Regioselective glycosylation method using partially protected arabino- and galactofuranosyl thioglycosides as key glycosylating substrates and its application to one-pot synthesis of oligofuranoses

Article abstract of DOI:10.1021/jo300084g

We describe in this paper the development of a novel regioselective furanosylation methodology using partially protected furanosyl thioglycosides as central glycosylating building blocks and its application in the efficient one-pot synthesis of a series of linear and branched-type arabino- and galactofuranoside fragments structurally related to the cell wall polysaccharides of Mycobacterium tuberculosis, Streptococcus pneumoniae serostype 35A, and sugar beet.

Full text of DOI:10.1021/jo300084g

Featured Article
pubs.acs.org/joc
Regioselective Glycosylation Method Using Partially Protected
Arabino- and Galactofuranosyl Thioglycosides as Key Glycosylating
Substrates and Its Application to One-Pot Synthesis of
Oligofuranoses
Li-Min Deng, Xia Liu, Xing-Yong Liang, and Jin-Song Yang*
Key Laboratory of Drug Targeting, Ministry of Education, and Department of Chemistry of Medicinal Natural Products, West China
School of Pharmacy, Sichuan University, Chengdu 610041, People’s Republic of China
S
* Supporting Information
ABSTRACT: We describe in this paper the development of a
novel regioselective furanosylation methodology using partially
protected furanosyl thioglycosides as central glycosylating
building blocks and its application in the efficient one-pot
synthesis of a series of linear and branched-type arabino- and
galactofuranoside fragments structurally related to the cell wall
polysaccharides of Mycobacterium tuberculosis, Streptococcus
pneumoniae serostype 35A, and sugar beet.
substrates for mycobacterial Galf Ts, Lowary et al.10l reported
the particularly great efficiency of a one-pot strategy for
INTRODUCTION
Arabinofuranose (Araf) and galactofuranose (Galf) are very
■
producing two linear galactofuranosyl trimers. The rapidity and
common structural constituents of polysaccharides present in
many lower organisms including bacteria,1,2 parasites,3 and
simplicity of this strategy was also demonstrated by our
group10s for assembly of a tri- and tetraarabinofuranoses. More
recently, during the synthesis of tetrasaccharide fragments of
mycobacterial AG, a one-pot procedure was developed by
Gallo-Rodriguez et al.10m for the synthesis of a 5,6-branched
trisaccharide lactone intermediate which involved a glycosyla-
tion−deprotection−glycosylation sequence. However, com-
pared with the considerable progress in the one-pot synthesis
of pyranosidic oligosaccharides,11 similar studies of furanosidic
oligosaccharides have been little explored so far. Furthermore,
the one-pot approach is not applicable to all furanosides. For
instance, the synthesis of oligoarabinofuranosides with 3,5-
branched framework in a one-pot manner has not been
forthcoming. Therefore, there has been a continuous pursuit of
a new one-pot glycosylation protocol for the convenient
synthesis of furanosides.
fungi.4 The most impressive examples of these polysaccharides
are two important glycoconjugates, an arabinogalactan (AG)
and a lipoarabinomannan (LAM), which are major components
of the cell wall of mycobacterial, including the human
pathogens Mycobacterium tuberculosis and Mycobacterium
leprae.5 The ability of the organism to make these
polysaccharides is crucial to its survival and pathogenicity,
and therefore, the enzymes, such as mycobacterial arabino- and
galactofuranosyltransferases (Araf Ts and Galf Ts), involved in
the biosynthesis of the mycobacterial biopolymers are
promising therapeutic targets of new drugs for treatment of
mycobacterial diseases.6 Chemical synthesis of the structural
fragments of AG and LAM is holding current appeal, as the
synthetic fragments play significant roles not only in probing
the biosynthetic pathway by which these glycans are assembled7
but also in exploring new oligosaccharide-based inhibitors that
target the enzymes.8 In this aspect, a variety of synthetic
strategies have been developed,9,10 among which one-pot
multistep glycosylations, wherein several glycosylation steps are
sequentially completed in a single reaction vessel, are very
attractive and produce target oligosaccharides without the need
both for selectively removing protecting groups and for
purifying the reaction intermediates. In 2003, Ning et al.10r
first focused on the application of a one-pot method in furanose
synthesis and realized a concise preparation of a 5,6-branched
trisaccharide portion present in motif E of the M. tuberculosis
cell wall by taking advantage of the reactivity difference
between the secondary C-5 and primary C-6 hydroxyl (OH)
groups of galactofuranose. On the synthesis of Galf-containing
In 1997, Boons and co-workers12a,b developed a novel “two-
directional approach”. The basic concept of their approach
relies on the use of partially protected central building blocks,
such as glycosyl fluorides and thioglycosides, which are capable
of displaying both donor and acceptor properties. The method
has the advantage that once the central building block has been
regioselectively glycosylated with a sugar alcohol, the free OH-
containing di- or trisaccharide product can be utilized as an
acceptor in the next glycosylation process without a single
protecting group manipulation. The effectiveness of the
methodology was further demonstrated by Boons et al. in
Received: January 11, 2012
Published: February 27, 2012
© 2012 American Chemical Society
3025
dx.doi.org/10.1021/jo300084g | J. Org. Chem. 2012, 77, 3025−3037

The Journal of Organic Chemistry
Featured Article
efficient syntheses of trisaccharide libraries12c and other
biologically important oligosaccharides.12d,e Later, an accept-
or-mediated regioselective glycosylation strategy13 and an
iterative orthogonal strategy14 for oligosaccharide synthesis
were reported, respectively, by the groups of Seeberger and
Fraser-Reid. These strategies are also based on the
regioselective glycosyl coupling of the key partially protected
glycosyl phosphates and mannosyl n-pentenyl orthoester
donors with glycosyl acceptors. We envisioned that if the
two-directional approach employed in pyranoses could be
adopted to one-pot glycosylation of furanose systems, it would
be an attractive way for the preparation of arabino- and
galactofuranosyl oligosaccharides. On the basis of these
considerations, a series of furanose thioglycosides 1−6 (Figure
1), all with one or two hydroxyl groups unprotected, were
RESULTS AND DISCUSSION
■
The D-arabino- and D-galactofuranose derivatives 1,10s 4,10l and
510s were synthesized according to the literature procedures.
The preparation of monosaccharide alcohols 2, 3, and 6 was
carried out as outlined in Scheme 1. The synthesis of D-
arabinofuranose derivative 2 began with the known methyl 2,5-
di-O-benzoyl-α-D-arabinofuranoside (7), which was easily
prepared in three steps from the commercial D-arabinose.15
Protection of the 3-OH group in 7 as tert-butyldiphenylsilyl
(TBDPS) ether gave saccharide 8 in 90% yield. The latter was
in turn coupled with thiophenol (PhSH) under the agency of
boron trifluoride etherate (BF3·Et2O) to give an 81% yield of 9,
which was transformed into 2 in 80% yield by treatment with n-
tetrabutylammonium fluoride (TBAF) in tetrahydrofuran
(THF) (Scheme 1, eq 1). Compound 3 was obtained as the
major product in a yield of 45% from p-tolyl 5,6-O-
isopropylidene-1-thio-β-D-galactofuranoside (10)16 via regiose-
lective benzoylation conditions (Scheme 1, eq 2). L-Arabinose
diol 6 was synthesized easily from 3,5-O-di-tert-butylsilylene
acetal 11,17 which was prepared by the known methods in five
steps from L-arabinofuranose, by benzoylation of the C-2
hydroxyl group to benzoate 12 (94% yield), followed by simple
unmasking of the 3,5-di-OH groups with fluoride ion (71%
yield) (Scheme 1, eq 3).
With the partially protected thioglycosides in hand, we first
investigated the glycosyl donor properties of thioglycosides 1−
4, each bearing only one hydroxyl group (Table 1).
Glycosylation between 1 and 1 equiv of arabinofuranosyl
acceptor 13,18 both carrying free 5-OH, under the promotion
of N-iodosuccinimide (NIS, 1.25 equiv) and a catalytic amount
of trifluoromethanesulfonic acid (TfOH) in anhydrous
dichloromethane (CH2Cl2) at −40 to −20 °C gave (1→5)-
linked disaccharide alcohol 14a as a single α-isomer in 65%
yield, along with trisaccharide 14b in 22% yield (Table 1, entry
1). The stereochemical outcome resulted from the neighboring
group participation of the benzoyl group at the C-2 position of
the donor. The trisaccharide product turned out to be the result
of the second glycosylation of 14a with donor 1. Likewise,
arabinosylation of 1 with another 5-OH acceptor 1510h also
gave a mixture of disaccharide 16a19 as the major product and a
Figure 1. Partially protected furanosyl thioglycosides 1−6.
designed to serve as candidate glycosylating substrates.
Incorporation of a benzoyl protecting group serving as a
neighboring participating group at the C-2 position of each
thioglycoside is to ensure the control of the stereochemistry of
each glycosylation. Here, we present the development of a new
regioselective glycosylation method that uses these furanosyl
thioglycosides as well as the demonstration of the efficiency the
method possesses with one-pot solution-phase syntheses of five
linear and branched-type arabino- and galactofuranosides.
Scheme 1. Preparation of Monosaccharides 2, 3, and 6
3026
dx.doi.org/10.1021/jo300084g | J. Org. Chem. 2012, 77, 3025−3037

The Journal of Organic Chemistry
Featured Article
greater reactivity of the primary hydroxyl groups of 15 and 18
relative to the secondary hydroxyl functionality of 2.
Furthermore, coupling of 2 (1.25 equiv) with acceptor 7 (1.0
equiv), in which the regioselective choice was between two
secondary hydroxyl groups, also gave a single disaccharide
product 20 but in a relatively low isolated yield (61%, entry 5).
In order to broaden the substrate scope, we further tested the
couplings between galactofuranose donors 3 or 4 having
secondary 3- or 5-OH and galactofuranose acceptor 2120
having primary 6-OH (Table 1, entries 6 and 7, respectively).
The former coupling (entry 6) led to the formation of
disaccharide 22a accompanied by double glycosylation product
22b in 75 and 14% yields, respectively. Complete regiose-
lectivity is still retained in the reaction of 4 (1.1 equiv) with 21
(1.0 equiv) (entry 7), as only the disaccharide 23 with β-(1→6)
linkage was formed in 80% yield. For another glycosylation of 3
with 3-OH glucopyranose 24,21 only disaccharide 25 was
obtained in 79% yield (entry 8), displaying that the reactivity of
the equatorial C-3 OH group of the glucopyranose ring was
higher than that of the pseudoaxial C-3 OH of the
galactofuranose ring.
Table 1. Glycosylations with Partially Protected Arabino-
and Galactofuranosyl Thioglycosides
a
After establishing the regioselective glycosylation of thio-
glycosides exposing one hydroxyl group, we set out to examine
the glycosylation of 3,5-unprotected thioglycosides 5 and 6. We
envisaged that, due to the reactivity difference between the
secondary C-3 and primary C-5 OH groups, the C-5
glycosylation events should be preferable over the C-3
glycosylation in chemoselective couplings of 5 or 6 with
glycosyl trichloroacetimidates 2610r or 28, respectively, thereby
resulting in (1→5)-linked products. The synthesis of di-L-
arabinofuranosyl imidate 28 is shown in Scheme 2. Thioglyco-
side 32, a L-isomer of 2, was readily prepared in three steps
from the known methyl 2,5-di-O-benzoyl-α-L-arabinofuranoside
(29)22 by using the same procedures for the synthesis of 2 from
7 as outlined above (see the Experimental Section).
Glycosylation of 32 with 2,3,5-tri-O-benzoyl-α-L-arabinofur-
anosyl trichloroacetimidate (33)10p using a chemoselective
Scheme 2. Preparation of Disaccharide Trichloroacetimidate
28
a
Glycosylations were performed with donor (1.1−1.25 equiv),
acceptor (1.0 equiv), NIS (1.25 equiv), TfOH (0.02 equiv), 4 Å
molecular sieves (MS) in anhydrous CH2Cl2 at −40 → −20 °C (for
entries 1−8), or with donor (1.3 equiv), acceptor (1.0 equiv),
TMSOTf (0.13 equiv), 4 Å MS in CH2Cl2 at −45 °C (for entries 9
b
and 10). Isolated yield.
minor quantity of doubly glycosylated trisaccharide 16b19
(entry 2). By contrast, condensations of 3-OH donor 2 with
primary acceptors 15 (Table 1, entry 3) and its perbenzylated
counterpart 1810j (entry 4) at −40 to −20 °C, respectively,
afforded solely α-(1→5)-linked disaccharides 17 and 19 with
complete regioselectivities and in excellent 93 and 94% yields.
Importantly, no other coupled product was detected under
these reaction conditions. The result can be attributed to the
3027
dx.doi.org/10.1021/jo300084g | J. Org. Chem. 2012, 77, 3025−3037

