Polymer-supported synthesis of oligosaccharides using a diisopropylsiloxane linker and trichloroacetimidate donors

Article abstract of DOI:10.1002/ejoc.200901445

We describe herein the polymer-supported synthesis of biologically relevant oligosaccharides using a diisopropylsiloxane linker and trichloroacetimidates as glycosyl donors. Siloxane linkers offer important advantages over closely related silyl ethers since even sterically hindered alcohols can be directly loaded onto commercially available polymers, such, as soluble polyethylene glycol (PEG), without prior manipulation of the support. Final products can be easily detached by mild fluoridolysis to afford OH-tagged sugar probes. We followed an acceptor-bound approach that fixed, the nucleophile on the polymer, and we selected soluble PEG as the support due to higher reactivity of bound sugars and easy reaction monitoring. Following this strategy, the trisaccharide repeating unit of the capsular polysaccharide of Neisseria meningitidis (serogroup L) and the disaccharide containing the structural, motif of hyaluronic acid were successfully synthesized.

Full text of DOI:10.1002/ejoc.200901445

FULL PAPER
DOI: 10.1002/ejoc.200901445
Polymer-Supported Synthesis of Oligosaccharides Using a Diisopropylsiloxane
Linker and Trichloroacetimidate Donors
M. Mar Kayser,[a] José L. de Paz,*[a] and Pedro M. Nieto*[a]
Keywords: Carbohydrates / Glycosylation / Oligosaccharides / Solid-phase synthesis
We describe herein the polymer-supported synthesis of biolo-
gically relevant oligosaccharides using a diisopropylsiloxane
linker and trichloroacetimidates as glycosyl donors. Siloxane
linkers offer important advantages over closely related silyl
ethers since even sterically hindered alcohols can be directly
loaded onto commercially available polymers, such as solu-
ble polyethylene glycol (PEG), without prior manipulation of
the support. Final products can be easily detached by mild
fluoridolysis to afford OH-tagged sugar probes. We followed
an acceptor-bound approach that fixed the nucleophile on
the polymer, and we selected soluble PEG as the support due
to higher reactivity of bound sugars and easy reaction moni-
toring. Following this strategy, the trisaccharide repeating
unit of the capsular polysaccharide of Neisseria meningitidis
(serogroup L) and the disaccharide containing the structural
motif of hyaluronic acid were successfully synthesized.
the loading at relatively hindered OH groups. To solve this
problem, Danishefsky and coworkers described a new strat-
egy for the solid-phase synthesis of oligosaccharides using
a diisopropylsiloxane linker.[10] The siloxane linkage is
formed by first reacting the sugar alcohol with dialkyldi-
chlorosilane in solution prior to the attachment of the re-
sultant chlorosiloxane intermediate to a polymer-bound
alcohol (see part B in Scheme 1). This approach has been
applied to the synthesis of glycopeptides following a donor-
Introduction
The traditional synthesis of oligosaccharides is a time-
consuming process, mainly due to the extensive need for
purification steps and protecting-group manipulations.
Polymer-supported, synthetic methodologies accelerate oli-
gosaccharide production, facilitating intermediate purifica-
tions by the simple washing of the support and, therefore,
minimizing the number of chromatographic steps re-
quired.[1,2] Additionally, the polymer-supported reactions
can ideally be driven to completion by running several reac-
tion cycles with excess reagents. The linker, the connection
between the polymer support and the first monosaccharide,
is of utmost importance for the entire synthetic process. Its
chemical nature determines the reaction conditions that can
be used during the oligosaccharide assembly and the cleav-
age conditions required to release the final product from
the support. Moreover, the linker should render the final
oligosaccharide with an orthogonal functional group that
allows for the creation of glycoconjugates.
Among others, silyl ether linkers have been successfully
employed for the polymer-supported synthesis of oligosac-
charides.[3,4] Typically, sugar attachment to a solid support
through a silyl ether linkage involves the synthesis of silyl
halide resin by direct lithiation of polystyrene-like supports
and reaction with dialkyldichlorosilane and subsequent
silylation with a OH-bearing carbohydrate (see part A in
Scheme 1).[5–9] Poor efficiencies are found when conducting
bound strategy and employing glycal-derived donors.[10]
A
siloxane linker has also been employed in the solid-phase
synthesis of natural polyketide fragments,[11,12] oligonucleo-
tides[13] and streptogramin antibiotics[14] and for the explo-
ration of hetero-Diels–Alder reactions of dienes with poly-
mer-supported acyl- and arylnitroso dienophiles.[15,16]
Therefore, siloxane linkers[17,18] are attractive alternatives
to silyl ethers. They exhibit stability under basic and acidic
conditions,[19,20] and no prior manipulation of commer-
cially available polymers is required (Scheme 1, B). This ad-
vantage is particularly useful for soluble polyethylene glycol
(PEG), since the preparation of noncommercially available
silyl halide PEG is avoided, and OH-terminated PEG can
be directly used. Siloxane linkers can be cleaved readily at
the end of the synthesis by exposure to fluoride (Scheme 1,
B). This treatment affords the original polymer support,
which can be recycled for further use, dialkyldifluorosilane
as a side product and a OH-functionalized sugar. This OH
group, generated by fluoridolysis of the linker, can be con-
sidered an orthogonal tag for further manipulation and bio-
conjugation of the carbohydrate sample.[21] For instance, to-
sylation and subsequent substitution by azide gives azido-
terminated oligosaccharides ready for 1,3-dipolar cycload-
dition with alkyne probes or Staudinger reduction to afford
amines.
[a] Instituto de Investigaciones Químicas, Centro de Investiga-
ciones Científicas Isla de La Cartuja, CSIC-US,
Americo Vespucio 49, 41092 Sevilla, Spain
Fax: +34-954-460565
E-mail: jlpaz@iiq.csic.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901445.
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Polymer-Supported Synthesis of Oligosaccharides
Results and Discussion
We chose, as our first goal, the synthesis of 13
(Scheme 3), the fully protected, trisaccharide, repeating unit
of the capsular polysaccharide of both Neisseria meningi-
tidis (serogroup L)[28,29] and Actinobacillus pleuropneumo-
niae (serotype 12).[30] Capsular polysaccharides are com-
monly important virulence factors, and synthetic oligosac-
charide–protein conjugates are promising vaccines, in-
ducing protective antibodies against bacterial infec-
tion.[31–34] Thus, the oligosaccharides related to the bacte-
rial capsule are an attractive target. We followed an ac-
ceptor-bound strategy, attaching the reducing-end glucos-
amine to the support through the anomeric position by a
diisopropylsiloxane linker. Our approach used as key build-
ing blocks the differentially protected monosaccharide 6
and the corresponding trichloroacetimidate 7 (Scheme 2).
The levulinoyl (Lev) group served as a temporary protect-
ing group to liberate the glycosyl acceptor in anticipation of
chain elongation, while the N-phthalimido (NPhth) group
ensured the desired β stereochemistry of the glycosidic link-
age.
Scheme 1. A): General strategy for sugar attachment to polystyrene
resins through a silyl ether linker. B): Alternative approach for
sugar loading onto commercially available polymers, both soluble
and insoluble supports, using a diisopropylsiloxane linker.
In the framework of a project on the development of
polymer-supported syntheses of glycosaminoglycans
(GAG), we report herein the synthesis of oligosaccharides
using a diisopropylsiloxane linker and trichloroacetimidates
as glycosylating agents. To the best of our knowledge, tri-
chloroacetimidates have not been previously used with si-
loxane linkers, following an acceptor-bound strategy. We
chose soluble PEG as the polymer support[22,23] because it
combines advantages of solution-phase chemistry with the
easy workup of solid-phase synthesis.[24–27] While all reac-
tions are carried out in homogeneous solutions, the poly-
mer is precipitated after each step by the addition of diethyl
ether. In this way, excess reagents and other side products
are easily removed by washing the PEG precipitate, as in
solid-phase synthesis. Specific advantages of soluble poly-
mers as compared to the alternative, insoluble resins in-
clude: a) easy monitoring of the reactions using standard
techniques and b) higher reactivity of PEG-bound sugars
Scheme 2. Reagents and conditions: a) NaOMe, MeOH;
PhCH(OMe)2, p-TsOH, CH3CN/DMF; LevOH, DCC, DMAP,
CH2Cl2, 82%; b) (HF)n·Pyr, THF, 0 °C Ǟ r.t., 77%; c) Cl3CCN,
DBU, CH2Cl2, 88%; d) TBAF, AcOH, THF, 0 °C, 30% 4 + 32%
aldehyde 5; TDS = dimethylthexylsilyl.
