New synthesis of idraparinux, the non-glycosaminoglycan analogue of the antithrombin-binding domain of heparin

Article abstract of DOI:10.1016/j.tet.2014.03.033

Idraparinux, the fully O-sulfated, O-methylated, heparin-related pentasaccharide possessing selective factor Xa inhibitory activity, was prepared by a new synthetic pathway. This route was based on a [2+3] block synthesis utilizing a 6-O-silyl-protected l-idose-containing trisaccharide acceptor, which was glycosylated with a disaccharide donor containing a non-oxidized precursor of the glucuronic acid. The unique strategy of multiple functionalizations at pentasaccharide levels, involving triple methylation followed by oxidation of the glucose and the idose precursors into d-glucuronic and l-iduronic acids in one step, proved to be highly efficient, providing the target pentasaccharide through a 39-step synthesis starting from d-glucose and methyl α-d-glucopyranoside.

Full text of DOI:10.1016/j.tet.2014.03.033

Tetrahedron 70 (2014) 2919e2927
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New synthesis of idraparinux, the non-glycosaminoglycan analogue
of the antithrombin-binding domain of heparin
a
a
,
b
a
,
b
a
b,
*
ꢀ
}
ꢀ
ꢀ
ꢀ
ꢀ
Mihaly Herczeg , Erika Mezo , Daniel Eszenyi , Sandor Antus , Aniko Borbas
a Department of Organic Chemistry, University of Debrecen, H-4010 Debrecen, PO Box 20, Hungary
b Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, H-4010 Debrecen, PO Box 70, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 January 2014
Received in revised form 24 February 2014
Accepted 11 March 2014
Available online 15 March 2014
Idraparinux, the fully O-sulfated, O-methylated, heparin-related pentasaccharide possessing selective
factor Xa inhibitory activity, was prepared by a new synthetic pathway. This route was based on a [2þ3]
block synthesis utilizing a 6-O-silyl-protected L-idose-containing trisaccharide acceptor, which was
glycosylated with a disaccharide donor containing a non-oxidized precursor of the glucuronic acid. The
unique strategy of multiple functionalizations at pentasaccharide levels, involving triple methylation
followed by oxidation of the glucose and the idose precursors into
one step, proved to be highly efficient, providing the target pentasaccharide through a 39-step synthesis
starting from -glucose and methyl -glucopyranoside.
D-glucuronic and L-iduronic acids in
Keywords:
Anticoagulation
D
a-D
Heparinoid pentasaccharide
Glycosylation reactions
Orthogonal protecting groups
Multiple functionalization
Uronic acids
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Heparin is a complex, highly sulfated natural polysaccharide
that has been used as an anticoagulant for more than seven decades
in a broad range of clinical thrombotic conditions.1 Heparin dis-
plays anticoagulant activity through activation of antithrombin,
a serine protease inhibitor that blocks thrombin and, to a lesser
extent, factor Xa in the blood-coagulation cascade.2 Fondaparinux
(2) is a synthetic analogue of the antithrombin-binding DEFGH
domain of heparin (1), which exclusively potentiates the anti-factor
Xa activity of antithrombin and has no effect on thrombin (Fig. 1).3
Fondaparinux (Arixtra, GlaxoSmithKline) provided the proof of
principle that selective inhibition of the specific coagulation en-
zyme factor Xa could afford clinically effective anticoagulation.4
Idraparinux (3)3b,5 is an analogue of fondaparinux inwhich the N-
sulfates are replaced by O-sulfates and the hydroxyl groups are
methylated. Idraparinux binds to AT significantly stronger than
fondaparinux through hydrophobic interactions and also exhibits
superioranti-Xa-activity and a longer half-life allowing once-a-week
administration. Although the antithrombotic efficacy in men was
proven in clinical studies, the development of idraparinux was
stopped due to major bleeding events during treatment for more
Fig. 1. The specific antithrombin-binding DEFGH pentasaccharide unit of heparin (1)
and its synthetic analogues fondaparinux (2) and idraparinux (3).
than six months.6 Notwithstanding, the feasible synthesis and spe-
cific activity make idraparinux a potential lead and an ideal reference
compound for further development of selective factor Xa inhibitors.
* Corresponding author. Tel.: þ36 52512900/22475; fax: þ36 52512914; e-mail
addresses: borbas.aniko@pharm.unideb.hu, borbas.aniko@science.unideb.hu (A.
ꢀ
Borbas).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.033

2920
M. Herczeg et al. / Tetrahedron 70 (2014) 2919e2927
In the frame of our ongoing research aimed at the synthesis of
acid, and a DE disaccharide donor containing the non-oxidized
precursor of the -glucuronic acid. The hydroxyls to be methyl-
ated were masked in the form of acetates, whereas benzyl groups
were introduced to mask the hydroxyls that were to be sulfated.
This protecting group strategy also ensures the stereocontrol in the
glycosylation steps.
sulfonic acid-containing heparinoid anticoagulants,7e11 idrapar-
inux is planned to be applied as a reference compound in STD NMR
and competition STD titration experiments to investigate the
binding specificity and activity of the pentasaccharide sulfonic acid
derivatives against antithrombin. To provide a sufficient amount of
3 for the NMR binding studies, an efficient synthesis is required.
One of the most challenging feature of the target structure is the
presence of methyl ethers at the uronic acid residues, which are
D
The -idopyranosyl donor 4, useful for the synthesis of the FGH
L
trisaccharide unit has been described recently as a building block
for heparinoid sulfonic acids.11,14 Condensation of donor 4 and ac-
ceptor 515 in the presence of trimethylsilyl triflate (TMSOTf), and
subsequent removal of the benzylidene acetal ring by acidic hy-
prone to suffer b-elimination in the basic conditions of the ether-
ification. In this context, prior syntheses of 3 followed two different
strategies.5,12,13 In the first approach, the methyl ethers were in-
troduced into the non-oxidized precursors of the uronic acids at
a monosaccharide level, and formation of the uronic acids was
achieved at disaccharide levels.5,12 This method, elaborated by
Westerduin et al. in 1994 and also applied by Chinese authors 15
years later, had the drawback that the partially methylated
drolysis furnished the a-linked disaccharide diol 6 in 73% yield over
two steps. To protect the primary hydroxyl that is to be oxidized at
a pentasaccharide level, a silyl ether was chosen because of its or-
thogonality both to the acetyl and the benzyl protecting groups.17
Therefore, tert-butyldimethylsilyl (TBDMS) group was installed to
the primary position of 6 to provide 7 in 96% yield (Scheme 1).
Scheme 1. Synthesis of the L-idose-containing disaccharide acceptor 7. Reagents and conditions: (a) CH2Cl2, TMSOTf, ꢀ40 to ꢀ10 ꢁC, 2 h; (b) H2O, TFA, 0 ꢁC to rt, 3 h, 73% for two
steps; (c) py, TBDMSCl, 24 h, 96%.
monosaccharide building blocks were achieved via lengthy multi-
step processes, and overall syntheses of 3 required more than 50
steps from commercially available starting monosaccharides. In the
other approach, published by our group, three of the methyl ethers
of the uronic acid residues were introduced in one step at a pen-
tasaccharide level, hence, the length of the procedure could be
reduced to 41 synthetic steps. The weakness of this strategy was
that the base-sensitivity of the uronic acid residues did not allow
the usual sodium hydride mediated etherification. Therefore,
freshly prepared silver(I) oxide was used to assist the methylation
that, however, showed moderate efficacy.
The fully protected thioglucoside 9, serving as a glycosyl donor
for the synthesis of the FGH trisaccharide acceptor, was prepared by
benzylation of 816 possessing a selectively removable 4-O-(2-
naphthyl)methyl protecting group. Surprisingly, glycosylation of
acceptor 7 with donor 9 in the presence of N-iodosuccinimide (NIS)
and TfOH led to the formation of a plethora of products. Besides the
desired trisaccharide 10 in a 9% yield, cleavage of the tert-butyldi-
methylsilyl group of the -idose unit also occurred affording 11 in
L
49% yield and also leading to further side reactions to give mono-
saccharide 12 and tetrasaccharide 13, both isolated as anomeric
mixtures.
We envisioned an improved route to 3, combining the strengths
of the above two strategies. Hence, we decided to accomplish the
To avoid the loss of the tert-butyldimethylsilyl group, mediated
by the acid catalyst of the coupling reaction, condensation of 7 and
9 was carried out again in the presence of sym-collidine. Due to the
buffering effect of the hindered base, the side reactions could be
suppressed and the glycosylation reaction provided the fully pro-
tected trisaccharide 10 in 71% yield (Scheme 2).
Despite the success of the above glycosylation reaction, we de-
cided to accomplish the synthesis of the FGH trisaccharide building
block by changing the tert-butyldimethylsilyl moiety to the tert-
butyldiphenylsilyl (TBDPS) protecting group. TBDPS has two mag-
nitude higher stability under acidic conditions then TBDMS,17 and
we expected that this higher stability might give rise to higher
glycosylation efficacy throughout the synthesis of 3. Hence, the
disaccharide diol 6 was treated with tert-butyldiphenylsilyl chlo-
ride in pyridine to provide acceptor 14, glycosylation of which with
donor 9 furnished smoothly, the required trisaccharide 15 in 77%
yield (Scheme 3).
synthesis by assembling
a pentasaccharide containing non-
oxidized precursor of the uronic acids followed by introduction of
three methyl ethers in one step at a pentasaccharide level by effi-
cient sodium hydride mediated methylation, and subsequent oxi-
dation of the two uronic acid precursors in one step. Through this
pathway, the inefficient glycosylations with the uronic acid build-
ing blocks of inherent low reactivity observed in earlier synthe-
sis,5,12,13 could also be avoided. Herein, synthesis of idraparinux by
this novel strategy is described.
