4 equiv.) were added. The reaction mixture was
stirred at 75 °C for 30 min then cooled to room temperature. To the stirred
mixture NaHCO3 (210 mg) in water (2.6 mL) was added at room
temperature. After 5 min 10% aqueous solution of Na2S2O3 (5.0 mL) was
added and the mixture was diluted with EtOAc (125 mL) and washed with
H2O (2 x 35 mL). The organic layer was separated, dried over MgSO4 and
concentrated under reduced pressure. The crude product was purified by
column chromatography (8:2 n-hexane/EtOAc) to give 7 (450 mg, 84%) as
Data of the mixture of 6 and 9: Characteristic NMR signals: 1H NMR (CDCl3,
400 MHz) δ 5.45 (d, J = 5.1 Hz, 1H, H-1 d-gluco), 5.12 (d, J = 2.2 Hz, 0.5H,
H-1 l-ido-sulfoxide); MS (MALDI-TOF): m/z calcd for C21H28NaO5S (6):
415.155 [M+Na]+; found: 415.292; m/z calcd for C21H28NaO6S (9): 431.151
[M+Na]+; found: 431.246.
25
white crystals. [α]D +146.0 (c 0.40, CHCl3); M.p.: 82-84 °C (EtOAc/n-
hexane); Rf 0.41 (8:2 n-hexane/EtOAc); 1H NMR (CDCl3, 400 MHz) δ 7.85-
7.45 (m, 7H, arom), 5.50 (d, J = 4.7 Hz, 1H, H-1), 5.08 (d, J = 11.2 Hz, 1H,
NAP-CH2a), 4.88 (d, J = 11.2 Hz, 1H, NAP-CH2b), 3.87-3.83 (m, 1H, H-5),
3.64, 3.50 (2 x s, 6H, 2 x OCH3), 3.55-3.53 (m, 2H, H-2, H-3), 3.49-3.47
(m, 1H, H-6a), 3.40 (dd, J = 5.5 Hz, J = 10.7 Hz, 1H, H-6b), 3.34 (t, J = 8.8
Hz, 1H, H-4), 2.69-2.58 (m, 2H, SCH2CH3), 1.29 (t, J = 7.4 Hz, 3H,
SCH2CH3) ppm; 13C NMR (CDCl3, 100 MHz) δ 135.7, 133.4, 133.1 (3C, 3
x Cq arom), 128.4-126.0 (7C, arom), 84.0 (1C, C-2), 82.6 (1C, C-1), 81.9
(1C, C-3), 81.5 (1C, C-4), 75.3 (1C, NAP-CH2), 69.4 (1C, C-5), 61.2, 58.2
(2C, 2 x OCH3), 24.0 (1C, SCH2CH3), 14.8 (1C, SCH2CH3), 8.2 (1C, C-6)
ppm; MS (ESI-TOF): m/z calcd for C21H27INaO4S: 525.0567 [M+Na]+;
found: 525.0567.
Data of 8: [α]D25 +52.0 (c 0.55, CHCl3); Rf 0.25 (7:3 n-hexane/acetone); 1H
NMR (CDCl3, 400 MHz) δ 7.85-7.47 (m, 7H, arom), 4.81 (d, J = 12.4 Hz,
1H, NAP-CH2a), 4.80 (d, J = 1.6 Hz, 1H, H-1), 4.70 (d, J = 12.5 Hz, 1H,
NAP-CH2b), 4.02 (dd, J = 7.9 Hz, J = 11.5 Hz, 1H, H-6a), 3.78 (ddd, J =
1.9 Hz, J = 4.3 Hz, J = 6.6 Hz, 1H, H-5), 3.60-3.57 (m, 2H, H-3, H-6b), 3.51
(s, 3H, OCH3), 3.41 (s, 1H, H-4), 3.30 (s, 4H, H-2, OCH3), 2.71 (qd, J = 2.8
Hz, J = 7.4 Hz, 2H, SCH2CH3), 1.99 (s, 1H, H-6-OH), 1.28 (t, J = 7.4 Hz,
3H, SCH2CH3) ppm; 13C NMR (CDCl3, 100 MHz) δ 135.4, 133.2, 133.1
(3C, 3 x Cq arom), 128.5-126.2 (7C, arom), 83.4 (1C, C-1), 78.5 (1C, C-2),
77.3 (1C, C-5), 73.3 (1C, C-3), 72.4 (1C, NAP-CH2), 71.4 (1C, C-4), 62.8
(1C, C-6), 59.2, 58.1 (2C, 2 x OCH3), 25.8 (1C, SCH2CH3), 15.5 (1C,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801349
European Journal of Organic Chemistry
FULL PAPER
SCH2CH3) ppm; MS (ESI-TOF): m/z calcd for C21H28NaO5S: 415.1550
80.2 (2C, C-2’, C-3’), 78.2 (1C, C-4’), 75.7, 73.5, 73.4 (3C, 3 x Bn-CH2),
73.0 (1C, C-4), 70.6 (1C, C-5), 68.7 (1C, C-6’), 68.5 (1C, C-6), 62.0 (1C,
C-5’), 59.8, 58.6 (2C, 2 x OCH3), 55.2 (1C, C-1-OCH3) ppm; MS (ESI-
TOF): m/z calcd for C47H52NaO11: 815.3402 [M+Na]+; found: 815.3399.
[M+Na]+; found: 415.1552.
Data of 10: [α]D25 +184.0 (c 0.20, CHCl3); Rf 0.64 (6:4 n-hexane/acetone);
1H NMR (CDCl3, 400 MHz) δ 7.85-7.44 (m, 7H, arom), 5.51 (d, J = 4.0 Hz,
1H, H-1), 5.05 (d, J = 11.3 Hz, 1H, NAP-CH2a), 4.80 (d, J = 11.3 Hz, 1H,
NAP-CH2b), 4.67 (ddd, J = 3.3 Hz, J = 10.3 Hz, Hz, J = 47.2 Hz , 1H, H-
6a), 4.55 (ddd, J = 1.5 Hz, J = 10.3 Hz, J = 47.3 Hz, 1H, H-6b), 4.24-4.14
(m, H-5), 3.66 (s, 3H, OCH3), 3.55-3.52 (m, 3H, H-2, H-3, H-4), 3.51 (s, 3H,
OCH3), 2.57 (tdd, J = 5.4 Hz, J = 7.4 Hz, J = 12.8 Hz, 2H, SCH2CH3), 1.29
(t, J = 7.4 Hz, 3H, SCH2CH3) ppm; 13C NMR (CDCl3, 100 MHz) δ 135.7,
133.4, 133.2 (3C, 3 x Cq arom), 128.4-126.0 (7C, arom), 84.3 (1C, C-1),
82.3 (d, J = 172 Hz, 1C, C-6), 83.0, 81.8 (2C, C-2, C-3), 76.7 (d, J = 5.9
Hz, 1C, C-4), 75.3 (1C, NAP-CH2), 70.2 (d, J = 18.1 Hz, 1C, C-5), 61.3,
58.3 (2C, 2 x OCH3), 24.1 (1C, SCH2CH3), 14.8 (1C, SCH2CH3) ppm; MS
(ESI-TOF): m/z calcd for C21H27FNaO4S: 417.1506 [M+Na]+; found:
417.1506.
Methyl [2,3-di-O-methyl-6-O-(2-naphthyl)methyl-α-L-idopyranosyl]-
(1→4)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (14) and methyl (2,3-di-
O-methyl-α-L-idopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-α-D-
glucopyranoside (15).
Method I.: To a solution of compound 13 (250 mg, 0.315 mmol) in
anhydrous CH2Cl2 (3.2 mL) at 0 °C Et3SiH (604 µL, 3.784 mmol, 12.0
equiv.) and BF3∙Et2O (80 µL, 0.631 mmol, 2.0 equiv.) were added. The
reaction mixture was stirred for 2 h at 0 °C. Than the mixture was diluted
with CH2Cl2 (100 mL), washed with saturated aqueous solution of NaHCO3
(2 x 20 mL), dried over MgSO4 and concentrated. The crude product was
purified by column chromatography on silica gel (1:1 n-hexane/EtOAc) to
give compound 14 (52 mg, 20%) as a colourless syrup and compound 15
(105 mg, 42%) as a colourless syrup.
Ethyl
2,3-di-O-methyl-4,6-O-(2-naphthyl)methylene-1-thio-β-L-
idopyranoside (11). To a vigorously stirred solution of 8 (160 mg, 0.407
mmol) in dry CH2Cl2 (11 mL) DDQ (139 mg, 0.611 mmol, 1.5 equiv.) and
4 Å MS (115 mg) were added. After 50 min the mixture was diluted with
CH2Cl2 (100 mL), filtered, extracted with a saturated aqueous solution of
NaHCO3 (2 x 25 mL) and H2O (2 x 25 mL), dried and concentrated. The
crude product was purified by silica gel chromatography (7:3 n-
Method II.: To a solution of compound 13 (126 mg, 0.159 mmol) in
anhydrous THF (500 µL) 4 Å MS (121 mg) and Me3N∙BH3 (70 mg, 0.953
mmol, 6.0 equiv.) were added and stirred for 30 min at room temperature.
