De novo synthesis of differentially protected l-iduronic acid glycosylating agents

Article abstract of DOI:10.1016/j.carres.2010.02.004

A divergent de novo synthesis of six differentially protected l-iduronic acid thioglycosides from a common advanced precursor is described. The key step of this synthetic sequence is the stereoselective elongation of dithioacetal protected C5-dialdehyde 11 via a highly diastereoselective MgBr₂·OEt₂-mediated cyanation. Orthogonally protected l-iduronic acid building blocks obtained by this synthesis are expected to facilitate access to differentially sulfated heparins for microarray-based structure-activity relationship studies.

Full text of DOI:10.1016/j.carres.2010.02.004

Carbohydrate Research 345 (2010) 948–955
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
De novo synthesis of differentially protected L-iduronic acid
glycosylating agents
à
*
Pascal Bindschädler , Alexander Adibekian , Dan Grünstein, Peter H. Seeberger
Max Planck Institute for Colloids and Interfaces, Department of Biomolecular Systems, Am Mühlenberg 1, 14476 Potsdam, Germany
Freie Universität Berlin, Arnimallee 22, 14195 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 January 2010
Received in revised form 2 February 2010
Accepted 3 February 2010
Available online 7 February 2010
A divergent de novo synthesis of six differentially protected L-iduronic acid thioglycosides from a com-
mon advanced precursor is described. The key step of this synthetic sequence is the stereoselective elon-
gation of dithioacetal protected C5-dialdehyde 11 via a highly diastereoselective MgBr2ꢀOEt2-mediated
cyanation. Orthogonally protected L-iduronic acid building blocks obtained by this synthesis are expected
to facilitate access to differentially sulfated heparins for microarray-based structure–activity relationship
studies.
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Heparin
Iduronic acid
Oligosaccharides
Carbohydrates
Total synthesis
The modular assembly of heparin oligosaccharides1 requires
large quantities of differentially protected monosaccharides. Tradi-
tionally, carbohydrates and related natural products were mainly
synthesized by transformation of readily available sugars.2 One
fundamental difficulty of this process is the differentiation of up
to five chemically similar hydroxyl groups in hexoses that requires
temporary protecting groups as well as selective masking of the
anomeric hydroxyl in order to establish the desired protecting
group pattern. Consequently, a typical monosaccharide synthesis
relies on tedious protection and deprotection steps in order to ac-
cess the required protecting group pattern.3
OBn
O
OBn
O
MeO2C
LevO
MeO2C
FmocO
SEt
SEt
OR1
OR2
1
2
1
2
4
5
R = Ac
R = Ac
R = Bz
1
2
R = Bz
3 R1 = Piv
6 R2 = Piv
Figure 1. L-Iduronic acid thioglycosides 1–6.
pivaloates.13 However, they can be cleaved selectively in the pres-
ence of benzoates or pivaloates.14 Furthermore, the stability of O-
sulfates toward strongly basic media required for ester cleavage
has been reported previously to generate heparin oligosaccharides
with various sulfation at the C2 hydroxyl group.15,10
As part of our program aimed at the synthesis of libraries of
heparin oligosaccharides4 we herein report an efficient de novo
synthesis5,6 of six differentially protected
L-iduronic acid (IdoA)
thioglycosides7 1–6 (Fig. 1). Starting from a common advanced pre-
cursor, these building blocks were prepared as basis for automated
oligosaccharide assembly.8 Levulinoyl esters (Lev)1,9 or 9-fluore-
nylmethyl carbonates (Fmoc)6b,10 will be installed as temporary
protecting groups for the C4 hydroxyl group, and acetyl (Ac), ben-
zoyl (Bz), or pivaloyl (Piv) esters serve as participating groups at
the C2 hydroxyl group.1,11,12 It should be noted that acetates are
more prone to undesired orthoester formation than benzoates or
The synthesis started from dioxolane 7 that is readily obtained
from D
-xylose in six steps.6d,§ Protection of the free hydroxyl using
allylbromide (AllBr) and sodium hydride furnished allyl ether 8 in
98% yield. Treatment with aqueous acetic acid cleaved the acetonide,
and selective tritylation of the primary alcohol with triphenylchlo-
romethane (TrCl) in pyridine afforded alcohol 9 in 86% yield over
two steps. The secondary hydroxyl group in 9 was alkylated using
(2-naphthyl)methylbromide (NapBr) and sodium hydride as base
to give fully protected dithioacetal 10. After cleavage of the
* Corresponding author. Tel.: +49 331 567 9300; fax: +49 331 567 9302.
E-mail address: peter.seeberger@mpikg.mpg.de (P.H. Seeberger).
Present address: Department of Chemistry and Chemical Biology, Harvard
University, 12 Oxford Street, Cambridge, MA 02138, USA.
à
§
Present address: Department of Chemical Physiology, The Scripps Research
For the preparation of multigram quantities of dioxolane 7, see Supplementary
Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
data.
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.02.004

P. Bindschädler et al. / Carbohydrate Research 345 (2010) 948–955
949
SEt
NapO
NC
OAll
OBn
O
OR OAll
O
OR
a
b
NC
SEt
SEt
O
SEt
OH OBn SEt
NapO
OAll
OTr
OBn SEt
OBn SEt
12
15 (α/β = 1:3)
9
R = H
7 R = H
c
a
10
8 R = All
R = Nap
OBn
O
NC
SEt
NapO
O
OAll
e
d
NapO
OAll
15β
SEt
OBn SEt
11
NapO
NC
OAll
SEt
NapO
MeO2C
OAll
Scheme 2. Synthesis of nitrile 15; ORTEP.20 Representation of the crystal structure
of 15b. Reagents: (a) NIS, CH2Cl2, 84%.
f
SEt
OH OBn SEt
OH OBn SEt
12
13
The configuration of cyanohydrin 12 could be determined after
cyclization with NIS to obtain nitrile 15 as an a/b mixture of ano-
SEt
mers (Scheme 2). It was possible to crystallize selectively b anomer
15b and its absolute configuration was determined by X-ray
analysis.||
OBn
g
MeO2C
NapO
14
O
OAll
(α/β = 1:3)
To simplify 1H and 13C NMR analysis of subsequent products, b-
anomer 14b was used solely to complete the synthesis. Cleavage of
the Nap-group with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)
in a mixture of CH2Cl2 and methanol21 afforded alcohol 16 in 94%
yield (Scheme 3). Diversity in the protection pattern of the C4 hy-
droxyl group was introduced using either levulinic acid (LevOH),
N,N0-diisopropyl carbodiimide (DIPC) and 4-dimethylamino pyri-
dine (DMAP) or Fmoc-Cl in pyridine, leading to Lev- (17) and
Fmoc-protected (18) thioglycosides in high yields. The allyl ether
was most efficiently cleaved by a two-step sequence.22 Isomeriza-
tion to the corresponding enol ether was achieved by the iridium
complex Ir[COD(PCH3Ph2)2]PF6, followed by hydrolysis of the enol
ether with methanol and para-toluenesulfonic acid (pTsOH) to af-
ford the corresponding alcohols 19 and 20, respectively.
Scheme 1. Synthesis of common intermediate 14. Reagents and conditions: (a)
AllBr, NaH, DMF, 98%; (b) (1) AcOH (aq); (2) TrCl, Py, 93% (two steps); (c) NapBr,
NaH, DMF, 91%; (d) (1) TFA, Et3SiH, CH2Cl2; (2) SO3ꢀPy, DIPEA, DMSO, CH2Cl2, 88%
(two steps); (e) TMS–CN, MgBr2ꢀOEt2, CH2Cl2, 89%; (f) AcCl, MeOH, toluene; then
H2O, 69%; (g) NIS, CH2Cl2, 80%.
H
SEt
H
H
OBn
OBn
H
H
O
O
SEt
MeO2C
NapO
MeO2C
NapO
OAll
14α
OAll
14β
Standard acylating conditions were used to conclude the syn-
thesis, converting alcohols 19 and 20 into six
glycosides 1–6 in 84–99% yield (Scheme 3).
L-iduronic acid thio-
Figure 2. NOE difference experiments for 14
a
and 14b.
In summary, a divergent and efficient synthesis of six differen-
tially protected
-iduronic acid thioglycosides7 is presented. Access
to large amounts of
triphenylmethyl ether with trifluoroacetic acid (TFA) and triethylsi-
lane, the primary alcohol was obtained. Oxidation of the crude prod-
uct, using a Parikh–Doering oxidation16 yielded aldehyde 11 in
excellent yield (88%) over two steps (Scheme 1).
L
L
-iduronic acid building blocks bearing orthog-
onal acyl groups at the C2 hydroxyl group11 is expected to greatly
facilitate the synthesis of libraries of differentially sulfated hepa-
rins by means of automated oligosaccharide assembly.8
Next, the chelate-controlled syn-selective cyanation17 of alde-
hyde 11 was investigated. Chelating halide salts in combination
with trimethylsilyl cyanide as a safe source of cyanide17b were
1. Experimental
used to obtain selectively L-ido-configured cyanohydrin 12. Use
of MgBr2ꢀOEt2 as chelating activator17b,18 proved to be the method
1.1. General methods
of choice and provided L-ido-isomer 12 in 89% yield with excellent
diastereoselectivity (d.r. >12:1) as revealed by 1H NMR analysis of
the crude product showing only traces of by-products. Nitrile 12
underwent a Pinner reaction19 when treated with an excess of
methanolic HCl in toluene. Subsequent hydrolysis furnished
methyl ester 13 in 69% yield.– The N-iodosuccinimide (NIS)-medi-
ated cyclization of alcohol 13 delivered pyranose 14 in 80% yield,
All chemicals used were reagent grade and used as supplied ex-
cept where noted. Dichloromethane (CH2Cl2) and toluene were
purified by a Cycle-Tainer Solvent Delivery System. Tetrahydrofu-
ran (THF) was distilled from sodium. Pyridine was refluxed over
calcium hydride and distilled. Acetyl chloride was distilled. Sol-
vents for chromatography and workup procedures were distilled.
