Study of the glycosidation properties of 1-thiomannosazidopyranosides and 1-thiomannosaziduronic acid esters

Article abstract of DOI:10.1002/ejoc.200600759

A study of the glycosylation properties of 1-thiomannosazides with a variety of electron-withdrawing substituents in combination with the Ph ₂SO/Tf₂O and NIS/TMSOTf reagent systems is presented. Further, assembly of the fully protect

Full text of DOI:10.1002/ejoc.200600759

FULL PAPER
DOI: 10.1002/ejoc.200600759
Study of the Glycosidation Properties of 1-Thiomannosazidopyranosides
and 1-Thiomannosaziduronic Acid Esters
Leendert J. van den Bos,[a] Boudewijn A. Duivenvoorden,[a] Martijn C. de Koning,[a]
Dmitri V. Filippov,[a] Herman S. Overkleeft,[a] and Gijsbert A. van der Marel*[a]
Keywords: Carbohydrates / Glycosylation / Thioglycosides / β-Mannosamine / Mannuronic acids
A study of the glycosylation properties of 1-thiomannos-
azides with a variety of electron-withdrawing substituents in
combination with the Ph2SO/Tf2O and NIS/TMSOTf reagent
systems is presented. Further, assembly of the fully protected
trisaccharide 26, which corresponds to the repeating unit of
the enterobacterial common antigen, using both an orthogo-
nal and a chemoselective coupling strategy and based on the
outcome of our glycosylation studies, is discussed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
the stereochemical outcome of glycosylation reactions
involving 4,6-O-benzylidenemannoside donors.[15] The de-
cisive effect of 4,6-O-benzylidene protection in mannopyr-
anose donors is further underscored by the finding that
variations in the glycosylation procedures and promoter
systems only led to minor fluctuations in the stereochemical
outcome of the β-mannosylation reaction.[16] In addition,
we have published the results of a study of the glycosylation
properties of 4,6-O-benzylidene-protected 1-phenylthio--
mannosazidopyranoside donors using diphenyl sulfoxide
(Ph2SO, 1b)/Tf2O[17] as the activation system (Figure 1).[18]
Introduction
N-Acetylmannosamine and N-acetylmannosaminuronic
acids are constituents of various bacterial capsular polysac-
charides and lipopolysaccharides.[1] In most cases, these
mannoside residues are connected to the next monosaccha-
ride residue through a 1,2-cis linkage.[2] This β-oriented
linkage is notoriously difficult to install by chemical synthe-
sis.[3] This is, amongst other reasons, caused by the anom-
eric effect in the manno series, which is enlarged by the ∆2
effect of the axially oriented C-2 function, favoring forma-
tion of 1,2-trans-oriented linkages. Several methodologies
for the synthesis of β-linked mannopyranoside residues
have been explored.[4] These include methods in which the
O-2 position of β--glucopyranosides is oxidized and re-
duced[5] or displaced in an SN2-type fashion by an azido
nucleophile.[6] Other procedures involve silver silicate medi-
ated SN2 displacement of α-bromides[7] or intramolecular
aglycon delivery[8] as the key step. The finding by Crich and
co-workers that activation of 4,6-O-benzylidene-protected
mannopyranosyl sulfoxide donors with triflic anhydride
leading to the formation of β-mannoside linkages proved to
be a breakthrough in this field of research.[9] Later studies
demonstrated that comparable β-selectivities can be at-
tained using 4,6-O-benzylidene-protected 1-thiomannosides
in combination with phenylsulfenyl triflate[10] (PhSOTf) or
1-(phenylsulfinyl)piperidine (BSP, 1a)/triflic anhydride
(Tf2O) as activation systems (Figure 1).[11,12] The β-direct-
ing effect of the 4,6-O-benzylidene protecting group on β-
selective mannosylations was initially explained by in-
creased torsional strain.[13] Recently, Bols and co-workers
argued that electronic effects[14] have a major influence on
Figure 1. Sulfonium activator systems used for the activation of 1-
thioglycosides.
The finding that the deactivating effect of a 4,6-O-benzyl-
idene protective group on glycosyl transfer is at least par-
tially governed by electronic effects suggests that the intro-
duction of sufficient electron-withdrawing functionalities in
the mannose core may also lead to β-mannosylation.[19] In
fact, Schuerch and co-workers demonstrated in 1980 that
mannopyranose donors having a strongly electronegative
non-participating substituent at C-2 (such as tosyl) and a
highly reactive electronegative leaving group at C-1 (such as
tosyl or chloride) results in high β-selectivities.[20] Applica-
tion of this approach is limited by the harsh conditions re-
quired for removal of the C-2 tosyl functionality and the
moderate selectivities obtained with sterically encumbered
acceptor nucleophiles. We recently revealed that installation
of a carboxylic acid functionality at the C-5 position of
suitably protected 1-thiomannosides strongly favours SN2-
[a] Leiden Institute of Chemistry, Leiden University,
P. O. Box 9502, 2300 RA Leiden, The Netherlands
Fax: +31-71-527-4307
E-mail: marel_g@chem.leidenuniv.nl
116
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1-Thiomannosazidopyranosides and 1-Thiomannosaziduronic Acid Esters
FULL PAPER
type displacement of the putative α-triflate intermediate re- tyl donor 7 with secondary alcohol acceptor 14[27] was exe-
sulting in high to exclusive β-selectivities.[21] In line with cuted under the conditions described above giving disaccha-
these studies we have investigated the glycosylation proper- ride 15 in good yield and with a slight preference for α-
ties, in terms of yield and stereoselectivity, of 1-thio-α-- anomer formation (Entry 3). This lower α/β ratio agrees
mannosazidopyranoside donors 4, 7 and 10 having elec- with the reported trend that glycosylation of a specific do-
tron-withdrawing functionalities on different positions of nor with a series of acceptors of decreasing nucleophilicity
the pyranoside core. The outcome of these studies and their leads to a change in the anomeric ratio in favour of the α-
application in the assembly of the fully protected repeating product.[28] Next, the reactivity of the mannosazide donor
unit trisaccharide 26 of the enterobacterial common antigen was further reduced by replacement of the 3-O-benzyl with
(ECA) are presented here.
the 3-O-acetyl protective group (4). Phenyl 3,4,6-tri-O-ace-
tyl-2-azido-2-deoxy-1-thio-α--mannopyranoside (4) was
effectively condensed with the highly reactive 11, the less
reactive 17 and the sterically demanding acceptor 14 to give
disaccharides 16, 18 and 19, respectively (Entries 3–5). In
all cases only the α-product was isolated suggesting that the
stereochemical outcome of these reactions is independent of
the reactivity of the acceptor. These results support earlier
observations that 3-O-acyl groups in mannopyranose[29]
and glucopyranose[30] donors are α-directing as a result of
neighbouring-group participation, which proceeds via a six-
membered transition state that shields attack at the β-site.
Finally, the glycosylation properties of 1-thio-α-mannos-
aziduronic acid donor 10, bearing an electron-withdrawing
ester moiety at the C-5 position, were investigated. Coup-
ling of donor 10 with primary alcohol 11 gave exclusively
β-linked disaccharide 20 in 69% yield. An attempt to glyco-
sylate the secondary alcohol acceptor 14 using the same
Ph2SO/Tf2O activation protocol did not result in satisfac-
tory product formation. Monitoring of the reaction by TLC
analysis showed that the initial preactivation of donor 10
with Ph2SO/Tf2O proceeded uneventfully, while addition of
the acceptor and warming of the reaction mixture showed,
besides the formation of several side-products, partial re-
generation of the donor 10. This indicates that under
Ph2SO/Tf2O activation conditions the donor glycoside is
not always fully converted into the intermediate α-tri-
flate.[31] Changing of the activation system to NIS/
TMSOTf[21,32] led to productive coupling of 1-thio-α-man-
nosaziduronic acid donor 10 with acceptor 14 affording di-
saccharide 21 in 53% yield as an anomeric mixture (α/β =
1:2).
Results and Discussion
Donor glycosides 4, 7 and 10 were obtained starting from
commercially available -mannosamine hydrochloride 3 as
follows. Subjection of 3 to diazo transfer, followed by acety-
lation and finally Lewis acid catalyzed introduction of the
anomeric phenylthio group gave tri-O-acetylmannosazide
4.[22] Deacetylation followed by installation of the 4,6-O-
benzylidene acetal, introduction of the benzyl group at the
C-3 position and acidic removal of the benzylidene acetal
yielded diol 6 in good yield. Acetylation of diol 6 afforded
O-3-benzylated glycoside 7. Chemo- and regioselective oxi-
dation of the diol 6 using the TEMPO/BAIB {[bis(acetoxy)-
iodo]benzene} reagent combination[23] afforded the corre-
sponding mannosaziduronic acid 8 in 65% yield. Methyl-
ation of the free carboxylic acid to give 9 and acetylation
of the residual C-4 position afforded uronic ester donor 10
(Scheme 1).