The Journal of Organic Chemistry
Featured Article
glycosylation approach activated with catalytic amounts of
trifluoromethanesulfonate (TMSOTf) furnished disaccharide
thioglycoside 34 (94% yield), which was elaborated into
imidate 28 by hydrolysis with N-bromosuccinimidate (NBS) in
wet ethyl acetate, followed by activation of the resulting
hemiacetal with trichloroacetonitrile (CCl3CN) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) in CH2Cl2.
the respective Araf Ts and GalfTs involved in the biosynthesis
of the mycobacterial cell wall, which suggests that the glycans
or their analogues are likely to be the inhibitors of the enzymes.
Meanwhile, the preparation of the dec-9-enyl glycoside
homologue of 37 was reported by de Lederkremer’s group10k
via a glycosylaldonolactone/trichloroacetimidate assembly
strategy. In the case of Lowary’s preparation10l of the octyl
glycoside homologue of 37, they found that migration of
benzoyl groups usually occurred from C-5 (secondary) to C-6
(primary) in selective deacetylation steps under acidic reaction
conditions. Then, Lowary et al. employed a chemoselective
glycosylation-based one-pot protocol in which the target
substance was assembled from nonreducing to reducing end,
thus not only enabling the rapid production of the molecule but
also solving the unwanted acyl migration problem. Here, on the
basis of our regioselective glycosylation methodology, we
explored a new one-pot synthesis for these trisaccharide
skeletons, and the general strategy depends on the utility of
thioglycosides 2 and 4. Take the retrosynthetic analysis of 36
for example (Scheme 3). The sequence of its assembly includes
two consecutive glycosylation steps: (i) coupling of thioar-
abinoside 2, serving as a key between building block, with
arabinofuranosyl acceptor 15, and (ii) glycosylation of the
resulting disaccharide alcohol with thioglycoside donor 38.24
One-pot glycosylation with 2, 15, and 38 was examined (cf.
Scheme 4). Treatment of the acceptor 15 (1.0 equiv) with the
partially protected donor 2 (1.1 equiv) mediated by coupling
agent NIS/TfOH in CH2Cl2 at −40 to −20 °C within 30 min
resulted in the intermediate 17. Next, the condensation of 17
with donor 38 proceeded at −40 to −20 °C within 30 min with
the addition of NIS and TfOH. The fully protected
trisaccharide 39 was produced in good yield as only a product
in 70% overall yield based on the acceptor 15. Accomplishment
of each glycosylation reaction was checked by TLC analysis.
Parallel study was done by the one-pot assembly of trigalacto-
side 41, a precursor to 37 (Scheme 5). In the event, the
galactofuranose derivative 21 was used for the first
glycosylation step with 4 under the activation of NIS/TfOH.
Then, the resulting disaccharide 23 was glycosylated in situ
with the second donor 4010l to yield the perbenzoylated
galactofuranosyl trimer 41 (67% overall yield based on 21). So,
these processes demonstrate the viability of thioglycosides 2
and 4 in sequential one-pot syntheses of linear furanosides.
Global deprotection of 39 and 41 with the aid of sodium
methoxide (NaOCH3) in methanol furnished the desired 36
and 37, respectively, in 85 and 90% yields. It is worth pointing
out that all glycosyl linkages were built stereoselectively, and
the overall yields after two-step one-pot assembly and one
deprotection step were ca. 60% for both 36 and 37. Therefore,
our method provides a new expeditious way to these
trisaccharides that are suitable for use in assays of mycobacterial
ArafTs and Galf Ts. The structure of triarabinofuranose 36 was
Activation of imidate donor 26 (1.3 equiv) with catalytic
TMSOTf at −45 °C in the presence of diol acceptor 5 (1.0
equiv) in CH2Cl2 (Table 1, entry 9) furnished α-(1→5)-linked
disaccharide 27, isolated as the only coupled material in a good
86% yield. The regioselectivity in this process was assured by
gHMBC experiment of 27, namely, the strong correlationship
observed between the C-5 signal (δC 65.4 ppm) and the
anomeric H-1′ resonance (δH 5.40 ppm, s) confirmed a (1→5)
linkage. Products arising from the C-3 glycosylation and the
intermolecular aglycon transformation23 of 5 were not isolated.
Likewise, another regioselective glycosylation of L-arabinofur-
anosyl 3,5-diol 6 with imidate 28 (Table 1, entry 10), tried
under similar conditions, also followed the same trend and led
to exclusive formation of the corresponding 5-O-α-di-L-
arabinofuranosylated trisaccharide 35 in a good 76% isolated
yield. These examples indicate that the difference in the
reactivity between 3- and 5-hydroxyl groups of arabinofuranose
makes it possible to regioselectively glycosylate at the C-5
position.10q The newly formed products (i.e., thioglycosides 27
and 35) can be directly elongated without further protecting
group removal and aglycon leaving group adjustment.
This regioselective glycosylation method may prove useful
for synthesizing natural arabino- and galactofuranosides and
their analogues. To examine the synthetic application, we
decided to build various oligofuranose structures by using a
one-pot glycosylation procedure based on the developed
method. In this way, two linear trisaccharides 36 (α-D-Araf-
(1→3)-α-D-Araf-(1→5)-D-Araf, Scheme 3) and 37 (β-D-Galf-
Scheme 3. Retrosynthetic Analysis of Triarabinofuranose 36
1
confirmed by comparison of its H and 13C NMR data with
those published in literature.8a,10h The structure of trigalacto-
furanose 37 was determined through the use of NMR and ESI-
MS spectral analysis. Accordingly, in the 1H NMR spectrum of
37, the characteristic resonances brought by the three H-1
signals appeared as singlets at δH 5.25, 5.04, and 4.94 ppm, and
the 13C NMR spectrum revealed that the chemical shifts of the
anomeric carbons were at δC 110.5, 110.1, and 109.5 ppm.
Therefore, both 1H and 13C NMR data are consistent with the
β-galactofuranoside anomeric stereochemistry.25 The structure
of 37 was further confirmed by its high-resolution MS at m/z
(1→5)-β-D-Galf-(1→6)-D-Galf, Scheme 5) were first selected as
the synthetic targets. These homotrimers are composed of 1,2-
trans-D-arabino- and galactofuranosyl residues, respectively, and
are crucial constituents of the mycolyl-arabinogalactan (mAG)
complex from the cell wall of M. tuberculosis. Lowary et al.
previously synthesized compounds 368a,10h and the octyl
glycoside homologues of 368e and 3710l with a thioglycoside
glycosylation method. Notably, Lowary et al.7a,8a further
revealed that these small oligosaccharides were substrates for
3028
dx.doi.org/10.1021/jo300084g | J. Org. Chem. 2012, 77, 3025−3037

The Journal of Organic Chemistry
Featured Article
Scheme 4. Synthesis of Triarabinofuranose 36
Scheme 5. Synthesis of Trigalactofuranose 37
Scheme 6. Synthesis of Trisaccharide 42
Scheme 7. Retrosynthetic Analysis of Protected Hexa-D-Arabinose 46
541.1740 (M + Na)+, which was identical with the calculated
exact mass of the molecule (calcd 541.1745).
The power of this method was also demonstrated by the
construction of another linear heterotrisaccharide glycoside 42
(β-D-Galp-(1→3)-β-D-Galf-(1→3)-D-Glup, Scheme 6), which is
contained in the pentasaccharide repeating unit of the capsular
polysaccharide (CPS) antigen of Streptococcus pneumoniae
serotype 35A.26 Since the CPSs of S. pneumoniae are
responsible for stimulation of the host’s immune system,
synthesis of the common antigen determinant is possibly useful
for immunological studies. As illustrated in Scheme 6, the
synthesis of protected 44, a protected precursor to 42, was
performed in a one-pot manner in which three monosaccharide
units, galactofuranose thioglycoside alcohol 3, methyl glucopyr-
3029
dx.doi.org/10.1021/jo300084g | J. Org. Chem. 2012, 77, 3025−3037

The Journal of Organic Chemistry
Featured Article
Scheme 8. One-Pot Synthesis of Hexa-D-Arabinose 46
Scheme 9. One-Pot Synthesis of Penta-L-Arabinose 47
anoside 24, and perbenzoylated galactopyranose thioglycoside
43,27 were assembled together through a similar series of
reactions via the intermediate 25 to give 44 in a satisfying 65%
overall yield (based on 24). A complete deprotection of 44 was
accomplished as follows: acidic hydrolysis of 44 (HOAc/H2O
(4:1), 70 °C, 4 h) followed by methanolysis of the formed
trisaccharide alcohol (NaOCH3, CH3OH, rt, 2 h) secured 45 in
80% yield over two steps. Finally, the remaining benzyl
protecting group on 45 was removed with Pd−C-catalyzed
hydrogenolysis (H2, Pd−C, CH3OH, 30 °C, 24 h) to afford the
deprotected 42. As was done for 36 and 37, the combination of
NMR and MS data could be used to establish the structure of
42.
Success in the one-pot synthesis of linear furans led us to
explore the use of the regioselective glycosylation methodology
for synthesis of more complex oligofuranoses with branched
architectures, such as 46 and 47 (Schemes 7 and 9,
respectively). Compound 46, a protected hexaarabinan motif
which is linked to the core arabinomannan (AM) domain from
M. tuberculosis, has α-(1→3) and α-(1→5) branch points at the
central D-arabinofuranose unit. Creating such branched sugar
backbones has long been considered a difficult task in synthetic
carbohydrate chemistry. Recently, a protected hexaarabinosyl
trichloroacetimidate possessing the same sugar array as that of
46 was prepared by Seeberger and co-workers10c to be used as
an intermediate in the total synthesis of an AM dodeca-
saccharide. However, their process is a typical example of
oligasaccharide synthesis involving tediously selective protec-
tion and deprotection steps and laborious intermediate
purifications. We anticipated that the incorporation of our
regioselective glycosylation method in the synthesis of the
target 46 could simplify this complicated synthetic operation.
Here, we present an alternative three-step one-pot synthetic
route to 46 by using the 3,5-di-OH thioglycoside 5 as a central
building block. As retrosynthetically depicted in Scheme 7, the
reaction sequence involves three steps: (i) chemo- and
regioselective glycosylation of the primary alcohol of 5 in the
presence of the secondary one with trichloroacetimidate 26,
3030
dx.doi.org/10.1021/jo300084g | J. Org. Chem. 2012, 77, 3025−3037

The Journal of Organic Chemistry
Featured Article
followed by (ii) coupling of the resulting disaccharide
thioglycoside with acceptor 16a based on the difference in
reactivity between the secondary OH on donor and the primary
OH on acceptor, and (iii) glycosylation of the remaining
secondary alcohol of 5 with donor 4810s to give 46.28
investigated the glycosylating properties of partially protected
arabino- and galactofuranosyl thioglycosides. Compounds 2−4
each containing one secondary OH group could function as
glycosyl donors to couple regioselectively with glycosyl
acceptors under the promotion of NIS/TfOH, giving the
corresponding disaccharide alcohols as a sole product. The
regioselectivity is based on the relative reactivity difference
between OH groups carried on the donors and the acceptors.
As for the chemoselective glycosylations of 3,5-dihydroxy-D-
and L-arabinothioglycosides 5 and 6 with 1.3 equiv of glycosyl
trichloroacetimidates 26 and 28 promoted by catalytic
TMSOTf, the C-5 glycosylations took place preferentially
over the C-3 glycosylations and afforded solely the (1→5)-
linked products in high isolated yields. Next, the use of the
method in one-pot glycosylations allowed for the facile and
rapid generation of a series of important linear as well as more
synthetically challenging branched oligofuranoses that are
fragments of the cell wall polysaccharides of M. tuberculosis, S.
pneumoniae serostype 35A, and sugar beet. Application of this
new pathway to the synthesis of structurally diverse
oligofuranose libraries is currently underway.
The successful implementation of this protocol is shown in
Scheme 8. Thus, 26 (1.3 equiv) was used to regioselectively
glycosylate diol 5 (1.0 equiv) by activation with TMSOTf (cat.)
in CH2Cl2 at −45 °C to ambient temperature to give
disaccharide 27 as the only detected product. Next, the
reaction mixture was recooled to −40 °C, and subsequent
addition of the 5′-OH disaccharide acceptor 16a along with
NIS/TfOH reagent system to the reaction flask drove the
second glycosylation to proceed and afforded the tetrasacchar-
ide intermediate 49 as the sole product after 30 min. Finally,
NIS/TfOH-mediated glycosylation of the remaining secondary
hydroxyl group of 49 with thioglycoside donor 48 at −40 to
−20 °C within half an hour completed the synthesis of the
desired 46. Upon purification by silica gel column chromatog-
raphy, 46 was acquired as an amorphous solid in an acceptable
40% overall yield based on 5. This protocol illustrates the
usefulness of the diol 5, able to function as an acceptor, a
donor, and an acceptor. Overall, when compared with the
existing method, the four-component one-pot approach greatly
speeds up the preparation of the target molecule because the
entire synthetic route can be accomplished without the need of
protecting group manipulation and intermediate workup and
thus offers a more practical access to the 3,5-branched
arabinofuranosides.
The usefulness of this remarkably efficient synthetic
technique is also proved by a similar four-component one-pot
synthesis of α-L-arabinofuranosyl pentamer 47 (Scheme 9), and
it represents a fully protected form of structural component
which belongs to the arabinan found in sugar beet cell wall.29
This molecule contains a linear α-(1→5)-linked tri-L-arabinose
backbone to which two α-(1→3)-linked L-arabinosyl residues
are attached. For the one-pot preparation of 47, the
thioglycoside diol 6 was selected to function as the central
building block. Glycosylation of the di-L-furanosyl imidate
donor 28 with 6 affected by TMSOTf activation at −45 °C to
ambient temperature, followed by sequential coupling of the
resulting 35 with acceptor 5022 promoted again by NIS in
combination with catalytic TfOH at low temperature (−40 to
−20 °C), provided 51 with the 3′-OH exposed. Its subsequent
glycosylation with thioglycosyl building block 5210l delivered
the required pentasaccharide glycan 47 in 51% overall yield
(based on 6).
EXPERIMENTAL SECTION
■
Methyl 2,5-Di-O-benzoyl-3-O-tert-butyldiphenylsilyl-α-D-
arabinofuranoside (8). To a solution of 7 (1.02 g, 2.74 mmol) in
dry DMF (7 mL) was added imidazole (560.1 mg, 8.22 mmol),
followed by TBDPSCl (1.1 mL, 4.11 mmol) at 0 °C, and the resulting
mixture was warmed gradually to room temperature. The mixture was
stirred overnight at the same temperature at the end of which time
TLC indicated the reaction was complete. Then the mixture was
dissolved with CH2Cl2, and the resulting organic solution was washed
with water and brine. The organic layer was separated and dried over
anhydrous Na2SO4, filtered, and concentrated. The crude material was
purified by column chromatography (30:1, petroleum ether−EtOAc)
to afford 8 as a colorless syrup (1.5 g, 90%): Rf10.52 (4:1, petroleum
20
ether−EtOAc); [α]D +41.3 (c 1.10, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.88 (dd, 2H, J = 1.2, 8.4 Hz), 7.78 (dd, 2H, J = 1.2, 8.4 Hz),
7.60−7.65 (m, 4H), 7.51−7.57 (m, 2H), 7.17−7.38 (m, 10H), 5.28,
4.90 (2 × s, each 1H), 4.43−4.47 (m, 3H), 4.07 (dd, 1H, J = 4.0, 12.4
Hz), 3.47 (s, 3H), 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
165.6, 165.2, 135.5, 135.48, 133.0, 132.7, 132.6, 132.2, 129.8, 129.7,
129.5, 128.0, 127.6, 127.5, 106.7, 84.8, 81.3, 77.2, 62.7, 54.7, 26.6, 18.9;
IR (KBr) 2932, 2858, 1725, 1602, 1452, 1367 cm−1; HRMS (ESI)
calcd for C36H38O7Si [M + Na]+ 633.2248, found 633.2278.
Phenyl 2,5-Di-O-benzoyl-3-O-tert-butyldiphenylsilyl-1-thio-
α-D-arabinofuranoside (9). To a solution of 8 (2.05 g, 3.36 mmol)
in CH2Cl2 (23.6 mL) was added slowly PhSH (0.41 mL, 4.03 mmol)
at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, then
BF3·Et2O (2.56 mL, 20.16 mmol) was slowly added and the resulting
mixture was warmed gradually to room temperature. The mixture was
stirred for 8 h at the same temperature at the end of which time TLC
indicated that it was finished. The reaction was quenched with Et3N,
and the mixture was concentrated. The crude product was purified by
column chromatography (30:1, petroleum ether−EtOAc) to give 9 as
a colorless syrup (1.87 g, 81%): Rf 0.48 (8:1, petroleum ether−
EtOAc); [α]D20 +98.3 (c 1.40, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.87 (d, 2H, J = 7.6 Hz), 7.82 (d, 2H, J = 7.6 Hz), 7.64−7.68 (m,
4H), 7.50−7.58 (m, 4H), 7.17−7.37 (m, 13H), 5.60, 5.47 (2 × s, each
1H), 4.72 (td, 1H, J = 3.2, 5.2 Hz), 4.45 (dd, 1H, J = 1.2, 5.2 Hz), 4.35
(dd, 1H, J = 2.8, 12.0 Hz), 4.07 (dd, 1H, J = 2.8, 12.0 Hz), 1.12 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 166.0, 165.1, 135.8, 135.7,
134.5, 133.3, 132.9, 132.6, 132.2, 131.8, 130.1, 130.0, 129.7, 129.66,
129.1, 128.9, 128.3, 128.2, 127.9, 127.8, 127.4, 91.3, 85.0, 82.4, 77.5,
63.0, 26.8, 19.2; IR (KBr) 2931, 2858, 1725, 1602, 1585, 1452 cm−1;
HRMS (ESI) calcd for C41H40O6SSi [M + Na]+ 711.2213, found
711.2225.
Analysis of the products 46 and 47 by 1D (1H, 13C, 400
MHz) and 2D NMR spectroscopy (gCOSY, HMQC, and
gHMBC) confirmed the correct anomeric configuration of each
glycosidic linkage. Take D-hexaarabinose 46 for example. In its
1H NMR spectrum, the six anomeric protons appeared as six
signals at δH 5.55, 5.42, 5.41, 5.39, 5.33, and 5.12 ppm, and in
the 13C NMR spectrum, the six anomeric carbon resonances
appeared clearly in the range of δC 105.3 to 106.8 ppm. Both
are characteristic of α-Araf linkages.10s,24 Further support for its
structure came from high-resolution MS data, which gave an
(M + Na)+ signal at m/z 2199.6082 (calcd 2199.6103).
CONCLUSION
■
In conclusion, the development of a novel regioselective
furanosylation methodology and its application in one-pot
synthesis of oligofuranosides have been described. We first
3031
dx.doi.org/10.1021/jo300084g | J. Org. Chem. 2012, 77, 3025−3037

