Synthesis of a C-linked hyaluronic acid disaccharide mimetic

Article abstract of DOI:10.1016/j.carres.2007.05.031

The synthesis of a C-disaccharide that is designed as a mimetic for the repeating unit disaccharide of hyaluronic acid is described. The target compound was obtained via the SmI₂-promoted coupling reaction of the sulfone, 2-acetamido-4,6-O-benz

Full text of DOI:10.1016/j.carres.2007.05.031

Carbohydrate Research 342 (2007) 1668–1679
Synthesis of a C-linked hyaluronic acid disaccharide mimetic
Zhong-Xu Ren, Qiang Yang, Kenneth N. Price, Tianniu Chen, Cara Nygren,
John F. C. Turner and David C. Baker*
Department of Chemistry, The University of Tennessee, Knoxville, TN 37996-1600, USA
Received 11 May 2007; received in revised form 26 May 2007; accepted 29 May 2007
Available online 2 June 2007
Abstract—The synthesis of a C-disaccharide that is designed as a mimetic for the repeating unit disaccharide of hyaluronic acid is
described. The target compound was obtained via the SmI2-promoted coupling reaction of the sulfone, 2-acetamido-4,6-O-benzyl-
idene-3-O-tert-butyldimethylsilyl-1,2-dideoxy-1-pyridinylsulfonyl-b-D-glucopyranose (6), and the aldehyde, p-methoxyphenyl 2,3-
di-O-benzyl-4-deoxy-4-C-formyl-6-O-p-methoxybenzyl-b-D-glucopyranoside (14).
ꢀ 2007 Elsevier Ltd. All rights reserved.
Keywords: C-Glycosyl compounds; C-Glycosides; C-Disaccharide; Hyaluronic acid mimetic; Samarium diiodide
1. Introduction
cancer cell’s CD44 receptor to HA performs a critical
role in the metastasis of certain cancers, especially the
migration of melanoma cells to the lung.3 Several lines
of evidence further implicate that this CD44–HA inter-
action facilitates cell movement in cancer cells during
metastasis.4–6
As a part of an ongoing project, the goal was to syn-
thesize a ‘C-disaccharide’ that would be a mimetic for
the repeating unit of HA and would be totally resistant,
due to the interresidue C–C–C linkages, to enzymes that
degrade the natural polymer. Further objectives are to
study its conformation and incorporate it into a syn-
thetic oligosaccharide in such a way that the oligomer
would be resistant to enzymes that degrade HA. Herein
is presented a total synthesis of the target C-disaccharide
as its p-methoxyphenyl glycoside.
Hyaluronic acid (hyaluronan, HA, Fig. 1) is a poly-
saccharide of high molecular weight (Mr >106) that is
composed of a repeating disaccharide unit in which D-
glucuronic acid is linked to the 3-position of 2-acet-
amido-2-deoxy-D-glucose (N-acetyl-D-glucosamine), that
is, [!3)-b-D-GlcNAc-(1!4)-b-D-GlcA-(1!)]n. HA,
which is synthesized in the plasma membrane and is
associated with the complement of glycosaminoglycans
(GAGs) located in the extracellular matrix, has a variety
of functions in the human body. For example, it serves
as the gelling agent of the vitreous body of the eye, is
a component in the lubricants associated with the syno-
vial fluid in joints, and is found in significant quantities
in the placenta.1,2 A process that has come to the fore-
front in recent years concerns the role that HA plays
in the metastasis of cancer: the binding of a migrating
2. Results and discussion
2.1. Synthetic approaches
O
OH
OH
OH
O
OH
O
O
O
O
HO
O
HO
O
O
O
HO
HO
NHAc
OH
NHAc
OH
n
Approaches to C-linked disaccharides (C-glycosylic
compounds, often referred to as ‘C-glycosides’) are var-
ied;7,8 however, the success in any C-glycosylic coupling
depends on the peculiar reactivities of the sugar units
(i.e., whether primary or secondary carbon atoms are
Figure 1. Hyaluronic acid (hyaluronan, HA).
*
Corresponding author. Tel.: +1 865 974 1066; fax: +1 865 974
1536; e-mail: dcbaker@utk.edu
0008-6215/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2007.05.031

Z.-X. Ren et al. / Carbohydrate Research 342 (2007) 1668–1679
1669
targeted in the glycosyl acceptor), as well as the stabili-
ties of the protecting groups involved and their influence
on the reactivity of both the glycosyl donor and accep-
tor. For our purposes, several processes were attempted
in this laboratory,9–11 among them the Henry coupling
advocated by Martin and Lei,12,13 the olefin metathesis
method of Postema and co-workers,14,15 as well as the
dianion approach advocated by Kessler and co-work-
ers.16,17 Of these, only the latter method, which had been
developed for simple C-glycosyl–alkyl conjugates, gave
good results with our specific compounds that have mul-
tiple functionalities present; however, this rather harsh
organometallic reaction limited the type of OH protec-
tion that could be employed, which limited future possi-
bilities in construction of more complex C-glycosylic
compounds. Another approach that involves the use of
samarium diiodide-mediated coupling of a glycosyl sul-
fone (donor) with a C-formyl sugar (an aldehyde, the
acceptor), as developed by Beau and co-workers for glu-
cosamine derivatives18–22 and by Linhardt and co-work-
ers23,24 for the synthesis of sialic acid mimetics, was
carried out and gave the most promising results. Using
this SmI2 strategy, the synthesis, which makes use of
the glycosyl donor 6 and the acceptor 14, was carried
out as described in the following sections.
compound 3 that was directly reacted with benzaldehyde
and ZnCl2 at room temperature for 16 h to give the 4,6-
O-benzylidenated 4.26,27 Treatment of 4 with tert-butyl-
chlorodimethylsilane (TBDMSCl) in the presence of
imidazole in DMF at room temperature overnight28 gave
compound 5, which was readily converted to the corre-
sponding protected sulfone 6 in 79% yield via treatment
with m-chloroperoxybenzoic acid (m-CPBA) in CH2Cl2
at 0 ꢁC.19 The b configuration for 6 was clearly indicated
by the doublet for H-1 at d 5.81 (J1,2 = 10.3 Hz); further-
more, there was no resonance indicative of any a anomer.
2.3. Synthesis of protected aldehyde 14
The synthesis of aldehyde 14 proceeded from known
compound 729 as shown in Scheme 2. Deacetylation of
7 with NaOMe in 1:5 CH2Cl2 and MeOH gave the cor-
responding tetraol 8 in nearly quantitative yield. Regio-
selective bis-protection of the 4-OH and 6-OH positions
with a p-methoxybenzylidene group was accomplished
via treatment of 8 with anisaldehyde dimethyl acetal
(ADMA) in the presence of a catalytic amount of p-
TsOH in dry CH3CN to afford diol 9 as a precipitate
in 84% yield.30 The resulting diol 9 was then treated with
NaH at 0 ꢁC for 10 min, followed by addition of benzyl
bromide in DMF, to give O-dibenzylated 10 in 95%
yield. Regioselective reductive cleavage of the benzyl-
idene ring of compound 10 was achieved via treatment
2.2. Synthesis of protected sulfone 6
˚
with NaBH3CN and CF3CO2H in the presence of 4 A
The synthesis of sulfone 6 was carried out as shown in
Scheme 1. Thus, the reaction of glycosyl chloride 1 with
K2CO3 and 2-mercaptopyridine in dry acetone at 50 ꢁC
gave the desired pyridinyl thioglycoside 2.25 In order to
manipulate the protective groups, 2 was treated with
NaOMe in 1:5 CH2Cl2–MeOH to afford the free-hydroxy
MS in DMF at room temperature for 10 h to render
4-OH isomer 11 in 74% yield as the major product,
along with the 6-OH isomer as a byproduct (21%, data
not provided).31 Treatment of compound 11 with
AcO
AcO
HO
HO
OAc
O
OH
O
ADMA
TsOH
CH3CN
NaOMe
OMP
OMP
MeOH
97%
OAc
O
OAc
O
OH
OAc
NaOMe
HS
N
AcO
AcO
AcO
AcO
84%
8
S
7
N
MeOH
95%
K2CO3
Cl Toluene acetone
86%
NHAc
AcHN
MP
−
MP
1
2
O
O
O
O
OH
O
O
NaBH3CN
O
NaH
O
Ph
PhCHO
S
O
O
BnO
OMP
OMP
HO
OMP
OMP
HO
HO
BnBr
DMF
95%
TFA, DMF
74%
S
HO
OBn
ZnCl2
80%
N
N
OH
NHAc
NHAc
10
9
4
3
TfO
BnO
HO
BnO
OPMB
O
OPMB
O
O
Bu4NCN,
TBDMSCl
Ph
Tf2O
m
-CPBA
O
O
Imidazole
DMF
78%
CH2Cl2
79%
S
THF
63%
−
TBDMSO
CH2Cl2
Pyridine
N
OBn
OBn
NHAc
11
12
5
OPMB
O
OPMB
O
O
Ph
O
O
DIBALH
OHC
BnO
O
NC
BnO
OMP
S
TBDMSO
OMP
N
−
THF, 78 ˚C
71%
OBn
NHAc
O
OBn
6
13
14
Scheme 1. Synthesis of the C-glycosyl donor, protected sulfone 6.
Scheme 2. Synthesis of C-glycosyl acceptor, aldehyde 14.