Having our target donor mannosides in hand, we turned
our attention to the investigation of their glycosylation
properties. Phenyl 4,6-di-O-acetyl-2-azido-3-O-benzyl-2-de-
oxy-1-thio-α--mannopyranoside (7) was condensed, under
the influence of in situ generated diphenylsulfonium bis-
(triflate) (2b), with methyl 2,3,4-tri-O-benzyl-α--glucopyr-
anoside (11) (Table 1, Entry 1). Donor 7 was preactivated
by treatment with 1.4 equiv. of Ph2SO (1b) and 1.4 equiv.
of Tf2O at –60 °C in the presence of the acid scavenger
2,4,6-tri-tert-butylpyrimidine (TTBP).[24] After 15 min, dur-
ing which time the temperature gradually rose to –50 °C,
acceptor 11[25] was added and then the reaction mixture was
At this stage we decided to investigate the assembly of
warmed to room temperature. Disaccharide 12 was isolated the fully protected trisaccharide 26 (Scheme 2). In its un-
in 86% yield as an anomeric mixture (α/β = 1:4).[26] The protected form, this trisaccharide, (Ǟ3)-α--Fucp4NAc-
outcome of this glycosylation procedure in terms of yield (1Ǟ4)-β--ManpNAcA-(1Ǟ4)-α--GlcpNAc-(1Ǟ), is the
and anomeric ratio does not substantially differ from that repeating unit of the polysaccharide that constitutes 70%
of the condensation of 4,6-O-benzylidene-protected donor or more of the enterobacterial common antigen
5 with the same acceptor (Entry 2). Condensation of diace- (ECA).[33,34] The synthetic route to trimer 26 was investi-
Scheme 1. Synthesis of the donor building blocks. Reagents and conditions: (a) pTsOH, MeOH; (b) Ac2O, pyridine; 7: 88% (from 4), 10:
quant.; (c) TEMPO, BAIB, DCM/H2O (4:1), 65% (from 6); (d) MeI, K2CO3, DMF, 71%.
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G. A. van der Marel et al.
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Table 1. Glycosylation reactions of 2-azido-2-deoxy-1-thio-α--mannosides and the corresponding methyl uronates.
gated starting from the non-reducing end -fucose residue efficient modulator in chemoselective glycosylation reac-
using both a chemoselective glycosylation[28a] and an or- tions of this type,[28b] would possibly be detrimental to the
thogonal condensation strategy.[35] In the first instance, two azide functionalities in the product disaccharide. We set
known 4-azidothiofucose donor 22[36] was condensed with out to compare this result with an orthogonal glycosyla-
1-thiomannosaziduronic acid ester 9 under the agency of tion[37] in which 1-hydroxy donor 23 was condensed with
Ph2SO/Tf2O to afford, in a chemoselective fashion, α-linked acceptor 9. To this end, fucose donor 23 was prepared by
thiodisaccharide 24 in 55% yield. No deterioration of disac- hydrolysis of the phenylthio function in compound 22 using
charide 24 in the presence of the transiently formed di- the NIS/TFA reagent system.[38] Activation of donor 23
phenyl(phenylthio)sulfonium triflate was detected. This is with 2.8 equiv. of Ph2SO and 1.3 equiv. of Tf2O at
fortunate, because quenching of the reaction with triethyl –40 °C for 1 h followed by the addition of acceptor 9 gave
phosphite (TEP), which we previously reported to be an α-linked thiodisaccharide 24 in 67% yield. Treatment of a
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Scheme 2. Synthesis of protected trisaccharide 26. Reagents and conditions: (a) NIS, TFA, DCM/H2O (10:1), 73%; (b) 22, Ph2SO, Tf2O,
TTBP, DCM, –60 °C then 9, 55%; (c) 23, Ph2SO, Tf2O, TTBP, DCM, –40 °C then 9, 67%; (d) 25, NIS, TMSOTf, DCM, 65% (α/β =
1:2).
in ethanol followed by charring at around 150 °C or by spraying
with a solution of (NH4)6Mo7O24·H2O (25 g/L) and (NH4)4-
Ce(SO4)4·2H2O (10 g/L) in 10% aqueous sulfuric acid followed by
charring at around 150 °C. PE = petroleum ether; pMP = p-meth-
oxyphenyl.
mixture of 1-thiodisaccharide donor 24 with 1,6-anhydro
acceptor 25[39] and the NIS/TMSOTf reagent combination
finally afforded trisaccharide 26 in 65% yield as a 1:2 (α/β)
separable anomeric mixture.
General Procedure for Glycosidation Reactions with Ph2SO/Tf2O:
A solution of 1-thiomannopyranoside uronic acid ester (1 equiv.),
diphenyl sulfoxide (1.3 equiv.) and tri-tert-butylpyrimidine
(2.5 equiv.) in DCM (0.05 ) was stirred in the presence of acti-
vated MS (3 Å) for 30 min. The mixture was cooled to –60 °C be-
Conclusions
This paper describes the glycosylation properties of 1-
thiomannosazidopyranosides bearing electron-withdrawing
substituents at different positions of the carbohydrate core. fore triflic anhydride (1.3 equiv.) was added. The mixture was then
warmed to –50 °C in 15 min and acceptor (1.5 equiv.) in DCM
(0.15 ) was added. Stirring was continued and the reaction mix-
ture was warmed to room temperature. The reaction mixture was
diluted with EtOAc and washed with water. The aqueous layer was
extracted twice with EtOAc. The collected organic layers were dried
(MgSO4), filtered and concentrated under reduced pressure. Flash
chromatography (EtOAc/PE) and removal of the eluent afforded
the corresponding disaccharides.
We found that 4,6-di-O-acetyl protection of 1-thiomannos-
azides sufficiently influences the electronic environment
around the anomeric centre leading to reasonable β-selec-
tivities, whereas acyl protection at the C-3 position gives
exclusive α-glycoside formation. Furthermore, uronic acid
ester functionalized mannosazides (e.g., 10) also showed
good to excellent β-selectivities.
Phenyl
4,6-Di-O-acetyl-2-azido-3-O-benzyl-2-deoxy-1-thio-α-D-
mannopyranoside (7): Compound 4 (381 mg, 0.9 mmol) was dis-
solved in MeOH (3 mL) before a catalytic amount of KOtBu was
added. After TLC analysis indicated complete reaction, the reac-
tion mixture was neutralized using Amberlite IR120, H+-form. The
reaction mixture was filtered and concentrated under reduced pres-
sure. The crude oil was suspended in acetonitrile (3 mL) followed
by addition of benzaldehyde dimethyl acetal (0.15 mL, 1 mmol)
and a catalytic amount of p-toluenesulfonic acid hydrate. After
TLC analysis indicated complete reaction, triethylamine (1 mL)
was added and the reaction mixture was concentrated under re-
duced pressure. The crude oil was dissolved in DMF (3 mL) and
cooled to 0 °C. Benzyl bromide (0.14 mL. 1.2 mmol) and sodium
hydride (48 mg, 1.2 mmol) were added. After TLC analysis indi-
cated complete conversion, the reaction mixture was dissolved in
Et2O (50 mL) and washed with water. The organic layer was dried
(MgSO4), filtered and concentrated under reduced pressure. The
crude oil was suspended in MeOH (10 mL) and a catalytic amount
of p-toluenesulfonic acid hydrate was added. The reaction mixture
was refluxed for 1 h followed by the addition of triethylamine
(1 mL) and concentration under reduced pressure. The crude oil
was treated with a mixture of pyridine (5 mL) and acetic anhydride
(2 mL). After TLC analysis indicated complete reaction, the reac-
tion mixture was quenched by the addition of MeOH (1 mL), taken
Experimental Section
1
General Procedures: H and 13C NMR spectra were recorded with
Bruker DMX-400, AV-400 (both 400/100 MHz) and AV500 (500/
125 MHz) spectrometers. Chemical shifts (δ) are given in ppm rela-
tive to tetramethylsilane as internal standard. Coupling constants
are given in Hz. All 13C spectra are proton-decoupled. Mass spectra
were recorded with a PE/SCIEX API 165 instrument with an elec-
trospray interface and Q-Star Applied Biosystems Q-TOF (TOF
section) system. Optical rotations were measured with a Propol
automatic polarimeter. IR spectra were recorded with a Shimadzu
FTIR-8300 spectrometer. Traces of water in the donor and ac-
ceptor glycosides, diphenyl sulfoxide and TTBP were removed by
coevaporation with toluene. TTBP was synthesized as described by
Crich et al.[24] Dichloromethane (DCM, Baker p.a.) was refluxed
in the presence of P2O5 for 2 h and distilled prior to use. Trifluoro-
methanesulfonic anhydride was distilled from P2O5. Molecular
sieves (MS) (3 Å) were flame-dried before use. Solvents used for
flash chromatography and TLC were of technical grade and dis-
tilled before use. Flash chromatography was performed with Fluka
silica gel 60 (0.04–0.063 mm). TLC was conducted with DC-Alu-
folien (Merck, Kieselgel60, F254) with detection by UV absorption
(254 nm) where applicable and by spraying with 20% sulfuric acid
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G. A. van der Marel et al.