The Journal of Organic Chemistry
Featured Article
Phenyl 2,5-Di-O-benzoyl-1-thio-α-D-arabinofuranoside (2).
To a solution of 9 (500 mg, 0.73 mmol) in THF (1.5 mL) was
added slowly TBAF (0.45 mL, 1.0 M in THF, 0.45 mmol) at 0 °C, and
the resulting mixture was warmed gradually to 15 °C. The mixture was
stirred for 3 h at the same temperature at the end of which time TLC
indicated the reaction was complete. After the solvent was removed
under reduced pressure, the residue was dissolved with CH2Cl2. The
resulting organic solution was washed with saturated aqueous NH4Cl
and brine and then dried over anhydrous Na2SO4 and concentrated to
dryness. The crude material was purified by column chromatography
(5:1, petroleum ether−EtOAc) to afford compound 2 as a white solid
(262 mg, 80%): Rf 0.25 (4:1, petroleum ether−EtOAc); [α]D20 +160.0
(c 0.85, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.00−8.04 (m, 4H),
7.52−7.63 (m, 4H), 7.45 (t, 2H, J = 8.0 Hz), 7.36 (t, 2H, J = 8.0 Hz),
7.30−7.32 (m, 3H), 5.78 (d, 1H, J = 3.2 Hz), 5.19 (t, 1H, J = 3.2 Hz),
4.61−4.69 (m, 2H), 4.57 (dd, 1H, J = 4.8, 11.2 Hz), 4.28−4.32 (m,
1H), 3.55 (d, 1H, J = 3.2 Hz); 13C NMR (100 MHz, CDCl3) δ 167.2,
166.3, 133.8, 133.3, 133.1, 132.2, 129.9, 129.7, 129.6, 129.0, 128.6,
128.57, 128.3, 127.9, 89.2, 87.0, 80.5, 77.4, 63.4; IR (KBr) 3521, 2932,
1711, 1601, 1583, 1453 cm−1; HRMS (ESI) calcd for C25H22O6S [M +
Na]+ 473.1035, found 473.1039.
67.2, 27.4, 27.0, 22.6, 20.1; IR (KBr) 3526, 2930, 1714, 1601, 1583,
1452 cm−1; HRMS (ESI) calcd for C26H34O5SSi [M + Na]+ 509.1788,
found 509.1785.
Phenyl 2-O-Benzoyl-1-thio-α-D-arabinofuranoside (6). Pre-
pared from glycoside 12 (223 mg, 0.46 mmol) and TBAF (1.8 mL, 1.0
M in THF, 1.8 mmol) in THF (1.2 mL) following the procedure
similar to that for 9 → 2. The crude product was purified by column
chromatography (2:1, petroleum ether−EtOAc) to give 6 (113 mg,
71%) as a colorless syrup: Rf 0.34 (1:1, petroleum ether−EtOAc);
[α]D20 −180.5 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.03 (d,
2H, J = 8.0 Hz), 7.61 (t, 1H, J = 6.8 Hz), 7.54−7.56 (m, 2H), 7.47 (t,
2H, J = 8.0 Hz), 7.29−7.37 (m, 3H), 5.77 (d, 1H, J = 2.8 Hz), 5.15 (t,
1H, J = 3.2 Hz), 4.35−4.39 (m, 1H), 4.29−4.32 (m, 1H), 3.96−4.01
(m, 1H), 3.80−3.86 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 167.2,
133.8, 133.5, 132.0, 129.9, 129.0, 128.7, 128.5, 127.8, 89.3, 87.3, 82.7,
76.1, 61.2; IR (KBr) 3431, 2926, 1719, 1601, 1583, 1450 cm−1; HRMS
(ESI) calcd for C18H18O5S [M + Na]+ 369.0767, found 369.0774.
General Procedure for the NIS/TfOH-Promoted Glycosyla-
tions with Partially Protected Arabino- and Galactofuranosyl
Thioglycosides 1−4. To a stirred ca. 0.025 M solution of donor
(1.1−1.25 equiv) and acceptor (1.0 equiv) in dry CH2Cl2 was added
freshly activated 4 Å molecular sieves (150 wt % with respect to the
donor). The reaction mixture was stirred for 15 min at room
temperature and then was cooled to −40 °C. The suspension was
stirred for 15 min at −40 °C, then NIS (1.25 equiv) and TfOH (0.02
equiv) were added and the resulting mixture was warmed gradually to
−20 °C. The reaction mixture was stirred for 0.5 h at the same
temperature, at the end of which time TLC indicated it was finished.
The reaction was quenched with Et3N, diluted with CH2Cl2, filtered,
and concentrated. The resulting residue was purified by column
chromatography. Products 16a and 16b are known compounds and
their spectroscopic data matched the reported data.19 Spectral data of
new compounds are listed below.
p-Tolyl 2-O-Benzoyl-5,6-O-isopropylidene-1-thio-β-D-galac-
tofuranoside (3) and p-Tolyl 3-O-Benzoyl-5,6-O-isopropyli-
dene-1-thio-β-D-galactofuranoside (3a). To a solution of 10
(147.1 mg, 0.45 mmol) in pyridine/CH2Cl2 (0.6 mL/6.0 mL) was
added PhCOCl (58 μL, 0.50 mmol) dropwise at 0 °C, and the
resulting mixture was warmed gradually to room temperature. The
reaction was stirred for 4 h at the same temperature, at the end of
which time TLC indicated it was finished. The reaction was quenched
with methanol, diluted with CH2Cl2, and then the mixture was washed
with water and brine. The organic layer was separated and dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by column chromatography (4:1, petroleum ether−EtOAc) to
afford compound 3 (87.1 mg, 45%) and 3a (50.3 mg, 26%) as
colorless syrups: Rf 0.37 (3) and 0.50 (3a) (2.5:1, petroleum ether−
2,3-Di-O-benzoyl-α-D-arabinofuranosyl-(1→5)-3-O-benzyl-
1,2-O-isopropylidene-β-D-arabinofuranose (14a) and 2,3-Di-O-
benzoyl-α-D-arabinofuranosyl-(1→5)-2,3-di-O-benzoyl-α-D-
arabinofuranosyl-(1→5)-3-O-benzyl-1,2-O-isopropylidene-β-D-
arabinofuranose (14b). Prepared from 13 (45.0 mg, 0.161 mmol)
and 1 (90.4 mg, 0.201 mmol). The residue was purified by column
chromatography (3:1, petroleum ether−EtOAc) to afford compound
14a (65.0 mg, 65%) and 14b (33.8 mg, 22%) as colorless syrups: Rf
0.24 (14a) and 0.16 (14b) (3:1, petroleum ether−EtOAc). 14a:
20
1
EtOAc). 3: [α]D −166.9 (c 0.95, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.13−8.04 (m, 9H), 5.64 (d, 1H, J = 3.6 Hz), 5.09 (t, 1H, J
= 3.6 Hz), 4.31−4.36 (m, 1H), 4.19−4.26 (m, 2H), 4.07 (dd, 1H, J =
6.8, 8.4 Hz), 4.00 (dd, 1H, J = 7.6, 8.4 Hz), 3.55 (br s, 1H), 2.34, 1.43,
1.37 (3 × s, each 3H); 13C NMR (100 MHz, CDCl3) δ 167.4, 138.2,
133.8, 133.0, 129.9, 129.8, 129.3, 128.8, 128.5, 109.7, 89.3, 86.9, 82.0,
77.4, 75.4, 65.3, 26.3, 25.4, 21.1; IR (KBr) 3433, 2919, 1723, 1596,
1492, 1374 cm−1; HRMS (ESI) calcd for C23H26O6S [M + Na]+
[α]D20 −15.0 (c 1.20, CHCl3); H NMR (400 MHz, CDCl3) δ 8.03−
1
8.09 (m, 4H), 7.22−7.61 (m, 11H), 5.91 (d, 1H, J = 4.0 Hz), 5.52 (d,
1H, J = 1.2 Hz), 5.41 (d, 1H, J = 4.0 Hz), 5.27 (s, 1H), 4.66 (d, 1H, J =
4.0 Hz), 4.59 (d, 1H, J = 11.6 Hz), 4.47 (d, 1H, J = 11.6 Hz), 4.27 (td,
1H, J = 3.2, 5.6 Hz), 4.21 (q, 1H, J = 4.0 Hz), 4.10 (d, 1H, J = 3.2 Hz),
3.93−3.97 (m, 3H), 3.69 (dd, 1H, J = 6.0, 10.4 Hz), 2.24−2.27 (m,
1H), 1.56, 1.35 (2 × s, each 3H); 13C NMR (100 MHz, CDCl3) δ
166.1, 165.2, 133.62, 133.6, 130.0, 129.9, 129.1, 129.0, 128.6, 128.53,
128.5, 128.0, 127.7, 113.1, 105.7, 105.6, 85.3, 83.8, 83.1, 82.5, 81.6,
77.6, 71.7, 66.7, 62.3, 27.2, 26.5; IR (KBr) 3497, 2924, 2854, 1724,
1600, 1453 cm−1; HRMS (ESI) calcd for C34H36O11 [M + Na]+
20
1
453.1348, found 453.1351. 3a: [α]D −175.9 (c 0.85, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.12−8.13 (m, 9H), 5.58 (s, 1H), 5.26 (d,
1H, J = 2.0 Hz), 4.61 (td, 1H, J = 1.6, 7.6 Hz), 4.47−4.49 (m, 1H),
4.43 (t, 1H, J = 1.6 Hz), 4.12 (t, 1H, J = 8.0 Hz), 4.05 (t, 1H, J = 8.0
Hz), 2.33, 1.43, 1.42 (3 × s, each 3H); 13C NMR (100 MHz, CDCl3)
δ 167.2, 137.5, 133.6, 132.0, 131.1, 130.0, 129.8, 129.1, 128.6, 110.2,
95.6, 82.4, 81.1, 79.5, 75.5, 65.5, 25.7, 25.6, 21.1; IR (KBr) 3421, 2987,
1716, 1601, 1452, 1373 cm−1; HRMS (ESI) calcd for C23H26O6S [M +
Na]+ 453.1348, found 453.1353.
20
643.2155, found 643.2164. 14b: [α]D −2.7 (c 0.65, CHCl3); 1H
Phenyl 2-O-Benzoyl-3,5-O-(di-tert-butylsilylene)-1-thio-α-D-
arabinofuranoside (12). To a solution of 11 (382 mg, 1.0 mmol)
in pyridine (4.5 mL) was added PhCOCl (0.24 mL, 2.0 mmol) at 0
°C, and the resulting mixture was warmed gradually to room
temperature. The reaction was stirred overnight at the same
temperature, at the end of which time TLC indicated it was finished.
The reaction was quenched with methanol, diluted with CH2Cl2, and
then the mixture was washed with water and brine. The organic layer
was separated and dried over anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by column chromatography
(100:1, petroleum ether−EtOAc) to afford 12 (457 mg, 94%) as a pale
NMR (400 MHz, CDCl3) δ 8.00−8.06 (m, 6H), 7.90 (d, 2H, J = 7.2
Hz), 7.21−7.61 (m, 17H), 5.90 (d, 1H, J = 4.0 Hz), 5.62 (d, 1H, J =
1.2 Hz), 5.60 (d, 1H, J = 4.8 Hz), 5.51 (s, 1H), 5.42 (d, 1H, J = 4.0
Hz), 5.40, 5.26 (2 × s, each 1H), 4.66 (d, 1H, J = 4.0 Hz), 4.59 (d, 1H,
J = 12.0 Hz), 4.49 (d, 1H, J = 12.0 Hz), 4.47−4.49 (m, 1H), 4.31 (q,
1H, J = 4.0 Hz), 4.26 (q, 1H, J = 6.0 Hz), 4.15 (dd, 1H, J = 4.0, 11.2
Hz), 4.10 (d, 1H, J = 3.2 Hz), 3.90−4.02 (m, 4H), 3.66 (dd, 1H, J =
6.8, 10.0 Hz), 2.28−2.31 (m, 1H), 1.55, 1.34 (2 × s, each 3H); 13C
NMR (100 MHz, CDCl3) δ 166.1, 165.7, 165.3, 165.1, 137.1, 133.5,
133.49, 133.4, 133.3, 130.0, 129.84, 129.8, 129.2, 129.1, 128.92, 128.9,
128.5, 128.46, 128.3, 127.9, 127.7, 113.0, 105.8, 105.6, 105.5, 85.2,
83.6, 83.0, 82.5, 82.2, 81.6, 81.5, 77.7, 77.1, 71.6, 66.5, 66.0, 62.3, 27.2,
26.4; IR (KBr) 3443, 2925, 2855, 1724, 1602, 1455 cm−1; HRMS
(ESI) calcd for C53H52O17 [M + Na]+ 983.3102, found 983.3094.
Methyl 2,5-Di-O-benzoyl-α-D-arabinofuranosyl-(1→5)-2,3-
di-O-benzoyl-α-D-arabinofuranoside (17). Prepared from 15
(52.1 mg, 0.140 mmol) and 2 (69.3 mg, 0.154 mmol). The residue
20
yellow oil: Rf 0.5 (30:1, petroleum ether−EtOAc); [α]D −79.5 (c
1
1.10, CHCl3); H NMR (400 MHz, CDCl3) δ 8.09 (d, 2H, J = 7.2
Hz), 7.46−7.62 (m, 5H), 7.26−7.33 (m, 3H), 5.53 (dd, 1H, J = 4.8,
6.8 Hz), 5.47 (d, 1H, J = 4.8 Hz), 4.43 (dd, 1H, J = 4.8, 9.6 Hz), 4.36
(dd, 1H, J = 6.8, 9.6 Hz), 4.11−4.17 (m, 1H), 4.06 (t, 1H, J = 9.6 Hz),
1.06, 1.01 (2 × s, each 9H); 13C NMR (100 MHz, CDCl3) δ 165.6,
133.9, 133.4, 131.7, 129.9, 128.9, 128.5, 127.6, 89.5, 81.4, 79.7, 73.5,
3032
dx.doi.org/10.1021/jo300084g | J. Org. Chem. 2012, 77, 3025−3037