After 30 min AlCl3 (127 mg, 0.953 mmol, 6.0 equiv.) was added and the
reaction mixture was stirred at room temperature for 30 min. The mixture
was diluted with CH2Cl2 (100 mL), washed with water (2 x 20 mL), dried
over MgSO4 and concentrated. The crude product was purified by column
chromatography on silica gel (1:1 n-hexane/EtOAc) to give compound 14
(101 mg, 80%) as a colourless syrup.
25
hexane/acetone) to give 11 (106 mg, 67%) as a colourless syrup. [α]D
1
+55.7 (c 0.21, CHCl3); Rf 0.35 (7:3 n-hexane/acetone); H NMR (CDCl3,
400 MHz) δ 7.96-7.44 (m, 7H, arom), 5.62 (s, 1H, Hac), 4.87 (d, J = 1.3 Hz,
1H, H-1), 4.36 (d, J = 12.5 Hz, 1H, NAP-CH2a), 4.07 (dd, J = 2.0 Hz, J =
12.5 Hz, 1H, NAP-CH2b), 3.97 (s, 1H, H-4), 3.70 (t, J = 2.2 Hz, 1H, H-3),
3.58 (d, J = 1.1 Hz, 1H, H-5), 3.49, 3.47 (2 x s, 6H, 2 x OCH3), 3.36 (s, 1H,
H-2), 2.76 (q, J = 7.4 Hz, 2H, SCH2CH3), 1.31 (t, J = 7.4 Hz, 3H, SCH2CH3)
ppm; 13C NMR (CDCl3, 100 MHz) δ 135.8, 133.8, 133.0 (3C, 3 x Cq arom),
128.4-124.6 (7C, arom), 101.6 (1C, Cac), 82.3 (1C, C-1), 77.2 (1C, C-2),
75.4 (1C, C-3), 71.7 (1C, C-4), 70.1 (1C, C-6), 68.6 (1C, C-5), 58.4, 58.2
(2C, 2 x OCH3), 25.6 (1C, SCH2CH3), 15.1 (1C, SCH2CH3) ppm; MS (ESI-
TOF): m/z calcd for C21H26NaO5S: 413.1393 [M+Na]+; found: 413.1393.
Data of 14: [α]D25 +3.3 (c 0.12, CHCl3); Rf 0.40 (1:1 n-hexane/EtOAc); 1H
NMR (CDCl3, 400 MHz) δ 7.80-7.20 (m, 22H, arom), 5.08 (s, 1H, H-1’),
4.95-4.43 (m, 9H, NAP-CH2, 3 x Bn-CH2, H-1), 4.39 (td, J = 1.3 Hz, J = 5.7
Hz, 1H, H-5’), 3.94-3.86 (m, 2H), 3.79-3.57 (m, 5H), 3.52-3.46 (m, 3H),
3.40, 3.34, 3.27 (3 x s, 9H, 3 x OCH3), 3.20 (s, 1H), 3.14 (d, J = 9.3 Hz,
1H, C-4-OH) ppm; 13C NMR (CDCl3, 100 MHz) δ 139.2, 138.2, 138.0,
135.9, 133.3, 132.9 (6C, 6 x Cq arom), 128.4-125.7 (22C, arom), 98.1 (2C,
C-1, C-1’), 80.4, 80.3, 77.5, 77.4, 74.6, 70.1, 66.9, 66.8 (8C, skeleton
carbons), 75.4, 73.5, 73.3 (4C, NAP-CH2, 3 x Bn-CH2), 69.8, 68.9 (2C, C-
6, C-6’), 58.5, 58.3 (2C, 2 x OCH3), 55.2 (1C, C-1-OCH3) ppm; MS (MALDI-
TOF): m/z calcd for C47H54NaO11: 817.356 [M+Na]+; found: 817.381.
Methyl
[2,3-di-O-methyl-4,6-O-(2-naphthyl)methylene-α-L-
idopyranosyl]-(1→4)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (13). To
a solution of compound 11 (200 mg, 0.512 mmol) and compound 12[26]
(357 mg, 0.768 mmol, 1.5 equiv.) in dry CH2Cl2 (6.0 mL) 4 Å molecular
sieves (0.25 g) were added. After stirring at room temperature for 30 min,
the mixture was cooled to −40 °C and solutions of NIS (173 mg, 0.768
mmol, 1.5 equiv.) in dry THF (240 µL) and AgOTf (32 mg, 0.123 mmol,
0.24 equiv.) in dry toluene (240 µL) were added. After stirring at −40 °C to
−20 °C for 4 h, TLC analysis (6:4 n-hexane/EtOAc) showed complete
consumption of the donor. The reaction mixture was neutralized with Et3N
(50 µL), diluted with CH2Cl2 (150 mL), and filtered. The filtrate was washed
with an aqueous solution of Na2S2O3 (10%, 25 mL), a saturated aqueous
solution of NaHCO3 (2 x 25 mL), and water (2 x 25 mL), dried, and
concentrated. The crude product was purified by column chromatography
on silica gel (6:4 n-hexane/EtOAc) to give compound 13 (294 mg, 72%) as
white crystals. [α]D25 +1.1 (c 0.09, CHCl3); Rf 0.36 (6:4 n-hexane/EtOAc);
Data of 15: [α]D25 −5.5 (c 0.20, CHCl3); Rf 0.13 (1:1 n-hexane/EtOAc); 1H
NMR (CDCl3, 400 MHz) δ 7.27-7.18 (m, 15H, arom), 4.96 (d, J = 10.5 Hz,
1H, Bn-CH2a), 4.89 (s, 1H, H-1’), 4.72-4.45 (m, 6H, Bn-CH2b, 2 x Bn-CH2,
H-1), 4.08-4.06 (m, 1H, H-5’), 3.84-3.78 (m, 2H, H-3, H-3’), 3.72-3.70 (m,
1H, H-4), 3.56 (s, 2H, H-6a,b), 3.51 (dd, J = 3.3 Hz, J = 8.8 Hz, 1H, H-2),
3.45-3.40 (m, 1H, H-5), 3.37 (s, 3H, OCH3), 3.35-3.31 (m, 1H, H-4’), 3.29,
3.17 (2 x s, 6H, 2 x OCH3), 3.28-3.12 (m, 2H, H-6’a,b), 3.07-3.05 (m, 1H,
H-2’), 1.83 (s, 1H, C-6’-OH), 1.24 (s, 1H, C-4’-OH) ppm; 13C NMR (CDCl3,
100 MHz) δ 138.5, 138.0, 137.7 (3C, 3 x Cq arom), 128.5-127.7 (15C,
arom), 98.0, (1C, C-1), 97.0 (1C, C-1), 80.3 (1C, C-2), 80.1 (1C, C-3), 76.9,
76.8 (2C, C-2’, C-4’), 75.8, 73.6 (2C, 2 x Bn-CH2), 73.5 (1C, C-3’), 73.4
(1C, Bn-CH2), 70.2 (1C, C-4), 68.9 (1C, C-6), 67.1, 67.0 (2C, C-5, C-5’),
63.0 (1C, C-6’), 58.4, 58.2 (2C, 2 x OCH3), 55.2 (1C, C-1-OCH3) ppm; MS
(MALDI-TOF): m/z calcd for C36H46NaO11: 667.293 [M+Na]+; found:
667.344.
1
M.p.: 162-164 °C (EtOAc/n-hexane); H NMR (CDCl3, 400 MHz) δ 7.91-
7.22 (m, 22H, arom), 5.43 (s, 1H, Hac), 5.05 (d, J = 11.2 Hz, 1H, Bn-CH2a),
4.85 (d, J = 4.9 Hz, 1H, H-1’), 4.78-4.56 (m, 6H, Bn-CH2b, 2 x Bn-CH2, H-
1), 3.98-3.77 (m, 5H, H-3, H-4, H-4’, H-5’, H-6’a), 3.70-3.69 (m, 2H, H-
6a,b), 3.59 (dd, J = 3.6 Hz, J = 9.5 Hz, 1H, H-2), 3.54 (s, 1H, H-5), 3.51 (s,
3H, OCH3), 3.46-3.43 (m, 1H, H-3’), 3.44, 3.38 (2 x s, 6H, 2 x OCH3), 3.20
(dd, J = 4.9 Hz, J = 9.1 Hz, 1H, H-2’), 3.16 (dd, J = 2.2 Hz, J = 13.2 Hz,
1H, H-6’b) ppm; 13C NMR (CDCl3, 100 MHz) δ 139.2, 138.1, 137.8, 135.5,
133.6, 132.9 (6C, 6 x Cq arom), 128.5-124.0 (22C, arom), 100.4, (1C, C-
1’), 100.0 (1C, Cac), 98.1 (1C, C-1), 82.3 (1C, C-3), 80.6 (1C, C-2), 80.3,
Methyl
(6-O-tert-butyldiphenylsilyl-2,3-di-O-methyl-α-L-
idopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (16). To
a solution of 15 (103 mg, 0.157 mmol) in dry pyridine (540 µL), tert-
butyldiphenylsilyl chloride (81 µL, 0.314 mmol, 2 equiv.) was added. The
mixture was stirred for 24 h at room temperature. After the complete
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801349
European Journal of Organic Chemistry
FULL PAPER
disappearance of the starting material, the mixture was concentrated. The
residue was dissolved in EtOAc (75 mL), washed with 1 M aqueous
solution of HCl (2 x 10 mL), water (10 mL), saturated aqueous solution of
NaHCO3 (2 x 10 mL), and water (2 x 10 mL), dried, and concentrated. The
crude product was purified by column chromatography on silica gel (7:3 n-
hexane/acetone) to give compound 16 (114 mg, 81%) as a colourless
syrup. [α]D25 +5.4 (c 0.13, CHCl3); Rf 0.41 (7:3 n-hexane/acetone); 1H NMR
(CDCl3, 400 MHz) δ 7.69-7.15 (m, 25H, arom), 5.08 (s, 1H, H-1’), 4.88-
4.49 (m, 7H, 3 x Bn-CH2, H-1), 4.26 (t, J = 5.1 Hz, 1H, H-5’), 3.93-3.84 (m,
2H), 3.83-3.75 (m, 4H), 3.69-3.61 (m, 2H), 3.51-3.47 (m, 2H), 3.41, 3.36,
3.24 (3 x s, 9H, 3 x OCH3), 3.18 (s, 1H), 1.26 (s, 1H, C-4’-OH), 1.02 (s, 9H,
3 x t-Bu-CH3) ppm; 13C NMR (CDCl3, 100 MHz) δ 139.0, 138.3, 138.1,
133.4, 133.3 (5C, 5 x Cq arom), 129.6-127.3 (25C, arom), 98.4, 98.3 (2C,
C-1, C-1’), 80.8, 80.2, 77.8, 77.6, 74.4, 70.0, 68.1, 66.7 (8C, skeleton
carbons), 75.6, 73.6 (2C, 2 x Bn-CH2), 69.0 (1C, C-6), 63.5 (1C, C-6’), 58.4,
58.3 (2C, 2 x OCH3), 55.2 (1C, C-1-OCH3), 26.9 (3C, 3 x t-Bu-CH3), 19.2
(1C, Cq t-Bu) ppm; MS (MALDI-TOF): m/z calcd for C52H64NaO11Si:
915.411 [M+Na]+; found: 915.550.