Reactions were performed under an argon atmosphere except
where noted. Analytical thin-layer chromatography was performed
on E. Merck Silica Gel 60 F254 plates (0.25 mm). Compounds were
visualized by UV-light at 254 nm and by dipping the plates in a
as a 1:3 mixture of
umn chromatography on silica. At this stage, NOE experiments
served to distinguish anomer 14 from its b analogue 14b: upon
saturation of H5, NOE enhancement at H4 and H1 was observed
a/b anomers that were readily separated by col-
a
a
for 14b but solely at H4 for 14a (Fig. 2).
||
CCDC-715131 (15b) contains the supplementary crystallographic data for this
–
A cyclization of product 13 to form directly pyranose 14 was observed as a side-
reaction during the Pinner reaction.
paper. These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

950
P. Bindschädler et al. / Carbohydrate Research 345 (2010) 948–955
OBn
O
OBn
O
OBn
O
OBn
O
b or c
e, f or g
d
MeO2C
a
MeO2C
MeO2C
MeO2C
SEt
SEt
SEt
SEt
OR OAll
OR OAll
R = Lev
OLev OH
OLev OR
1
2
3
R = Ac
R = Bz
R = Piv
14β
17
R = Nap
R = H
19
16
18 R = Fmoc
h
OBn
OBn
i, j or k
MeO2C
FmocO
O
MeO2C
FmocO
O
SEt
SEt
OR
OH
20
4 R = Ac
5 R = Bz
6 R = Piv
Scheme 3. Synthesis of L-iduronic acid building blocks 1–6. Reagents and conditions: (a) DDQ, CH2Cl2/MeOH (9:1), 94%; (b) LevOH, DIPC, DMAP, CH2Cl2, 86% (17); (c) Fmoc-
Cl, Py, 66% (18) (+24% recovered 16); (d) (1) Ir[COD(PCH3Ph2)2]PF6, THF; (2) pTsOHꢀH2O, MeOH, 62% (from 17) (+30% recovered 17); (e) Ac2O, Py, DMAP, 85% (1); (f) BzCl, Py,
92% (2); (g) PivCl, DMAP, CH2Cl2, 84% (3); (h) (1) Ir[COD(PCH3Ph2)2]PF6, THF, 45 °C; (2) pTsOHꢀH2O, MeOH, 65% (from 18); (i) AcCl, Py, 0 °C to rt, 85% (4); (j) BzCl, Py, 86% (5);
(k) PivCl, Py, 99% (6).
cerium sulfate ammonium molybdate (CAM) solution followed by
heating. Liquid chromatography was performed using forced flow
of the indicated solvent on Fluka Silica Gel 60 (230–400 mesh).
1H NMR spectra were obtained on a Varian VXR300 (300 MHz)
and Bruker DRX400 (400 MHz) and are reported in parts per mil-
lion (d) relative to the resonance of the solvent or to TMS
(0.00 ppm). Coupling constants (J) are reported in hertz (Hz). 13C
NMR spectra were obtained on a Varian VXR-300 (75 MHz), and
Bruker DRX400 (100 MHz) and are reported in d relative to the res-
onance of the solvent. IR Spectra: Measured as 1–2% CHCl3 solution
on a Perkin–Elmer-782 spectrophotometer or neat on a Perkin–El-
1.2.2. 2-O-Allyl-3-O-benzyl-5-O-triphenylmethyl-D-xylose
di(ethylthio)acetal (9)
Acetonide 8 (11.4 g, 26.7 mmol) was dissolved in 75% aqueous
AcOH (440 mL). The mixture was heated at 50 °C (rotavapor,
200 mbar) for 3 h and concentrated. The residue was coevaporated
three times with toluene. The crude diol was dissolved in pyridine
(180 mL) and at 0 °C treated with triphenylmethyl chloride (5.58 g,
20.0 mmol). The mixture was stirred at room temperature for 7 h.
Then, more triphenylmethyl chloride (5.58 g, 20.0 mmol) was
added and the mixture stirred for another 17 h at room tempera-
ture, and concentrated. The residue was taken in EtOAc (1 L) and
washed twice with 10% aqueous citric acid solution, with saturated
aqueous NaHCO3 solution and with brine, dried over MgSO4,
filtered, and concentrated. Flash column chromatography on sil-
ica gel (1:1:0?0:1:0?9:0:1?4:0:1, cyclohexane–CH2Cl2–EtOAc)
afforded 9 (15.7 g, 93%) as a pale yellow oil. Rf = 0.36 (cyclohex-
ane–EtOAc 6:1). 1H NMR (300 MHz, CDCl3: d 1.30 (t, J = 4 Hz, 3H),
1.34 (t, J = 7.4 Hz, 3H), 2.32 (d, J = 8.4 Hz, 1H), 2.66–2.78 (m, 2H),
2.80–2.88 (m, 2H), 3.11 (dd, J = 8.6, 7.7 Hz, 1H), 3.40 (dd, J = 8.8,
6.1 Hz, 1H), 3.94–4.04 (m, 3H), 4.17 (dd, J = 7.6, 1.3 Hz, 1H), 4.23–
4.38 (m, 3H), 4.74 (d, J = 10.6 Hz, 1H), 5.15 (dd, J = 10.4, 1.3 Hz,
1H), 5.28 (dd, J = 17.2, 1.5 Hz, 1H), 5.91–6.04 (m, 1H), 7.03–7.07
(m, 2H), 7.22–7.34 (m, 12H), 7.45–7.49 (m, 6H). 13C NMR
(75 MHz, CDCl3): d 14.7, 25.4, 26.0, 53.4, 64.3, 70.4, 74.7, 75.4,
79.9, 83.5, 86.8, 116.4, 127.0, 127.6, 127.8, 128.1, 128.2, 128.6,
mer-100 FT-IR spectrometer. Optical rotations ½a drt
ꢁ
were measured
on a Jasco DIP-370 polarimeter (10 cm, 1 mL cell); the solvents and
concentrations (in g/100 mL) are indicated. High-resolution mass
spectra were performed by the MS service at the Laboratory for Or-
ganic Chemistry, ETH Zürich, and are given in m/z.
1.2. Syntheses
1.2.1. 2-O-Allyl-3-O-benzyl-4,5-O-isopropylidene-D-xylose
di(ethylthio)acetal (8)
At 0 °C, a solution of dioxolane 76d (15 g, 38.8 mmol) in DMF
(400 mL) was treated portionwise with sodium hydride (1.86 g,
78 mmol, 60% in mineral oil), followed by addition of allyl bromide
(8.34 mL, 97 mmol, filtered over ALOX). The mixture was stirred at
0 °C for 1.5 h, then quenched with MeOH (25 mL), warmed to rt,
and diluted with H2O (65 mL). The aqueous layer was extracted
with Et2O (3 ꢂ 450 mL) and the combined organic layers were
washed with H2O (450 mL) and brine (450 mL), dried over MgSO4,
filtered, and concentrated. Flash column chromatography on silica
gel (19:1?9:1, cyclohexane–EtOAc) afforded 8 (16.3 g, 98%) as a
pale yellow oil. Rf = 0.50 (cyclohexane–EtOAc 6:1). 1H NMR
(300 MHz, CDCl3): d 1.25 (t, J = 7.4 Hz, 3H), 1.26 (t, J = 7.4 Hz, 3H),
1.36 (s, 3H), 1.44 (s, 3H), 2.63 (q, J = 7.4 Hz, 2H), 2.69–2.81 (m,
2H), 3.77–3.84 (m, 3H), 4.05 (dd, J = 8.2, 6.4 Hz, 1H), 4.10 (d,
J = 3.6 Hz, 1H), 4.20 (dd, J = 12.4, 5.8 Hz, 1H), 4.31–4.41 (m, 2H),
4.75 (d, J = 11.6 Hz, 1H), 4.80 (d, J = 11.6 Hz, 1H), 5.11–5.15 (m,
1H), 5.21–5.27 (m, 1H), 5.93 (ddt, J = 17.1, 10.7, 5.6 Hz, 1H),
7.27–7.39 (m, 5H). 13C NMR (75 MHz, CDCl3): d 14.6, 14.6, 25.4,
25.6, 25.7, 26.7, 52.5, 66.0, 73.9, 74.7, 76.5, 79.8, 83.0, 108.9,
135.0, 138.0, 143.7. ½a drt
ꢁ
ꢃ12.7 (c 1.0, CHCl3). IR (CHCl3);
m 3616,
3456, 3062, 3007, 2975, 2928, 1491, 1449, 1379, 1077, 1052,
990 cmꢃ1. MALDI-HRMS: m/z calcd for C38H44O4S2Na [M+Na]+
651.2573, obsd 651.2579.
1.2.3. 2-O-Allyl-3-O-benzyl-4-O-(2-naphthyl)methyl-5-O-
triphenylmethyl-D-xylose di(ethylthio)acetal (10)
To a solution of alcohol 9 (5.55 g, 8.83 mmol) in DMF (95 mL) at
0 °C, sodium hydride (0.53 g, 13.2 mmol, 60% in mineral oil) was
added portionwise, followed by addition of 2-naphthylmethyl bro-
mide (2.93 g, 13.2 mmol). After stirring at 0 °C for 5 h, MeOH
(20 mL) was added to quench the reaction, the mixture was
warmed to room temperature, and diluted with H2O (200 mL).
The aqueous layer was extracted with a 1:1 mixture of cyclohex-
ane–EtOAc (3 ꢂ 300 mL). The combined organic layers were
washed with water (200 mL) and brine (200 mL), dried over
MgSO4, filtered, and concentrated. Flash column chromatography
on silica gel (3:1?1:3, cyclohexane–CH2Cl2) afforded 10 (6.16 g,
91%) as a pale yellow oil. Rf = 0.30 (cyclohexane–CH2Cl2 2:3). 1H
116.6, 127.5, 127.9, 128.2, 134.7, 138.5. ½a drt
ꢁ ꢃ8.4 (c 1.0, CHCl3).
IR (CHCl3);
m 2989, 2930, 2872, 1492, 1454, 1372, 1063,
931 cmꢃ1. MALDI-HRMS: m/z calcd for C22H34O4S2Na [M+Na]+
449.1791, obsd 449.1791.