2. Results and discussion
The synthesis of the fully O-sulfated, O-methylated penta-
saccharide 3 was planned by condensation of a FGH trisaccharide
acceptor containing the non-oxidized precursor of the L-iduronic

M. Herczeg et al. / Tetrahedron 70 (2014) 2919e2927
2921
Scheme 2. Synthesis of the fully protected FGH trisaccharide 10 bearing TBDMS- and NAP-ethers as orthogonal protecting groups. Reagents and conditions: (a) NaH, BnBr, DMF,
93%; (b) CH2Cl2, NIS, TfOH, ꢀ40 to ꢀ10 ꢁC, 2 h, 9% for 10, 49% for 11, 15% for 12, 24% for 13; (c) CH2Cl2, NIS, AgOTf, sym-collidine, ꢀ40 to 10 ꢁC, 3 h, 71% for 10.
(15/18, 74%), transformation of the TBDMS-containing 10 into
16 proceeded in only 47% yield that could be explained, again, with
the moderate stability of the TBDMS-ether under acidic conditions.
During the reaction, a hydroquinone derivative was formed from
the reagent, the acidity of which led to partial cleavage of the
TBDMS group. Trisaccharide 11, one of the by-products of the 7þ9
coupling was also transformed to acceptor 18 via removal of the
NAP-ether (11/17) followed by selective silylation of the primary
hydroxyl of the L-idose unit with tert-butyldiphenylsilyl chloride.
Compound 19,10 prepared recently by our group to heparinoid
sulfonic acids, was chosen as the non-glucuronide type donor
bearing a (2-naphthyl)methyl group to temporarily protect the
hydroxyl destined to be oxidized. Condensation of disaccharide 19
and the trisaccharide acceptors 16 or 18 upon NISeAgOTf activa-
tion, provided the needed pentasaccharides 20 and 21, respectively.
As we expected, a significantly higher yield was achieved with the
TBDPS-protected trisaccharide 18 compared to its TBDMS-
counterpart 16 (Scheme 5).
Scheme 3. Synthesis of the orthogonally protected FGH trisaccharide possessing 6-O-
TBDPS group at the L-idose unit. Reagents and conditions: (a) TBDPSCl, py, rt, 24 h, 92%;
(b) CH2Cl2, NIS, AgOTf, ꢀ40 to ꢀ10 ꢁC, 2 h, 77%.
The synthesis was continued with the TBDPS-containing pen-
tasaccharide 21 of which we had a sufficient amount for the
remaining transformations. First, compound 21 was subjected to
Next, trisaccharides 16 and 18, useful as acceptors for the
planned [DEþFGH] couplings, were prepared (Scheme 4). Selective
demasking of the 4-OH group of the terminal glucose unit of both
10 and 15 by cleavage of the 2-naphthylmethyl (NAP) ether with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)18 furnished di-
rectly the glycosyl acceptors 16 and 18, respectively, however, with
significantly different yields. While efficient oxidative removal of
the NAP-group was observed in the presence of the TBDPS-ether
ꢀ
Zemplen deacetylation to produce triol 22 (Scheme 6). Introduction
of the methyl ethers to the liberated hydroxyls was accomplished
by standard alkylation using methyl iodide and sodium hydride to
afford the desired compound 23 in a rapid reaction in 85% yield. It is
worth mentioning that our previous approach to idraparinux in-
volved a triple methylation step at the pentasaccharide level in the
presence of uronic acids. That reaction was assisted by silver(I)
Scheme 4. Synthesis of trisaccharide acceptors 16 and 18. Reagents and conditions: (a)
CH2Cl2, H2O, DDQ, rt, 30 min, 47% for 16, 69% for 17, 74% for 18; (b) TBDPSCl, py, rt, 24 h,
82%.
Scheme 5. Synthesis of the pentasaccharide skeleton. Reagents and conditions: (a)
CH2Cl2, NIS, AgOTf, ꢀ40 to þ5 ꢁC, 3 h, 58% for 20, 76% for 21.

2922
M. Herczeg et al. / Tetrahedron 70 (2014) 2919e2927
in a 39-step synthesis using the commercially available
D-glucose
and methyl -glucopyranoside as the starting materials.
a-D
4. Experimental
4.1. General information
Optical rotations were measured at room temperature with
a PerkineElmer 241 automatic polarimeter. TLC was performed on
Kieselgel 60F254 (Merck) plates with detection by immersing into
5% ethanolic sulfuric acid solution followed by heating. Column
chromatography was performed on Silica gel 60 (Merck
0.063e0.200 mm) and Sephadex G-25 (SigmaeAldrich, Bead size
25e100 mm). Organic solutions were dried over MgSO4, and con-
centrated in vacuum. The 1H NMR (360 MHz) and 13C NMR
(90.54 MHz) spectra were recorded with Bruker DRX-360 spec-
trometer at 25 ꢁC. Chemical shifts are referenced to Me4Si or DSS
(0.00 ppm for 1H) and to the solvent signals (CDCl3: 77.00 ppm,
CD3OD: 49.15 ppm for 13C). IR spectra were recorded on a Per-
kineElmer 16 PC FTIR spectrometer. MALDI-TOF MS analyses of the
compounds were carried out in the positive reflectron mode using
a BIFLEX III mass spectrometer (Bruker, Germany) equipped with
delayed-ion extraction. The matrix solution was a saturated 2,4,6-
trihydroxy-acetophenone (THAP) solution in MeCN. Elemental
analyses (C, H, S) were performed using an Elementar Vario
MicroCube instrument.
Scheme 6. Novel route to 3 involving simultaneous introduction of three methyl
ethers followed by simultaneous formation of two carboxylic functions at a penta-
saccharide level. Reagents and conditions: (a) MeOH, NaOMe, rt, 24 h, 79%; (b) DMF,
NaH, MeI, 0 ꢁC to rt, 3 h, 85%; (c) CH2Cl2, H2O, DDQ, rt, 30 min, 71%; (d) THF, Bu4NF, rt,
72 h, 96%; (e) CH2Cl2, H2O, TEMPO, BAIB, 0 ꢁC to rt, 24 h, 94%; (f) EtOH, AcOH, 10%
Pd(C), 10 atm, H2, rt, 24 h, 91%; (g) SO3/Et3N, DMF, 50 ꢁC, 24 h, 78%.
4.2. Methyl (2-O-acetyl-3-O-methyl-a-L-idopyranosyl)-(1/4)-
2,3,6-tri-O-benzyl- -glucopyranoside (6)
a-D
To a solution of acceptor 515 (5.580 g, 11.90 mmol) and donor 414
ꢁ
oxide because of base-sensitivity of the uronide residues, and it
required a long reaction time of 2 days and showed moderate ef-
ficacy to produce the desired product in only 51% yield.
(4.400 g, 9.50 mmol) in dry CH2Cl2 (250 mL), 4 A molecular sieves
(4.00 g) were added. The stirred mixture was cooled to ꢀ40 ꢁC
under argon. After 30 min at this temperature, TMSOTf (215 mL,
1.190 mmol) in CH2Cl2 (5.0 mL) was added. After stirring at ꢀ10 ꢁC
Next, the primary hydroxyls that were to be oxidized were lib-
erated in two steps involving oxidative cleavage of the NAP ether
with DDQ followed by removal of the TBDPS ether with tetrabutyl
ammonium fluoride (TBAF). Both deprotection procedures showed
good selectivity to provide diol 25 in 68% overall yield. The two
carboxylic functions were formed by (2,2,6,6-tetramethylpiperidin-
1-yl)oxyl TEMPO-based oxidation using [bis(acetoxy)iodo]benzene
(BAIB) as co-oxidant,19 affording the disodium salt 26, which was
ready for the final two transformations. The seven hydroxyls to be
sulfated were deprotected by catalytic hydrogenolysis. Sub-
sequently, simultaneous O-sulfation of the liberated hydroxyls was
achieved in one step using excess SO3$Et3N to give, after treatment
with Dowex Naþ ion-exchange resin, the target compound 3 in 78%
yield (Scheme 6).
for 2 h, Et3N (500 mL) was added and the reaction mixture was
concentrated. The crude product was dissolved in a mixture of
CH2Cl2 (170 mL) and H2O (7.68 mL), and F3CCOOH (14.96 mL) was
added at 0 ꢁC. After the reaction had been completed (3 h), the
mixture was neutralized with aqueous solution of NaHCO3
(16.320 g), diluted with CH2Cl2 (400 mL), washed with satd aq
NaHCO3 (2ꢂ150 mL) and H2O (2ꢂ100 mL), dried and concentrated.
The crude product was purified by silica gel chromatography (9:1
CH2Cl2/acetone) to give 6 (4.698 g, 73% for two steps) as a colourless
25
syrup; [
a
]
D
ꢀ8.9 (c 0.12, CHCl3); Rf 0.45 (9:1 CH2Cl2/acetone); IR
nmax (KBr): 3464, 3087, 3063, 3030, 2933, 2369, 2349, 2318, 2246,
1737, 1496, 1454, 1371, 1320, 1234, 1167, 1103, 1027, 911, 739, 698,
609, 466, 418 cmꢀ1
;
1H NMR (CDCl3, 360 MHz):
d
¼7.34e7.25 (m,
15H, arom), 5.08e4.50 (m, 9H, 3ꢂCH2Ph, H-1, H-10, H-20), 4.27e4.24
(m, 1H), 3.98e3.84 (m, 2H), 3.77e3.72 (m, 2H), 3.65e3.57 (m, 2H),
3.52e3.49 (m, 4H), 3.39e3.27 (m, 5H), 3.12e3.09 (m, 1H),
2.65e2.62 (m, 1H), 1.99 (s, 3H, AcCH3), 1.69 (s, 1H, OH) ppm; 13C
3. Conclusion
In prior syntheses of 3, the uronic acid units were prepared in-
dependently at the mono- or disaccharide levels. Our novel ap-
proach was based on the synthesis of the pentasaccharide by
utilizing non-oxidized precursors of the uronic acids, and their
oxidation in one step at the pentasaccharide level. By this strategy,
not only could the synthesis be shortened, but the glycosylation
efficacy, which was decreased in previous methods by the inherent
low reactivity of the uronic acid residues, could also be enhanced.