and the mixture was stirred at room temperature for 2 h. After 2.5 h the
reaction mixture was diluted with CH2Cl2 (5.0 mL), and washed with H2O
(2 x 5 mL). The organic layer was dried over MgSO4 and concentrated.
The crude product was purified by silica gel chromatography (7:3 n-
hexane/acetone) to give 19a (40 mg, 65%) as a colourless syrup and 19b
(13 mg, 21%) as a colourless syrup.
Data of 19a: [α]D25 +13.0 (c 0.13, CHCl3); Rf 0.36 (7:3 n-hexane/acetone);
1H NMR (CDCl3, 500 MHz) δ 7.72-7.12 (m, 40H, arom), 5.27 (d, J = 3.5
Hz, 1H, H-1”), 4.99 (d, J = 7.2 Hz, 1H, H-1’), 4.97-4.62 (m, 8H, 4 x Bn-CH2),
4.60 (d, J = 3.6 Hz, 1H, H-1), 4.52-4.40 (m, 4H, 2 x Bn-CH2), 3.93 (dd, J =
4.7 Hz, J = 11.3 Hz, 1H, H-6’a), 3.89-3.83 (m, 6H, H-3, H-3’, H-4, H-4’, H-
5’, H-6a), 3.81-3.79 (m, 1H, H-6’b), 3.67-3.56 (m, 4H, H-3”, H-4”, H-5, H-
6b), 3.54-3.49 (m, 2H, H-2”, H-6”a), 3.50 (s, 3H, C-3’-OCH3), 3.47-3.46 (m,
1H, H-2), 3.45 (s, 3H, C-2’-OCH3), 3.41 (s, 3H, C-1-OCH3), 3.42-3.35 (m,
2H, H-5”, H-6”b), 3.01 (t, J = 7.2 Hz, 1H, H-2’), 2.24 (d, J = 2.5 Hz, 1H, C-
4”-OH), 1.04 (s, 9H, 3 x t-Bu-CH3) ppm; 13C NMR (CDCl3, 125 MHz) δ
139.6, 139.0, 138.6, 138.5, 138.3, 138.0, 133.2, 132.9 (8C, 8 x Cq arom),
129.9-127.2 (40C, arom), 100.8 (1C, C-1’), 98.6 (1C, C-1”), 98.2 (1C, C-
1), 85.1 (1C, C-2’), 82.1 (1C, C-3’), 81.4 (1C, C-3”), 80.6 (1C, C-3), 79.2
(1C, C-2), 79.1 (1C, C-2”), 78.8 (1C, C-4”), 76.0 (1C, C-4’), 75.6, 75.3, 73.8,
73.7 (4C, 4 x Bn-CH2), 73.6 (1C, C-4), 73.4, 72.5 (2C, 2 x Bn-CH2), 70.9,
70.8, 70.7 (3C, C-5, C-5’, C-5”), 69.3 (1C, C-6), 69.1 (1C, C-6”), 62.8 (1C,
C-6’), 60.5, 60.4 (2C, 2 x OCH3), 55.3 (1C, C-1-OCH3), 27.1 (3C, 3 x t-Bu-
CH3), 19.3 (1C, Cq t-Bu) ppm; MS (ESI-TOF): m/z calcd for C79H92NaO16Si:
1347.6047 [M+Na]+; found: 1347.6037.
Methyl
(2,3-di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranosyl)-
(1→4)-(6-O-tert-butyldiphenylsilyl-2,3-di-O-methyl-α-L-idopyranosyl)-
(1→4)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (18). To a solution of
compound 16 (54 mg, 0.060 mmol) and compound 17[31] (52 mg, 0.096
mmol, 1.6 equiv.) in dry CH2Cl2 (708 µL) 4 Å molecular sieves (50 mg)
were added. After stirring at room temperature for 30 min, the mixture was
cooled to −40 °C and solutions of NIS (33 mg, 0.145 mmol, 1.5 equiv.) in
dry THF (45 µL) and AgOTf (6.0 mg, 0.023 mmol, 0.24 equiv.) in dry
toluene (45 µL) were added. After stirring at −40 °C to −20 °C for 4 h, TLC
analysis (7:3 n-hexane/EtOAc) showed complete consumption of the
donor. The reaction mixture was neutralized with Et3N (25 µL), diluted with
CH2Cl2 (75 mL), and filtered. The filtrate was washed with an aqueous
solution of Na2S2O3 (10%, 10 mL), a saturated aqueous solution of
NaHCO3 (2 x 10 mL), and water (2 x 10 mL), dried, and concentrated. The
crude product was purified by column chromatography on silica gel (7:3 n-
hexane/EtOAc) to give compound 18 (70 mg, 88%) as a colourless syrup.
[α]D25 −1.8 (c 0.11, CHCl3); Rf 0.30 (7:3 n-hexane/EtOAc); 1H NMR (CDCl3,
500 MHz) δ 7.74-7.19 (m, 40H, arom), 5.50 (s, 1H, Hac), 5.28 (d, J = 3.9
Hz, 1H, H-1”), 5.01 (d, J = 7.2 Hz, 1H, H-1’), 4.99-4.62 (m, 8H, 4 x Bn-CH2),
4.62 (d, J = 3.6 Hz, 1H, H-1), 4.49 (q, J = 12.2 Hz, 2H, Bn-CH2), 4.01 (dd,
J = 4.5 Hz, J = 10.1 Hz, 1H, H-6”a), 3.93-3.84 (m, 7H, H-3, H-3’, H-3”, H-
4’, H-5, H-6a, H-6’a), 3.77-3.75 (m, 2H, H-5’, H-6’b), 3.65-3.56 (m, 5H, H-
2”, H-4, H-4”, H-6b, H-6”b), 3.55-3.52 (m, 1H, H-5”), 3.51 (s, 3H, C-3’-
OCH3), 3.49-3.48 (m, 1H, H-2), 3.46 (s, 3H, C-2’-OCH3), 3.42 (s, 3H, C-1-
Data of 19b: [α]D25 +17.2 (c 0.97, CHCl3); Rf 0.31 (7:3 n-hexane/acetone);
1H NMR (CDCl3, 500 MHz) δ 7.70-7.18 (m, 40H, arom), 5.24 (d, J = 3.6
Hz, 1H, H-1”), 4.99 (d, J = 10.6 Hz, 1H, Bn-CH2a), 4.96 (d, J = 7.0 Hz, 1H,
H-1’), 4.91-4.61 (m, 9H, Bn-CH2b, 4 x Bn-CH2), 4.60 (d, J = 3.0 Hz, 1H, H-
1), 4.47 (q, J = 12.2 Hz, 2H, Bn-CH2), 3.91 (dd, J = 4.9 Hz, J = 11.3 Hz,
1H, H-6’a), 3.88-3.76 (m, 8H, H-3, H-3’, H-3”, H-4’, H-5, H-5’, H-6a, H-6’b),
3.65 (t, J = 9.4 Hz, 1H, H-4), 3.58 (dd, J = 7.0 Hz, J = 10.8 Hz, 1H, H-6b),
3.53-3.46 (m, 5H, H-2, H-2”, H-4”, H-6”a,b), 3.50 (s, 3H, C-3’-OCH3), 3.46
(s, 3H, C-2’-OCH3), 3.41 (s, 3H, C-1-OCH3), 3.38-3.36 (m, 1H, H-5”), 3.00
(t, J = 7.2 Hz, 1H, H-2’), 1.48-1-45 (m, 1H, C-6”-OH), 1.04 (s, 9H, 3 x t-Bu-
CH3) ppm; 13C NMR (CDCl3, 125 MHz) δ 139.6, 138.5, 138.4, 133.2, 132.8,
131.2 (8C, 8 x Cq arom), 128.5-127.2 (40C, arom), 100.7 (1C, C-1’), 98.6
(1C, C-1”), 98.2 (1C, C-1), 85.2 (1C, C-2’), 82.3 (1C, C-3’), 81.8 (1C, C-3”),
80.6 (1C, C-3), 79.7 (1C, C-2”), 79.2 (1C, C-2), 78.8 (1C, C-4), 77.5 (1C,
C-4”), 76.2 (1C, C-4’), 75.6, 75.2 (4C, 4 x Bn-CH2), 74.2 (1C, C-5’), 73.4,
72.8 (2C, 2 x Bn-CH2), 71.8 (1C, C-5”), 70.8 (1C, C-5), 69.3 (1C, C-6), 62.6
(1C, C-6’), 61.8 (1C, C-6”), 60.5, 60.4 (2C, 2 x OCH3), 55.3 (1C, C-1-OCH3),
27.1 (3C, 3 x t-Bu-CH3), 19.2 (1C, Cq t-Bu) ppm; MS (MALDI-TOF): m/z
calcd for C79H92NaO16Si: 1347.605 [M+Na]+; found: 1347.877.