The Journal of Organic Chemistry
Featured Article
was purified by column chromatography (3:1, petroleum ether−
EtOAc) to afford compound 17 as a colorless syrup (92.5 mg, 93%):
Rf 0.24 (3:1, petroleum ether−EtOAc); [α]D20 +16.5 (c 0.65, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.99−8.08 (m, 8H), 7.29−7.61 (m,
12H), 5.57 (dd, 1H, J = 1.6, 5.2 Hz), 5.51 (d, 1H, J = 1.6 Hz), 5.44 (s,
1H), 5.22 (d, 1H, J = 2.0 Hz), 5.16 (s, 1H), 4.63 (dd, 1H, J = 3.2, 11.2
Hz), 4.49−4.57 (m, 2H), 4.43 (q, 1H, J = 4.8 Hz), 4.19−4.23 (m, 2H),
3.96 (dd, 1H, J = 3.2, 11.2 Hz), 3.48 (s, 3H), 3.45 (d, 1H, J = 6.4 Hz);
13C NMR (100 MHz, CDCl3) δ 166.5, 166.3, 165.8, 165.5, 133.6,
133.56, 133.5, 133.0, 129.95, 129.9, 129.8, 129.7, 129.67, 129.1, 129.0,
128.9, 128.5, 128.46, 128.3, 106.8, 105.3, 85.4, 82.3, 82.1, 81.5, 77.3
(2C), 65.8, 63.8, 55.0; IR (KBr) 3053, 2930, 2857, 1723, 1602, 1453,
1274 cm−1; HRMS (ESI) calcd for C39H36O13 [M + Na]+ 735.2054,
found 735.2041.
3H); 13C NMR (100 MHz, CDCl3) δ 166.9, 165.8, 165.7, 165.5,
165.2, 133.6, 133.5, 133.3, 133.1, 130.0, 129.93, 129.9, 129.6, 129.1,
129.0, 128.9, 128.45, 128.4, 128.36, 128.3, 109.9, 109.8, 106.8, 105.8,
104.6, 86.9, 84.1, 83.9, 82.3, 81.7, 81.2, 80.8, 77.9, 77.3, 76.2, 75.8,
71.3, 65.7, 65.24, 65.2, 55.1, 26.4, 26.37, 25.4, 25.3; IR (KBr) 3443,
2935, 1725, 1603, 1453, 1376 cm−1; HRMS (ESI) calcd for C60H62O21
[M + Na]+ 1141.3681, found 1141.3690.
Methyl 2,3,6-Tri-O-benzoyl-β-D-galactofuranosyl-(1→6)-
2,3,5-tri-O-benzoyl-β-D-galactofuranoside (23). Prepared from
21 (40.0 mg, 0.079 mmol) and 4 (52.6 mg, 0.088 mmol). The residue
was purified by column chromatography (4.5:1, petroleum ether−
EtOAc) to afford compound 23 as a colorless syrup (62.1 mg, 80%):
20
Rf 0.48 (2:1, petroleum ether−EtOAc); [α]D −4.4 (c 1.95, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.25−8.06 (m, 30H), 5.87−5.90 (m,
1H), 5.62 (d, 1H, J = 4.8 Hz), 5.56 (d, 1H, J = 5.2 Hz), 5.47, 5.42,
5.36, 5.13 (4 × s, each 1H), 4.68 (dd, 1H, J = 3.6, 5.2 Hz), 4.59 (dd,
1H, J = 8.4, 12.8 Hz), 4.45−4.52 (m, 3H), 4.16 (dd, 1H, J = 6.0, 10.0
Hz), 3.99 (dd, 1H, J = 6.0, 10.0 Hz), 3.37 (s, 3H), 2.72 (d, 1H, J = 8.0
Hz); 13C NMR (100 MHz, CDCl3) δ 166.5, 166.0, 165.7, 165.68,
165.5, 165.1, 133.5, 133.4, 133.3, 133.1, 133.0, 129.9, 129.88, 129.86,
129.8, 129.77, 129.7, 129.5, 128.9, 128.89, 128.8, 128.5, 128.4, 128.33,
128.3, 106.8, 106.1, 83.6, 82.2, 81.2, 81.0, 78.0, 77.5, 71.0, 69.1, 66.2,
65.8, 54.9; IR (KBr) 3492, 2932, 1724, 1602, 1492, 1452 cm−1; HRMS
(ESI) calcd for C55H48O17 [M + Na]+ 1003.2789, found 1003.2782.
Methyl 2-O-Benzoyl-5,6-O-isopropylidene-β-D-galactofura-
nosyl-(1→3)-2-O-benzyl-4,6-O-benzylidene-α-D-glucopyrano-
side (25). Prepared from 24 (82 mg, 0.22 mmol) and 3 (105 mg, 0.24
mmol). The residue was purified by column chromatography (4.5:1,
petroleum ether−EtOAc) to afford compound 25 as an amorphous
Methyl 2,5-Di-O-benzoyl-α-D-arabinofuranosyl-(1→5)-2,3-
di-O-benzyl-α-D-arabinofuranoside (19). Prepared from 18 (49.1
mg, 0.143 mmol) and 2 (70.7 mg, 0.157 mmol). The residue was
purified by column chromatography (3.5:1, petroleum ether−EtOAc)
to afford compound 19 as a colorless syrup (91.7 mg, 94%): Rf 0.31
(3:1, petroleum ether−EtOAc); [α]D +58.7 (c 1.25, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.98−8.03 (m, 4H), 7.25−7.60 (m, 16H),
5.32 (s, 1H), 5.19 (d, 1H, J = 1.6 Hz), 4.96 (s, 1H), 4.42−4.60 (m,
6H), 4.27 (q, 1H, J = 5.2 Hz), 4.18−4.26 (m, 2H), 3.99 (d, 1H, J = 1.6
Hz), 3.88−3.92 (m, 2H), 3.74 (dd, 1H, J = 3.2, 10.8 Hz), 3.48 (d, 1H,
J = 7.2 Hz), 3.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3,
166.26, 137.5, 137.2, 133.6, 133.1, 129.8, 129.7, 129.67, 129.0, 128.6,
128.5, 128.48, 128.4, 128.1, 128.0, 127.9, 107.2, 105.1, 87.3, 84.4, 83.3,
82.8, 80.8, 77.1, 72.1, 72.0, 66.3, 63.9, 55.0; IR (KBr) 3369, 2921,
2852, 1723, 1583, 1439 cm−1; HRMS (ESI) calcd for C39H40O11 [M +
Na]+ 707.2468, found 707.2474.
20
1
20
solid (118 mg, 79%): Rf 0.44 (2:1, petroleum ether−EtOAc); [α]D
−19.8 (c 1.10, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 2H, J
= 7.6 Hz), 7.57 (t, 1H, J = 7.2 Hz), 7.22−7.49 (m, 12H), 5.63, 5.49 (2
× s, each 1H), 5.09 (d, 1H, J = 1.6 Hz), 4.71 (d, 1H, J = 12.0 Hz), 4.66
(d, 1H, J = 12.0 Hz), 4.65 (d, 1H, J = 3.6 Hz), 4.35 (t, 1H, J = 9.2 Hz),
4.27 (dd, 1H, J = 4.8, 10.4 Hz), 4.02−4.09 (m, 3H), 3.85 (td, 1H, J =
4.8, 10.0 Hz), 3.68 (t, 1H, J = 10.4 Hz), 3.57−3.61 (m, 2H), 3.46−
3.52 (m, 2H), 3.40 (s, 3H), 3.13 (d, 1H, J = 6.8 Hz), 1.30, 1.29 (2 × s,
each 3H); 13C NMR (100 MHz, CDCl3) δ 166.3, 137.6, 137.1, 133.4,
129.7, 129.2, 128.4, 128.37, 128.2, 128.0, 127.9, 126.2, 109.5, 105.1,
101.8, 98.5, 85.0, 83.2, 79.9, 79.8, 77.1, 74.7, 73.1, 72.3, 65.2, 62.5,
55.3, 26.0, 25.5; IR (KBr) 3528, 2928, 1727, 1603, 1456, 1376 cm−1;
HRMS (ESI) calcd for C37H42O12 [M + Na]+ 701.2574, found
701.2578.
Methyl 2,5-Di-O-benzoyl-α-D-arabinofuranosyl-(1→3)-2,5-
di-O-benzoy-α-D-arabinofuranoside (20). Prepared from 7 (42.0
mg, 0.113 mmol) and 2 (63.2 mg, 0.141 mmol). The residue was
purified by column chromatography (4:1, petroleum ether−EtOAc) to
afford compound 20 as a colorless syrup (49.2 mg, 61%): Rf 0.12 (4:1,
20
1
petroleum ether−EtOAc); [α]D +43.8 (c 0.54, CHCl3); H NMR
(400 MHz, CDCl3) δ 7.23−8.06 (m, 20H), 5.70, 5.33 (2 × s, each
1H), 5.22 (d, 1H, J = 2.0 Hz), 5.16 (s, 1H), 4.78 (dd, 1H, J = 2.8, 12.0
Hz), 4.55−4.60 (m, 2H), 4.45−4.50 (m, 4H), 4.19−4.22 (m, 1H),
3.49 (d, 1H, J = 4.4 Hz), 3.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
167.0, 166.25, 166.2, 165.6, 133.8, 133.5, 133.1, 130.0, 129.8, 129.7,
129.6, 128.8, 128.6, 128.5, 128.33, 128.3, 106.9, 105.0, 86.5, 82.5, 81.6,
81.3, 81.1, 77.7, 63.7, 63.1, 54.9; IR (KBr) 3498, 2926, 2854, 1723,
1602, 1453 cm−1; HRMS (ESI) calcd for C39H36O13 [M + Na]+
735.2054, found 735.2057.
Methyl 2,5-Di-O-benzoyl-3-O-tert-butyldiphenylsilyl-α-L-ara-
binofuranoside (30). Prepared from methyl glycoside 29 (2.06 g,
5.54 mmol), imidazole (1.13 g, 16.62 mmol), and TBDPSCl (2.23 mL,
8.31 mmol) in dry DMF (14 mL) following a procedure similar to that
for 7 → 8. The crude product was purified by column chromatography
(30:1, petroleum ether−EtOAc) to give 30 as a colorless syrup (3.01 g,
Methyl 2-O-Benzoyl-5,6-O-isopropylidene-β-D-galactofura-
nosyl-(1→6)-2,3,5-tri-O-benzoyl-β-D-galactofuranoside (22a)
and Methyl 2-O-Benzoyl-5,6-O-isopropylidene-β-D-galactofur-
anosyl-(1→3)-2-O-benzoyl-5,6-O-isopropylidene-β-D-galacto-
furanosyl-(1→6)-2,3,5-tri-O-benzoyl-β-D-galactofuranoside
(22b). Prepared from 21 (32 mg, 0.063 mmol) and 3 (30.1 mg, 0.070
mmol). The residue was purified by column chromatography (3:1,
petroleum ether−EtOAc) to afford compound 22a (38.4 mg, 75%)
and 22b (9.8 mg, 14%) as colorless syrups: Rf 0.30 (22a) and 0.22
20
89%): Rf 0.51 (4:1, petroleum ether−EtOAc); [α]D −43.7 (c 1.00,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.88 (dd, 2H, J = 1.2, 8.4
Hz), 7.78 (dd, 2H, J = 1.2, 8.4 Hz), 7.60−7.65 (m, 4H), 7.51−7.57 (m,
2H), 7.17−7.38 (m, 10H), 5.28, 4.90 (2 × s, each 1H), 4.43−4.47 (m,
3H), 4.06 (dd, 1H, J = 4.4, 12.4 Hz), 3.46 (s, 3H), 1.07 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 165.8, 165.3, 135.7, 135.66, 133.2, 132.9,
132.8, 132.4, 130.0, 129.9, 129.7, 128.2, 127.8, 127.7, 106.9, 85.0, 81.5,
77.4, 62.9, 54.9, 26.8, 19.1; IR (KBr) 2931, 2858, 1725, 1602, 1452,
1366 cm−1; HRMS (ESI) calcd for C36H38O7Si [M + Na]+ 633.2248,
found 633.2280.
20
(22b) (1:1, petroleum ether−EtOAc). 22a: [α]D −40.8 (c 1.4,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.28−8.10 (m, 20H), 5.82−
5.86 (m, 1H), 5.60 (d, 1H, J = 5.2 Hz), 5.45, 5.28, 5.20 (3 × s, each
1H), 5.00 (d, 1H, J = 1.6 Hz), 4.62 (dd, 1H, J = 3.6, 5.6 Hz), 4.12−
4.25 (m, 3H), 3.95−4.04 (m, 3H), 3.87 (dd, 1H, J = 7.2, 8.8 Hz), 3.55
(d, 1H, J = 7.2 Hz) 3.50 (s, 3H), 1.34 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 166.3, 166.0, 165.7, 165.5, 133.6, 133.5, 133.4, 133.2, 129.9,
129.8, 129.77, 129.5, 128.9, 128.5, 128.4, 109.8, 106.7, 105.2, 85.2,
84.9, 82.3, 81.1, 77.6, 77.4, 75.9, 71.3, 66.1, 65.4, 55.0, 26.3, 25.4; IR
(KBr) 3453, 2934, 1725, 1602, 1453, 1372 cm−1; HRMS (ESI) calcd
Phenyl 2,5-Di-O-benzoyl-3-O-tert-butyldiphenylsilyl-1-thio-
α-L-arabinofuranoside (31). Prepared from glycoside 30 (3.37 g,
5.52 mmol), PhSH (0.67 mL, 6.63 mmol), and BF3·Et2O (4.2 mL,
33.1 mmol) in CH2Cl2 (38.7 mL) following a procedure similar to that
for 8 → 9. The crude product was purified by column chromatography
(30:1, petroleum ether−EtOAc) to give 31 as a colorless syrup (3.2 g,
20
for C44H44O15 [M + Na]+ 835.2578, found 835.2567. 22b: [α]D
−43.4 (c 0.70, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.25−8.07 (m,
25H), 5.80−5.84 (m, 1H), 5.64 (s, 1H), 5.60 (d, 1H, J = 5.6 Hz), 5.43,
5.28, 5.21, 5.17 (4 × s, each 1H), 5.06 (d, 1H, J = 2.4 Hz), 4.68 (dd,
1H, J = 4.0, 5.2 Hz), 3.93−4.27 (m, 11H), 3.85 (dd, 1H, J = 6.8, 8.0
Hz), 3.67 (d, 1H, J = 4.0 Hz), 3.50, 1.42, 1.39, 1.35, 1.34 (5 × s, each
84%): Rf 0.45 (8:1, petroleum ether−EtOAc); [α]D −95.6 (c 1.35,
20
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.86 (dd, 2H, J = 1.2, 7.2
Hz), 7.81 (dd, 2H, J = 1.2, 7.2 Hz), 7.64−7.68 (m, 4H), 7.50−7.57 (m,
4H), 7.22−7.37 (m, 13H), 5.60, 5.47 (2 × s, each 1H), 4.71−4.74 (m,
1H), 4.45 (dd, 1H, J = 0.8, 4.8 Hz), 4.35 (dd, 1H, J = 2.8, 12.0 Hz),
3033
dx.doi.org/10.1021/jo300084g | J. Org. Chem. 2012, 77, 3025−3037