P. Bindschädler et al. / Carbohydrate Research 345 (2010) 948–955
951
NMR (400 MHz, CDCl3): d 1.09 (t, J = 7.4 Hz, 3H), 1.17 (t, J = 7.4 Hz,
1377, 1071, 1021, 933 cmꢃ1
.
MALDI-HRMS: m/z calcd for
3H), 2.42 (qd, J = 7.4, 2.9 Hz, 2H), 2.61 (q, J = 7.4 Hz, 2H), 3.40 (dd,
J = 10.0, 5.5 Hz, 1H), 3.49 (dd, J = 10.0, 4.5 Hz, 1H), 3.75 (d,
J = 4.6 Hz, 1H), 3.79 (dd, J = 6.0, 4.7 Hz, 1H), 3.88 (dd, J = 9.6,
4.6 Hz, 1H), 4.05 (dd, J = 12.4, 5.7 Hz, 1H), 4.23–4.29 (m, 2H), 4.64
(d, J = 11.1 Hz, 1H), 4.68 (d, J = 12.1 Hz, 1H), 4.78 (J = 11.1 Hz, 1H),
4.88 (d, J = 12.1 Hz, 1H), 5.03–5.07 (m, 1H), 5.14 (ddd, J = 17.2,
3.4, 1.6 Hz, 1H), 5.81–5.90 (m, 1H), 7.17–7.32 (m, 14H), 7.47–
7.51 (m, 9H), 7.77–7.87 (m, 4H). 13C NMR (100 MHz, CDCl3): d
14.2, 14.4, 25.0, 25.2, 53.6, 63.1, 72.4, 74.2, 75.2, 78.2, 80.1, 82.5,
86.9, 116.1, 125.9, 126.1, 126.3, 126.9, 127.0, 127.4, 127.7, 127.8,
127.9, 128.1, 128.2, 128.3, 128.8, 133.0, 133.3, 135.2, 135.8,
C30H36O4S2Na [M+Na]+ 547.1947, obsd 547.1951.
1.2.5. 5-O-Allyl-4-O-benzyl-3-O-(2-naphthyl)methyl-6,6-
di(ethylthio)-L-idonitrile (12)
Aldehyde 11 (802 mg, 1.53 mmol) was dissolved in CH2Cl2
(15 mL) and cooled to 0 °C. MgBr2ꢀOEt2 (1.18 g, 4.58 mmol) was
added and the suspension was stirred vigorously for 15 min. Then,
the mixture was cooled to ꢃ20 °C and trimethylsilyl cyanide
(244 lL, 1.83 mmol) was added dropwise over 5 min. The mixture
was warmed to 0 °C over 2 h, then slowly warmed to room temper-
ature and stirred for totally 18 h before it was quenched with brine
(15 mL). The phases were separated, and the aqueous phase was
extracted with CH2Cl2 (2 ꢂ 30 mL). The combined organic phases
were dried over MgSO4, filtered, and concentrated. Flash column
chromatography on silica gel (9:1?6:1, cyclohexane–EtOAc) affor-
ded 12 (749 mg, 89%) as a pale yellow oil. Rf = 0.33 (cyclohexane–
EtOAc 4:1). 1H NMR (400 MHz, CDCl3): d 1.20 (t, J = 7.4 Hz, 3H),
1.23 (t, J = 7.4 Hz, 3H), 2.58 (qd, J = 7.4, 1.9 Hz, 2H), 2.68 (q,
J = 7.4 Hz, 2H), 3.52 (br, 1H), 3.96 (br, 1H), 4.09 (d, J = 3.8 Hz, 1H),
4.13–4.14 (m, 2H), 4.19–4.23 (m, 1H), 4.26–4.31 (m, 1H), 4.75 (s,
2H), 4.92 (br s, 1H), 4.97 (d, J = 11.1 Hz, 1H), 5.02 (d, J = 11.1 Hz,
1H), 5.19 (dd, J = 10.4, 1.5 Hz, 1H), 5.25–5.29 (m, 1H), 5.88–5.98
(m, 1H), 7.30–7.33 (m, 5H), 7.48–7.52 (m, 3H), 7.78–7.86 (m,
4H). 13C NMR (100 MHz, CDCl3): d 14.3, 25.5, 25.5, 51.6, 61.5,
73.1, 75.0, 75.1, 78.5, 78.6, 81.5, 117.9, 119.3, 126.2, 126.2, 126.3,
127.5, 127.7, 128.0, 128.1, 128.2, 128.4, 128.5, 133.2, 133.2,
138.6, 144.0. ½a drt
ꢁ
ꢃ26.4 (c 1.0, CHCl3). IR (CHCl3);
m 3062, 3008,
2929, 1600, 1491, 1449, 1344, 1069, 908 cmꢃ1. MALDI-HRMS: m/
z calcl for C49H52O4S2Na [M+Na]+ 791.3199, obsd 791.3208.
1.2.4. 2-O-Allyl-3-O-benzyl-4-O-(2-naphthyl)methyl-D-xylo-
dialdose di(ethylthio)acetal (11)
To a solution of 10 (0.51 g, 0.66 mmol) in CH2Cl2 (30 mL) at 0 °C
was added triethylsilane (0.53 mL, 3.32 mmol), followed by fast
addition of trifluoroacetic acid (1 mL, 1.94 mmol). After stirring
the mixture at 0 °C for 5 min, saturated aqueous NaHCO3 solution
(30 mL) was added to adjust to pH 6. The layers were separated
and the aqueous layer extracted with CH2Cl2 (2 ꢂ 30 mL). The com-
bined organic layers were washed with brine (60 mL), dried over
MgSO4, filtered, and concentrated. An analytical sample of the res-
idue was purified by flash column chromatography on silica gel
(6:1?7:3, cyclohexane–EtOAc) to give the corresponding primary
alcohol as a pale yellow oil. Rf = 0.17 (cyclohexane–EtOAc 4:1).
1H NMR (300 MHz, CDCl3): d 1.13–1.21 (m, 6H), 2.19 (dd, J = 6.8,
5.3 Hz, 1H), 2.54 (q, J = 7.4 Hz, 2H), 2.65 (qd, J = 7.4, 1.6 Hz, 2H),
3.68–3.80 (m, 2H), 3.86–4.00 (m, 3H), 4.17 (dd, J = 5.8, 4.6 Hz,
1H), 4.30 (ddt, J = 12.4, 5.7, 1.4 Hz, 1H), 4.40 (ddt, J = 12.3, 5.4,
1.4 Hz, 1H), 4.73 (d, J = 11.3 Hz, 1H), 4.75 (d, J = 11.9 Hz, 1H), 4.82
(d, J = 11.9 Hz, 1H), 4.85 (d, J = 11.3 Hz, 1H), 5.16 (ddd, J = 10.4,
3.0, 1.3 Hz, 1H), 5.29 (ddd, J = 17.2, 1.6, 1.6 Hz, 1H), 5.91–6.05 (m,
1H), 7.26–7.39 (m, 5H), 7.44–7.50 (m, 3H), 7.76–7.85 (m, 4H). 13C
NMR (75 MHz, CDCl3): d 14.5, 25.3, 25.4, 53.2, 61.7, 72.2, 74.0,
75.0, 78.2, 80.0, 82.2, 116.6, 125.9, 126.0, 126.1, 126.8, 127.6,
134.1, 134.3, 137.6. ½a drt
ꢁ
ꢃ21.1 (c 1.0, CHCl3). IR (CHCl3);
m 3536,
2928, 1496, 1454, 1378, 1060, 937, 857 cmꢃ1. MALDI-HRMS: m/z
calcd for C31H37NO4S2Na [M+Na]+ 574.2056, obsd 574.2051.
1.2.6. Methyl 2-O-allyl-3-O-benzyl-4-O-(2-naphthyl)methyl-L-
iduronate di(ethylthio)acetal (13)
To a suspension of nitrile 12 (162 mg, 0.29 mmol) and silica gel
(0.68 g) in toluene (4 mL) at 0 °C was added an ice-cold solution of
distilled acetyl chloride (0.84 mL, 11.8 mmol) in MeOH (2.4 mL).
The mixture was slowly warmed to room temperature, and stirred
for totally 16 h. At 0 °C, H2O (4 mL) was added, and the mixture
was slowly warmed to room temperature, and stirred for totally
26 h. At 0 °C, the reaction was quenched by addition of saturated
aqueous NaHCO3 solution. The aqueous phase was extracted twice
with CH2Cl2. The combined organic layers were dried over MgSO4,
filtered, and concentrated. Flash column chromatography on silica
gel (7:1?3:1, cyclohexane–EtOAc) afforded 13 (118 mg, 69%) as a
colorless oil. Rf = 0.44 (cyclohexane–EtOAc 4:1). 1H NMR (400 MHz,
CDCl3): d 1.24 (t, J = 7.4 Hz, 3H), 1.26 (t, J = 7.4 Hz, 3H), 2.66 (q,
J = 7.3 Hz, 2H), 2.70–2.78 (m, 2H), 3.14 (d, J = 7.5 Hz, 1H), 3.52 (s,
3H), 3.98 (t, J = 5.1 Hz, 1H), 4.16 (dd, J = 7.0, 1.6 Hz, 1H), 4.29–
4.33 (m, 2H), 4.38 (dd, J = 6.9, 5.3 Hz, 1H), 4.43 (dd, J = 12.4,
5.4 Hz, 1H), 4.52 (d, J = 6.1 Hz, 1H), 4.64 (d, J = 11.7 Hz, 1H), 4.80
(d, J = 11.5 Hz, 1H), 4.86 (d, J = 11.5 Hz, 1H), 4.90 (d, J = 11.7 Hz,
1H), 5.18 (dd, J = 10.4, 1.7 Hz, 1H), 5.32 (dd, J = 17.2, 1.7 Hz, 1H),
5.97–6.07 (m, 1H), 7.30–7.37 (m, 6H), 7.47–7.51 (m, 2H), 7.63
(br, 1H), 7.79–7.84 (m, 3H). 13C NMR (100 MHz, CDCl3): d 14.3,
14.5, 24.9, 25.5, 52.3, 52.8, 70.4, 73.6, 74.0, 75.1, 79.2, 79.6, 82.2,
116.8, 126.0, 126.1, 126.1, 126.9, 127.6, 127.6, 127.9, 128.0,
127.8, 128.3, 128.4, 128.4, 133.0, 133.1, 134.9, 135.3, 138.1. ½a drt
ꢁ
ꢃ15.7 (c 0.1, CHCl3). IR (neat);
m 3456, 3061, 2963, 2925, 1603,
1510, 1454, 1345, 1265, 1100, 927 cmꢃ1. MALDI-HRMS: m/z calcd
for C30H38O4S2Na [M+Na]+ 549.2104, obsd 549.2103.