OCH3), 3.00 (t, J = 7.7 Hz, 1H, H-2’), 1.03 (s, 9H, 3 x t-Bu-CH3) ppm; 13
C
NMR (CDCl3, 125 MHz) δ 139.5, 139.0, 138.6, 138.5, 138.3, 137.5, 132.9,
132.7 (8C, 8 x Cq arom), 129.9-126.2 (40C, arom), 101.2 (1C, Cac), 101.0
(1C, C-1’), 99.4 (1C, C-1”), 98.1 (1C, C-1), 85.5 (1C, C-2’), 82.5 (1C, C-3’),
82.4 (1C, C-4”), 80.6 (1C, C-3), 79.2 (1C, C-2), 79.1 (1C, C-2”), 78.9 (1C,
C-4), 78.7 (1C, C-3”), 75.9 (1C, C-4’), 75.6, 75.2 (2C, 2 x Bn-CH2), 73.8
(1C, C-5’), 73.7, 73.4 (3C, 3 x Bn-CH2), 70.8 (1C, C-5), 69.4 (1C, C-6),
68.8 (1C, C-6”), 63.2 (1C, C-5”), 62.8 (1C, C-6’), 60.6, 60.5 (2C, 2 x OCH3),
55.3 (1C, C-1-OCH3), 27.1 (3C, 3 x t-Bu-CH3), 19.1 (1C, Cq t-Bu) ppm; MS
(MALDI-TOF): m/z calcd for C79H90NaO16Si:1345.589 [M+Na]+; found:
1345.662.
Methyl
(2,3-di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranosyl)-
(1→4)-(2,3-di-O-methyl-6-O-(2-naphthyl)methyl-α-L-idopyranosyl)-
(1→4)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (20). To a solution of
compound 14 (90 mg, 0.113 mmol) and compound 17[31] (98 mg, 0.181
mmol, 1.6 equiv.) in dry CH2Cl2 (1320 µL) 4 Å molecular sieves (80 mg)
were added. After stirring at room temperature for 30 min, the mixture was
cooled to −40 °C and solutions of NIS (61 mg, 0.272 mmol, 1.5 equiv.) in
dry THF (84 µL) and AgOTf (11 mg, 0.043 mmol, 0.24 equiv.) in dry toluene
(84 µL) were added. After stirring at −40 °C to −20 °C for 4 h, TLC analysis
(7:3 n-hexane/EtOAc) showed complete consumption of the donor. The
reaction mixture was neutralized with Et3N (200 µL), diluted with CH2Cl2
(100 mL), and filtered. The filtrate was washed with an aqueous solution
of Na2S2O3 (10%, 20 mL), a saturated aqueous solution of NaHCO3 (2 x
20 mL), and water (2 x 20 mL), dried, and concentrated. The crude product
was purified by column chromatography on silica gel (65:35 n-
hexane/EtOAc) to give compound 20 (111 mg, 80%) as a colourless syrup.
Methyl
(2,3,6-tri-O-benzyl-α-D-glucopyranosyl)-(1→4)-(6-O-tert-
butyldiphenylsilyl-2,3-di-O-methyl-α-L-idopyranosyl)-(1→4)-2,3,6-tri-
O-benzyl-α-D-glucopyranoside (19a) and methyl (2,3,4-tri-O-benzyl-α-
D-glucopyranosyl)-(1→4)-(6-O-tert-butyldiphenylsilyl-2,3-di-O-
methyl-α-L-idopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-α-D-
glucopyranoside (19b). To a solution of 18 (63 mg, 0.048 mmol) in dry
THF (144 µL) 4 Å MS (36 mg) and Me3N·BH3 (21 mg, 0.286 mmol, 6
equiv.) were added and the reaction mixture was stirred for 30 min at room
temperature. After 30 min AlCl3 (38 mg, 0.286 mmol, 6 equiv.) was added
25
[α]D +11.0 (c 0.10, CHCl3); Rf 0.50 (6:4 n-hexane/EtOAc); 1H NMR
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801349
European Journal of Organic Chemistry
FULL PAPER
(CDCl3, 500 MHz) δ 7.72-7.19 (m, 37H, arom), 5.52 (s, 1H, Hac), 5.25 (d,
J = 3.8 Hz, 1H, H-1”), 4.98 (d, J = 6.9 Hz, 1H, H-1’), 4.98-4.60 (m, 8H, 4 x
Bn-CH2), 4.58 (d, J = 4.0 Hz, 1H, H-1), 4.48-4.38 (m, 4H, NAP-CH2, Bn-
CH2), 4.15 (dd, J = 4.7 Hz, J = 10.1 Hz, 1H, H-6”a), 4.04 (dd, J = 4.6 H, J
= 9.5 Hz, 1H, H-5’), 3.93-3.88 (m, 4H, H-3, H-3”, H-4, H-4’), 3.79-3.74 (m,
5H, H-3’, H-5, H-5”, H-6a, H-6’a), 3.71-3.64 (m, 3H, H-6b, H-6’b, H-6”b),
3.60 (t, J = 9.4 Hz, 1H, H-4”), 3.58 (dd, J = 3.8 Hz, J = 9.4 Hz, 1H, H-2”),
3.52 (s, 3H, C-3’-OCH3), 3.50-3.47 (m, 1H, H-2), 3.49 (s, 3H, C-2’-OCH3),
3.36 (s, 3H, C-1-OCH3), 3.05 (t, J = 7.4 Hz, 1H, H-2’) ppm; 13C NMR (CDCl3,
125 MHz) δ 139.4, 138.8, 138.5, 138.3, 137.5, 135.8, 133.3, 132.8 (9C, 9
x Cq arom), 129.9-125.6 (37C, arom), 101.2 (1C, Cac), 100.0 (1C, C-1’),
99.1 (1C, C-1”), 98.4 (1C, C-1), 84.8 (1C, C-2’), 82.5 (1C, C-3’), 82.3 (1C,
C-4”), 80.2 (1C, C-3), 79.4 (1C, C-2), 79.0 (1C, C-2”), 78.3 (1C, C-4’), 76.6
(1C, C-4), 76.3 (1C, C-3”), 75.3, 75.0, 73.6, 73.2 (6C, NAP-CH2, 5 x Bn-
CH2), 72.2 (1C, C-5’), 70.4 (1C, C-5), 69.1 (1C, C-6’), 68.9 (1C, C-6”), 68.3
(1C, C-6), 63.3 (1C, C-5”), 60.4, 60.3 (2C, 2 x OCH3), 55.3 (1C, C-1-OCH3)
ppm; MS (ESI-TOF): m/z calcd for C74H80NaO16: 1247.5339 [M+Na]+;
found: 1247.5331.
138.6, 138.4, 138.3, 135.9, 133.4, 132.9 (9C, 9 x Cq arom), 128.6-125.7
(37C, arom), 100.1 (1C, C-1’), 98.5 (1C, C-1), 98.0 (1C, C-1”), 84.7 (1C,
C-2’), 82.5 (1C, C-3’), 81.7 (1C, C-3”), 80.3 (1C, C-3), 79.9 (1C, C-2”), 79.5
(1C, C-2), 77.3 (1C, C-4”), 76.7 (1C, C-4), 76.1 (1C, C-4’), 75.5, 75.4, 75.2,
73.7, 73.3, 72.8 (7C, NAP-CH2, 6 x Bn-CH2), 72.0 (1C, C-5’), 71.7 (1C, C-
5”), 70.5 (1C, C-5), 69.2 (1C, C-6’), 68.4 (1C, C-6), 61.7 (1C, C-6”), 60.4
(2C, 2 x OCH3), 55.4 (1C, C-1-OCH3) ppm; MS (ESI-TOF): m/z calcd for
C74H82NaO16: 1249.5495 [M+Na]+; found: 1249.5483.