1670
Z.-X. Ren et al. / Carbohydrate Research 342 (2007) 1668–1679
(CF3SO)2O in pyridine at 0 ꢁC overnight gave the corre-
sponding triflate 12 in nearly quantitative yield. Reac-
tion of triflate 12 with Bu4NCN in THF afforded the
SN2 product 13 in 63% yield. The major byproduct
was the E2 elimination product, which is slightly less
polar than the substitution product on TLC (data not
provided). Reduction of compound 13 with DIBALH
in THF at ꢀ78 ꢁC, followed by treatment with 1.0 N
H3PO4 at 0 ꢁC, afforded aldehyde 14 in 71% yield.32,33
Aldehyde 14 was definitively shown to be the equatorial
isomer (D-gluco configuration) by the appearance of H-4
at d 3.01 as a broad doublet of doublets (pseudo-triplet)
with J3,4 ꢁ J4,5 = 10.2 Hz.
15b, after deoxygenation at the 4a-position, gave the
same disaccharide as that derived from 15a (as described
in the section which follows). Both 15a and 15b gave
large, negative optical rotations (ꢀ41.2 and ꢀ97.1,
respectively). Disaccharide 15c was assigned as the a
anomer, as the deoxygenated derivative of 15c is differ-
ent from that derived from either 15a or 15b. From
the appearance of the H-1I and H-1II signals and other
resonances in the 1H NMR spectrum of 15c, a single epi-
mer at H-4a was indicated; however, little support for
firm epimeric and anomeric assignments was otherwise
afforded by either the NMR spectra or optical rotations
(see data in Section 3). The structural relationship of 15c
to the b anomers 15a and 15b was established chemically
as described in the following section.
2.4. Synthesis of the C-disaccharides
Conversion of the presumed a isomer 15c to the b iso-
mers (15a and 15b) was achieved via a series of reactions
as shown in Scheme 4. Compound 15c was oxidized to
the corresponding a ketone 16 (H-1II, J1,2 6.0 Hz) with
pyridinium chlorochromate (PCC) in CH2Cl2, and sub-
sequent isomerization of the resulting a ketone to the b
ketone 17 (H-1II, J1,2 10.8 Hz) was cleanly effected with
NaOMe in MeOH. The yield of the b anomer was 36%,
with 50% recovery of starting material 16. No side prod-
ucts from elimination reactions or epimerization at the
C-4 carbon were observed. Reduction of b ketone 17
to a ꢂ1:3 mixture of 15a and 15b was carried out with
NaBH4 in EtOH, which served to increase the amounts
of these compounds that were required for synthesis of
the targeted disaccharide.
Deoxygenation at the 4a-position was achieved
according to the procedure of Barton and McCombie,34
as modified by Dietrich and Schmidt (Scheme 5).35 Thus
treatment of 15a or 15b with NaH in the presence of
imidazole in THF at room temperature, followed by
addition of CS2 and then MeI after 40 min, afforded thi-
onocarbonate 18a or 18b in 54% or 50% yield, respec-
tively. The modest yields of these compounds are most
likely due to their limited stability to column chroma-
tography. Treatment of 18a or 18b with Bu3SnH and
azoisobutyronitrile (AIBN) in refluxing toluene afforded
the desired C-linked disaccharide 19 in 91% yield, which
after removal of the tert-butyldimethylsilyl (TBDMS)
group with Bu4NF (TBAF) in THF28 gave disaccharide
20 in 93% yield. The disaccharide showed the expected
[M+H], [M+NH4], [M+Na], and [M+K] peaks in the
positive-ion ESIMS. The NMR spectra, in general, sup-
ported the assigned structure; however, while the 1H
NMR spectrum showed a distinct signal for H-1I, H-
1II was hopelessly buried in an envelope of signals at d
3.47–3.34, which prevented firm confirmation of the b-
linkage, although the b assignment is not in doubt,
beginning with the series of reactions from 15a. Disac-
charide 20 will also serve as an acceptor in the synthesis
of C-/O-linked HA tetrasaccharide mimetics (details to
be published).
With sulfone 6 and aldehyde 14 in hand, the stage was
set for the synthesis of C-disaccharides as shown in
Scheme 3. Thus, treatment of sulfone 6 and aldehyde
14 with samarium diiodide (SmI2) in THF at room tem-
perature, following the general protocols of Beau and
co-workers,20,21 gave three disaccharides, 15a, 15b, and
15c, as shown in Scheme 3. The b anomers 15a
and 15b appeared as the high- and low-running zones
on TLC, with a anomer 15c situated between them.
All three of the disaccharides were easily identified by
positive-ion ESI mass spectroscopy, which gave inter
alia [M+H], [M+Na], and [M+K] ions as expected
(see Section 3). The NMR spectra of the pure anomeric
compounds were complex, even at 600 MHz, and did
not lend themselves to complete assignments of all reso-
nances. However, H-1II for 15a showed J1,2 8.4 Hz,
which is indicative of the b anomer. Further corrobora-
tion of the b-linkage for 15a was provided by single-
crystal X-ray diffraction analysis that showed the
b-(1!4)-C-linkage and the configuration of the linking
CHOH group, as shown in Figure 2. Thus 15a is the
b-(4aR)-isomer. Disaccharide 15b, which showed J1,2
9.6 Hz, was also assigned the b-linkage. Furthermore
Ph
O
OPMB
O
H
SmI2
THF
OH
O
O
6
+ 14
C
TBDMSO
+
+
OMP
BnO
NHAc
OBn
15a
(20%)
O
H
OPMB
O
Ph
HO
O
O
C
TBDMSO
OMP
BnO
NHAc
OBn
15b
(15%)
Ph
O
O
O
TBDMSO
OPMB
O
AcHN
HO
OMP
BnO
OBn
15c (30%)
Scheme 3. SmI2-promoted coupling reaction.

Z.-X. Ren et al. / Carbohydrate Research 342 (2007) 1668–1679
1671
Figure 2. ORTEP depiction of compound 15a.
Ph
O
plet at d 3.26–3.21, and resonances for H-6, 6aI of 20 dis-
appeared and were replaced by a 13C resonance at d
174.3, which is indicative of a carboxylic acid.37 The
other resonances were supportive of the structure.
O
O
NaOMe
TBDMSO
OPMB
O
PCC
15c
AcHN
MeOH
36% with 50%
recovery of 16
CH2Cl2
66%
OMP
BnO
O
OBn
16
2.5. Conclusions
Ph
O
O
O
O
OPMB
O
NaBH4
EtOH
C
TBDMSO
15a
+
15b
(21%) (62%)
The target C-linked disaccharide that constitutes the
repeat unit of HA was synthesized as its p-methoxyphenyl
glycoside using SmI2-mediated coupling of the sugar
units. Extension of this methodology to higher oligosac-
charides that incorporate the C/O linked sugars, as well
as extensive biological studies of these synthetic HA
mimetics, is underway.
OMP
BnO
NHAc
OBn
17
Scheme 4. Conversion of 15c to 15a and 15b.
Following removal of the p-methoxybenzyl (PMB)
group on 20 with DDQ,36 the resulting primary hydro-
xyl group was selectively oxidized to the corresponding
carboxylic (uronic) acid with 5% aq NaClO in the pres-
ence of a catalytic amount of 2,2,6,6-tetramethyl-1-pipe-
ridinyloxy (TEMPO).37 Debenzylation with Pearlman’s
catalyst (1 atm) afforded target C-disaccharide 21. The
structure of 21 was supported by the negative-ion HRE-
SIMS that showed the expected ion for [MꢀH]. In the
1H NMR spectrum H-1II appeared as a complex multi-
3. Experimental
3.1. General methods
1H (250 MHz, 300 MHz, and 600 MHz) and 13C
(62.5 MHz, 75 MHz, and 150 MHz) NMR spectra were

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Z.-X. Ren et al. / Carbohydrate Research 342 (2007) 1668–1679
S
OCSCH3
C
OPMB
O
O
Ph
1. NaH, Imidazole
THF
O
O
15a or 15b
OMP
BnO
H
TBDMSO
2. CS2
3. CH3I
NHAc
OBn
18a 18b
or
(54%) (50%)
OPMB
O
O
Ph
O
O
Bu4NF
Bu3SnH
CH
TBDMSO
2 BnO
OMP
THF
93%
AIBN
Toluene
91%
NHAc
OBn
19
−
1. DDQ, 20:1 CH2Cl2 H2O
2. TEMPO, NaOCl, 6:1 CH2Cl2 H2O
OPMB
O
O
Ph
O
−
O
CH
HO
2 BnO
3. Pd(OH)2/C, H2, 20:1 EtOAc MeOH
OMP
−
NHAc
OBn
21% (over 3 steps)
20
OH
OH
O
O
HO
HO
O
CH2
OMP
HO
NHAc
OH
21
Scheme 5. Synthesis of the C-disaccharide.
recorded at 25 ꢁC as designated. Chemical shifts are
expressed in d units (parts per million) and were mea-
sured relative to an internal standard of TMS for H,
rotations were carried out at the sodium D line in a
1-dm cell at 20 ꢁC; units are (degrees mL)/(g dm).
Microanalyses were carried out by Atlantic Microlabs,
Inc., Atlanta, GA.
1
and relative to the signal for CDCl3 (d 77.0) or
DMSO-d6 (d 39.5) for 13C, unless otherwise stated.