The Journal of Organic Chemistry
Featured Article
4.07 (dd, 1H, J = 2.8, 12.0 Hz), 1.12 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 166.1, 165.2, 135.9, 135.8, 134.6, 133.4, 133.0, 132.7, 132.3,
131.9, 130.2, 130.1, 129.8, 129.7, 129.2, 129.0, 128.4, 128.3, 128.0,
127.9, 127.5, 91.4, 85.1, 82.5, 77.6, 63.0, 26.9, 19.3; IR (KBr) 2930,
2858, 1724, 1602, 1585, 1452 cm−1; HRMS (ESI) calcd for
C41H40O6SSi [M + Na]+ 711.2213, found 711.2226.
Phenyl 2,5-Di-O-benzoyl-1-thio-α-L-arabinofuranoside (32).
Prepared from 31 (600 mg, 0.87 mmol) and TBAF (0.53 mL, 1.0 M in
THF, 0.53 mmol) in THF (1.8 mL) following a procedure similar to
that for 9 → 2. The crude product was purified by column
chromatography (5:1, petroleum ether−EtOAc) to give 32 as a
white solid (310 mg, 79%): Rf 0.21 (4:1, petroleum ether−EtOAc);
[α]D20 −160.4 (c 0.80, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.00−
8.07 (m, 4H), 7.52−7.63 (m, 4H), 7.45 (t, 2H, J = 8.0 Hz), 7.36 (t,
2H, J = 8.0 Hz), 7.28−7.32 (m, 3H), 5.78 (d, 1H, J = 2.8 Hz), 5.18 (t,
1H, J = 3.2 Hz), 4.57−4.69 (m, 3H), 4.27−4.31 (m, 1H), 3.53 (d, 1H,
J = 3.2 Hz); 13C NMR (100 MHz, CDCl3) δ 167.4, 166.5, 134.0,
133.5, 133.3, 132.4, 120.1, 129.9, 129.8, 129.2, 128.8, 128.77, 128.5,
128.1, 89.4, 87.2, 80.7, 77.6, 63.5; IR (KBr) 3520, 2932, 1710, 1601,
1583, 1453 cm−1; HRMS (ESI) calcd for C25H22O6S [M + Na]+
473.1035, found 473.1038.
Phenyl 2,3,5-Tri-O-benzoyl-α-L-arabinofuranosyl-(1→3)-2,5-
di-O-benzoyl-α-L-arabinofuranoside (34). The donor 33 (876
mg, 1.44 mmol) and the acceptor 32 (500 mg, 1.11 mmol) were dried
together under high vacuum for 0.5 h. The mixture was dissolved in
CH2Cl2 (47 mL) and followed by addition of freshly activated 4 Å
molecular sieves (1.4 g). The resulting slurry was cooled to 0 °C, then
a solution of TMSOTf (26.1 μL, 0.14 mmol) in CH2Cl2 (1.0 mL) was
added. After being stirred for 30 min at the same temperature, the
reaction mixture was quenched with triethylamine and filtered. The
filtrates were concentrated to give a residue, which was purified by
column chromatography (6:1, petroleum ether−EtOAc) to afford 34
as a colorless syrup (932.5 mg, 94%): Rf 0.20 (4:1, petroleum ether−
EtOAc); [α]D20 −77.0 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.21−8.17 (m, 30H), 5.82, 5.71, 5.67 (3 × s, each 1H), 5.59−5.60
(m, 2H), 4.82 (q, 1H, J = 4.4 Hz), 4.66−4.74 (m, 3H), 4.56−4.64 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 166.1, 166.08, 165.7, 165.5,
165.3, 133.6, 133.55, 133.1, 133.0, 132.0, 130.1, 130.0, 129.8, 129.7,
129.6, 129.5, 129.49, 129.0, 128.9, 128.8, 128.5, 128.3, 127.6, 105.6,
91.2, 83.3, 82.2, 81.7, 81.4, 81.1, 77.4, 63.7, 62.9; IR (KBr) 2924, 2854,
1723, 1602, 1584, 1452 cm−1; HRMS (ESI) calcd for C51H42O13S [M
+ Na]+ 917.2244, found 917.2245.
General Procedure for the Chemo- and Regioselective
Glycosylations of Diol Thioglycosides 5 and 6 with Trichlor-
oacetimidates 26 and 28. A mixture of trichloroacetimidate donor
(0.26 mmol, 1.3 equiv), diol thioglycoside acceptor (1.0 equiv), and
freshly activated 4 Å molecular sieves (300 mg) in dry CH2Cl2 (8.5
mL) was cooled to −45 °C. The suspension was stirred for 15 min,
then a solution of TMSOTf (0.026 mmol) in CH2Cl2 (1 mL) was
added dropwise at −45 °C. The reaction was stirred for 0.5 h at the
same temperature, at the end of which time TLC indicated it was
finished. The reaction was quenched with Et3N, diluted with CH2Cl2,
filtered, and concentrated. The resulting residue was purified by
column chromatography eluted with petroleum ether−EtOAc to
afford the corresponding di- or trisaccharide thioglycoside products.
Phenyl 2,3,5-Tri-O-benzoyl-α-D-arabinofuranosyl-(1→5)-2-
O-benzoyl-α-D-arabinofuranoside (27). Prepared from thioglyco-
side 5 (69.2 mg, 0.20 mmol) and imidate 26 (157.7 mg, 0.26 mmol).
The residue was purified by column chromatography (5:1, petroleum
ether−EtOAc) to afford compound 27 as a colorless syrup (135.8 mg,
20
86%): Rf 0.25 (4:1, petroleum ether−EtOAc); [α]D +71.4 (c 1.00,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.22−8.04 (m, 25H), 5.77
(d, 1H, J = 3.6 Hz), 5.57 (br s, 2H), 5.40 (s, 1H), 5.17 (t, 1H, J = 3.6
Hz), 4.79 (dd, 1H, J = 3.2, 11.6 Hz), 4.59−4.67 (m, 2H), 4.44−4.48
(m, 1H), 4.33−4.37 (m, 1H), 4.07 (dd, 1H, J = 4.0, 11.6 Hz), 3.94
(dd, 1H, J = 4.0, 11.6 Hz), 3.60 (d, 1H, J = 2.8 Hz); 13C NMR (100
MHz, CDCl3) δ 167.0, 165.9, 165.4, 165.0, 133.4, 133.3, 133.2, 133.1,
132.7, 131.3, 129.6, 129.5, 129.4, 129.3, 128.7, 128.6, 128.56, 128.4,
128.2, 128.16, 128.1, 128.0, 127.3, 105.6, 88.6, 86.7, 81.6, 81.0, 80.8,
77.3, 76.2, 65.4, 63.3; IR (KBr) 3467, 2925, 1724, 1602, 1584, 1452
cm−1; HRMS (ESI) calcd for C44H38O12S [M + Na]+ 813.1982, found
813.1979.
Phenyl 2,3,5-Tri-O-benzoyl-α-L-arabinofuranosyl-(1→3)-2,5-
di-O-benzoyl-α-L-arabinofuranosyl-(1→5)-2-O-benzoyl-α-L-
arabinofuranoside (35). Prepared from thioglycoside 6 (65.8 mg,
0.19 mmol) and imidate 28 (233.7 mg, 0.25 mmol). The residue was
purified by column chromatography (3.5:1, petroleum ether−EtOAc)
to afford compound 35 as a colorless syrup (163.5 mg, 76%): Rf 0.45
20
1
(2:1, petroleum ether−EtOAc); [α]D −59.3 (c 0.95, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.19−8.06 (m, 35H), 5.77 (d, 1H, J = 3.6
Hz), 5.70 (s, 1H), 5.48 (d, 1H, J = 4.4 Hz), 5.46 (br s, 2H), 5.42 (s,
1H), 5.19 (t, 1H, J = 3.6 Hz), 4.62−4.67 (m, 2H), 4.46−4.58 (m, 7H),
4.11 (dd, 1H, J = 4.0, 11.6 Hz), 3.90 (dd, 1H, J = 4.0, 11.6 Hz), 3.66
(d, 1H, J = 2.4 Hz); 13C NMR (100 MHz, CDCl3) δ 167.3, 166.4,
166.38, 165.8, 165.7, 165.6, 134.1, 133.9, 133.8, 133.78, 133.4, 133.3,
132.0, 130.2, 130.17, 130.12, 130.1, 130.0, 129.9, 129.7, 129.3, 129.26,
129.2, 129.1, 129.0, 128.9, 128.8, 128.7, 128.69, 128.6, 128.56, 127.8,
106.2, 105.0, 89.4, 86.8, 82.3, 81.9, 81.8, 81.7, 81.6, 80.6, 77.6, 76.8,
65.7, 63.9, 63.6; IR (KBr) 3447, 2925, 1724, 1602, 1452, 1272 cm−1;
HRMS (ESI) calcd for C63H54O18S [M + Na]+ 1153.2929, found
1153.2917.
2,3,5-Tri-O-benzoyl-α-L-arabinofuranosyl-(1→3)-2,5-di-O-
benzoyl-α-L-arabinofuranosyl trichloroacetimidate (28). To a
solution of 34 (680 mg, 0.76 mmol) in EtOAc (105 mL) were added
NBS (1.35 g, 7.6 mmol) and water (21 mL) at room temperature. The
reaction mixture was allowed to stir for 4 h at the same temperature,
and then saturated aqueous Na2S2O3 was added. The organic layer was
washed with water and brine, dried, and the solvent was evaporated.
The crude product was purified by column chromatography (3:1,
petroleum ether−EtOAc) to afford a colorless syrup which was
directly used for the next step without further purification. To a stirred
solution of the obtained syrup (439.5 mg, 0.55 mmol) in CH2Cl2 (2.9
mL) were added CCl3CN (0.27 mL, 2.75 mmol) and DBU (0.16 mL,
1.1 mmol) at 0 °C, and the resulting mixture was warmed gradually to
room temperature. The mixture was stirred for 2 h at the same
temperature, at the end of which time TLC indicated the reaction was
complete. The resulting mixture was concentrated and the residue was
purified by column chromatography (5:1, petroleum ether−EtOAc) to
afford compound 28 as a colorless syrup (404 mg, 56% over two
One-Pot Synthesis of the Protected Oligosaccharides 39, 41,
and 44. Methyl 2,3,5-Tri-O-acetyl-α-D-arabinofuranosyl-(1→3)-
2,5-di-O-benzoyl-α-D-arabinofuranosyl-(1→5)-2,3-di-O-benzo-
yl-α-D-arabinofuranoside (39). A mixture of donor 2 (139 mg, 0.31
mmol), methyl glycoside 15 (103 mg, 0.28 mmol), and freshly
activated 4 Å molecular sieves (250 mg) in dry CH2Cl2 (10 mL) was
cooled to −40 °C. The suspension was stirred for 15 min at −40 °C,
then NIS (79 mg, 0.35 mmol) and TfOH (0.6 μL, 0.006 mmol) were
added and the resulting mixture was gradually warmed to −20 °C. The
reaction mixture was stirred for 30 min at the same temperature, at the
end of which time TLC indicated the complete consumption of the
starting materials. A solution of donor 38 (129 mg, 0.35 mmol) in
CH2Cl2 (1 mL) was added to the reaction mixture when the
temperature was recooled to −40 °C. Then NIS (79 mg, 0.35 mmol)
and TfOH (0.6 μL, 0.006 mmol) were added, and the resulting
mixture was gradually warmed to −20 °C. After being stirred for 30
min at the same temperature, the reaction mixture was quenched with
Et3N, diluted with CH2Cl2, filtered, and concentrated. The resulting
residue was purified by column chromatography (3:1, petroleum
ether−EtOAc) to afford protected trisaccharide 39 (190 mg, 70%) as a
20
steps): Rf 0.46 (3:1, petroleum ether−EtOAc); [α]D +4.4 (c 1.05,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.18−8.08 (m,
25H), 6.63, 5.82, 5.61 (3 × s, each 1H), 5.57−5.61 (m, 2H), 4.54−
4.76 (m, 7H); 13C NMR (100 MHz, CDCl3) δ 166.1, 166.0, 165.6,
165.3, 165.2, 160.5, 133.7, 133.6, 133.5, 133.2, 133.0, 129.9, 129.86,
129.83, 129.8, 129.74, 129.7, 129.6, 129.5, 129.2, 128.9, 128.8, 128.7,
128.5, 128.4, 128.37, 128.3, 128.2, 105.0, 103.2, 97.3, 83.9, 81.9, 81.7,
81.1, 80.2, 77.6, 63.5, 62.9. Attempts to further purify this compound
for HRMS analysis were unsuccessful.
20
colorless syrup: Rf 0.18 (3:1, petroleum ether−EtOAc); [α]D +36.3
(c 0.95, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.96−8.12 (m, 8H),
3034
dx.doi.org/10.1021/jo300084g | J. Org. Chem. 2012, 77, 3025−3037