Out of the two applied silyl protecting groups, the tert-butyl-
diphenylsilyl-ether proved to be better than the tert-butyldime-
NMR (CDCl3, 90 MHz):
d
¼169.3 (CO), 138.2, 137.8, 137.7 (3C, 3ꢂCq
arom), 128.3e127.3 (15C, arom), 97.8, 96.8 (C-1, C-10), 80.2, 80.0,
77.4, 72.7, 70.0, 67.7, 66.5, 66.2 (8C, skeleton carbons), 75.9, 73.2,
73.0 (3C, 3ꢂCH2Ph), 68.2 (C-6), 62.4 (C-60), 57.9 (C-30-OCH3), 55.0
(C-1-OCH3), 20.8 (AcCH3) ppm; MALDI-TOF (positive ion): m/z calcd
for [MþNa]þ 705.29. Found: 705.37. Anal. Calcd for C37H46O12
(682.75): C, 65.09; H, 6.79. Found: C, 65.33; H, 6.87.
4.3. Methyl (2-O-acetyl-6-O-tert-butyldimethylsilyl-3-O-
thylsilyl-ether to temporarily protect the primary position of the
L-
methyl-a-L-idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl-a-D-glu-
idose unit, because of its higher stability under acidic conditions.
copyranoside (7)
Introduction of three methyl ethers and simultaneous formation
of two carboxylic functions at the pentasaccharide level proceeded
with high yields, and the target pentasaccharide could be achieved
To a solution of 6 (2.000 g, 2.93 mmol) in dry pyridine (10 mL),
tert-butyldimethylsilyl chloride (883 mg, 5.96 mmol) was added.

M. Herczeg et al. / Tetrahedron 70 (2014) 2919e2927
2923
ꢁ
The mixture was stirred for 24 h at room temperature. After com-
plete disappearance of the starting material the mixture was con-
centrated. The residue was dissolved in EtOAc (250 mL), washed
with 1 M HCl (2ꢂ20 mL), water (20 mL), satd aq NaHCO3 (2ꢂ20 mL)
and water (2ꢂ20 mL), dried and concentrated. The crude product
was purified by column chromatography on silica gel (6:4 n-hex-
CH2Cl2 (72 mL), 4 A molecular sieves (2.00 g) were added. The stirred
mixture was cooled to ꢀ40 ꢁC under argon. After 30 min at this
temperature, a mixture of NIS (1.397 g, 6.21 mmol) and TfOH (162 mL,
1.86 mmol) dissolved in THF (3.6 mL) was added. After 2 h stirring at
ꢀ10 ꢁC, Et3N (500
mL) was added. The reaction mixture was diluted
with CH2Cl2 (400 mL) and filtered through a pad of Celite. The filtrate
was washed successively with 10% aq Na2S2O3 (2ꢂ60 mL), H2O
(60 mL), satd aq NaHCO3 (60 mL) and H2O (2ꢂ60 mL), dried and
concentrated. The crude product was purified by silica gel chroma-
tography (9:1 to 7:3 n-hexane/EtOAc) to give compounds 10 (325 mg,
9%), 11 (1.831 g, 49%), 12 (572 mg, 15%) and 13 (881 mg, 24%).
ane/EtOAc) to give 7 (2.250 g, 96%) as a colourless syrup; [
a
]
D
25 þ4.0
(c 0.33, CHCl3); Rf 0.51 (6:4 n-hexane/EtOAc); IR nmax (KBr): 3585,
3480, 3088, 3063, 3030, 2929, 2895, 2857, 1739, 1605, 1496, 1471,
1455, 1370, 1248, 1098, 1050, 912, 836, 777, 739, 698, 606, 548, 466,
419 cmꢀ1; 1H NMR (CDCl3, 360 MHz):
d
¼7.54e7.41 (m, 15H, arom),
5.16e4.67 (m, 9H, 3ꢂCH2Ph, H-1, H-10, H-20), 4.36e4.31 (m, 1H),
4.12e4.01 (m, 2H), 3.98e3.91 (m, 2H), 3.85e3.72 (m, 4H), 3.16 (s,
3H, OCH3), 3.58e3.54 (m, 2H), 3.52 (s, 3H, OCH3), 3.47e3.43 (m,1H),
2.15 (s, 3H, AcCH3), 1.04 (s, 9H, 3ꢂt-Bu-CH3), 0.19, 0.16 (2ꢂs, 6H,
4.5.2. Method B. To
a solution of disaccharide 7 (210 mg,
0.273 mmol) and monosaccharide 9 (279 mg, 0.41 mmol) in dry
ꢁ
CH2Cl2 (7 mL), 4 A molecular sieves (0.50 g) and sym-collidine
2ꢂCH3) ppm; 13C NMR (CDCl3, 90 MHz):
d¼169.4 (CO), 138.8, 137.8,
(6.500 mL, 0.05 mmol) were added. The stirred mixture was cooled
137.7 (3C, 3ꢂCq arom), 127.9e126.9 (15C, arom), 97.7, 97.5 (C-1, C-
10), 80.6, 79.9, 77.7, 73.4, 69.8, 67.9, 67.3, 65.7 (8C, skeleton carbons),
75.1, 73.0, 72.9 (3C, 3ꢂCH2Ph), 68.3 (C-6), 63.8 (C-60), 57.7 (C-30-
OCH3), 54.8 (C-1-OCH3), 25.5 (3C, 3ꢂt-Bu-CH3), 20.7 (AcCH3), 17.9
(Cq, t-Bu), ꢀ5.8 (2C, 2ꢂCH3) ppm; MALDI-TOF (positive ion): m/z
calcd for [MþNa]þ 819.37. Found: 819.20. Anal. Calcd for
to ꢀ40 ꢁC under argon. After 30 min at this temperature, NIS
(138 mg, 0.61 mmol) dissolved in THF (360 mL) and AgOTf (25 mg,
0.10 mmol) dissolved in toluene (300
mL) were added. After 3 h
stirring at 10 ꢁC, Et3N (50
mL) was added. The reaction mixture was
diluted with CH2Cl2 (250 mL) and filtered through a pad of Celite.
The filtrate was washed successively with 10% aq Na2S2O3
(2ꢂ50 mL), H2O (50 mL), satd aq NaHCO3 (50 mL) and H2O
(2ꢂ50 mL), dried and concentrated. The crude product was purified
by silica gel chromatography (7:3 n-hexane/EtOAc) to give 10
(265 mg, 71%) as the only isolated product.
C
43H60O12Si (796.39): C, 64.80; H, 7.59. Found: C, 64.95; H, 7.68.
4.4. Phenyl 2,3,6-tri-O-benzyl-4-O-(2-naphthyl)methyl-1-
thio- -glucopyranoside (9)
b-D
25
To a solution of compound 816 (10.92 g, 18.43 mmol) in dry DMF
(65 mL) NaH (60% dispersion in oil, 1.180 g, 29.49 mmol) was added
in portions at 0 ꢁC. After stirring for 30 min at 0 ꢁC under Ar, benzyl
bromide (2.630 mL, 22.12 mmol) was added. When complete
conversion of the starting material was observed by TLC analysis
(3 h at 0 ꢁC), MeOH (2 mL) was added. The reaction mixture was
stirred for 5 min and the solvents were evaporated. The crude
product was purified by crystallization from EtOAc/n-hexane (1:4,
4.5.3. Compound 10. Colourless syrup; [
a
]
D
þ15.6 (c 0.09, CHCl3);
Rf 0.40 (7:3 n-hexane/EtOAc); IR nmax (KBr): 3087, 3061, 3029, 2927,
2857, 1736, 1603, 1585, 1496, 1454, 1363,1235, 1094, 1050,1027, 910,
836, 817, 777, 736, 697, 606, 553, 475 cmꢀ1 1H NMR (CDCl3,
;
360 MHz):
d
¼7.88e7.21 (m, 37H, arom), 5.21e4.48 (m, 18H,
6ꢂCH2Ph, CH2NAP, H-1, H-10, H-100, H-20), 4.18e3.79 (m, 14H),
3.69e3.66 (m, 2H), 3.59e3.55 (m, 1H), 3.44 (s, 3H, OCH3), 3.41 (s,
3H, OCH3), 2.04 (s, 3H, AcCH3), 1.01 (s, 9H, 3ꢂt-Bu-CH3), 0.15, 0.13
60 mL) to give 9 (11.68 g, 93%) as white needles; mp: 92e94 ꢁC;
(2ꢂs, 6H, 2ꢂCH3) ppm; 13C NMR (CDCl3, 90 MHz):
¼169.6 (CO),
d
25
[
a]
ꢀ3.1 (c 0.23, CHCl3); Rf 0.48 (7:3 n-hexane/EtOAc); IR nmax
139.1, 138.4, 138.2, 138.1, 138.0, 137.6, 135.7, 133.0, 132.6 (9C, 9ꢂCq
arom), 128.1e125.5 (37C, arom), 98.4, 98.0, 97.8 (C-1, C-10, C-100),
81.7, 80.0, 79.6, 79.4, 78.4, 77.3, 76.2, 74.3, 71.3, 71.2, 70.8, 70.0 (12C,
skeleton carbons), 75.2, 75.0, 74.8, 74.6, 73.3, 73.2, 72.9 (7C,
6ꢂCH2Ph, CH2NAP), 68.8, 68.0 (C-6, C-600), 62.3 (C-60), 58.7 (C-30-
OCH3), 54.9 (C-1-OCH3), 25.8 (3C, 3ꢂt-Bu-CH3), 20.8 (AcCH3), 17.9
(Cq, t-Bu), ꢀ5.4, ꢀ5.6 (2C, 2ꢂCH3) ppm; MALDI-TOF (positive ion):
m/z calcd for [MþNa]þ 1391.63. Found: 1391.72. Anal. Calcd for
C81H96O17Si (1368.64): C, 71.03; H, 7.06. Found: C, 71.20; H, 7.12.