Apparent, first-order multiplicities are indicated by s,
singlet; d, doublet; dd, doublet of doublets; t, triplet;
dt, doublet of triplets; q, quartet, and m, multiplet. All
assignments were confirmed with the aid of two-dimen-
sional experiments (gCOSY, HSQC, HMBC, and
TOCSY as needed) at 600 MHz. Sugar units are num-
bered analogously to O-glycosides using the Whelan sys-
tem (Rule 2-Carb-37.2)38 where ‘I’ designates the
reducing end unit, ‘II’ the next unit, etc.; NMR reso-
nances are indicated by the appropriate superscript.
Nomenclature follows the use of the ‘carba’ designation
for C replacement of O in sugar units (Rule 2-Carb-
37.5).38 Electrospray-ionization mass spectrometry
(ESIMS) was carried out at low resolution using a
Micromass Quattro-II triple quadrupole instrument
operating in the positive-ion mode; the HRESIMS mea-
surement (negative-ion) was made on an Applied Bio-
systems QSTAR XL quadrupole instrument. Column
3.2. 2-Pyridinyl 2-acetamido-4,6-O-benzylidene-2-deoxy-
1-thio-b-D-glucopyranoside (4)
To a solution of compound 225 (20.0 g, 45.5 mmol) in
MeOH (150 mL) and CH2Cl2 (30 mL) was added
NaOMe (25% in MeOH, 1.0 mL). The reaction was stir-
red at room temperature for 1 h, after which time 1 mL
of satd NH4Cl solution was added, and the solvent was
evaporated to afford compound 3 (13.6 g, 43.2 mmol,
95%) as a white amorphous solid that was used directly
in the next step; mp 154–156 ꢁC; [a]D +9.5 (c 1.0,
DMSO). Compound 3 (16.0 g, 51.0 mmol) was stirred
with dry ZnCl2 (14 g, 0.10 mol) in benzaldehyde
(100 mL) at room temperature for 16 h, after which time
the reaction was quenched with water (250 mL). The
suspension was filtered, and the solid was sequentially
washed with EtOAc and MeOH to afford compound 4
as a white amorphous solid (16.3 g, 40.5 mmol, 80%).
TLC (10:1 CHCl3–MeOH): Rf 0.4; mp 164–166 ꢁC;
[a]D +4.6 (c 0.5, DMSO); 1H NMR (250 MHz,
DMSO-d6): d 8.43–7.12 (m, 4H, ArH), 7.47–7.32 (m,
5H, ArH), 5.62 (s, 1H, PhCH), 5.54 (d, 1H, H-1,
J1,2 = 10.5 Hz), 5.46 (d, 1H, NH), 4.19–4.17 (m, 1H,
H-6), 3.85 (dd, 1H, H-2), 3.74–3.63 (m, 2H, H-3, H-4),
3.59–3.48 (m, 2H, H-6, H-5), 3.16 (d, 1H, OH), 1.80
(s, 3H, CH3CO); 13C NMR (62.5 MHz, DMSO-d6): d
˚
chromatography was performed on 60 A (63–200 mm,
termed ‘coarse’) silica gel (Sorbent Technologies, Atlan-
ta, GA), and fractions were monitored by TLC on Silica
Gel UV254 [0.2-mm aluminum-backed plates (Sorbent
Technologies)] by detection with 254-nm UV light and
then spray–heat development using a p-anisaldehyde–
sulfuric acid reagent.39 Melting points were measured
with a capillary melting point apparatus, and optical

Z.-X. Ren et al. / Carbohydrate Research 342 (2007) 1668–1679
1673
169.2, 157.2, 149.4, 137.7, 137.2, 128.9, 128.0, 126.4,
122.0, 120.5, 100.7, 83.3, 81.0, 71.7, 70.2, 67.6, 54.0,
23.0; ESIMS (positive-ion): m/z 403.1 [M+H], 425.1
[M+Na], 441.1 [M+K]. Anal. Calcd for C20H22N2O5SÆ
0.16CH2Cl2 (416.06): C, 58.20; H, 5.41; N, 6.73. Found:
C, 58.19; H, 5.56; N, 6.50. CH2Cl2 complexed with 4 was
confirmed by NMR spectroscopy.
(250 MHz, CDCl3): d 8.85 (d, 1H, ArH), 8.16 (d, 1H,
ArH), 8.02 (t, 1H, ArH), 7.62 (t, 1H, ArH), 7.50–7.39
(m, 5H, ArH), 6.84 (d, 1H, NH), 5.81 (d, 1H, H-1,
J1,2 = 10.3 Hz), 4.72–4.61 (m, 1H, H-6), 4.12–4.02 (m,
2H, H-2, H-3), 3.69–3.48 (m, 3H, H-6, H-5, H-4), 2.06
(s, 3H, CH3CO), 0.09 (s, 9H, C(CH3)3), 0.06 (s, 3H,
SiCH3), ꢀ0.01 (s, 3H, SiCH3); 13C NMR (62.5 MHz,
CDCl3): d 171.0, 155.1, 150.2, 137.8, 136.8, 128.9,
127.9, 127.6, 126.1, 124.2, 101.7, 86.1, 81.6, 71.0, 70.1,
67.9, 53.5, 25.6, 23.5, 17.9, ꢀ4.4, ꢀ5.1; ESIMS (posi-
tive-ion): m/z 549.0 [M+H], 571.0 [M+Na], 587.0
[M+K]. Anal. Calcd for C26H36N2O7SSi (548.74): C,
56.91; H, 6.61; N, 5.11. Found: C, 56.72; H, 6.60; N,
4.96.
3.3. 2-Pyridinyl 2-acetamido-4,6-O-benzylidene-3-O-tert-
butyldimethylsilyl-2-deoxy-1-thio-b-D-glucopyranoside
(5)
To a solution of compound 4 (16.30 g, 40.54 mmol) and
imidazole (6.25 g, 96.0 mmol) in dry DMF was added
tert-butylchlorodimethylsilane (10.4 g, 69.0 mmol) at
0 ꢁC. The reaction was allowed to stir and warm to
room temperature over 15 h, after which time it was
quenched with water, washed with satd aq NaHCO3,
and extracted with CH2Cl2. The organic phase was dried
with anhyd Na2SO4 and then evaporated to dryness.
The residue was submitted to silica gel column chroma-
tography (2.5:1 to 1:1 hexanes–EtOAc) to yield com-
pound 5 as a pale-yellow solid (16.3 g, 31.6 mmol,
78%). TLC (1:2 hexanes–EtOAc): Rf 0.5; mp 210–
212 ꢁC; [a]D +4.3 (c 1.0, CH2Cl2); 1H NMR
(250 MHz, CDCl3): d 8.44–7.03 (m, 4H, ArH), 7.55–
7.34 (m, 5H, ArH), 5.98 (d, 1H, NH), 5.85 (d, 1H, H-
1, J1,2 = 10.6 Hz), 5.51 (s, 1H, PhCH), 4.31 (dd, 1H,
H-6), 4.20–3.96 (m, 2H, H-2, H-3), 3.82–3.48 (m, 3H,
H-6, H-5, H-4), 1.91 (s, 3H, CH3CO), 0.82 (s, 9H,
C(CH3)3), 0.05 (s, 3H, SiCH3), ꢀ0.02 (s, 3H, SiCH3);
13C NMR (62.5 MHz, CDCl3): d 170.1, 156.6, 149.4,
137.2, 136.6, 129.0, 128.1, 126.3, 123.5, 120.6, 101.8,
83.2, 82.1, 74.0, 70.8, 68.7, 56.2, 25.6, 23.5, 18.1, ꢀ4.1,
ꢀ5.0; ESIMS (positive-ion): m/z 517.2 [M+H], 539.2
[M+Na], 555.2 [M+K]. Anal. Calcd for C26H36N2O5SSi
(516.74): C, 60.43; H, 7.02; N, 5.42. Found: C, 60.41; H,
6.83; N, 5.36.
3.5. p-Methoxyphenyl 4,6-O-p-methoxybenzylidene-b-D-
galactopyranoside (9)
To a solution of compound 740 (20.5 g, 45.4 mmol) in
dry CH2Cl2 (50 mL) and dry MeOH (250 mL) was
added NaOMe (25% in MeOH, 0.25 mL). The reaction
was stirred at room temperature for 1 h, after which
time the reaction was quenched with Dowex 50 · 2-100
(H+ form). The suspension was filtered and evaporated
to afford 8 as a white amorphous solid (12.7 g,
44.0 mmol, 97%), which was used in the next step with-
out characterization. TLC (9:1 CH2Cl2–MeOH): Rf 0.1;
mp 158–160 ꢁC; [a]D ꢀ35.7 (c 1.1, H2O). To a suspen-
sion of 8 (11.0 g, 38.5 mmol) in dry CH3CN (250 mL)
were added anisaldehyde dimethyl acetal (ADMA,
69.0 mL, 0.40 mol) and p-toluenesulfonic acid (0.75 g,
3.9 mmol, 0.1 equiv). The solution was stirred at room
temperature for about 4 h. After this time the reaction
was quenched with Et3N. The suspension was filtered,
and the solid was sequentially washed with EtOAc and
hexanes to afford compound 9 as a white amorphous
solid (13.1 g, 32.2 mmol, 84%). TLC (9:1 CH2Cl2–
MeOH): Rf 0.5; mp 224–226 ꢁC; [a]D ꢀ74.9 (c 1.0,
DMSO); 1H NMR (250 MHz, DMSO-d6): d 7.37 (d,
2H, ArH), 7.01 (d, 2H, ArH), 6.91 (d, 2H, ArH), 6.86
(d, 2H, ArH), 5.51 (s, 1H, CH3OPhCH), 5.26 (d, 1H,
H-2), 5.02 (d, 1H, H-3), 4.83 (d, 1H, H-1,
J1,2 = 6.5 Hz), 4.10 (s, 1H, H-4), 4.02 (s, 2H, H-6), 3.74
(s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.67 (s, 1H, H-5),
3.58 (m, 1H, OH); 13C NMR (62.5 MHz, DMSO-d6): d
159.4, 154.3, 151.3, 131.0, 127.5, 117.6, 114.4, 113.2,
101.5, 99.7, 75.8, 71.7, 69.7, 68.4, 66.0, 55.3, 55.1; ESIMS
(positive-ion): m/z 404.7 [M+H], 426.7 [M+Na], 442.6
[M+K]. Anal. Calcd for C21H24O8 (404.72): C, 62.37;
H, 5.98. Found: C, 62.30; H, 5.99.