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up in Et2O (50 mL) and washed with water. The organic layer was
dried (MgSO4), filtered and concentrated under reduced pressure.
Flash column chromatography using EtOAc/PE afforded com-
pound 7 (391 mg, 0.79 mmol, 88% over the five steps) as a colour-
less oil. TLC: 50% EtOAc/PE. [α]2D2 = +12 (c = 0.8, CHCl3). IR
COOMe) ppm. ESI-MS: m/z = 453.2 [M + K]+. HRMS [M +
NH4]+: calcd. for C20H21O5N3S 433.15457; found 433.15418.
Methyl (Phenyl 4-O-acetyl-2-azido-3-O-benzyl-2-deoxy-1-thio-α-D-
mannopyranosid)uronate (10): Compound 9 (245 mg, 0.6 mmol)
was treated with pyridine/Ac2O (3:1, 3 mL) solution for 8 h fol-
lowed by the addition MeOH (2 mL). The reaction mixture was
taken up in EtOAc and washed with 2  HCl and saturated
NaHCO3. The organic layer was dried (MgSO4), filtered and con-
centrated under reduced pressure. Flash column chromatography
(EtOAc/PE) afforded the title compound 10 (274 mg, 0.6 mmol,
quant.) as a colourless oil. TLC: 50% EtOAc/PE (5% AcOH).
(neat): ν = 740, 1001, 1118, 1218, 1373, 2102 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 2.02 (s, 3 H, CH3 Ac), 2.03 (s, 3 H, CH3
Ac), 3.95 (dd, J = 9.2 Hz, J = 3.6 Hz, 1 H, 3-H), 4.05–4.09 (m, J
= 2.4 Hz, 2 H, 2-H, 6-H), 4.20 (dd, J = 12.4 Hz, J = 6.0 Hz, 1 H,
6-H), 4.33–4.38 (m, J = 6.0 Hz, J = 2.4 Hz, 1 H, 5-H), 4.62 (d, J
= 12.0 Hz, 1 H, CHHPh), 4.70 (d, J = 12.0 Hz, 1 H, CHHPh), 5.31
(t, J = 9.6 Hz, 1 H, 4-H), 5.48 (d, J = 1.6 Hz, 1 H, 1-H), 7.26–7.55
(m, 10 H, H arom) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.7
(CH3 Ac), 20.8 (CH3 Ac), 62.2 (C-2), 62.4 (C-6), 67.6 (C-4), 69.9
(C-5), 72.6 (CH2 Bn), 76.7 (C-3), 85.9 (C-1), 127.9–131.8 (CH
arom), 132.7 (Cq SPh), 137.1 (Cq Bn), 169.5 (C=O Ac), 170.7 (C=O
Ac) ppm. ESI-MS: m/z = 472.2 [M + H]+, 489.3 [M + NH4]+, 494.2
[M + Na]+. HRMS [M + Na]+: calcd. for C23H25O6N3S 494.13563;
found 494.13583.
[α]22= +37 (c = 1, CHCl ). IR (neat): ν = 740, 1001, 1118, 1218,
˜
D
3
1
1373, 1747, 2102 cm–1. H NMR (500 MHz, CDCl3): δ = 2.05 (s,
3 H, CH3 Ac), 3.85 (br. s, 4 H, 2-H, CH3 COOMe), 3.95 (t, J =
3.5 Hz, 1 H, 3-H), 4.56 (d, J = 2.5, 1 H, 5-H), 4.62 (d, J = 11.5 Hz,
1 H, CHHPh), 4.65 (d, J = 11.5 Hz, 1 H, CHHPh), 5.54 (t, J =
3.5 Hz, J = 2.5 Hz, 1 H, 4-H), 5.72 (d, J = 9.0 Hz, 1 H, 1-H), 7.25–
7.66 (m, 10 H, H arom) ppm. 13C NMR (100 MHz, CDCl3): δ =
20.7 (CH3 Ac), 52.2 (CH3 COOMe), 57.7 (C-2), 68.2 (C-4), 72.9
(CH2 Bn), 73.2 (C-5), 74.8 (C-3), 80.7 (C-1), 127.8–132.2 (CH
arom), 131.7 (Cq SPh), 136.3 (Cq Bn), 167.9 (C=O COOMe or Ac),
169.5 (C=O Ac or COOMe) ppm. HRMS [M + H]+: calcd. for
C22H23O6N3S 458.13803; found 458.13934.
Phenyl 2-Azido-3-O-benzyl-2-deoxy-1-thio-α-D-mannopyranosidu-
ronic Acid (8): TEMPO (41 mg, 0.26 mmol, 0.2 equiv.) and BAIB
(966 mg, 3 mmol, 2.5 equiv.) were added to a vigorously stirred
solution of compound 6 (505 mg, 1.3 mmol) in DCM (10 mL) and
H2O (2 mL) . Stirring was continued until TLC indicated complete
conversion of the starting material to a lower running spot. The
reaction mixture was quenched by the addition of an Na2S2O3 solu-
tion (10% in H2O, 25 mL). The mixture was then extracted twice
with EtOAc (10 mL) and the combined organic layers were dried
(MgSO4), filtered and concentrated. Flash column chromatography
using EtOAc/PE and 2% (v/v) AcOH afforded 1-thiomannuronic
acid 8 (340 mg, 0.85 mmol, 65%) as a colourless oil. TLC: 50%
EtOAc/PE (5% AcOH). 1H NMR (600 MHz, CDCl3): δ = 3.90
(dd, J = 8.4 Hz, J = 3.4 Hz, 1 H, 3-H), 3.99 (s, 1 H, 2-H), 4.25 (t,
J = 8.6 Hz, 1 H, 4-H), 4.64 (d, J = 8.4 Hz, 1 H, 5-H), 4.74 (d, J =
11.7 Hz, 1 H, CHHPh), 4.84 (d, J = 11.7 Hz, 1 H, CHHPh), 5.51
(d, J = 3.9 Hz, 1 H, 1-H), 7.26–7.59 (m, 10 H, H arom) ppm. 13C
NMR (100 MHz, CDCl3): δ = 61.1 (C-2), 68.5 (C-4), 71.8 (C-5),
73.4 (CH2 Bn), 77.9 (C-3), 85.9 (C-1), 127.9–132.2 (CH arom),
132.1 (Cq SPh), 137.2 (Cq Bn), 172.57 (C=O COOH) ppm. 13C-
GATED NMR (100 MHz, CDCl3): δ = 85.9 (JC1,H1 = 169 Hz, C-
1) ppm. ESI-MS: m/z = 424.0 [M + Na]+, 440.0 [M + K]+, 825.2
[2 M + Na]+. HRMS [M + Na]+: calcd. for C19H19O5N3S
424.09376; found 424.09389.