Sulfur trioxide pyridine complex (0.42 g, 2.64 mmol) was added
to a solution of the crude primary alcohol (0.66 mmol) in CH2Cl2
(12 mL) at 0 °C, followed by the addition of DIPEA (0.8 mL,
4.62 mmol). The mixture was stirred for 10 min and DMSO
(0.66 mL, 9.24 mmol) was added. After stirring at 0 °C for another
15 min, the reaction was quenched with brine (10 mL), and diluted
with CH2Cl2. The phases were separated and the aqueous phase
was extracted with CH2Cl2 (2 ꢂ 20 mL). The combined organic lay-
ers were dried over MgSO4, filtered, and concentrated. Flash col-
umn chromatography on silica gel (9:1?4:1, cyclohexane–EtOAc)
afforded 11 (0.31 g, 88%) as a pale yellow oil. Rf = 0.40 (cyclohex-
ane–EtOAc 4:1). 1H NMR (300 MHz, CDCl3): d 1.17–1.27 (m, 6H),
2.54–2.66 (m, 4H), 3.81–3.84 (m, 2H), 3.95 (d, J = 7.0 Hz, 1H),
4.12 (dd, J = 11.7, 5.7 Hz, 1H), 4.33 (dd, J = 11.7, 5.9 Hz, 1H), 4.38
(dd, J = 5.2, 3.8 Hz, 1H), 4.58 (d, J = 11.6 Hz, 1H), 4.61 (d,
J = 12.2 Hz, 1H), 4.75 (d, J = 11.5 Hz, 1H), 4.99 (d, J = 12.2 Hz, 1H),
5.14 (dd, J = 10.4, 1.6 Hz, 1H), 5.26 (dd, J = 17.2, 1.7 Hz, 1H), 5.92
(ddt, J = 16.2, 10.4, 5.8 Hz, 1H), 7.18–7.26 (m, 5H), 7.43–7.54 (m,
3H), 7.70 (br s, 1H), 7.81–7.88 (m, 3H), 9.78 (s, 1H). 13C NMR
(75 MHz, CDCl3): d 14.6, 24.9, 26.0, 52.5, 73.0, 73.9, 74.6, 80.2,
80.3, 80.4, 117.2, 125.8, 126.1, 126.2, 127.1, 127.7, 127.9, 127.9,
128.1, 128.3, 133.0, 133.2, 135.0, 135.2, 138.5, 173.6. ½a drt
ꢁ ꢃ19.7
(c 1.0, CHCl3). IR (neat);
m 3501, 3058, 2927, 1742, 1497, 1454,
1267, 1124, 1075, 1028 cmꢃ1
. MALDI-HRMS: m/z calcd for
C32H40O6S2Na [M+Na]+ 607.2142, obsd 607.2159.
1.2.7. Methyl (ethyl 2-O-allyl-3-O-benzyl-4-O-(2-naphthyl)-
methyl-1-thio-a/b-L-idopyranosyl) uronate (14)
To a solution of alcohol 13 (1.77 g, 3.03 mmol) in CH2Cl2
(100 mL) at room temperature was added NIS (0.75 g, 3.34 mmol).
The mixture was stirred for 15 min at room temperature and then
128.3, 128.4, 133.1, 134.3, 134.4, 137.5, 200.3. ½a drt
ꢁ ꢃ14.7 (c 1.0,
CHCl3). IR (CHCl3);
m 3007, 2954, 2929, 2874, 1727, 1497, 1455,

952
P. Bindschädler et al. / Carbohydrate Research 345 (2010) 948–955
quenched by the addition of saturated aqueous sodium thiosulfate
solution. The aqueous phase was extracted three times with
CH2Cl2. The combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated. Flash column chro-
matography on silica gel (9:1?7:3, cyclohexane–EtOAc) afforded
512.1866, obsd 512.1871. Analytical data of 15b: Pale yellow solid.
Rf = 0.33 (cyclohexane–EtOAc 4:1). 1H NMR (400 MHz, CDCl3): d
1.24 (t, J = 7.4 Hz, 3H), 2.61–2.70 (m, 2H), 3.43 (dd, J = 6.5, 3.9 Hz,
1H), 3.52 (dd, J = 6.5, 4.8 Hz, 1H), 3.80 (t, J = 6.6 Hz, 1H), 4.00–
4.01 (m, 2H), 4.51–4.58 (m, 3H), 4.79 (d, J = 12.4 Hz, 1H), 4.84 (d,
J = 12.4 Hz, 1H), 5.08–5.11 (m, 2H), 5.17 (dd, J = 17.2, 1.6 Hz, 1H),
5.76–5.86 (m, 1H), 7.10–7.22 (m, 5H), 7.40–7.45 (m, 3H), 7.70–
7.78 (m, 4H). 13C NMR (100 MHz, CDCl3): d 14.4, 24.8, 64.2, 72.1,
73.8, 74.2, 74.4, 74.9, 76.5, 84.1, 116.6, 118.0, 126.0, 126.2, 126.3,
127.2, 127.8, 128.0, 128.0, 128.0, 128.5, 128.5, 133.2, 133.2,
14
a
(289 mg, 18%) and 14b (987 mg, 62%). Analytical data of
14a
: Pale yellow oil. Rf = 0.63 (cyclohexane–EtOAc 3:2). 1H NMR
(400 MHz, CDCl3): d 1.32 (t, J = 7.4 Hz, 3H, SCH2CH3), 2.60–2.80
(m, 2H, SCH2), 3.40 (t, J = 5.1 Hz, 1H, H-2), 3.74 (s, 3H, OMe), 3.84
(t, J = 5.3 Hz, 1H, H-3), 3.92 (t, J = 4.8 Hz, 1H, H-4), 4.08–4.13 (m,
1H, OCHHC2H3), 4.16–4.21 (m, 1H, OCHHC2H3), 4.62
(d, J = 11.7 Hz, 1H, OCHH), 4.66 (d, J = 11.7 Hz, 1H, OCHH), 4.74
(d, J = 12.1 Hz, 1H, OCHH), 4.79 (d, J = 12.1 Hz, 1H, OCHH), 4.95
(d, J = 4.2 Hz, 1H, H-5), 5.18 (dd, J = 10.4, 1.6 Hz, 1H, CH@CHH),
5.27 (dd, J = 17.2, 1.7 Hz, 1H, CH@CHH), 5.44 (d, J = 5.0 Hz, 1H, H-
1), 5.87–5.97 (m, 1H, CH@CH2), 7.25–7.33 (m, 5H, HAr), 7.42–7.51
(m, 3H, HAr), 7.74–7.86 (m, 4H, HAr). 13C NMR (100 MHz, CDCl3):
d 15.0, 25.8, 52.0, 70.6, 72.4, 73.1, 73.6, 75.9, 76.1, 77.5, 82.8,
117.4, 126.0, 126.0, 126.1, 126.7, 127.7, 127.8, 127.8, 127.9,
134.3, 134.7, 137.6. ½a drt
ꢁ
+91.3 (c 1.0, CHCl3). IR (neat); m 3062,
2929, 2871, 1497, 1455, 1366, 1268, 1124, 1079, 1041 cmꢃ1. MAL-
DI-HRMS: m/z calcd for C29H31NO4SNa [M+Na]+ 512.1866, obsd
512.1873.
1.2.9. Methyl (ethyl 2-O-allyl-3-O-benzyl-1-thio-b-L-idopyran-
osyl) uronate (16)
To a solution of 14b (922 mg, 1.76 mmol) in a mixture of CH2Cl2
(40 mL) and MeOH (4 mL) at room temperature was added DDQ
(1.20 g, 5.3 mmol). The reaction was stirred for 3 h and then
quenched by the addition of saturated aqueous NaHCO3 solution.