3.4. 2-Acetamido-4,6-O-benzylidene-3-O-tert-butyldi-
methylsilyl-1,2-dideoxy-1-pyridinylsulfonyl-b-D-gluco-
pyranose (6)
To a stirred solution of compound 5 (16.3 g, 31.6 mmol)
in CH2Cl2 (200 mL) was added m-CPBA (50–60%,
33.0 g) at 0 ꢁC. The reaction was allowed to stir and
warm to room temperature over 1.5 h, after which time
the reaction mixture was diluted with CH2Cl2, washed
consecutively with satd Na2S2O3, satd Na2CO3 and
brine, and extracted with CH2Cl2. The organic phase
was dried with anhyd Na2SO4 and then concentrated
to dryness. The residue was submitted to silica gel col-
umn chromatography (1:1 hexanes–EtOAc) to give
compound 6 as a white amorphous solid (13.9 g,
25.4 mmol, 79%). TLC (1:2 hexanes–EtOAc): Rf 0.4;
3.6. p-Methoxyphenyl 2,3-di-O-benzyl-4,6-O-p-methoxy-
benzylidene-b-D-galactopyranoside (10)
To a solution of diol 9 (7.35 g, 18.1 mmol) in dry DMF
(40 mL) was added NaH (60% in mineral oil, 2.17 g,
1
mp 162–164 ꢁC; [a]D ꢀ34.8 (c 1.0, CH2Cl2); H NMR

1674
Z.-X. Ren et al. / Carbohydrate Research 342 (2007) 1668–1679
54.3 mmol) at 0 ꢁC. The reaction was stirred at 0 ꢁC for
10 min, and then BnBr (8.49 mL, 72.4 mmol) was added
dropwise. The reaction was allowed to stir and warm to
room temperature over 10 h, after which time it was
quenched with water and extracted with CH2Cl2. The
organic phase was dried with anhyd Na2SO4 and then
concentrated to dryness. The residue was submitted to
silica gel column chromatography (3:1 to 2:1 hexanes–
EtOAc) to give compound 10 as a white amorphous
solid (10.0 g, 17.1 mmol, 95%). TLC (1:1 hexanes–EtOAc):
Rf 0.5; mp 167–169 ꢁC; [a]D ꢀ6.3 (c 1.0, CHCl3); 1H NMR
(250 MHz, CDCl3): d 7.49 (d, 2H, ArH), 7.40–7.25 (m,
10H, ArH), 7.06 (d, 2H, ArH), 6.90 (d, 2H, ArH), 6.80
(d, 2H, ArH), 5.47 (s, 1H, MeOPhCH), 5.00 (d, 1H, H-
1, J1,2 = 10.7 Hz), 4.86 (m, 2H, H-2, H-3), 4.78 (s, 2H,
ArCH2O), 4.31 (d, 1H, ArCH2O), 4.15–3.99 (m, 3H, H-
6, H-4, ArCH2O), 3.81 (s, 3H, OCH3), 3.77 (s, 3H,
OCH3), 3.61 (dd, 1H, H-5), 3.39 (s, 1H, H-6); 13C NMR
(62.5 MHz, CDCl3): d 160.0, 155.2, 151.6, 138.6, 138.3,
130.4, 128.3, 128.2, 128.0, 127.8, 127.7, 127.5, 118.9,
114.4, 113.4, 103.1, 101.2, 79.1, 78.1, 75.4, 73.6, 71.9,
69.0, 66.4, 55.6, 55.2; ESIMS (positive-ion): m/z 585.2
[M+H], 607.2 [M+Na], 623.2 [M+K]. Anal. Calcd for
C35H36O8 (584.67): C, 71.90; H, 6.21. Found: C, 71.84;
H, 6.30.
C35H38O8 (586.69): C, 71.65; H, 6.53. Found: C, 71.54;
H, 6.60.
3.8. p-Methoxyphenyl 2,3-di-O-benzyl-4-C-cyano-4-
deoxy-6-O-p-methoxybenzyl-b-D-glucopyranoside (13)
To a solution of compound 11 (10.0 g, 17.06 mmol) in
dry CH2Cl2 (80 mL) and pyridine (3.5 mL, 43.3 mmol)
was
added
trifluoromethanesulfonic
anhydride
(3.5 mL, 21.3 mmol) dropwise at 0 ꢁC. The reaction
was stirred at 0 ꢁC for 10 h, after which time it was con-
centrated and passed through a short plug of silica gel
(3:1 hexanes–EtOAc) to give triflate 12 as an unstable,
pale-yellow syrup that was used in the nest step without
characterization. TLC (2:1 hexanes–EtOAc): Rf 0.72. To
a solution of triflate 12 (12.26 g, 17.06 mmol) in dry
THF (40 mL) was added Bu4NCN (50 mL, 0.44 M in
THF, 1.2 equiv) dropwise at ꢀ45 ꢁC. The solution was
allowed to stir and warm to room temperature over
4 h, at which time TLC (3:1 hexanes–EtOAc) showed
complete consumption of starting material and forma-
tion of two main spots. The reaction was concentrated
to dryness, and the residue was subjected to silica gel
column chromatography (7:1 to 5.5:1 hexanes–EtOAc)
to afford compound 13 as a yellow syrup (6.40 g,
10.75 mmol, 63%). TLC (3:1 hexanes–EtOAc): Rf 0.4;
[a]D ꢀ19.1 (c 1.0, CHCl3); 1H NMR (250 MHz, CDCl3):
d 7.34–7.20 (m, 12H, ArH), 6.99 (d, 2H, ArH), 6.83 (d,
2H, ArH), 6.79 (d, 2H, ArH), 5.01 (d, 1H, ArCH2O),
3.7. p-Methoxyphenyl 2,3-di-O-benzyl-6-O-p-methoxy-
benzyl-b-D-galactopyranoside (11)
A suspension of compound 10 (0.900 g, 1.54 mmol),
NaBH3CN (0.390 g, 6.16 mmol), and 4 A MS (0.41 g)
4.87 (s, 2H, ArCH2O), 4.85 (d, 1H, H-1, J1,2 =
˚
7.5 Hz), 4.78 (d, 1H, ArCH2O), 4.47 (dd, 2H, ArCH2O),
3.71 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.78–3.64 (m,
4H, H-2, H-5, H-6), 3.55 (t, 1H, H-3), 2.98 (t, 1H,
H-4); 13C NMR (62.5 MHz, CDCl3): d 158.4, 154.6,
150.2, 136.9, 136.4, 128.7, 128.4, 127.5, 127.4, 127.2,
127.1, 127.0, 117.6, 116.6, 113.7, 112.9, 101.9, 80.5,
78.4, 74.9, 74.2, 72.5, 71.4, 68.2, 54.6, 54.3, 35.0; ESIMS
(positive-ion): m/z 618.2 [M+Na], 634.2 [M+K]. Anal.