First, the gram-scale synthesis of 7 was undertaken, em-
than that of resin-bound sugars. The latter point involves ploying 1[35] as starting material (Scheme 2). The removal
the use of smaller amounts of glycosyl donors to complete of the three acetates on 1 followed by the formation of the
glycosylation reactions, which is particularly useful when 4,6-benzylidene acetal and subsequent levulinoylation at
using valuable, orthogonally protected, building blocks. Po- position 3 afforded monosaccharide 2 in 82% yield over
tential restrictions are the loss of material during the pre- three steps. Turning 2 into trichloroacetimidate 7 first re-
cipitation, which lowers the overall yield in the assembly of quired selective desilylation. The treatment of the closely
large structures, and the limited temperature range under related, 3-O-acetyl monosaccharide 3 with TBAF/AcOH
which PEG is soluble (above –45 °C). Despite these limita- gave the corresponding hemiacetal 4 in low yield (30%,
tions, soluble PEG has been extensively used for oligosac- Scheme 2). Aldehyde 5, derived from 2-H/3-H-acetate elimi-
charide synthesis.
nation, was detected as a side product. The structure of 5
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M. Mar Kayser, J. L. de Paz, P. M. Nieto
FULL PAPER
was unambiguously identified from the characteristic chem- diethyl ether (Scheme 3). The β anomer was exclusively ob-
1
ical shifts of 1-H and 3-H (9.58 and 7.22 ppm, respectively). tained, as deduced by H NMR (J1,2 = 7.5 Hz). The unre-
Additionally, the treatment of 4 with trichloroacetonitrile acted polymer sites were capped by reaction with acetic an-
in the presence of K2CO3 also gave aldehyde 5 as the major hydride/pyr. The integration of diagnostic 1H NMR signals
product. Similar results were recently reported by Mulard (see the Supporting Information) indicated a sugar loading
and coworkers in the synthesis of a 3-O-acyl-2-deoxy-4,6- of approximately 55% (1:0.81 mole ratio). The Lev group
O-isopropylidene-2-trichloroacetamido--glucopyranosyl of 8 was easily removed by treatment with hydrazine mono-
trichloroacetimidate.[36] This side reaction was overcome by hydrate in CH2Cl2/Pyr/AcOH to give polymer-supported
the use of (HF)n·Pyr complex in THF followed by trichloro- acceptor 9, which was efficiently glycosylated with tri-
acetimidate formation with catalytic DBU. Taking advan- chloroacetimidate 7 to afford bound disaccharide 10
tage of this optimization process, donor 7 was obtained in (Scheme 3). The Lev deprotection and glycosylation se-
good yield on a multigram scale.
quence was then carried out on 10 to give the bound trisac-
Monosaccharide 6 was attached to the support through charide 12. Treatment with (HF)n·Pyr complex in THF re-
the anomeric position (Scheme 3) by a two-stage procedure, leased trisaccharide 13 in 45% overall yield from polymer
which took advantage of the enhanced reactivity of a dialk- 8 (five steps). As expected, 13 was liberated as a reducing
yldihalosilane relative to its monohalogenated counter- sugar (ca. 4:1 β/α). To facilitate structural characterization
part.[10] This difference in reactivity minimized the forma- and NMR assignment, 13 was treated with BzCl in Pyr to
tion of the diisopropylsiloxane-linked pseudodisaccharide yield trisaccharide 14 (Ն 8:1 β/α).
resulting from two-fold silylation. The exposure of 6 to
Having demonstrated that the diisopropylsiloxane linker
1 equiv. of dichlorodiisopropylsilane (iPr2SiCl2) in the pres- allows for the successful synthesis of trisaccharide 13 using
ence of imidazole gave the corresponding chlorosiloxane in- trichloroacetimidates and an acceptor-bound approach, we
termediate, which was directly treated with 1 equiv. of OH- next turned to the synthesis of more complex hyaluronic
terminated PEG monomethyl ether to yield bound mono- acid oligosaccharides.[37–41] Hyaluronic acid is a linear
saccharide 8 after selective precipitation by the addition of GAG featuring the β-(1Ǟ3)-linked, 2-acetamido-2-deoxy-
Scheme 3. Reagents and conditions: a) iPr2SiCl2, imidazole, CH2Cl2; MeO–(CH2CH2O)n–CH2CH2OH, CH2Cl2; Ac2O, Pyr, 55% loading;
b) NH2NH2·H2O, Pyr/AcOH, CH2Cl2; c) 7, TMSOTf, CH2Cl2, –10 °C; d) NH2NH2·H2O, Pyr/AcOH, CH2Cl2; e) 7, TMSOTf, CH2Cl2,
–15 °C; f) (HF)n·Pyr, THF, 0 °C, 45% from 8, five steps; g) BzCl, Pyr.
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Polymer-Supported Synthesis of Oligosaccharides
-glucose-β-(1Ǟ4)--glucuronic acid disaccharide as the re- hydrolysis of the 2,3-isopropylidene acetal (Ǟ20) and exten-
peating unit.[42–44] The synthesis of GAG oligosaccharide sive pivaloylation at positions 2 and 3 for 5 d. Interestingly,
sequences is crucial for the establishment of specific struc- diol 20 was cleanly converted into 3-O-pivaloylated deriva-
ture-activity relationships in order to elucidate the role of tive 22 with shorter reaction times (2 h), thus opening the
these complex sugars in nature.[45–53] GAG synthesis is a way for the preparation of alternative building blocks, or-
challenging objective since it generally involves handling thogonally protected at positions 2 and 3. Compound 21
electron-poor, uronic acid, building blocks.[54–57] In particu- was then desilylated to give 23, which was activated as tri-
lar, the synthesis of hyaluronic acid oligosaccharides usually chloroacetimidate 24 (Scheme 4).
requires the condensation of highly disarmed glucuronic
Next, we explored the synthesis of hyaluronic acid disac-
acid building blocks due to the presence of both the elec- charide 32 having a glucuronic acid unit at the reducing
tron-withdrawing carboxylic acid and an acyl group at posi- end (Scheme 5). Attaching glucuronic acid 23 to the PEG
tion 2 to control the 1,2-trans stereochemistry of the gly- support through the anomeric position, as described above
cosidic bond.
for the synthesis of trisaccharide 13, would probably lead
Thus, in addition to the glucosamine monomer 7, the to anomeric mixture on the support, hampering reaction
preparation of a differentially protected, glucuronic acid monitoring and would afford a final product as α/β ano-
monosaccharide is essential to the synthesis of hyaluronic mers, complicating released oligosaccharide characteriza-
acid fragments. Triol 16 (Scheme 4) was prepared from tion. Therefore, we envisaged attaching the glucuronic acid
methyl 1,2,3,4-tetra-O-acetyl-α,β--glucopyranosuronate unit through the OH group of derivative 27, bearing a fixed
(15)[58] by standard anomeric deacetylation, silylation and β configuration. This OH group, which can be regenerated
subsequent acetate hydrolysis. The key differentiation of by fluoride treatment at the end of the synthesis, is a poten-
OH groups on triol 16 was achieved by selective 2,3-iso- tial point for further functionalization.