The aqueous phase was extracted twice with CH2Cl2. The combined
organic layers were washed with brine, dried over MgSO4, filtered,
and concentrated. Flash column chromatography on silica gel
(4:1?7:3, cyclohexane–EtOAc) afforded 16 (630 mg, 94%) as a pale
yellow oil. Rf = 0.39 (cyclohexane–EtOAc 3:2). 1H NMR (400 MHz,
CDCl3): d 1.31 (t, J = 7.4 Hz, 3H, SCH2CH3), 2.72–2.81 (m, 2H, SCH2),
3.51–3.53 (m, 1H, H-2), 3.63 (d, J = 11.9 Hz, 1H, OH), 3.79 (s, 3H,
OMe), 3.84 (t, J = 3.1 Hz, 1H, H-3), 4.04–4.11 (m, 3H, 2xOCHHC2H3,
H-4), 4.48 (d, J = 1.5 Hz, 1H, H-5), 4.57 (d, J = 12.0 Hz, 1H, CHHPh),
4.68 (d, J = 12.0 Hz, 1H, CHHPh), 4.94 (d, J = 1.2 Hz, 1H, H-1), 5.17–
5.29 (m, 2H, CH@CH2), 5.85 (ddt, J = 16.4, 10.3, 6.1 Hz, 1H, CH@CH2),
7.31–7.40 (m, 5H, HAr). 13C NMR (100 MHz, CDCl3): d 15.1, 25.8, 52.1,
67.6, 72.3, 72.7, 72.9, 75.9, 76.6, 82.8, 118.9, 127.8, 128.2, 128.6,
128.0, 128.4, 133.1, 133.2, 134.6, 135.3, 137.9, 170.0. ½a drt
ꢁ ꢃ80.5
(c 1.0, CHCl3). IR (neat);
m 3058, 2925, 2868, 1765, 1737, 1497,
1454, 1370, 1268, 1211, 1071, 1027 cmꢃ1. MALDI-HRMS: m/z calcd
for C30H34O6SNa [M+Na]+ 545.1968, obsd 545.1968. Analytical data
of 14b: Pale yellow oil. Rf = 0.46 (cyclohexane–EtOAc 3:2). 1H NMR
(400 MHz, CDCl3): d 1.32 (t, J = 7.4 Hz, 3H, SCH2CH3), 2.73–2.81 (m,
2H, SCH2), 3.39 (br s, 1H, H-2), 3.66 (t, J = 2.7 Hz, 1H, H-3), 3.75 (s,
3H, OMe), 3.88 (br s, 1H, H-4), 3.95 (dd, J = 12.9, 6.1 Hz, 1H,
OCHHC2H3), 4.05 (dd, J = 12.9, 5.8 Hz, 1H, OCHHC2H3), 4.29 (d,
J = 12.2 Hz, 1H, OCHH), 4.46 (d, J = 13.0 Hz, 1H, OCHH), 4.48 (d,
J = 2.3 Hz, 1H, H-5), 4.65 (d, J = 12.4 Hz, 1H, OCHH), 4.72 (d,
J = 12.4 Hz, 1H, OCHH), 4.88 (d, J = 1.8 Hz, 1H, H-1), 5.10–5.19 (m,
2H, CH@CH2), 5.82–5.92 (m, 1H, CH@CH2), 7.06–7.08 (m, 2H,
HAr), 7.23–7.29 (m, 3H, HAr), 7.43–7.53 (m, 3H, HAr), 7.74–7.87
(m, 4H, HAr). 13C NMR (100 MHz, CDCl3): d 15.2, 25.7, 52.1, 71.1,
72.1, 72.2, 72.9, 73.1, 75.0, 76.4, 83.5, 117.7, 126.0, 126.2, 126.4,
127.0, 127.7, 127.8, 127.9, 128.0, 128.1, 128.5, 133.1, 133.2,
133.5, 137.2, 169.3. ½a drt
ꢁ
+74.5 (c 1.0, CHCl3). IR (neat); m 3508,
2954, 2926, 2871, 1765, 1736, 1455, 1306, 1211, 1120, 1064,
1046 cmꢃ1. MALDI-HRMS: m/z calcd for C19H26O6SNa [M+Na]+
405.1342, obsd 405.1338.
134.8, 135.5, 137.2, 169.6. ½a drt
ꢁ
+37.6 (c 1.0, CHCl3). IR (neat); m
3058, 2925, 2867, 1767, 1732, 1496, 1454, 1315, 1208, 1140,
1074 cmꢃ1. MALDI-HRMS: m/z calcd for C30H34O6SNa [M+Na]+
545.1968, obsd 545.1972.
1.2.10. Methyl (ethyl 2-O-allyl-3-O-benzyl-4-levulinoyl-1-thio-
b-L
-idopyranosyl) uronate (17)
1.2.8. Ethyl 2-O-Allyl-3-O-benzyl-6-deoxy-4-O-(2-naphthyl)-
To a solution of alcohol 16 (0.32 g, 0.84 mmol) in CH2Cl2
methyl-1-thio-
To a solution of alcohol 12 (30.9 mg, 53
(3.5 mL) at room temperature was added NIS (14.3 mg, 63
The mixture was stirred for 20 min at room temperature and then
quenched with saturated aqueous Na2S2O3 solution. The aqueous
phase was extracted three times with CH2Cl2. The combined organ-
ic layers were washed with brine, dried over MgSO4, filtered, and
concentrated. Flash column chromatography on silica gel (9:1 ?
L
-idopyranosyl nitrile (15)
(10 mL) at 0 °C DMAP (0.98 g, 8.0 mmol), DIPC (1.18 mL, 9.0 mmol)
and levulinic acid (0.83 mL, 9.6 mmol) were added. The mixture
was stirred for 5 h at room temperature and directly applied to
flash column chromatography on silica gel (7:3?3:2, cyclohex-
ane–EtOAc) to afford 17 (0.344 g, 86%) as a pale yellow oil.
Rf = 0.36 (cyclohexane–EtOAc 1:1). 1H NMR (400 MHz, CDCl3): d
1.31 (t, J = 7.4 Hz, 3H, SCH2CH3), 2.17 (s, 3H, O@CCH3), 2.46–2.81
(m, 6H, SCH2, CH2CH2), 3.38 (br s, 1H, H-2), 3.77 (s, 3H, OMe),
3.88–3.98 (m, 3H, 2xOCHHC2H3, H-3), 4.56 (d, J = 2.0 Hz, 1H, H-
5), 4.62 (d, J = 11.8 Hz, 1H, CHHPh), 4.77 (d, J = 11.8 Hz, 1H, CHHPh),
4.91 (d, J = 1.7 Hz, 1H, H-1), 5.08–5.18 (m, 3H, CH@CH2, H-4), 5.81
l
mol) in CH2Cl2
lmol).
6:1, cyclohexane–EtOAc) afforded 15
a
(5.8 mg, 22%) and 15b
(16.1 mg, 62%). Analytical data of 15
a: Pale yellow oil. Rf = 0.46
(cyclohexane–EtOAc 4:1). 1H NMR (400 MHz, CDCl3): d 1.22 (t,
J = 7.4 Hz, 3H), 2.56–2.67 (m, 2H), 3.12 (dd, J = 9.5, 8.5 Hz, 1H),
3.58 (dd, J = 9.2, 5.9 Hz, 1H), 3.75 (t, J = 8.9 Hz, 1H), 4.15 (dd,
J = 12.1, 5.9 Hz, 1H), 4.25 (dd, J = 12.0, 5.7 Hz, 1H), 4.50 (d,
J = 5.8 Hz, 1H), 4.71 (d, J = 12.1 Hz, 1H), 4.75 (d, J = 9.5 Hz, 1H),
4.79 (d, J = 11.0 Hz, 1H), 4.82 (d, J = 10.9 Hz, 1H), 4.89 (d,
J = 12.1 Hz, 1H), 5.11 (dd, J = 10.4, 1.7 Hz, 1H), 5.21 (dd, J = 17.1,
1.8 Hz, 1H), 5.81–5.91 (m, 1H), 7.19–7.27 (m, 5H), 7.38–7.45 (m,
3H), 7.68–7.77 (m, 4H). 13C NMR (100 MHz, CDCl3): d 15.0, 25.6,
66.0, 74.2, 74.3, 76.1, 76.3, 79.6, 82.0, 83.5, 115.1, 117.5, 125.7,
126.4, 126.4, 127.2, 127.7, 127.9, 128.0, 128.0, 128.5, 128.7,
(ddt, J = 16.2, 10.3, 5.9 Hz, 1H, CH@CH2), 7.30–7.39 (m, 5H, HAr). 13
C
NMR (100 MHz, CDCl3): d 15.0, 25.7, 28.1, 29.8, 37.7, 52.3, 67.3,
71.0, 72.1, 72.5, 74.3, 75.1, 83.4, 117.7, 128.0, 128.2, 128.5, 134.4,
137.2, 168.2, 172.2, 206.2. ½a drt
ꢁ
+50.4 (c 1.0, CHCl3). IR (neat); m
2927, 2870, 1768, 1738, 1720, 1455, 1371, 1312, 1213, 1157,
1053 cmꢃ1. MALDI-HRMS: m/z calcd for C24H32O8SNa [M+Na]+
503.1710, obsd 503.1714.
1.2.11. Methyl (ethyl 2-O-allyl-3-O-benzyl-4-O-fluorenylmeth-
oxycarbonyl-1-thio-b-L-idopyranosyl) uronate (18)
A solution of alcohol 16 (251 mg, 0.656 mmol) in pyridine
(14 mL) was treated at room temperature with FmocCl (1.7 g,
6.56 mmol). The yellowsuspension was stirred at room temperature
133.2, 133.3, 134.4, 134.5, 138.1. ½a drt
ꢁ
ꢃ22.8 (c 0.41, CHCl3). IR
(neat);
m 3061, 2926, 2874, 1497, 1455, 1365, 1266, 1125, 1078,
1020 cmꢃ1. MALDI-HRMS: m/z calcd for C29H31NO4SNa [M+Na]+

P. Bindschädler et al. / Carbohydrate Research 345 (2010) 948–955
953
for 20 h, concentrated and co-evaporated twice with toluene. Flash
column chromatography on silica gel (7:1?3:2, cyclohexane–
EtOAc) afforded 18 (261 mg, 66%) as a colorless foam and unreacted
alcohol 16 (59 mg, 24%) as a pale yellow oil. Analytical data of 18:
Rf = 0.48 (cyclohexane–EtOAc 7:3). 1H NMR (400 MHz, CDCl3): d
1.33 (t, J = 7.4 Hz, 3H, SCH2CH3), 2.74–2.83 (m, 2H, SCH2), 3.42 (br
s, 1H, H-2), 3.79 (s, 3H, OMe), 3.91 (d, J = 5.9 Hz, 2H, OCH2C2H3),
4.04 (t, J = 2.7 Hz, 1H, H-3), 4.22 (t, J = 7.5 Hz, 1H, CHCH2OC@O),
4.35–4.42 (m, 2H, CH2OC@O), 4.61 (d, J = 2.0 Hz, 1H, H-5), 4.64
(d, J = 11.9 Hz, 1H, CHHPh), 4.79 (d, J = 11.9 Hz, 1H, CHHPh), 4.94
(d, J = 1.6 Hz, 1H, H-1), 5.01 (dd, J = 10.3, 1.6 Hz, 1H, CH@CHH),
5.06 (br, 1H, H-4), 5.10 (dd, J = 17.2, 1.6 Hz, 1H, CH@CHH), 5.74
(ddt, J = 16.2, 10.3, 5.9 Hz, 1H, CH@CH2), 7.27–7.42 (m, 9H, HAr),
7.61–7.64 (m, 2H, HAr), 7.74–7.76 (m, 2H, HAr). 13C NMR (100 MHz,
CDCl3): d 15.1, 25.7, 46.7, 52.4, 70.2, 70.5, 71.2, 72.1, 72.6, 74.4,
74.9, 83.5, 117.8, 120.0, 125.3, 125.4, 127.1, 127.2, 127.9, 128.0,
(m, 1H, H-2), 3.80 (s, 3H, OMe), 3.98 (t, J = 2.8 Hz, 1H, H-3), 4.25 (t,
J = 7.5 Hz, 1H, CHCH2OC@O), 4.39 (dd, J = 10.4, 7.4 Hz, 1H,
CHHOC@O), 4.44 (dd, J = 10.4, 7.8 Hz, 1H, CHHOC@O), 4.66 (s,
1H, H-5), 4.68 (d, J = 11.8 Hz, 1H, CHHPh), 4.77 (d, J = 11.7 Hz, 1H,
CHHPh), 5.07 (s, 1H, H-1), 5.18 (br s, 1H, H-4), 7.31–7.44 (m, 9H,
HAr), 7.58–7.59 (m, 2H, HAr), 7.77–7.79 (m, 2H, HAr). 13C NMR
(100 MHz, CDCl3): d 15.1, 25.4, 46.5, 52.6, 69.1, 70.5, 71.1, 72.7,
74.2, 74.6, 84.3, 120.1, 120.1, 125.2, 127.2, 127.3, 127.9, 128.0,
128.3, 128.6, 136.9, 141.3, 141.3, 143.0, 143.1, 153.9, 167.8. ½a drt
ꢁ
+35.7 (c 1.0, CHCl3). IR (neat);
m 3572, 2954, 1747, 1451, 1386,
1319, 1231, 1072, 1025 cmꢃ1
. MALDI-HRMS: m/z calcd for
C31H32O8SNa [M+Na]+ 587.1710, obsd 587.1720.