Calcd for C36H37NO7 (595.70): C, 72.59; H, 6.26; N,
2.35. Found: C, 72.59; H, 6.45; N, 2.24.
in dry DMF (20 mL) was stirred at 0 ꢁC for 15 min,
and then a solution of CF3CO2H (0.95 mL, 12.3 mmol)
in dry DMF (3 mL) was added dropwise. The reaction
was allowed to stir and warm to room temperature over
10 h, after which time the mixture was filtered through a
bed of Celite, washed with satd aq NaHCO3, and
extracted with CH2Cl2. The organic phase was dried with
anhyd Na2SO4 and then concentrated to dryness. The
residue was submitted to silica gel column chromatogra-
phy (4:1 to 3.5:1 hexanes–EtOAc) to give compound 11
as colorless crystals (0.670 g, 1.14 mmol, 74%). TLC (2:1
hexanes–EtOAc): Rf 0.5; mp 93–95 ꢁC; [a]D ꢀ6.2 (c 1.0,
3.9. p-Methoxyphenyl 2,3-di-O-benzyl-4-deoxy-4-C-
formyl-6-O-p-methoxybenzyl-b-D-glucopyranoside (14)
1
CHCl3); H NMR (250 MHz, CDCl3): d 7.38–7.22 (m,
12H, ArH), 7.03 (d, 2H, ArH), 6.85 (d, 2H, ArH),
6.80 (d, 2H, ArH), 5.01 (d, 1H, ArCH2O), 4.84 (d, 1H,
H-1, J1,2 = 7.5 Hz), 4.81 (d, 1H, ArCH2O), 4.74 (s,
2H, ArCH2O), 4.50 (s, 2H, ArCH2O), 4.05 (d, 1H, H-
6), 3.91 (dd, 1H, H-2), 3.80 (s, 3H, OCH3), 3.74 (s,
3H, OCH3), ꢂ3.7 (m, 1H, H-6a), 3.63 (dd, 1H, H-3),
3.56 (m, 1H, H-5), 2.56 (s, 1H, OH); 13C NMR
(62.5 MHz, CDCl3): d 159.3, 155.2, 151.5, 138.4, 137.8,
130.1, 129.4, 128.5, 128.3, 128.1, 127.9, 127.8, 127.7,
118.6, 114.5, 113.8, 102.9, 80.6, 78.7, 75.3, 73.5, 73.4,
72.5, 68.9, 66.8, 55.6, 55.2; ESIMS (positive-ion): m/z
609.3 [M+Na], 625.2 [M+K]. Anal. Calcd for
To a solution of compound 13 (1.06 g, 1.78 mmol) in dry
THF (25 mL) was added Bu2AlH [DIBALH (Aldrich),
7.11 mL, 1.5 M in toluene, 6 equiv] at ꢀ78 ꢁC. The reac-
tion was allowed to stir and warm to room temperature
over 10 h, after which time it was quenched with EtOAc,
and the solution was stirred with 1.0 N H3PO4 (10 mL)
for another 30 min at 0 ꢁC. The mixture was then neu-
tralized with satd aq NaHCO3, filtered through a bed
of Celite and extracted with CH2Cl2. The organic phase
was dried with anhyd Na2SO4 and then concentrated to
dryness. The residue was adsorbed onto a short plug of
silica gel and eluted (3.5:1 hexanes–EtOAc) to give com-

Z.-X. Ren et al. / Carbohydrate Research 342 (2007) 1668–1679
1675
pound 14 as a pale-yellow syrup (0.76 g, 1.26 mmol,
71%). TLC (3:1 hexanes–EtOAc): Rf 0.3; [a]D ꢀ31.7 (c
171.2, 158.9, 155.0, 151.5, 138.8, 138.1, 137.1, 130.8,
129.8, 129.0, 128.6, 128.4, 128.1, 127.8, 127.7, 126.2,
118.2, 114.5, 113.6, 102.7, 101.8, 83.1, 82.0, 78.5,
78.4, 74.6, 74.2, 73.7, 73.5, 72.8, 71.4, 70.5, 68.6,
67.3, 55.5, 55.1, 53.5, 46.0, 25.6, 23.2, 18.0, ꢀ4.0,
ꢀ4.9; ESIMS (positive-ion): m/z 1028.4 [M+Na],
1044.5 [M+K]. Anal. Calcd for C57H71NO13Si
(1006.28): C, 68.04; H, 7.11; N, 1.39. Found: C,
67.76; H, 7.22; N, 1.34.
1
0.5, CH2Cl2); H NMR (250 MHz, CDCl3): d 9.65 (d,
1H, CHO), 7.33–7.16 (m, 12H, ArH), 6.99 (d, 2H,
ArH), 6.83 (d, 2H, ArH), 6.80 (d, 2H, ArH), 5.05 (d,
1H, ArCH2O), 4.84 (m, 3H, ArCH2O, H-1, J1,2
=
10.0 Hz), 4.56 (d, 1H, ArCH2O), 4.40 (dd, 2H,
ArCH2O), 4.00 (dd, 1H, H-3), 3.74 (s, 3H, OCH3),
3.72 (s, 3H, OCH3), 3.81–3.67 (m, 2H, H-5, H-3), 3.58
(m, 2H, H-6), 3.01 (dd, 1H, J = 10.2 Hz, H-4); 13C
NMR (62.5 MHz, CDCl3): d 200.1, 159.4, 155.5,
151.4, 138.3, 138.0, 129.8, 129.5, 128.5, 128.5, 128.3,
128.1, 127.9, 118.5, 114.7, 113.9, 102.8, 82.6, 78.8,
75.2, 75.1, 73.2, 72.1, 70.3, 57.3, 55.7, 55.3; ESIMS (po-
sitive-ion): m/z 621.1 [M+Na], 637.2 [M+K]. Anal.
Calcd for C36H38O8 (598.70): C, 72.22; H, 6.40. Found:
C, 72.44; H, 6.28.
3.10.2. p-Methoxyphenyl C-(2-acetamido-4,6-O-benzyl-
idene-3-O-tert-butyldimethylsilyl-2-deoxy-b-D-glucopyr-
anosyl)-(1!4a)-(4aS)-2,3-di-O-benzyl-4a-hydroxy-6-O-
p-methoxybenzyl-4a-carba-b-D-glucopyranoside (15b).
TLC (1:2 hexanes–EtOAc): Rf 0.2; mp 90–92 ꢁC; [a]D
1
ꢀ97.1 (c 0.5, CH2Cl2); H NMR (600 MHz, CDCl3):
d 7.47–7.24 (m, 17H, ArH), 7.04 (d, 2H, ArH), 6.87
(d, 2H, ArH), 6.79 (d, 2H, ArH), 5.40 (s, 1H, PhCH),
5.09 (d, 1H, ArCH2O), 5.03 (d, 1H, ArCH2O), 4.99
(d, 1H, NH), 4.94 (d, 1H, H-1I, J1,2 = 6.6 Hz), 4.77
(d, 1H, ArCH2O), 4.65 (d, 1H, ArCH2O), 4.50 (d,
1H, ArCH2O), 4.43 (d, 1H, ArCH2O), 4.17 (dd, 1H,
H-6II), 3.88–3.74 (m, 5H, H-5I, H-3II, H-2I, CH–OH,
H-3I), 3.78 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.72
(dd, 1H, H-6I), 3.61 (dd, 1H, H-6I), 3.58–3.52 (m,
2H, H-6II, H-1II, J1,2 = 9.6 Hz), 3.48 (dd, 1H, H-2II),
3.28 (t, 1H, H-4II), 3.26–3.21 (m, 1H, H-5II), 2.25–
2.08 (m, 1H, H-4I), 1.89 (s, 3H, CH3CO), 0.08 (s, 9H,
C(CH3)3), ꢀ0.03 (s, 3H, SiCH3), ꢀ0.07 (s, 3H, SiCH3);
13C NMR (62.5 MHz, CDCl3): d 170.8, 159.3, 155.1,
151.4, 138.5, 138.0, 137.2, 130.0, 129.7, 129.0, 128.7,
128.4, 128.1, 128.1, 127.8, 127.7, 126.3, 126.2, 114.5,
113.8, 102.8, 101.7, 83.2, 82.2, 79.5, 78.7, 74.4, 73.1,
72.9, 71.5, 71.5, 69.6, 68.6, 56.9, 55.6, 55.2, 45.3,
25.7, 23.5, 18.1, ꢀ4.1, ꢀ5.0; ESIMS (positive-ion): m/z
1006.4 [M+H], 1028.5 [M+Na], 1044.6 [M+K]. Anal.
Calcd for C57H71NO13Si (1006.28): C, 68.04; H, 7.11;
N, 1.39. Found: C, 67.74; H, 6.95; N, 1.38.
3.10. Samarium diiodide-promoted coupling reaction:
synthesis of 15a–c
To a stirred solution of sulfone 6 (2.90 g, 5.3 mmol) and
aldehyde 14 (2.50 g, 4.2 mmol) in THF (50 mL) was
added a solution of SmI2 (Aldrich) in dry THF
(0.1 M, 150 mL, 15 mmol) under N2. The reaction was
stirred at room temperature for 1 h, after which time it
was quenched with satd NH4Cl and extracted with
CH2Cl2. The organic phase was dried with anhyd
Na2SO4, and then evaporated to dryness. The residue
was submitted to silica gel column chromatography
(3:1 to 1:1 hexanes–EtOAc) to afford 15a (845 mg,
0.84 mmol, 20%), 15b (630 mg, 0.63 mmol, 15%), and
15c (1.25 g, 1.24 mmol, 30%) as white amorphous solids.
Physicochemical data for 15a–c are provided in the
paragraphs that follow.
3.10.1. p-Methoxyphenyl C-(2-acetamido-4,6-O-benzyl-
idene-3-O-tert-butyldimethylsilyl-2-deoxy-b-D-glucopyr-
anosyl)-(1!4a)-(4aR)-2,3-di-O-benzyl-4a-hydroxy-6-O-
p-methoxybenzyl-4a-carba-b-D-glucopyranoside (15a).