D
(KBr): 3436, 3059, 3030, 2949, 2900, 2870, 1603, 1586, 1509, 1497,
1482,1469,1454,1441,1398,1376,1356,1289,1270,1211,1175,1135,
1093, 1064, 1029, 1009, 987, 957, 854, 816, 755, 733, 697, 641,
477 cmꢀ1
;
1H NMR (CDCl3, 360 MHz)
d¼7.82e7.70 (m, 3H),
7.64e7.55 (m, 3H), 7.48e7.19 (m, 21H), 5.02e4.84 (m, 4H),
4.78e4.65 (m, 3H), 4.50 (d, 1H, 12.0 Hz), 4.44 (d, 1H, 12.0 Hz),
3.85e3.67 (m, 4H), 3.58e3.44 (m, 2H); 13C NMR (CDCl3, 90 MHz)
d
¼138.6, 138.4, 138.2, 135.6, 133.9, 133.3, 133.1, 132.0, 129.0, 128.5,
128.3, 128.0, 127.8, 127.6, 127.5, 126.7, 126.2, 126.0 (34C, arom), 87.6,
86.9, 81.0, 79.2, 77.9 (5C, C-1eC-5), 75.9, 75.5, 75.2, 73.5 (4C,
4ꢂCH2Ar), 69.1 (C-6). Anal. Calcd for C44H42O5S (682.87): C, 77.39;
H, 6.20; S, 4.70. Found: C, 77.17; H, 6.27; S, 4.91.
4.5.4. Compound 11. Colourless syrup; [
a
]
25 þ17.7 (c 0.12, CHCl3); Rf
D
0.16 (7:3 n-hexane/EtOAc); IR nmax (KBr): 3466, 3087, 3061, 3029,
2928, 2867, 1733, 1630, 1604, 1496, 1454, 1368, 1239, 1157, 1098,
1050, 1027, 908, 855, 818, 738, 698, 474 cmꢀ1 1H NMR (CDCl3,
;
4.5. Methyl (2,3,6-tri-O-benzyl-4-O-(2-naphthyl)methyl-
glucopyranosyl)-(1/4)-(2-O-acetyl-6-O-tert-butyldime-
a
-
D
-
360 MHz):
d
¼7.77e7.27 (m, 37H, arom), 5.07e4.38 (m, 18H,
6ꢂCH2Ph, CH2NAP, H-1, H-10, H-100, H-20), 4.25e4.21 (m, 1H),
thylsilyl-3-O-methyl-
benzyl- -glucopyranoside (10), methyl (2,3,6-tri-O-benzyl-
4-O-(2-naphthyl)methyl- -glucopyranosyl)-(1/4)-(2-O-
acetyl-3-O-methyl- -idopyranosyl)-(1/4)-2,3,6-tri-O-ben-
zyl- -glucopyranoside (11), tert-butyldimethylsilyl 2,3,6-tri-
O-benzyl-4-O-(2-naphthyl)methyl- -glucopyranoside (12)
and methyl (2,3,6-tri-O-benzyl-4-O-(2-naphthyl)methyl-
glucopyranosyl)-(1/4)-[2-O-acetyl-6-O-(2,3,6-tri-O-benzyl-4-
O-(2-naphthyl)methyl- -glucopyranosyl)-3-O-methyl-
a-L-idopyranosyl)-(1/4)-2,3,6-tri-O-
4.00e3.58 (m, 17H), 3.39 (s, 3H, OCH3), 3.32 (s, 3H, OCH3), 1.93 (s,
a
-D
3H, AcCH3) ppm; 13C NMR (CDCl3, 90 MHz):
d
¼169.6 (CO), 138.3,
a-
D
138.2, 137.7, 137.5, 137.3, 135.4, 132.8, 132.5 (9C, 9ꢂCq arom),
128.0e125.3 (37C, arom), 98.2, 97.6, 96.8 (C-1, C-10, C-100), 81.5, 79.9,
79.1, 77.4, 76.5, 73.2, 70.9, 69.8, 68.5, 67.5 (12C, skeleton carbons),
75.3, 75.0, 74.5, 73.1, 72.9 (7C, 6ꢂCH2Ph, CH2NAP), 68.1, 68.0 (C-6, C-
600), 60.9 (C-60), 57.7 (C-30-OCH3), 54.7 (C-1-OCH3), 20.6
(AcCH3) ppm; MALDI-TOF (positive ion): m/z calcd for [MþNa]þ
1277.54. Found: 1277.76. Anal. Calcd for C75H82O17 (1254.56): C,
71.75; H, 6.58. Found: C, 71.83; H, 6.63.
a-L
a-D
a,b-D
a-D-
a
,b-
D
a-L-
idopyranosyl]-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyranoside
(13)
4.5.5. Compound 12. Colourless syrup (
0.44, CHCl3); Rf 0.84 (7:3 n-hexane/EtOAc); IR nmax (KBr): 3058,
3030, 2926, 2856, 1578, 1476, 1438, 1361, 1252, 1156, 1072, 1023,
a
/
b
ratio¼3:1); [
a
]
25 þ6.1 (c
D
4.5.1. Method A. To a solution of disaccharide acceptor 7 (2.200 g,
2.76 mmol) and monosaccharide donor 9 (2.820 g, 4.14 mmol) in dry

2924
M. Herczeg et al. / Tetrahedron 70 (2014) 2919e2927
999, 837, 817, 780, 737, 687, 471 cmꢀ1; 1H NMR (CDCl3, 360 MHz):
¼7.74e7.09 (m, 30H, arom), 5.27 (d, 1H, J 3.4 Hz, H-1- ), 5.00e4.37
), 4.07e3.45 (m, 8H), 0.96 (s,
CH2Cl2 (22 mL), 4 A molecular sieves (0.500 g) were added. The
ꢁ
d
a
stirred mixture was cooled to ꢀ40 ꢁC under argon. After 30 min at
this temperature, NIS (483 mg, 2.151 mmol) dissolved in THF
(1.00 mL) and AgOTf (88 mg, 0.34 mmol) dissolved in toluene
(m, 12H, 6ꢂCH2Ph, 2ꢂCH2NAP, H-1-
b
3H, 3ꢂt-Bu-CH3), 0.93 (s, 9H, 3ꢂt-Bu-CH3), 0.20, 0.17 (2ꢂs, 2H,
2ꢂCH3) 0.14, 0.13 (2ꢂs, 6H, 2ꢂCH3) ppm; 13C NMR (CDCl3, 90 MHz):
(1.00 mL) were added. After 2 h stirring at ꢀ10 ꢁC, Et3N (100
mL) was
d
¼138.8, 138.6, 138.4, 138.3, 138.1, 137.8, 136.8, 135.7, 133.1, 132.8
added. The reaction mixture was diluted with CH2Cl2 (250 mL) and
filtered through a pad of Celite. The filtrate was washed succes-
sively with 10% aq Na2S2O3 (2ꢂ50 mL), H2O (50 mL), satd aq
NaHCO3 (50 mL) and H2O (2ꢂ50 mL), dried and concentrated. The
(14C, 14ꢂCq arom), 128.8e125.6 (44C, arom), 98.1 (C-1-
b), 91.7 (C-
1- ), 84.6, 83.8, 81.6, 80.9, 77.7, 75.0, 70.2 (8C, skeleton carbons),
a
75.4, 75.3, 75.1, 74.7, 74.6, 73.3, 73.1, 72.7 (8C, 6ꢂCH2Ph,
2ꢂCH2NAP), 68.9, 68.5 (2ꢂC-6), 25.7, 25.6 (6C, 6ꢂt-Bu-CH3), 18.0,
17.9 (2C, 2ꢂCq, t-Bu), ꢀ4.1, ꢀ4.6, ꢀ5.1, ꢀ5.4 (4C, 4ꢂCH3) ppm;
MALDI-TOF (positive ion): m/z calcd for [MþNa]þ 727.34. Found:
727.24. Anal. Calcd for C44H52O6Si (704.35): C, 74.96; H, 7.43. Found:
C, 75.06; H, 7.57.