1.2.14. Methyl (ethyl 2-O-acetyl-3-O-benzyl-4-levulinoyl-1-
thio-b-
To a solution of alcohol 19 (23 mg, 52
at room temperature was added Ac2O (4 mL) and DMAP (10 mg,
82 mol). The mixture was stirred at room temperature for 3 h,
L-idopyranosyl) uronate (1)
l
mol) in pyridine (4 mL)
128.2, 128.6, 134.3, 137.1, 141.3, 143.3, 143.3, 154.7, 168.3. ½a drt
ꢁ
+41.1 (c 1.0, CHCl3). IR (neat);
m
2925, 2868, 1740, 1451, 1387,
l
1326, 1260, 1143, 1073, 1045 cmꢃ1. MALDI-HRMS: m/z calcd for
and concentrated. Flash column chromatography on silica gel
(4:1?3:2, cyclohexane–EtOAc) afforded 1 (21.4 mg, 85%) as a col-
orless oil. Rf = 0.30 (cyclohexane–EtOAc 1:1). 1H NMR (400 MHz,
CDCl3): d 1.30 (t, J = 7.4 Hz, 3H, SCH2CH3), 2.14 (s, 3H, O@CCH3),
2.17 (s, 3H, O@CCH3), 2.43–2.66 (m, 3H, CH2CHH), 2.74–2.84 (m,
3H, CH2CHH, SCH2), 3.78 (s, 3H, OMe), 3.88 (t, J = 2.6 Hz, 1H, H-
3), 4.59 (d, J = 1.9 Hz, 1H, H-5), 4.75 (s, 2H, CH2Ph), 5.00–5.02 (m,
2H, H-1, H-2), 5.18 (br, 1H, H-4), 7.30–7.39 (m, 5H, HAr). 13C
NMR (100 MHz, CDCl3): d 14.9, 20.7, 25.7, 27.8, 29.7, 37.6, 52.5,
67.1, 68.6, 72.5, 72.9, 74.3, 81.4, 127.8, 128.2, 128.5, 137.0, 167.9,
C34H36O8SNa [M+Na]+ 627.2023, obsd 627.2012.
1.2.12. Methyl (ethyl 3-O-benzyl-4-levulinoyl-1-thio-b-L-
idopyranosyl) uronate (19)
A solution of allyl ether 17 (169 mg, 0.35 mmol) in THF (12 mL)
was degassed by argon bubbling (15 min). At room temperature,
Ir[COD(PCH3Ph2)2]PF6 (25 mg, 0.03 mmol) was added and the light
pink solution again degassed by argon bubbling (10 min). After
bubbling with H2 (10 min), the reaction was stirred at room tem-
perature under H2 atmosphere for 20 min and under argon for
additional 21 h. The mixture was concentrated, taken up in MeOH
(15 mL) and treated with pTsOHꢀH2O (250 mg, 1.3 mmol). The
reaction was stirred for 20 h at room temperature, then quenched
with pyridine (1 mL), concentrated, and coevaporated twice with
toluene. Flash column chromatography on silica gel (1:0?9:1, tol-
uene–acetone) afforded 19 (96 mg, 62%) as a colorless oil and unre-
acted allyl ether 17 (51 mg, 30%) as a colorless oil. Analytical data
of 19: Rf = 0.21 (cyclohexane–EtOAc 1:1). 1H NMR (400 MHz,
CDCl3): d 1.32 (t, J = 7.4 Hz, 3H, SCH2CH3), 2.18 (s, 3H, O@CCH3),
2.47–2.79 (m, 7H, SCH2, CH2CH2, OH), 3.72–3.75 (m, 1H, H-2),
3.79 (s, 3H, OMe), 3.85 (t, J = 2.9 Hz, 1H, H-3), 4.60 (d, J = 1.8 Hz,
1H, H-5), 4.64 (d, J = 11.7 Hz, 1H, CHHPh), 4.74 (d, J = 11.7 Hz, 1H,
CHHPh), 5.01 (d, J = 1.2 Hz, 1H, H-1), 5.27 (t, J = 2.9 Hz, 1H, H-4),
7.30–7.38 (m, 5H, HAr). 13C NMR (100 MHz, CDCl3): d 15.1, 25.3,
27.9, 29.6, 37.8, 52.5, 67.8, 69.1, 72.6, 74.3, 74.6, 84.0, 127.8,
170.2, 171.8, 205.8. ½a drt
ꢁ
+36.0 (c 1.0, CHCl3). IR (neat); m 2959,
2928, 2873, 1767, 1742, 1719, 1438, 1373, 1317, 1213, 1155,
1074, 1038 cmꢃ1
. MALDI-HRMS: m/z calcd for C23H30O9SNa
[M+Na]+ 505.1503, obsd 505.1499.
1.2.15. Methyl (ethyl 2-O-benzoyl-3-O-benzyl-4-levulinoyl-1-
thio-b-
To a solution of alcohol 19 (17.2 mg, 39
at room temperature was added BzCl (45
L-idopyranosyl) uronate (2)
l
mol) in pyridine (2 mL)
lL, 0.39 mmol). The mix-
turewasstirredatroomtemperaturefor1 h, andconcentrated. Flash
column chromatography on silica gel (4:1?3:2, cyclohexane–
EtOAc) afforded 2 (19.5 mg, 92%) as a colorless oil. Rf = 0.42 (cyclo-
hexane–EtOAc 1:1). 1H NMR (400 MHz, CDCl3): d 1.32 (t, J = 7.4 Hz,
3H, SCH2CH3), 2.01 (s, 3H, O@CCH3), 2.18 (dt, J = 17.0, 6.8 Hz, 1H,
CH2CHH), 2.30–2.36 (m, 1H, CH2CHH), 2.46–2.50 (m, 2H, CH2CH2),
2.81 (qd, J = 7.4, 1.5 Hz, 2H, SCH2), 3.81 (s, 3H, OMe), 4.06 (t,
J = 2.7 Hz, 1H, H-3), 4.67 (d, J = 1.8 Hz, 1H, H-5), 4.83 (s, 2H, CH2Ph),
5.15 (d, J = 1.6 Hz, 1H, H-1), 5.21 (br, 1H, H-2), 5.25 (br, 1H, H-4),
7.33–7.51 (m, 7H, HAr), 7.56–7.64 (m, 1H, HAr) 8.12–8.17 (m, 2H,
HAr). 13C NMR (100 MHz, CDCl3): d 14.9, 25.8, 27.8, 29.5, 37.6, 52.5,
67.1, 69.4, 72.5, 73.1, 74.3, 81.6, 127.8, 128.2, 128.4, 128.5, 128.6,
129.3, 130.1, 130.2, 133.5, 133.7, 137.0, 165.5, 167.9, 171.6, 205.6.
128.2, 128.6, 137.1, 167.9, 171.3, 206.1. ½a drt
ꢁ
+29.5 (c 1.0, CHCl3).
m 3567, 3483, 2956, 2928, 2875, 1765, 1743, 1718,
IR (neat);
1455, 1375, 1315, 1211, 1153, 1075, 1029 cmꢃ1. MALDI-HRMS:
m/z calcd for C21H28O8SNa [M+Na]+ 463.1397, obsd 463.1388.
1.2.13. Methyl (ethyl 3-O-benzyl-4-O-fluorenylmethoxy-
carbonyl-1-thio-b-
L-idopyranosyl) uronate (20)
½
a rdt
+66.2 (c 1.0, CHCl3). IR (neat); m 2958, 2927, 2872, 1767, 1742,
1720, 1602, 1452, 1367, 1317, 1269, 1216, 1155, 1119, 1069,
1027 cmꢃ1. MALDI-HRMS: m/z calcd for C28H32O9SNa [M+Na]+
567.1659, obsd 567.1647.
ꢁ
A solution of allyl ether 19 (263 mg, 0.435 mmol) in THF (10 mL)
was degassed by argon bubbling (15 min). At room temperature, Ir[-
COD(PCH3Ph2)2]PF6 (40 mg, 0.047 mmol) was added and the light
pink solution again degassed by argon bubbling (10 min). After bub-
bling with H2 (10 min), the reaction was stirred at room temperature
under H2 atmosphere for 20 min and under argon for additional 2 h
at room temperature and for 21 h at 45 °C. The mixture was concen-
trated, the residue was taken up in MeOH (10 mL) and treated with
pTsOHꢀH2O (331 mg, 1.74 mmol). Thereactionwas stirred for24 h at
room temperature, then quenched with pyridine (1 mL), concen-
trated and coevaporated twice with toluene. Flash column chroma-
tography on silica gel (20:1?6:1, cyclohexane–acetone) afforded 20
(159 mg, 65%) as a colorless oil. Rf = 0.44 (cyclohexane–EtOAc 7:3).