TLC (2:1 hexanes–EtOAc): Rf 0.5; mp 176–178 ꢁC;
[a]D ꢀ41.2 (c 0.5, CH2Cl2); 1H NMR (600 MHz,
CDCl3): d 7.51–7.19 (m, 17H, ArH), 7.07 (d, 2H,
ArH), 6.84 (d, 2H, ArH), 6.75 (d, 2H, ArH), 5.44 (s,
1H, PhCH), 5.07 (d, 1H, ArCH2O), 4.99 (d, 1H,
ArCH2O), 4.99 (d, 1H, NH), 4.91 (d, 1H, H-1I,
J1,2 = 7.2 Hz), 4.80 (d, 1H, ArCH2O), 4.59 (d, 1H,
ArCH2O), 4.45 (dd, 2H, ArCH2O), 4.21 (dd, 1H, H-
6II), 4.02 (s, 1H, CH–OH), 3.97 (dd, 1H, H-6I), 3.91–
3.83 (m, 2H, H-5I, H-2II), 3.80–3.76 (m, 3H, H-2I, H-
3I, CH–OH), 3.78 (s, 3H, CH3O), 3.76 (s, 3H,
CH3O), 3.62–3.57 (m, 2H, H-6I, H-6II), 3.43–3.36 (m,
2H, H-4II, H-1II, J1,2 = 8.4 Hz), 3.29–3.21 (m, 2H, H-
3II, H-5II), 2.32–2.26 (m, 1H, H-4I), 1.76 (s, 3H,
CH3CO), 0.77 (s, 9H, C(CH3)3), ꢀ0.05 (s, 3H, SiCH3),
ꢀ0.08 (s, 3H, SiCH3); 13C NMR (62.5 MHz, CDCl3): d
3.10.3. p-Methoxyphenyl C-(2-acetamido-4,6-O-benzyl-
idene-3-O-tert-butyldimethylsilyl-2-deoxy-a-D-glucopyr-
anosyl)-(1!4a)-2,3-di-O-benzyl-4a-hydroxy-6-O-p-meth-
oxybenzyl-4a-carba–D-glucopyranoside (15c). TLC (2:1
hexanes–EtOAc): Rf 0.4; mp 96–98 ꢁC; [a]D ꢀ2.9 (c 0.1,
1
CH2Cl2); H NMR (600 MHz, CDCl3): d 7.47–7.26 (m,
15H, ArH), 7.21 (d, 2H, ArH), 7.00 (d, 2H, ArH), 6.84
(d, 2H, ArH), 6.81 (d, 2H, ArH), 6.10 (d, 1H, NH),
5.44 (s, 1H, PhCH), 5.11 (d, 1H, ArCH2O), 5.05 (d, 1H,
ArCH2O), 4.93 (d, 1H, H-1I, J1,2 = 7.2 Hz), 4.75 (d,
1H, ArCH2O), 4.74 (d, 1H, ArCH2O), 4.46 (d, 1H,
ArCH2O), 4.35 (d, 1H, ArCH2O), 4.27 (m, 1H, H-2II)
4.12 (dd, 1H, H-6II), 4.02 (m, 1H, H-4II), 3.95 (m, 2H,
H-3I, H-3II), 3.84–3.71 (m, 4H, H-6I, H-5I, H-1II, CH–
OH), 3.78 (s, 3H, CH3O), 3.78 (s, 3H, CH3O), 3.68 (t,
1H, H-2I), 3.65–3.61 (m, 1H, H-6I), 3.56 (t, 1H, H-6II),
3.50–3.40 (m, 1H, H-5II), 2.05–1.98 (m, 1H, H-4I), 1.86

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Z.-X. Ren et al. / Carbohydrate Research 342 (2007) 1668–1679
(s, 3H, CH3CO), 0.75 (s, 9H, C(CH3)3), ꢀ0.08 (s, 3H,
SiCH3), ꢀ0.13 (s, 3H, SiCH3); 13C NMR (62.5 MHz,
CDCl3): d 169.7, 159.1, 155.1, 150.9, 137.5, 137.3,
137.1, 129.6, 129.0, 128.8, 128.6, 128.3, 128.1, 128.1,
128.0, 127.7, 127.7, 126.1, 118.2, 114.4, 113.5, 102.5,
101.6, 83.0, 82.7, 80.0, 75.2, 74.3, 73.5, 73.2, 71.9, 71.4,
71.3, 69.1, 67.6, 65.4, 55.6, 55.2, 54.5, 48.3, 25.7, 23.4,
18.0, ꢀ4.0, ꢀ4.9; ESIMS (positive-ion): m/z 1006.2
[M+H], 1023.2 [M+NH4], 1028.2 [M+Na], 1044.2
[M+K]. Anal. Calcd for C57H71NO13Si (1006.28): C,
68.04; H, 7.11; N, 1.39. Found: C, 67.79; H, 7.03; N, 1.47.
after which time it was neutralized with Dowex
50W · 2 (H+) and concentrated to dryness. The residue
was submitted to silica gel column chromatography (3:1
to 2:1 hexanes–EtOAc) to give starting material 16
(125 mg, 50%) and product 17 as a white solid (89 mg,
36%). TLC (2:1 hexanes–EtOAc): Rf 0.4; mp 94–95 ꢁC;
[a]D +0.2 (c 0.5, CH2Cl2); 1H NMR (600 MHz, CDCl3):
d 7.45–7.43 (m, 2H, ArH), 7.38–7.25 (m, 13H, ArH),
7.17 (d, 2H, ArH), 7.02 (d, 2H, ArH), 6.85 (d, 2H,
ArH), 6.81 (d, 2H, ArH), 5.44 (s, 1H, PhCH), 5.09 (d,
1H, ArCH2O), 5.05 (d, 1H, ArCH2O), 4.95 (d, 1H, H-
1I, J1,2 = 7.2 Hz), 4.81 (d, 1H, ArCH2O), 4.65–4.62 (m,
2H, H-1II, J1,2 = 10.8 Hz, NH), 4.56 (t, 1H, H-3II),
4.47 (d, 1H, ArCH2O), 4.38 (dd, 2H, ArCH2O), 4.15
(dd, 1H, H-6II), 4.06 (dd, 1H, H-3I), 3.78 (s, 3H,
CH3O), 3.78 (s, 3H, CH3O), 3.76–3.70 (m, 2H, H-5I,
H-2I), 3.63 (t, 1H, H-6II), 3.49–3.41 (m, 4H, H-4I, H-
5II, H-6I,), 3.29 (t, 1H, H-4II), 2.81–2.76 (m, 1H,
H-2II), 1.64 (s, 3H, COCH3), 0.76 (s, 9H, C(CH3)3),
ꢀ0.12 (s, 3H, SiCH3), ꢀ0.16 (s, 3H, SiCH3); 13C
NMR (62.5 MHz, CDCl3): d 204.8, 170.3, 159.2,
155.3, 151.2, 138.4, 137.8, 137.1, 129.6, 129.2, 129.0,
128.8, 128.4, 128.2, 128.0, 128.0, 127.8, 126.7, 126.3,
118.2, 114.5, 113.8, 102.9, 101.9, 82.7, 82.5, 80.6, 79.4,
75.2, 74.6, 74.1, 72.9, 70.5, 70.1, 69.3, 68.4, 55.6, 55.5,
55.2, 51.5, 25.8, 23.6, 18.1, ꢀ4.5, ꢀ5.0; ESIMS: m/z
1026.6 [M+Na], 1042.5 [M+K]. Anal. Calcd for
C57H69NO13Si: C, 68.17; H, 6.93; N, 1.39. Found: C,
68.09; H, 6.90; N, 1.45.
3.11. p-Methoxyphenyl C-(2-acetamido-4,6-O-benzyl-
idene-3-O-tert-butyldimethylsilyl-2-deoxy-a-D-gluco-
pyranosyl)-(1!4a)-2,3-di-O-benzyl-4a-oxo-6-O-p-
methoxybenzyl-4a-carba-b-D-glucopyranoside (16)
To a solution of compound 15c (640 mg, 0.636 mmol) in
dry CH2Cl2 (15 mL) was added PCC (1.35 g, 6.26 mmol,
ꢂ10 equiv). The reaction was stirred for 12 h, after
which time it was concentrated to dryness, and the res-
idue was submitted to silica gel column chromatography
(3:1 to 2:1 hexanes–EtOAc) to yield 16 as a white solid
(420 mg, 0.418 mmol, 66%). TLC (2:1 hexanes–EtOAc):
1
Rf 0.5; mp 68–69 ꢁC; [a]D ꢀ10.6 (c 0.5, CH2Cl2); H
NMR (600 MHz, CDCl3): d 7.46–7.43 (m, 2H, ArH),
7.36–7.26 (m, 11H, ArH), 7.21 (d, 2H, ArH), 7.16 (d,
2H, ArH), 7.00 (d, 2H, ArH), 6.82 (d, 2H, ArH), 6.80
(d, 2H, ArH), 6.05 (d, 1H, NH), 5.46 (s, 1H, PhCH),
5.07 (d, 1H, ArCH2O), 4.95 (d, 1H, ArCH2O), 4.92 (d,
1H, H-1I, J1,2 = 7.2 Hz), 4.75 (d, 1H, ArCH2O), 4.61
(d, 1H, H-1II, J1,2 = 6.0 Hz), 4.52–4.45 (m, 3H,
ArCH2O, H-2II), 4.20 (dd, 1H, H-6II), 3.89–3.84 (m,
2H, ArCH2O, H-3I), 3.82–3.71 (m, 3H, H-3II, H-5I, H-
2I), 3.78 (s, 3H, CH3O), 3.76 (s, 3H, CH3O), 3.68–3.65
(m, 1H, H-5I), 3.62–3.50 (m, 4H, H-6II, H-6I, H-6I, H-
4I), 3.45 (t, 1H, H-4II), 1.79 (s, 3H, COCH3), 0.77 (s,
9H, C(CH3)3), ꢀ0.06 (s, 3H, CH3Si), ꢀ0.08 (s, 3H,
CH3Si); 13C NMR (62.5 MHz, CDCl3): d 211.9, 169.1,
159.0, 155.3, 151.0, 137.6, 137.0, 136.8, 129.4, 129.1,
128.8, 128.5, 128.3, 128.0, 127.8, 127.7, 127.5, 126.1,
118.4, 114.4, 113.6, 102.7, 101.6, 82.6, 82.5, 81.2, 80.2,
75.2, 74.6, 73.0, 72.9, 70.7, 69.1, 68.6, 67.8, 55.4, 54.9,
52.5, 51.6, 25.4, 23.2, 17.8, ꢀ4.2, ꢀ5.1; ESIMS: m/z
1026.6 [M+Na], 1042.5 [M+K]. Anal. Calcd for
C57H69NO13Si: C, 68.17; H, 6.93; N, 1.39. Found: C,
68.16; H, 6.89; N, 1.44.