crude product was purified by silica gel chromatography (7:3 n-
25
hexane/EtOAc) to give 15 (1.10 g, 77%) as a colourless syrup; [a]
D
þ4.9 (c 0.12, CHCl3); Rf 0.35 (7:3 n-hexane/EtOAc); IR nmax (KBr):
3479, 3063, 3029, 2931, 2856, 1736, 1496, 1454, 1428, 1363, 1236,
1159, 1110, 1027, 910, 855, 820, 748, 699, 614, 505, 476 cmꢀ1 1H
;
NMR (CDCl3, 360 MHz):
d
¼7.78e7.15 (m, 47H, arom), 5.15e4.49 (m,
25
4.5.6. Compound 13. Colourless syrup (
a
/
b
ratio¼1:1); [
a]
þ14.6
18H, 6ꢂCH2Ph, CH2NAP, H-1, H-10, H-100, H-20), 4.31e4.22 (m, 2H),
3.97e3.47 (m, 14H), 3.36 (s, 3H, OCH3), 3.35 (s, 3H, OCH3), 3.20e3.17
(m, 1H), 1.94 (s, 3H, AcCH3), 1.07 (s, 9H, 3ꢂt-Bu-CH3) ppm; 13C NMR
D
(c 0.37, CHCl3); Rf 0.33 (7:3 n-hexane/EtOAc); IR nmax (KBr): 3167,
3087, 3061, 3029, 2924, 2863, 1952, 1869, 1809, 1736, 1603, 1585,
1496, 1454, 1365, 1327, 1235, 1162, 1098, 1026, 1001, 911, 856, 818,
(CDCl3, 90 MHz):
d
¼169.5 (CO), 139.1, 138.6, 138.5, 138.0, 137.9,
736, 698, 605, 476 cmꢀ1
;
1H NMR (CDCl3, 360 MHz):
d
¼7.79e7.18
137.8, 137.5, 135.6, 133.0, 132.9, 132.6 (11C, 11ꢂCq arom),
135.3e125.5 (47C, arom), 98.8, 97.8, 97.7 (C-1, C-10, C-100), 81.6, 81.4,
80.2, 79.3, 77.8, 75.7, 74.7, 70.9, 70.5, 70.3, 69.9, 69.8 (12C, skeleton
carbons), 75.1, 74.5, 73.2, 73.0, 72.9, 72.7 (7C, 6ꢂCH2Ph, CH2NAP),
68.8, 67.5 (C-6, C-600), 63.1 (C-60), 58.5 (C-30-OCH3), 54.8 (C-1-OCH3),
26.7 (3C, 3ꢂt-Bu-CH3), 20.7 (AcCH3), 18.8 (Cq, t-Bu) ppm; MALDI-
TOF (positive ion): m/z calcd for [MþNa]þ 1515.66. Found:
1515.61. Anal. Calcd for C91H100O17Si (1492.67): C, 73.17; H, 6.75.
Found: C, 73.29; H, 7.02.
(m, 118H, arom), 5.14e4.24 (m, 54H, 18ꢂCH2Ph, 4ꢂCH2NAP, 2ꢂH-1,
2ꢂH-10, 2ꢂH-100, 2ꢂH-20, H-1000-
a b), 4.11e4.28 (m, 58H), 2.01,
, H-1000-
1.96 (2ꢂs, 6H, 2ꢂAcCH3) ppm; 13C NMR (CDCl3, 90 MHz):
¼169.9,
d
169.8 (2C, 2ꢂCO), 139.3, 139.2, 138.7, 138.6, 138.5, 138.1, 138.0, 137.9,
137.7, 135.9, 135.8, 135.7, 133.1, 132.8 (30C, 30ꢂCq arom),
128.2e125.7 (C, arom), 103.4, 99.1, 98.9, 98.2, 98.0, 97.8, 97.4, 97.3
(2ꢂC-1, 2ꢂC-10, 2ꢂC-100, C-1000-
a b), 82.2, 81.8, 80.2, 80.0, 79.7,
, C-1000-
79.4, 79.3, 77.7, 77.5, 77.3, 76.6, 71.4, 70.6, 70.1 (32C, skeleton car-
bons), 75.4, 75.3, 75.1, 74.9, 74.6, 73.3, 73.2, 73.0, 72.0 (22C,
18ꢂCH2Ph, 4ꢂCH2NAP), 68.5, 68.4, 68.2, 66.9, 66.4 (8C, 8ꢂC-6),
58.7, 58.2 (2C, 2ꢂC-30-OCH3), 55.0 (2C, 2ꢂC-1-OCH3), 25.9, 25.6 (2C,
2ꢂAcCH3) ppm; MALDI-TOF (positive ion): m/z calcd for [MþNa]þ
1849.80. Found: 1850.03. Anal. Calcd for C113H118O22 (1826.81): C,
74.24; H, 6.51. Found: C, 74.29; H, 6.57.
4.8. Methyl (2,3,6-tri-O-benzyl-
(2-O-acetyl-6-O-tert-butyldimethylsilyl-3-O-methyl-
pyranosyl)-(1/4)-2,3,6-tri-O-benzyl- -glucopyranoside (16)
a
-D
-glucopyranosyl)-(1/4)-
a-L
-ido-
a-D
To a vigorously stirred solution of 10 (300 mg, 0.22 mmol) in
CH2Cl2 (3.5 mL) and H2O (0.50 mL), DDQ (75 mg, 0.33 mmol) was
added. After 30 min the mixture was diluted with CH2Cl2 (150 mL)
and extracted with satd aq NaHCO3 (2ꢂ20 mL) and H2O (2ꢂ20 mL),
dried and concentrated. The crude product was purified by silica gel
chromatography (9:1 CH2Cl2/acetone) to give 16 (128 mg, 47%) as
4.6. Methyl (2-O-acetyl-6-O-tert-butyldiphenylsilyl-3-O-
methyl-
copyranoside (14)
a-L-idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl-a-D-glu-
Compound 6 (730 mg, 1.07 mmol) was silylated with tert-
butyldiphenylsilyl chloride (556 L, 2.14 mmol) as described for the
a colourless syrup; [
a
]
25 þ15.8 (c 0.09, CHCl3); Rf 0.63 (9:1 CH2Cl2/
D
m
acetone); IR nmax (KBr): 3481, 3088, 3063, 3030, 2927, 2856, 2348,
2310, 1944, 1747, 1626, 1496, 1455, 1428, 1362, 1235, 1116, 1026, 904,
836, 778, 736, 697, 606, 505, 421 cmꢀ1; 1H NMR (CDCl3, 360 MHz):
synthesis of 7. The crude product was purified by column chro-
matography on silica gel (6:4 n-hexane/EtOAc) to give 14 (895 mg,
91%) as a colourless syrup; [
a]
25 þ4.8 (c 0.05, CHCl3); Rf 0.47 (6:4 n-
d
¼7.41e7.18 (m, 30H, arom), 5.11e4.49 (m, 16H, 6ꢂCH2Ph, H-1, H-10,
D
hexane/EtOAc); IR nmax (KBr): 3481, 3030, 2931, 2892, 2857, 1738,
H-100, H-20), 4.03e4.02 (m, 1H), 3.88e3.67 (m, 13H), 3.58e3.45 (m,
3H), 3.36 (s, 3H, OCH3), 3.30 (s, 3H, OCH3), 2.54 (s, 1H, OH), 1.94 (s,
3H, AcCH3), 0.89 (s, 9H, 3ꢂt-Bu-CH3), 0.05, 0.02 (2ꢂs, 6H,
1472, 1428, 1232, 1048, 822, 737, 699, 613, 504, 489 cmꢀ1; 1H NMR
(CDCl3, 360 MHz):
d
¼7.69e7.08 (m, 25H, arom), 4.99e4.49 (m, 9H,
3ꢂCH2Ph, H-1, H-10, H-20), 4.25e4.32 (m, 1H), 3.92e3.63 (m, 7H),
3.48e3.41 (m, 3H), 3.45 (s, 3H, OCH3), 3.35 (s, 3H, OCH3), 3.31e3.27
(m, 1H), 1.98 (s, 3H, AcCH3), 1.02 (s, 9H, 3ꢂt-Bu-CH3) ppm; 13C NMR
2ꢂCH3) ppm; 13C NMR (CDCl3, 90 MHz):
¼169.6 (CO), 139.2, 138.6,
d
138.2, 138.1, 138.0, 137.7 (6C, 6ꢂCq arom), 128.4e127.0 (30C, arom),
98.5, 98.2, 97.9 (C-1, C-10, C-100), 81.0, 80.1, 79.4, 79.3, 78.8, 76.5, 74.8,
71.8, 71.2, 71.0, 70.8, 70.2 (12C, skeleton carbons), 75.2, 75.1, 73.6,
73.4, 73.3, 72.7 (6C, 6ꢂCH2Ph), 69.4, 68.9 (C-6, C-600), 62.5 (C-60),
59.0 (C-30-OCH3), 55.0 (C-1-OCH3), 25.8 (3C, 3ꢂt-Bu-CH3), 20.8
(AcCH3), 18.0 (Cq, t-Bu), ꢀ5.4, ꢀ5.6 (2C, 2ꢂCH3) ppm; MALDI-TOF
(positive ion): m/z calcd for [MþNa]þ 1251.57. Found: 1251.62.
Anal. Calcd for C70H88O17Si (1229.54): C, 68.38; H, 7.21. Found: C,
68.33; H, 7.31.
(CDCl3, 90 MHz):
d
¼169.6 (CO), 138.7, 138.0, 137.8, 133.0, 132.6 (5C,
5ꢂCq arom), 135.7e127.0 (25C, arom), 98.0, 97.6 (C-1, C-10), 80.1,
80.0, 77.9, 73.3, 69.9, 68.0, 67.5, 65.9 (8C, skeleton carbons), 75.3,
73.2 (3C, 3ꢂCH2Ph), 68.9 (C-6), 64.6 (C-60), 58.0 (C-30-OCH3), 55.0
(C-1-OCH3), 26.6 (3C, 3ꢂt-Bu-CH3), 20.9 (AcCH3), 19.0 (Cq, t-
Bu) ppm; MALDI-TOF (positive ion): m/z calcd for [MþNa]þ 943.41.