The Journal of Organic Chemistry
Featured Article
7.18−7.61 (m, 12H), 5.65 (d, 1H, J = 5.2 Hz), 5.51 (s, 1H), 5.41−5.44
(m, 3H), 5.14 (s, 1H), 5.04 (d, 1H, J = 1.2 Hz), 4.89 (dd, 1H, J = 1.6,
5.2 Hz), 4.74 (dd, 1H, J = 2.4, 12.0 Hz), 4.60−4.64 (m, 1H), 4.53 (dd,
1H, J = 4.4, 12.0 Hz), 4.42−4.46 (m, 1H), 4.36 (d, 1H, J = 5.6 Hz),
4.31 (dd, 1H, J = 3.2, 11.6 Hz), 4.21−4.25 (m, 2H), 4.11 (dd, 1H, J =
6.0, 12.0 Hz), 3.95 (dd, 1H, J = 2.4, 11.2 Hz), 3.48, 2.01, 1.97, 1.91 (4
× s, each 3H); 13C NMR (100 MHz, CDCl3) δ 170.6, 170.1, 169.2,
166.2, 165.7, 165.5, 165.4, 133.51, 133.5, 133.1, 129.9, 129.8, 129.6,
129.2, 129.1, 128.6, 128.53, 128.5, 128.3, 106.7, 105.4, 105.37, 82.8,
82.0, 81.9, 81.3, 81.2 (2C), 80.5, 77.2, 76.9, 65.4, 63.2, 63.0, 54.9, 20.8,
20.6, 20.5; IR (KBr) 2939, 1724, 1603, 1453, 1372, 1274 cm−1; HRMS
(ESI) calcd for C50H50O20 [M + Na]+ 993.2793, found 993.2801.
Methyl 2,3,5,6-Tetra-O-benzoyl-β-D-galactofuranosyl-(1→5)-
2,3,6-tri-O-benzoyl-β-D-galactofuranosyl-(1→6)-2,3,5-tri-O-
benzoyl-β-D-galactofuranoside (41). Using the same procedures as
described for the one-pot preparation of 39, thioglycoside donor 4
(158 mg, 0.26 mmol) and acceptor 21 (118 mg, 0.23 mmol) were
coupled first by activation with NIS (66 mg, 0.29 mmol) and TfOH
(0.5 μL, 0.005 mmol), then the resulting disaccharide methyl glycoside
23 was glycosylated with the donor 40 (204 mg, 0.29 mmol)
promoted by NIS (66 mg, 0.29 mmol) and TfOH (0.5 μL, 0.005
mmol) to give a crude product, which was purified by column
chromatography (4:1, petroleum ether−EtOAc) to afford protected
trisaccharide 41 (241 mg, 67%) as a colorless syrup: Rf 0.47 (2:1,
petroleum ether−EtOAc); [α]D −14.9 (c 1.10, CHCl3); H NMR
(400 MHz, CDCl3) δ 7.22−8.07 (m, 50H), 6.03−6.07 (m, 1H), 5.86−
5.90 (m, 1H), 5.83 (d, 1H, J = 4.4 Hz), 5.80, 5.67 (2 × s, each 1H),
5.61 (d, 1H, J = 4.2 Hz), 5.56 (d, 1H, J = 4.2 Hz), 5.49, 5.41, 5.31, 5.10
(4 × s, each 1H), 5.06 (t, 1H, J = 4.2 Hz), 4.61−4.79 (m, 7H), 4.16
(dd, 1H, J = 6.8, 10.0 Hz), 3.97 (dd, 1H, J = 6.8, 10.0 Hz), 3.34 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 166.0, 165.95, 165.7, 165.68,
165.67, 165.65, 165.5 165.48, 165.2, 165.1, 133.35, 133.3, 133.2,
133.16, 133.1, 132.9, 132.88, 129.94, 129.92, 129.9, 129.8, 129.78,
129.7, 129.64, 129.6, 129.56, 129.5, 129.46, 129.0, 128.9, 128.8, 128.7,
128.6, 128.4, 128.37, 128.35, 128.3, 128.27, 128.2, 128.1, 106.8, 105.8,
105.0, 83.0, 82.2, 82.0, 81.9, 81.5, 80.9, 77.8, 77.5, 77.0, 73.4, 70.8,
70.5, 65.4, 64.7, 63.8, 55.00; IR (KBr) 2926, 2854, 1726, 1602, 1492,
1452 cm−1; HRMS (ESI) calcd for C89H74O26 [M + Na]+ 1581.4366,
found 1581.4368.
Methyl 2,3,4,6-Tetra-O-benzoyl-β-D-galactopyranosyl-(1→
3)-2-O-benzoyl-5,6-O-isopropylidene-β-D-galactofuranosyl-
(1→3)-2-O-benzyl-4,6-O-benzylidene-α-D-glucopyranoside
(44). Using the same procedures as described for the one-pot
preparation of 39, thioglycoside donor 3 (129 mg, 0.30 mmol) and
acceptor 24 (100 mg, 0.27 mmol) were coupled first by activation with
NIS (76 mg, 0.34 mmol) and TfOH (0.5 μL, 0.006 mmol), then the
resulting disaccharide methyl glycoside 25 was glycosylated with the
donor 43 (234 mg, 0.34 mmol) promoted by NIS (76 mg, 0.34 mmol)
and TfOH (0.5 μL, 0.006 mmol) to give a crude product, which was
purified by column chromatography (4:1, petroleum−EtOAc) to
afford protected trisaccharide 44 (220.5 mg, 65%) as a colorless syrup:
Rf 0.43 (2:1, petroleum ether−EtOAc); [α]D20 +53.6 (c 1.00, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.16−8.13 (m, 35H), 6.05 (d, 1H, J =
3.2 Hz), 5.92 (dd, 1H, J = 8.0, 10.4 Hz), 5.74 (dd, 1H, J = 3.6, 10.4
Hz), 5.56 (d, 1H, J = 8.4 Hz), 5.56, 5.40, 5.09 (3 × s, each 1H), 4.65
(dd, 1H, J = 5.2, 9.2 Hz), 4.41−4.49 (m, 3H), 4.27−4.39 (m, 4H),
4.22 (dd, 1H, J = 4.4 10.0 Hz), 4.11 (t, 1H, J = 9.2 Hz), 3.95−3.98 (m,
1H), 3.64 (td, 1H, J = 4.4, 9.6 Hz), 3.52−3.60 (m, 2H), 3.47 (t, 1H, J
= 8.0 Hz), 3.31 (s, 3H), 2.76 (t, 1H, J = 9.6 Hz), 2.58 (dd, 1H, J = 3.2,
9.2 Hz), 1.15 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 166.0, 165.8,
165.50, 165.47, 165.0, 138.0, 137.7, 133.5, 133.47, 133.2, 133.17,
133.0, 130.2, 129.9, 129.8, 129.76, 129.6, 129.3, 129.0, 128.8, 128.7,
128.6, 128.5, 128.3, 128.26, 128.0, 127.9, 127.7, 126.4, 109.4, 104.7,
101.2, 99.1, 98.3, 82.2, 81.9, 81.1, 80.6, 79.2, 75.0, 73.0, 71.8, 71.3,
71.2, 69.5, 68.9, 68.2, 65.2, 62.3, 61.9, 55.0, 25.8, 25.5; IR (KBr) 2982,
2934, 1730, 1603, 1453, 1376 cm−1; HRMS (ESI) calcd for C71H68O21
[M + Na]+ 1279.4151, found 1279.4136.
NaOCH3 (4 mg) at 0 °C, and the resulting mixture was warmed
gradually to room temperature. The mixture was stirred for 2 h at the
same temperature, at the end of which time TLC indicated it was
finished. The reaction was quenched with acetic acid, and the resulting
mixture was concentrated to dryness. The resulting residue was
purified by column chromatography.
Methyl α-D-Arabinofuranosyl-(1→3)-α-D-arabinofuranosyl-
(1→5)-α-D-arabinofuranoside (36). Prepared from 39 (29 mg,
0.03 mmol). The residue was purified by column chromatography
(3:1, CH2Cl2−MeOH) to afford 36 as a colorless syrup in a yield of
85%. The spectroscopic data for 36 were identical with that previously
reported.8a,10h
Methyl β-D-Galactofuranosyl-(1→5)-β-D-galactofuranosyl-
(1→6)-β-D-galactofuranoside (37). Prepared from 41 (41 mg,
0.026 mmol). The residue was purified by column chromatography
(3:1, CH2Cl2−MeOH) to afford 37 (12.2 mg, 90%) as a colorless
20
syrup: Rf 0.24 (2.5:1, CH2Cl2−MeOH); [α]D −110.6 (c 0.70,
1
CH3OH); H NMR (400 MHz, D2O) δ 5.25, 5.04, 4.94 (3 × s, each
1H), 4.08−4.18 (m, 8H), 3.95−4.05 (m, 3H), 3.81−3.92 (m, 4H),
3.62−3.74 (m, 3H), 3.44 (m, 3H); 13C NMR (100 MHz, D2O) δ
110.5, 110.1, 109.5, 85.4, 84.9, 84.2, 83.7, 83.3, 83.1, 79.1 (2C), 78.9,
78.3, 72.9, 72.0, 71.4, 65.2, 63.4, 57.3; IR (KBr) 3352, 2931, 2856,
1354, 1070, 1027 cm−1; HRMS (ESI) calcd for C19H34O16 [M + Na]+
541.1745, found 541.1740.
20
1
Methyl β-D-Galactopyranosyl-(1→3)-β-D-galactofuranosyl-
(1→3)-2-O-benzyl-α-D-glucopyranoside (45). Trisaccharide 44
(181 mg, 0.144 mmol) was dissolved in HOAc−H2O (4:1, v/v, 10
mL), and the resulting mixture was warmed gradually to 70 °C. The
mixture was stirred for 4 h at the same temperature, at the end of
which time TLC indicated it was finished. The mixture was cooled and
concentrated to give a residue. To a stirred solution of the obtained
residue in CH3OH (3 mL) was added NaOCH3 (22 mg) at 0 °C, and
the resulting mixture was warmed gradually to room temperature. The
mixture was stirred for 2 h at the same temperature, at the end of
which time TLC indicated it was finished. The reaction was quenched
with acetic acid, and the resulting mixture was concentrated to dryness.
The resulting residue was purified by column chromatography (3.5:1,
CH2Cl2−MeOH) to afford compound 45 as a colorless syrup (70 mg,
20
80% over two steps): Rf 0.17 (3.5:1, CH2Cl2−MeOH); [α]D −13.2
(c 1.50, CH3OH); 1H NMR (400 MHz, D2O) δ 7.47 (br s, 5H), 5.28
(s, 1H), 4.72 (br s, 2H), 4.54 (d, 1H, J = 7.6 Hz), 4.24−4.28 (m, 2H),
4.20 (br s, 1H), 3.94−3.97 (m, 2H), 3.83−3.88 (m, 2H), 3.76−3.80
(m, 2H), 3.60−3.73 (m, 7H), 3.54 (dd, 1H, J = 8.0, 10.0 Hz), 3.36−
3.44 (m, 2H), 3.40 (s, 3H); 13C NMR (100 MHz, D2O) δ 139.6,
131.2, 131.15, 130.9, 110.7, 105.0, 99.5, 87.1, 84.5, 82.2, 81.2, 80.5,
77.6, 75.2, 74.9, 73.8, 73.0, 72.8, 70.9, 70.2, 65.3, 63.4, 62.8, 57.2; IR
(KBr) 3342, 2982, 2934, 1604, 1453, 1374 cm−1; HRMS (ESI) calcd
for C26H40O16 [M + Na]+ 631.2214, found 631.2208.
Methyl β-D-Galactopyranosyl-(1→3)-β-D-galactofuranosyl-
(1→3)-α-D-glucopyranoside (42). To a solution of 45 (32 mg,
0.053 mmol) in CH3OH (2 mL) was added 10% Pd/C (30 mg), and
the reaction mixture was stirred under a hydrogen atmosphere at 30
°C. The mixture was stirred for 24 h at the same temperature, at the
end of which time TLC indicated it was finished. The reaction mixture
was filtered, and the filtrate was concentrated to give a residue, which
was purified by column chromatography (1:1, CH2Cl2−MeOH) to
afford compound 42 as a colorless syrup (23 mg, 84%): Rf 0.27 (1:1,
20
CH2Cl2−MeOH); [α]D +4.1 (c 1.15, CH3OH); 1H NMR (400
MHz, D2O) δ 5.28 (s, 1H), 4.81 (d, 1H, J = 3.6 Hz), 4.56 (d, 1H, J =
7.6 Hz), 4.35 (br s, 1H), 4.27−4.32 (m, 2H), 3.96−4.00 (m, 1H), 3.93
(d, 1H, J = 3.2 Hz), 3.88 (dd, 1H, J = 2.0, 12.4 Hz), 3.66−3.84 (m,
10H), 3.54 (dd, 1H, J = 8.0, 10.0 Hz), 3.43−3.47 (m, 1H), 3.45 (s,
3H); 13C NMR (100 MHz, D2O) δ 110.8, 105.0, 101.6, 86.7, 84.4,
82.2, 82.1, 77.6, 74.9, 73.9, 73.6, 73.0, 72.6, 70.9, 70.2, 65.3, 63.4, 62.8,
57.4; IR (KBr) 3342, 2934, 2858, 1360, 1070, 1028 cm−1; HRMS
(ESI) calcd for C19H34O16 [M + Na]+ 541.1745, found 541.1742.
One-Pot Synthesis of the Protected Oligosaccharides 46
and 47. Methyl 2,3,5-Tri-O-benzoyl-α-D-arabinofuranosyl-(1→
5)-2,3-di-O-benzoyl-α-D-arabinofuranosyl-(1→3)-(2,3,5-tri-O-
benzoyl-α-D-arabinofuranosyl)-(1→5)-2-O-benzoyl-α-D-arabi-
nofuranosyl-(1→5)-2,3-di-O-benzoyl-α-D-arabinofuranosyl-
General Procedure for the Deacylation of Trisaccharides
Intermediates 39 and 41. To a solution of trisaccharide 39/41
(0.03 mmol) in CH2Cl2−CH3OH (1:7, v/v, 2 mL) was added
3035
dx.doi.org/10.1021/jo300084g | J. Org. Chem. 2012, 77, 3025−3037