Methyl 2,3,4-Tri-O-benzyl-6-O-(4,6-di-O-acetyl-2-azido-3-O-ben-
zyl-2-deoxy-α/β-D-mannopyranosyl)-α-D-glucopyranoside (12): Di-
saccharide 12 was obtained from donor 7 and acceptor 11 accord-
ing to the general glycosidation procedure using the Ph2SO/Tf2O
activator system. Anomers were separated by flash column
chromatography: α-anomer: 16 mg, 0.019 mmol, 19%; β-anomer:
55 mg, 0.067 mmol, 67%. TLC: 30% EtOAc/PE. α-Anomer: 1H
NMR (500 MHz, CDCl3): δ = 2.00 (s, 3 H, CH3 Ac), 2.03 (s, 3 H,
CH3 Ac), 3.33 (s, 3 H, CH3 COOMe), 3.39 (t, J = 9.0 Hz, 1 H, 4-
H), 3.49 (dd, J = 10.0 Hz, J = 4.0 Hz, 1 H, 2-H), 3.61 (d, J =
11.5 Hz, 1 H, 6-H), 3.67–3.74 (m, 2 H, 5-H, 5Ј-H), 3.78 (dd, J =
11.5 Hz, J = 4.5 Hz, 1 H, 6-H), 3.86 (dd, J = 9.5 Hz, J = 3.5 Hz,
1 H, 3Ј-H), 3.89 (d, J = 1.5 Hz, 1 H, 2Ј-H), 3.95 (dd, J = 12.0 Hz,
J = 2.5 Hz, 1 H, 6Ј-H), 3.99 (t, J = 9.0 Hz, 1 H, 3-H), 4.03 (dd, J
= 12.0 Hz, J = 4.5 Hz, 1 H, 6Ј-H), 4.45 (d, J = 11.0 Hz, 1 H,
CHHPh), 4.53 (d, J = 12.0 Hz, 1 H, CHHPh), 4.61 (d, J = 3.5 Hz,
1 H, 1-H), 4.64 (d, J = 12.0 Hz, 1 H, CHHPh), 4.67 (d, J = 11.5 Hz,
1 H, CHHPh), 4.80 (d, J = 11.0 Hz, 2 H, CHHPh, CHHPh), 4.85
(s, 1 H, 1Ј-H), 4.92 (d, J = 11.5 Hz, 1 H, CHHPh), 5.02 (d, J =
11.0 Hz, 1 H, CHHPh), 5.23 (t, J = 9.5 Hz, 1 H, 4Ј-H), 7.21–7.40
(m, 20 H, H Arom) ppm. 13C NMR (125 MHz, CDCl3): δ = 20.7
(CH3 Ac), 20.8 (CH3 Ac), 55.2 (CH3 OMe), 60.6 (C-2Ј), 62.1 (C-
Methyl (Phenyl 2-azido-3-O-benzyl-2-deoxy-1-thio-α-
D-mannopyr-
anosid)uronate (9): MeI (0.06 mL, 1 mmol, 1.2 equiv.) and K2CO3 6Ј), 66.8 (C-6), 67.2 (C-4Ј), 68.9 (C-5Ј), 68.6 (C-5), 71.9 (CH2 Bn),
(200 mg) were added to a stirred solution of compound 8 (340 mg,
0.85 mmol) in DMF (5 mL). The solution was stirred overnight,
taken up in EtOAc and washed with H2O. The aqueous layer was
extracted with EtOAc. The collected organic layers were dried
(MgSO4), filtered and concentrated under reduced pressure. Flash
column chromatography (EtOAc/PE) afforded title compound 9
(245 mg, 0.6 mmol, 71%) as a colourless oil. TLC: 50% EtOAc/
73.2 (CH2 Bn), 74.9 (CH2 Bn), 75.7 (C-3Ј), 75.8 (CH2 Bn), 77.6 (C-
4), 79.9 (C-2), 82.0 (C-3), 97.9 (C-1), 98.4 (C-1Ј), 127.3–128.6 (CH
arom), 137.2 (Cq Bn), 137.9 (Cq Bn), 138.1 (Cq Bn), 138.6 (Cq Bn),
169.4 (C=O Ac), 170.7 (C=O Ac) ppm. 13C-GATED NMR
(125 MHz, CDCl3): δ = 97.9 (JC1,H1 = 171 Hz, C-1), 98.4 (JC1Ј,H1Ј
= 175 Hz, C-1Ј) ppm. ESI-MS: m/z = 843.4 [M + NH4]+. HRMS
[M + H]+: calcd. for C45H51O12N3 826.35455; found 826.35550. β-
PE. [α]22= +69 (c = 1.4, CHCl ). IR (neat): ν = 740, 1001, 1118,
Anomer: [α]2D2 = –17 (c = 0.8, CHCl ). IR (neat): ν = 698, 738, 754,
˜
˜
D
3
3
1218, 1373, 1747, 2102 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1004, 1039, 1068, 1132, 1240, 1367, 1743, 2104 cm–1. 1H NMR
3.04 (br. s, 1 H, O4-H), 3.71 (s, 1 H, CH3 COOMe), 3.87 (dd, J =
(400 MHz, CDCl3): δ = 2.01 (s, 3 H, CH3 Ac), 2.03 (s, 3 H, CH3
8.0 Hz, J = 3.4 Hz, 1 H, 3-H), 3.95 (t, J = 3.4 Hz, 1 H, 2-H), 4.31 Ac), 3.34 (s, 3 H, CH3 OMe), 3.36 (t, J = 9.2 Hz, 1 H, 4-H), 3.38–
(dq, J = 7.9 Hz, J = 2.1 Hz, 1 H, 4-H), 4,60 (d, J = 7.9 Hz, 1 H, 3.41 (m, 1 H, 5Ј-H), 3.46 (dd, J = 9.6 Hz, J = 4.5 Hz, 1 H, 3-H),
5-H), 4.72 (d, J = 11.6 Hz, 1 H, CHHPh), 4.78 (d, J = 11.6 Hz, 1
3.49 (d, J = 8.0 Hz, 1 H, 2-H), 3.51 (m, J = 3.6 Hz, 1 H, 6-H), 3.75
H, CHHPh), 5.52 (d, J = 1.4 Hz, 1 H, 1-H), 7.24–7.51 (m, 10 H, (d, J = 4.5 Hz, 1 H, 2-H), 4.00 (t, J = 9.2 Hz, 1 H, 3-H), 4.07–4.11
H arom) ppm. 13C NMR (100 MHz, CDCl3): δ = 52.6 (CH3 CO-
OMe), 61.0 (C-2), 68.3 (C-4), 72.9 (C-5), 73.2 (CH2 Bn), 77.9 (C-
3), 85.4 (C-1), 127.9–131.9 (CH arom), 137.1 (Cq Bn), 169.8 (C=O
(m, 2 H, 6-H, 6Ј-H), 4.17 (dd, J = 12.0 Hz, J = 5.2 Hz, 1 H, 6Ј-H),
4.26 (s, 1 H, 1Ј-H), 4.53 (d, J = 11.6 Hz, 1 H, CHHPh), 4.55 (d, J
= 12.4 Hz, 1 H, CHHPh), 4.56 (s, 1 H, 1-H), 4.62 (d, J = 12.0 Hz,
120
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Eur. J. Org. Chem. 2007, 116–124

1-Thiomannosazidopyranosides and 1-Thiomannosaziduronic Acid Esters
1 H, CHHPh), 4.67 (d, J = 12.4 Hz, 1 H, CHHPh), 4.77 (d, J = H, H arom) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.5 (CH3
FULL PAPER
12.0 Hz, 1 H, CHHPh), 4.80 (d, J = 10.8 Hz, 1 H, CHHPh), 4.87
(d, J = 11.6 Hz, 1 H, CHHPh), 5.00 (d, J = 10.8 Hz, 1 H, CHHPh),
Ac), 20.6 (CH3 Ac), 20.7 (CH3 Ac), 55.2 (CH3 OMe), 60.5 (C-2Ј),
61.8 (C-6Ј), 65.8 (C-4Ј), 66.5 (C-6), 68.5 (C-5Ј), 69.9 (C-5), 70.9 (C-
5.15 (t, J = 9.6 Hz, 1 H, 4Ј-H), 7.23–7.36 (m, 20 H, H arom) ppm. 3Ј), 73.3 (CH2 Bn), 75.2 (CH2 Bn), 75.8 (CH2 Bn), 80.0 (C-4), 81.1
13C NMR (100 MHz, CDCl3): δ = 20.7 (CH3 Ac), 20.7 (CH3 Ac),
(C-2), 82.1 (C-3), 97.9 (C-1), 98.2 (C-1Ј), 127.5–128.5 (CH arom),
55.1 (CH3 OMe), 61.3 (C-2Ј), 62.6 (C-6Ј), 67.3 (C-4Ј), 68.7 (C-6), 138.0 (Cq Bn), 138.1 (Cq Bn), 138.5 (Cq Bn), 169.5 (C=O Ac), 169.8
69.5 (C-5), 71.8 (CH2 Bn), 72.4 (C-5Ј), 73.4 (CH2 Bn), 74.6 (CH2 (C=O Ac), 170.6 (C=O Ac) ppm. 13C-GATED NMR (100 MHz,
Bn), 75.7 (CH2 Bn), 77.2 (C-3Ј), 77.6 (C-4), 79.8 (C-2), 81.9 (C-3), CDCl3): δ = 97.9 (JC1,H1 = 164 Hz, C-1), 98.2 (JC1Ј,H1Ј = 174 Hz,
97.8 (C-1), 99.8 (C-1Ј), 137.2 (Cq Bn), 138.0 (Cq Bn), 138.2 (Cq
C-1Ј) ppm. ESI-MS: m/z = 795.1 [M + NH4]+. HRMS [M +
Bn), 138.6 (Cq Bn), 169.3 (C=O Ac), 170.8 (C=O Ac) ppm. 13C- NH4]+: calcd. for C40H47O13N3 795.34471; found 795.34144.
GATED NMR (100 MHz, CDCl3): δ = 97.8 (JC1,H1 = 171 Hz, C-
3-O-(3,4,6-Tri-O-acetyl-2-azido-2-deoxy-α-
D-mannopyranosyl)-
1), 99.8 (JC1Ј,H1Ј = 158 Hz, C-1Ј) ppm. ESI-MS: m/z = 848.4 [M +
Na]+. HRMS [M + Na]+: calcd. for C45H51O12N3 848.33650; found
848.33642.
1,2;5,6-di-O-isopropylidene-α- -glucofuranose (18): Disaccharide 18
D
(45 mg, 0.079 mmol, 79%) was obtained from donor 4 and ac-
ceptor 17 according to the general glycosidation procedure using
p-Methoxyphenyl 2-O-Benzyl-4,6-O-benzylidene-3-O-(4,6-di-O-ace- the Ph2SO/Tf2O activator system. TLC: 30% EtOAc/PE. IR (neat):
tyl-2-azido-3-O-benzyl-2-deoxy-α/β- -mannopyranosyl)-β- -galac- ν = 698, 734, 819, 999, 1026, 1101, 1132, 1217, 1506, 1747,
D
D
˜
topyranoside (15): Disaccharide 15 (65 mg, 0.082 mmol, 82%) was
obtained from donor 7 and acceptor 14 according to the general
glycosidation procedure using the Ph2SO/Tf2O activator system.