1H NMR (400 MHz, CDCl3): d 1.37 (t, J = 7.4 Hz, 3H, SCH2CH3), 2.75
(d, J = 11.7 Hz, 1H, OH), 2.82 (q, J = 7.4 Hz, 2H, SCH2), 3.78–3.82
1.2.16. Methyl (ethyl 3-O-benzyl-4-levulinoyl-2-O-pivaloyl-1-
thio-b-
To a solution of alcohol 19 (23 mg, 52
room temperature was added DMAP (67 mg, 0.55 mmol) and PivCl
(34 L, 0.28 mmol). The mixture was stirred at room temperature
L-idopyranosyl) uronate (3)
l
mol) in CH2Cl2 (2 mL) at
l
for 1 h and then quenched with saturated aqueous NaHCO3 solu-
tion. The aqueous phase was extracted three times with CH2Cl2.
The combined organic layers were dried over MgSO4, filtered,
and concentrated. Flash column chromatography on silica gel
(4:1?3:2, cyclohexane–EtOAc) afforded 3 (23 mg, 84%) as a pale
yellow oil. Rf = 0.49 (cyclohexane–EtOAc 1:1). 1H NMR (400 MHz,

954
P. Bindschädler et al. / Carbohydrate Research 345 (2010) 948–955
CDCl3): d 1.27 (s, 9H, tBu), 1.30 (t, J = 7.4 Hz, 3H, SCH2CH3), 2.18 (s,
3H, O@CCH3), 2.50–2.54 (m, 2H, CH2CH2), 2.64–2.81 (m, 4H,
CH2CH2, SCH2), 3.79 (s, 3H, OMe), 3.81 (t, J = 2.5 Hz, 1H, H-3),
4.56 (d, J = 1.8 Hz, 1H, H-5), 4.78 (s, 2H, CH2Ph), 5.00 (br, 1H, H-
2), 5.02 (d, J = 1.9 Hz, 1H, H-1), 5.24 (br, 1H, H-4), 7.33–7.40 (m,
5H, HAr). 13C NMR (100 MHz, CDCl3): d 14.9, 25.9, 27.1, 27.8,
29.7, 37.7, 39.2, 52.4, 67.1, 68.4, 73.0, 73.7, 74.5, 82.2, 127.7,
1451, 1386, 1318, 1272, 1249, 1095, 1067, 1026 cmꢃ1. MALDI-
HRMS: m/z calcd for C38H36O9SK [M+K]+ 707.1712, obsd 707.1728.
1.2.19. Methyl (ethyl 3-O-benzyl-4-O-
fluorenylmethoxycarbonyl-2-O-pivaloyl-1-thio-b-l-
idopyranosyl) uronate (6)
To a solution of alcohol 20 (21 mg, 37
lmol) in pyridine (2 mL)
128.1, 128.5, 137.1, 167.9, 171.9, 177.7, 205.8. ½a drt
ꢁ
+21.0 (c 1.0,
2971, 2932, 2873, 1767, 1721, 1480, 1455,
at 0 °C was added PivCl (45 L, 0.36 mmol). The mixture was stir-
l
CHCl3). IR (neat);
m
red at room temperature for 4.5 h, then quenched with MeOH
(0.5 mL), and concentrated. The residue was coevaporated with
toluene and taken up in CH2Cl2. The organic phase was washed
with saturated aqueous NaHCO3 solution, and the aqueous phase
was re-extracted twice with CH2Cl2. The combined organic layers
were dried over MgSO4, filtered, and concentrated. Flash column
chromatography on silica gel (7:1?4:1 cyclohexane–EtOAc) affor-
ded 6 (24 mg, 99%) as a colorless oil. Rf = 0.52 (cyclohexane–EtOAc
7:3). 1H NMR (400 MHz, CDCl3): d 1.21 (s, 9H, tBu), 1.32 (t,
J = 7.4 Hz, 3H, SCH2CH3), 2.75–2.82 (m, 2H, SCH2), 3.77 (s, 3H,
OMe), 3.97 (t, J = 2.6 Hz, 1H, H-3), 4.17 (t, J = 7.2 Hz, 1H,
CHCH2OC@O), 4.25 (dd, J = 10.3, 7.4 Hz, 1H, CHHOC@O), 4.46 (dd,
J = 10.3, 7.4 Hz, 1H, CHHOC@O), 4.61 (d, J = 1.7 Hz, 1H, H-5), 4.77
(d, J = 11.6 Hz, 1H, CHHPh), 4.79 (d, J = 11.6 Hz, 1H, CHHPh), 4.99
(br s, 1H, H-2), 5.05 (d, J = 1.8 Hz, 1H, H-1), 5.11 (br, 1H, H-4),
7.28–7.42 (m, 9H, HAr), 7.54–7.59 (m, 2H, HAr), 7.75–7.77 (m, 2H,
HAr). 13C NMR (100 MHz, CDCl3): d 15.0, 26.0, 27.0, 39.1, 46.6,
52.5, 68.3, 70.1, 70.3, 73.1, 73.1, 74.3, 82.2, 120.0, 125.2, 125.2,
127.2, 127.2, 127.8, 127.9, 127.9, 128.2, 128.6, 137.0, 141.3,
1366, 1279, 1210, 1144, 1071, 1036 cmꢃ1. MALDI-HRMS: m/z calcd
for C26H36O9SNa [M+Na]+ 547.1972, obsd 547.1963.
1.2.17. Methyl (ethyl 2-O-acetyl-3-O-benzyl-4-O-
fluorenylmethoxycarbonyl-1-thio-b-
To a solution of alcohol 20 (33 mg, 58
(2.5 mL) at 0 °C was added AcCl (42 L, 0.60 mmol). The mixture
L
-idopyranosyl) uronate (4)
lmol) in pyridine
l
was stirred at room temperature for 1 h, then cooled to 0 °C,
quenched with MeOH (0.5 mL), and concentrated. The residue
was coevaporated with toluene and taken up in CH2Cl2. The organ-
ic phase was washed with saturated aqueous NaHCO3 solution, and
the aqueous phase was re-extracted twice with CH2Cl2. The com-
bined organic layers were dried over MgSO4, filtered, and concen-
trated. Flash column chromatography on silica gel (4:1?3:1,
cyclohexane–EtOAc) afforded 4 (30 mg, 85%) as a colorless oil.
Rf = 0.44 (cyclohexane–EtOAc 7:3). 1H NMR (400 MHz, CDCl3): d
1.32 (t, J = 7.4 Hz, 3H, SCH2CH3), 2.02 (s, 3H, CH3C@O), 2.76–2.82
(m, 2H, SCH2), 3.70 (s, 3H, OMe), 3.98 (t, J = 2.7 Hz, 1H, H-3), 4.19
(t, J = 7.2 Hz, 1H, CHCH2OC@O), 4.33 (dd, J = 10.4, 7.4 Hz, 1H,
CHHOC@O), 4.48 (dd, J = 10.4, 7.1 Hz, 1H, CHHOC@O), 4.63 (d,
J = 1.9 Hz, 1H, H-5), 4.68 (s, 2H, CH2Ph), 4.98 (br, 1H, H-2), 5.05
(d, J = 1.5 Hz, 1H, H-1), 5.10 (br, 1H, H-4), 7.28–7.42 (m, 9H, HAr),
7.56–7.59 (m, 2H, HAr), 7.75–7.77 (m, 2H, HAr). 13C NMR
(100 MHz, CDCl3): d 15.0, 20.6, 25.8, 46.7, 52.5, 68.7, 70.1, 70.2,
72.3, 73.0, 74.3, 81.4, 120.1, 125.0, 125.1, 127.1, 127.2, 127.9,
127.9, 127.9, 128.3, 128.6, 136.8, 141.3, 141.3, 143.0, 143.2,
143.1, 143.2, 154.6, 167.9, 177.9. ½a drt
ꢁ
+17.9 (c 1.0, CHCl3). IR (neat);
2958, 2930, 2873, 1744, 1732, 1479, 1451, 1386, 1260, 1145,
m
1071, 1028 cmꢃ1
. MALDI-HRMS: m/z calcd for C36H40O9SNa
[M+Na]+ 671.2285, obsd 671.2291.
Acknowledgments
We are grateful to the ETH Zürich, the Swiss National Science
Foundation (SNF), the Max-Planck Gesellschaft, Novartis (fellow-
ship to P.B.), and the Fonds der Chemischen Industrie (Kekulé fel-
lowship to A.A.) for financial support. We wish to thank Dr. W.
Bernd Schweizer for obtaining the crystallographic data.
154.4, 167.8, 170.4. ½a drt
ꢁ
+23.9 (c 1.0, CHCl3). IR (neat); m 3065,
3034, 2956, 2928, 2873, 1743, 1451, 1374, 1318, 1264, 1230,
1211, 1072, 1028 cmꢃ1. MALDI-HRMS: m/z calcd for C33H34O9SNa
[M+Na]+ 629.1816, obsd 629.1815.
1.2.18. Methyl (ethyl 2-O-benzoyl-3-O-benzyl-4-O-
Supplementary data
fluorenylmethoxycarbonyl-1-thio-b-
To a solution of alcohol 20 (30 mg, 53
(2.5 mL) at 0 °C was added BzCl (62 L, 0.54 mmol). The mixture
L
-idopyranosyl) uronate (5)
l
mol) in pyridine
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2010.02.004.
l
was stirred at room temperature for 1 h, then cooled to 0 °C,
quenched with MeOH (0.5 mL), and concentrated. The residue
was coevaporated with toluene and taken up in CH2Cl2. The organ-
ic phase was washed with saturated aqueous NaHCO3 solution, and
the aqueous phase was re-extracted twice with CH2Cl2. The com-
bined organic layers were dried over MgSO4, filtered, and concen-
trated. Flash column chromatography on silica gel (6:1?4:1
cyclohexane–EtOAc) afforded 5 (30 mg, 86%) as a colorless oil.