propylidene acetal formation under kinetic control.[59]
Treatment with 2-methoxypropene and CSA followed by
the addition of MeOH gave 2,3-isopropylidene derivative
17 as the main product (50%) together with the 3,4-iso-
propylidene isomer (36%), which can be easily recycled by
acidic hydrolysis. We note that mixed bisacetal 18 was de-
tected by NMR and mass spectroscopy (see the Supporting
Information) when the reaction was directly quenched with
Et3N before MeOH addition. A similar bisacetal was re-
cently reported by Gardiner et al. in the synthesis of 1,2-
isopropylidene-protected -ido cyanopyranosides.[60] Com-
pound 17 was then transformed in good yield into 21
(Scheme 4) through levulinoylation at position 4 (Ǟ19),
Scheme 5. Reagents and conditions: a) TMSOTf, CH2Cl2, 0 °C,
70%; b) TBAF, AcOH, THF, 0 °C Ǟ r.t., 63% + 18% recovered 26;
c) iPr2SiCl2, imidazole, CH2Cl2; MeO–(CH2CH2O)n–CH2CH2OH,
CH2Cl2; Ac2O, Pyr, 54% loading; d) NH2NH2·AcOH, CH2Cl2; e)
7, TMSOTf, CH2Cl2, 0 °C; f) TBAF, AcOH, THF/CH2Cl2, 0 °C
Ǟ r.t., 71% from 28, three steps.
Scheme 4. Reagents and conditions: a) 2-methoxypropene, CSA,
DMF, 0 °C; MeOH, 0 °C, 50%; b) LevOH, DCC, DMAP, CH2Cl2,
88%; c) DOWEX acidic resin, MeOH; d) PivCl, DMAP, Pyr, 5 d,
1,5-pentanediol.[61] Glycosylation of 24 with alcohol 25 fol-
78% from 19, two steps; e) PivCl, DMAP, Pyr, 2 h, quantitative by
TLC analysis; f) (HF)n·Pyr, THF, 0 °C Ǟ r.t., 89%; g) Cl3CCN,
K2CO3, CH2Cl2, 85%.
Monosilylated alcohol 25 (Scheme 5) was obtained from
lowed by desilylation with TBAF/AcOH afforded 27. Fol-
lowing an analogous sequence of reaction steps as that de-
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M. Mar Kayser, J. L. de Paz, P. M. Nieto
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scribed for the attachment of glucosamine 6, we reacted countered when applying this strategy to the synthesis of
iPr2SiCl2 with 27 and, subsequently, with OH-terminated GAG oligosaccharides. The preparation of these complex
PEG monomethyl ether. After capping the unreacted poly- carbohydrates is a challenging task, since it usually requires
mer sites by reaction with acetic anhydride/pyr, the sugar the condensation of electron-poor, disarmed building
loading (54%; 1:0.86 mole ratio) was deduced from the inte- blocks, involving harsh reaction conditions for glycosyl-
1
gration of key H NMR signals (see the Supporting Infor- ations. A partial cleavage of the diisopropylsiloxane linker
mation). It is noteworthy that valuable, unbound, gluc- was detected during the synthesis of a GAG disaccharide.
uronic acid derivatives were transformed into starting 27 Therefore, further improvements are required to extend our
by treatment with TBAF/AcOH. We speculate that these strategy to the synthesis of large GAG oligomers. In order
derivatives could be silanol formed by hydrolysis of the to address this point, we are now working on the synthesis
chlorosiloxane and/or cross-linked pseudodisaccharide de- of glucuronic acid units with electron-donating protecting
rived from double addition on iPr2SiCl2. The Lev group of groups to enhance their glycosylation power, thereby avoid-
28 was easily removed by treatment with hydrazine acetate ing the use of severe reaction conditions that cleave the
to give polymer-supported acceptor 29 (Scheme 5). At this linker. Alternatively, the preparation of more stable siloxane
stage, we investigated the challenging glycosylation reaction linkers is also being considered for GAG synthesis using
between electron-poor acceptor 29 and donor 7 to produce traditional, disarmed building blocks. We will further report
hyaluronic acid disaccharide 30. TMSOTf-mediated cou- on our progress in future publications.
pling was carried out at 0 °C. After two glycosylation cycles,
the 1H NMR spectrum indicated the complete consumption
Experimental Section
of the glucuronic acid acceptor and formation of bound
disaccharide as the main product. However, a second set of
minor, NMR, sugar signals was observed and assigned to
monosaccharide 31. This side product derived from the par-
tial release of the sugar acceptor from the polymeric sup-
port and the subsequent glycosylation of the generated OH-
terminated PEG with donor 7. Cleavage from the support
by TBAF/AcOH led to disaccharide 32 in 71% yield.
Bound monosaccharide 31 remained linked to the support
(see the Supporting Information) and was easily removed
during the workup procedure. Therefore, this side product
did not complicate the purification of the final target, al-
though it reduced the applicability of this strategy for the
synthesis of longer hyaluronic acid oligosaccharides.
Attempts to avoid the partial cleavage of siloxane linker by
lowering the reaction temperature or decreasing the
TMSOTf amount did not afford any disaccharide. The di-
rect anchoring of the reducing end sugar through the anom-
General Procedures: PEG monomethyl ether (average molecular
weight of 5000 Da) was purchased from Sigma Aldrich. Thin-layer
chromatography (TLC) analyses were performed with silica gel 60
F254 precoated with aluminum plates (Merck), and the compounds
were detected by staining with sulfuric acid/ethanol (1:9) or with
anisaldehyde solution [anisaldehyde (25 mL) with sulfuric acid
(25 mL), ethanol (450 mL) and HOAc (1 mL)] followed by heating
at over 200 °C. Column chromatography was carried out with silica
gel 60 (0.2–0.5 mm, 0.2–0.063 mm or 0.040–0.015 mm; Merck).
Optical rotations were determined with a Perkin–Elmer 341 polari-
meter. 1H and 13C NMR spectra were acquired with Bruker DPX-
300 and DRX-500 spectrometers, and chemical shifts are given in
ppm (δ) relative to tetramethylsilane. Electrospray mass spectra
(ES-MS) were recorded with an Esquire 6000 ESI-Ion Trap from
Bruker Daltonics. High resolution FAB mass spectra (HRMS) were
recorded by Mass Spectrometry Service, Citius, University of Se-
ville.
Dimethylthexylsilyl
4,6-O-Benzylidene-2-deoxy-3-O-levulinoyl-2-
(20.0 g,
eric position, as described for 8, also failed to reduce partial phthalimido-β- -glucopyranoside (2): Compound
D
1
34.6 mmol) was dissolved in MeOH (280 mL) and NaOMe
(2.3 mL, 2.17  solution in MeOH) was added. After 1 h, Am-
berlite acidic resin was added, and the mixture was stirred until the
pH reached 7. The Amberlite resin was filtered off, and the solvent
was removed in vacuo. The residue [TLC (16:1 CH2Cl2/MeOH) Rf
= 0.10] was coevaporated with CH2Cl2 and toluene and dissolved
in acetonitrile/DMF (70:3, 146 mL). Benzaldehyde dimethyl acetal
(5.73 mL, 38.1 mmol) and p-toluenesulfonic acid (600 mg,
3.2 mmol) were added. After the mixture was stirred at room tem-
perature for 2 h, EtOAc was added, and the mixture was washed
cleavage.
Conclusions
We conclude that the combination of a diisopropylsilox-
ane linker and trichloroacetimidate donors is an attractive
approach for the polymer-supported synthesis of oligosac-
charides. Accordingly, we have synthesized two biologically
relevant oligosaccharides on a PEG support. The use of with saturated aqueous NaHCO3. The organic phase was dried
with Na2SO4, filtered and concentrated in vacuo. The residue [TLC
(4:1 hexane/EtOAc) Rf = 0.30] was dissolved in CH2Cl2 (175 mL),
and levulinic acid (15.4 mL, 150 mmol), 1,3-dicyclohexylcarbodi-
imide (9.26 g, 44.9 mmol) and DMAP (800 mg) were added. After
1.5 h, the mixture was diluted with CH2Cl2 and washed with satu-
rated aqueous NaHCO3. The organic phase was dried with
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by flash chromatography on silica gel (2:1 hexane/EtOAc) to
soluble PEG allowed for direct reaction monitoring by
standard analytical techniques. As compared to silyl ethers,
the siloxane linker involves a more straightforward sugar
loading onto the support, without the prior manipulation
of commercially available polymers. Moreover, this linker
is stable under the reaction conditions usually required to
assemble the oligosaccharide chain and can be selectively
cleaved by fluoride treatment at the end of the synthesis.