The anomers could not be separated by flash column chromatog-
2106 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.27 (s, 3 H, CH3
isoprop), 1.32 (s, 3 H, CH3 isoprop), 1.37 (s, 3 H, CH3 isoprop),
1.41 (s, 3 H, CH3 isoprop), 2.06 (s, 3 H, CH3 Ac), 2.10 (s, 3 H,
CH3 Ac), 2.12 (s, 3 H, CH3 Ac), 3.97–4.05 (m, 2 H, 5Ј-H, 6Ј-H),
4.06 (dd, J = 3.0 Hz, J = 1.0 Hz, 1 H, 2Ј-H), 4.07 (dd, J = 8.5 Hz,
raphy. TLC: 30% EtOAc/PE. IR (neat): ν = 696, 1028, 1035, 1217,
˜
1506, 1733, 2102 cm–1. H NMR (400 MHz, CDCl3, β-anomer): δ J = 2.5 Hz, 1 H, 4-H), 4.12–4.17 (m, 3 H, 6-H, 5Ј-H and 6Ј-H),
= 1.98 (s, 3 H, CH3 Ac), 2.05 (s, 3 H, CH3 Ac), 3.27 (dd, J = 4.25 (dd, J = 12.0 Hz, J = 5.5 Hz, 1 H, 6-H), 4.28 (d, J = 3.0 Hz,
9.5 Hz, J = 3.6 Hz, 1 H, 3Ј-H), 3.51 (s, 1 H, 5-H), 3.68 (d, J = 1 H, 3-H), 4.57 (d, J = 3.5 Hz, 1 H, 2-H), 5.19 (d, J = 1.0 Hz, 1
1
9.8 Hz, 1 H, 5Ј-H), 3.71 (s, 3 H, CH3 OMe pMP), 3.76 (br. s, 1 H,
H, 1Ј-H), 5.28 (t, J = 9.5 Hz, 1 H, 4Ј-H), 5.23 (dd, J = 10.0 Hz, J
2Ј-H), 3.77 (s, 3 H, CH3 COOMe), 3.89 (dd, J = 10.0 Hz, J = = 4.0 Hz, 1 H, 3Ј-H), 5.91 (d, J = 3.5 Hz, 1 H, 1-H) ppm. 13C
3.4 Hz, 1 H, 3-H), 4.07 (dd, J = 12.5 Hz, J = 1.2 Hz, 1 H, 6-H), NMR (100 MHz, CDCl3): δ = 20.5 (CH3 Ac), 20.6 (CH3 Ac), 20.7
4.17 (dd, J = 10.0 Hz, J = 7.8 Hz, 1 H, 2-H), 4.20 (d, J = 13.2 Hz,
1 H, 6-H), 4.36 (s, 1 H, 4-H), 4.43 (d, J = 12.2 Hz, 1 H, CHHPh),
4.56 (d, J = 12.2 Hz, 1 H, CHHPh), 4.66 (d, J = 11.7 Hz, 1 H,
(CH3 Ac), 25.2 (CH3 isoprop), 26.2 (CH3 isoprop), 26.8 (2ϫCH3
isoprop), 61.2 (C-2Ј), 62.3 (C-6), 66.0 (C-3Ј), 67.9 (C-6Ј), 69.3 (C-
5Ј), 70.4 (C-4Ј), 72.5 (C-5), 81.3 (C-4), 81.7 (C-3), 83.9 (C-2), 99.1
CHHPh), 4.88 (s, 1 H, 1Ј-H), 4.90 (d, J = 7.8 Hz, 1 H, 1-H), 5.07 (C-1Ј), 105.3 (C-1), 109.5 (Cq isoprop), 112.1 (Cq isoprop), 169.5
(d, J = 11.7 Hz, 1 H, CHHPh), 5.23 (t, J = 9.6 Hz, 1 H, 4Ј-H),
5.59 (s, 1 H, CHPh), 6.81 (d, J = 9.1 Hz, 1 H, 2ϫCH pMP), 7.05
(d, J = 9.1 Hz, 1 H, 2ϫCH pMP), 7.25–7.59 (m, 15 H, H arom)
(C=O Ac), 169.9 (C=O Ac), 170.7 (C=O Ac) ppm. 13C-GATED
NMR (100 MHz, CDCl3): δ = 99.1 (JC1Ј,H1Ј = 171 Hz, C-1Ј), 105.3
(JC1,H1 = 181 Hz, C-1Ј) ppm. ESI-MS: m/z = 596.0 [M + Na]+.
ppm. 13C NMR (100 MHz, CDCl3): δ = 20.8 (CH3 Ac), 20.9 (CH3 HRMS [M + Na]+: calcd. for C24H35O13N3 596.20621; found
Ac), 52.7 (CH3 COOMe), 55.6 (CH3 OMe pMP), 60.9 (C-2Ј), 66.7
(C-5), 68.1 (C-4), 68.8 (C-6), 72.2 (CH2 Bn), 72.9 (C-5Ј), 75.3 (CH2
Bn), 75.6 (C-4), 77.1 (C-3), 77.3 (C-3Ј), 78.9 (C-2), 100.4 (C-1Ј),
100.7 (CHPh), 103.2 (C-1), 114.4 (CH arom pMP), 118.8 (CH
arom pMP), 126.4–128.9 (CH arom), 137.2 (Cq Bn), 137.7 (Cq Bn),
151.3 (Cq pMP), 155.4 (Cq pMP), 167.4 (C=O Ac or COOMe),
169.3 (C=O Ac or COOMe) ppm. 13C-GATED NMR (100 MHz,
CDCl3): δ = 100.4 (JC1Ј,H1Ј = 161 Hz, C-1Ј), 103.2 (JC1,H1 = 163 Hz,
C-1) ppm. ESI-MS: m/z = 913.4 [M + HNEt3]+. HRMS [M +
NH4]+: calcd. for C43H45O13N3 829.32961; found 829.32829.
596.20586.
p-Methoxyphenyl 2-O-Benzyl-4,6-O-benzylidene-3-O-(3,4,6-tri-O-
acetyl-2-azido-2-deoxy-α-D-mannopyranosyl)-β-D-galactopyranoside
(19): Disaccharide 19 (50 mg, 0.064 mmol, 64%) was obtained from
donor 4 and acceptor 14 according to the general glycosidation
procedure using the Ph2SO/Tf2O activator system. TLC: 30 %
EtOAc/PE. IR (neat): ν = 698, 734, 819, 999, 1026, 1101, 1132,
˜
1217, 1506, 1747, 2106 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.97 (s, 3 H, CH3 Ac), 2.03 (s, 3 H, CH3 Ac), 2.09 (s, 3 H, CH3
Ac), 3.49 (s, 1 H, 5-H), 3.78 (s, 3 H, CH3 OMe pMP), 3.86 (dd, J
= 10.0 Hz, J = 3.6 Hz, 1 H, 3-H), 3.93 (d, J = 3.2 Hz, 1 H, 6Ј-H),
4.03–4.06 (m, 2 H, 2-H, 2Ј-H), 4.08 (dt, J = 11.6 Hz, J = 1.6 Hz,
1 H, 6-H), 4.14 (dq, J = 10.4 Hz, J = 2.8 Hz, 1 H, 5Ј-H), 4.32 (s,
J = 3.2 Hz, 1 H, 4-H), 4.37 (dd, J = 12.4 Hz, J = 1.2 Hz, 1 H, 6-
H), 4.78 (d, J = 10.4 Hz, 1 H, CHHPh), 4.90 (d, J = 8.0 Hz, 1 H,
1-H), 5.05 (d, J = 1.2 Hz, 1 H, 1Ј-H), 5.06 (d, J = 10.4 Hz, 1 H,
CHHPh), 5.32 (t, J = 10.0 Hz, 1 H, 4Ј-H), 5.47 (dd, J = 10.0 Hz,
J = 4.0 Hz, 1 H, 3Ј-H), 5.56 (s, 1 H, CHPh), 6.82 (d, J = 9.1 Hz,
1 H, CH arom pMP), 7.05 (d, J = 9.1 Hz, 1 H, CH arom pMP),
Methyl 2,3,4-Tri-O-benzyl-6-O-(3,4,6-tri-O-acetyl-2-azido-2-deoxy-
α-D-mannopyranosyl)-α-D-glucopyranoside (16): Disaccharide 16
(68 mg, 0.088 mmol, 88%) was obtained from donor 4 and ac-
ceptor 11 according to the general glycosidation procedure using
the Ph2SO/Tf2O activator system. TLC: 30% EtOAc/PE. IR (neat):
ν = 698, 734, 819, 999, 1026, 1101, 1132, 1217, 1506, 1747,
˜
2106 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.06 (s, 3 H, CH3
Ac), 2.07 (s, 3 H, CH3 Ac), 2.13 (s, 3 H, CH3 Ac), 3.83 (s, 3 H,
CH3 OMe), 3.45 (t, J = 9.2 Hz, 1 H, 4-H), 3.53 (dd, J = 9.6 Hz, J
= 3.6 Hz, 1 H, 3-H), 3.64 (d, J = 9.6 Hz, 1 H, 6-H), 3.76–3.80 (m, 7.25–7.59 (m, 15H CH arom) ppm. 13C NMR (100 MHz, CDCl3):
1 H, 5-H), 3.81 (dd, J = 9.6 Hz, J = 4.0 Hz, 1 H, 6-H), 3,82–3.86 δ = 20.5 (CH3 Ac), 20.7 (CH3 Ac), 20.7 (CH Ac), 55.6 (CH3 pMP),
(m, 1 H, 5Ј-H), 3.97–4.03 (m, 3 H, 3-H, 2Ј-H and 6Ј-H), 4.09 (dd, 61.5 (C-2Ј), 61.6 (CH2 Bn), 65.6 (C-4Ј), 66.3 (C-5), 68.5 (C-5Ј), 69.2
J = 12.0 Hz, J = 4.8 Hz, 1 H, 6Ј-H), 4.58 (d, J = 3.6 Hz, 1 H, 1- (C-6), 71.0 (C-3Ј), 71.1 (C-4), 74.3 (C-3), 76.3 (C-2), 93.8 (C-1Ј),
H), 4 59 (d, J = 11.2 Hz, 1 H, CHHPh), 4.68 (d, J = 12.0 Hz, 1 H,
CHHPh), 4.78 (d, J = 12.0 Hz, 1 H, CHHPh), 4.80 (d, J = 10.8 Hz,
1 H, CHHPh), 4.88 (d, J = 1.6 Hz, 1 H, 1Ј-H), 4.97 (d, J = 11.2 Hz,
1 H, CHHPh), 4.99 (d, J = 10.8 Hz, 1 H, CHHPh), 5.25 (t, J =
101.1 (CHPh), 103.3 (C-1), 114.5 (CH arom pMP), 118.9 (CH
arom pMP), 126.4–129.1 (CH arom), 137.5 (Cq Bn), 138.0 (Cq Bn),
151.4 (Cq pMP), 155.5 (Cq pMP), 169.4 (C=O Ac), 169.7 (C=O
Ac), 170.6 (C=O Ac) ppm. 13C-GATED NMR (100 MHz, CDCl3):
10.0 Hz, 1 H, 4Ј-H), 5.31 (t, J = 10.0 Hz, 1 H, 3Ј-H), 7.30–7.43 (15 δ = 93.8 (JC1Ј,H1Ј = 172 Hz, C-1Ј), 103.3 (JC1,H1 = 158 Hz, C-1)
Eur. J. Org. Chem. 2007, 116–124
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121