Found: 943.45. Anal. Calcd for C53H64O12Si (920.42): C, 69.11; H,
7.00. Found: C, 69.21; H, 7.10.
4.9. Methyl (2,3,6-tri-O-benzyl-
(2-O-acetyl-3-O-methyl- -idopyranosyl)-(1/4)-2,3,6-tri-O-
benzyl- -glucopyranoside (17)
a-D-glucopyranosyl)-(1/4)-
4.7. Methyl (2,3,6-tri-O-benzyl-4-O-(2-naphthyl)methyl-
glucopyranosyl)-(1/4)-(2-O-acetyl-6-O-tert-butyldiphe-
nylsilyl-3-O-methyl- -idopyranosyl)-(1/4)-2,3,6-tri-O-ben-
zyl- -glucopyranoside (15)
a
-
D
-
a-L
a-D
a-L
a
-D
Compound 11 (1.820 g, 1.45 mmol) was deprotected in an
analogous manner to that described for the synthesis of compound
16. The crude product was purified by silica gel chromatography
(1:1 n-hexane/acetone) to give 17 (1.110 g, 69%) as a colourless
To a solution of disaccharide acceptor 14 (880 mg, 0.96 mmol)
and thiophenyl-glycoside donor 9 (978 mg, 1.43 mmol) in dry

M. Herczeg et al. / Tetrahedron 70 (2014) 2919e2927
2925
syrup; [
a
]
25 þ2.1 (c 0.08, CHCl3); Rf 0.42 (1:1 n-hexane/acetone); IR
H2O (2ꢂ50 mL), dried and concentrated. The crude product was
D
nmax (KBr): 3445, 3063, 3030, 2928, 1734, 1633, 1496, 1454, 1370,
purified by silica gel chromatography (7:3 n-hexane/acetone) to
25
1238, 1098, 1051, 1027, 912, 739, 698 cmꢀ1
360 MHz):
;
1H NMR (CDCl3,
give 20 (116 mg, 58%) as a colourless syrup; [
a]
þ32.6 (c 0.10,
D
d
¼7.38e7.21 (m, 30H, arom), 4.99e4.49 (m, 16H,
CHCl3); Rf 0.35 (7:3 n-hexane/acetone); IR nmax (KBr): 3459, 3062,
6ꢂCH2Ph, H-1, H-10, H-100, H-20), 4.16e4.06 (m, 2H), 3.92e3.88 (m,
2H), 3.79e3.25 (m, 14H), 3.37 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 2.58
(s, 1H, OH), 1.91 (s, 3H, AcCH3) ppm; 13C NMR (CDCl3, 90 MHz):
3029, 2928, 2857, 1753, 1734, 1454, 1364, 1240, 1219, 1100, 1049,
836, 747, 698 cmꢀ1
;
1H NMR (CDCl3, 360 MHz):
d¼7.80e7.12 (m,
42H, arom), 5.14e4.26 (m, 24H, 7ꢂCH2Ph, CH2NAP, 5ꢂH-1, H-20, H-
2000, H-3000), 4.08e3.68 (m, 19H), 3.55e3.04 (m, 8H), 3.54, 3.41, 3.35,
3.21 (4ꢂs, 15H, 5ꢂOCH3), 2.02, 1.90, 1.87 (3ꢂs, 9H, 3ꢂAcCH3), 0.87
(s, 9H, 3ꢂt-Bu-CH3), 0.00 (s, 6H, 2ꢂCH3) ppm; 13C NMR (CDCl3,
d
¼169.6 (CO), 138.4, 138.3, 137.8, 137.7, 137.6, 135.5 (6C, 6ꢂCq arom),
128.2e127.5 (30C, arom), 97.8, 97.7, 96.9 (C-1, C-10, C-100), 80.0, 79.9,
78.8, 76.7, 72.9, 72.7, 70.9, 70.8, 68.8, 67.8, 67.7 (12C, skeleton car-
bons), 75.6, 75.0, 73.4, 73.2, 73.0 (6C, 6ꢂCH2Ph), 69.1 (2C, C-6, C-600),
60.9 (C-60), 58.0 (C-30-OCH3), 54.9 (C-1-OCH3), 20.8 (AcCH3) ppm;
MALDI-TOF (positive ion): m/z calcd for [MþNa]þ 1137.48. Found:
1137.71. Anal. Calcd for C64H74O17 (1114.46): C, 68.92; H, 6.69.
Found: C, 69.11; H, 6.75.
90 MHz):
d¼169.8, 169.3 (3C, 3ꢂCO), 139.3, 138.2, 138.1, 137.9, 137.4,
136.0, 133.2, 132.7 (10C, 10ꢂCq arom), 132.3e125.5 (42C, arom),
99.7, 99.0, 97.9, 97.7 (5ꢂC-1), 83.1, 81.7, 80.2, 79.8, 79.6, 79.2, 77.7,
75.9, 75.2, 75.0, 74.8, 74.6, 72.7, 71.2, 71.1, 70.2, 70.1, 69.8 (20C,
skeleton carbons), 75.1, 74.9, 73.7, 73.5, 73.4, 73.2 (8C, 7ꢂCH2Ph,
CH2NAP), 69.0, 68.7, 68.3, 67.5 (4C, 4ꢂC-6), 62.3 (C-60), 60.6, 60.3,
59.1, 58.5 (4C, 4ꢂOCH3), 55.0 (C-1-OCH3), 25.9 (3C, 3ꢂt-Bu-CH3),
20.9, 20.6 (3C, 3ꢂAcCH3), 18.0 (Cq, t-Bu), ꢀ5.4, ꢀ5.5 (2C,
2ꢂCH3) ppm; MALDI-TOF (positive ion): m/z calcd for [MþNa]þ
1931.85. Found: 1932.27. Anal. Calcd for C107H132O29Si (1908.86): C,
67.28; H, 6.96. Found: C, 67.37; H, 7.12.
4.10. Methyl (2,3,6-tri-O-benzyl-
(2-O-acetyl-6-O-tert-butyldiphenylsilyl-3-O-methyl-
pyranosyl)-(1/4)-2,3,6-tri-O-benzyl- -glucopyranoside (18)
a
-D
-glucopyranosyl)-(1/4)-
a-L
-ido-
a-D
4.10.1. Method A. Compound 15 (980 mg, 0.66 mmol) was depro-
tected in an analogous manner to that described for the synthesis of
compound 16. The crude product was purified by silica gel chro-
matography (7:1 n-hexane/acetone) to give 18 (654 mg, 74%) as
a colourless syrup.
4.12. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-
anosyl)-(1/4)-(2,3-di-O-acetyl-6-O-(2-naphthyl)methyl-
glucopyranosyl)-(1/4)-(2,3,6-tri-O-benzyl- -glucopyr-
anosyl)-(1/4)-(2-O-acetyl-6-O-tert-butyldiphenylsilyl-3-O-
methyl- -idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl- -glu-
copyranoside (21)
a-D-glucopyr-
b-D-
a-D
4.10.2. Method B. Compound 17 (1.100 g, 0.987 mmol) was tert-
butyldiphenylsilylated with tert-butyldiphenylsilyl chloride
a
-L
a-D
(514 mL, 1.974 mmol) in an analogous manner to that described for
the synthesis of compound 14. The crude product was purified by
silica gel chromatography (6:4 n-hexane/EtOAc) to give 18 (1.092 g,
Compound 18 (1.080 g, 0.80 mmol) was glycosylated with 1910
(948 mg, 1.20 mmol) in an analogous manner to that described
for the synthesis of compound 20. The crude product was purified
82%) as a colourless syrup; [
n-hexane/EtOAc); IR nmax (KBr): 3479, 3087, 3064, 3030, 2930,
a
]
25 þ35.5 (c 0.10, CH2Cl2); Rf 0.56 (6:4
D
by silica gel chromatography (1:1 n-hexane/EtOAc) to give 21
25
2856, 1735, 1605, 1496, 1454, 1428, 1365, 1236, 1111, 1046, 1027, 910,
(1.238 g, 76%) as a colourless syrup; [
a]
þ34.8 (c 0.09, CHCl3); Rf
D
822, 738, 698, 613, 505 cmꢀ1
;
1H NMR (CDCl3, 360 MHz):
0.54 (1:1 n-hexane/EtOAc); IR nmax (KBr): 3445, 3062, 3029, 2931,
d
¼7.71e7.14 (m, 40H, arom), 5.12e4.34 (m, 16H, 6ꢂCH2Ph, H-1, H-
2858,1754,1731,1496,1472,1454,1428,1365,1295,1241,1157,1143,
10, H-100, H-20), 4.21e4.17 (m, 1H), 3.93e3.42 (m, 15H), 3.37 (s, 3H,
OCH3), 3.33 (s, 3H, OCH3), 3.28e3.25 (m, 1H), 2.38 (s, 1H, OH), 1.94
(s, 3H, AcCH3), 1.05 (s, 9H, 3ꢂt-Bu-CH3) ppm; 13C NMR (CDCl3,
1103, 1028, 903, 820, 740, 699, 613, 502 cmꢀ1 1H NMR (CDCl3,
;
360 MHz):
d
¼7.79e7.12 (m, 52H, arom), 5.08e4.24 (m, 24H,
7ꢂCH2Ph, CH2NAP, 5ꢂH-1, H-20, H-2000, H-3000), 4.12e3.62 (m, 15H),
3.47e3.04 (m, 12H), 3.59, 3.41, 3.39, 3.35, 3.23 (5ꢂs, 15H, 5ꢂOCH3),
2.00, 1.90, 1.73 (3ꢂs, 9H, 3ꢂAcCH3), 1.04 (s, 9H, 3ꢂt-Bu-CH3) ppm;
90 MHz):
d
¼169.6 (CO), 139.1, 138.6, 138.2, 138.1, 137.9, 137.7, 133.0,
132.7 (8C, 8ꢂCq arom), 135.5e126.9 (40C, arom), 98.7, 98.0, 97.9 (C-
1, C-10, C-100), 81.2, 80.4, 79.4, 79.1, 78.3, 76.3, 74.7, 71.2, 71.0, 70.8,
70.7, 70.1 (12C, skeleton carbons), 75.3, 74.9, 73.4, 73.3, 73.1, 72.9
(6C, 6ꢂCH2Ph), 68.9 (2C, C-6, C-600), 63.1 (C-60), 58.8 (C-30-OCH3),
55.0 (C-1-OCH3), 26.8 (3C, 3ꢂt-Bu-CH3), 20.9 (AcCH3), 19.0 (Cq, t-
Bu) ppm; MALDI-TOF (positive ion): m/z calcd for [MþNa]þ
1375.60. Found: 1375.74. Anal. Calcd for C80H92O17Si (1352.61): C,
70.98; H, 6.85. Found: C, 71.14; H, 7.03.