The Journal of Organic Chemistry
Featured Article
20
1
(1→5)-2,3-di-O-benzoyl-α-D-arabinofuranoside (46). A solution
of trichloroacetimidate 26 (137.2 mg, 0.226 mmol), 3,5-diol
thioglycoside 5 (60.2 mg, 0.174 mmol), and freshly activated 4 Å
molecular sieves (520 mg) in dry CH2Cl2 (6.5 mL) was stirred at
room temperature for 15 min. Then the suspension was cooled to −45
°C, and a solution of TMSOTf (4.2 μL, 0.023 mmol) in CH2Cl2 (1
mL) was added dropwise. After being stirred for 30 min at the same
temperature, the reaction was gradually warmed to ambient temper-
ature. The reaction mixture was stirred for a further 1 h at the same
temperature, at the end of which time TLC indicated the complete
consumption of the starting materials. The resulting slurry was
recooled to −40 °C, and a solution of 5′-OH disaccharide acceptor 16a
(123.9 mg, 0.174 mmol) in CH2Cl2 (0.3 mL) was added. Then NIS
(49.1 mg, 0.218 mmol) and TfOH (0.35 μL, 0.004 mmol) were added
at −40 °C, and the resulting mixture was warmed to −20 °C. The
reaction mixture was stirred for 30 min at the same temperature, at the
end of which time TLC indicated it was finished. A solution of
thioglycoside donor 48 (198.0 mg, 0.218 mmol) in CH2Cl2 (0.3 mL)
was added when the temperature was recooled to −40 °C. Then NIS
(49.1 mg, 0.218 mmol) and TfOH (0.35 μL, 0.004 mmol) were added,
and the resulting mixture was warmed to −20 °C. After being stirred
for 30 min at the same temperature, the reaction mixture was
quenched with Et3N, diluted with CH2Cl2, filtered, and concentrated.
The resulting residue was purified by column chromatography (3:1,
petroleum ether−acetone) to afford 46 (151.5 mg, 40% based on 5) as
an amorphous solid: Rf 0.26 (2:1, petroleum ether−acetone).
Tetrasaccharide intermediate 49: [α]D +13.4 (c 1.05, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.24−8.06 (m, 40H), 5.61−5.63 (m, 2H),
5.50−5.54 (m, 4H), 5.44 (s, 1H), 5.40 (br s, 2H), 5.18 (d, 1H, J = 2.0
Hz), 5.13 (s, 1H), 4.80 (dd, 1H, J = 3.2, 12.0 Hz), 4.57−4.67 (m, 3H),
4.39−4.46 (m, 2H), 4.20−4.27 (m, 2H), 4.15 (dd, 1H, J = 4.8, 11.2
Hz), 4.02 (dd, 1H, J = 4.8, 11.6 Hz), 3.84−3.97 (m, 3H), 3.47 (d, 1H,
J = 7.2 Hz), 3.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6,
166.2, 165.7, 165.67 (2C), 165.4, 165.22, 165.2, 133.5, 133.49, 133.4,
133.38, 133.2, 132.0, 129.9, 129.8, 129.77, 129.7, 129.6, 129.1, 129.0,
128.96, 128.93, 128.9, 128.5, 128.4, 128.3, 128.25, 106.8, 105.8,
105.78, 105.1, 85.7, 82.8, 81.9, 81.8, 81.79, 81.7, 81.6, 81.2, 77.7, 77.3,
77.28, 76.6, 66.1, 65.9, 65.7, 63.6, 54.8; IR (KBr) 3436, 2926, 1724,
1602, 1491, 1452 cm−1; HRMS (ESI) calcd for C77H68O25 [M + Na]+
1415.3947, found 1415.3937. Hexasaccharide 46: [α]D20 +13.0 (c 1.05,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.17−8.08 (m, 65H), 5.59−
5.65 (m, 4H), 5.55 (s, 1H), 5.50−5.54 (m, 7H), 5.42, 5.41, 5.39, 5.33,
5.12 (5 × s, each 1H), 4.74−4.79 (m, 2H), 4.58−4.68 (m, 5H), 4.54
(br s, 2H), 4.41−4.46 (m, 2H), 4.16−4.23 (m, 3H), 4.07−4.12 (m,
1H), 3.92−3.97 (m, 3H), 3.85 (dd, 1H, J = 2.4, 11.2 Hz), 3.44 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 166.2, 166.1, 165.7, 165.67, 165.64,
165.6, 165.57, 165.5, 165.32, 165.3, 165.12, 165.1, 164.9, 133.4, 133.3,
133.1, 133.0, 129.9, 129.8, 129.76, 129.6, 129.2, 129.1, 129.05, 129.0,
128.9, 128.8, 128.5, 128.47, 128.4, 128.37, 128.3, 128.26, 106.8, 105.9,
105.85, 105.8, 105.7, 105.3, 82.7, 82.5, 82.2, 82.0, 81.9, 81.7 (2C), 81.6
(2C), 81.5 (2C), 81.0, 80.6, 77.7 (2C), 77.3, 77.1, 77.0, 66.0, 65.7
(2C), 65.5, 63.6, 63.58, 54.9; IR (KBr) 2928, 1725, 1602, 1492, 1452,
1271 cm−1; HRMS (ESI) calcd for C122H104O38 [M + Na]+ 2199.6103,
found 2199.6082.
Methyl 2,3,5-Tri-O-benzoyl-α-L-arabinofuranosyl-(1→3)-2,5-
di-O-benzoyl-α-L-arabinofuranosyl-(1→5)-(2,3,5-tri-O-benzoyl-
α-L-arabinofuranosyl)-(1→3)-2-O-benzoyl-α-L-arabinofurano-
syl-(1→5)-2,3-di-O-benzoyl-α-L-arabinofuranoside (47). Using
the same procedures as described for the one-pot preparation of 46,
trichloroacetimidate donor 28 (178.1 mg, 0.189 mmol) and 3,5-diol
thioglycoside 6 (50.1 mg, 0.145 mmol) were coupled first by activation
with TMSOTf (3.44 μL, 0.019 mmol), then the resulting trisaccharide
thioglycoside 35 was glycosylated with the acceptor 50 (53.9 mg,
0.145 mol) promoted by NIS (40.8 mg, 0.181 mmol) and TfOH (0.3
μL, 0.003 mmol) to give tetrasaccharide 51. Finally, thioglycoside
donor 52 (100.1 mg, 0.181 mmol) and promoters NIS (40.8 mg, 0.181
mmol) and TfOH (0.3 μL, 0.003 mmol) were added to glycosylate
with it. The resulting residue was purified by column chromatograph
(3:1, petroleum ether−EtOAc) to afford 47 (135.7 mg, 51% based on
6) as a colorless syrup: Rf 0.27 (2:1, petroleum ether−EtOAc).
Tetrasaccharide intermediate 51: [α]D −20.5 (c 1.00, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.17−8.06 (m, 40H), 5.68 (s, 1H), 5.55
(d, 1H, J = 4.0 Hz), 5.48 (s, 1H), 5.44−5.46 (m, 2H), 5.43 (s, 1H),
5.40 (br s, 2H), 5.16 (d, 1H, J = 2.4 Hz), 5.13 (s, 1H), 4.62−4.68 (m,
2H), 4.49−4.55 (m, 3H), 4.36−4.49 (m, 5H), 4.17 (dd, 1H, J = 4.8,
11.2 Hz), 4.04 (dd, 1H, J = 4.0, 11.2 Hz), 3.93 (dd, 1H, J = 4.0, 11.2
Hz), 3.87 (dd, 1H, J = 4.8, 11.2 Hz), 3.52 (d, 1H, J = 5.2 Hz), 3.43 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 166.6, 166.1, 166.0, 165.7,
165.5, 165.48, 165.3, 165.1, 133.5, 133.45, 133.4, 133.1, 132.9, 129.9,
129.8, 129.76, 129.7, 129.6, 129.5, 129.4, 129.1, 129.06, 129.0, 128.96,
128.9, 128.8, 128.5, 128.47, 128.4, 128.38, 128.24, 128.2, 106.7, 105.9,
105.3, 104.8, 85.9, 82.5, 82.0, 81.8 (2C), 81.76, 81.4, 81.2, 80.3, 77.3
(2C), 76.5, 66.0, 65.5, 63.7, 63.2, 54.9; IR (KBr) 3444, 2927, 1724,
1603, 1492, 1452 cm−1; HRMS (ESI) calcd for C77H68O2520[M + Na]+
1415.3947, found 1415.3936. Pentasaccharide 47: [α]D −17.1 (c
1
1.05, CHCl3); H NMR (400 MHz, CDCl3) δ 7.14−8.07 (m, 55H),
5.70 (s, 1H), 5.68 (s, 1H), 5.66 (d, 1H, J = 4.8 Hz), 5.57 (s, 1H),
5.49−5.51 (m, 4H), 5.41−5.43 (m, 4H), 5.11 (s, 1H), 4.76−4.81 (m,
1H), 4.65−4.68 (m, 5H), 4.48−4.57 (m, 6H), 4.40−4.43 (m, 1H),
4.23 (dd, 1H, J = 4.0, 10.8 Hz), 4.11 (dd, 1H, J = 4.8, 11.6 Hz), 4.00
(dd, 1H, J = 4.8, 11.6 Hz), 3.91 (dd, 1H, J = 4.0, 10.8 Hz), 3.43 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 166.0, 165.95, 165.9, 165.6,
165.5, 165.49, 165.4, 165.36, 165.2, 165.0, 164.9, 133.4, 133.3, 133.2,
133.15, 133.0, 132.9, 132.8, 129.8, 129.77, 129.7, 129.66, 129.6,
129.55, 129.5, 129.4, 129.1, 129.06, 129.0, 128.94, 128.9, 128.86,
128.8, 128.4, 128.38, 128.32, 128.3, 128.2, 128.15, 128.1, 106.5, 105.6,
105.5, 105.47, 104.8, 82.7, 82.2, 82.0, 81.96, 81.7, 81.63 (2C), 81.6,
81.4, 81.2, 80.9, 80.4, 77.7, 77.5, 77.0, 65.5, 65.4, 63.6, 63.5, 63.0, 54.9;
IR (KBr) 2928, 1724, 1602, 1492, 1452, 1271 cm−1; HRMS (ESI)
calcd for C103H88O32 [M + Na]+ 1859.5156, found 1859.5137.
20
1
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yjs@scu.edu.cn, yjscd@163.com.
ACKNOWLEDGMENTS
■
We appreciate financial support from NSFC (21172156,
21021001), the National Basic Research Program of China
(973 Program, 2010CB833202), Ministry of Education
(NCET-08-0377, 20100181110082), and Sichuan Province
(08ZQ026-029) of China.
REFERENCES
■
(1) Brennan, P. J.; Nikaido, H. Annu. Rev. Biochem. 1995, 64, 29.
(2) Lindberg, B. Adv. Carbohydr. Chem. Biochem. 1990, 48, 279.
(3) de Lederkremer, R. M.; Colli, W. Glycobiology 1995, 5, 547.
(4) Notermans, S.; Veeneman, G. H.; Van Zuylen, C. W. E. M.;
Hoogerhout, P.; Van Boom, J. H. Mol. Immunol. 1988, 25, 975.
(5) (a) Lowary, T. L. In Glycoscience: Chemistry and Chemical Biology;
Fraser-Reid, B., Tatsuta, K., Thiem, J., Eds.; Springer: Berlin, 2001; p
2005. (b) Brennan, P. J. Tuberculosis 2003, 83, 91.
(6) (a) Schroeder, E. K.; De Souza, O. N.; Santos, D. S.; Blanchard, J.
S.; Basso, L. A. Curr. Pharm. Biotechnol. 2002, 3, 197. (b) Kremer, L.;
Besra, G. S. Expert Opin. Invest. Drugs 2002, 11, 153. (c) Janin, Y. L.
Bioorg. Med. Chem. 2007, 15, 2479. (d) Lee, R. E.; Brennan, P. J.;
Besra, G. S. Glycobiology 1997, 7, 1121. For a review, see: (e) Lowary,
T. L. Mini-Rev. Med. Chem. 2003, 3, 689.
(7) (a) Rose, N. L.; Completo, G. C.; Lin, S.-J.; McNeil, M.; Palcic,
M. M.; Lowary, T. L. J. Am. Chem. Soc. 2006, 128, 6721.
(b) Rademacher, C.; Shoemaker, G. K.; Kim, H.-S.; Zheng, R. B.;
Taha, H.; Liu, C.-J.; Nacario, R. C.; Schriemer, D. C.; Klassen, J. S.;
Peters, T.; Lowary, T. L. J. Am. Chem. Soc. 2007, 129, 10489.
3036
dx.doi.org/10.1021/jo300084g | J. Org. Chem. 2012, 77, 3025−3037