G. A. van der Marel et al.
ppm. ESI-MS: m/z = 795.4 [M + NH4]+. HRMS [M + NH4]+: H CH arom) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.6 (CH3
FULL PAPER
calcd. for C39H43O14N3 795.30833; found 795.30491.
Ac), 52.7 (CH3 pMP or COOMe), 55.6 (CH3 COOMe or pMP),
60.9 (C-2Ј), 66.7 (C-5), 68.2 (C-5), 68.8 (C-6), 72.1 (CH2 Bn), 73.2
(C-5Ј), 75.3 (CH2 Bn), 75.6 (C-4), 77.1 (C-3), 77.3 (C-3Ј), 78.9 (C-
2), 100.4 (C-1Ј), 100.7 (CHPh), 103.2 (C-1), 114.4 (CH arom pMP),
118.7 (CH arom pMP), 126.4–128.9 (CH arom), 137.2 (Cq Bn),
137.7 (Cq Bn), 138.6 (Cq Bn), 151.4 (Cq pMP), 155.4 (Cq pMP),
167.5 (C=O COOMe or Ac), 169.3 (C=O Ac or COOMe) ppm.
Methyl 2,3,4-Tri-O-benzyl-6-O-[methyl (4-O-acetyl-2-azido-3-O-
benzyl-2-deoxy-β-D-mannopyranosyl)uronate]-α-D-glucopyranoside
(20): Disaccharide 20 (56 mg, 0.069 mmol, 69%) was obtained from
donor 10 and acceptor 11 according to the general glycosidation
procedure using the Ph2SO/Tf2O activator system. TLC: 30 %
EtOAc/PE. [α]22= –16 (c = 1, CHCl ). IR (neat): ν = 698, 736, 754,
˜
D
3
13C-GATED NMR (100 MHz, CDCl3): δ = 100.4 (JC1Ј,H1Ј
=
1033, 1070, 1105, 1180, 1224, 2113 cm–1
.
1H NMR (500 MHz,
163 Hz, C-1Ј), 103.2 (JC1,H1 = 161 Hz, C-1) ppm. α-Anomer: 13C-
GATED NMR (100 MHz, CDCl3): δ = 93.0 (JC1Ј,H1Ј = 170 Hz, C-
1Ј), 101.0 (JC1,H1 = 161 Hz, C-1) ppm. HRMS [M + Na]+: calcd.
for C43H45O13N3 834.28446; found 834.28513.
CDCl3): δ = 2.04 (s, 3 H, CH3 Ac), 3.31 (s, 3 H, CH3 OMe), 3.35
(t, J = 9.5 Hz, 1 H, 4-H), 3.44 (dd, J = 10.5 Hz, J = 6.5 Hz, 1 H,
6-H), 3.48 (dd, J = 9.5 Hz, J = 3.5 Hz, 1 H, 2-H), 3.55 (dd, J =
9.0 Hz, J = 3.5 Hz, 1 H, 3Ј-H), 3.69 (s, 4 H, 2-H and CH3 CO-
OMe), 3.73 (d, J = 9.5 Hz, 1 H, 5Ј-H), 3.79 (m, J = 8.0 Hz, J =
4-Azido-2,3-di-O-benzyl-4-deoxy-α/β-D-fucopyranose (23): NIS
6.5 Hz, J = 1.5 Hz, 1 H, 5-H), 4.00 (t, J = 9.5 Hz, 1 H, 3-H), 4.10 (58 mg, 0.26 mmol, 1 equiv.) and TFA (20 µL, 0.26 mmol, 1 equiv.)
(dd, J = 8.0 Hz, J = 1.5 Hz, 1 H, 6-H), 4.28 (s, 1 H, 1Ј-H), 4.53 (d,
J = 11.0 Hz, 1 H, CHHPh), 4.54 (s, 1 H, 1-H), 4.61 (d, J = 11.0 Hz,
were added to a vigorously stirred solution of compound 22[40]
(119 mg, 0.26 mmol) in DCM/H2O (10:1 v/v, 1 mL). The mixture
1 H, CHHPh), 4.62 (d, J = 11.0 Hz, 1 H, CHHPh), 4.66 (d, J = was stirred for 15 min before Na2S2O3 (10% in H2O, 10 mL) and
11.0 Hz, 1 H, CHHPh), 4.76 (d, J = 11.0 Hz, 1 H, CHHPh), 4.79
(d, J = 11.0 Hz, 1 H, CHHPh), 4.86 (d, J = 11.0 Hz, 1 H, CHHPh),
NaHCO3 (satd. aq., 10 mL) were added. The biphasic mixture was
diluted with EtOAc (50 mL) and extracted. The aqueous layers
4.98 (d, J = 11.0 Hz, 1 H, CHHPh), 5.31 (t, J = 9.0 Hz, 1 H, 4Ј- were extracted twice with EtOAc (25 mL). The combined organic
H), 7.23–7.37 (m, 20 H, CH arom) ppm. 13C NMR (125 MHz,
CDCl3): δ = 20.7 (CH3 Ac), 52.7 (CH3 COOMe), 55.1 (CH3 OMe),
68.2 (C-4Ј), 68.8 (C-6), 69.6 (C-5), 72.2 (CH2 Bn), 73.2 (C-5Ј), 73.4
layers were dried (MgSO4), filtered and concentrated under re-
duced pressure. Flash column chromatography using (EtOAc/PE)
afforded the title compound 23 (69 mg, 0.19 mmol, 73 %) as a
(CH2 Bn), 74.6 (CH2 Bn), 75.7 (CH2 Bn), 75.7 (C-3Ј), 77.6 (C-4), colourless oil. TLC: 50 % EtOAc/PE. IR (neat): ν = 609, 1041,
˜
1
79.8 (C-2), 81.9 (C-3), 97.6 (C-1), 99.7 (C-1Ј), 127.6–128.6 (CH 1091, 1222, 2098 cm–1. α -Anomer: H NMR (500 MHz, CDCl3):
arom), 137.1 (Cq Bn), 138.0 (Cq Bn), 138.3 (Cq Bn), 138.4 (Cq Bn),
138.6 (Cq Bn), 167.5 (C=O Ac or COOMe), 169.3 (C=O Ac or
δ = 1.24 (d, J = 6.5 Hz, 3 H, 6-H), 3.26 (br. s, 1 H, O1-H), 3.74 (d,
J = 3.5 Hz, 1 H, 4-H), 3.86 (dd, J = 9.5 Hz, J = 3.5 Hz, 1 H, 2-
COOMe) ppm. 13C-GATED NMR (125 MHz, CDCl3): δ = 97.8 H), 4.03 (dd, J = 9.5 Hz, J = 3.5 Hz, 1 H, 3-H), 4.18 (q, J = 6.5 Hz,
(JC1,H1 = 170 Hz, C-1), 99.7 (JC1,H1 = 160 Hz, C-1Ј) ppm. ESI-MS:
m/z = 829.3 [M + NH4]+, 834.4 [M + Na]+. HRMS [M + Na]+:
calcd. for C41H49O12N3 834.32084; found 834.32100.