13C NMR (CDCl3, 90 MHz):
d
¼169.8, 169.7, 169.2 (3C, 3ꢂCO), 139.2,
139.1, 138.1, 138.0, 137.9, 137.8, 137.4, 135.9, 133.1, 133.0, 132.7, 132.6
(12C, 12ꢂCq arom), 135.4e125.4 (52C, arom), 99.4, 99.1, 97.8, 97.6
(5C, 5ꢂC-1), 83.0, 81.6, 80.3, 79.8, 79.5, 79.2, 79.1, 77.2, 76.2, 75.6,
75.0, 74.9, 74.3, 72.5, 71.0, 69.9, 69.6, 69.5 (20C, skeleton carbons),
75.2, 74.7, 73.6, 73.5, 73.2, 73.1 (8C, 7ꢂCH2Ph, CH2NAP), 69.0, 68.6,
68.2, 67.3 (4C, 4ꢂC-6), 63.0 (C-60), 60.4, 60.1, 59.0, 58.2 (4C,
4ꢂOCH3), 54.9 (C-1-OCH3), 26.7 (3C, 3ꢂt-Bu-CH3), 20.8, 20.3 (3C,
3ꢂAcCH3), 18.9 (Cq, t-Bu) ppm; MALDI-TOF (positive ion): m/z calcd
for [MþNa]þ 2055.88. Found: 2056.30. Anal. Calcd for C117H136O29Si
(2032.89): C, 69.07; H, 6.74. Found: C, 69.19; H, 6.83.
4.11. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-
anosyl)-(1/4)-(2,3-di-O-acetyl-6-O-(2-naphthyl)methyl-
glucopyranosyl)-(1/4)-(2,3,6-tri-O-benzyl- -glucopyr-
anosyl)-(1/4)-(2-O-acetyl-6-O-tert-butyldimethylsilyl-3-O-
methyl- -idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl- -glu-
copyranoside (20)
a-D-glucopyr-
b-D-
a-D
a-
L
a
-D
4.13. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-
anosyl)-(1/4)-(6-O-(2-naphthyl)methyl- -glucopyranosyl)-
(1/4)-(2,3,6-tri-O-benzyl- -glucopyranosyl)-(1/4)-(6-O-
tert-butyldiphenylsilyl-3-O-methyl- -idopyranosyl)-(1/4)-
2,3,6-tri-O-benzyl- -glucopyranoside (22)
a-D-glucopyr-
b-D
a-D
To a solution of trisaccharide acceptor 16 (128 mg, 0.10 mmol),
and disaccharide donor 1910 (123 mg, 0.16 mmol) in dry CH2Cl2
a-L
a-D
ꢁ
(5 mL), 4 A molecular sieves (0.500 g) were added. The stirred
mixture was cooled to ꢀ40 ꢁC under argon. After 30 min at this
To a solution of 21 (1.220 g, 0.60 mmol) in MeOH (20 mL)
a catalytic amount of NaOMe (40 mg, 0.74 mmol) was added. After
24 h stirring, the mixture was neutralized with Amberlite IR-120 Hþ
ion-exchange resin, filtered and concentrated. The crude product
temperature, NIS (52 mg, 0.23 mmol) dissolved in THF (150
m
L) and
L) were
mL) was added. The
AgOTf (10 mg, 0.04 mmol) dissolved in toluene (150
m
added. After 3 h stirring at þ5 ꢁC, Et3N (50
reaction mixture was diluted with CH2Cl2 (150 mL), and filtered
through a pad of Celite. The filtrate was washed successively with
10% aq Na2S2O3 (2ꢂ25 mL), H2O (25 mL), satd aq NaHCO3 (25 mL),
was purified by silica gel chromatography (1:1 n-hexane/EtOAc) to
25
give 22 (899 mg, 79%) as a colourless syrup; [
a
]
D
þ35.3 (c 0.09,
CHCl3); Rf 0.44 (1:1 n-hexane/EtOAc); IR nmax (KBr): 3437, 3062,

2926
M. Herczeg et al. / Tetrahedron 70 (2014) 2919e2927
3029, 2930, 2858, 1632, 1605, 1496, 1454, 1428, 1362, 1098, 1048,
913, 856, 821, 739, 699, 612, 505, 476 cmꢀ1 1H NMR (CDCl3,
360 MHz):
2.9 Hz), 5.29 (d, 1H, J 2.9 Hz), 5.03e4.43 (m, 16H, 7ꢂCH2Ph, 2ꢂH-1),
4.24 (d, 1H, J 7.6 Hz), 3.88e3.75 (m, 14H), 3.40e2.88 (m, 16H), 3.62,
3.57, 3.54, 3.49, 3.45, 3.43, 3.41, 3.27 (8ꢂs, 24H, 8ꢂOCH3), 2.07 (s,
1H, OH), 1.05 (s, 9H, 3ꢂt-Bu-CH3) ppm; 13C NMR (CDCl3, 90 MHz):
;
d
¼7.79e7.18 (m, 52H, arom), 5.13e4.31 (m, 21H,
7ꢂCH2Ph, CH2NAP, 5ꢂH-1), 3.98e3.68 (m, 10H), 3.63e3.30 (m,
15H), 3.61, 3.58, 3.43, 3.37, 3.26 (5ꢂs, 15H, 5ꢂOCH3), 3.21e3.14 (m,
7H), 2.61 (s, 1H, OH), 1.03 (s, 9H, 3ꢂt-Bu-CH3) ppm; 13C NMR (CDCl3,
d
¼139.2, 138.9, 138.1, 137.8, 137.5, 132.8, 132.3 (9C, 9ꢂCq arom),
135.4e126.6 (45C, arom), 102.5, 100.7, 98.1, 97.7, 96.5 (5C, 5ꢂC-1),
86.2, 84.5, 84.4, 83.2, 81.8, 81.5, 80.2, 79.7, 79.2, 78.9, 78.5, 76.9,
74.0, 73.0, 71.0, 70.7, 70.4 (20C, skeleton carbons), 75.0, 73.2, 72.9,
72.7 (7C, 7ꢂCH2Ph), 68.9, 68.2, 67.1 (3C, 3ꢂC-6), 62.8 (C-60), 61.6
(C-6000), 60.5, 60.1, 59.9, 59.7, 59.3 (7C, 7ꢂOCH3), 54.9 (C-1-OCH3),
26.7 (3C, 3ꢂt-Bu-CH3), 18.8 (Cq, t-Bu) ppm; MALDI-TOF (positive
ion): m/z calcd for [MþNa]þ 1831.84. Found: 1831.91. Anal.
Calcd for C103H128O26Si (1808.85): C, 68.34; H, 7.13. Found: C,
68.47; H, 7.25.
90 MHz):
d
¼139.1, 138.2, 137.9, 137.7, 137.5, 137.4, 136.1, 133.4, 133.0,
132.8, 132.6 (12C, 12ꢂCq arom), 135.5e125.4 (52C, arom), 102.4,
100.4, 100.3, 97.9, 95.8 (5C, 5ꢂC-1), 83.8, 82.6, 81.9, 80.6, 79.8, 79.2,
77.9, 75.8, 75.7, 74.6, 74.2, 73.5, 71.1, 70.7, 69.9, 67.3, 67.0 (20C,
skeleton carbons), 75.0, 74.9, 73.9, 73.2, 73.1 (8C, 7ꢂCH2Ph,
CH2NAP), 69.1, 68.8, 68.2, 67.5 (4C, 4ꢂC-6), 63.7 (C-60), 60.5, 60.2,
60.0, 57.7 (4C, 4ꢂOCH3), 54.9 (C-1-OCH3), 26.8 (3C, 3ꢂt-Bu-CH3),
18.9 (Cq, t-Bu) ppm; MALDI-TOF (positive ion): m/z calcd for
[MþNa]þ 1929.85. Found: 1929.96. Anal. Calcd for C111H130O26Si
(1906.86): C, 69.86; H, 6.87. Found: C, 69.99; H, 6.93.