The released, final product contains a OH group that en-
give 2 (18.0 g, 82%). TLC (1:1 hexane/EtOAc) Rf = 0.55; [α]D20
=
1
–20.1 (c = 1.17, CHCl3); H NMR (300 MHz, CDCl3): δ = 7.89–
ables further conjugation. However, limitations were en- 7.72 (m, 4 H, NPhth), 7.49–7.36 (m, 5 H, Ph), 5.96 (dd, 1 H, 3-H),
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Polymer-Supported Synthesis of Oligosaccharides
5.64 (d, J1,2 = 7.8 Hz, 1 H, 1-H), 5.55 (s, 1 H, PhCHO), 4.38 (dd,
J5,6 = 4.2, J6,6Ј = 10.2 Hz, 1 H, 6-H), 4.29 (dd, J2,3 = 10.5 Hz, 1
H, 2-H), 3.89–3.74 (m, 3 H, 4-H, 5-H, 6Ј-H), 2.57–2.41 [m, 4 H,
hydrazine monohydrate (1.52 mL, 0.5  solution in Pyr/AcOH, 3:2)
was added. After stirring at room temperature for 2 h, the reaction
mixture was quenched with acetone (4 mL), and diethyl ether
OCO(CH2)2], 1.92 (s, 3 H, COCH3), 1.42 [m, 1 H, CH(CH3)2], (120 mL) was added at 0 °C. The precipitated solid was collected
0.68–0.63 [4 s, 12 H, C(CH3)2 and CH(CH3)2], 0.13–0.00 [2 s, 6 H,
Si(CH3)2] ppm. 13C NMR (75 MHz, CDCl3): δ = 205.7, 171.9,
137.0–123.4 (Ph, NPhth), 101.6, 93.8, 79.6, 69.7, 68.8, 66.3, 57.3,
37.8, 33.8, 29.4, 27.9, 24.5, 19.8, 19.6, 18.3, 18.2, –1.9, –3.8 ppm.
HRMS: calcd. for C34H43O9NSiNa 660.2605 [M]+; found
660.2632.
by filtration, washed with cold diethyl ether (120 mL) and dried
under high vacuum to give polymer 9 (2.03 g) as a white solid.
Selected 1H NMR spectroscopic data (500 MHz, CDCl3): δ = 7.89–
7.72 (m, 4 H, NPhth), 7.53–7.35 (m, 5 H, Ph), 5.64 (d, J1,2 = 8.0 Hz,
1 H, 1-H), 5.59 (s, 1 H, PhCHO), 4.71 (dd, J2,3 = J3,4 = 9.6 Hz, 1
H, 3-H), 4.36 (dd, J5,6a = 4.4, J6a,6b = 10.7 Hz, 1 H, 6a-H) ppm.
4,6-O-Benzylidene-2-deoxy-3-O-levulinoyl-2-phthalimido-α,β-D-gluco-
Polymer-Bound Disaccharide 10: PEG-supported glucosamine 9
(300 mg, approximately 31 µmol of sugar) and glycosyl donor 7
(173 mg, 0.27 mmol), previously coevaporated with toluene and
dried under vacuum, were dissolved in CH2Cl2 (1 mL). TMSOTf
(120 µL, 0.1  solution in CH2Cl2) was added at –10 °C. After stir-
ring at –10 °C for 40 min, the reaction mixture was quenched with
Et3N (0.4 mL), and then an excess of diethyl ether (100 mL) was
added at 0 °C. The precipitated white solid was collected by fil-
tration, rinsed with cold diethyl ether (100 mL) and dried under
high vacuum. This glycosidation procedure was repeated once more
to give polymer 10 (280 mg). Selected 1H NMR spectroscopic data
(500 MHz, CDCl3): δ = 7.92–7.50 (m, 8 H, NPhth), 7.49–7.31 (m,
10 H, Ph), 5.65 (dd, J2,3 = J3,4 = 9.6 Hz, 1 H, 3Ј-H), 5.56 (s, 1 H,
PhCHO), 5.51 (d, J1,2 = 8.4 Hz, 1 H, 1Ј-H), 5.43 (s, 1 H, PhCHO),
5.35 (d, J1,2 = 8.0 Hz, 1 H, 1-H), 4.91 (dd, J2,3 = J3,4 = 9.7 Hz, 1
H, 3-H), 4.29 (dd, J5,6a = 4.8, J6a,6b = 10.2 Hz, 1 H, 6a-H or 6Јa-
H), 4.25–4.11 (m, 3 H, 6a-H or 6Јa-H, 2-H, 2Ј-H), 1.82 (s, 3 H,
COCH3) ppm.
pyranose (6): (HF)n·Pyr complex (6.8 mL) was added to 2 (1.42 g,
2.22 mmol) in dry THF (34 mL) at 0 °C. After stirring for 48 h at
0 °C and then for 8 h at room temperature, the reaction mixture
was diluted with CH2Cl2 and washed with H2O and saturated
aqueous NaHCO3. The organic layer was dried with Na2SO4 and
filtered, and the solvents were removed in vacuo to give a yellow
oil. Hexane (15 mL) and EtOAc (5 mL) were added at 0 °C, and a
white precipitate formed. The precipitate was filtered and washed
with cold hexane to afford 6 (850 mg, 77%) as a white solid: TLC
1
(1:1 hexane/EtOAc) Rf = 0.25; H NMR (300 MHz, CDCl3, data
for the β anomer): δ = 7.86–7.69 (m, 4 H, NPhth), 7.49–7.35 (m, 5
H, Ph), 5.97 (dd, 1 H, 3-H), 5.67 (d, J1,2 = 8.4 Hz, 1 H, 1-H), 5.56
(s, 1 H, PhCHO), 4.39 (dd, 1 H, 6-H), 4.27 (dd, J2,3 = 10.5 Hz, 1
H, 2-H), 3.89–3.76 (m, 3 H, 4-H, 5-H, 6Ј-H), 2.61–2.39 [m, 4 H,
OCO(CH2)2], 1.89 (s, 3 H, COCH3) ppm. ES-MS: calcd. for
C26H25O9NNa 518.1 [M]+; found 517.7.
O-(4,6-O-Benzylidene-2-deoxy-3-O-levulinoyl-2-phthalimido-α,β-D-
glucopyranosyl) Trichloroacetimidate (7): Trichloroacetonitrile
(1.50 mL, 15.1 mmol) and catalytic DBU were added to 6 (750 mg,
1.51 mmol) in dry CH2Cl2 (10 mL). After stirring at room tempera-
ture for 1.5 h, the mixture was concentrated in vacuo. Flash
chromatography on silica gel (99:1 CH2Cl2/Et3N) afforded 7
(850 mg, 88%) as an α/β mixture. TLC (1:1 hexane/EtOAc) Rf =
0.47; 1H NMR (300 MHz, CDCl3, data for the β anomer): δ = 8.67
(s, 1 H, NH), 7.90–7.72 (m, 4 H, NPhth), 7.51–7.36 (m, 5 H, Ph),
6.71 (d, J1,2 = 8.7 Hz, 1 H, 1-H), 6.08 (dd, 1 H, 3-H), 5.59 (s, 1 H,
PhCHO), 4.64 (dd, J2,3 = 10.5 Hz, 1 H, 2-H), 4.52 (dd, J5,6 = 3.9,
J6,6Ј = 9.6 Hz, 1 H, 6-H), 3.99–3.92 (m, 3 H, 4-H, 5-H, 6Ј-H), 2.64–
2.43 [m, 4 H, OCO(CH2)2], 1.91 (s, 3 H, COCH3) ppm. ES-MS:
calcd. for C28H25O9N2Cl3Na 661.0 [M]+; found 660.5.