Methyl
(6-O-benzyl-2,3,4-tri-O-methyl-α-D-glucopyranosyl)-(1→4)-
[2,3-di-O-acetyl-6-O-(2-naphthyl)methyl-β-D-glucopyranosyl]-(1→4)-
(2,3,6-tri-O-benzyl-α-D-glucopyranosyl)-(1→4)-(6-O-tert-
butyldiphenylsilyl-2,3-di-O-methyl-α-L-idopyranosyl)-(1→4)-2,3,6-tri-
O-benzyl-α-D-glucopyranoside (23) and methyl (6-O-benzyl-2,3,4-tri-
O-methyl-α-D-glucopyranosyl)-(1→4)-[2,3-di-O-acetyl-6-O-(2-
naphthyl)methyl-β-D-glucopyranosyl]-(1→4)-2,3,6-tri-O-benzyl-α-D-
glucopyranoside (24). To a solution of trisaccharide acceptor 19a (32 mg,
0.024 mmol) and disaccharide donor 2232 (28.6 mg, 0.036 mmol, 1.5
equiv.) in dry CH2Cl2 (1.2 mL) 4 Å MS (150 mg) were added and the
reaction mixture was stirred at room temperature. After 30 min the stirred
mixture was cooled to −20 °C under argon. After at this temperature, NIS
(12 mg, 0.054 mmol, 1.5 equiv. to the donor) was dissolved in dry THF (30
µL) and AgOTf (2 mg, 0.009 mmol, 0.24 equiv. to the donor) dissolved in
dry toluene (30 µL) were added. The temperature was allowed to warm up
to +5 °C and the reaction mixture was stirred for 4 h. After 4 h the reaction
mixture was quenched with Et3N (150 µL), diluted with CH2Cl2 (25 mL),
filtered and the mixture was washed with saturated aqueous solution of
Na2S2O3 (2 x 5 mL), saturated aqueous solution of NaHCO3 (5 mL) and
with H2O (2 x 5 mL) until neutral pH. The organic layer was dried on MgSO4
and concentrated. The crude product was purified by silica gel
chromatography (6:4 n-hexane/EtOAc to 1:1 n-hexane/EtOAc) to give 23
(5 mg, 11%) as a colourless syrup and 24 (22 mg, 46%) as a colourless
syrup.
Methyl
(2,3,6-tri-O-benzyl-α-D-glucopyranosyl)-(1→4)-(2,3-di-O-
methyl-6-O-(2-naphthyl)methyl-α-L-idopyranosyl)-(1→4)-2,3,6-tri-O-
benzyl-α-D-glucopyranoside (21a) and methyl (2,3,4-tri-O-benzyl-α-D-
glucopyranosyl)-(1→4)-(2,3-di-O-methyl-6-O-(2-naphthyl)methyl-α-L-
idopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-α-D-glucopyranoside
(21b).
To a solution of 20 (95 mg, 0.077 mmol) in dry THF (235 µL) 4 Å MS (60
mg) and Me3N·BH3 (34 mg, 0.465 mmol, 6 equiv.) were added and the
reaction mixture was stirred for 30 min at room temperature. After 30 min
AlCl3 (62 mg, 0.465 mmol, 6 equiv.) was added and the mixture was stirred
at room temperature for 2 h. After 2 h the reaction mixture was diluted with
CH2Cl2 (50 mL), and washed with H2O (2 x 15 mL). The organic layer was
dried over MgSO4 and concentrated. The crude product was purified by
silica gel chromatography (6:4 n-hexane/EtOAc) to give 21a (66 mg, 70%)
as a colourless syrup and 21b (18 mg, 19%) as a colourless syrup.
Data of 21a: [α]D25 +26.7 (c 0.12, CHCl3); Rf 0.66 (1:1 n-hexane/EtOAc);
1H NMR (CDCl3, 500 MHz) δ 7.74-7.16 (m, 37H, arom), 5.27 (d, J = 3.5
Hz, 1H, H-1”), 4.98 (d, J = 7.4 Hz, 1H, H-1’), 4.96-4.60 (m, 8H, 4 x Bn-CH2),
4.58 (d, J = 4.3 Hz, 1H, H-1), 4.49-4.36 (m, 6H, NAP-CH2, 2 x Bn-CH2),
4.10 (dd, J = 4.8 Hz, J = 9.8 Hz, 1H, H-5’), 3.94-3.86 (m, 3H, H-3, H-4, H-
4’), 3.80 (dd, J = 3.7 Hz, J = 10.7 Hz, 1H, H-6a), 3.77-3.73 (m, 3H, H-3’,
H-5, H-6’a), 3.69-3.60 (m, 5H, H-3”, H-4”, H-5”, H-6b, H-6’b), 3.55-3.50 (m,
2H, H-2”, H-6”a), 3.51 (s, 3H, C-3’-OCH3), 3.49-3.44 (m, 2H, H-2, H-6”b),
3.47 (s, 3H, C-2’-OCH3), 3.36 (s, 3H, C-1-OCH3), 3.06 (t, J = 7.3 Hz, 1H,
H-2’), 2.23 (s, 1H, C-4”-OH) ppm; 13C NMR (CDCl3, 125 MHz) δ 139.4,
138.8, 138.6, 138.4, 138.0, 135.9, 133.4, 132.9 (9C, 9 x Cq arom), 128.6-
125.8 (37C, arom), 100.0 (1C, C-1’), 98.4 (1C, C-1), 98.0 (1C, C-1”), 84.5
(1C, C-2’), 82.2 (1C, C-3’), 80.9 (1C, C-3”), 80.3 (1C, C-3), 79.5 (1C, C-2),
79.3 (1C, C-2”), 76.6 (1C, C-4), 76.0 (1C, C-4’), 75.5, 75.2, 73.7, 73.6, 73.3,
72.4 (7C, NAP-CH2, 6 x Bn-CH2), 71.9 (1C, C-5’), 70.9, 70.8 (2C, C-4”, C-
5”), 70.5 (1C, C-5), 69.4 (1C, C-6’), 69.2 (1C, C-6”), 68.4 (1C, C-6), 60.3,
60.2 (2C, 2 x OCH3), 55.4 (1C, C-1-OCH3) ppm; MS (ESI-TOF): m/z calcd
for C74H82NaO16: 1249.5495 [M+Na]+; found: 1249.5487.
Data of 23: [α]D25 +27.0 (c 0.10, CHCl3); Rf 0.48 (1:1 n-hexane/EtOAc); 1H
NMR (CDCl3, 500 MHz) δ 7.80-7.10 (m, 52H, arom), 5.27 (d, J = 3.8 Hz,
1H, H-1”), 5.12-4.25 (m, 22H, 7 x Bn-CH2, NAP-CH2, 4 x H-1, H-2-E, H-3-
E), 3.96-2.98 (m, 46H, 6 x OCH3, 28 skeleton hydrogen), 2.02, 1.95 (2 x s,
6H, 2 x Ac-CH3), 1.03 (s, 9H, t-Bu-CH3) ppm; 13C NMR (CDCl3, 125 MHz)
δ 148.7, 147.5, 144.8, 143.8, 143.5, 139.5, 138.3, 137.6, 133.3, 133.2,
132.9, 132.8 (12C, 12 x Cq arom), 135.7-125.6 (52C, arom), 101.1, 100.0,
98.9, 98.2, 98.0 (5C, 5 x C-1), 85.0, 83.4, 82.0, 80.6, 80.4, 79.4, 79.2, 76.8,
75.6, 75.3, 75.2, 73.0, 71.4, 71.1, 69.0, 68.5, 67.7 (20C, skeleton carbons),
75.1, 73.5, 73.1 (9C, 7 x Bn-CH2, 2 x NAP-CH2), 70.9, 70.8, 70.7 (3C, C-
5, C-5’, C-5”), 67.7, 68.5, 68.7, 69.0 (4C, 4 x C-6), 63.2 (1C, C-6-G), 60.9,
60.5, 59.4 (5C, 5 x OCH3), 55.4 (1C, C-1-OCH3), 21.2, 20.9 (2C, 2 x Ac-
CH3), 27.1 (3C, 3 x t-Bu-CH3), 19.2 (1C, Cq t-Bu) ppm; MS (MALDI-TOF):
m/z calcd for C116H136NaO28Si: 2027.888 [M+Na]+; found: 2027.809.