The Journal of Organic Chemistry
Featured Article
(c) Belan
Rose, N. L.; Lowary, T. L.; Mikuso
́
̌
ova,
́
M.; Dianisk
̌
ova,
́
P.; Brennan, P. J.; Completo, G. C.;
va, K. J. Bacteriol. 2008, 190, 1441.
(18) Knijnenburg, A. D.; Tuin, A. W.; Spalburg, E.; de Neeling, A. J.;
Mars-Groenendijk, R. H.; Noort, D.; Otero, J. M.; Llamas-Saiz, A. L.;
van Raaij, M. J.; van der Marel, G. A.; Overkleeft, H. S.; Overhand, M.
Chem.Eur. J. 2011, 17, 3995.
̌
́
(8) (a) Ayers, J. D.; Lowary, T. L.; Morehouse, C. B.; Besra, G. S.
Bioorg. Med. Chem. Lett. 1998, 8, 437. (b) Maddry, J. A.; Bansal, N.;
Bermudez, L. E.; Comber, R. N.; Orme, I. M.; Suling, W. J.; Wilson, L.
N.; Reynolds, R. C. Bioorg. Med. Chem. Lett. 1998, 8, 237. (c) Pathak,
A. K.; Pathak, V.; Maddry, J. A.; Suling, W. J.; Gurcha, S. S.; Besra, G.
S.; Reynolds, R. C. Bioorg. Med. Chem. 2001, 9, 3129. (d) Pathak, A.
K.; Pathak, V.; Suling, W. J.; Gurcha, S. S.; Morehouse, C. B.; Besra, G.
S.; Maddry, J. A.; Reynolds, R. C. Bioorg. Med. Chem. 2002, 10, 923.
(e) Han, J.; Gadikota, R. R.; McCarren, P. R.; Lowary, T. L. Carbohydr.
Res. 2003, 338, 581. (f) Pathak, A. K.; Pathak, V.; Riordan, J. R.;
Suling, W. J.; Gurcha, S. S.; Besra, G. S.; Reynolds, R. C. Bioorg. Med.
Chem. Lett. 2007, 17, 4527. (g) Pathak, A. K.; Pathak, V.; Suling, W. J.;
Riordan, J. R.; Gurcha, S. S.; Besra, G. S.; Reynolds, R. C. Bioorg. Med.
Chem. 2009, 17, 872.
(9) For reviews on synthesis of furanosides, see: (a) Lowary, T. L. J.
Carbohydr. Chem. 2002, 21, 691. (b) Lowary, T. L. Curr. Opin. Chem.
Biol. 2003, 7, 749. (c) Peltier, P.; Euzen, R.; Daniellou, R.; Nugier-
̀
Chauvin, C.; Ferrieres, V. Carbohydr. Res. 2008, 343, 1897.
(10) Selected examples. Convergent strategy: (a) Mei, X.-D.; Ning, J.
Synlett 2005, 2267. (b) Lu, J.; Fraser-Reid, B. Chem. Commun. 2005,
862. (c) Holemann, A.; Stocker, B. L.; Seeberger, P. H. J. Org. Chem.
2006, 71, 8071. (d) Fraser-Reid, B.; Lu, J.; Jayaprakash, K. N.; Lopez,
́
J. C. Tetrahedron: Asymmetry 2006, 17, 2449. (e) Joe, M.; Bai, Y.;
Nacario, R. C.; Lowary, T. L. J. Am. Chem. Soc. 2007, 129, 9885.
(f) Ishiwata, A.; Ito, Y. J. Am. Chem. Soc. 2011, 133, 2275. Stepwise
approach: (g) D’Souza, F. W.; Lowary, T. L. Org. Lett. 2000, 2, 1493.
(h) D’Souza, F. W.; Ayers, J. D.; McCarren, P. R.; Lowary, T. L. J. Am.
Chem. Soc. 2000, 122, 1251. (i) Gurjar, M. K.; Reddy, L. K.; Hotha, S.
J. Org. Chem. 2001, 66, 4657. (j) Yin, H.-F.; D’Souza, F. W.; Lowary,
T. L. J. Org. Chem. 2002, 67, 892. (k) Gandolfi-Donadío, L.; Gallo-
Rodriguez, C.; de Lederkremer, R. M. J. Org. Chem. 2003, 68, 6928.
(l) Completo, G. C.; Lowary, T. L. J. Org. Chem. 2008, 73, 4513.
(m) Gandolfi-Donadío, L.; Santos, M.; de Lederkremer, R. M.; Gallo-
Rodriguez, C. Org. Biomol. Chem. 2011, 9, 2085. (n) Abronina, P. I.;
Sedinkin, S. L.; Podvalnyy, N. M.; Fedina, K. G.; Zinin, A. I.; Torgov,
V. I.; Kononov, L. O. Tetrahedron Lett. 2011, 52, 1794. Regioselective
glycosidation strategy: (o) Du, Y.-G.; Pan, Q.-F.; Kong, F.-Z. Synlett
1999, 1648. (p) Du, Y.-G.; Pan, Q.-F.; Kong, F.-Z. Carbohydr. Res.
2000, 329, 17. (q) Baldoni, L.; Marino, C. J. Org. Chem. 2009, 74,
1994. One-pot glycosylation strategy: (r) Wang, H.-R.; Ning, J. J. Org.
Chem. 2003, 68, 2521. (s) Liang, X.-Y.; Deng, L.-M.; Liu, X.; Yang, J.-
S. Tetrahedron 2010, 66, 87. Chemoenzymatic method: (t) See ref 7a.
(19) Lee, Y. J.; Lee, K. H.; Jung, E. H.; Jeon, H. B.; Kim, K. S. Org.
Lett. 2005, 7, 3263.
(20) Marino, K.; Marino, C.; de Lederkremer, R. M. Anal. Biochem.
̃
2002, 301, 325.
(21) Xue, J.; Wu, J.; Guo, Z.-W. Org. Lett. 2004, 6, 1365.
(22) Kawabata, Y.; Kaneko, S.; Kusakabe, I.; Gama, Y. Carbohydr. Res.
1995, 267, 39.
(23) For examples of aglycon transfer reactions of thioglycosides, see:
(a) Yu, H.; Yu, B.; Wu, X.-Y.; Hui, Y.-Z.; Han, X.-W. J. Chem. Soc.,
Perkin Trans. 1 2000, 1445. (b) Zhu, T.; Boons, G. J. Carbohydr. Res.
2000, 329, 709. (c) Li, Z.-T.; Gildersleeve, J. C. J. Am. Chem. Soc.
2006, 128, 11612.
(24) Wang, Y.-X.; Maguire-Boyle, S.; Dere, R. T.; Zhu, X.-M.
Carbohydr. Res. 2008, 343, 3100.
(25) (a) Mizutani, K.; Kasai, R.; Nakamura, M.; Tanaka, O.;
Matsuura, H. Carbohydr. Res. 1989, 185, 27. (b) Bundle, D. R.;
Lemieux, R. U. Methods Carbohydr. Chem. 1976, 7, 79. (c) de Oliveira,
M. T.; Hughes, D. L.; Nepogodiev, S. A.; Field, R. A. Carbohydr. Res.
2008, 343, 211. (d) Bock, K.; Pedersen, C. Adv. Carbohydr. Chem.
1983, 41, 177.
(26) Beynon, L. M.; Richards, J. C.; Perry, M. B. Eur. J. Biochem.
1997, 250, 163.
(27) Fukunaga, K.; Yoshida, M.; Nakajima, F.; Uematsu, R.; Hara,
M.; Inoue, S.; Kondo, H.; Nishimura, S.-I. Bioorg. Med. Chem. Lett.
2003, 13, 813.
(28) For a similar strategy used in the one-pot synthesis of a
heptasaccharide and glycosyl amino acids with branched structures,
see: (a) Tanaka, H.; Adachi, M.; Tsukamoto, H.; Ikeda, T.; Yamada,
H.; Takahashi, T. Org. Lett. 2002, 4, 4213. (b) Tanaka, H.; Adachi, M.;
Takahashi, T. Tetrahedron Lett. 2004, 45, 1433.
̈
(29) Westphal, Y.; Kuhnel, S.; de Waard, P.; Hinz, S. W. A.; Schols,
̈
H. K.; Voragen, A. G. J.; Gruppen, H. Carbohydr. Res. 2010, 345, 1180.
NOTE ADDED AFTER ASAP PUBLICATION
■
This paper was published ASAP on March 1, 2012. References
9 and 10 were updated. The revised paper was reposted on
March 9, 2012
(u) Euzen, R.; Lopez, G.; Nugier-Chauvin, C.; Ferrier
Plusquellec, D.; Remond, C.; O'Donohue, M. Eur. J. Org. Chem.
2005, 4860. (v) Lopez, G.; Nugier-Chauvin, C.; Remond, C.;
O'Donohue, M. Carbohydr. Res. 2007, 342, 2202. (w) Chlubnova, I.;
Filipp, D.; Spiwok, V.; Dvorakova, H.; Daniellou, R.; Nugier-Chauvin,
C.; Kralova, B.; Ferrieres, V. Org. Biomol. Chem. 2010, 8, 2092 and
references cited therein.
̀
es, V.;
́
́
́
́
́
́
́
̀
(11) Recent reviews on one-pot glycosylation: (a) Yu, B.; Yang, Z.-Y.;
Cao, H.-Z. Curr. Org. Chem. 2005, 9, 179. (b) Wang, Y.-H.; Ye, X.-S.;
Zhang, L.-H. Org. Biomol. Chem. 2007, 5, 2189.
(12) (a) Zhu, T.; Boons, G.-J. Synlett 1997, 809. (b) Zhu, T.; Boons,
G.-J. Tetrahedron Lett. 1998, 39, 2187. (c) Zhu, T.; Boons, G.-J. Angew.
Chem., Int. Ed. 1998, 37, 1898. (d) Zhu, T.; Boons, G.-J. J. Chem. Soc.,
Perkin Trans. 1 1998, 857. (e) Zhu, T.; Boons, G.-J. Angew. Chem., Int.
Ed. 1999, 38, 3495.
(13) Plante, O. J.; Palmacci, E. R.; Andrade, R. B.; Seeberger, P. H. J.
Am. Chem. Soc. 2001, 123, 9545.
(14) Lop
Chem. Commun. 2005, 5088.
́ ́
ez, J. C.; Agocs, A.; Uriel, C.; Gomez, A. M.; Fraser-Reid, B.
(15) Wang, Z.-W.; Prudhomme, D. R.; Buck, J. R.; Park, M.; Rizzo,
C. J. J. Org. Chem. 2000, 65, 5969.
(16) Bai, Y.; Lowary, T. L. J. Org. Chem. 2006, 71, 9658.
(17) Zhu, X.-M.; Kawatkar, S.; Rao, Y.; Boons, G.-J. J. Am. Chem. Soc.
2006, 128, 11948.
3037
dx.doi.org/10.1021/jo300084g | J. Org. Chem. 2012, 77, 3025−3037