Polymer-Bound Disaccharide 11: Compound 10 (280 mg, approxi-
mately 28 µmol of sugar) was dissolved in CH2Cl2 (1 mL), and hy-
drazine monohydrate (180 µL, 0.5  solution in Pyr/AcOH, 3:2)
was added. After stirring at room temperature for 2 h, the reaction
mixture was quenched with acetone (0.8 mL), and diethyl ether
(100 mL) was added at 0 °C. The precipitated solid was collected
by filtration, washed with cold diethyl ether (100 mL) and dried
under high vacuum to give polymer 11 (270 mg) as a white solid.
Selected 1H NMR spectroscopic data (500 MHz, CDCl3): δ = 7.73–
7.45 (m, 8 H, NPhth), 7.45–7.31 (m, 10 H, Ph), 5.56 (s, 1 H,
PhCHO), 5.46 (s, 1 H, PhCHO), 5.35 (m, 2 H, 1-H, 1Ј-H), 4.91
(dd, J2,3 = J3,4 = 9.7 Hz, 1 H, 3-H), 4.36 (dd, J2,3 = J3,4 = 9.7 Hz,
1 H, 3Ј-H), 4.32–4.12 (m, 4 H, 6a-H, 6Јa-H, 2-H, 2Ј-H) ppm.
Polymer-Bound Monosaccharide 8: Dichlorodiisopropylsilane
(iPr2SiCl2, 108 µL, 0.6 mmol) was added dropwise to imidazole
(204 mg, 3.0 mmol) in CH2Cl2 (6 mL), and this mixture was stirred
for 5 min before 6 (300 mg, 0.6 mmol) in CH2Cl2 (9 mL) was added
dropwise. The mixture was stirred for 1 h at room temperature and
then added dropwise to a solution of PEG monomethyl ether
(3.0 g, approximately 0.6 mmol) in CH2Cl2 (16 mL). After the mix-
ture was stirred for 24 h, diethyl ether (150 mL) was added at 0 °C.
The precipitated solid was collected by filtration, washed with cold
diethyl ether (150 mL) and dried under high vacuum. The unre-
acted polymer sites were capped by treating the polymer with acetic
anhydride (16 mL) in pyr (32 mL) for 12 h. Diethyl ether (150 mL)
was then added at 0 °C. The precipitated solid was collected by
filtration, washed with cold diethyl ether (150 mL) and dried under
high vacuum to yield polymer 8 (3.2 g) as a white solid. Selected
1H NMR spectroscopic data (500 MHz, CDCl3): δ = 7.89–7.71 (m,
4 H, NPhth), 7.50–7.33 (m, 5 H, Ph), 5.99 (dd, J2,3 = J3,4 = 9.7 Hz,
1 H, 3-H), 5.76 (d, J1,2 = 7.5 Hz, 1 H, 1-H), 5.55 (s, 1 H, PhCHO),
4.38 (dd, J5,6a = 4.5, J6a,6b = 10.5 Hz, 1 H, 6a-H), 4.29 (dd, 1 H,
2-H), 1.92 (s, 3 H, COCH3) ppm.
Polymer-Bound Trisaccharide 12: PEG-supported glucosamine 11
(270 mg, approximately 27 µmol of sugar) and glycosyl donor 7
(147 mg, 0.23 mmol), previously coevaporated with toluene and
dried under vacuum, were dissolved in CH2Cl2 (1 mL). TMSOTf
(105 µL, 0.1  solution in CH2Cl2) was added at –15 °C. After stir-
ring at –15 °C for 25 min, the reaction mixture was quenched with
Et3N (0.4 mL), and then an excess of diethyl ether (100 mL) was
added at 0 °C. The precipitated white solid was collected by fil-
tration, rinsed with cold diethyl ether (100 mL) and dried under
high vacuum to give polymer 12 (280 mg) as a white solid. Selected
1H NMR spectroscopic data (500 MHz, CDCl3): δ = 7.94–7.33 (m,
27 H, NPhth, Ph), 5.58–5.48 (m, 3 H, 3ЈЈ-H, PhCHO), 5.38–5.31
(m, 2 H, PhCHO, 1ЈЈ-H), 5.27 (d, J1,2 = 8.5 Hz, 1 H, 1-H), 5.08 (d,
J1,2 = 8.5 Hz, 1 H, 1Ј-H), 4.82 (dd, J2,3 = J3,4 = 9.9 Hz, 1 H, 3-H),
4.63 (dd, J2,3 = J3,4 = 9.9 Hz, 1 H, 3Ј-H), 1.81 (s, 3 H, COCH3)
ppm.
O-(4,6-O-Benzylidene-2-deoxy-3-O-levulinoyl-2-phthalimido-β-
glucopyranosyl)-(1Ǟ3)-O-(4,6-O-benzylidene-2-deoxy-2-phthal-
imido-β- -glucopyranosyl)-(1Ǟ3)-4,6-O-benzylidene-2-deoxy-2-
phthalimido-α,β- -glucopyranose (13): (HF)n·Pyr complex (720 µL)
was added to 12 (150 mg, approximately 14 µmol of sugar) in dry
D-
D
Polymer-Bound Monosaccharide 9: Compound 8 (2.14 g, approxi-
mately 0.22 mmol of sugar) was dissolved in CH2Cl2 (11 mL) and
D
Eur. J. Org. Chem. 2010, 2138–2147
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2143

M. Mar Kayser, J. L. de Paz, P. M. Nieto
FULL PAPER
THF (3.6 mL) at 0 °C. After stirring for 24 h at 0 °C, the reaction 28.8, 27.2, 22.3, 22.1, 20.7, 20.6, 0.0, –0.8 ppm. HRMS: calcd. for
mixture was diluted with CH2Cl2 and washed with H2O and satu-
rated aqueous NaHCO3. The organic layer was dried with Na2SO4
and filtered, and the solvents were removed in vacuo. The residue
was dissolved in CH2Cl2 (1 mL), and then an excess of diethyl ether
(60 mL) was added at 0 °C. The precipitated white solid was filtered
off and washed with cold diethyl ether (60 mL). The filtrate and
the washes were combined and concentrated in vacuo. The residue
was purified by flash chromatography (160:1 CH2Cl2/MeOH) to
afford 13 (8.1 mg, 45% from 8, five steps): TLC (160:1 CH2Cl2/
MeOH) Rf = 0.15; 1H NMR (500 MHz, CDCl3, data for the β
anomer): δ = 7.80–7.50 (m, 12 H, NPhth), 7.51–7.38 (m, 15 H, Ph),
5.55 (dd, 1 H, 3ЈЈ-H), 5.51 (s, 1 H, PhCHO), 5.46 (s, 1 H, PhCHO),
5.38 (s, 1 H, PhCHO), 5.36 (d, J1,2 = 8.5 Hz, 1 H, 1ЈЈ-H), 5.11 (d,
J1,2 = 8.5 Hz, 1Ј-H), 5.08 (m, 1 H, 1-H), 4.91 (dd, 1 H, 3-H), 4.65
(dd, 1 H, 3Ј-H), 4.32 (dd, J5,6a = 4.9, J6a,6b = 10.4 Hz, 1 H, 6a-H),
4.20 (m, 1 H, 6aЈ-H), 4.15–4.06 (m, 3 H, 2Ј-H, 2ЈЈ-H, 6aЈЈ-H), 3.99
(m, 1 H, 2-H), 3.80–3.53 (m, 7 H, 4-H, 4Ј-H, 4ЈЈ-H, 5-H, 6b-H,
6bЈ-H, 6bЈЈ-H), 3.40 (m, 1 H, 5Ј-H), 3.34 (m, 1 H, 5ЈЈ-H), 3.01 (br.
d, 1 H, OH), 2.38–2.24 [m, 4 H, OCO(CH2)2], 1.81 (s, 3 H, COCH3)
ppm. Selected 13C NMR spectroscopic data (from HMQC experi-
ment, 125 MHz, CDCl3): δ = 101.4, 101.2, 101.0 (3 PhCHO), 97.3
(C-1Ј), 96.9 (C-1ЈЈ), 93.5 (C-1), 73.7 (C-3), 69.7 (C-3ЈЈ) ppm.