Data of 24: [α]D25 +25.8 (c 0.12, CHCl3); Rf 0.35 (1:1 n-hexane/EtOAc); 1H
NMR (CDCl3, 500 MHz) δ 7.81-7.13 (m, 27H, arom), 5.11 (t, J = 9.1 Hz,
1H, H-3’), 5.07 (d, J = 3.5 Hz, 1H, H-1”), 5.02 (d, J = 11.6 Hz, 1H, Bn-CH2a),
4.85 (dd, J = 9.4 Hz J = 8.2 Hz, 1H, H-2’), 4.77-4.58 (m, 5H, Bn-CH2b, 2 x
Bn-CH2), 4.56-4.52 (m, 2H, H-1, H-1’), 4.48-4.27 (m, 4H, NAP-CH2, Bn-
CH2), 3.92 (t, J = 9.2 Hz, 1H, H-4’), 3.90-3.85 (m, 2H, H-3, H-4), 3.75 (dd,
J = 10.7 Hz, J = 3.2 Hz, 1H, H-6a), 3.69-3.60 (m, 5H, H-5, H-5”, H-6b, H-
6’a,b), 3.58 (s, 3H, C-3’-OCH3), 3.44 (dd, J = 10.1 Hz, J = 3.3 Hz, 1H, H-
6”a), 3.42-3.37 (m, 3H, H-2, H-3”, H-6”b), 3.41, 3.40 (2 x s, 6H, C-4”-OCH3,
C-2”-OCH3), 3.34 (s, 3H, C-1-OCH3), 3.23-3.21 (m, 1H, H-5’), 3.17 (t, J =
9.5 Hz, 1H, H-4”), 3.05 (dd, J = 9.8 Hz, J = 3.5 Hz, 1H, H-2”), 2.01, 1.94 (2
x s, 6H, 2 Ac-CH3) ppm; 13C NMR (CDCl3, 125 MHz) δ 170.1, 169.8 (2C,
2 x Cq Ac), 139.6, 138.4, 138.2, 137.8, 136.2, 133.4, 133.0 (7C, 7 x Cq
arom), 128.8-125.8 (27C, arom), 100.0 (1C, C-1’), 98.5 (1C, C-1), 97.9 (1C,
C-1”), 83.3 (1C, C-3”), 81.9 (1C, C-2”), 80.3 (1C, C-3), 79.4 (1C, C-4”),
Data of 21b: [α]D25 +31.8 (c 2.70, CHCl3); Rf 0.46 (1:1 n-hexane/EtOAc);
1H NMR (CDCl3, 500 MHz) δ 7.72-7.19 (m, 37H, arom), 5.24 (d, J = 3.6
Hz, 1H, H-1”), 4.97 (d, J = 10.8 Hz, 1H, Bn-CH2a), 4.98 (d, J = 6.9 Hz, 1H,
H-1’), 4.89-4.69 (m, 7H, Bn-CH2b, 3 x Bn-CH2), 4.60-4.58 (m, 2H, Bn-CH2),
4.57 (d, J = 4.6 Hz, 1H, H-1), 4.49-4.36 (m, 4H, NAP-CH2, Bn-CH2), 4.06
(dd, J = 4.6 Hz, J = 9.6 Hz, 1H, H-5’), 3.93-3.84 (m, 4H, H-3, H-3”, H-4, H-
4’), 3.79 (dd, J = 3.7 Hz, J = 10.7 Hz, 1H, H-6a), 3.76-3.72 (m, 3H, H-3’,
H-5, H-6’a), 3.69-3.66 (m, 2H, H-6b, H-6’b), 3.60-3.55 (m, 3H, H-5”, H-
6”a,b), 3.52-3.46 (m, 3H, H-2, H-2”, H-4”), 3.51 (s, 3H, C-3’-OCH3), 3.48
(s, 3H, C-2’-OCH3), 3.37 (s, 3H, C-1-OCH3), 3.05 (t, J = 7.3 Hz, 1H, H-2’),
1.70 (s, 1H, C-6”-OH) ppm; 13C NMR (CDCl3, 125 MHz) δ 139.4, 138.8,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801349
European Journal of Organic Chemistry
FULL PAPER
25
79.3 (1C, C-2), 77.1 (1C, C-4), 75.3 (1C, C-3’), 75.2 (1C, C-5’), 75.0 (1C,
C-4’), 74.0, 73.8, 73.4 (5C, 4 x Bn-CH2, NAP-CH2), 73.0 (1C, C-2’), 71.3
(1C, C-5”), 70.0 (1C, C-5), 68.8 (1C, C-6’), 68.5 (1C, C-6”), 67.9 (1C, C-6),
60.8 (1C, C-3”-OCH3), 60.5 (1C, C-4”-OCH3), 59.4 (1C, C-2”-OCH3), 55.4
(1C, C-1-OCH3), 21.2, 20.9 (2C, 2 x Ac-CH3) ppm; MS (ESI-TOF): m/z
calcd for C65H76NaO18: 1167.4924 [M+Na]+; found: 1167.4885.
a colourless syrup. [α]D +55.0 (c 0.06, CHCl3); Rf 0.29 (7:3 n-
hexane/acetone); 1H NMR (CDCl3, 500 MHz) δ 7.77-7.13 (m, 49H, arom),
5.22 (d, J = 3.7 Hz, 1H, H-1-F), 5.03 (d, J = 3.5 Hz, 1H, H-1-D), 4.96 (d, J
= 5.9 Hz, 1H, H-1-G), 4.95-4.28 (m, 20H, H-1-H, H-1-E, 2 x NAP-CH2, 7 x
Bn-CH2), 4.00-3.96 (m, 2H, H-4-F, H-5-G), 3.90-3.82 (m, 3H, H-3-F, H-4-
G, H-6a-F), 3.79-3.65 (m, 9H, H-3-H, H-3-G, H-4-H, H-5-H, H-5-F, H-6a,b-
H, H-6a,b-G), 3.61 (s, 3H, C-3-D-OCH3), 3.59-3.57 (m, 1H, H-5-D), 3.56
(s, 3H, C-2-D-OCH3), 3.54-3.50 (m, 2H, H-3-E-OH, H-6a-E), 3.48 (s, 4H,
H-2-F, C-3-G-OCH3), 3.47-3.40 (m, 13H, H-2-H, H-3-D, H-3-E, H-4-E, H-
6a-D, H-6b-F, H-6b-E, C-2-G-OCH3, C-4-D-OCH3), 3.36 (s, 3H, C-1-H-
OCH3), 3.33-3.29 (m, 2H, H-2-E, H-6b-D), 3.22 (s, 1H, C-2-E-OH), 3.19-
3.13 (m, 3H, H-2-D, H-4-D, H-5-E), 3.05-3.02 (m, 1H, H-2-G) ppm; 13C
NMR (CDCl3, 125 MHz) δ 139.5, 138.6, 138.4, 138.1, 137.7, 136.4, 136.0,
133.4, 133.0, 132.9 (13C, 13 x Cq arom), 128.6-125.8 (49C, arom), 103.1
(1C, C-1-E), 100.6 (1C, C-1-D), 100.0 (1C, C-1-G), 98.5 (1C, C-1-H), 98.3
(1C, C-1-F), 84.7 (1C, C-2-G), 84.1 (1C, C-3-D), 82.9 (1C, C-2-D), 82.5
(1C, C-3-G), 82.0 (1C, C-4-E), 80.6 (1C, C-3-F), 80.3 (1C, C-3-H), 79.5
(2C, C-2-H, C-4-D), 79.4 (1C, C-2-F), 76.7 (2C, C-4-F, C-4-H), 76.3 (1C,
C-4-G), 76.1 (1C, C-3-E), 75.3, 74.8 (2C, 2 x NAP-CH2), 74.7, (1C, C-5-E),
74.0 (1C, C-2-E), 73.7, 73.6, 73.4, 73.3, 72.9 (7C, 7 x Bn-CH2), 72.0 (1C,
C-5-G), 71.4 (1C, C-5-D), 70.8 (1C, C-5-F), 70.5 (1C, C-5-H), 69.3 (1C, C-
6-G), 69.0 (1C, C-6-E), 68.5 (2C, C-6-D, C-6-H), 68.3 (1C, C-6-F), 60.9
(1C, C-3-D-OCH3), 60.6 (1C, C-4-D-OCH3), 60.3 (3C, C-2-G-OCH3, C-3-
G-OCH3, C-2-D-OCH3), 55.4 (1C, C-1-H-OCH3) ppm; MS (MALDI-TOF):
m/z calcd for C107H122NaO26: 1845.812 [M+Na]+; found: 1845.714.
Methyl
(6-O-benzyl-2,3,4-tri-O-methyl-α-D-glucopyranosyl)-(1→4)-
[2,3-di-O-acetyl-6-O-(2-naphthyl)methyl-β-D-glucopyranosyl]-(1→4)-
(2,3,6-tri-O-benzyl-α-D-glucopyranosyl)-(1→4)-[2,3-di-O-methyl-6-O-
(2-naphthyl)methyl-α-L-idopyranosyl]-(1→4)-2,3,6-tri-O-benzyl-α-D-
glucopyranoside (25). To a solution of trisaccharide acceptor 21a (38 mg,
0.031 mmol) and disaccharide donor 22[32] (37 mg, 0.047 mmol, 1.5 equiv.)