1 H, 5-H), 4.70 (d, J = 11.5 Hz, 1 H, CHHPh), 4.77 (d, J = 11.5 Hz,
1 H, CHHPh), 4.80 (d, J = 11.5 Hz, 1 H, CHHPh), 4.84 (d, J =
11.5 Hz, 1 H, CHHPh), 5.18 (d, J = 3.5 Hz, 1 H, 1-H), 7.29–7.42
(m, 10 H, H arom) ppm. 13C NMR (125 MHz, CDCl3): δ = 17.3
(C-6), 64.5 (C-4), 64.6 (C-5), 72.8 (CH2 Bn), 73.7 (CH2 Bn), 76.0
(C-2), 77.8 (C-3), 91.6 (C-1), 127.7–128.4 (CH arom), 137.8 (Cq
p-Methoxyphenyl 2-O-Benzyl-4,6-O-benzylidene-3-O-[methyl (4-O-
acetyl-2-azido-3-O-benzyl-2-deoxy-α/β-
D-mannopyranosyl)uronate]-
β-D-galactopyranoside (21): A solution of donor 10 (41 mg,
1
Bn), 137.9 (Cq Bn) ppm. β-anomer: H NMR (500 MHz, CDCl3):
0.09 mmol) and acceptor 14 (70 mg, 0.15 mmol, 1.5 equiv.) in
DCM (3 mL) was stirred in the presence of activated MS (3 Å) for
30 min before N-iodosuccinimide (29 mg, 0.13 mmol, 1.3 equiv.)
was added. The mixture was cooled to –40 °C before trimethylsilyl
trifluoromethanesulfonate (5 µL, cat.) was added. Stirring was con-
tinued and the reaction mixture was warmed to room temperature.
When TLC analysis indicated complete reaction, triethylamine
(0.2 mL) was added. The reaction mixture was diluted with EtOAc
and washed with water. The aqueous layer was extracted twice with
EtOAc. The collected organic layers were dried (MgSO4), filtered
and concentrated under reduced pressure. Flash chromatography
(EtOAc/PE) and removal of the eluent afforded the title compound
21 (40 mg, 0.048 mmol, 53%, α/β = 1:2) as a colourless oil. The
anomers could not be separated using flash column chromatog-
δ = 1.31 (d, J = 6.5 Hz, 3 H, 6-H), 3.55 (q, J = 6.5 Hz, 1 H, 5-H),
3.61 (t, J = 9.5 Hz, J = 8.5 Hz, 1 H, 2-H), 3.64 (d, J = 3.5 Hz, 1
H, 4-H), 3.68 (dd, J = 9.5 Hz, J = 3.5 Hz, 1 H, 3-H), 3.70 (br. s, 1
H, O1-H), 4.57 (br. d, J = 8.5 Hz, 1 H, 1-H), 4.76 (d, J = 11.5 Hz,
1 H, CHHPh), 4.82 (d, J = 11.5 Hz, 1 H, CHHPh), 4.83 (d, J =
11.5 Hz, 1 H, CHHPh), 4.91 (d, J = 11.5 Hz, 1 H, CHHPh), 7.29–
7.42 (m, 10 H, H arom) ppm. 13C NMR (125 MHz, CDCl3): δ =
17.4 (C-6), 63.6 (C-4), 69.2 (C-5), 72.9 (CH2 Bn), 75.2 (CH2 Bn),
80.2 (C-2), 81.1 (C-3), 97.5 (C-1), 127.7–128.4 (CH arom), 137.7
(Cq Bn), 138.3 (Cq Bn) ppm. ESI-MS: m/z = 387.2 [M + NH4]+,
392.1 [M + Na]+. HRMS [M + Na]+: calcd. for C20H23O4N3
392.15808; found 392.15813.
Methyl [Phenyl 2-azido-3-O-benzyl-2-deoxy-4-O-(4-azido-2,3-di-O-
raphy. TLC: 30% EtOAc/PE. IR (neat): ν = 696, 734, 746, 819,
benzyl-4-deoxy-α-
(24): Chemoselective glycosylation: Disaccharide 24 (42 mg,
D-fucopyranosyl)-α-D-mannopyranosid]uronate
˜
1045, 1083, 1220, 1365, 1506, 1743, 2108 cm–1. β-Anomer: 1H
NMR (400 MHz, CDCl3): δ = 2.04 (s, 3 H, CH3 Ac), 3.28 (dd, J 0.055 mmol, 55%) was obtained from donor 22 and acceptor 9
= 9.5 Hz, J = 3.6 Hz, 1 H, 3Ј-H), 3.51 (br. s, 1 H, 5-H), 3.65 (d, J
= 9.8 Hz, 5Ј-H), 3.71 (s, 3 H, CH3 pMP or COOMe), 3.75 (d, J =
3.6 Hz, 1 H, 2Ј-H), 3.77 (s, 3 H, CH3 COOMe or pMP), 3.89 (dd,
J = 10.0 Hz, J = 3.4 Hz, 1 H, 3-H), 4.03–4.08 (m, 1 H, 6-H), 4.18
according to the general glycosidation procedure using the Ph2SO/
Tf2O activator system. Orthogonal glycosylation: A solution of do-
nor 23 (55 mg, 0.15 mmol), diphenyl sulfoxide (85 mg, 0.42 mmol,
2.8 equiv.) and tri-tert-butylpyrimidine (112 mg, 0.45 mmol,
(dd, J = 10.0 Hz, J = 7.8 Hz, 1 H, 2-H), 4.34 (d, J = 13.2 Hz, 1 H, 3 equiv.) in DCM (3 mL) was stirred in the presence of activated
6-H), 4.37 (s, 1 H, 4-H), 4.45 (d, J = 12.2 Hz, 1 H, CHHPh), 4.58
(d, J = 12.2 Hz, 1 H, CHHPh), 4.66 (d, J = 11.7 Hz, 1 H, CHHPh),
MS (3 Å) (100 mg) for 30 min. The mixture was cooled to –60 °C
before triflic anhydride (33 µL, 0.20 mmol, 1.3 equiv.) was added.