3.13. Reduction of 17 to 15a and 15b
To a solution of 17 (120 mg, 0.117 mmol) in abs EtOH
(10 mL) was added NaBH4 (15 mg). The reaction was
stirred for 4 h, after which time 1 M HCl was added,
and the mixture was diluted with wet CH2Cl2 (20 mL),
poured into water (50 mL), and extracted with CH2Cl2.
The organic phase was dried with anhyd Na2SO4 and
evaporated to dryness. The residue was submitted to sil-
ica gel column chromatography to yield 15a (25.0 mg,
0.024 mmol, 21%) and 15b (75.0 mg, 0.075 mmol, 62%)
as white solids. The physicochemical and spectral data
for these compounds matched those of 15a and 15b syn-
thesized using SmI2 as the promoter.
3.14. p-Methoxyphenyl C-(2-acetamido-4,6-O-benzyl-
idene-3-O-tert-butyldimethylsilyl-2-deoxy-b-D-gluco-
pyranosyl)-(1!4a)-(4aR)-2,3-di-O-benzyl-4a-O-methyl-
thiothiocarbonyl-6-O-p-methoxybenzyl-4a-carba-b-D-
glucopyranoside (18a)
3.12. p-Methoxyphenyl C-(2-acetamido-4,6-O-benzyl-
idene-3-O-tert-butyldimethylsilyl-2-deoxy-b-D-gluco-
pyranosyl)-(1!4a)-2,3-di-O-benzyl-4a-oxo-6-O-p-
methoxybenzyl-4a-carba-b-D-glucopyranoside (17)
To a solution of compound 15a (1.90 g, 1.68 mmol) and
imidazole (10 mg, 0.15 mmol) in dry THF (15 mL) was
added NaH (60% in mineral oil, 135 mg, 3.38 mmol).
The reaction was stirred for 30 min, after which time
CS2 (1.74 mL, 3.78 mmol) was added. MeI (0.42 mL,
To a solution of compound 16 (250 mg, 0.244 mmol) in
MeOH (5 mL) was added NaOMe (0.75 mmol, 3 equiv).
The reaction was stirred at room temperature for 2 h,

Z.-X. Ren et al. / Carbohydrate Research 342 (2007) 1668–1679
1677
6.72 mmol) was then added after another 40 min. The
mixture was stirred for 40 min, after which time it was
quenched with wet CH2Cl2 (20 mL), poured into water
(50 mL), and extracted with CH2Cl2. The organic phase
was dried with anhyd Na2SO4 and then evaporated to
dryness. The residue was submitted to silica gel column
chromatography (3:1 to 2:1 hexanes–EtOAc) to yield
compound 18a as a white amorphous solid (1.01 g,
0.91 mmol, 54%). TLC (2:1 hexanes–EtOAc): Rf 0.5;
mp 85–87 ꢁC; [a]D ꢀ4.3 (c 0.1, CH2Cl2); 1H NMR
(600 MHz, CDCl3): d 7.46–7.23 (m, 17H, ArH), 7.06 (d,
2H, ArH), 6.85 (d, 2H, ArH), 6.74 (d, 2H, ArH), 6.33
(m, 1H, CHOC@S), 5.44 (s, 1H, PhCH), 5.09 (d, 1H,
ArCH2O), 5.08 (d, 1H, ArCH2O), 4.86 (d, 1H, H-1I,
J1,2 = 7.8 Hz), 4.75 (d, 1H, ArCH2O), 4.67 (d, 1H,
ArCH2O), 4.51 (d, 1H, ArCH2O), 4.42 (d, 1H, ArCH2O),
4.23 (dd, 1H, H-6II) 4.00–3.95 (m, 2H, H-6I, H-5I), 3.80–
3.74 (m, 1H, H-2I), 3.77 (s, 3H, OCH3), 3.73 (s, 3H,
OCH3), 3.66–3.32 (m, 8H, H-3I, H-6II, H-6I, H-3II, H-
2II, H-1II, H-5II, H-4II), 2.72–2.52 (m, 1H, H-4I), 2.55
(s, 3H, SCH3), 1.49 (s, 3H, CH3CO), 0.77 (s, 9H,
C(CH3)3), ꢀ0.08 (s, 3H, SiCH3), ꢀ0.09 (s, 3H, SiCH3);
13C NMR (62.5 MHz, CDCl3): d 216.3, 169.7, 158.9,
155.1, 151.5, 139.0, 138.0, 137.1, 130.8, 129.0, 128.3,
128.0, 127.7, 127.4, 127.3, 126.3, 118.3, 114.4, 113.5,
102.9, 101.9, 83.4, 82.3, 78.9, 75.5, 74.5, 74.3, 73.4, 72.9,
71.8, 71.0, 70.6, 68.5, 55.5, 55.1, 54.5, 44.9, 25.6, 23.3,
19.4, 18.0, ꢀ4.2, ꢀ5.1; ESIMS (positive-ion): m/z
1096.4 [M+H], 1118.5 [M+Na], 1134.6 [M+K]. Anal.
Calcd for C59H73NO13S2Si (1096.45): C, 64.63; H, 6.71;
N, 1.28. Found: C, 64.58; H, 6.71; N, 1.26.
128.9, 128.3, 128.2, 128.0, 127.8, 126.3, 126.2, 118.0,
114.5, 113.7, 102.7, 101.8, 83.1, 82.5, 80.4, 79.1, 76.8,
75.0, 74.3, 73.9, 73.0, 72.3, 69.7, 68.9, 68.3, 56.9, 55.5,
55.1, 42.2, 25.6, 23.4, 19.0, 18.1, ꢀ4.3, ꢀ5.1; ESIMS (po-
sitive-ion): m/z 1118.1 [M+Na], 1134.1 [M+K]. Anal.
Calcd for C59H73NO13S2Si (1096.45): C, 64.63; H, 6.71;
N, 1.28. Found: C, 64.39; H, 6.86; N, 1.22.
3.16. p-Methoxyphenyl C-(2-acetamido-4,6-O-benzyl-
idene-3-O-tert-butyldimethylsilyl-2-deoxy-b-D-gluco-
pyranosyl)-(1!4a)-2,3-di-O-benzyl-6-O-p-methoxy-
benzyl-4a-carba-b-D-glucopyranoside (19)
To a refluxing solution of Bu3SnH (1.33 mL, 5.0 mmol)
in dry toluene (10 mL) was added dropwise a solution of
compound 18a or 18b (1.00 g, 0.91 mmol) and AIBN
(11 mg) in dry toluene (10 mL). The reaction was stirred
for 30 min, and then the reaction mixture was extracted
with CH2Cl2. The organic phase was dried with anhyd
Na2SO4 and concentrated to dryness. The residue was
submitted to silica gel column chromatography (2:1 hex-
anes–EtOAc) to yield compound 19 as a white amor-
phous solid (820 mg, 0.83 mmol, 91%). TLC (2:1
hexanes–EtOAc): Rf 0.3; mp 67–69 ꢁC; [a]D ꢀ21.3 (c
0.5, CH2Cl2); 1H NMR (600 MHz, CDCl3): d 7.47–
7.25 (m, 20H, ArH), 7.04 (d, 2H, ArH), 6.89 (d, 2H,
ArH), 6.80 (d, 2H, ArH), 5.44 (s, 1H, PhCH), 5.08 (d,
1H, ArCH2O), 5.02 (d, 1H, ArCH2O), 4.84 (d, 1H, H-
1I, J1,2 = 7.8 Hz), 4.79 (d, 1H, ArCH2O), 4.60 (d, 1H,
ArCH2O), 4.57 (d, 1H, NH), 4.51 (d, 1H, ArCH2O),
4.44 (d, 1H, ArCH2O), 4.19 (dd, 1H, H-6II), 3.79 (s,
3H, OCH3), 3.77 (s, 3H, OCH3), 3.74–3.68 (m, 3H, H-
6I, H-2I, H-3II), 3.60–3.50 (m, 4H, H-6I, H-6II, H-2II,
H-3I), 3.50–3.44 (m, 2H, H-5I, H-4II), 3.34–3.28 (m,
1H, H-1II, J1,2 = 8.4 Hz), 3.25–3.20 (m, 1H, H-5II),
2.12–2.05 (m, 1H, H-4I), 1.73 (m, 1H, CH2), 1.67 (s,
3H, CH3CO), 1.61 (dd, 1H, CH2), 0.77 (s, 9H,
C(CH3)3), ꢀ0.03 (s, 3H, SiCH3), ꢀ0.08 (s, 3H, SiCH3);
13C NMR (62.5 MHz, CDCl3): d 169.5, 159.1, 155.1,
151.5, 139.1, 138.1, 137.1, 130.2, 129.5, 128.9, 128.4,
128.3, 128.1, 128.0, 127.5, 126.2, 118.3, 114.4, 113.7,
103.0, 101.7, 83.2, 82.4, 80.7, 75.8, 74.5, 73.8, 73.3,
73.0, 70.0, 68.7, 57.0, 55.4, 55.1, 39.8, 28.8, 25.5, 23.3,
17.9, ꢀ4.1, ꢀ5.1; ESIMS (positive-ion): m/z 1012.4
[M+Na], 1028.5 [M+K]. Anal. Calcd for C57H71NO12Si
(990.28): C, 69.13; H, 7.23; N, 1.41. Found: C, 68.57; H,
7.28; N, 1.34.