HRMS: calcd. for C68H59N3O21Na 1276.3539 [M]+; found
1276.3524.
C18H34O7SiNa 413.1972 [M]+; found 413.1965.
Methyl (Dimethylthexylsilyl 2,3-O-isopropylidene-4-O-levulinoyl-β-
D-glucopyranoside)uronate (19): Compound 17 (1.87 g, 4.78 mmol),
levulinic acid (2.78 g, 23.9 mmol), 1,3-dicyclohexylcarbodiimide
(1.48 g, 7.17 mmol) and DMAP (80 mg) were dissolved in CH2Cl2
(20 mL), and the reaction was stirred at room temperature for 3 h.
The mixture was diluted with CH2Cl2 and washed with saturated
aqueous NaHCO3. The organic phase was dried with Na2SO4, fil-
tered and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (4:1 hexane/EtOAc) to give 19 (2.04 g,
88%). [α]2D0 = –29.0 (c = 0.42, CHCl3); TLC (2:1 hexane/EtOAc) Rf
1
= 0.29; H NMR (300 MHz, CDCl3): δ = 5.30 (dd, J3,4 = 9.9, J4,5
= 8.4 Hz, 1 H, 4-H), 4.94 (d, J1,2 = 7.5 Hz, 1 H, 1-H), 3.93 (d, 1
H, 5-H), 3.75 (s, 3 H, COOCH3), 3.65 (dd, 1 H, 3-H), 3.47 (dd,
J2,3 = 9.6 Hz, 1 H, 2-H), 2.77–2.61 [m, 4 H, OCO(CH2)2], 2.19 (s, 3
H, COCH3), 1.65 [m, 1 H, CH(CH3)2], 1.45–1.44 [2 s, 6 H, C(CH3)2
isopropylidene acetal], 0.90–0.83 [m, 12 H, C(CH3)2 and CH-
(CH3)2], 0.20 [s, 6 H, Si(CH3)2] ppm. 13C NMR (75 MHz, CDCl3):
δ = 206.1, 171.6, 167.9, 111.7, 96.9, 78.1, 77.2, 74.6, 71.4, 52.7,
37.7, 33.9, 29.9, 27.7, 26.60, 26.57, 24.9, 20.1, 19.9, 18.5, 18.4, –2.2,
–3.0 ppm. HRMS: calcd. for C23H40O9SiNa 511.2339 [M]+; found
511.2341.
Methyl (Dimethylthexylsilyl 4-O-levulinoyl-2,3-di-O-pivaloyl-β-D-
glucopyranoside)uronate (21): Compound 19 (7.14 g, 14.6 mmol)
was dissolved in MeOH (110 mL), and DOWEX 50WX2 acidic
resin (9 g) was added. After 3 h, the DOWEX resin was filtered off,
and the solvent was removed in vacuo. The residue was dissolved
in pyr (75 mL). Pivaloyl chloride (11.3 mL, 91.8 mmol) and DMAP
(1.0 g, 8.19 mmol) were added. After the mixture was stirred at
room temperature for 3 d, an additional aliquot of DMAP (1.0 g,
8.19 mmol) was added. After a further 2 d, CH2Cl2 was added, and
the mixture was washed with aqueous HCl (1 ). The organic phase
was dried with Na2SO4, filtered and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (4:1 hex-
ane/EtOAc) to afford 21 (7.04 g, 78%). [α]2D0 = –7.8 (c = 0.67,
O-(4,6-O-Benzylidene-2-deoxy-3-O-levulinoyl-2-phthalimido-β-
copyranosyl)-(1Ǟ3)-O-(4,6-O-benzylidene-2-deoxy-2-phthalimido-β-
-glucopyranosyl)-(1Ǟ3)-1-O-benzoyl-4,6-O-benzylidene-2-deoxy-
2-phthalimido-α,β- -glucopyranose (14): TLC (3:2 toluene/EtOAc)
Rf = 0.26; H NMR (500 MHz, CDCl3, data for the β anomer): δ
= 7.83–7.34 (m, 32 H, Ph, NPhth), 6.25 (d, J1,2 = 8.9 Hz, 1 H, 1-
H), 5.55 (m, 2 H, 3ЈЈ-H, PhCHO), 5.47 (s, 1 H, PhCHO), 5.38 (s,
D-glu-
D
D
1
1 H, PhCHO), 5.36 (d, J1,2 = 8.4 Hz, 1 H, 1ЈЈ-H), 5.13 (d, J1,2
=
8.4 Hz, 1 H, 1Ј-H), 5.06 (dd, J2,3 = J3,4 = 9.6 Hz, 1 H, 3-H), 4.65
(dd, J2,3 = J3,4 = 9.7 Hz, 1 H, 3Ј-H), 4.44 (dd, 1 H, 2-H), 4.37 (m,
1 H, 6a-H), 4.24 (m, 1 H, 6aЈ-H), 4.15 (dd, 1 H, 2Ј-H), 4.12–4.05
(m, 2 H, 2ЈЈ-H, 6aЈЈ-H), 3.80–3.53 (m, 7 H, 4-H, 4Ј-H, 4ЈЈ-H, 6b-
H, 6bЈ-H, 6bЈЈ-H, 5-H), 3.43 (m, 1 H, 5Ј-H), 3.35 (m, 1 H, 5ЈЈ-H),
2.42–2.24 [m, 4 H, OCO(CH2)2], 1.82 (s, 1 H, COCH3) ppm. Se-
lected 13C NMR spectroscopic data (from HMQC experiment,
125 MHz, CDCl3): δ = 101.4, 101.24, 101.18 (3 PhCHO), 97.4 (C-
1Ј), 96.8 (C-1ЈЈ), 91.1 (C-1), 74.2 (C-3Ј), 73.5 (C-3), 69.6 (C-3ЈЈ)
ppm. HRMS: calcd. for C75H63N3O22Na 1380.3801 [M]+; found
1380.3816.
1
CHCl3); TLC (2:1 hexane/EtOAc) Rf = 0.55; H NMR (300 MHz,
CDCl3): δ = 5.29 (m, 2 H, 3-H, 4-H), 5.03 (dd, 1 H, 2-H), 4.84 (d,
J1,2 = 7.5 Hz, 1 H, 1-H), 4.05 (d, J4,5 = 9.9 Hz, 1 H, 5-H), 3.77 (s,
3 H, COOCH3), 2.72–2.49 [m, 4 H, OCO(CH2)2], 2.18 (s, 3 H,
COCH3), 1.61 [m, 1 H, CH(CH3)2], 1.17–1.13 [2 s, 18 H, OC-
OC(CH3)3], 0.88–0.83 [m, 12 H, C(CH3)2 and CH(CH3)2], 0.20–
0.13 [2 s, 6 H, Si(CH3)2] ppm. 13C NMR (75 MHz, CDCl3): δ =
205.7, 177.3, 176.3, 171.1, 167.2, 95.9, 72.7, 72.3, 71.8, 69.8, 52.7,
38.7, 37.5, 33.7, 29.8, 27.6, 27.2, 27.0, 24.7, 20.0, 19.8, 18.5, 18.4,
–2.0, –3.2 ppm. HRMS: calcd. for C30H52O11SiNa 639.3177 [M]+;
found 639.3191.