in dry CH2Cl2 (1.2 mL) 4 Å MS (250 mg) were added and the reaction
mixture was stirred at room temperature. After 30 min the stirred mixture
was cooled to −20 °C under argon. After at this temperature, NIS (16 mg,
0.070 mmol, 1.5 equiv. to the donor) and TfOH (2.0 µL, 0.020 mmol, 0.3
equiv. to the NIS) dissolved in dry THF (28 µL) were added. The
temperature was allowed to warm up to +5 °C and the reaction mixture
was stirred for 4 h. Than reaction mixture was quenched with Et3N (150
µL), diluted with CH2Cl2 (25 mL), filtered and the mixture was washed with
saturated aqueous solution of Na2S2O3 (2 x 5 mL), saturated aqueous
solution of NaHCO3 (5 mL) and H2O (2 x 5 mL) until neutral pH. The
organic layer was dried on MgSO4 and concentrated. The crude product
was purified by silica gel chromatography (55:45 n-hexane/EtOAc to 1:1
25
n-hexane/EtOAc) to give 25 (41 mg, 70%) as a colourless syrup. [α]D
+60.0 (c 0.10, CHCl3); Rf 0.45 (1:1 n-hexane/EtOAc); 1H NMR (CDCl3, 500
MHz) δ 7.77-7.07 (m, 49H, arom), 5.22 (d, J = 3.7 Hz, 1H, H-1-F), 5.09-
5.05 (m, 2H, H-1-D, H-3-E), 4.97-4.95 (m, 2H, 2 x Bn-CH2a), 4.89 (d, J =
6.9 Hz, 1H, H-1-G), 4.82 (t, J = 8.3 Hz, 1H, H-2-E), 4.80-4.25 (m, 18H, H-
1-H, H-1-E, 2 x NAP-CH2, 2 x Bn-CH2b, 5 x Bn-CH2), 4.05 (dd, J = 5.0 Hz,
J = 9.7 Hz, 1H, H-5-G), 3.95-3.84 (m, 5H, H-3-H, H-4-E, H-4-F, H-4-G, H-
4-H), 3.79-3.68 (m, 7H, H-3-F, H-5-F, H-5-H, H-6a-F, H-6a-G, H-6a,b-H),
3.67-3.61 (m, 4H, H-3-G, H-6b-G, H-6a,b-E), 3.60-3.55 (m, 4H, H-5-D, C-
3-D-OCH3), 3.50-3.44 (m, 10H, H-2-F, H-2-H, H-6b-F, H-6a-D, C-2-G-
OCH3, C-3-G-OCH3), 3.43-3.39 (m, 8H, H-3-D, H-6b-D, C-2-D-OCH3, C-
3-D-OCH3), 3.34 (s, 3H, C-1-H-OCH3), 3.20-3.15 (m, 2H, H-4-D, H-5-E),
3.06-3.00 (m, 2H, C-2-D, H-2-G), 2.00, 1.82 (2 x s, 6H, 2 x Ac-CH3) ppm;
13C NMR (CDCl3, 125 MHz) δ 170.1, 169.7 (2C, 2 x Ac-CH3), 139.6, 139.5,
138.6, 138.5, 138.3, 138.2, 137.7, 136.2, 135.9, 133.4, 133.9 (13C, 13 x
Cq arom), 128.9-125.8 (49C, arom), 100.0 (1C, C-1-E), 99.8 (1C, C-1-G),
98.6 (1C, C-1-F), 98.4 (1C, C-1-H), 97.9 (1C, C-1-D), 84.5 (1C, C-2-G),
83.3 (1C, C-3-D), 82.2 (1C, C-3-G), 81.9 (1C, C-2-D), 80.3 (1C, C-3-H),
80.0 (1C, C-3-F), 79.5 (1C, C-2-H), 79.4 (1C, C-4-D), 79.0 (1C, C-2-F),
76.8 (1C, C-4-F), 76.6 (1C, C-4-H), 76.5 (1C, C-4-G), 75.5 (1C, NAP-CH2),
75.3, (1C, C-3-E), 75.2 (1C, C-5-E), 75.0 (1C, NAP-CH2), 74.9 (1C, C-4-
E), 73.8, 73.7, 73.4, 73.3, 73.1 (7C, 7 x Bn-CH2), 72.9 (1C, C-2-E), 72.2
(1C, C-5-G), 71.3 (1C, C-5-D), 71.0 (1C, C-5-F), 70.5 (1C, C-5-H), 68.9
(1C, C-6-G), 68.8 (1C, C-6-E), 68.5 (1C, C-6-D), 68.3 (1C, C-6-H), 67.6
(1C, C-6-F), 60.8 (1C, C-3-D-OCH3), 60.5 (2C, C-3-G-OCH3, C-4-D-OCH3),
60.3 (1C, C-2-G-OCH3), 59.3 (1C, C-2-D-OCH3), 55.4 (1C, C-1-H-OCH3),
21.1, 20.8 (2C, 2 x Ac-CH3) ppm; MS (MALDI-TOF): m/z calcd for
C111H126NaO28: 1931.190 [M+Na]+; found: 1931.124.
Methyl
(6-O-benzyl-2,3,4-tri-O-methyl-α-D-glucopyranosyl)-(1→4)-
[2,3-di-O-methyl-6-O-(2-naphthyl)methyl-β-D-glucopyranosyl]-(1→4)-
(2,3,6-tri-O-benzyl-α-D-glucopyranosyl)-(1→4)-[2,3-di-O-methyl-6-O-
(2-naphthyl)methyl-α-L-idopyranosyl]-(1→4)-2,3,6-tri-O-benzyl-α-D-
glucopyranoside (27). To a solution of 26 (21 mg, 0.0115 mmol) in dry
DMF (250 µL) was added NaH (60%, 10 mg, 0.250 mmol) at 0 °C. After
stirring for 30 min at 0 °C, MeI (20 µL, 0.321 mmol) was added and stirred
for 24 h at room temperature. When complete conversion of the starting
material into a main spot had been observed by TLC analysis, CH3OH (500
µL) was added. The reaction mixture was stirred for 5 min and the solvents
were evaporated. The residue was dissolved in CH2Cl2 (25 mL), and
washed with H2O (2 x 5.0 mL), the organic layer was filtered, dried and
evaporated. The crude product was purified by silica gel chromatography
(6:4 = n-hexane/acetone) to give 27 (16 mg, 80%) as a colourless syrup.
25
[α]D +45.7 (c 0.07, CHCl3); Rf 0.58 (6:4 n-hexane/acetone); 1H NMR
(CDCl3, 500 MHz) δ 7.78-7.08 (m, 49H, arom), 5.58 (d, J = 3.7 Hz, 1H),
5.23 (d, J = 3.6 Hz, 1H), 5.02-4.06 (m, 21H, 3 x H-1, 7 x Bn-CH2, 2 x NAP-
CH2), 4.06 (dd, J = 4.7 Hz, J = 9.6 Hz, 1H), 3.98 (t, J = 9.4 Hz, 1H), 3.89-
3.62 (m, 17H), 3.62-3.32 (m, 4H), 3.60, 3.54, 3.48, 3.45, 3.38, 3.36, 3.33
(7 x s, 24H, 8 x OCH3), 3.29-3.21 (m, 4H), 3.15 (dd, J = 3.7 Hz, J = 9.8 Hz,
1H), 3.04-3.00 (m, 1H), 2.94-2.91 (m, 1H) ppm; 13C NMR (CDCl3, 125
MHz) δ 139.7, 139.4, 138.6, 138.4, 138.2, 138.0, 136.5, 135.9, 133.4,
133.0, 132.9 (13C, 13 x Cq arom), 128.7-125.7 (49C, arom), 102.9, 100.0,
98.5, 96.3 (5C, 5 x C-1), 86.7, 84.7, 84.6, 83.6, 82.4, 81.9, 80.4, 79.9, 79.5,
79.4, 79.0, 77.0, 76.7, 76.2, 74.8, 72.4, 72.2, 71.4, 70.9, 70.5 (20C
skeleton carbons), 75.6, 74.9, 73.8, 73.5, 73.4, 73.3, 73.2 (9C, 2 x NAP-
CH2, 7 x Bn-CH2), 69.4, 68.3, 68.2, 67.8 (5C, 5 x C-6), 60.9, 60.5, 60.3,
59.8, 59.6 (7C, 7 x OCH3), 55.4 (1C, C-1-H-OCH3) ppm; MS (MALDI-TOF):
m/z calcd for C109H126NaO26: 1873.843 [M+Na]+; found: 1873.749.
Methyl (6-O-benzyl-2,3,4-tri-O-methyl-α-D-glucopyranosyl)-(1→4)-[6-
O-(2-naphthyl)methyl-β-D-glucopyranosyl]-(1→4)-(2,3,6-tri-O-benzyl-
α-D-glucopyranosyl)-(1→4)-[2,3-di-O-methyl-6-O-(2-naphthyl)methyl-
α-L-idopyranosyl]-(1→4)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (26).
Compound 25 (33 mg, 0.017 mmol) was dissolved in MeOH (1.0 mL) and
NaOMe was added (5 mg, 0.092 mmol, pH ≈ 10) and the reaction mixture
was stirred at room temperature for 24 h. Than the reaction mixture was
neutralized by Amberlite IR-120 (H+) ion-exchange resin, filtrated, washed
with MeOH and concentrated. The crude product was purified by column
chromatography (65:35 = n-hexane/acetone) to give 26 (25 mg, 78 %) as
Methyl
(6-O-benzyl-2,3,4-tri-O-methyl-α-D-glucopyranosyl)-(1→4)-
(2,3-di-O-methyl-β-D-glucopyranosyl)-(1→4)-(2,3,6-tri-O-benzyl-α-D-
glucopyranosyl)-(1→4)-(2,3-di-O-methyl-α-L-idopyranosyl)-(1→4)-
2,3,6-tri-O-benzyl-α-D-glucopyranoside (28). To a vigorously stirred
solution of 27 (14 mg, 0.007 mmol) in CH2Cl2 (2.0 mL) and H2O (250 µL),
DDQ (5.0 mg, 0.021 mmol) was added. After 30 min the mixture was
diluted with CH2Cl2 (20 mL) and extracted with saturated aqueous
NaHCO3 (2 x 5 mL) and H2O (2 x 5 mL), dried and concentrated. The crude
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801349
European Journal of Organic Chemistry
FULL PAPER
product was purified by silica gel chromatography (6:4 n-hexane/acetone)
to give 28 (8 mg, 71%) as a colourless syrup. [α]D25 +61.4 (c 0.08, CH2Cl2);
Rf 0.52 (6:4 n-hexane/acetone); 1H NMR (CDCl3, 360 MHz) δ 7.39-7.18
(m, 35H, arom), 5.52 (d, J = 3.7 Hz, 1H), 5.15 (d, J = 3.4 Hz, 1H), 4.93-
4.50 (m, 16H, 7 x Bn-CH2, 2 x H-1), 4.28 (d, J = 7.8 Hz, 1H), 3.93-3.63 (m,
15H), 3.62-3.15 (m, 12H), 3.61, 3.58, 3.54, 3.49, 3.44, 3.42, 3.39, 3.35 (8
x s, 24H, 8 x OCH3), 3.03-2.94 (m, 3H), 2.36, 2.08 (2 x s, 2H, 2 x OH) ppm;
13C NMR (CDCl3, 90 MHz) δ 138.7, 138.4, 138.0, 137.8, 137.7, 137.5,
137.4 (7C, 7 x Cq arom), 128.2-127.3 (35C, arom), 102.3, 98.6, 97.8, 97.0,
96.3 (5C, 5 x C-1), 86.1, 84.4, 83.1, 82.6, 81.5, 81.4, 80.1, 79.6, 79.2, 78.4,
75.2, 74.1, 73.9, 71.2, 70.8, 70.6, 70.1 (20C, skeleton carbons), 75.5, 74.9,
73.2, 73.1, 72.7 (7C, 7 x Bn-CH2), 68.1, 68.0, 67.4, 61.6 (5C, 5 x C-6), 60.4,
60.1, 60.0, 59.6, 59.4, 59.3, 59.2 (7C, 7 x OCH3), 54.9 (C-1-H-OCH3) ppm;
MS (ESI-TOF): m/z calcd for C87H110NaO26: 1593.7178 [M+Na]+; found:
1593.7163.