3.15. p-Methoxyphenyl C-(2-acetamido-4,6-O-benzyl-
idene-3-O-tert-butyldimethylsilyl-2-deoxy-b-D-gluco-
pyranosyl)-(1!4a)-(4aS)-2,3-di-O-benzyl-4a-O-methyl-
thiothiocarbonyl-6-O-p-methoxybenzyl-4a-carba-b-D-
glucopyranoside (18b)
Compound 18b was synthesized from 15b using the same
procedure as that for 18a. (50% yield). TLC (2:1 hex-
anes–EtOAc): Rf 0.45; mp 80–82 ꢁC; [a]D ꢀ9.0 (c 0.5,
1
CH2Cl2); H NMR (600 MHz, CDCl3): d 7.46–7.23 (m,
17H, ArH), 7.11 (d, 2H, ArH), 6.85 (d, 2H, ArH), 6.75
(d, 2H, ArH), 6.42 (m, 1H, CHOC@S), 5.37 (s, 1H,
PhCH), 5.32 (d, 1H, ArCH2O), 5.05 (d, 1H, ArCH2O),
5.00 (d, 1H, NH), 4.93 (d, 1H, H-1I, J1,2 = 7.2 Hz),
4.78 (dd, 2H, ArCH2O), 4.58 (t, 1H, H-4II), 4.48 (dd,
2H, ArCH2O), 4.43 (d, 1H, H-1II, J1,2 = 10.8 Hz), 4.14
(d, 1H, H-6II), 4.02 (d, 1H, H-6I), 3.77 (s, 3H, CH3O),
3.76 (s, 3H, CH3O), 3.79–3.73 (m, 3H, H-3II, H-2I, H-
3I), 3.49–3.43 (m, 4H, H-5I, H-1II, H-6II, H-6I), 3.19 (t,
1H, H-5II), 2.73 (m, 1H, H-2II), 2.55 (s, 3H, SCH3),
2.21 (t, 1H, H-4I), 1.33 (s, 3H, CH3CO), 0.79 (s, 9H,
C(CH3)3), ꢀ0.11 (s, 3H, SiCH3), ꢀ0.14 (s, 3H, SiCH3);
13C NMR (62.5 MHz, CDCl3): d 216.7, 170.2, 159.1,
155.0, 151.5, 138.8, 137.8, 137.2, 130.6, 129.2, 129.1,
3.17. p-Methoxyphenyl C-(2-acetamido-4,6-O-benzyl-
idene-2-deoxy-b-D-glucopyranosyl)-(1!4a)-2,3-di-O-
benzyl-6-O-p-methoxybenzyl-4a-carba-b-D-glucopyran-
oside (20)
To a solution of compound 19 (1.22 g, 1.23 mmol) in dry
THF (20 mL) was added Bu4NF (1.35 mL, 1.0 M in
THF, 1.1 equiv). The reaction was stirred at room tem-

1678
Z.-X. Ren et al. / Carbohydrate Research 342 (2007) 1668–1679
perature for 1.5 h, after which time it was quenched with
water, and the mixture was extracted with CH2Cl2. The
organic phase was dried with anhyd Na2SO4 and evap-
orated to dryness. The residue was submitted to silica
gel column chromatography (50:1 CH2Cl2–MeOH) to
give compound 20 as a white amorphous solid (1.00 g,
1.14 mmol, 93%). TLC (10:1 CH2Cl2–MeOH): Rf 0.5;
to silica gel chromatography (20:1:1 CH2Cl2–MeOH–
AcOH) to give compound 21 as a white solid (61 mg,
0.12 mmol, 21%). 1H NMR (600 MHz, CD3OD): d
7.07 (d, 2H, ArH), 6.82 (d, 2H, ArH), 4.73 (d, 1H, H-
1I, J1,2 = 7.8 Hz), 3.90–3.82 (m, 2H, H-6II, H-5I), 3.73
(s, 3H, OCH3), 3.61–3.56 (m, 1H, H-6II), 3.56–3.50
(dd, 1H, H-4II), 3.46 (t, 1H, H-2I), 3.40–3.27 (m, 4H,
H-3I, H-2II, H-5II, H-3II), 3.26–3.21 (m, 1H, H-1II),
2.03–1.92 (m, 1H, H-4I), 1.99 (s, 3H, COCH3), 1.81–
1.72 (m, 1H, CH2), 1.68–1.56 (m, 1H, CH2). 13C NMR
(62.5 MHz, CD3OD): d 174.3, 156.5, 153.0, 119.4,
115.5, 103.5, 81.3, 77.5, 77.2, 76.1, 75.1, 72.3, 63.0,
57.2, 56.2, 43.0, 30.0, 23.1. ESIMS (negative-ion): calcd
for C22H31NO12 501.1846; found: 501.1840 [M];
500.1773 [MꢀH] (calcd 500.1768).
1
mp 234–236 ꢁC; [a]D ꢀ36.7 (c 0.5, CH2Cl2); H NMR
(600 MHz, CDCl3): d 7.53–7.24 (m, 15H, ArH), 7.21
(d, 2H, ArH), 7.04 (d, 2H, ArH), 6.82 (dd, 4H, ArH),
6.67 (d, 1H, NH), 5.52 (s, 1H, PhCH), 5.16 (d, 1H,
ArCH2O), 5.11 (d, 1H, ArCH2O), 4.90 (d, 1H, H-1I,
J1,2 = 7.8 Hz), 4.89 (d, 1H, ArCH2O), 4.60 (d, 1H,
ArCH2O), 4.48 (s, 2H, ArCH2O), 4.29–4.24 (m, 1H,
H-6I), 4.16–4.13 (dd, 1H, H-6II), 3.90–3.87 (m, 1H, H-
5I), 3.79 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.70–3.67
(m, 2H, H-2I, H-3II), 3.64–3.60 (m, 1H, H-6I), 3.54
(dd, 1H, H-3I), 3.47–3.34 (m, 5H, H-6II, H-5II, H-1II,
H-2II, H-4II), 2.04–1.98 (m, 1H, H-4I), 1.81–1.76 (m,
1H, CH2), 1.57 (s, 3H, COCH3), 1.39–1.36 (m, 1H,
CH2); 13C NMR (62.5 MHz, CDCl3): d 171.4, 159.2,
155.3, 151.3, 137.9, 137.2, 136.8, 129.8, 129.4, 129.3,
129.1, 129.0, 128.8, 128.5, 128.3, 128.2, 127.9, 126.3,
118.4, 114.5, 113.7, 102.9, 101.7, 83.1, 83.0, 82.7, 76.8,
74.5, 74.0, 73.2, 70.1, 69.1, 69.0, 64.8, 55.6, 55.2, 53.5,
41.6, 28.9, 22.5; ESIMS (positive-ion): m/z 876.3
[M+H], 893.3 [M+NH4], 898.2 [M+Na], 914.3
[M+K]. Anal. Calcd for C51H57NO12 (876.01): C,
69.93; H, 6.56; N, 1.60. Found: C, 69.86; H, 6.66; N,
1.67.
Acknowledgement
This work was supported, in part, by grant no.
CA-71584 from the National Cancer Institute of the
National Institutes of Health.
Supplementary data
Crystallographic data, excluding structure factors, have
been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication with CCDC
No. 646876. Copies of the data can be obtained free
of charge on application to the Director, CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: +44-
1223-336-033; e-mail: deposit@ccdc.cam.ac.uk). Supple-
mentary data associated with this article can be found,
in the online version, at doi:10.1016/j.carres.2007.
05.031.
3.18. p-Methoxyphenyl C-(2-acetamido-2-deoxy-b-D-
glucopyranosyl)-(1!4a)-4a-carba-b-D-glucopyranosid-
uronic acid (21)
To a solution of compound 20 (505 mg, 0.58 mmol) in
CH2Cl2 (20 mL) and H2O (1 mL) was added DDQ
(308 mg, 1.1 equiv). The reaction was stirred at room
temperature for 1.5 h, after which time the mixture
was washed with satd aq NaHCO3 and extracted with
CH2Cl2. The combined organic layers were dried with
anhyd Na2SO4 and evaporated to dryness. To a solution
of the resulting white solid in CH2Cl2 (6 mL) and H2O
(1 mL) were added sequentially NaBr (2.66 mg),
Bu4NBr (2.66 mg), TEMPO (2.66 mg), a satd aq NaH-
CO3 solution (1.33 mL), and a 5% solution of NaOCl
(1.73 mL) at 0 ꢁC. After 2 h the reaction was quenched
with MeOH (1.5 mL), neutralized with 1 M HCl, and
extracted with CH2Cl2. The combined organic extracts
were dried with anhyd MgSO4 and then concentrated
to dryness. To a solution of the residue in 20:1 EtOAc
and MeOH (10 mL) was added Pd(OH)2/C (20%,
50 mg), and the reaction was stirred in a H2 atmosphere
(1 atm) for 60 h at room temperature. At the end of this
time, the reaction mixture was filtered through Celite
and concentrated to dryness. The residue was submitted
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