4.88 (s, 1 H, 1Ј-H), 4.87 (s, 1 H, 1Ј-H), 4.90 (d, J = 7.8 Hz, 1 H, 1- The mixture was warmed to –40 °C in 1 h followed by addition of
H), 5.08 (d, J = 11.7 Hz, 1 H, CHHPh), 5.21 (t, J = 9.6 Hz, 1 H, acceptor 9 (78 mg, 0.17 mmol, 1.1 equiv.) in DCM (1 mL). Stirring
4Ј-H), 5.60 (s, 1 H, CHPh), 6.82 (d, J = 9.1 Hz, 1 H, CH arom was continued and the reaction mixture was warmed to 0 °C. The
pMP), 7.05 (d, J = 9.1 Hz, 1 H, CH arom pMP), 7.25–7.59 (m, 15 reaction mixture was taken up in EtOAc (25 mL) and washed with
122
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Eur. J. Org. Chem. 2007, 116–124

1-Thiomannosazidopyranosides and 1-Thiomannosaziduronic Acid Esters
water. The organic layer was dried (MgSO4), filtered and concen- (JC1ЈЈ,H1ЈЈ = 166 Hz, C-1ЈЈ), 99.8 (JC1Ј,H1Ј = 167 Hz, C-1Ј), 100.6
FULL PAPER
trated under reduced pressure. Flash chromatography (10 % (JC1,H1 = 168 Hz, C-1) ppm. β-Anomer: [α]2D2 = +2 (c = 0.3, CHCl3)
EtOAc/PE) and removal of the eluent afforded the title compound
ppm. IR (neat): ν = 609, 1041, 1091, 1222, 1710, 2098 cm–1. 1H
˜
24 (73 mg, 0.095 mmol, 67 %) as a colourless oil. TLC: 30 %
NMR (400 MHz, CDCl3): δ = 1.19 (d, J = 6.4 Hz, 3 H, 6ЈЈ-H),
3.17 (s, 1 H, 2-H), 3.67 (dd, J = 8.7 Hz, J = 3.5 Hz, 1 H, 3Ј-H),
3.73 (s, 3 H, CH3 COOMe), 3.74–3.77 (m, 2 H, 4ЈЈ-H, 5ЈЈ-H), 3.78–
3.81 (m, 2 H, 3-H, 6-H), 3.82 (d, J = 3.8 Hz, 1 H, 2ЈЈ-H), 3.89 (d,
J = 9.3 Hz, 1 H, 5Ј-H), 3.93 (d, J = 3.8 Hz, 1 H, 3ЈЈ-H), 3.96 (s, 1
EtOAc/PE. [α]2D2 = +3 (c = 0.3, CHCl ). IR (neat): ν = 609, 1041,
˜
3
1091, 1222, 1710, 2098 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.21 (d, J = 6.5 Hz, 1 H, C-6Ј), 3.45 (dd, J = 10.0 Hz, J = 3.5 Hz,
1 H, 4-H), 3.47 (s, 3 H, CH3 COOMe), 3.67–3.69 (m, 1 H, 3Ј-H,
4Ј-H), 3.77 (dd, J = 9.5 Hz, J = 3.5 Hz, 1 H, 2Ј-H), 3.83 (q, J = H, 4-H), 3.98 (d, J = 3.5 Hz, 1 H, 2Ј-H), 4.15 (d, J = 7.3 Hz, 1 H, 6-
6.5 Hz, 1 H, 5Ј-H), 3.93 (t, J = 3.5 Hz, 1 H, 3-H), 4.23 (dd, J = H), 4.32 (t, J = 9.0 Hz, 1 H, 4Ј-H), 4.56–4.61 (m, 5 H, 2ϫCHHPh,
4.3 Hz, J = 2.0 Hz, 1 H, 2-H), 4.51 (d, J = 11.5 Hz, 2 H, 3ϫCHHPh), 4.63 (d, J = 2.5 Hz, 1 H, 5-H), 4.68 (d, J = 11.8 Hz,
2ϫCHHPh), 4.56 (d, J = 11.5 Hz, 1 H, CHHPh), 4.61 (d, J =
2.0 Hz, 1 H, 1-H), 4.68 (d, J = 11.5 Hz, 1 H, CHHPh), 4.75 (d, J
= 11.5 Hz, 1 H, CHHPh), 4.76 (d, J = 11.5 Hz, 1 H, CHHPh), 4.77
(d, J = 3.5 Hz, 1 H, 1Ј-H), 5.62 (d, J = 10.0 Hz, 1 H, 5-H), 7.25–
7.67 (m, 20 H, H arom) ppm. 13C NMR (100 MHz, CDCl3): δ =
17.3 (C-6Ј), 52.1 (CH3 COOMe), 57.1 (C-4), 64.4 (C-3Ј or C-4Ј),
65.3 (C-5Ј), 72.9 (CH2 Bn), 73.1 (CH2 Bn), 73.8 (CH2 Bn), 75.0 (C-
1), 75.3 (C-2), 75.9 (C-2Ј), 76.1 (C-3), 77.8 (C-4Ј or C-3Ј), 79.6 (C-
5), 99.7 (C-1Ј), 124.7–134.1 (CH arom), 130.9 (Cq SPh), 136.6 (Cq
Bn), 137.9 (Cq Bn), 138.2 (Cq Bn), 168.9 (C=O COOMe) ppm. 13C-
GATED NMR (100 MHz, CDCl3): δ = 75.0 (JC1,H1 could not be
determined), 96.1 (JC1Ј,H1Ј = 166 Hz, C-1Ј) ppm. HRMS [M +
Na]+: calcd. for C40H42O8N6S 789.26770; found 789.26819.
1 H, CHHPh), 4.72 (d, J = 11.9 Hz, 1 H, CHHPh), 4.79 (d, J =
11.9 Hz, 1 H, CHHPh), 4.81 (s, 1 H, 1Ј-H), 5.35 (d, J = 3.8 Hz, 1
H, 1ЈЈ-H), 5.51 (s, 1 H, 1-H), 7.25–7.36 (m, 20 H, H arom) ppm.
13C NMR (100 MHz, CDCl3): δ = 17.2 (C-6ЈЈ), 52.7 (CH3 CO-
OMe), 58.9 (C-2), 60.6 (C-2Ј), 64.7 (C-4ЈЈ or C-5ЈЈ), 64.8 (C-6),
65.2 (C-5ЈЈ or C-4ЈЈ), 71.5 (C-5), 72.0 (CH2 Bn), 72.5 (C-3ЈЈ), 72.6
(CH2 Bn), 72.8 (CH2 Bn), 73.1 (C-4Ј), 73.4 (CH2 Bn), 75.5 (C-2ЈЈ),
75.9 (C-5Ј), 77.6 (C-4), 77.8 (C-3), 79.7 (C-3Ј), 96.1 (C-1Ј), 98.2 (C-
1ЈЈ), 100.9 (C-1), 127.4–128.5 (CH arom), 137.2 (Cq Bn), 137.9 (Cq
Bn), 138.1 (Cq Bn), 167.8 (C=O COOMe) ppm. 13C-GATED
NMR (100 MHz, CDCl3): δ = 96.1 (JC1Ј,H1Ј = 160 Hz, C-1Ј), 98.2
(JC1ЈЈ,H1ЈЈ = 172 Hz, C-1ЈЈ), 100.9 (JC1,H1 = 175 Hz, C-1) ppm.
HRMS [M + Na]+: calcd. for C47H51O12N9 956.35494; found
956.36039.
1,6-Anhydro-2-azido-3-O-benzyl-4-O-{methyl [2-azido-3-O-benzyl-
2-deoxy-4-O-(4-azido-2,3-di-O-benzyl-4-deoxy-α-
D-fucopyranosyl)-
Acknowledgments
α/β- -mannopyranosyl]uronate}-2-deoxy-β- -glucopyranose (26): A
D
D
solution of donor 24 (38 mg, 0.050 mmol) and acceptor 25 (21 mg,
0.075 mmol, 1.5 equiv.) in DCM (2 mL) was stirred in the presence
of activated MS (3 Å) for 30 min before N-iodosuccinimide (17 mg,
0.075 mmol, 1.5 equiv.) was added. The mixture was cooled to
–40 °C before trimethylsilyl trifluoromethanesulfonate (2 µL, cat.)
was added. Stirring was continued and the reaction mixture was
warmed to room temperature. When TLC analysis indicated com-
plete reaction, triethylamine (0.2 mL) was added. The reaction mix-
ture was diluted with EtOAc and washed with water. The aqueous
layer was extracted twice with EtOAc. The collected organic layers
were dried (MgSO4), filtered and concentrated under reduced pres-
sure. Flash chromatography (EtOAc/PE) and removal of the eluent
afforded the title compound 26 (32 mg, 0.032 mmol, 65%, α/β =
1:2) as a colourless oil. Anomers were separated using flash column
chromatography: α-anomer: 10 mg, 0.010 mmol, 20%; β-anomer:
22 mg, 0.022 mmol, 45%. TLC: 30% EtOAc/PE. α-Anomer: 1H
NMR (400 MHz, CDCl3): δ = 1.20 (d, J = 6.4 Hz, 1 H, 6ЈЈ-H),
3.23 (s, 1 H, 2-H), 3.51 (s, 3 H, CH3 COOMe), 3.72 (s, 1 H, 3-H),
3.74–3.82 (m, 4 H, 6-H, 4Ј-H, 5Ј-H and 2ЈЈ-H), 3.90–3.92 (m, 2 H,
4-H, 2Ј-H), 3.91 (t, J = 3.2 Hz, 1 H, 3ЈЈ-H), 4.00 (dd, J = 10.0 Hz,
J = 3.6 Hz, 1 H, 3Ј-H), 4.13 (d, J = 7.2 Hz, 1 H, 6-H), 4.19 (t, J =
4.0 Hz, 1 H, 4ЈЈ-H), 4.50 (d, J = 12.0 Hz, 1 H, CHHPh), 4.56 (d,
J = 12.0 Hz, 1 H, CHHPh), 4.63 (d, J = 2.4 Hz, 1 H, 5ЈЈ-H), 4.66
(d, J = 12.0 Hz, 1 H, CHHPh), 4.74 (d, J = 12.0 Hz, 1 H, CHHPh),
4.76 (d, J = 11.6 Hz, 1 H, CHHPh), 4.80 (d, J = 11.6 Hz, 1 H,
CHHPh), 4.81 (br. s, 1 H, 1Ј-H), 4.81–4.83 (m, 3 H, 3ϫCH Bn),
This work was supported by the Council for Chemical Sciences of
the Netherlands Organization for Scientific Research (CW-NWO).
The authors thank C. Erkelens and F. Lefeber for recording the
NMR spectra.
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the two glycosides participating in a glycosylation event can
be used as either donor or acceptor at will, depending on the
conditions applied. Here we use the word orthogonal in ac-
cordance with common practice in synthetic carbohydrate
chemistry, namely, to indicate that a donor glycoside (here
hemiacetal 23) is condensed with an acceptor glycoside (thio-
uronic ester 9) which has an anomeric functional group that
can be activated in its own right allowing a second glycosyl-
ation event (here condensation with acceptor 25) without the
necessity of intermediate functional group manipulations. As
such the orthogonal glycosylation strategy is complementary
to the so-called “chemoselective glycosylation” in which both
donor and acceptor have the same anomeric functionality. See
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Received: August 29, 2006
Published Online: November 13, 2006
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