V. R. Vaidya and S. J. Asirvatham, Vasc. Health Risk Manag. 2016, 12,
35–44.
[10] S. Mohamed, V. Ferro, Adv. Carbohydr. Chem. Biochem. 2015, 72, 21-
61.
[11] C. Chen, B. Yu, Bioorg. Med. Chem. Lett. 2009, 19, 3875–3879.
[12] M. Herczeg, L. Lázár, Zs. Bereczky, K. E. Kövér, I. Timári, J.
Kappelmayer, A. Lipták, S. Antus, A. Borbás, Chem. Eur. J. 2012, 18,
10643–10652.
[13] M. Herczeg, E. Mező, L. Lázár, A. Fekete, K. E. Kövér, S. Antus, A.
Borbás, Tetrahedron 2013, 69, 3149–3158.
[14] M. Herczeg, E. Mező, D. Eszenyi, S. Antus, A. Borbás, Tetrahedron 2014,
70, 2919–2927.
[15] G. Łopatkiewicz, S. Buda, J. Mlynarski, J. Org. Chem. 2017, 82, 12701–
12714.
[16] M. Herczeg, F. Demeter, T. Balogh, V. Kelemen, A. Borbás, Eur. J. Org.
Chem. 2018, 3312–3316.
[17] E. Mező, M. Herczeg, D. Eszenyi, A. Borbás, Carbohydr. Res. 2014, 388,
19–29.
Acknowledgements
[18] E. Mező, D. Eszenyi, E. Varga, M. Herczeg, A. Borbás, Molecules, 2016,
21, (11), 1497.
The authors gratefully acknowledge financial support for this
research from the National Research, Development and
Innovation Office of Hungary (PD 115645 and TÉT_15_IN-1-
2016-0071) and from the János Bolyai Research Scholarship of
the Hungarian Academy of Sciences (M. Herczeg). The research
was also supported by the EU and co-financed by the European
Regional Development Fund under the projects GINOP-2.3.3-15-
2016-00004 and GINOP-2.3.2-15-2016-00008.
[19] a) M. Haller & G.-J. Boons, J. Chem. Soc., Perkin Trans. 1, 2001, 814–
822; b) J. D. Codée, A. E. Christina, M. T. Walvoort, H. S. Overkleeft, G.
A. van der Marel, Top Curr Chem. 2011, 301, 253-289.
[20] M. Herczeg, E. Mező, D. Eszenyi, L. Lázár, M. Csávás, I. Bereczki, S.
Antus, A. Borbás, Eur. J. Org. Chem. 2013, 25, 5570–5573.
[21] L. Lázár, M. Csávás, M. Herczeg, P. Herczegh, A. Borbás, Org. Lett.
2012, 14, 4650−4653.
[22] D. Eszenyi, V. Kelemen, F. Balogh, M. Bege, M. Csávás, P. Herczegh,
A. Borbás, Chem. Eur. J. 2018, 24, 4532-4536.
[23] A. Lipták, A. Borbás, L. Jánossy, L. Szilágyi, Tetrahedron Lett. 2000, 41,
4949-4953.
Keywords: L-idose, hydroboration-oxidation, stereoselective,
[24] L. Rochepeau-Jobron, J. C. Jacquinet, Carbohydr. Res. 1997, 303, 395–
406.
cyclic acetal-directed glycosylation, heparin
[25] H. Takahashi, N. Miyama, H. Mitsuzuka, S. Ikegami, Synthesis 2004, 18,
2991-2994.
[1]
B. Casu, U. Lindahl, Adv. Carbohydr. Chem. Biochem. 2001, 57, 159–
206.
[26] M. Ek, P. J. Garegg, H. Hultberg, S. Oscarson, J. Carbohydr. Chem.
1983, 2, 305–311.
[2]
[3]
R. D. Rosenberg, P. S. Damus, J. Biol. Chem. 1973, 248, 6490–6505.
a) C. A. A. van Boeckel, M. Petitou, Angew. Chem. Int. Ed. 1993, 32,
1671–1690; b) C. A. A. van Boeckel, M. Petitou, Angew. Chem. Int. Ed.
2004, 43 (24), 3118–3133.
[27] D. Crich, M. de la Mora and A. U. Vinod, J. Org. Chem. 2003, 68, (21),
8142-8148.
[28] A. Imamura, N. Matsuzawa, S. Sakai, T. Udagawa, S. Nakashima, H.
Ando, H. Ishida, M. Kiso, J. Org. Chem. 2016, 81, (19), 9086-9104.
[29] S. D. Debenham, E. J. Toone, Tetrahedron: Asymmetry, 2000, 11, 385–
387.
[4]
[5]
M. Petitou, P. Duchaussoy, I. Lederman, J. Choay, J. C. Jacquinet, P.
Sinäy and G. Torri, Carbohydr. Res. 1987, 167, 67–75.
P. Westerduin, C. A. A. van Boeckel, J. E. M. Basten, M. A. Broekhoven,
H. Lucas, A. Rood, H. van der Heiden, R. G. M. van Amsterdam, T. G.
van Dinther, D. G. Meuleman, A. Visser, G. M. T. Vogel, J. B. L. Damm,
G. T. Overklift, Bioorg. Med. Chem. 1994, 2, 1267–1280.
J. Harenberg, Thromb. Haemost. 2009, 102, 811–815.
R. Tummala, A. Kavtaradze, A. Gupta, R. K. Ghosh, Int. J. Cardiol. 2016,
214, 292–298.
[30] A. Borbás, Z. B. Szabó, L. Szilágyi, A. Bényei, A. Lipták, Tetrahedron
2002, 58, 5723-5732.
[31] E. Dubois, J.-M. Beau, Carbohydr. Res. 1992, 228, 103–120.
[32] L. Lázár, E. Mező, M. Herczeg, A. Lipták, S. Antus, A. Borbás,
Tetrahedron 2012, 68, 7386–7399.
[6]
[7]
[33] J. Xia, S. A. Abbas, R. D. Locke, C. F. Piskorz, J. L. Alderfer, K. L. Matta,
Tetrahedron Lett. 2000, 41, 169–173.
[8]
[9]
G. Lu, F. R. DeGuzman, S. J. Hollenbach, M. J. Karbarz, K. Abe, G. Lee,
P. Luan, A. Hutchaleelaha, M. Inagaki, P. B. Conley, D. R. Phillips, U.
Sinha, Nat. Med. 2013, 19, 446–451.
[34] S. Mohamed, Q. Q. He, R. J. Lepage, E. H. Krenske, V. Ferro, Eur. J.
Org. Chem. 2018, 2214–2227.
a) B. Laulicht, S. Bakhru, C. Lee, C. Baker, X. Jiang, E. Mathiowitz, J.
Costin and S. Steiner, Circulation 2012, 126, (21), A11395; b) T. Y. Hu,
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10.1002/ejoc.201801349
European Journal of Organic Chemistry
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Fruzsina Demeter, Fanni Veres, Mihály
Herczeg* and Anikó Borbás*
Page No. – Page No.
Short synthesis of idraparinux by
applying a 2-O-methyl-4,6-O-
arylmethylene thioidoside as a 1,2-
trans α-selective glycosyl donor
The α-L-iduronic acid is a key component of heparin-related anticoagulants like
idraparinux. Hitherto, L-idose or iduronic acid donors with a C2 participating group,
obtained via lengthy procedures, have been exclusively applied for the construction
of the α-idosidic linkage. Our new route to idraparinux is based on short and
straightforward synthesis of a 4,6-cyclic-acetal-protected L-idosyl thioglycoside
bearing a C2-nonparticipating group, which can be used directly as an α-selective
glycosyl donor building block. The assembly of idraparinux was achieved by an
F+GH and DE+FGH coupling sequence with full stereoselectivity in each
glycosylation step.
This article is protected by copyright. All rights reserved.