4.16. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-
anosyl)-(1/4)-(2,3-di-O-methyl- -glucopyranosyl)-(1/4)-
(2,3,6-tri-O-benzyl- -glucopyranosyl)-(1/4)-(2,3-di-O-
methyl- -idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl- -glu-
copyranoside (25)
a-D-glucopyr-
b-D
4.14. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-
anosyl)-(1/4)-(2,3-di-O-methyl-6-O-(2-naphthyl)methyl-
glucopyranosyl)-(1/4)-(2,3,6-tri-O-benzyl- -glucopyr-
anosyl)-(1/4)-(6-O-tert-butyldiphenylsilyl-2,3-di-O-methyl-
-idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl- -glucopyrano-
side (23)
a
-D
-glucopyr-
a-D
b-D
-
a
-L
a-D
a-D
a
-L
a
-
D
To a solution of compound 24 (350 mg, 0.19 mmol) in THF
(2 mL) was added 1 M solution of (n-Bu)4NF (289 L, 0.29 mmol).
m
After 72 h, the mixture was concentrated and the residue was
To a solution of pentasaccharide triol 22 (885 mg, 0.46 mmol) in
purified by column chromatography (6:4 n-hexane/acetone) to
25
dry DMF (17 mL) NaH (60% dispersion in oil, 67 mg, 1.66 mmol) was
give 25 (292 mg, 96%) as a colourless syrup [
a
]
þ61.4 (c 0.08,
D
added at 0 ꢁC. After stirring for 30 min at 0 ꢁC under Ar, MeI (108
mL,
CH2Cl2); Rf 0.52 (6:4 n-hexane/acetone); IR nmax (KBr): 3465, 1638,
1.73 mmol) was added. When complete disappearance of the
starting material was observed by TLC analysis (3 h at 0 ꢁC), MeOH
(2 mL) was added. The reaction mixture was stirred for 5 min and
the solvents were evaporated. The crude product was purified by
1454, 1363, 1102, 1040, 739, 698 cmꢀ1; 1H NMR (CDCl3, 360 MHz):
d
¼7.39e7.18 (m, 35H, arom), 5.52 (d, 1H, J 3.7 Hz), 5.15 (d, 1H, J
3.4 Hz), 4.93e4.50 (m, 16H, 7ꢂCH2Ph, 2ꢂH-1), 4.28 (d, 1H, J 7.8 Hz),
3.93e3.63 (m, 15H), 3.62e3.15 (m, 12H), 3.61, 3.58, 3.54, 3.49, 3.44,
3.42, 3.39, 3.35 (8ꢂs, 24H, 8ꢂOCH3), 3.03e2.94 (m, 3H), 2.36, 2.08
column chromatography (7:3 n-hexane/acetone) to give 23
25
(771 mg, 85%) as a colourless syrup. [
a]
þ45.2 (c 0.08, CHCl3); Rf
(2ꢂs, 2H, 2ꢂOH) ppm; 13C NMR (CDCl3, 90 MHz):
¼138.7, 138.4,
d
D
0.43 (7:3 n-hexane/acetone); IR nmax (KBr): 3465, 3062, 3029, 2931,
138.0, 137.8, 137.7, 137.5, 137.4 (7C, 7ꢂCq arom), 128.2e127.3 (35C,
arom), 102.3, 98.6, 97.8, 97.0, 96.3 (5C, 5ꢂC-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, 7ꢂCH2Ph),
68.1, 68.0, 67.4 (3C, 3ꢂC-6), 61.6 (C-6000), 60.4, 60.1, 60.0, 59.6, 59.4,
59.3, 59.2 (7C, 7ꢂOCH3), 54.9 (C-1-OCH3) ppm; MALDI-TOF (pos-
itive ion): m/z calcd for [MþNa]þ 1593.72. Found: 1593.81. Anal.
Calcd for C87H110O26 (1570.73): C, 66.48; H, 7.05. Found: C, 66.56;
H, 7.23.
2858, 1636, 1496, 1454, 1428, 1363, 1103, 1070, 1026, 911, 856, 819,
735, 697, 614, 504 cmꢀ1
;
1H NMR (CDCl3, 360 MHz):
d
¼7.78e7.11
(m, 52H, arom), 5.59 (d, 1H, J 3.5 Hz), 5.29 (d,1H, J 3.7 Hz), 5.17e4.29
(m, 19H, 7ꢂCH2Ph, CH2NAP, 3ꢂH-1), 4.12e3.68 (m, 16H), 3.63e3.15
(m, 12H), 3.60, 3.57, 3.53, 3.49, 3.44, 3.41, 3.37, 3.26 (8ꢂs, 24H,
8ꢂOCH3), 3.04e2.96 (m, 2H), 1.04 (s, 9H, 3ꢂt-Bu-CH3) ppm; 13C
NMR (CDCl3, 90 MHz):
d
¼139.6, 139.2, 138.2, 137.8, 137.6, 136.2,
133.0, 132.7, 132.6, 132.3 (12C, 12ꢂCq arom), 135.4e125.3 (52C,
arom), 102.5, 100.9, 98.2, 97.7, 96.0 (5C, 5ꢂC-1), 86.4, 84.6, 84.5,
83.2, 82.0, 81.6, 80.3, 80.1, 79.1, 79.0, 78.7, 78.5, 76.7, 75.3, 74.5, 73.3,
72.3, 71.1, 70.5, 70.4 (20C, skeleton carbons), 75.2, 74.6, 73.2, 73.1,
72.9, 72.8 (8C, 7ꢂCH2Ph, CH2NAP), 69.2, 69.0, 67.9, 67.3 (4C, 4ꢂC-6),
63.0 (C-60), 60.5, 60.1, 60.0, 59.5, 59.2 (7C, 7ꢂOCH3), 54.9 (C-1-
OCH3), 26.7 (3C, 3ꢂt-Bu-CH3), 18.8 (Cq, t-Bu) ppm; MALDI-TOF
(positive ion): m/z calcd for [MþNa]þ 1971.90. Found: 1972.03.
Anal. Calcd for C114H136O26Si (1948.91): C, 70.20; H, 7.03. Found: C,
70.37; H, 7.12.
4.17. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-
anosyl)-(1/4)-(sodium 2,3-di-O-methyl- -glucopyr-
anosyluronate)-(1/4)-(2,3,6-tri-O-benzyl- -glucopyr-
anosyl)-(1/4)-(sodium 2,3-di-O-methyl- -idopyranosyluro
nate)-(1/4)-2,3,6-tri-O-benzyl- -glucopyranoside (26)
a-D-glucopyr-
b-D
a-D
a-L
a-D
Pentasaccharide 25 (310 mg, 0.20 mmol) was dissolved in
CH2Cl2 (5 mL) and H2O (2.50 mL), and TEMPO (11 mg, 0.07 mmol)
and BAIB (382 mg, 1.19 mmol) were added at 0 ꢁC. The solution was
stirred vigorously for 24 h at room temperature. The reaction
mixture was quenched by the addition of 10% aq Na2S2O3 solution
(17 mL) and extracted with CH2Cl2 (3ꢂ25 mL), and the combined
organic layers were dried, and concentrated. The crude product
4.15. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-
anosyl)-(1/4)-(2,3-di-O-methyl- -glucopyranosyl)-(1/4)-
(2,3,6-tri-O-benzyl- -glucopyranosyl)-(1/4)-(6-O-tert-bu-
tyldiphenylsilyl-2,3-di-O-methyl- -idopyranosyl)-(1/4)-
2,3,6-tri-O-benzyl- -glucopyranoside (24)
a-D-glucopyr-
b-D
a-D
a-L
a
-D
was purified by silica gel chromatography (95:5 CH2Cl2/MeOH) to
25
give 26 (306 mg, 94%) as a colourless syrup; [
a
]
þ6.3 (c 0.03,
D
Compound 23 (550 mg, 0.28 mmol) was deprotected in an
analogous manner to that described for the synthesis of 16. The
MeOH); Rf 0.38 (95:5 CH2Cl2/MeOH); IR nmax (KBr): 2919, 2359,
1219, 1026, 772, 673 cmꢀ1 1H NMR (CD3OD, 360 MHz):
;
crude product was purified by silica gel chromatography (1:1 n-
d
¼7.37e7.21 (m, 35H, arom), 5.41 (d, 1H, J 3.6 Hz), 5.21 (d, 1H, J
25
hexane/EtOAc) to give 24 (363 mg, 71%) as a colourless syrup; [
a
]
5.5 Hz), 5.08 (d, 1H, J 3.4 Hz), 4.99 (d, 1H, J 10.8 Hz), 4.89e4.40 (m,
16H), 4.02e3.95 (m, 2H), 3.88e3.63 (m, 12H), 3.61e3.30 (m, 2H),
3.58, 3.52, 3.48, 3.45, 3.41, 3.36, 3.33 (8ꢂs, 24H, 8ꢂOCH3),
D
þ56.8 (c 0.06, CHCl3); Rf 0.40 (1:1 n-hexane/EtOAc); IR nmax (KBr):
3445, 3063, 3029, 2930, 2858, 1624, 1496, 1454, 1428, 1363, 1326,
1104, 1071, 1028, 913, 859, 822, 737, 699, 614, 505 cmꢀ1
;
1H NMR
3.29e2.94 (m, 9H) ppm; 13C NMR (CD3OD, 90 MHz):
d
¼140.3,
(CDCl3, 360 MHz):
d
¼7.73e7.11 (m, 45H, arom), 5.51 (d, 1H, J
139.8, 139.7, 139.6, 139.4 (7C, 7ꢂCq arom), 129.8e128.3 (35C,

M. Herczeg et al. / Tetrahedron 70 (2014) 2919e2927
2927
arom), 104.1, 101.1, 99.0, 97.9 (5C, 5ꢂC-1), 86.9, 85.5, 84.4, 83.1, 81.1,
Supplementary data
81.0, 80.4, 80.3, 78.6, 77.8, 76.8, 72.1, 71.9, 71.7 (20C, skeleton car-
bons), 76.6, 76.2, 74.6, 74.5, 74.1 (7C, 7ꢂCH2Ph), 69.6, 69.4, 69.0 (3C,
3ꢂC-6), 61.2, 61.1, 60.9, 60.7, 60.3, 59.8, 55.6 (8C, 8ꢂOCH3) ppm;
MALDI-TOF (positive ion): m/z calcd for [MþNa]þ 1621.69. Found:
1621.65. Anal. Calcd for C87H104Na2O28 (1642.65): C, 63.57; H, 6.38.
Found: C, 63.60; H, 6.41.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.03.033.
References and notes
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ꢀ
The work is supported by the TAMOP 4.2.4.A/1-11-1-2012-0001
Project (National Excellence Program). The project is co-financed
by the European Union and the European Social Fund. Financial
support of the Hungarian Research Fund (K 105459) is also
acknowledged.