Methyl (Dimethylthexylsilyl 2,3-O-isopropylidene-β-D-glucopyran-
oside)uronate (17): 2-methoxypropene (27 mL, 282 mmol) was
added to 16 (4.94 g, 14.1 mmol) in dry DMF (30 mL). The reaction
mixture was cooled to 0 °C. A solution of (1S)-(+)-camphorsul-
fonic acid (327 mg, 1.41 mmol) in DMF (5 mL) was added drop-
wise whilst the mixture was stirred at 0 °C. After 2 h, MeOH
(5 mL) was added, and the mixture was stirred for 30 min at 0 °C.
Et3N (1 mL) was added, and the mixture was diluted with EtOAc
and washed with H2O. The organic phase was dried with Na2SO4,
filtered and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel (4:1 hexane/EtOAc) to yield 17
Methyl 4-O-Levulinoyl-2,3-di-O-pivaloyl-α,β-D-glucopyranosuronate
(23): (HF)n·Pyr complex (5 mL) was added to 21 (1.10 g,
1.78 mmol) in dry THF (25 mL) at 0 °C. After stirring for 24 h at
0 °C and then for 10 h at room temperature, the reaction mixture
was diluted with CH2Cl2 and washed with H2O and saturated
aqueous NaHCO3. The organic layer was dried with Na2SO4 and
filtered, and the solvents were removed in vacuo to yield 23
(754 mg, 89%) as an α/β mixture: TLC (2:1 hexane/EtOAc) Rf =
(2.74 g, 50%). [α]2D0 = –20.4 (c = 0.75, CHCl3); TLC (2:1 hexane/
EtOAc) Rf = 0.37; H NMR (300 MHz, CDCl3): δ = 4.91 (d, J1,2 0.15. 1H NMR (300 MHz, CDCl3, data for the α anomer): δ = 5.65
1
= 7.5 Hz, 1 H, 1-H), 4.10 (dd, J3,4 = J4,5 = 9.2 Hz, 1 H, 4-H), 3.84– (dd, 1 H, 3-H or 4-H), 5.57 (d, 1 H, 1-H), 5.22 (dd, 1 H, 3-H or 4-
3.81 (m, 4 H, 5-H, COOCH3), 3.55 (dd, 1 H, 3-H), 3.33 (dd, J2,3 H), 4.88 (dd, J1,2 = 3.6, J2,3 = 10.2 Hz, 1 H, 2-H), 4.61 (d, J4,5
=
= 9.3 Hz, 1 H, 2-H), 1.66 [m, 1 H, CH(CH3)2], 1.46–1.45 [2 s, 6 H,
C(CH3)2 isopropylidene acetal], 0.90–0.88 [m, 12 H, C(CH3)2 and
10.2 Hz, 1 H, 5-H), 3.77 (s, 3 H, COOCH3), 3.40 (br. s, 1 H, OH),
2.70–2.48 [m, 4 H, OCO(CH2)2], 2.19 (s, 3 H, COCH3), 1.18–1.16
CH(CH3)2], 0.20 [s, 6 H, Si(CH3)2] ppm. 13C NMR (75 MHz, [2 s, 18 H, OCOC(CH3)3] ppm. ES-MS: calcd. for C22H34O11Na
CDCl3): δ = 172.4, 113.8, 99.3, 81.5, 80.3, 77.9, 73.2, 55.0, 36.1,
497.2 [M]+; found 497.2.
2144
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2138–2147

Polymer-Supported Synthesis of Oligosaccharides
O-(Methyl 4-O-levulinoyl-2,3-di-O-pivaloyl-α,β-
uronate) Trichloroacetimidate (24): Trichloroacetonitrile (1.59 mL,
15.9 mmol) and K2CO3 (242 mg, 1.75 mmol) were added to 23
(754 mg, 1.59 mmol) in dry CH2Cl2 (7 mL). After stirring at room
temperature for 3 h, the mixture was filtered off and concentrated
in vacuo. Flash chromatography on silica gel (4:1 hexane/EtOAc)
afforded 24 (834 mg, 85%) as an α/β mixture.
D
-glucopyranosyl-
27.0, 26.9, 22.1 ppm. HRMS: calcd. for C27H44O12Na 583.2730
[M]+; found 583.2753.
Polymer-Bound Monosaccharide 28: iPr2SiCl2 (41 µL, 0.23 mmol)
was added dropwise to imidazole (78 mg, 1.14 mmol) in CH2Cl2
(2 mL), and this mixture was stirred for 5 min before 27 (128 mg,
0.23 mmol) in CH2Cl2 (2 mL) was added dropwise. The mixture
was stirred for 1 h at room temperature and then added dropwise
α
Anomer: TLC (2:1 hexane/EtOAc) Rf
=
0.45; 1H NMR to PEG monomethyl ether (1.14 g, approximately 0.23 mmol) in
(300 MHz, CDCl3): δ = 8.74 (s, 1 H, NH), 6.67 (d, J1,2 = 3.3 Hz, CH2Cl2 (5 mL). After the mixture was stirred for 24 h, diethyl ether
1 H, 1-H), 5.71 (dd, J2,3 = J3,4 = 9.9 Hz, 1 H, 3-H), 5.33 (dd, 1 H,
4-H), 5.20 (dd, 1 H, 2-H), 4.53 (d, J4,5 = 10.2 Hz, 1 H, 5-H), 3.77
(s, 3 H, COOCH3), 2.74–2.50 [m, 4 H, OCO(CH2)2], 2.19 (s, 3 H,
COCH3), 1.17–1.14 [2 s, 18 H, OCOC(CH3)3] ppm.
(120 mL) was added at 0 °C. The precipitated solid was collected
by filtration, washed with cold diethyl ether (120 mL) and dried
under high vacuum. The unreacted polymer sites were capped by
treating the polymer with acetic anhydride (6 mL) in pyr (12 mL)
for 12 h. Diethyl ether (120 mL) was then added at 0 °C. The pre-
cipitated solid was collected by filtration, washed with cold diethyl
ether (120 mL) and dried under high vacuum to yield polymer 28
(1.24 g) as a white solid. Selected 1H NMR spectroscopic data
(500 MHz, CDCl3): δ = 5.31 (dd, 1 H, 3-H or 4-H), 5.26 (dd, 1 H,
β
Anomer: TLC (2:1 hexane/EtOAc) Rf =
0.26; 1H NMR
(300 MHz, CDCl3): δ = 8.77 (s, 1 H, NH), 6.04 (d, J1,2 = 7.2 Hz,
1 H, 1-H), 5.40–5.37 (m, 3 H, 2-H, 3-H, 4-H), 4.26 (d, J4,5 = 9.0 Hz,
1 H, 5-H), 3.77 (s, 3 H, COOCH3), 2.72–2.52 [m, 4 H, OCO-
(CH2)2], 2.19 (s, 3 H, COCH3), 1.16–1.15 [2 s, 18 H, OCOC(CH3)
3] ppm. ES-MS: calcd. for C24H34O11NCl3Na 640.1 [M]+; found
640.1.
3-H or 4-H), 5.05 (dd, J2,3 = 8.5 Hz, 1 H, 2-H), 4.57 (d, J1,2
=
7.5 Hz, 1 H, 1-H), 4.06 (d, J4,5 = 9.5 Hz, 1 H, 5-H), 2.71–2.46 [m,
4 H, OCO(CH2)2], 2.18 (s, 3 H, COCH3), 1.17–1.14 [2 s, 18 H,
OCOC(CH3)3] ppm.