Rf = 0.49 (cyclohexane–EtOAc 7:3). 1H NMR (400 MHz, CDCl3): d
1.31 (t, J = 7.4 Hz, 3H, SCH2CH3), 2.80 (q, J = 7.4 Hz, 2H, SCH2),
3.79 (s, 3H, OMe), 3.92 (t, J = 7.6 Hz, 1H, CHCH2OC@O), 4.09 (dd,
J = 10.4, 7.1 Hz, 1H, CHHOC@O), 4.13 (t, J = 2.7 Hz, 1H, H-3), 4.18
(dd, J = 10.4, 8.2 Hz, 1H, CHHOC@O), 4.69 (d, J = 1.7 Hz, 1H, H-5),
4.80 (d, J = 11.7 Hz, 1H, CHHPh), 4.83 (d, J = 11.8 Hz, 1H, CHHPh),
5.14 (br, 1H, H-4), 5.15 (d, J = 1.7 Hz, 1H, H-1), 5.30 (br, 1H, H-2),
7.13–7.51 (m, 14H, HAr), 7.70–7.71 (m, 2H, HAr), 8.18–8.20 (m,
2H, HAr). 13C NMR (100 MHz, CDCl3): d 14.9, 25.8, 46.5, 52.6,
68.9, 70.2, 70.2, 72.7, 73.1, 74.3, 81.7, 120.0, 125.0, 125.3, 127.1,
127.2, 127.9, 128.3, 128.3, 128.6, 129.2, 130.3, 133.4, 136.9,
References
1. (a) Yeung, B. K. S.; Chong, P. Y. C.; Petillo, P. A. J. Carbohydr. Chem. 2002, 21, 799–
865; (b) Poletti, L.; Lay, L. Eur. J. Org. Chem. 2003, 2999–3024; (c) Petitou, M.;
van Boeckel, C. A. A. Angew. Chem., Int. Ed. 2004, 43, 3118–3133; (d) Codée, J. D.
C.; Overkleeft, H. S.; van der Marel, G. A.; van Boeckel, C. A. A. Drug Discovery
Today Technol. 2004, 1, 317–326; (e) Noti, C.; Seeberger, P. H. Chem. Biol. 2005,
12, 731–756; (f) van den Bos, L. J.; Codée, J. D. C.; Litjens, R. E. J. N.; Dinkelaar, J.;
Overkleeft, H. S.; van der Marel, G. A. Eur. J. Org. Chem. 2007, 3963–3976; (g)
Werz, D. B.; Ranzinger, R.; Herget, S.; Adibekian, A.; von der Lieth, C.-W.;
Seeberger, P. H. ACS Chem. Biol. 2007, 2, 685–691.
2. (a) Hanessian, S. Acc. Chem. Res. 1979, 12, 159–165; (b) Schmidt, R. R.; Maier, M.
Synthesis 1982, 747–748.
3. (a) Ogawa, T. Chem. Soc. Rev. 1994, 23, 397–407; (b) Danishefsky, S. J.; Bilodeau,
M. T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380–1419.
4. (a) de Paz, J. L.; Noti, C.; Seeberger, P. H. J. Am. Chem. Soc. 2006, 128, 2766–2767;
(b) Noti, C.; de Paz, J. L.; Polito, L.; Seeberger, P. H. Chem. Eur. J. 2006, 12, 8664–
8686; (c) Bindschädler, P.; Castagnetti, E.; Seeberger, P. H. Helv. Chim. Acta
2006, 89, 2591–2610; (d) Bindschädler, P.; Dialer, L. O.; Seeberger, P. H. J.
Carbohydr. Chem. 2009, 28, 395–420.
5. For reviews on de novo synthesis of carbohydrates, see: (a) Schmidt, R. R. Pure
Appl. Chem. 1987, 59, 415–424; (b) Kirschning, A.; Jesberger, M.; Schöning, K.-U.
Synthesis 2001, 507–540.
141.1, 141.2, 142.9, 143.4, 154.4, 165.7, 167.9. ½a drt
ꢁ
+51.5 (c 1.0,
6. (a) Lubineau, A.; Gavard, O.; Alais, J.; Bonnaffé, D. Tetrahedron Lett. 2000, 41,
307–311; (b) Timmer, M. S. M.; Adibekian, A.; Seeberger, P. H. Angew. Chem.,
Int. Ed. 2005, 44, 7605–7607; (c) Timmer, M. S. M.; Stocker, B. L.; Seeberger, P.
CHCl3). IR (neat);
m 3065, 3033, 2954, 2928, 2872, 1746, 1720,

P. Bindschädler et al. / Carbohydrate Research 345 (2010) 948–955
955
H. J. Org. Chem. 2006, 71, 8294–8297; (d) Adibekian, A.; Bindschädler, P.;
Timmer, M. S. M.; Noti, C.; Schützenmeister, N.; Seeberger, P. H. Chem. Eur. J.
2007, 13, 4510–4522; (e) Stallforth, P.; Adibekian, A.; Seeberger, P. H. Org. Lett.
2008, 10, 1573–1576; (f) Adibekian, A.; Timmer, M. S. M.; Stallforth, P.; van
Rijn, J.; Werz, D. B.; Seeberger, P. H. Chem. Commun. 2008, 3549–3551.
13. For examples, see: (a) Ojeda, R.; Angulo, J.; Nieto, P. M.; Martín-Lomas, M. Can.
J. Chem. 2002, 80, 917–936; (b) Ref. 11.; (c) Ref. 12.
14. Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 4th
ed.; John Wiley & Sons, Inc.: Hoboken, New Jersey, 2007.
15. (a) Kovensky, J.; Duchaussoy, P.; Petitou, M.; Sinaÿ, P. Tetrahedron: Asymmetry
1996, 7, 3119–3128; (b) Kovensky, J.; Duchaussoy, P.; Bono, F.; Salmivirta, M.;
Sizun, P.; Herbert, J.-M.; Petitou, M.; Sinaÿ, P. Bioorg. Med. Chem. 1999, 7, 1567–
1580; (c) Ke, W.; Whitfield, D. M.; Gill, M.; Larocque, S.; Yu, S.-H. Tetrahedron
Lett. 2003, 44, 7767–7770; (d) Ke, W.; Whitfield, D. M.; Brisson, J.-R.; Enright,
G.; Jarrell, H. C.; Wu, W.-g. Carbohydr. Res. 2005, 340, 355–372.
16. (a) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505–5507; (b)
Evans, D. A.; Ripin, D. H. B.; Halstead, D. P.; Campos, K. R. J. Am. Chem. Soc. 1999,
121, 6816–6826.
7. For the use of L-iduronic acid thioglycosides as glycosylating agents, see: (a)
Tabeur, C.; Machetto, F.; Mallet, J.-M.; Duchaussoy, P.; Petitou, M.; Sinaÿ, P.
Carbohydr. Res. 1996, 281, 253–276; (b) Kuszmann, J.; Medgyes, G.; Boros, S.
Carbohydr. Res. 2004, 339, 1569–1579; (c) Codée, J. D. C.; Stubba, B.;
Schiattarella, M.; Overkleeft, H. S.; van Boeckel, C. A. A.; van Boom, J. H.; van
der Marel, G. A. J. Am. Chem. Soc. 2005, 127, 3767–3773; (d) Zhou, Y.; Lin, F.;
Chen, J.; Yu, B. Carbohydr. Res. 2006, 341, 1619–1629; (e) Tatai, J.; Osztrovszky,
G.; Kajtár-Peredy, M.; Fügedi, P. Carbohydr. Res. 2008, 343, 596–606; (f) Tatai, J.;
Fügedi, P. Tetrahedron 2008, 64, 9865–9873.
17. (a) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556–569; (b) Reetz, M. T.;
Kesseler, K.; Jung, A. Angew. Chem., Int. Ed. Engl. 1985, 24, 989–991.
18. Ward, D. E.; Hrapchak, M. J.; Sales, M. Org. Lett. 2000, 2, 57–60.
19. (a) Pinner, A.; Klein, F. Ber. Dtsch. Chem. Ges. 1877, 10, 1889–1897; (b) Berrien,
J.-F.; Royer, J.; Husson, H.-P. J. Org. Chem. 1994, 59, 3769–3774.
8. For automated synthesis of oligosaccharides, see: (a) Plante, O. J.; Palmacci, E.
R.; Seeberger, P. H. Science 2001, 291, 1523–1527; (b) Seeberger, P. H.; Werz, D.
B. Nature 2007, 446, 1046–1051.
9. Beetz, T.; van Boeckel, C. A. A. Tetrahedron Lett. 1986, 27, 5889–5892.
10. Arungundram, S.; Al-Mafraji, K.; Asong, J.; Leach, F. E., III; Amster, I. J.; Venot,
A.; Turnbull, J. E.; Boons, G.-J. J. Am. Chem. Soc. 2009, 131, 17394–17405.
11. For a detailed evaluation and comparison of acetates, benzoates and pivaloates
at the C2 hydroxyl group of IdoA, see: de Paz, J.-L.; Ojeda, R.; Reichardt, N.;
Martín-Lomas, M. Eur. J. Org. Chem. 2003, 3308–3324.
20. Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
21. (a) Xia, J.; Abbas, S. A.; Locke, R. D.; Piskorz, C. F.; Alderfer, J. L.; Matta, K. L.
Tetrahedron Lett. 2000, 41, 169–173; (b) Borbás, A.; Szabó, Z. B.; Szilágyi, L.;
Bényei, A.; Lipták, A. Tetrahedron 2002, 58, 5723–5732.
22. (a) Baudry, D.; Ephritikhine, M.; Felkin, H. J. Chem. Soc., Chem. Commun. 1978,
694–695; (b) Oltvoort, J. J.; van Boeckel, C. A. A.; de Koning, J. H.; van Boom, J. H.
Synthesis 1981, 305–308; (c) Peri, F.; Nicotra, F.; Leslie, C. P.; Micheli, F.; Seneci,
P.; Marchioro, C. J. Carbohydr. Chem. 2003, 22, 57–71.
12. For a remote effect of the C2 ester group on the coupling selectivity of an IdoA
acceptor, see: Lohman, G. J. S.; Seeberger, P. H. J. Org. Chem. 2004, 69, 4081–
4093.