Methyl [O-(tert-Butyldimethylsilyl)-5-hydroxypentyl 4-O-levulinoyl-
2,3-di-O-pivaloyl-β-D-glucopyranoside]uronate (26): Acceptor 25
Polymer-Bound Monosaccharide 29: Compound 28 (400 mg, ap-
proximately 40 µmol of sugar) was dissolved in CH2Cl2 (4 mL),
and hydrazine acetate (197 µL, 0.66  solution in MeOH) was
added. After stirring at room temperature for 2 h, the reaction mix-
ture was quenched with acetone (1 mL), and diethyl ether (60 mL)
was added at 0 °C. The precipitated solid was collected by fil-
tration, washed with cold diethyl ether (60 mL) and dried under
high vacuum to give polymer 29 (360 mg) as a white solid. Selected
1H NMR spectroscopic data (500 MHz, CDCl3): δ = 5.09 (dd, J2,3
(741 mg, 3.39 mmol) and glucuronic acid trichloroacetimidate 24
(700 mg, 1.13 mmol) were combined in a flask, coevaporated with
toluene and dried under vacuum. The starting materials were dis-
solved in CH2Cl2 (7 mL) and further dried by stirring over acti-
vated molecular sieves (650 mg) for 30 min. TMSOTf (10 µL,
57 µmol) was added at 0 °C. After 15 min, the reaction was
quenched with Et3N (1 mL) and filtered, and the solvent was re-
moved under reduced pressure. Purification by flash chromatog-
raphy (hexane/EtOAc, 4:1) yielded 26 (536 mg, 70%). TLC (3:1
hexane/EtOAc) Rf = 0.39; [α]2D0 = –9.3 (c = 0.42, CHCl3); 1H NMR
(500 MHz, CDCl3): δ = 5.29 (dd, J2,3 = J3,4 = 9.5 Hz, 1 H, 3-H),
5.23 (dd, J4,5 = 9.5 Hz, 1 H, 4-H), 5.02 (dd, J1,2 = 8 Hz, 1 H, 2-
= J3,4 = 9.0 Hz, 1 H, 3-H), 4.95 (dd, 1 H, 2-H), 4.50 (d, J1,2
7.8 Hz, 1 H, 1-H), 1.15–1.13 [2 s, 18 H, OCOC(CH3)3] ppm.
=
Polymer-Bound Disaccharide 30: PEG-supported glucuronic acid
H), 4.54 (d, 1 H, 1-H), 4.04 (d, 1 H, 5-H), 3.87 (m, 1 H, OCH2), 29 (360 mg, approximately 36 µmol of sugar) and glycosyl donor 7
3.75 (s, 3 H, COOCH3), 3.56 (m, 2 H, OCH2), 3.45 (m, 1 H, (139 mg, 0.22 mmol), previously coevaporated with toluene and
OCH2), 2.68–2.45 [m, 4 H, OCO(CH2)2], 2.16 (s, 3 H, COCH3), dried under vacuum, were dissolved in CH2Cl2 (3 mL). TMSOTf
1.58–1.30 (m, 6 H, CH2), 1.14–1.11 [2 s, 18 H, OCOC(CH3)3], 0.87 (102 µL, 0.11  solution in CH2Cl2) was added at 0 °C. After stir-
[s, 9 H, SiC(CH3)3], 0.03 [2 s, 6 H, Si(CH3)2] ppm. 13C NMR
(125 MHz, CDCl3): δ = 177.3, 176.3, 171.1, 167.4, 101.0, 72.6, 71.5,
ring at 0 °C for 30 min, the reaction mixture was quenched with
Et3N (0.3 mL), and excess diethyl ether (80 mL) was added at 0 °C.
70.6, 70.3, 69.8, 62.9, 52.9, 38.73, 38.68, 37.5, 32.5, 29.7, 29.2, 27.6, The precipitated white solid was collected by filtration, rinsed with
27.1, 27.0, 26.0, 22.1, 18.3 ppm. HRMS: calcd. for C33H58O12SiNa
cold diethyl ether (80 mL) and dried under high vacuum. Precipi-
tation from diethyl ether was repeated until no low-molecular-
weight byproducts were detected by TLC and DOSY NMR experi-
ments.[62] This glycosidation procedure was repeated once more to
give polymer 30 (320 mg). Selected 1H NMR spectroscopic data
for PEG-bound disaccharide (500 MHz, CDCl3): δ = 7.86–7.72 (m,
4 H, NPhth), 7.44–7.32 (m, 5 H, Ph), 5.88 (dd, J2,3 = J3,4 = 9.5 Hz,
1 H, 3Ј-H), 5.48 (s, 1 H, PhCHO), 5.31 (d, J1,2 = 8.2 Hz, 1 H, 1Ј-
H), 5.14 (dd, J2,3 = J3,4 = 9 Hz, 1 H, 3-H), 4.86 (dd, J1,2 = 8.4 Hz,
1 H, 2-H), 4.42 (dd, 1 H, 6Јa-H), 4.36 (d, 1 H, 1-H), 4.27 (dd, 1
H, 4-H), 4.11 (dd, 1 H, 2Ј-H), 1.86 (s, 3 H, COCH3), 1.22–1.12 [2
s, 18 H, OCOC(CH3)3] ppm.
697.3595 [M]+; found 697.3651.
Methyl (5-hydroxypentyl 4-O-levulinoyl-2,3-di-O-pivaloyl-β-D-gluco-
pyranoside)uronate (27): Monosaccharide 26 (380 mg, 0.56 mmol)
was dissolved in anhydrous THF (5 mL). Glacial HOAc (39 µL,
0.68 mmol) and TBAF (1  in THF, 0.68 mL, 0.68 mmol) were
added at 0 °C, and the mixture was stirred at room temperature for
12 h. The mixture was diluted with EtOAc and washed with satu-
rated aqueous NaHCO3. The organic layer was dried with MgSO4
and filtered, and the solvents were removed in vacuo. Purification
by flash chromatography on silica gel (hexanes/EtOAc, 1:1) af-
forded 27 (200 mg, 63%) and unreacted starting material (70 mg,
18%). TLC (1:1 hexane/EtOAc) Rf = 0.2; [α]2D0 = –20.5 (c = 0.83,
Methyl [5-Hydroxypentyl 4-O-(4,6-O-benzylidene-2-deoxy-3-O-
1
CHCl3); H NMR (300 MHz, CDCl3): δ = 5.21 (m, 2 H, 3-H, 4- levulinoyl-2-phthalimido-β-
D-glucopyranosyl)-2,3-di-O-pivaloyl-β-
D-
H), 4.97 (dd, 1 H, 2-H), 4.50 (d, J1,2 = 7.8 Hz, 1 H, 1-H), 4.00 (d,
J4,5 = 9.3 Hz, 1 H, 5-H), 3.82 (m, 1 H, OCH2), 3.70 (s, 3 H, CO-
OCH3), 3.54 (m, 2 H, OCH2), 3.42 (m, 1 H, OCH2), 2.65–2.43 [m,
glucopyranoside]uronate (32): Polymer 30 (274 mg, approximately
26 µmol of sugar) was dissolved in THF/CH2Cl2 (3:2, 5 mL). Gla-
cial HOAc (17 µL, 0.29 mmol) and TBAF (1  in THF, 0.29 mL,
4 H, OCO(CH2)2], 2.11 (s, 3 H, COCH3), 1.55–1.29 (m, 6 H, CH2), 0.29 mmol) were added at 0 °C, and the mixture was stirred at
1.09–1.06 [2 s, 18 H, OCOC(CH3)3] ppm. 13C NMR (75 MHz, room temperature for 12 h. Diethyl ether (50 mL) was added at
CDCl3): δ = 205.8, 177.3, 176.4, 171.1, 167.3, 101.0, 72.5, 71.4,
0 °C. The precipitated solid was filtered off and washed with cold
70.6, 70.1, 69.7, 62.5, 52.9, 38.70, 38.67, 37.4, 32.3, 29.7, 29.1, 27.5, diethyl ether (50 mL). The filtrate and the washes were combined,
Eur. J. Org. Chem. 2010, 2138–2147
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2145

M. Mar Kayser, J. L. de Paz, P. M. Nieto
FULL PAPER
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Acknowledgments
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We thank the Spanish Research Council (CSIC) (Grant
200880I041), the Spanish Ministry of Science and Innovation
(Grants CTQ2006–01123 and CTQ2009–07168), Junta de Andal-
ucía (Grant P07-FQM-02969, “Incentivo a Proyecto Internacional”
and a fellowship to M. M. K.) and the European Union (FEDER
support and Marie Curie Reintegration Grant) for financial sup-
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